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Neonatology and Blood Transfusion (Developments in Hematology and Immunology, Vol. 39)

2010-06-04T00:10:00.000-07:00

Proceedings of the Twenty-Eighth International Symposium on Blood Transfusion, Groningen, NL, Organized by the Sanquin Division Blood Bank North-East, Groningen.
It is in many ways fitting that the last of these international symposia on blood transfusion should end with neonatal blood transfusion. The most fragile, least well studied and most at risk population requires special care and concern. We need to expand our knowledge of their unique physiology, biochemical pathways and in planning treatment and interventions, always "do no harm."
This proceedings of the last Groningen symposium presents a wealth of information on developmental immunology, the molecular basis of haematopoeisis, physiological basis of bleeding and thrombosis, transfusion risks and benefits and lastly, future therapies. Infants provide us with much to learn but in turn they will be the providers of (through cord blood) and the recipients of (through cellular engineering) the best that science can offer. Translational research, which has been the thrust of these presentations for 28 years, will benefit them in a way that no scientist could have ever predicted.

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Lippincott's Illustrated Reviews: Pharmacology, 4th Edition

2010-06-02T20:47:00.000-07:00

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Product Description
Lippincott's Illustrated Reviews: Pharmacology, Fourth Edition enables rapid review and assimilation of large amounts of complex information about the essentials of medical pharmacology. Clear, sequential pictures of mechanisms of action actually show students how drugs work, instead of just telling them. As in previous editions, the book features an outline format, over 500 full-color illustrations, cross-references to other volumes in the series, and over 125 review questions. Content has been thoroughly updated, and a new chapter covers toxicology. New to this edition will be a companion Website containing all of the illustrations, fully searchable text, and an interactive question bank. NOTE: International Edition available for sales outside North America and Caribbean (ISBN: 978-1-60547-200-3) "Doody's Core Titles™ 2009."

Product Details
* Paperback: 560 pages
* Publisher: Lippincott Williams & Wilkins; Fourth Edition edition (July 1, 2008)
* Language: English
* ISBN-10: 0781771552
* ISBN-13: 978-0781771559
* Product Dimensions: 10.8 x 8.4 x 0.9 inches
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Pathophysiology of Disease An Introduction to Clinical Medicine, Sixth Edition (Lange Medical Books) (Paperback)

2010-06-02T05:21:00.000-07:00

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Review
"The book does an excellent job of integrating basic science concepts with clinical medicine. Each of the organ system chapters reviews the normal anatomy, physiology and histology, then follows with the pathophysiology, clinical findings, and pathology of the more commonly encountered disorders. Additionally there are chapters on genetic diseases, immune diseases and neoplasia which similarly link basic science principles with clinical disease entities. Each chapter contains periodic "checkpoint" questions which guide the reader to the most important concepts. Each chapter also ends with several case studies with questions and discussions, similar to those encountered on board examinations."

Product Description

A complete case-based review of the essentials of pathophysiology – covering all major organs and systems

This trusted text introduces you to clinical medicine by reviewing the pathophysiologic basis of the signs and symptoms of 100 diseases commonly encountered in medical practice. Each chapter first describes normal function of a major organ or organ system, then turns attention to the pathology and disordered physiology, including the role of genetics, immunology, and infection in pathogenesis. Underlying disease mechanisms are described, along with their systems, signs, and symptoms, and the way these mechanisms themselves determine the most effective treatment.

This unique interweaving of physiological and pathological concepts will put you on the path towards thinking about signs and symptoms in terms of their pathologic basis, giving you an understanding of the “whys” behind both illness and treatment.

Features
* NEW full-color presentation
* 111 case studies (22 new ones) provide an opportunity for you to test your understanding of the pathophysiology of each clinical entity discussed
* A complete chapter devoted to detailed analyses of the cases
* “Checkpoint” review questions appear throughout every chapter
* Numerous tables and diagrams encapsulate important information
* References for each chapter topic
* NEW sections in the chapters on liver disease and inflammatory rheumatic diseases and a completely rewritten chapter on male reproductive tract disorders

Product Details
* Paperback: 752 pages
* Publisher: McGraw-Hill Medical; 6 edition (October 20, 2009)
* Language: English
* ISBN-10: 0071621679
* ISBN-13: 978-0071621670
* Product Dimensions: 10.9 x 8.5 x 1.2 inches
* Shipping Weight: 3.3 pounds (View shipping rates and policies)

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Blood Supply of the Heart

2009-10-17T05:04:00.000-07:00

Heart Structure and Blood Supply

It seems odd that the tissues making up the heart must have their own separate blood supply. You might think that the torrent of blood rushing through the heart every minute would more than adequately meet the needs of the organ. The walls of the heart, however, consist of layers of specialized muscle. These walls are quite thickâ€”the wall of the left ventricle is often over 1 inch thick. Since the lining of the heart is watertight, the blood cannot seep through the layers of muscle to provide the nourishment essential to these constantly working masses. Blood is carried through the muscle layers that form the heart wall by means of the two coronary arteries. These two small vessels branch off the aorta just after it leaves the heart and curl back across the surface of the chambers, sending twigs through the walls (Fig. 4-1).
The coronary arteries are so named because of the supposed resemblance to a crown or â€œcoronaâ€ of the little arteries as they encircle the heart. These arteries divide into smaller and smaller branches, like all blood vessels in the body, until they become so small that only one blood cell at a time can move through them. At this point the vessels are called capillaries. After the blood has passed through the capillaries, and the tissues have extracted the needed oxygen, it returns by way of veins, which become larger and larger until they, like all other veins in the body, empty into the right atrium. The veins from the wall of the heart, or coronary veins, empty into the right atrium through a structure called the coronary sinus.
The blood supply of the tissues in the wall of the heart is not very good; thousands of people die every year because of this curious fact. Most organs and tissues of the body have a â€œreserveâ€ or collateral blood supply. Each finger, for instance, has two arteries, one on each side. These arteries are connected by many cross-channels, or collateral vessels. If the artery is cut on one side, the collateral or cross-connections from the artery on the other side would probably provide sufficient blood to maintain life in the tissues of the finger. The same â€œsafetyâ€ feature is true in most of the major areas of the body. It is not true in the wall of the heart.
The coronary arteries tend to be end arteries, meaning that each branch follows its own course to some area of the heart muscle with relatively few connections to other branches nearby. If one of these coronary branches is plugged by hardening or by a blood clot, the muscle that depends on it for blood will die. A form of gangrene actually sets in. (Some people's coronary arteries have many more cross-connections than others. The more of these cross-connections an individual has, the less likely he or she is to die of coronary artery disease. In 10,000 or 20,000 years the process of evolution may result in a race with a good coronary blood supply by virtue of the early death of those without it.)
The names of the chief branches of the coronary arteries are important because they will be used repeatedly in this book. Learn them now; they're very simple.
There are two main coronary arteries leading out of the aortaâ€”the right and left coronary arteries. After about an inch, the left coronary artery divides into two principal branches. The left anterior descending branch comes down the front of the heart, roughly along the septum between the two ventricles. The circumflex branch of the left coronary artery coils around the left side and back of the heart. The right coronary artery divides into a number of branches that course through the right chambers of the heart as well as through a large part of the left ventricle.

Note: There are four coronary arteries to remember:
The left main coronary artery (before it divides): LMCA.
The right coronary artery: RCA.
The left anterior descending branch of the left main coronary artery: LAD.
The circumflex branch of the left main coronary artery: LCA or LCirc.

Pumping Action of the Heart

2009-10-17T04:59:00.000-07:00

Blood Flow Through the Heart
Blood is pumped through the chambers of the heart and out through the great vessels by a simple squeezing action of the heart chambers. You have probably seen a bulb syringe with a glass nozzle like the one pictured in Figure 3-1. Suppose it is full of water. If you squeeze forcefully, expelling the water, you would be imitating the contraction of a heart chamber. This is called systole (sis-toe-lee). After the syringe had been emptied, imagine that you placed the nozzle in a container of water and let the bulb expand so that it filled. This is what a heart chamber does when it relaxes and fills with blood. The movement is called diastole (die-as-toe-lee). You can picture the process by holding your left hand over your right, fists clenched. If your left hand represents the atria, your right hand will represent the ventricles. Now clench your left fist (the atria) while opening your right fist (the ventricles). This is what happens during atrial systole when the atria are pumping blood down into the ventricles. Next, open your left fist and clench your right. This is what happens during ventricular systole when the ventricles are pumping blood out into the two great arteries and the atria are refilling. By alternately opening and clenching your two fists you can similate the coordinated beat of the heart.
Note: The cycle of a heartbeat, in other words, goes through these stages:
Atrial systole: The atria contract, forcing the blood down into the ventricles.
Ventricular systole: The ventricles contract, forcing the blood out the pulmonary artery and aorta.
Atrial diastole: This starts during ventricular systole as the atria begin refilling with blood from the great veins.
Ventricular diastole: This takes place during atrial systole as blood from the atria fills the ventricles.

The rhythmic contraction and relaxation of the ventricles does the work of pumping the blood: atrial contraction is much less important and, in fact, many patients live for years without any pumping action from the atria. If the ventricles stop beating, death follows within minutes.

Valves of the Heart

2009-10-17T04:26:00.000-07:00

Valve Structure and Function
Like any pump, the heart has valves to keep the blood flowing in the right direction. Proper function of these small flaps of tissue spells the difference between good health and sickness, and often between life and death.
Almost everyone is familiar with the word valve. Very few people, however, really know what a valve is or what it does. Imagine pumping water through a pipe with a farm pump. To keep the water from flowing back toward the pump between strokes, you could place a valve in the pipe leading out of the pump. The simplest kind of valve would consist of two semicircular flaps hinged to open only one wayâ€”forward with the flow of water. These flaps would close the pipe completely when they swung shut. When the water flowed forward from the pump, the flaps of the valve would swing open allowing the water to pass. Between strokes the valves would snap shut if any water attempted to flow back toward the pump (Fig. 2-1).

Note: The heart is equipped with four sets of valves that function on this simple principle:
tricuspid valve
mitral valve
pulmonic valve
aortic valve
The valves between the atria and ventricles are called the atrioventricular (AV) valves. The AV valve leading into the right ventricle has three flaps and is called the tricuspid valve (a cusp is a valve flap or leaflet).
The AV valve that swings into the left ventricle is called the mitral valve. (It has two cusps and therefore looks something like a bishop's miter.)
Each of the outlet valves from the ventricles has three cusps. The valve at the entry to the pulmonary artery is called the pulmonic valve. The valve at the entry to the aorta is called the aortic valve.
As stated, an AV valve is located between each atrium and ventricle (Fig. 2-2). This valve opens downward into the ventricle. During diastole, or relaxation, the valves swing open, allowing the blood to flow down into the ventricles. When the ventricles contract, these valves snap shut, preventing any blood from flowing back up into the atria.

A valve is also located at the outlet from each ventricle into the great vessel leaving the chamber. When the ventricles contract, these valves are forced open; the blood rushes into the pulmonary artery and the aorta. When the ventricles relax, the valves close, shutting off any backward flow into the ventricles.
If the heart is to function efficiently, these valves must be absolutely watertight, or more properly, bloodtight. Further, they must open freely and widely to let the blood flow forward with the pumping action of the heart. If the valves leak or if they are partly closed by adhesions or hardening, the heart works against a mechanical load, often an impossible and fatal load, as will be discussed in later chapters.
Layers of the Heart
The heart does not simply hang freely in the chest cavity; around it is a loose protective sack of tissue called the pericardium. The heart lies inside this sack, which is loose enough to permit the heart to beat easily. Picture a turnip held in a heavy, double thickness plastic bag. This is about the way the heart looks inside the pericardium (Fig. 2-3).
If the pericardium is cut open, the surface of the heart itself appears shiny and reddish in color. You can actually peel away a thin, shiny membrane from the outer surface of the heart. This membrane is called the epicardium. The mass of the heart is muscle; under the epicardium is a thick layer of muscle called the myocardium, which forms the actual working part of the heart. The myocardium is thickest in the left ventricle; it is thinnest in the atria. The cells in the myocardium are a specialized type of muscle, different from anything else in the body.
The inside of the heart, or cavity, is lined with another smooth, shiny membrane much like the inside surface of the cheek. This thin membrane, called the endocardium, covers the inside of the chambers of the heart. It also covers the heart valves and the small muscles associated with the opening and closing of these valves.

Structure and Function of the Normal Heart

2009-10-15T21:06:00.001-07:00

Before you begin to learn about heart disease, you must learn how the normal heart is constructed and how it functions. This is easier than you might think, because the heart is a surprisingly simple organ. An hour's easy reading will give you all the information you need to begin.
The Chambers of the Heart and their Connections
The heart is a hollow organ divided into four chambers, two on the top and two on the bottom (Fig. 1-1). Study this simple diagram until you know it as well as your own name: it's basic to everything else in the book.
The top two chambers are thin-walled structures that act primarily as holding chambers for the blood. They are called atria. This is the plural of the Latin word atrium, meaning â€œanteroomâ€ or â€œporch,â€ and, in fact, these chambers do act as entryways to the great chambers below. The ventricles are large, thick-walled chambers that do the real work of pumping the blood. (This name comes from the Latin ventriculum, meaning a â€œcavityâ€ or â€œpouch.â€)
Look again at Figure 1-1 and note the wall, or septum, that divides the left atrium from the right atrium and the left ventricle from the right ventricle. This wall of tissue is much like the septum in your nose that separates the two nostrils. The important thing to remember about the heart's septum is that it is absolutely watertight, or, more properly, â€œbloodtight.â€ Normally, no blood can pass through this septum from one side to the other. (It took the human race about 4,000 years to discover this simple fact. The ancient Greeks and Romans were convinced that blood somehow oozed through the septum from one side to the other. It doesn't.)
Physicians commonly refer to the right atrium and right ventricle together as the right heart and to the left atrium and left ventricle as the left heart.

The Motion of the Blood Through the Heart
The function of the heart can be described as a simple pump that forces blood forward by squeezing, in exactly the way that a bulb syringe forces out fluid when it's compressed.
The alert reader will at once ask, â€œIf the blood doesn't flow from one side of the heart to the other through the septum, how does it ever move forward?â€ The answer to that question eluded philosophers and scientists until the English medical doctor William Harvey, in the early seventeenth century, discovered the simple circuit that is the basis of all modern cardiology.
The blood moves from the right heart to the left heart by way of the lungs. In other words, the right heart pulls the blood out of the veins and pumps it into the lungs. The left heart pulls the blood out of the lungs and pumps it on to the body.
(The outraged squalling of Harvey's contemporaries and the hoots of disbelief that greeted this profound truth are amusing to contemplate; they are also a little frightening.) Thus the heart and lungs together form a machine that takes oxygen out of the air, dissolves it in the blood, and pumps it to the tissues of the body.

Back to Structure: How Are the Heart and Lungs Connected?
The blood that has completed its course through the tissues of the body flows back to the heart through the veins. The veins come together, growing larger, like streams combining into a river, until they end in two great veins that empty into the top and bottom of the right atrium. The word cava in Latin refers to something large or cavelike; hence the vein that empties into the top of the right atrium is called the superior vena cava, or, literally, â€œlarge top vein.â€ The great vein that empties into the bottom of the right atrium is logically called the inferior vena cava (Fig. 1-2). Blood flows from the right atrium down into the right ventricle and out to the lungs through the pulmonary artery (Fig. 1-3).

Within the lungs, the pulmonary artery branches into ever smaller arteries until it ends in a mass of capillariesâ€”tiny vessels just wide enough to let one blood cell through at a time (Fig. 1-4). After the blood has been oxygenated it flows back to the heart through the four veins that empty into the left atrium (Fig. 1-5). Since these veins flow from the lungs to the heart they are called the pulmonary veins.

From the left atrium, blood flows down into the left ventricle and then out the aorta to the body (Fig. 1-6).
You must be thoroughly familiar with this circuit and with the names and function of the great vessels of the heart and lungs. The great vessels of the heart is the term used to include both arteries and veins.
Note: The great vessels of the heart are as follows:
The superior and inferior vena cavae, that empty all the blood from the body into the right atrium.
The pulmonary artery, which carries blood from the right ventricle to the lungs.
The pulmonary veins, which carry oxygenated blood from the lungs to the left atrium.
The aorta, or great artery, which carries the oxygenated blood out of the left ventricle to the body.

Pediatric History and Physical Examination History

2009-02-11T23:33:00.000-08:00

Identifying Data: Patient's name; age, sex. List the
patient’s significant medical problems. Name and
relationship to child of informant (eg, patient, parent, legal
guardian).
Chief Complaint: Reason given for seeking medical care
and the duration of the symptom(s).
History of Present Illness (HPI): Describe the course of
the patient's illness, including when it began and the
character of the symptom(s); aggravating or alleviating
factors; pertinent positives and negatives. Past diagnostic
testing.
Past Medical History (PMH): Past diseases, surgeries,
hospitalizations; medical problems; history of asthma.
Birth History: Gestational age at birth, whether preterm,
obstetrical problems.
Developmental History: Motor skills, language
development, self-care skills.
Medications: Include prescription and over-the-counter
drugs, vitamins, herbal products, homeopathic drugs,
natural remedies, nutritional supplements.
Feedings: Diet, volume of formula per day.
Immunizations: Up-to-date?
Drug Allergies: Penicillin, codeine?
Food Allergies:
Family History: Medical problems in family, including the
patient's disorder. Asthma, cancer, tuberculosis, HIV,
diabetes, allergies.
Social History: Family situation, living conditions,
alcohol, smoking, drugs. Level of education.
Review of Systems (ROS): General: Weight loss or weight gain, fever, chills, fatigue, night sweats. Skin: Rashes, skin discolorations. Head: Headaches, dizziness, seizures. Eyes: Visual changes. Ears: Tinnitus, vertigo, hearing loss. Nose: Nose bleeds, nasal discharge. Mouth and Throat: Dental disease, hoarseness, throat pain. Respiratory: Cough, shortness of breath, sputum (color and consistency). Cardiovascular: Dyspnea on exertion, edema, valvular disease. Gastrointestinal: Abdominal pain, vomiting, diarrhea, constipation. Genitourinary: Dysuria, frequency, hematuria. Gynecological: Last menstrual period (frequency, duration), age of menarche; dysmenorrhea, contraception, vaginal bleeding, breast masses. Endocrine: Polyuria, polydipsia. Musculoskeletal: Joint pain or swelling, arthritis, myalgias. Skin and Lymphatics: Easy bruising, lymphadenopathy. Neuropsychiatric: Weakness, seizures. Pain: Quality (sharp/stabbing, aching, pressure), location, duration

Physical Examination
General appearance: Note whether the patient looks “ill,”
well, or malnourished.
Physical Measurements: weight, height; head
circumference if less than 36 months, body mass index
(BMI). Plot on age-appropriate growth charts.
Vital Signs: Temperature, heart rate, respiratory rate,
blood pressure.
Skin: Rashes, scars, moles, skin turgor, capillary refill (in
seconds).
Lymph Nodes: Cervical, axillary, inguinal nodes: size,
tenderness.
Head: Bruising, masses, fontanels.
Eyes: Pupils: equal, round, and reactive to light and
accommodation (PERRLA); extra ocular movements
intact (EOMI). Funduscopy (papilledema, hemorrhages,
exudates).
Ears: Acuity, tympanic membranes (dull, shiny, intact,
infected, bulging).
Mouth and Throat: Mucous membrane color and
moisture; oral lesions, dentition, pharynx, tonsils.
Neck: Thyromegaly, lymphadenopathy, masses.
Chest: Equal expansion, rhonchi, crackles, rubs, breath
sounds.
Heart: Regular rate and rhythm (RRR), first and second
heart sounds (S1, S2); gallops (S3, S4), murmurs (grade
1-6), pulses (graded 0-2+).
Breast: Discharge, masses; axillary masses.
Abdomen: Bowel sounds, bruits, tenderness, masses;
hepatomegaly, splenomegaly; guarding, rebound,
percussion note (tympanic), suprapubic tenderness.
Genitourinary: Inguinal masses, hernias, scrotum,
testicles.
Pelvic Examination: Vaginal mucosa, cervical discharge,
uterine size, masses, adnexal masses, ovaries.
Extremities: Joint swelling, range of motion, edema
(grade 1-4+); cyanosis, clubbing, edema (CCE);
peripheral pulses.
Rectal Examination: Sphincter tone, masses, fissures;
test for occult blood
Neurological: Mental status and affect; gait, strength
(graded 0-5), sensation, deep tendon reflexes (biceps,
triceps, patellar, ankle; graded 0-4+).
Labs: Electrolytes [sodium, potassium, bicarbonate,
chloride, blood urea nitrogen (BUN), creatinine], CBC
(hemoglobin, hematocrit, WBC count, platelets,
differential); X-rays, ECG, urine analysis (UA), liver
function tests (LFTs).
Assessment (Impression): Assign a number to each
problem and discuss separately. Discuss differential
diagnosis and give reasons that support the working
diagnosis; give reasons for excluding other diagnoses.
Plan: Describe therapeutic plan for each numbered
problem, including testing, laboratory studies,
medications.

HYPERBILIRUBINEMIA

2009-02-11T06:56:00.000-08:00

DEF: Elevated serum bilirubin.
ETIOL: In the first 3 to 4 postnatal days, healthy term infants can experience a physiologic increase in unconjugated serum bilirubin from cord levels of 1.5 mg/dL or less at birth to a mean value of 6.5 ± 2.5 mg/dL, with means of 7.3 ± 3.9 mg/dL and 5.7 ± 3.3 mg/dL for breast-fed infants and formula-fed infants, respectively. Although most new-borns have hyperbilirubinemia by adult standards, physiologic jaundice is linked to normal development and is usually benign and self-limited. It arises from a developmental delay in the conjugation and excretion of bilirubin; thus, preterm infants can have maximum serum bilirubin levels 30% to 50% higher than term babies, with elevated levels persisting for 6 to 7 days postnatally. Unconjugated or indirect hyperbilirubinemia is also caused by isoimmune hemolytic disease (e.g., ABO, Rh, or minor blood group incompatibilities); structural or metabolic abnormalities of RBCs (e.g., G6PD deficiency, hereditary spherocytosis); hereditary defects in bilirubin conjugation (e.g., Crigler-Najjar syndrome, Gilbert disease); bacterial sepsis; poly-cythemia; hypothyroidism; hemorrhage/hematoma; and breast milk jaundice. Conjugated, or direct, hyperbilirubinemia can be caused by congenital biliary atresia, extrahepatic biliary obstruction, neonatal hepatitis, inspissated bile syndrome, postasphyxia, a1-antitrypsin deficiency, and neonatal hemosiderosis.
CLIN: Jaundice in the first day of life is pathologic and mandates a thorough evaluation. Neonates who are not clinically jaundiced do not require routine bilirubin level determination. Visible cutaneous and scleral jaundice in the newborn is noted when the bilirubin level exceeds 7 to 8 mg/dL. Jaundice progresses from the head downward with increaseing severity of hyperbilirubinemia (i.e., scleral and facial icterus, 6 to 8 mg/dL; shoulder and trunk, 8 to 10 mg/dL; lower body, 10 to 12 mg/dL;generalized, > 12 to 15 mg/dL). When visible jaundice is detected, the rapidity of onset, the presence of blood group incompatibilities between mother and infant, the presence of hematomas or signs of infection, the method of feeding, and the duration and clinical course of jaundice beyond the third day should be noted. Daily inspection of the baby, undressed and in adequate light, is required for monitoring the progression of jaundice. A thorough abdominal examination includes palpation of the liver and spleen to evaluate for hepatosplenomegaly. Clinical manifestations of bilirubin toxicity include opisthotonos, extensor rigidity, tremors, oculomotor paralysis, and hearing loss (i.e., manifestations of basal ganglia and cranial nerve involvement). Fatal cases in the new-born period are characterized by a loss of the suck response and lethargy, followed by hyperirritability, seizures, and death.
STUDIES: A serum bilirubin concentration is obtained when significant visible jaundice is detected on the physical examination. When the indirect bilirubin is ³10 mg/dL and the calculated rate of increase exceeds 0.2 mg/dL/hour, repeat levels should be determined every 12 hours until the levels stabilize or a clear indication for treatment exists. Important studies to review include maternal blood type, infant's blood type, Coombs tests, hematocrit, hemoglobin, reticulocyte count, RBC indices, and RBC smear. Elevation of direct bilirubin (above 1.5 to 2.0 mg/dL) should prompt evaluation for intrinsic liver disease or biliary tract obstruction.
TX: Most cases of neonatal hyperbilirubinemia are developmental, benign, and self-limited, and therefore can be managed with observation, serial bilirubin determinations, and reassurance. For more severe or complicated cases, a specific diagnosis should be sought after initial stabilization of the neonate. Phototherapy can be used to stabilize indirect hyperbilirubinemia resulting from any cause and is generally used to manage hyperbilirubinemia of greater than 15 to 20 mg/dL. When the levels of bilirubin exceed 25 to 30 mg/dL or are rising rapidly in association with hemolysis, exchange transfusion (with phototherapy) is the treatment of choice. Hyperbilirubinemia occurring within the first 3 to 5 days of life in breast-fed infants may be a result of infrequent feedings and/or delayed production of adequate milk (breast-feeding jaundice); continued, frequent feedings usually lead to resolution. Prolonged hyperbilirubinemia in breast-fed infants may be caused by specific factors in breast milk (breast milk jaundice) and resolves with temporary cessation of nursing (24 to 48 hours); serum bilirubin level usually declines promptly (2 to 4 mg/dL), and nursing is subsequently resumed with little or no further increase in bilirubin.

HEPATITIS

2009-02-11T06:47:00.000-08:00

DEF: Infectious or idiopathic inflammation of the liver.
ETIOL: Neonatal hepatitis can be caused by a variety of infectious agents, including cytomegalovirus (CMV), rubella, reovirus type 3, herpes simplex, herpes zoster, herpesvirus type 6, adenovirus, enteroviruses, parvovirus B19, hepatitis viruses, human immunodeficiency virus, bacterial sepsis (gram-negative rods, staphylococci, streptococci), syphilis, listeriosis, tuberculosis, and toxoplasmosis. Idiopathic neonatal hepatitis describes neonatal cholestatic liver disease for which all other known causes, including metabolic, infectious, and extrahepatic obstruction, have been ruled out. The incidence of idiopathic neonatal hepatitis is 1 in 5,000 births and accounts for 50% of cases of prolonged neonatal jaundice.
CLIN/STUDIES/TX: The history should focus on maternal infection during pregnancy and delivery and family history of pediatric liver disease. The major types of neonatal hepatitis are as follows:
Idiopathic: More common in premature or small-for-gestational-age (SGA) infants. Fifty percent have jaundice in the first week of life. Hepatosplenomegaly is common. One-third of these infants fail to thrive. Acholic stools may or may not be present. Radionuclide hepatobiliary imaging shows slow liver uptake with positive intestinal excretion. Liver histology is variable, with inflammation, hepatocellular unrest, multinucleated giant cells, and extramedullary hematopoiesis. Diagnosis is made through exclusion of other etiologies, including biliary atresia. Therapy is directed at addressing the malabsorptive consequences of cholestasis, which include malnutrition, growth retardation, fat-soluble vitamin deficiencies, and calcium deficiency.
Toxoplasmosis: Sixty percent have hepatomegaly, and 40% have hyperbilirubinemia. Hepatic pathology is nonspecific and includes mononuclear periportal inflammation and canalicular bile stasis. Diagnosis is made serologically or through identification of the parasite in cerebrospinal fluid (CSF) sediment. Antiparasitic therapy (pyrimethamine and sulfadiazine) may arrest disease progression.
Rubella: Sixty-five percent have hepatomegaly, and 15% have jaundice. Clinical presentation and hepatic pathology are nonspecific. Elevated aspartate aminotransferase (AST) and alanine amino transferase (ALT) levels may occur in addition to acholic stools. Progressive hepatic disease, including fibrosis and failure, is uncommon. No specific therapy is indicated.
Cytomegalovirus (CMV): Hepatosplenomegaly, jaundice, and elevated AST and ALT levels may occur. Liver biopsy shows focal areas of hepatocyte necrosis with portal inflammation composed of lymphocytes and neutrophils. Intranuclear viral inclusions are more commonly noted in bile duct epithelia than in hepatocytes. Giant cell transformation, bile stasis, and extramedullary hematopoiesis may be seen. Diagnosis is made through culture of the organism from urine or tissue. Progression to severe chronic liver disease is rare. Severe disease may be treated with ganciclovir.
Herpes Simplex: Jaundice and massive hepatic necrosis with liver failure may occur. Coxsackievirus and echovirus (types 11, 14, and 19) infection may present similarly. Diagnosis is made through viral isolation and serology. Documented infection is treated with adenine arabinoside or acyclovir.
Syphilis: Eighty percent have hepatomegaly, and 40% are jaundiced. Biopsy may show extramedullary hematopoiesis, parenchymal or portal inflammatory infiltrates, and granulomatous lesions. Although spirochetes may be seen, the diagnosis is typically made by serologic studies. Although penicillin is essential for the therapy of infants infected with syphilis, it may exacerbate syphilitic hepatic disease.

BRONCHOPULMONARY DYSPLASIA (BPD)

2009-02-11T06:45:00.000-08:00

DEF: Chronic lung disease characterized by persistent tachypnea, dyspnea, hypoxemia, and hypercarbia in neonates surviving hyaline membrane disease.
ETIOL: BPD occurs in neonates with a history of pulmonary immaturity and acute lung injury who have been treated with ventilatory support. The premature lung is believed to be particularly susceptible oxygen (O2) toxicity and iatrogenic barotrauma, resulting in persistent respiratory insufficiency. Whether infection (e.g., Ureaplasma), oxidant injury, or barotrauma is the primary insult, the inflammatory process likely exacerbates the prolonged lung damage characteristic of BPD.
CLIN: Most neonates with acute lung disease recover completely within the first week of life. The diagnosis of BPD is suspected when an affected neonate (typically premature) fails to recover as anticipated and instead may have a gradual increase in O2 and ventilatory requirements during the first month of life.
STUDIES: No specific tests exist to confirm the diagnosis of BPD. However, chest radiographic findings of strandlike densities in both lung fields alternating with areas of normal or increased lucency are consistent with BPD. Other disorders to rule out include cystic fibrosis (sweat chloride test), a1-antitrypsin deficiency (a1-antitrypsin levels), patent ductus arteriosus (PDA) (murmur, echocardiography), and viral pneumonia (viral cultures).
TX: Ideally, management of acute lung disease in premature infants should be aimed at preventing BPD by limiting exposure to mechanical ventilation and O2 therapy (if possible), judicious fluid administration, prompt management of PDA, and attention to optimal nutrition. Once diagnosed with BPD, neonates benefit from chronic administration of O2 with maintenance of PaO2 greater than 60 mm Hg or an O2 saturation greater than 90%; this chronic O2 therapy reduces the risk of developing pulmonary hypertension and cor pulmonale, severe complications of BPD. Additional O2 may be required during sleep and feedings. Congestive heart failure can frequently complicate the treatment of BPD. The development of pulmonary and systemic edema often requires chronic parenteral fluid restriction. Enteral fluid is better tolerated. Diuretics may be used with care; thiazide diuretics are preferred because they decrease urinary calcium excretion and may help prevent osteopenia of prematurity. Increased airway resistance and bronchial hyperreactivity may be treated with theophylline or b-adrenergic agents. Antiinflammatory therapy may also reduce O2 requirements and shorten the period of ventilator support. The tachypnea and heightened respiratory effort associated with BPD require that these infants receive increased caloric intake to achieve adequate growth. Caloric intake should be adjusted to enable a sustained weight gain of at least 10 g/kg/day. Infants with BPD have an increased susceptibility for developing severe pneumonia; therefore, respiratory infections should be prevented by avoiding exposure of the infant to patients, hospital personnel, and family members with respiratory symptoms. When viral respiratory infections occur in infants with BPD, O2, bronchodilator, and diuretic use are often increased for at least 1 week. If respiratory failure develops and ventilator therapy is required, mortality is high and recovery prolonged. In comparison with premature infants lacking BPD, survivors of BPD may have an increased incidence of neurodevelopmental abnormalities, visual and hearing deficits, and rehospitalization for respiratory illness in the first year of life. Because lung growth continues for the first few years of life, pulmonary function improves over that time, with most survivors achieving normal exercise tolerance by school age; evidence of increased airway reactivity can persist into adult life in a high percentage of patients.

BOTULISM

2009-02-11T06:43:00.000-08:00

DEF: Neurotoxicity caused by Clostridium botulinum exotoxin, which irreversibly blocks acetylcholine release from presynaptic terminals of cholinergic neurons at the neuromuscular junction.
ETIOL: Infant botulism is distinct from food-borne and wound botulism in that it is caused by ingestion of C. botulinum spores rather than the exotoxin itself. Spores germinate in the intestine and generate exotoxin, which is distributed hematogenously. Infant botulism accounts for two-thirds of reported botulism cases in the United States. Although the toxin does not cross the blood–brain barrier, it accesses the cyto-plasmic membrane of peripheral cholinergic nerve endings, preventing exocytosis of acetylcholine at the neuromuscular junction. The resulting flaccid paralysis is potentially fatal. Infant botulism occurs almost exclusively within the first year of life and typically between 5 and 12 weeks of life. Honey has been implicated as the source of spores in 20% of cases; the contaminants have also been recovered from corn syrup. Yard soil is an environmental source of spores.
CLIN: History should focus on food intake and environmental exposures. Constipation often is the first sign of illness and typically is overlooked. Infants become listless and weak over the course of several days to weeks. Bulbar muscle involvement results in difficulty feeding and a weak cry. Drooling and pooling of food and secretions in the posterior pharynx may occur. Ptosis, ophthalmoplegia, diminished facial expression, and generalized muscle weakness and hypotonia (manifested initially as a loss of head control) are common findings. In severe cases, respiratory arrest can occur abruptly and may account for some cases of unexpected sudden death in infancy.
STUDIES: The diagnosis is confirmed by stool culture for C. botulinum, identification of toxin in the blood or stool, and electromyography.
TX: Treatment is directed toward aggressive supportive care, with particular attention to respiratory support. Infant botulism is a self-limited disease, typically lasting 2 to 6 weeks. Antitoxin and antibiotics do not influence the disease course; in fact, bacterial death caused by antibiotics can result in increased toxin release in the GI tract. In severe cases, infants may require prolonged ventilatory support. Constipation may persist for months and may improve with the use of stool softeners and adequate hydration. Close follow-up is required because relapse of infant botulism can occur after apparent resolution of clinical symptoms. The mortality rate of recognized cases of infant botulism is approximately 3%.

BILIARY ATRESIA

2009-02-11T06:30:00.000-08:00

DEF: Progressive atresia or hypoplasia of any portion of the biliary system.
ETIOL: The incidence of biliary atresia ranges from 1 in 8,000 to 1 in 20,000 live births. The disorder appears to be acquired rather than a result of abnormal development, based on the rarity of biliary atresia in autopsied fetuses and premature newborns. One causative factor is believed to be infection with reovirus type 3.
CLIN: Infants with biliary atresia are typically born at term and have a normal birth weight. Jaundice develops at age 3 to 6 weeks in otherwise well-appearing, thriving infants. Fifteen percent of infants may have associated defects, including polysplenia (i.e., splenic tissue divided into several equally sized masses), cardiovascular anomalies, and malrotation of the intestine. Family history is usually negative.
STUDIES: Stool is acholic, collected duodenal fluid lacks bilirubin pigment or bile acids, and abdominal ultrasound may show absence of the gallbladder. Radionuclide hepatobiliary imaging demonstrates rapid uptake by the liver without intestinal excretion. Characteristic pathologic findings from percutaneous liver biopsy include bile duct proliferation, bile plugs, and portal and perilobular fibrosis. If the diagnosis is still uncertain after biopsy, surgical exploration with intraoperative cholangiography is used. This procedure enables recognition of biliary atresia and exclusion of other forms of bile duct disease, including stenosis or common bile duct perforation.
TX: If biliary obstruction occurs as a discrete lesion, surgical intervention is directed at drainage of patent portions of bile duct proximal to the atresia. Commonly, the atretic area extends above the level of the porta hepatis and affects intrahepatic bile ducts, making drainage difficult. In 80% of cases, a noncorrectable atresia is found. In these infants, further exploration is indicated to establish drainage of any small, persisting bile duct remnants. This procedure, known as the Kasai hepatoportoenterostomy, consists of transection of the porta hepatis followed by apposition of a Roux-en-Y loop of intestine. The success rate is 90% in infants younger than 2 months. In addition to infant age, the size of the residual duct lumina found during surgery is a factor in the success of this procedure; diameters less than 150 µm are associated with a poor prognosis. Treatment is not definitive, and patients may have progressive liver disease and bouts of bacterial cholangitis, requiring prompt treatment and nutritional support. Biliary atresia without intervention is universally fatal, with the mean age of death younger than 1 year. The Kasai procedure offers valuable time for the infant to grow before hepatic transplantation is necessary. Liver transplantation is essential in infants in whom the Kasai procedure fails, who are referred late (older than 120 days), and who develop liver failure despite some degree of biliary drainage.

ANEMIA IN CHILDREN

2009-02-11T06:10:00.000-08:00

ANEMIA

DEF: Hematocrit and hemoglobin concentration below normal levels.
CONDITION: Physiologic anemia of infancy/anemia of prematurity.
ETIOL/CLIN: Soon after birth, erythropoiesis almost ceases because of the oxygen-rich milieu and relative excess of red blood cells (RBCs); this results in a decrease in hemoglobin values during the first several months of life, the severity of which is related to birth weight, perinatal complications, blood transfusion history, and vitamin E deficiency. Nadir hemoglobin values can reach 9.5 g/dL at 3 months in term infants and 6 g/dL in 6- to 8-week-old premature infants. Recovery is heralded by a slight elevation in the reticulocyte count and a rise in hemoglobin levels to those seen throughout the remainder of infancy.
Tx: Healthy term infants and asymptomatic growing premature infants require no therapy. Iron supplementation may be indicated during the recovery phase to support erythropoiesis.

CONDITION: Blood loss.
ETIOL/CLIN: Anemia owing to blood loss is more common in the new-born period than in any other time in childhood. Acute hemorrhage (>20% to 30% blood volume) results in shock. Jaundice is absent. External blood loss commonly occurs from the gastrointestinal (GI) tract. To determine whether hematemesis or melena derives from the infant's or mother's blood, the Apt test for fetal hemoglobin is used. The Kleihauer-Batke stain for fetal hemoglobin–containing RBCs in the mother's blood can provide an estimate of the degree of transplacental hemorrhage. In sick premature infants, the most common cause of blood loss is the iatrogenic withdrawal of multiple specimens for testing.
TX: Treatment depends on the amount and duration of blood loss. Signs of hypovolemia dictate that the infant receive immediate volume replacement [crystalloid, plasma protein fraction, whole blood, packed RBCs (pRBCs)]. pRBCs alone may be indicated for less acute degrees of anemia.

CONDITION: ABO incompatibility.
ETIOL/CLIN: Maternal alloantibody can cross the placenta and may bind antigens on fetal/neonatal RBCs, causing hemolytic anemia. Affected babies present with jaundice during the first several days of life. In some cases, symptomatic anemia does not manifest until 4 to 6 weeks after birth. Although the reticulocyte count is elevated (5% to 15%), anemia is absent or mild. The peripheral smear shows increased nucleated RBCs and microspherocytes. Maternal and fetal blood type testing show the corresponding ABO incompatibility “set-up” (mother is blood group O; baby is A or B). Direct and indirect Coombs testing is positive.
TX: Phototherapy or exchange transfusion may be required to treat hyperbilirubinemia.

CONDITION: Rh incompatibility.
ETIOL/CLIN: Incompatibility between the mother and child in the major antigen of the rhesus complex can cause erythroblastosis fetails. Rh-negative mothers sensitized to D-positive blood produce antibodies that cross the placenta and coat D-positive fetal blood, resulting in hemolytic anemia. Severely anemic fetuses may die in utero, or neonates may be born with hydrops fetails, characterized by anasarca (from hypoalbuminemia and congestive heart failure), severe anemia, and massive hepatosplenomegaly. Less severely affected neonates (benefiting from early detection and vigorous treatment during pregnancy and delivery) may have less severe anemia. Direct and indirect Coombs testing is positive. Hyperbilirubinemia is present. The peripheral smear shows polychromasia, nucleated RBCs, and no microspherocytes.
TX: Early detection during prenatal care and Rhogam therapy prevent maternal sensitization. Intrauterine transfusion of pRBCs can correct fetal anemia. Treatment during the neonatal period consists of exchange transfusion for marked anemia and hyperbilirubinemia and pRBCs for less severe anemia. Careful follow-up is required during the first 2 to 3 months of life to monitor for delayed anemia resulting from persistent anti-D antibody.

CONDITION: Glucose-6-phosphate dehydrogenase (G6PD) deficiency.
ETIOL/CLIN: G6PD deficiency is the most common inherited intrinsic disorder of RBCs. It typically occurs in black, Mediterranean, and Asian males. Oxidant stresses from drugs or infection cause hemoglobin to precipitate, forming Heinz bodies seen on the peripheral smear. Oxidant stresses at delivery and premature birth may trigger neonatal hemolysis and hyperbilirubinemia. The diagnosis is made with specific screening tests and enzyme assays.
TX: Hemolysis and hyperbilirubinemia may require exchange transfusion.

CONDITION: Hereditary spherocytosis.
ETIOL/CLIN: Hereditary spherocytosis is the most common congenital hemolytic anemia presenting with jaundice and anemia during the neonatal period. It is an autosomal dominant disorder common in whites of northern European descent. The blood smear contains numerous microspherocytes. There is no evidence of ABO incompatibility (i.e., negative Coombs test).
TX: Hemolysis and hyperbilirubinemia may require exchange transfusion.

CONDITION: Anemia related to mechanical or toxic factors.
ETIOL/CLIN: Mechanical or toxic factors. Damage to erythrocytes can occur from toxins produced by infection or from mechanical injury mediated by fibrin strands or altered microvasculature, such as in disseminated intravascular coagulation (DIC).
TX: Treatment depends on the etiology. Blood product transfusion may be required.

CONDITION: Decreased RBC production.
ETIOL/CLIN: Anemia resulting from diminished RBC production is uncommon at birth and is reflected by a diminished or absent reticulocyte count. Causes include malignancy, sepsis (relative myelosuppression), iron deficiency, Diamond-Blackfan syndrome (congenital pure RBC aplasia), and a-thalassemia syndromes.
TX: Treatment depends on the etiology. Vigorous resuscitation measures and blood transfusions may be required.

Ototoxicity

2009-02-04T06:12:00.000-08:00

Rita M. Schuman
Gregory J. Matz

Drug-induced inner ear damage is a common finding in present-day medical practice. In many developing countries, where drugs such as the aminoglycosides are frequently prescribed to treat pneumonia, diarrhea, and tuberculosis, the incidence of ototoxicity is high (1). Physicians in practice need to recognize that ototoxic drugs can cause significant auditory and in many instances, poorly recognized, vestibular toxicity. Physicians therefore need to be cognizant of the many categories of drugs that produce ototoxicity.

Early examples of drug ototoxicity are arsenic, the salicylates, and quinine. Salicylates, for example, administered in doses in excess of 2,700 mg a day, once commonly used to treat arthritis, were found to cause a transient flat, bilateral sensorineural hearing loss and tinnitus. There has never been a case of permanent hearing loss following salicylate use in therapeutic drug dosing; however, most patients experience complete reversal within 2 to 3 days. Later, in the 1960s, thalidomide, a well-known drug used at that time and now known to cause amelia and phocomelia, was also discovered to cause aplasia of the inner ear.

The introduction of the first aminoglycoside, streptomycin, in 1944 by Waxman, who was awarded the Nobel prize for this discovery, heralded a new era of antibiotic therapy for the treatment of tuberculosis. Unfortunately, Hinshaw and Feldman at the Mayo Clinic described a significant number of patients with vestibular toxicity from this drug (2). A few years later, an analog of streptomycin, dihydrostreptomycin, was used in clinical practice with the hopes of reducing the streptomycin ototoxicity. Dihydrostreptomycin, however, was also shown to have an unacceptably high incidence of cochlear toxicity and was subsequently withdrawn from the market. Likewise, other early aminoglycosides, such as kanamycin and neomycin had unacceptably high rates of cochlear toxicity when used systemically and therefore are rarely used in that manner today. Later, a newer aminoglycoside, gentamicin, was shown to have about a 3% incidence of vestibular injury (3). Subsequent aminoglycosides such as netilmicin, tobramycin, and amikacin were developed to reduce this incidence of toxicity. In fact, netilmicin has been found to be the least ototoxic of all of the aminoglycosides available (4).

Other considerations must include the cancer chemotherapeutic agents, such as cisplatin, which has been found to result in a moderate level of ototoxicity with resultant permanent bilateral hearing loss. Clinicians are also faced with a sporadic low incidence of ototoxicity with drugs such as vancomycin and the macrolides. Most studies in the literature regarding the ototoxicity of the macrolides have been found to be reversible. The mechanism by which these drugs are toxic is unknown. Finally, numerous case reports have also indicated that hydrocodone in combination with acetaminophen can cause a rapidly progressive sensorineural hearing loss. (5). The mechanism of toxicity at this time is unknown.

Ototoxicty of Ototopical Antibiotics
It is well known that systemic administrations of aminoglycosides can cause both cochlear and vestibular toxicity. This naturally leads to the question of whether these drugs, which are used extensively to treat ear infections through topical administration to the middle ear, can cause ototoxicity. Animal data have been quite uniform in that almost all of the aminoglycoside antibiotics used in the middle ear as topical otic preparations are ototoxic (6). The use of aminoglycoside ototopical drops confined to the external auditory canal, however, presents little, if any, risk of ototoxicity.

Current review of the literature reveals documentation of a total of 54 cases of gentamicin vestibular toxicity from ototopical use in the middle ear or open mastoid cavity (7) (Table 148.1). In addition, 24 of these patients developed an associated auditory toxicity. A review of the literature in the above cited study also included 11 patients who experienced auditory toxicity from the topical use of neomycin-polymyxin-based eardrops. It was therefore recommended that when possible,
topical antibiotic preparations free of potential ototoxic side effects should be used in preference to ototopical preparations that have had the potential for ototoxic injury if the middle ear or mastoid are open (17). Aminoglycoside-containing antibiotic topical drops are not FDA approved for use in the middle ear or open mastoid cavity. Indeed, current labels contain warnings against the use of these drugs if the tympanic membrane is not intact. Although the evidence suggests that otologic damage from topical preparations with ototoxic potential is infrequent, the evidence also indicates that they offer no advantage over nonototoxic agents (17). If these ototoxic agents are considered, potentially ototoxic, antibiotic preparations should be used only in acutely infected ears and use should be discontinued shortly after the infection has resolved. Finally, if the clinician must use potentially ototoxic antibiotics in the middle ear or mastoid space, the patient or parents should be warned of the risk of ototoxicity (17).

Ototoxicity of Systemic Drugs

Table 148.2 lists the major classes of drugs that cause ototoxicityâ€”the aminoglycoside antibiotics, the macrolides, loop diuretics, cisplatin, and the salicylates. These drugs are listed because they are commonly seen in otolaryngology consultation practice. There are currently no meta-analysis studies that evaluate ototoxicity for these drugs. Included in the bibliography are two reviews that include ototoxic evaluations for gentamicin and cisplatin in a large cohort of patients. Omitted for the sake of brevity in Table 148.2 are the low-incidence ototoxic drugs, such as chloroquine, which is rarely used in clinical practice in the United States.

For various reasons, the incidence of aminoglycoside ototoxicity in neonates and children is lower than adults (23). In children, it can be useful to obtain pretreatment audiograms to rule out preexisting hearing loss in patients who are to receive a course of aminoglycoside antibiotics. In the United States, that drug is usually gentamicin.

Genetics of Otoxicity

It is well known that aminoglycosides are some of the most common ototoxic drugs causing acquired hearing loss. It was observed that many patients were developing hearing loss, despite the low dosages of aminoglycosides administered. It was also noted that certain families had an exceptionally high number of members with similar findings of aminoglycoside ototoxicity. Based on these observations and the ongoing research regarding the pathophysiology of hearing loss, it has been proposed that certain individuals may have a genetic predisposition or susceptibility to the ototoxic effects of certain drugs and in particular, the aminoglycosides (24).
Recent advances have identified that certain mutations in mitochondrial DNA are found to be associated with a number of hearing disorders, including ototoxicity. Mitochondrial DNA is a double-stranded molecule forming a closed circle. Replication and transcription occurs within the mitochondria, ultimately forming proteins involved with ATP synthesis and electron transport. This specific type of DNA is transmitted exclusively by the maternal line, equally affecting both male and female offspring.

In the early 1990s it was first discovered that a mutation at position 1555 in the nucleotides of the mitochondrial 12S ribosomal RNA was responsible for aminoglycoside toxicity in several Chinese families (25). It was also cited as a cause for a number of cases of nonsyndromic deafness in patients with no previous aminoglycoside exposure. Since that discovery, similar research has been conducted on numerous other families, as well as on sporadic patients with documented sensorineural hearing loss following the administration of intravenous aminoglycosides. These subsequent studies confirmed that these patients also had identical nucleotide mutations of their mitochondrial DNA. It has been proposed that the specific mutation creates another binding site for the aminoglycosides, thus increasing the patient's sensitivity to ototoxicity (26). Most of this work was conducted on an international basis, where severe infections such as tuberculosis more often require widespread use of intravenous aminoglycosides.

A large quantity of research continues in this area. As more becomes known about the genetics of hearing loss and the specific mutations that predispose patients to the ototoxic effects of some drugs, it may be possible to develop molecular tests to identify these patients prior to treatment. With that information, it may be possible to reduce the number of patients suffering from the toxicities of these antibiotics.

Chemoprevention of Ototoxicity
In some instances, it may be necessary to use ototoxic drugs in order to effectively treat patients. In light of this fact, it is necessary to develop mechanisms by which it is possible to protect the inner ear from the toxicities of both the ototoxic intravenous antibiotics and the chemotherapeutic agents such as cisplatin. Some of the agents that have been proposed and studied include iron chelators (deferoxime) (27,28), antioxidants including L-N-acetyl cysteine (29), vitamin E, alpha-tocopherol (30,31,32), as well as the salicylates (33,34).

Recent research has demonstrated that administration of aminoglycosides causes the formation of an iron complex that is involved in the generation of free radicals, resulting in hair cell death and subsequent hearing loss (28). Based on this discovery, attempts have been made to use deferoxamine, an iron chelator, to help attenuate these toxic effects. Animal studies have been promising, but considerations must be taken so as to not alter the serum concentrations of the drugs, and a better understanding is needed of the side effects of administering iron chelators to patients and the potential of altering serum iron levels (27).
Cisplatin, a common chemotherapeutic agent used in head and neck cancer, is well known to cause bilateral, irreversible sensorineural hearing loss. Evidence suggests that glutathione reduction secondary to free radical production ultimately causes hair cell damage. Various chemoprotectants have been shown to exert antioxidant properties that ultimately reduce the ototoxic effects of cisplatin. Recent studies with vitamin E (31), L-N-Acetyl cysteine (29), and sodium thiosulfate (35) confirm this theory. Most of the research, however, has thus far been with animals. Further human studies must be done to truly know if these advances will be clinically significant and will ultimately reduce the ototoxic effects.

Summary

One of the authors of this chapter (GJM) has written previously about the use of high-frequency audiometry (8 to 12 Hz) as a predictor of drug-induced ototoxicity (36). Although conventional audiometry may still have a role in monitoring patients exposed to ototoxic medications, high frequency testing is often problematic. It is an extremely difficult test to do for all practical purposes and is often not done clinically for that reason. Few centers perform pretreatment conventional audiograms from 0.25 Hz to 8 Hz when the two most common ototoxic drugs, gentamicin and cisplatin, are given. The authors are not aware of any outcome studies that demonstrate that pretreatment and post-treatment audiograms reduce the incidence of predicted ototoxicity. Some centers have found, however, that it may be beneficial to perform one pretreatment audiogram followed by serial audiograms, in addition to closely monitoring the serum drug levels of the ototoxic medications being administered. The use of vestibular testing both pretreatment and post-treatment for patients receiving long-term gentamicin is also difficult to do in the clinical setting. This is an important factor because gentamicin is mostly a vestibular toxic drug. Some centers do perform electronystagmography, rotational testing, and platform posturography in working up possible vestibular symptoms and have found these tests to be helpful.
It is now well known that the aminoglycoside antibiotics act synergistically with some drugs, thus increasing the incidence of ototoxicity. For example, the use of aminoglycoside antibiotics with loop diuretics can produce an unexpectedly high incidence of ototoxicity. This has been extensively documented in human case reports as well as in animal studies. Ethacrynic acid, an ototoxic loop diuretic, has been shown to increase the permeability of the stria vascularis, facilitating the diffusion of the aminoglycoside into the endolymph. Finally, it has been found that diuretics given prior to the administration of aminoglycosides are less damaging than if done in the reverse (37). Most recently noted is a similar response to aminoglycoside antibiotics and the use of metronidazole (38).
It is unclear at this time if antiviral and protease inhibitors are responsible for the anecdotal reporting of neurosensory hearing loss in patients with human immunodeficiency virus (39). Prospective studies are needed to confirm whether nucleoside analog reverse transciptase inhibitor or antiviral agents cause hearing loss in this patient population. The use of chemoprevention measures as described in animal studies show promise, but so far no prospective clinical trials have been performed and the authors are not aware of any medical centers with protocols to address this issue at this time.
The two most common ototoxic drugs given today in clinical practice are gentamicin and cisplatin. The patients selected in these groups are different. Gentamicin is normally monitored not by audiograms but by serum peak and trough levels. When gentamicin has to be given for long-term therapy (i.e., osteomyelitis), consideration has to be given to genetic testing to see if a patient is going to be more susceptible to ototoxic injury, thus giving the clinician the opportunity to obtain informed consent from the patient. Likewise, accurate dosing during chemotherapy has reduced the incidence of ototoxicity. Further research is necessary to determine if any of the chemopreventative agents will be successful in further animal and ultimately human trials to reduce the unfortunate toxicities of these necessary drugs.

Balance Function Tests

2009-02-04T05:56:00.000-08:00

Colin L. W. Driscoll
J. Douglas Green Jr

Balance is maintained through complex interaction of the vestibular, visual, and somatosensory information that is combined within the brainstem to generate a motor response correcting the perturbation. Abnormalities within any portion of the system can cause a sensation of imbalance or dizziness. Dizziness is one of the most common reasons for seeking medical evaluation, and the otorhinolaryngologist is often the primary contact. Evaluating patients for dizziness can be frustrating for both patient and physician. The symptoms are difficult for patients to describe, the differential diagnosis is broad, and many tests have to be considered. An understanding of the balance tests currently available and the pathophysiologic principles on which they are based improves treatment of these challenging patients. The particular approach to dizziness is affected by type of practice, available resources, and patient population.
The main goals of the diagnostic evaluation are to determine the location and severity of lesions within the balance system and to help formulate and guide a treatment plan. The etiologic evaluation of the balance system dysfunction necessitates compilation of other data, including those from a comprehensive history and physical examination and other directed laboratory and radiologic examinations. In most cases, clues revealed during the history and physical examination lead to a diagnosis, and treatment can begin without additional testing. Balance function testing should be interpreted in light of the history and physical exam findings and often provides confirmatory information as to pathophysiologic processes involved. Formal balance function testing provides information as to the site and side of the lesion, to ascertain who is likely to benefit from vestibular rehabilitation, to assess recovery of vestibular function, and to document contralateral function when a destructive procedure is contemplated. Clinical decision support systems have been described to help office personnel determine which patients may need balance function testing (1).
This chapter reviews tests for assessing the balance system (Table 131.1). These balance system tests, usually administered by an audiologist or trained technician, require specialized equipment and dedicated space. The basic physiologic principles of the tests are reviewed.

Electronystagmography
The electronystagmography (ENG) test battery is the workhorse of balance function testing. It is a combination of tests that together provide complementary information about the vestibular and oculomotor systems. Rather than a diagnosis, the tests provide data that must be used in conjunction with the findings of the history, physical examination, and other studies to determine a diagnosis. The ENG battery typically consists of the vestibular and oculomotor tests listed in Table 131.2.
The ENG tests are based on the well-studied neurophysiologic characteristics of the vestibulo-ocular reflex. Motion of the head, or simulated motion through labyrinthine stimulation, produces compensatory eye movement. These eye movements are observable and recordable responses that provide the basis for interpretation of the various tests. Changes in eye position are recorded by means of taking advantage of the natural difference in electrical charge between the cornea (+) and the retina (-), the corneal-retinal potential. Electrodes record the changes in potential when the eye moves [electrooculography (EOG)]. The advantages of this recording technique are low cost, ease of administration, noninvasiveness, avoidance of head restraint, and extensive experience in interpreting the data. The technique does have technologic limitations. The signal is susceptible to changes in skin resistance due to perspiration, interference from eye-blink artifacts, and a poor signal-to-noise ratio. Although abnormal eye movements can be revealed by means of direct visualization during testing, it is preferable in most cases to have quantifiable data to characterize the abnormalities. Furthermore, some parts of the test require that the eyes be closed to prevent fixation suppression. Nystagmus is the primary ocular movement measured and is defined by its direction (horizontal, vertical, or torsional) and velocity (degrees per second). Direction is determined by the fast component, and velocity is calculated from the slow-phase component.
New technologies for observing and recording eye movement continue to be developed (2,3). Video ENG systems, vidoenystagmography, are now available that use small video cameras to observe and monitor horizontal, vertical, and torsional eye movement during vestibular evaluations (Fig. 131.1). With this system, tests that require the patient to move are performed with a lightweight goggle assembly. Pursuit, gaze, and saccade testing can be performed with an oculomotor module with tracking targets for each eye. The eyes are illuminated with near-infrared light that is not visible to the patient but allows the cameras to pick up and project images of the eyes on video monitors. This system has several advantages over traditional ENG testing techniques. Nonelectrode eye movement recording eliminates artifacts, the need for frequent recalibration, and impedance testing. Vertical eye movements can be accurately recorded. Torsional eye movements can be visualized and recorded without fixation suppression. Disconjugate eye movements are more easily identified. A portable unit allows testing at home, in an intensive care unit, or at any other remote location. The disadvantages are high cost, need to wear goggles, and unfamiliarity with the equipment. Most companies that manufacture ENG equipment now offer a videonystagmography system to make use of these advantages.
Virtual reality testing systems are being developed and promise to provide a means to produce visual stimuli that were previously impossible (4). Images can be produced on a visual display, and because the system is software driven, the images can be manipulated quickly and with tremendous flexibility. For example, cross-axis stimulation (head motion in one plane and eye motion in another) becomes easy to perform.
The sequence of ENG tests is important to prevent obtaining misleading results. For example, testing for benign paroxysmal positional vertigo is performed at the beginning of the test series to avoid fatiguing of the response. The tests must be performed with proper attention to detail and accurate calibration. Patient anxiety, fatigue, lack of cooperation, and medications can adversely affect test results.
Interpretation of ENG results is critical to proper diagnosis and treatment and should be performed by qualified audiologists and physicians who are trained and familiar with the equipment being used for testing. Increasingly, specialists in other fields, chiropractors, and poorly trained medical doctors are investing in ENG equipment in hopes of financial gain, often without knowledge of how to interpret the ENG test results and how to apply them in clinical practice. It is essential that otorhinolaryngologists offering ENG testing be familiar with interpretation of the results. Several excellent courses are available to otorhinolaryngologists offering ENG testing within their offices.

Spontaneous and Gaze Nystagmus
Spontaneous nystagmus refers to nystagmus that is present without visual or vestibular stimulation. Spontaneous nystagmus can sometimes be seen only with loss of visual fixation (e.g., milder forms of spontaneous vestibular nystagmus) or may be seen with both eyes open and with loss of visual fixation (e.g., congenital nystagmus and severe vestibular nystagmus). Spontaneous nystagmus can be observed both at the bedside and in the vestibular laboratory. However, although reduction of visual fixation can be achieved easily in the laboratory using infrared video goggles or EOG with eye closure, at the bedside, achieving a reduction in visual fixation while still maintaining an ability to observe eye movements can be challenging. Observing a patient's eye with an ophthalmoscope while the other eye is occluded allows the examiner to assess spontaneous nystagmus with reduced visual fixation. The most common type of spontaneous nystagmus, that is, spontaneous vestibular nystagmus, occurs with unilateral peripheral vestibular lesions. Spontaneous vestibular nystagmus is always unidirectional and increases when the patient gazes in the direction of the quick component of the nystagmus. This gaze dependent change in nystagmus intensity is called â€œAlexander's Law.â€ As noted previously, loss of visual fixation also increases the magnitude of spontaneous vestibular nystagmus. Thus, judicious use of gaze direction and presence or absence of visual fixation can aid the examiner both at the bedside and in the laboratory in judging whether or not a spontaneous nystagmus is a result of a vestibular abnormality. Failure of fixation suppression is highly suggestive of a central pathologic condition.
Gaze nystagmus, also known as gaze-evoked nystagmus, is a bidirectional nystagmus with right beating nystagmus on right gaze and left beating nystagmus on left gaze. Many patients with gaze-evoked nystagmus also will manifest an up-beating nystagmus on upward gaze. Note that down-beating nystagmus in any gaze position, even in downward gaze, is not considered a component of gaze-evoked nystagmus and should be regarded as a manifestation of a central nervous system abnormality at the level of the craniocervical junction unless proven otherwise. Gaze-evoked nystagmus can be seen in normal individuals when horizontal gaze exceeds 30 degrees from the straight-ahead position. Thus, it is best to limit the amount of gaze deviation when assessing a patient for gaze-evoked nystagmus to less than 30 degrees. Gaze-evoked nystagmus occurs as a result of inadequate gaze-holding, thereby leading to a slow drift of the eyes back toward the straight ahead gaze position with the drift interrupted intermittently by rapid, nystagmus fast phases in the direction of gaze. Bidirectional gaze-evoked nystagmus is always a result of a central nervous system abnormality and never is the result of a peripheral vestibular abnormality. There are many etiologies for gaze-evoked nystagmus. The most common cause of gaze-evoked nystagmus is a medication effect (e.g., from anticonvulsants).

Positional and Positioning Tests
Positional tests are designed to detect the response to changes in direction of gravitational force. The patient is moved slowly into a series of stationary positions with the eyes closed, and presence or absence of nystagmus is assessed. The nystagmus can be either fixed or direction changing. If nystagmus is elicited in the positional tests, the entire body is turned to determine whether neck torsion is responsible. Interpretation of results is controversial and necessitates consideration of the number of positions that elicit nystagmus and the velocity of the nystagmus. Positional nystagmus of peripheral origin can fatigue with repeated testing, is usually direction fixed, and often is associated with caloric weakness. The direction of nystagmus caused by a peripheral lesion typically does not change independently of head movement (5). Direction-changing nystagmus without an accompanying change in head position indicates the presence of a central disorder.
The positioning test used most often is the Dix-Hallpike maneuver. The patient is rapidly moved from sitting to supine with the head turned and hanging below the level of the table. If nystagmus is elicited, the maneuver is repeated to determine the existence of fatigability. A response that fatigues suggests a peripheral problem. The patient's eyes are kept open to allow the examiner to evaluate for torsional nystagmus, which can indicate benign positional vertigo due to loose otoconia within the labyrinth. Torsional nystagmus cannot be recorded with conventional ENG. Head hanging to the right produces counterclockwise torsional nystagmus, and head hanging to the left produces clockwise torsional nystagmus. A variant of benign positional vertigo affecting the horizontal semicircular canal produces pure horizontal nystagmus.

Bithermal Caloric Tests
Bithermal caloric tests are used to evaluate the function of the horizontal semicircular canals. Changes in temperature stimulate fluid flow (equivalent to a very slow frequency of only 0.002 to 0.004 Hz) within the horizontal semicircular canal; if the system is functioning, nystagmus is elicited. The very slow frequency of stimulation is not a condition normally experienced during daily life. Each ear is tested independently, and the responses are compared.
Caloric testing is performed with the patient supine and head elevated 30 degrees. The external auditory canal is irrigated directly with 250 mL of water at 7 degrees above and below body temperature for 30 seconds. An alternative is to place a small, distensible balloon in the ear canal and fill it with water (closed-loop system). Ocular movements are recorded for approximately 2 minutes, beginning with stimulation. Fixation suppression is evaluated during this time. The slow-phase velocity of elicited nystagmus is calculated and recorded as an objective measure of the response. Warm and cool air irrigation or a closed-loop system can be substituted for direct irrigation if the tympanic membrane is perforated. The responses of the right and the left ears are compared. A difference greater than 20% usually is considered abnormal and is reported as left- or right-sided weakness. The total right-beating responses is compared with the total left-beating responses, and the result is reported as a right or left directional preponderance. A difference greater than 30% is considered significant. Abnormal directional preponderance without unilateral weakness suggests a central pathologic condition. The results indicating central or peripheral disorders are summarized
A monothermal caloric screening test has been suggested to minimize procedure time and patient discomfort. This test has been criticized for a high false-negative rate. However, the results of a study by Jacobson et al. (6) suggest that if appropriate failure criteria are used, the sensitivity reaches 93% and the specificity 98%. Patients who fail the screening test need conventional bithermal testing.
Patients with a complete unilateral or bilateral caloric loss should be tested with ice caloric irrigation of the affected ear(s). Frequently, nystagmus can be elicited with this stronger stimulus. Ice caloric stimulation is uncomfortable for the patient and should be limited in use. It should be noted that the absence of caloric response to warm, cool, or ice water irrigations cannot be taken as an indication of complete lack of function. This should be confirmed by rotational chair testing.

Electronystagmography Fistula Test
If a fistula exists between the middle ear space and the inner ear fluid, application of positive or negative pressure in the external ear canal may produce a fluid shift resulting in nystagmus. Objective nystagmus or a clear subjective response suggests a perilymph fistula or dehiscence of the horizontal or superior semicircular canal.

Saccadic System
The saccadic system is used to move a target from theperiphery of the retina to the fovea. Targets more than20 degrees from the line of sight are normally located by means of a combination of eye and head movement, called gaze saccade (7). This test is performed while the patient sits facing a light bar and keeps his or her head stationary. Lights on the bar are activated to the left and right of center by 10 to 20 degrees, and the patient is asked to shift gaze to each new target. Electrooculographic recording techniques are used. Latency, maximum velocity, duration, gain (overshoot or undershoot), refixation saccade, glissade (postsaccadic drift, or slip of the eye), and other variables are measured and observed.
Abnormal saccades can be caused by lesions in a wide variety of locations. However, they are most commonly caused by a central pathologic disorder rather than a peripheral vestibular one. An abnormal saccadic response can be caused by lesions in the cerebellum (dorsal cerebellar vermis), brainstem (particularly the paramedian pontine reticular formation and medial longitudinal fasciculus), or ocular muscles and nerves. Cerebellar lesions typically manifest as saccadic overshoot or undershoot dysmetria. Dysmetria is an error in range, rate, or direction in performance of precision voluntary movement. It usually is found through past pointing in a finger-to-nose test (8). Different patterns of abnormalities and testing paradigms can help to localize a lesion (9). Age, fatigue, lack of attention, sedatives, drug intoxication (phenytoin), and other factors can cause slow saccades or increase latency.

Pursuit System
The smooth pursuit system stabilizes images of moving objects on the fovea (7). Healthy persons can pursue an object moving at a velocity of about 30 degrees per second. At faster rates, the image can slip, and a corrective saccade is used to catch up. Smooth pursuit usually is tested with sinusoidal stimuli, such as a pendulum, light-emitting diodes, or a laser, with a frequency range of 0.2 to 0.7 Hzand a horizontal range less than 20 degrees to the left and right. Electrooculographic techniques are used to record gain, phase lead or lag, symmetry, and other variables. Because the smooth pursuit system is distributed throughout the brainstem and cerebellum, anatomic localization is not possible (9). If age, alertness, medications, and congenital nystagmus are eliminated as causes of abnormal test results, a central cause is suggested. Saccadic pursuit suggests cerebellar disease. Reduced bilateral gain can be caused by a brainstem lesion. Patients with Alzheimer disease and schizophrenia can perform worse with sinusoidal stimuli than with fixed velocity stimuli (9).

Optokinetic System
The optokinetic system differs slightly from the pursuit system in that it allows persons to keep the visual field in focus while they or most of the environment are moving. The vestibulo-ocular reflex alone is not adequate to generate compensatory eye movements at low frequency. In clinical testing, this effect is achieved by keeping the patient stationary and moving the environment. About 90% of the visual field must be filled with the target to avoid simply testing the pursuit system. A rotating drum with thin vertical stripes or stripes projected on the wall are common stimuli. The patient is instructed to look straight ahead. As the targets pass by, there should be small amplitude excursions of the eye (stare nystagmus). If the patient fixes on the target, longer excursions occur, and the pursuit system is being tested (look nystagmus) (9). Separating the smooth pursuit system and the optokinetic system can be even more difficult. Experiments indicate that both systems are responsible for eye movement during stimulation. If, however, the lights are extinguished, the smooth pursuit system response drops to zero almost instantly. With the lights out, patients continue to have nystagmus for approximately 25 seconds. It is believed that this nystagmus [optokinetic afternystagmus (OKAN)] is caused by the optokinetic system alone (7). Because of the contribution of the pursuit system, it is not possible to conclude that the optokinetic system is normal without having nystagmus for approximately 25 seconds following optokinetic stimulation.
The optokinetic system is widely distributed throughout the brainstem and cerebellum; therefore, abnormalities are not site specific. Absence or asymmetry of the OKAN occurs with peripheral vestibular lesions. Bilateral labyrinthectomy profoundly reduces or eliminates OKAN (10). These findings suggest an interaction between the vestibuloocular reflex and the optokinetic system (7). The OKAN becomes asymmetric after unilateral vestibular ablation; the result is stronger and more prolonged nystagmus directed at the side of the lesion (10). A problem is that the sensitivity in identifying unilateral vestibular disease is not high (10). In a study involving 12 patients who had undergone removal of acoustic neuroma, OKAN helped identify the side of the lesion for only 7 of the patients (10). Baloh et al. (11) found abnormal test results among patients with cerebellar atrophy.
Optokinetic testing is not routinely used but can be indicated as a confirmatory examination when abnormal pursuit is identified. Combining the results of OKAN with those of rotary testing can be helpful in determining the side of the lesion. Another potential use might be to exclude vestibular disease, especially for patients who cannot undergo caloric testing (10). As more is learned about the production of optokinetic nystagmus, clinical usefulness can expand.

Rotary Chair, Sinusoidal Harmonic Acceleration
Rotational testing paradigms offer the theoretic ability to test the semicircular canals under more physiologic, that is, higher frequency, conditions than can be achieved with caloric testing. The stimulus can be precisely controlled and is repeatable. Because both ears are tested simultaneously, the results reflect the integrated function of both ears (12). In this test, the rotary chair is oscillated from side to side at a series of preprogrammed rates (Fig. 131.2). The acceleration frequencies tested range from 0.01 to1.28 Hz with a maximum velocity of 50 degrees per second.
More rapid rotational velocities may result in head slippage adversely affecting test results. An infrared camera is mounted to the chair to monitor the patient and eye movement. Mental alerting tests are used, as in ENG. As the chair begins to rotate to the right, standard EOG techniques are used to record slow compensatory eye movement to the left. Saccadic eye movement returns the eye to a central position. This movement is eliminated mathematically, and slow-phase movement is compared with chair movement. Three basic characteristics are measuredâ€”phase, gain, and symmetry of eye movement. Testing is comfortable for the patient and takes approximately 15 minutes.
Interpretation of the results requires integration with complementary data and the clinical history. Symmetry represents a comparison between the peak slow-wave velocity when the patient is rotated to the left and the peak slow-wave velocity with rotation to the right. For a patient with acute, uncomplicated unilateral peripheral weakness, the symmetry measure shows weakness on the affected side. A problem is that symmetry can be misleading in many cases. Spontaneous nystagmus, irritation of the labyrinth, vestibular compensation, and cerebellar lesions can produce erroneous data. The value of symmetry alone as an indicator of the side of a lesion is controversial. Caution is needed in interpretation of the results. Symmetry often improves with compensation after a vestibular insult and can be useful for monitoring recovery (11). Asymmetry or directional predominance can also be seen withmigraine-associated dizziness, a common form of dizziness.
The phase variable is the relation between maximum chair velocity and maximum slow-phase velocity. Eye velocity typically leads chair velocity, the so-called phase lead. The phase lead often is exaggerated among patients with central or peripheral vestibular disease. If abnormal, this value is nonlocalizing. Some laboratories also include a step test in addition to sinusoidal acceleration testing described previously. In the step test, the system time constant is measured by varying the speed at which the chair rotates. This test can be performed simultaneously with the sinusoidal acceleration testing, providing additional vestibulo-ocular reflex information.
Gain is the ratio of maximum eye velocity to maximum chair velocity. A gain of one indicates that slow-phase eye velocity equals chair velocity and is opposite in direction. If there is no eye movement, the gain is zero. A problem is that gain can fluctuate markedly with changes in alertness. Consistent testing is critical to obtain valid results. The gain values used in calculating phase and symmetry must be accurate. Low gain values alert the physician that the results may be inaccurate. Depressed gain values under good testing conditions suggest bilateral peripheral lesions. Abnormally high gain can indicate the presence of a cerebellar lesion that is decreasing vestibular inhibition. Another caution is that there can be considerable differences in results between laboratories, depending on the specific data analysis algorithms used and operator intervention (13).
Rotary testing is useful to (a) monitor changes in vestibular function over time, especially bilateral lesions or lesions due to vestibular toxicity, (b) monitor compensation after acute injury, and (c) identify residual labyrinthine function for patients with no response during caloric testing or low-frequency rotary chair testing (12,14).
Off-vertical-axis rotation is a variation of rotary chair evaluation (15). The testing procedure is similar, except that the chair can be tilted 30 degrees. Earth horizontal axis (barbecue spit) rotation is another variation. The proposed advantage is that otolith function is incorporated into the response. The role of this type of testing is being investigated. Data suggest that a single labyrinth is sufficient to produce normal semicircular canalâ€“otolith interaction; therefore, the value of the test may be limited (15). Another modification is to test unilateral otolith-ocular response. During constant angular rate rotation, the patient is displaced laterally on the rotating turntable, so that one labyrinth becomes aligned with the rotary axis and the second (eccentric) labyrinth is solely exposed to inertial acceleration (16).

Vestibular Autorotation Test
The vestibular autorotation test is a method of evaluating the vestibuloocular reflex (head-shaking nystagmus) that has distinct clinical and practical advantages over rotary chair testing and ENG (2,17,18,19,20,21). Patients are wired with conventional EOG electrodes to record horizontal and vertical eye movement and are fitted with a lightweight headband containing an EOG amplifier and rotational velocity sensor. The patient is instructed to fix on a target and to rotate the head in synchrony with an auditory cue. The auditory cue accelerates to a maximum of 6 Hz and maintains this velocity for 13 seconds for a total test time of 18 seconds. The test is repeated three times in the horizontal and vertical dimensions. Phase, gain, and symmetry data are collected over the frequency range of 2 to 6 Hz (17).
The vestibular autorotation test has several attractive characteristics. The vestibular system is evaluated at frequencies more physiologic than the ultralow frequencies used in conventional ENG or rotary chair testing (20,22,23,24). The vestibular autorotation test can be performed efficiently, does not require dedicated space, is portable, allows testing in the vertical plane, and is well tolerated by patients. A potential disadvantage is that it includes the cervical-ocular reflex, but this is thought to be an unimportant contribution at the frequencies used. Vestibular autorotation testing also requires patients to rotate their heads appropriately, which may be problematic for elderly patients or patients with cervical pathology. Interpretation of the results is the same as with ENG and rotary chair testing. The clinical value of headshake nystagmus in evaluating dizziness has been challenged. Jacobson et al. (21) reported a sensitivity of only 27% and a specificity of 85%.

Dynamic Posturography
Computerized dynamic posturography came into the clinical realm in 1985 with the introduction of the Equitest system developed by NeuroCom. Posturography consists of two testsâ€”the sensory organization test and the movement coordination test. The sensory organization test protocol calls for evaluation under six conditions in which sensory and proprioceptive inputs are varied (Fig. 131.3). During the sensory organization test portion, the patient's anterior and posterior body sway is recorded, and a performance index is calculated on a scale of 0% to 100% (fall, 0; no sway, 100). During the movement coordination test, the patient stands quietly on a platform, with the visual surround fixed (Fig. 131.4). The platform then undergoes a series of translational and rotational movements. The principal measurement recorded is the latency to onset of active recovery from destabilizing perturbation. Amplitude and symmetry of the neuromuscular responses also are recorded.
Several classification systems to assist with interpretation of results have been proposed (25). Table 131.4 summarizes one system (9). Although these patterns seem to suggest the site of the lesion, the test is not designed or suited for this purpose. A patient with abnormal scores on tests 5 and 6 can have a central or peripheral vestibular disorder. Patients with a compensated unilateral peripheral vestibular dysfunction have normal performance on tests 5 and 6. A patient with abnormal scores on conditions 1, 2, 3, and 4 is more likely to have a nonvestibular lesion or functional disorder (aphysiologic sway). A diagnosis of functional disorder is suggested when test results on the more difficult conditions (tests 4, 5, and 6) are equal to or better than those recorded during testing of the easier conditions (tests 1, 2, and 3).
The postural evoked responses in the movement coordination test portion of the evaluation are useful in validating the sensory responses and in identifying a central pathologic disorder. The tests are based on the automatic muscle responses thought to be triggered by proprioceptive changes. The response requires normal muscle, nerve, spinal cord, cerebellar, brainstem, and cortical function and is thus a diffusely distributed response. It is likely that the response is modulated by vestibular and other sensory input.
The most common test for perilymphatic fistula is ENG of the vestibuloocular reflex. Dynamic posturography offers an alternative testing strategy that eliminates potentially confounding effects from the visual and proprioceptive systems. Dynamic posturography can eliminate visual and somatosensory input and therefore better isolate the vestibular apparatus. Positive and negative pressures can be applied to the external auditory canal by means of standard tympanometry techniques, and postural adjustments can be analyzed (23). This test can be more sensitive than the traditional ENG fistula test (26,27). However, lack of a definitive test for the existence of a perilymph fistula impedes development of a clear relation.
Posturography can be combined with standard electro-myographic techniques. Electromyography is beneficial in identifying particular muscle response patterns triggered by changes in visual or somatosensory input controlled by the computerized dynamic posturography apparatus. These testing strategies are most useful in research aimed at understanding the complex interactions that allow maintenance of postural control.
Posturography is especially beneficial in documenting overall postural stability and in identifying particular balancing strategies. It is useful for vestibular rehabilitation and for monitoring improvement or decompensation. The computerized dynamic posturography evaluation is comfortable for patients, and they feel that their balance is being thoroughly tested. The test results correlate more closely than those of other balance function test results with the Dizziness Handicap Inventory, which is a subjective measure of overall balance limitations (28).

Pediatric Testing
Vestibular testing of children presents several challenges. Mental alerting, lack of tolerance of uncomfortable stimuli, inability to follow verbal commands, and inability to remain still all make testing difficult. Modifications of the standard adult ENG battery allow oculomotor, positional, and caloric testing (29). Simultaneous minimal caloric irrigations improve tolerability by reducing the degree of induced nystagmus and time of the procedure. Of course, the data obtained are not as informative as those provided by alternate binaural testing. Closed-loop irrigation systems can improve tolerance. Vestibular autorotation testing can prove useful in children, but more experience is needed. Rotational chair testing can be performed on most children, and very young children can sit on a parent's lap. Computerized dynamic posturography can be performed on older children, but normative data are not available. Most testing protocols can be shortened to minimize testing time and improve compliance.

Vestibular Evoked Myogenic Potentials
Standard caloric testing performed as part of an ENG battery evaluates the superior vestibular nerve because the lateral semicircular canal is being stimulated. A relatively new test can be performed using equipment traditionally used for auditory brainstem response testing to evaluate the function of the inferior vestibular nerve. Colebatch and Halmagyi (30) described the electromyographic response of the neck musculature to a loud, ipsilateral, broad band click. The afferent limb of the response is thought to be due to stimulation of the saccule with transmission via the inferior vestibular nerve to the brainstem and vestibular nuclei. The efferent limb of the response is via the spinocerebellar tract with the response typically recorded on the ipsilateral sternocleidomastoid muscle. The desire for inferior vestibular nerve evaluation has greatly increased the use of this test, which is termed the vestibular evoked myogenic potential (VEMP).
As experience with VEMP accumulates, the limitations and benefits of testing are becoming more apparent. Patients older than 60 years may have a reduced response in VEMP amplitude, which is thought to potentially be due to deterioration of saccular function (31). Pathologic changes in the brainstem, such as multiple sclerosis, may result in delayed potentials with variability noted in the response of the test to common conditions such as acoustic neuromas, MÃ©niÃ¨re disease, and vestibular neuritis (32). Surprisingly, early MÃ©niÃ¨re disease frequently demonstrates normal VEMP responses with progressive loss of the potentials with disease progression.

Dynamic Visual Acuity
Movement of the head causes significant retinal slip and loss of visual acuity unless the vestibulo-ocular reflex produces an appropriate compensatory response. Patients with dizziness frequently complain of visual blurring and unsteady visual sensations, particularly with head movement. The lack of visual stability on the retina can be quite disconcerting to patients and may prove dangerous forpatients during driving. Several commercial devices are available that can assess dynamic visual acuity. These tests use a rotational velocity sensor in combination with a computer screen to evaluate vision during head movement, giving a functional assessment of the vestibulo-ocular reflex in both horizontal and vertical planes (33).
Age does seem to affect dynamic visual acuity results with older patients demonstrating reduction in visual stability. Although some variability has been noted, the test does show good sensitivity and specificity in distinguishing normal patients from those with abnormalities.Patients with bilateral vestibular deficits were shown to have a greater degree of reduction in comparison with unilateral vestibular deficits and patients with nonvestibular dizziness. Surprisingly, oscillopsia did not correlate with abnormalities on vertical dynamic visual acuity in patients with bilateral vestibular loss. This seems to be due to the central preprogramming and the predictability of the head movements. Recent studies demonstrate recovery of the dynamic visual acuity following deterioration after traumatic brain injury associated with dizziness (34).

Vestibular Function and Anatomy

2009-02-04T05:10:00.000-08:00

The vestibular system, defined as the peripheral vestibular motion detectors and related central nervous system structures, senses motion in space and converts that motion into information that the remainder of the central nervous system can use to generate appropriate motor reflexes or facilitate complex processes such as the coordination of head, eye, and trunk movements or updating one's perception of his or her orientation in the world. The vestibular system, like the auditory system, converts physical stimuli into neural signals, but the vestibular system detects angular and linear acceleration, rather than sound. The vestibular system is present in all vertebrates and many invertebrates. Yet, despite the importance of spatial orientation in all mobile animals, the vestibular system is largely underappreciated until a malfunction occurs, at which point patients present to a physician, often an otolaryngologist, for treatment and education. This chapter discusses the anatomy of the peripheral vestibular system, the biophysics of sensory transduction, vestibular hair cell types and physiology, vestibular afferent types and physiology, and the organization of sensory inputs to the central nervous system, but it is only an introduction to this important, complex system.
The complexity of challenges presented to the vestibular system on a daily basis is elucidated with a simple example. Figure 130.1 follows an office worker through the simple processes of looking for a book on a shelf. She pushes her chair back, stands, and turns left to face the shelf. She then tilts her head (right ear down) to scan the book titles. One way to describe the motion the worker's head makes between the two positions is to decompose the movement into linear (straight-line) motion and angular (rotational) motion, by considering a path made by the center of her head. In this example, the linear motion can be described as backing away from the desk 2 m, with a leftward motion of 3 m and an upward motion of 1 m (Fig. 130.1B). In terms of rotary motion, the woman pitches her head upward 40 degrees from looking down at the paper to looking horizontal. She turns 90 degrees to the left around a vertical axis to face the bookshelf. She then tilts her head 75 degrees toward the right-ear-down position to read the book titles (Fig. 130.1A). Thus, the motion the worker uses to complete the movement between the starting and ending positions can be characterized by three linear movements and three angular movements.
The vestibular system must be able to detect both linear and angular motion in order for the brain to estimate the orientation of the body in space. An important additional piece of information needed for orientation is the direction of gravitational pull or the gravity vector. Among other things, the knowledge of the orientation of gravity allows humans to maintain a vertical stance. Even in the previous simple example, there is not only a complex interaction between the motions of the head, eyes, and body relative to one another, all of which use information generated by the vestibular system, but there is a visual, somatosensory, and vestibular system interaction that allows the worker to know her orientation relative to her surroundings

Gross Anatomy of Thevestibular System
Vertebrates have what amounts to an inertial guidance system made up of multiple sensors of linear acceleration and multiple sensors of angular acceleration in each inner ear.This guidance system, the vestibular labyrinth, is housed in a portion of the otic capsule in the petrous portion of the temporal bone. The bony labyrinth is the thick bone of the otic capsule that houses the membranous labyrinth suspended in perilymph. The membranous labyrinth holds endolymphatic fluid and the neuroepithelial structures of sensory transduction. The perilymphatic and endolymphatic spaces of the labyrinth are continuous with those of the cochlea; therefore, the composition and homeostatic mechanisms of the perilymph and endolymph discussed in the cochlea chapter (Chapter 129) apply to the vestibular system as well. As in the cochlea, proper function of the vestibular system depends on the unique composition of these fluids.
The vestibular labyrinth is a paired structure, with the right and left labyrinth mirroring one another. Subdivisions of the vestibular labyrinth include the three semicircular canals: the lateral or horizontal canal, the posterior canal, and the anterior or superior canal, all of which detect angular accelerations. The geometric layout of the canals is shown in Figure 130.2. The horizontal canals lie parallel to the line between the external auditory canal and the outer canthus of the eye, which is inclined 30 degrees above the horizontal axial plane. The vertical canals are roughly at right angles to the horizontal canals and to each other. When looking down at the top of the head, the anterior canal is oriented at approximately 45 degrees off midsagittal and 45 degrees anterior to the intraaural line. The posterior canal is aligned roughly 45 degrees behind the intraaural line; thus, the anterior canal on the left is roughly parallel to the posterior canal on the right, and the left posterior canal and the right anterior canal are similarly aligned.
Housed in the vestibule are the otolith organsâ€”the utricle and the sacculeâ€”which detect linear acceleration. Neither organ is perfectly planar, but the utricle is primarily aligned parallel to the earth and is roughly aligned with the ipsilateral horizontal canal (Fig. 130.3). At rest, the saccule is perpendicular and at right angles to the utricle. The sensitivity of detection of translational acceleration is greatest in the plane of the macula. Thus, the utricular macula is sensitive in the horizontal plane, and the saccular macula is sensitive in the sagittal plane

Basic Physics of Mechanotransduction
Both the linear (utricle and saccule) and the angular (semicircular canal) acceleration sensors for the inner ear use a three-step process to convert accelerations of the head into useful information for the nervous system (Fig. 130.4). The elements used in these three steps are inertial mass, one or more sensory hair cells, and the nerve fibers connected to the hair cells through synaptic junctions. Figure 130.4A shows the system at rest (no acceleration). Figure 130.4B shows the response when the system is accelerated to the left. The resulting rightward movement of the mass (M) relative to the sensory hair cell deflects the sensory hairs, depolarizes the cell body, and increases the discharge rate of the attached nerve fiber.

Neuroepithelium
The sensory hair cells in the membranous labyrinth are similar to those in the cochlea in that both detect small deflections and transmit the information provided by the displacement to the central nervous system (Fig. 130.5). However, significant differences are found between the cochlea and the vestibular neuroepithelia. The vestibular hair cell body is surrounded by supporting and other haircells. Sensory bundles extend from the apical surface of the vestibular hair cell body and are usually in contact with a gelatinous membrane, the motion of which is affected by displacement of the mass element: either the cupula of the semicircular canal or the otolithic membrane for the utricle and saccule. These sensory hair bundles have two distinct ciliary types. The kinocilium is the tallest cilia and is near the edge of the top of the hair cell. Kinocilia are not found on cochlear hair cells. The position of the kinocilium determines the orientation of the hair cell. There are many stereocilia, arranged in columns and rows, and the closer they are to the kinocilium, the taller they are. This arrangement produces an orderly array of stereocilia and a means by which alignment of an individual hair cell can be determined by its so-called morphologic polarization vector, which is shown as an arrow in Figure 130.6. Experimental data show that a functional axis of alignment corresponds with the morphologic one. It is in this axis that a cell responds most vigorously to the displacement of the stereocilia. Displacement of the stereocilia perpendicular to the polarization axis causes no change in the resting potential of the hair cells. On any one sensory organ, neighboring hair cells tend to have polarization vectors that are aligned.
The electrical potential inside the body of hair cells differs from that of the fluids surrounding them because of active transport at the cell membrane. Bending the stereocilia on top of the cell toward the kinocilium opens potassium channels and temporarily increases the resting potential, depolarizing the cell. Deflection away from the kinocilium hyperpolarizes the cell. The channels responsible for transduction are located at the top of stereocilia in the utricle and are opened by relative motion of the stereocilia (1). The hair cells release a neurotransmitter (believed to be glutamate) that is excitatory to the hair cell afferents with which they connect. At rest, there is a baseline release of the neurotransmitter. This release is important because not only does deflection of the hair cell bundle toward the kinocilium (depolarizing the hair cell) increase transmitter release, but deflection of the hair cell bundle away from the kinocilium (hyperpolarizing the hair cell) reduces transmitter release. Thus, one hair cell detects both acceleration and deceleration along the axis of the morphologic polarization vector.
There are two morphologically and physiologically distinct types of hair cell bodies: type I or chalice hair cells and type II or cylindrical hair cells. The body of a type I hair cell is entirely engulfed by one afferent terminal. Efferent innervation is indirect, as the efferent nerve has its synapse on the afferent nerve ending. Type II hair cells can have one or more afferent nerve endings on the body of the cell. Type II hair cells can also be directly or indirectly innervated by vestibular efferent terminals. Type I and type II hair cells are not evenly distributed throughout the neuroepithelium of either the semicircular canal ampullae or the utricular maculae. As discussed later, they are innervated by different classes of vestibular afferents.
The neuroepithelium contains other cell types as well. Supporting cells have the nuclei located at the basal end of the sensory epithelial, above the basement membrane. These cells are believed to make and secrete the extracellular macromolecules of the cupula and otolith membrane. Dark cells can be found at the margins of the transitional epithelium surrounding the neuroepithelium. These dark cells are located directly above pigmented cells and are thought to produce the ionic composition of the endolymph.

Microanatomy and Biophysics of the Semicircular Canals
The semicircular canal is a membranous structure shaped like a torus or hollow doughnut (Fig. 130.7). Maximum sensitivity is to rotation in the plane of the torus. At one end of the torus, there is an enlargement, the ampulla. A gelatinous flap, the cupula, completely seals one side of the ampulla from the other. Because the cupula is elastic, any pressure difference causes it to deflect. The interior of the torus is filled with endolymph, a liquid with the density and viscosity of water. The membranous portion of the canal is attached to the temporal bone. When the head is turned, the membranous labyrinth moves with it, but the endolymph inside has an inertial mass that tends to oppose the turning motion. This oppositional force causes pressure buildup across the cupula, deflecting the cupula from its equilibrium position. Within the physiologic range of motion, this deflection most nearly resembles the motion of the head of a drum or clamped diaphragm when pressure is uniformly applied to one side.
Cilia are embedded in the gelatinous cupula. As the cupula is deflected, the stereocilia bend either toward or away from the kinocilium, producing an increase or decrease, respectively, in the firing rate of the vestibular nerve. The kinocilia are parallel to the long axis of the canal. In the lateral semicircular canal, hair cells are arranged such that the kinocilia are closest to the vestibule; maximal excitation occurs with ampullopetal flow of endolymph. In the posterior and superior semicircular canals, this arrangement is reversedâ€”the kinocilium are farthest from the vestibule. Thus, ampullofugal flow is excitatory.
The crista ampullaris has been divided into central, intermediate, and peripheral zones. In humans and other mammals, type I hair cells are relatively more common in the central zone than in the intermediate and peripheral zones (2). In contrast, type II cells are relatively less common in the central zone than in other zones.
More than half a century ago, Steinhausen constructed a biophysical model of the semicircular canal known as the torsion pendulum model The behavior of this model is determined by the mass of the endolymph, the viscous damping properties of the endolymph, and the springlike restoring force of the cupula. Estimates of these physical properties and knowledge of the geometric properties of the semicircular canal allow observers to relate deflection of the cupula to angular acceleration of the head. With this model, it can be predicted that cupular deflection is proportional to head velocity over a frequency bandwidth of approximately 0.1 to 10 Hz. Above and below this frequency bandwidth, the cupular deflection is not as great, and the sensitivity of the semicircular canal to velocity decreases. At 0 Hz, which corresponds to constant-velocity rotation, the torsion-pendulum model predicts there will be no response at all. The prediction made with this model agrees with the perception of a person who is turned at a constant velocity around a vertical axis. Subjects sense initial acceleration, but in the absence of other cues such as vision, subjects feel they are no longer rotating after 30 to 60 seconds. Rotating subjects who are suddenly brought to a full stop feel a sensation of turning in the opposite direction. This sensation is due to the inertia of the endolymph, which continues to rotate, deflecting the cupula in the direction opposite to that experienced with the initial rotation. Reflexive eye movements measured during these steps of velocity mirror the sensation felt by the subjects and are the basis of cupulometry used in the BÃ¡rÃ¡ny test and other tests of the vestibuloocular reflex.

Microanatomy and Biophysics of the Otolith Organs
All the sensors in the vestibular system combine a mass element connected to sensory hair cells (Fig. 130.4). In the case of the otolith organs (utricle and saccule), the mass is composed of calcium carbonate crystals known as otoconia that are embedded in a gelatinous supporting substrate. Displacement of this structure due to linear acceleration or change in orientation with respect to gravity affects a number of sensory hair cells. Each cell has a polarization vector oriented in a slightly different direction, making each one maximally sensitive to acceleration in that particular direction.
The calcium carbonate crystals are suspended in the otolith membrane. Under this membrane are a number of sensory hair cells, each of which can have one or more afferent connections to the vestibular nerve. The drawing in Figure 130.8 is an exploded view. In reality, the stereocilia from the hair cells are in direct contact with the otolith membrane. In Figure 130.8, each of the sensory hair cells has a polarization vector with a small arrow indicating its direction of maximal excitation in the plane. The large arrow at the top of the otolithic mass represents linear acceleration that deflects the otolith mass in the direction of the arrow. Hair cells that have polarization vectors aligned with the arrow and in the same direction are excited maximally, whereas hair cells that have polarization vectors perpendicular to the acceleration are not stimulated.
In the maculae of the utricle and saccule, type I hair cells are relatively more prevalent close to the striola than in the peripheral zone areas. The striola is a zone that runs the length of the macula, is about 100 microns wide, and divides the macula into the medial and lateral extra striola zones. The orientation of the hair cells on either side of the striola is roughly 180 degrees out of phase. Because the striola is C-shaped in the utricle, orientation vectors of hair cells in the utricle are aligned in all directions of the plane of the utricular macula.
It is from an array of these hair cells that the brain can estimate the magnitude and direction of linear acceleration. If all polarization vectors were identically aligned, it would be impossible to determine the magnitude and direction of an acceleration vector in the plane of the otolithic macula. At least two different orientations are needed to resolve the vector in two dimensions. At least three separate orientations are needed to resolve the magnitude and direction of an acceleration vector in three dimensions.
As in the simple example described earlier, each otolith organ has sensory hair cells arranged in a wide variety of orientations of its polarization vectors (Fig. 130.9). Because of this architecture, the asymmetries inherent in the sensitivity of a single hair cell can be canceled out within one otolith organ itself. The orientation of the polarization vectors is toward the striola in the utricular macula and away from the striola in the saccular macula. The right and left otolith organs, like semicircular canals, have mirror symmetry around the sagittal plane. The exact neural connections of the otolith organs have not been as extensively studied as those of the pairs of semicircular canals. Thus, the exact circuitry for resolving linear acceleration in three-dimensional space has not been determined.
A simplified model of the response of the otolith organ to linear acceleration and changes in orientation with respect to gravity can be made with a mass, a spring, and a damper (Fig. 130.4). In this case, the mass is the otoconia macula minus the buoyant force placed on it by the surrounding endolymph. The spring and the damping factors come from the viscoelastic properties of the gelatinous structure in which the otoconia are embedded.
The response characteristics of the otolith organs can be predicted with the above model. Although the specific gravity of the otoconia has been found to be 2.7 times that of the endolymph, the damping forces of the otolithic membrane are more difficult to measure. These damping forces prevent oscillation of the otolith membrane in response to a given linear acceleration. However, when direct recordings are taken from otolith afferents, physiologic performance deviates from that predicted in the model. There are two types of neuronal otolith afferent populations that can be defined that are similar to those in the semicircular canals. The first population appears to respond to head position, and its responses closely follow those predicted with the model for sinusoidal stimulation at frequencies up to 0.1 Hz. A second population of neurons encodes information on linear acceleration. These neurons display increasing gain in proportion to higher-frequency stimuli.
theoretically, how two otolith organs operating in the same plane react to head tilt or to acceleration of the head in the plane of the otolithic macula. If there is no acceleration in that plane, the nerve firing rate of each otolith organ is constant and equal. When the head is tilted to the left, the firing rate of the nerve innervating the left otolith organ increases, while the firing rate of the nerve innervating the right otolith organ decreases. Maximum sensitivity is obtained by means of subtracting the firing rate of the right nerve from that of the left. Acceleration of the head to the right causes deflection of both otoconia to the left in a manner similar to a head tilt to the left. This acceleration produces an increase of the firing rate of the left nerve and decrease in the firing rate of the right nerve. This model (Fig. 130.10) shows that the asymmetry present in one hair cell innervating an otolith organ can be canceled by combining it with a signal from a hair cell that has the same polarization factor in the other side. It also shows that the otolith organs are influenced by both tilt orientation with respect to gravity and linear acceleration.
Einstein recognized that an ambiguity presented between linear acceleration and gravity, and in aviation, is a problem during the acceleration of takeoff, when pilots have trouble differentiating the acceleration of the airplane from the gravity vector. Because translational motion in one direction creates the same inertial force as gravity to tilt in the opposite direction (Fig. 130.10), this problem is known as a tilt-translational ambiguity. Recent research has demonstrated that the central nervous system uses semicircular canal information (activated during tilt but not during translation) in combination with the otolith input to distinguish, for example, tilting the head upward versus accelerating forward as in a car, sled, or airplane (3). This mechanism works poorly at low frequency rotations. In the circumstance where the rotational component of the motion is at low frequency (<0.1 Hz), the brain uses visual or tactile information to help interpret the otolith's signal. In the absence of non-otolith input, such as vision or rotation at frequencies above 0.1 Hz, the system defaults to interpreting linear acceleration as tilt (or gravity). Returning to the aviation example, fighter pilots taking off from an aircraft carrier deck at night will feel as if they are tilted backwards during forward acceleration. The natural correction for this feeling is to steer the plane downward, which could result in disaster.

Vestibular Afferents
Based on the anatomy of peripheral termination, there are three distinct vestibular afferent types: calyx, dimorphic, and bouton. Calyx afferents terminate exclusively on type I hair cells at the calyx endings. Calyx endings may terminate on one or several hair cells. Dimorphic afferents have both calyx endings on type I hair cells and bouton endings on type II hair cells. Dimorphic afferents are likely the most prevalent. Bouton afferents have only bouton endings and thus only terminate on type II hair cells. These three afferent types differ immunohistochemically. Calrentinin, a calcium binding protein, is seen only in calyx afferents; peripherin, which is an intermediate filament protein, is seen in bouton afferents; and neither of these markers is seen in dimorphic afferents.
There are other anatomic distinctions between these afferent types. Calyx afferents have characteristically thick axons, whereas bouton afferents are thinner. Dimorphic afferents, however, can be thick or thin. The processes to the calyx endings are thicker than the processes to the bouton endings. The distribution of the three fiber types is also characteristic. Calyx afferent endings are found in the central zone of the crista ampullaris, whereas dimorphic afferents terminate in the central, intermediate, and peripheral zones, and bouton fibers terminate in the peripheral zone. Similarly, utricular calyx afferents terminate in the striola region, whereas dimorphic afferent terminals are seen throughout the macula and bouton afferents and generally terminate peripherally.
Afferents also differ in their discharge regularity, conduction velocity, and sensitivity to vestibular and galvanic stimulation. Although response gains, conduction velocity, and discharge regularity over a population of neurons all fall along a continuum, based on these characteristics, vestibular afferents fall into three general groups that correspond well with the three groups (calyx, dimorphic, and bouton) determined by peripheral morphology. Calyx afferents innervating the central ampulla or striola are large fibers that are irregularly firing, sensitive to galvanic stimulation, and have a low sensitivity to angular motion. Dimorphic afferents may have thick or thin axons. Those terminating more centrally tend to have thicker axons and are irregularly firing, galvanically sensitive, and sensitive to (rotational or linear) stimulation. Dimorphic afferents terminating peripherally (either in the macula or crista) and bouton afferents tend to be thinner fibers with lower galvanic and natural stimulation thresholds and are regularly firing with slower conduction velocities (4). These different afferent types may be of more interest than just physiologic curiosity. The high sensitivity irregular afferents are sensitive to small perturbations but have nonlinear dynamics because they readily silence when the head moves in the inhibitory direction. These afferents may be best suited for quick, nonlinear reflexes such as vestibulospinal responses to inhibit a fall. In contrast, the linear characteristics of the thinner, more regular afferents are appropriate for linear vestibular reflexes, like the vestibuloocular reflex, that must work over a wide range of frequencies and peak velocities (5).
Both semicircular canal afferents and otolith afferents are cosine tuned, which means they have one best characteristic response vector. For utricular afferents, these vectors can lie anywhere in the horizontal plane and are dependent on the orientation vector of the hair cells that they innervate. The response of the afferent is proportional to the cosine angle between the direction of stimulation and the orientation vector of the afferent. Similarly, the rotational vector of maximum stimulation for semicircular canal afferents is in the plane of rotation of the canal. The response of the fiber decreases as cosine of the angle between the plane of rotation and the canal plane. The cosine tuning of the afferent is consistent with the fact that transmitter release by hair cells is proportional to the cosine of the angle between the displacement of the hair cell bundle and the direction of stimulation (Fig. 130.6). Thus, both the hair cells and the afferents are cosine tuned. The coding of the vestibular system is such that the direction of stimulation is encoded by the afferent population stimulated, and the intensity of the movement is encoded by the intensity of the response of the stimulated afferent.
All of the vestibular epithelium are also innervated by vestibular efferent neurons. These neurons have cell bodies in the brainstem in areas around the genu of the facial nerve. Their fibers in humans run mixed with the vestibular afferent fibers and can terminate either presynaptically (on type II hair cells) or postsynaptically on calyx or bouton endings. The function of the vestibular efferent system in mammals is unknown.

Vestibular Brainstem
Vestibular afferents are bipolar neurons that have cell bodies in the inferior and superior Scarpa (vestibular) ganglion. The peripheral (dendritic) processes of these neurons exit the neuroepithelium and collect in the inferior and superior vestibular nerves. The inferior division includes neurons from the posterior canal and saccule, and the anterior division includes utricular, horizontal canal, and anterior canal afferents (Fig. 130.11). Axonal branches of primary afferent ramify in the vestibular nuclei. Afferent terminals from the different end organs primarily innervate the various divisions of the vestibular nuclei, although terminations are seen in the cerebellum and other brainstem nuclei as well. The precise terminations by end organ (semicircular canal or otolith) in the central nervous system are similar in many species (6). Not only does the brainstem region receive convergent output from different branches of the vestibular nerve, but individual neurons receive afferent input from one, two, or more end organs (canal ampullae or otolith maculae). Thus, the vestibular nuclei integrate information from multiple ipsilateral receptors.
There are four major vestibular nuclei in the brainstem: the lateral (Deiters), superior, medial, and inferior (spinal, descending) nuclei. In addition, there are several minor vestibular nuclei, including nucleus y, that are identified in various species by various investigators. The vestibular nuclei not only receive vestibular information but other information pertaining to spatial orientation as well. These inputs include optokinetic signals through the accessory optic system, neck proprioceptive signals, and Purkinje cell projections from the cerebellar cortex. From the vestibular nuclei, vestibular signals are passed throughout the central nervous system. The dominant output of the vestibular nuclei are to the ocular motor nuclei, via the medial longitudinal fasciculus and the ascending tract of Deiters; to the spinal cord, via the medial and lateral vestibulospinal tracts; to the cerebellum, via the cerebellar peduncles; and to the contralateral vestibular nuclei, via the vestibular commissural system. Other pathways connect the vestibular nuclei with the autonomic system, which has implications in motion sickness and blood pressure control, and with the thalamus.
One important function of the vestibular commissural system is inhibition. Experimental data show that the discharge frequencies of neurons excited during ipsilateral angular acceleration are also excited due to a decrease of crossed inhibition, which is caused by a decrease in discharge rate from the contralateral paired semicircular canal. This reciprocal mechanism is the basis of the so-called push-pull connection that increases the sensitivity of the system through use of the difference in signals between the functionally paired semicircular canals (left horizontalâ€“right horizontal, left anteriorâ€“right posterior, left posteriorâ€“right anterior) in either ear. In this way, the paired canals complement one another and tend to cancel out the asymmetries inherent in the hair cell transduction mechanisms and afferent firing patterns mentioned earlier. The neural signals from these pairs of canals converge in a synergistic way in the nervous system, allowing the system to function even in the presence of a complete unilateral lesion. However, responses in patients with unilateral lesions are more asymmetric than those among healthy persons given high enough angular acceleration to reveal these inherent asymmetries, which are apparent when the push-pull redundancy is not available.
The best studied vestibular reflex is the vestibuloocular reflex. Vestibuloocular reflexes are of two types: compensatory reflexes that stabilize gaze during motion and orienting reflexes that align the eye with the gravitational vector. One of the challenges for the nervous system is to translate signals from the semicircular canal planes into coordinates appropriate for effector action. Those who study the vestibular system use an external frame of reference, as shown in Figure 130.3. Linear acceleration or rotational acceleration occurs around three axes that are perpendicular to each other: the interaural or pitch axis, the nasal-occipital or roll axis, and the rostral-caudal or yaw axis. The vestibule-oculo-motor system, however, is thought to use a coordinate system based on the orientation of the three pairs of semicircular canals. Experiments have shown that stimulation of afferent branches of the eighth cranial nerve that come exclusively from one semicircular canal produces reflexive eye movements that tend to rotate around the axis of greatest sensitivity for that canal. The three agonist-antagonist pairs of eye muscles themselves do not produce eye movements that completely correspond to these axes of orientation of the semicircular canals. Thus, there is a distribution of signals from the semicircular canals to produce compensatory eye movement of the desired magnitude and direction.
According to a simplified analysis, the connection between the three pairs of semicircular canals and the three pairs of eye muscles can be described with a set of nine constant coefficients. First-order analysis indicates that the translation of incoming vestibular systems needed to produce compensatory eye movement is a relatively simple operation for the brain to perform. This operation is contrasted to the more complicated series of commands that must be given when signals from the vestibular system are used to stabilize the head on the neck or the body with leg muscles.
The nervous system can adapt its response by comparing vestibular input to other sensory input. When the head moves, the vestibuloocular reflex tends to stabilize the image of an object in space on the retina by producing an eye movement compensatory to the head movement. At any time, the functional anatomic connections needed to stabilize an object can be thought of as a set of nine constant coefficients that distribute the incoming vestibular systems to the ocular motor neurons to form the reflexive eye movement response. For example, the motion of the head 10 degrees to the right produces eye movement 10 degrees to the left.
Provisions have been made in the nervous system for this response to adapt when necessary, owing to factors such as disease or aging. One such example is people with myopia who wear eyeglasses. If the magnification of the lens is 1.2 times, rotation of the head 10 degrees to the right produces rotation of the world as viewed by the eye 12 degrees to the left and therefore demands a corresponding reflexive eye movement 12 degrees to the left. The nervous system makes this form of adaptive change to resolve a conflict between afferent inputs, in this case vestibular and visual inputs. In this example, the nervous system can correspondingly increase the amount of eye movement produced for a given head movement so that the error between the head motion input and eye motion response is reduced to nearly zero. This gain plasticity requires participation of the floccular lobe of the cerebellum.

Current Vestibular Issues
Like most fields in basic sciences, the vestibular system is actively studied in a number of excellent laboratories. Among the many actively investigated areas are the pharmacology of the vestibular periphery, interactions between active head movements and the passive vestibular reflexes, the role of vestibular signals in spatial orientation, the function of vestibular efferent system, physiologic and cellular mechanisms of adaptation and compensation after vestibular injury, and the adaptation of the vestibular system to microgravity. In addition, efforts are ongoing to develop prosthetic devices to aid patients with vestibular deficits. This research holds the promise of improving our understanding of this vital, well conserved, and underappreciated â€œsixthâ€ sensory system.

Anatomy and Physiology of Hearing

2009-02-04T04:43:00.000-08:00

John H. Mills
Samir S. Khariwala
Peter C. Weber

This chapter provides a brief summary of the most basic features of the anatomy and physiology of the ear. It is divided into sections on the external and middle ear, cochlea, and central nervous system (CNS). The focus is on the anatomic and physiologic bases of audition with an effort directed at functional features. Surgical anatomy, vasculature, and eustachian tube function are not discussed.

External Ear

The external ear consists of the pinna (auricle) and the external auditory canal from the meatus to the tympanic membrane (Fig. 129.1). The pinna of humans is composed mostly of cartilage and has no useful muscles. The center of the pinna, the concha, leads to the external auditory meatus, which is about 2.5 cm long. The lateral third of the canal is the cartilaginous portion. It contains cerumen-producing glands and hair follicles. The remaining medial two thirds is the bony portion, including an epithelial lining over the tympanic membrane (1).
The external ear and the head have a passive but important role in hearing because of their acoustic properties. The concha, or bowl of the auricle, has a resonance of about 5 kHz, and the irregular surface of the pinna introduces other resonances and antiresonances. These acoustic features are useful to help differentiate whether sound sources are in front of the listener or behind.
The external auditory canal (EAC) is essentially a tube that is open at one end and closed at the other; thus the EAC behaves like a quarter-wave resonator. The resonant frequency (f0) is determined by the length of the tube; the curvature of the tube is irrelevant. For a tube of 2.5 cm, the resonant frequency is approximately 3.5 kHz:f0 = Velocity of sound @ 350m/s/(4Ã—2.5 cm)
A flat, wide-band sound measured in a sound field is changed considerably by the acoustic properties of the head and external ear. As Figure 129.2 demonstrates, a gain of about 15 dB occurs in the 3-kHz range of the human, cat, and chinchilla, and 10 dB between 2 and 5 kHz. The acoustic properties of the external ear are one of the reasons noise-induced hearing losses occur first and most prominently at the 4-kHz frequency region (boilermaker notch).
In addition to the prominence of noise-induced hearing loss in the 4-kHz region, the acoustic properties of the head and external ear have an important role in several hearing functions. In localization of sound sources, the head acts as an attenuator at frequencies at which the width of the head is greater than the wavelength of the sound. Thus at frequencies greater than 2 kHz, a head shadow effect occurs, in which interaural intensity differences of 5 to 15 dB are used to localize sound sources. At lower frequencies, at which the wavelength of the sound is larger than the width of the head, little attenuation is provided by the head. Interaural time differences (~0.6 ms for sound to travel across the head) are the salient cues for localization. The head-shadow effect is the reason right-handed hunters using rifles and shotguns have larger hearing losses in their left ears than in their right ears and vice versa. The muzzle of the gun, where the acoustic energy is greatest, is closer to the left ear, and the right ear is protected by the head-shadow effect.
The 10- to 15-dB gain provided by the external ear in the 3- to 5-kHz region is useful for improving the detection and recognition of low-energy, high-frequency sounds such as voiceless fricatives. The importance of the acoustic properties of the external ear and head is reflected in hearing-aid design and evaluations. Finally, the resonance of the external canal is approximately 8 kHz in infants and decreases to adult values after approximately 2.5 years of age. This developmental feature has several clinical implications, especially for sound-field testing and for hearing-aid design and evaluation of infants.

Middle Ear

The middle ear transmits acoustic energy from the air-filled EAC to the fluid-filled cochlea. It functions as an impedance-matching device inasmuch as it couples the low impedance of air to the high impedance of the fluid-filled cochlea. The impedance match is achieved in three ways. The first and most important factor is that the effective vibratory area of the tympanic membrane is approximately 17 to 20 times greater than the effective vibratory area of the stapes footplate (Fig. 129.3). A second factor involves the lever action of the ossicular chain. The arm of the long process of the incus is shorter, by a factor of 1.3, than the length of the manubrium and neck of the malleus. A third and minor factor is the shape of the tympanic membrane. The combined result of these three factors is a pressure gain of approximately 25 to 30 dB. The variance in published measurements of the transformer ratio is noteworthy. With the exception of studies of acoustic impedance of the ear, most data are from studies of human cadavers, with all of their shortcomings, or of animals, usually cats. In addition to its role in the transfer of power to the inner ear, the tympanic membrane protects the middle ear space from foreign material of the ear canal and maintains the air cushion that prevents insufflation of foreign material from the nasopharynx through the eustachian tube.
The vibratory behavior of the ossicular chain is described in Figure 129.3. The transformer action of the tympanic membrane and ossicular chain provides for relatively efficient transfer of power to the inner ear, and the fidelity of sound transmission across the middle ear is outstanding. Distortion of sound signals does not occur in the middle ear, even for input signals with sound levels greater than 130 dB sound pressure level (SPL).
The middle ear, including the tympanic membrane, ossicular chain with supporting ligaments, and middle ear space, can be viewed as a passive mechanical system with both mass and compliant elements and therefore resonant properties. This linear system is coupled to the cochlea, which contributes a large resistance. The result is a middle ear system that is highly damped and linear and has a wide frequency response. The inputâ€“output function or transfer function of the middle ear is shown in Figure 129.4A. The ratio of the volume velocity of the stapes to sound pressure at the tympanic membrane increases in humans to approximately 800 to 900 Hz, which is the resonant frequency of the middle ear, and decreases at higher frequencies. Phase shift or time lag between movement of the tympanic membrane and the stapes generally increases with frequency (Fig. 129.4B). Although the middle ear is an impressive system in terms of frequency response, linearity, and transformer properties, considerably less than half of the power entering the middle ear actually reaches the cochlea because of the absorption of energy by the ligaments and middle ear. As shown in Figure 129.5, the human middle ear is particularly inefficient at frequencies greater than 2 kHz, especially in comparison with the ears of cats and chinchillas. It also is important to recall that a 50% loss of power is a loss of only 3 dB.
Auditory function is profoundly affected by cochlear impedance as well as the combined acoustic effects of the head, external ear, and middle ear. The combined effects of the acoustic properties of the head, external ear, and middle ear, as well the input impedance of the cochlea, have a profound effect on auditory function. For example, these factors determine the shape of the audibility curve and therefore the frequency range of human hearing (Fig. 129.6). For example, humans do not detect and recognize sounds greater than approximately 20 kHz because such high-frequency sounds are not transmitted efficiently through the middle ear to the cochlea. A second example of this sound transformation is shown in Figure 129.7, in which the spectrum of a cannon measured in a sound field is compared with the spectrum of the cannon by the time it is transformed and shaped by the acoustic properties of the external ear, head, middle ear, and input impedance of the cochlea. Low-frequency energy is not transmitted to the cochlea, and the frequency region of greatest energy concentration is 3 to 4 kHz. Thus, these acoustic properties are primarily responsible for the ability of intense low-frequency sounds (measured in a sound field) to produce high-frequency hearing losses and injuries in the basal region of the cochlea.
Two striated muscles, the tensor tympani and the stapedius, are located in the middle ear. The former attaches to the malleus and is innervated by the trigeminal nerve. The stapedius muscle attaches to the stapes and is innervated by the stapedial branch of the facial nerve. Noticeably the stapedius and tensor tympani muscles are the smallest striated muscles in the body and also have a high innervation ratio, that is, nerve fibers per muscle fiber. Although no question remains that contraction of these muscles affects sound transmission through the middle ear, the details of the effect and the extent of the influence of the middle ear muscles are still not fully understood. A number of disparate functions have been attributed to the middle ear muscles.
One function of the middle ear muscles is to protect the cochlea from loud sounds (2). When sounds louder than approximately 80 dB SPL are presented monaurally or binaurally, consensual (bilateral) reflex contraction of the stapedius muscle occurs. This contraction increases the stiffness of the ossicular chain and tympanic membrane, attenuating sounds less than approximately 2 kHz. Although the tensor tympani contracts as part of a startle response, acoustic reflex data from human subjects with neurologic involvement of cranial nerves V and VII suggest that the tensor tympani does not normally respond to intense acoustic stimulation. Laboratory and field studies of noise-induced hearing loss have shown convincingly that the stapedial reflex protects the cochlea, particularly from low-frequency (<2 kHz) sounds in excess of 90 dB. Inasmuch as the latency of the acoustic reflex is greater than 10 ms, the cochlea may be unprotected from short-duration, unanticipated impulsive sounds.
The following functions have been attributed to the middle-ear muscles. Some of these functions include providing strength and rigidity to the ossicular chain; contributing to the blood supply of the ossicular chain; reducing physiologic noise caused by chewing and vocalization; improving the signal-to-noise ratio for high-frequency signals, especially high-frequency speech sounds such as voiceless frica-tives, by means of attenuating high-level, low-frequency background noise; functioning as an automatic gain control and increasing the dynamic range of the ear; and smoothing out irregularities in the middle-ear transfer function.

Cochlea

The human cochlea is a coiled, bony tube approximately 35 mm long, divided into the scala vestibuli, scala media, and scala tympani (Fig. 129.8). The scalae vestibuli and tympani contain perilymph, an extracellular fluid-like material with a potassium concentration of 4 mEq/L and a sodium concentration of 139 mEq/L. The scala media is bounded by the Reissner membrane, the basilar membrane and osseous spiral lamina, and the lateral wall. It contains endolymph, an intracellular-like fluid with a potassium concentration of 144 mEq/L and a sodium concentration of 13 mEq/L. The scala media has a positive direct current (DC) resting potential of approximately 80 mV that decreases slightly from base to apex. This endocochlear potential is produced by the heavily vascularized stria vascularis of the lateral wall of the cochlea. The sodiumâ€“potassiumâ€“adenosine triphosphatase (Na+-K+-ATPase) pumps in a number of specialized cells of the stria vascularis contribute to this potential (3).
Acoustic energy enters the cochlea through the piston-like action of the stapes footplate on the oval window and is coupled directly to the perilymph of the scala vestibuli. The perilymph of the scala vestibuli communicates with the perilymph of the scala tympani through a small opening at the apex of the cochlea known as the helicotrema. The organ of Corti rests on the basilar membrane and osseous spiral lamina (Fig. 129.9). The basilar membrane is approximately 0.12 mm wide at the base and increases to approximately 0.5 mm at the apex. The major components of the organ of Corti are the outer and inner hair cells, supporting cells (Deiters, Hensen, Claudius), tectorial membrane, and the reticular laminaâ€“cuticular plate complex (Fig. 129.10). Supporting cells provide structural and metabolic support for the organ of Corti. The phalangeal processes of the Deiters cells form tight cell junctions of the reticular lamina.
Outer and inner hair cells of the organ of Corti are important in transduction of mechanical (acoustic) energy into electrical (neural) energy. Outer hair cells are radically different from inner hair cells. Figure 129.11 and Table 129.1 detail these differences (4). In addition to the morphologic differences between outer and inner hair cells, neural innervation is different (Fig. 129.12). The spiral ganglion, the cell body of the auditory nerve, sends axons to the cochlear nucleus of the brainstem, whereas the dendrite projects through the osseous spiral lamina. Of the 50,000 neurons that innervate the cochlea, 90% to 95% synapse directly on inner hair cells. These are called type I neurons. Each inner hair cell is innervated by approximately 15 to 20 type I neurons. In contrast, 5% to 10% of the 50,000 neurons innervate the outer hair cells (type II neurons). Each type II neuron branches to innervate approximately 10 outer hair cells. In addition to the afferent innervation pattern of the cochlea, approximately 1,800 efferent fibers, originating from the ipsilateral and contralateral superior olivary complex, project to the cochlea (Fig. 129.13).
Transduction is initiated by displacement of the basilar membrane in response to displacement of the stapes due to acoustic energy. The displacement pattern of the basilar membrane is a traveling wave (Fig. 129.14). The basilar membrane is stiffer at the base than in the apex. The stiffness component is distributed continuously. Therefore, the traveling wave always progresses from base to apex. The maximal amplitude of basilar membrane displacement varies as a function of stimulus frequency. Traveling waves produced by high-frequency sounds (10 kHz) have maximal displacement near the base of the cochlea, whereas the waves to low-frequency sounds (125 Hz) have the maximum toward the apical region. Traveling waves generated by high-frequency sounds do not reach the apical region of the cochlea, whereas waves to low-frequency sounds can travel the entire length of the basilar membrane.
In the past, the mechanical traveling wave was considered a broadly tuned response, with finer tuning introduced subsequently by transduction, the auditory nerve, and the CNS. Data obtained with sensitive recording and detection methods, however, have shown that the traveling wave has an extremely sharply tuned response (Fig. 129.15) and that many of the remarkable frequency-selective abilities of the ear can be explained by the mechanical properties of the cochlea
The mechanism by which the sharply tuned peak is generated within the mechanical traveling wave involves an enhancement known as the cochlear modifier. This is an activity of the outer hair cells that enhances the motion of the basilar membrane at frequencies near the best frequency of the particular cochlear location. This enhancement contributes to the fine frequency-selective abilities of the ear and to the sensitivity of the ear and ability to detect extremely faint sounds. The notion of an active process in the cochlea, the cochlear amplifier, is supported by the phenomenon of otoacoustic emissions. That is, when a short-duration signal is presented to the ear, an echo emanating from the cochlea can be recorded in the external auditory meatus. Because the energy of the echo can be greater than the energy of the short-duration signal, an active process, the cochlear amplifier, is assumed. Factors that may contribute to the cochlear amplifier include motility of outer hair cells and the mechanical properties of the stereocilia and tectorial membrane.
The stereociliaâ€“hair cell complex is critical to transduction. Stereocilia are bundles of actin filaments that form tubes and are inserted into the cuticular plate. They also are cross-linked between themselves. Stereocilia of inner hair cells probably do not contact the tectorial membrane, but those of outer hair cells are in direct contact. Deflection of the stereocilia by the traveling wave opens and closes nonspecific ion channels at the tips of the stereocilia, resulting in current flow (potassium) into the sensory cell. The flow of potassium ions into the sensory cell is modulated by the opening and closing of ion channels of the stereocilia. The potassium flux is caused by the endocochlear potential of +80 mV added to the negative intracellular potentials of hair cells. The resulting intracellular depolarization causes an enzyme cascade involving calcium. This ultimately leads to the release of chemical transmitters, and the subsequent activation of the afferent nerve fibers.
Although the notion of the cochlea as an active rather than a passive organ is no longer debated, specific details of the cochlear amplifier and the biologic basis of its operation are under active investigation. One point of view attributes the cochlear amplifier to the ability of hair cells to contract and lengthen in response to electrical signals, a property called somatic electromotility. A protein named prestin has been identified in outer hair cells and is considered to be the motor protein of outer hair cells and the driving force of electromotility of hair cells (5). Another point of view focuses on rapidly acting potassium and calcium ion channels presumed to be the basis of the cochlear amplifier and its regulation (6). A third approach suggests that a collection of motor proteins within a hair cell can generate oscillations that depend on the elastic properties of the cell (7). The foregoing approaches are nonlinear models that involve rapidly acting calcium channels. Specification of the biologic basis of the cochlear amplifier (nonlinearity) is important inasmuch as many forms of hearing loss involve loss of the cochlear amplifier.
The neurotransmitters of the afferent and efferent systems are the subject of intense study. In regard to the afferent system, analysis of excitatory amino acid receptor expression by the techniques of reverse transcriptaseâ€“polymerase chain reaction, in situ hybridization, and immunochemical analysis indicates that glutamate is the afferent neurotransmitter. Glutamate has been detected in both spiral ganglion cells and sensory cells (8). The principal transmitter substance of cochlear efferent fibers is acetylcholine. It is possible that the organ of Corti is mechanically modified by means of motility changes of outer hair cells under the influence of the efferent system. Acetylcholine acts on receptors to produce hyperpolarization of the cell membrane and doubling of the input conductance of the cell. The acetylcholine receptor has both muscarinic and nicotinic features. In addition to acetylcholine, Î³-aminobutyric acid and several neuroactive peptides are neurotransmitters for the efferent system (9,10).

Gross Cochlear Potentials
Four gross (extracellular) potentials can be recorded in the cochlea (11)â€”endolymphatic (endocochlear) potential, cochlear microphonic, summating potential, and whole-nerve action potential (Fig. 129.16). Unlike the other cochlear potentials, the endolymphatic potential is not generated in response to acoustic stimulation; rather, it is a DC potential of 80 to 100 mV recorded in the scala media. It arises from the stria vascularis of the lateral wall of the cochlea. The stria vascularis is considered to be the energy source, or â€œbattery,â€� of the cochlea, crucial for transduction. The nature of the energy source is related to the heavy vasculature of the stria vascularis and to the Na+-K+-adenosine triphosphatase (ATPase). This pump has been localized to several types of cochlear cells, including marginal cells of the stria vascularis, outer sulcus cells, and fibrocytes near the attachment of the Reissner membrane and in the spiral ligament. Whereas Na+-K+-ATPase must play a significant role in ion transport in the cochlea, the nature of the energy source and the details of the ion exchange remain active research issues (3).
Malfunctioning of the mechanisms involved in production of endolymph and the endolymphatic potential can produce hearing loss, sometimes called metabolic presbycusis. When the flow of endolymph through the ductus reuniens is blocked, endolymphatic pressure increases, and hydrops occurs.
The cochlear microphonic is an alternating current (AC) voltage usually recorded within the cochlea or near the round window. It represents the potassium ion current flow through mainly the outer hair cells; that is, the electrical resistance of outer hair cells is altered by the motion of the basilar membrane. When stereocilia are bent away from the modiolus, the resistance of the hair cells decreases. The result is an increase in current flow and a small decrease in endolymphatic potential. When stereocilia are bent toward the modiolus, resistance increases and current flow decreases with an accompanying increase in the endolymphatic potential. The corresponding voltage fluctuations, the cochlear microphonic, depend on the presence of outer hair cells. Unlike neural potentials, the waveform of the cochlear microphonic mirrors the motion of the basilar membrane. The summating potential is a DC potential recorded in the cochlea in response to sound. It follows the envelope of the stimulating sound. Recordings of this DC potential can be made in the scala tympani, media, or vestibuli and in some circumstances from a gross electrode in the human ear canal. The potential can be positive or negative, and it can reverse polarity, depending on electrode location or stimulus frequency and level. The summating potential probably has several origins, but it largely reflects the DC shifts caused by stimulus-driven intracellular potentials of outer hair cells. Inner hair cells contribute to these to a lesser extent.
The whole-nerve or compound action potential arises from the all-or-none discharge of auditory nerve fibers. The compound action potential is recorded most effectively with a gross electrode placed near the round window or auditory nerve and with high-frequency signals with rapid onsets. Such signals produce synchronous neural activity, which is summed to become the compound action potential waveform. The amplitude of the compound action potential increases with stimulus intensity over a 40- to 50-dB range, whereas latency decreases as stimulus intensity is increased. At high levels, a second peak sometimes is observed that probably reflects activity of the cochlear nucleus. The compound action potential can be clinically recorded with scalp electrodes or electrodes in the external meatus or by means of a transtympanic approach in which an electrode is placed near the round window niche. The ratio of the amplitude of the summating potential to the amplitude of the compound action potential has been used as an indicator of perilymphatic fistula, but the validity of this indicator is doubtful.

Eighth Nerve Physiology
The auditory nerve has approximately 30,000 fibers in humans and approximately 50,000 in cats. Perhaps one of the most important research findings in recent years was the observation that 90% to 95% of neurons (type I, radial fibers) innervate inner hair cells, whereas 5% to 10% (type II, outer spiral fibers) innervate to the outer hair cells (Fig. 129.12). Most, if not all, recordings from auditory nerve fibers are from the larger type I fibers in contact with inner hair cells. These radial fibers have bipolar cell bodies in the spiral ganglion. Outer spiral fibers are monopolar and unmyelinated. Most recordings of single units of the auditory nerve are obtained by means of inserting a microelectrode into the auditory nerve where it exits the internal auditory meatus. The most basic measures of auditory nerve function are spontaneous rates, tuning curves, and intensity (rate-level) functions.
Most auditory nerve fibers in mammals discharge in the absence of acoustic stimulation. The nerve fibers have been classified into three categories on the basis of rate of spontaneous dischargeâ€”high (18 to 120 spikes per second), medium (0.5 to 18 spikes per second), and low (0 to 0.5 spikes per second). Fibers with high rates of spontaneous activity respond to auditory signals at lower levels than do fibers with medium or low rates of spontaneous activity. In other words, the most-sensitive fibers have the most-spontaneous activity. Fibers with high spontaneous rates have thick dendrites that tend to terminate on the side of inner hair cells facing outer hair cells. Fibers with low and medium spontaneous rates have thin dendrites that terminate on the side of the inner hair cell facing the modiolus. Ongoing studies indicate that fibers with high rates of spontaneous activity have different terminations in the auditory CNS (cochlear nucleus) than do fibers with low rates of spontaneous activity. In other words, spontaneous activity of nerve fibers is not random but is proving to be anatomically and functionally significant (12,13,14,15). The tuning curve of a single auditory nerve fiber is perhaps the most basic measure of auditory nerve function. A tone burst controlled in frequency and level is presented. The level is adjusted until a criterion change (one or two spikes per second) in firing rate is detected. Tone bursts covering a wide range of frequencies are used, and the lowest level of signal is recorded for a given frequency that produces a specific rate of discharge. The resulting isoresponse curve is called a tuning curve. Figure 129.17 shows tuning curves for six different fibers. The sharp tip of the tuning curve identifies the best, or characteristic, frequency of the fiber. Units with low characteristic frequency are fibers that innervate inner hair cells in the apical region of the cochlea, fibers with high characteristic frequency innervate inner hair cells from the basal region, and so on. Tuning curves are described according to the frequency of the tip or characteristic frequency, the high- and low-frequency side, and the tail. Fibers with a characteristic frequency less than 1 kHz are roughly V shaped. Fibers with a higher characteristic frequency have an obvious tip at the characteristic frequency and a tail that extends to the low frequencies. The high side of a tuning curve is the frequency region greater than characteristic frequency. As characteristic frequency increases, the high side of the tuning curve becomes steeper with a slope or rejection rate that can exceed 500 dB per octave. The characteristics of tuning curves of auditory nerve fibers are strikingly similar to isoamplitude curves of a mechanical traveling wave (Fig. 129.15).
Injury or damage to sensory cells, including stereocilia, can alter the shape of tuning curves dramatically (Fig. 129.18). The lower right portion of the figure shows that when outer hair cells are destroyed, the tuning curve of auditory nerve fibers from normal inner hair cells is changed in several ways. The sensitive tip region is missing; that is, the threshold of the fiber is elevated by approximately 40 to 45 dB. The high-frequency side no longer has a steep slope, and the low-frequency side becomes slightly more sensitive, or hypersensitive. The characteristic frequency of the fiber appears to be much lower in frequency, and the band width of the fiber appears broader. The upper left portion of Figure 129.18 shows the consequences of partial injury to the stereocilia of outer hair cells. A threshold shift of approximately 30 dB occurs, but a short, sharply tuned tip remains, and the low-frequency tail is again hypersensitive. Irregularities in this tuning curve may explain monaural diplacusis; that is, a tone in one ear (800 Hz) has two pitches, for example, one at 800 Hz and a second at approximately 2.8 kHz.
The upper left portion of Figure 129.18 shows a tuning curve in which stereocilia of inner hair cells are damaged or in disarray, whereas most of the stereocilia of outer hair cells appear normal or nearly so. The threshold of the unit is elevated approximately 30 dB, but the tuning curve is approximately normal. The lower left portion of the figure shows responses to signals in a narrow range of frequencies only at sound levels greater than 90 dB SPL. In this case, sensory cells are present, but stereocilia of inner hair cells are destroyed, and those of outer hair cells are destroyed or in disarray. Thus normal neural activity, including sensitivity (detection of faint sounds) and frequency-resolving power, depends on intact outer hair cells and normal stereocilia.
Although thresholds of auditory nerve fibers are related to the rate of spontaneous discharge, most afferent nerve fibers (60%) have high spontaneous rates and thresholds within 20 dB greater than the thresholds for the animal. The remaining low-spontaneous fibers have thresholds that cover approximately 60 dB. The dynamic range of most auditory nerve fibers is approximately 30 dB from threshold to saturation (Fig. 129.19), although some low-spontaneous fibers have a much wider dynamic range. Given the dynamic range of human hearing (0 dB SPL to â‰¥100 dB SPL), the auditory system must have neurons the thresholds of which cover a wide range and have firing rates that also cover a wide range of intensities. The ability of the human ear to respond appropriately to sounds over a 120-dB range (10,12) is remarkable. One way is with low-spontaneous fibers; another is recruitment of fibers of characteristic frequency.
One of the most common features of sensorineural hearing loss is recruitment of loudness. Figure 129.20 gives an explanation. It is assumed that loudness depends on the total activity of the auditory nerve. As Figure 129.20A shows, the number of fibers activated increases slowly as intensity is increased, and only the tips of tuning curves are activated. As the intensity increases further, the tails of the tuning curves are encountered, and the number of fibers activated increases rapidly. In the case of sensorineural hearing loss, the tips of the tuning curves are missing, and the fibers are not activated until the level of the signal is sufficient to reach the tails of the tuning curves. Abruptly, many fibers then are abruptly activated simultaneously.

Nonlinear Properties of the Ear
Some of the outstanding features of the middle ear transformer are its linear properties, but the outstanding features of the cochlea and auditory nerve are the nonlinear characteristics. Perhaps the most studied nonlinearities are combination tones, described herein in relation to cochlear emissions, and two-tone rate suppression, as recorded in auditory nerve fibers.
Two-tone rate suppression is the reduction in firing rate produced by one tone when a second tone is introduced. Figure 129.21 shows a tuning curve with a suppression area outlined above the characteristic frequency of the nerve fiber and an area below the characteristic frequency of the fiber. Tones presented in the dotted or suppression areas in the figure reduce the firing rate caused by the probe tone. Both the excitor and suppressor tones are presented simultaneously, and because little or no time lag is associated with this phenomenon nor is any evidence available that it is neurally produced, the effect is called suppression rather than inhibition. Two-tone suppression in single units is reflected in the compound action potential. Figure 129.21 (right) shows tuning curves of the compound action potential with suppression areas shown in the dotted areas. In this case, the amplitude of the compound action potential is altered by the suppressing signal, whereas in the single-unit case (left), the firing rate of a neuron is reduced by an arbitrary amount (20%). The single-unit and compound action potential suppression areas are similar. Inasmuch as two-tone suppression can be observed in the DC intracellular response of inner hair cells, it is probable that two-tone suppression originates in the active nature of cochlear mechanics and before the inner hair cells.In the presence of sensorineural hearing loss caused by exposure to noise or to ototoxic drugs, two-tone rate suppression is severely affected, if at all measurable. Two-tone rate suppression appears normal or nearly so in cases of cochlear hearing loss in which the sensory cells, including stereocilia, are normal or nearly so, but the stria vascularis is affected. The latter scenario leads to presbycusis (16).
Otoacoustic emissions (OAEs) are sounds that are detected in the ear canal when the tympanum receives vibrations transmitted through the middle ear from the cochlea. OAEs provide support for the notion that the cochlea is not just a passive receiver of acoustic energy but can also generate or amplify sounds. Several different types of OAEs are found (17). Spontaneous OAEs occur in the absence of acoustic stimulation and are typically highly stable pure tones of -10 to 30 dB SPL, which are found in 30% to 40% of healthy young ears (18,19). The precise frequency of a spontaneous OAE does not imply an origin at a precise place in the cochlea, but only a particular coincidence of travel time and reflection from an ill-defined region of high outer cell activity. Spontaneous OAEs can be recorded over long periods with only minor but seemingly systematic variations in frequency and amplitude.A second class of OAEs are produced after exposure to an acoustic signal. Transient-evoked OAEs (TEOAE) are made via a probe placed in the ear canal. The oscillatory sound pressure waveform seen in TEOAE responses actually corresponds to the motion of the eardrum resulting from pressure fluctuations generated within the cochlea (Fig. 129.22). Although stimulatory clicks excite the entire cochlea, TEOAE responses can be used to give frequency-specific information about the cochlea through splitting of the responses into different frequency bands. TEOAEs are highly sensitive to cochlear pathology in frequency-specific manner. Frequencies at which hearing thresholds exceed 20 to 30 dB hearing loss (HL) are typically absent in the TEOAE response (20,21). Because of their sensitivity to cochlear dysfunction, TEOAEs have found widespread application in newborn hearing screening programs (22).
Distortion-product OAEs also are used widely in clinical situations. The TEOAE and DPOAE techniques complement each other. DPOAEs offer a wider frequency range of observation with less sensitivity to minor and subclinical conditions in adults. When two primary tones, F1 and F2, are presented to the cochlea, several distortion products are produced. The most prominent of all these intermodulation distortion products is the cubic distortion tone, 2F1-F2. Measurement of DPOAEs at multiple stimulus levels can establish the OAE â€œgrowth rate.â€� Healthy ears tend to exhibit a DPOAE growth rate of 1 dB of OAE per 1 dB of stimulus or less. Ears with some impairment show steeper growth. Single DPOAE results can be misleading, and results must be averaged across a range of frequencies. The DPOAE is easily recordable in patients with a normal middle ear system (23).Auditory Central Nervous System
The ascending and descending auditory pathways are described briefly herein in relation to auditory evoked potentials. Schematics of the afferent and efferent pathways are shown in Figs. 129.23 and 129.13, respectively. These diagrams oversimplify the system but provide a rough introduction to the auditory CNS and its complexity. All eighth-nerve afferent fibers stop at the level of the cochlear nucleus. Five major cell types are found within the cochlear nucleus, each with distinct cell morphologic and physiologic features, such as response to stimulus onset, stimulus offset, and frequency modulation. From the cochlear nucleus, most fibers cross the brainstem to the contralateral superior olivary complex; a much smaller number of fibers run to the ipsilateral superior olivary complex.
The superior olivary complex is considered the first center in the ascending auditory system, where inputs from both ears converge. Auditory nuclei above the superior olivary complex can be excitatory or inhibitory with inputs from each ear. Stimulation of the contralateral ear typically is excitatory to cell bodies of the auditory CNS, whereas stimulation of the ipsilateral ear is inhibitory. As shown in Figure 129.13, the medial superior olivary complex is the origin of the crossed efferent fibers that terminate on outer hair cells, whereas the lateral superior olivary complex is the origin for the uncrossed efferent fibers that terminate on inner hair cells. Although many functions have been attributed to the efferent auditory system, especially protecting the cochlea from loud sounds, the functions of the system are unknown; those that have been proposed are easily debated
The inferior colliculus is a complex nucleus with at least 18 major cell types and at least five areas of specialization. It is involved in probably all forms of auditory behavior, including differential sensitivity for frequency and intensity, loudness, and binaural hearing. The inferior colliculus is clearly more than a relay center. The medial geniculate body of the thalamus sends projections to the auditory cortex, but its specific functions are unknown.
The auditory cortex is located in the sylvian fissure of the temporal lobe; many secondary auditory areas are clustered around the primary area. In each area, the cells are tonotopically organized in a columnar manner, each column having a special attribute. The cells in one column can have different tuning at a similar characteristic frequency, whereas another column can be associated with intensity encoding, another with providing inhibitory responses to stimulation of one ear and excitatory responses of the other ear, and so on. As is common for thalamic connections with the cortex, nuclei within the medial geniculate body that send fibers to the auditory cortex also receive fibers from the same area of the cortex. Bilateral lesions of the temporal lobe have been shown to produce wide-ranging effects (cortical deafness, in which several auditory behaviors are severely affected, including speech discrimination, localization of sound, temporal processing of information, and the detection of faint, short-duration signals) (25). Another important feature of the auditory system is its tonotopic nature. From the basilar membrane to the auditory cortex, the system is organized spatially with respect to frequency. Each place on the basilar membrane responds best to a specific frequencyâ€”high-frequency sounds are localized to the base, and low-frequency sounds, to the apex. The tonotopic organization of the cochlea is preserved at the cochlear nucleus. Figure 129.24 shows that as an electrode penetrates the cochlear nucleus, fibers with different characteristic frequencies are contacted, and the characteristic frequencies form an orderly progression. Similar data exist at all nuclei of the auditory CNS, including the auditory cortex
The most obvious clinical application of basic information on the auditory CNS involves interpretation of evoked potentials. The auditory brainstem response (ABR) is one component of auditory evoked potentials. The existence of the ABR was first reported by Sohmer and Feinmesser in 1967 (26). The ABR is recorded from electrodes attached to various positions on the head. The ABR consists of a series of seven waves occurring within about 10 milliseconds after stimulus onset. The convention in the United States is to label wave peaks with Roman numerals. It is generally accepted that the ABR is generated by the auditory nerve and subsequent fiber tracts and nuclei within the auditory brainstem pathways. It is widely believed that each wave is generated as follows: wave I and II are the eighth nerve, III is cochlear nucleus, IV is superior olive/lateral lemniscus, and V is lateral leminiscus/inferior colliculus.
The ABR is generated by a click stimulus because it yields the clearest response. The ABR is used clinically both in the estimation of auditory sensitivity and in otoneurologic assessment. In this way, it can be used to detect lesions along the auditory nerve and brainstem pathways. The study can be performed regardless of state of wakefulness, and the result is unaffected by most medications. As a result, children are often tested while under sedation or during sleep.
The field of clinical objective audiometry has recently gained an additional technique in the auditory evoked response battery. The auditory steady-state response (ASSR) promises to be a valuable study in the workup of auditory dysfunction. Unlike ABRs, which are obtained through the use of transient stimuli, ASSRs are evoked by using sustained continuous tones. The tones are frequency specific because the continuous tones do not have spectral distortion problems as do brief tone bursts or click (27). Of note, ASSR also can be performed regardless of the state of wakefulness.
There are several advantages of ASSR over ABR. First, ASSR is a better technique for evaluating hearing aid performance because hearing aids and cochlear implants process continuous stimuli with less signal distortion than transient stimuli. Furthermore, ASSR can provide threshold information in a frequency-specific manner at intensity levels of 120 dB or greater (28,29). This allows differentiation of severe and profound hearing loss, which cannot be accomplished with ABR. This characteristic of ASSR may allow it to be used in assessing pediatric patients for cochlear implant candidacy (30). Last, ASSR has been shown to be more time efficient by determining more thresholds in a shorter time compared with ABR (31). Future research and clinical use are likely to solidify the status of ASSR in the audiologic armamentarium.
The neuroanatomic features of the system are complicated. Processing of neural information probably involves both parallel and serial processing. The former is anatomically described by a single fiber with ramifications to many target areas. Serial processing involves a fiber going to one target, which in turn goes to another target, and so forth. In the auditory CNS, both serial and parallel processing are involved. Because the auditory CNS is a highly redundant, complicated, and extremely powerful system, interpretation of evoked-potential data, and of other CNS neural data, is not straightforward.

Pathophysiology of Glaucoma

2008-11-26T13:33:00.001-08:00

The major mechanism of visual loss in glaucoma is retinal ganglion cell atrophy, leading to thinning of the inner nuclear and nerve fiber layers of the retina and axonal loss in the optic nerve. The optic disk becomes atrophic, with enlargement of the optic cup (see below). The iris and ciliary body also become atrophic, and the ciliary processes show hyaline degeneration.

The pathophysiology of intraocular pressure elevation—whether due to open-angle or to angle-closure mechanisms—will be discussed as each disease entity is considered (see below). The effects of raised intraocular pressure are influenced by the time course and magnitude of the rise in intraocular pressure. In acute angle-closure glaucoma, the intraocular pressure reaches 60–80 mm Hg, resulting in acute ischemic damage to the iris with associated corneal edema and optic nerve damage. In primary open-angle glaucoma, the intraocular pressure does not usually rise above 30 mm Hg and retinal ganglion cell damage develops over a prolonged period, often many years. In normal-tension glaucoma, retinal ganglion cells may be susceptible to damage from intraocular pressures in the normal range or the major mechanism of damage may be optic nerve head ischemia

Mycrobiology of sinusitis

2008-08-04T06:26:00.000-07:00

A.Acute sinusitis
The most commonly identified organisms in children with acute sinusitis are Streptococcus pneumoniae in 30% to 40%, Haemophilus influenzae in 20% to 25%, and Moraxella catarrhalis in 20%. In adults, S. pneumoniae and H. influenzae are the two leading causes of acute sinusitis, whereas Moraxella is unusual. Anaerobic organisms are primarily identified in cases of acute sinusitis originating from dental root infections, but are otherwise uncommon. Hospital-acquired sinusitis is most often seen as a complication of nasogastric tube placement, and is typically caused by gram-negative enteric organisms, such as Pseudomonas and Klebsiella species.

B.Chronic sinusitis
1.Bacteria cultured from children with persistent symptoms are usually the same as those seen in acute disease. In children with more severe and protracted symptoms, anaerobic species (such as Bacteroides) and staphylococci are cultured more frequently. In adults with refractory symptoms, Staphylococcus epidermidis is frequently cultured from intraoperative specimens. The exact role of this species in the pathogenesis of chronic sinusitis is unclear. Although anaerobic organisms were once implicated in adults with chronic sinus disease, more recent evidence casts doubt upon those data.

2.Fungi, such as Aspergillus species, are a common cause of sinus disease in immunocompromised hosts, including diabetics and patients who have defective cell-mediated immunity. Increasingly, fungi have been identified as causes of sinusitis in patients who are otherwise healthy and should, therefore, be considered in cases of refractory sinusitis. Allergic fungal sinusitis is a syndrome that occurs in adults with asthma and has been attributed to Aspergillus, Bipolaris, and Curvularia species. It is characterized by severe, hyperplastic sinusitis and nasal polyposis, and is associated with significant eosinophilia of sinus tissue and blood.

Indications for Anticoagulation in Patients With Prosthetic Heart Valves

2008-07-11T06:15:00.000-07:00

All patients with mechanical valves require warfarin therapy. The risk of embolism is greater with a valve in the mitral position (mechanical or biological) than in the aortic position. With either type of prosthesis or valve location, the risk of emboli is higher in the first few days and months after valve insertion. Low-dose aspirin is recommended for all patients with prosthetic valves (see Table 1. For patients with mechanical valves, the addition of low-dose aspirin (80 to 100 mg/d) to warfarin therapy (INR 2.0 to 3.5) not only further decreases the risk thromboembolism but also decreases mortality due to other cardiovascular diseases. A slight increase in risk of bleeding with this combination should be kept in mind.
Recommendations for Antithrombotic Therapy in Patients With Prosthetic Heart Valves
Class I
1.First 3 months after valve replacement: Warfarin- INR 2.5 to 3.5
2.3 or more months after valve replacement:
A. Mechanical valve
AVR and no risk factor*:
Bileaflet valve or Medtronic Hall valve, Warfarin- INR 2 to 3
Other disk valves or Starr-Edwards valve, Warfarin- INR 2.5 to 3.5
AVR and risk factor,* Warfarin- INR 2.5 to 3.5
MVR, Warfarin- INR 2.5 to 3.5

B. Bioprosthesis
AVR and no risk factor,* Aspirin- 80 to 100 mg/d
AVR and risk factor,* Warfarin- INR 2 to 3
MVR and no risk factor,* Aspirin- 80 to 100 mg/d
MVR and risk factor,* Warfarin- INR 2.5 to 3.5

Class IIa
1.Addition of aspirin to warfarin: Aspirin- 80 to 100 mg daily
2.High-risk patients for whom aspirin cannot be used: Warfarin- INR 3.5 to 4.5
Class IIb
Starr-Edwards AVR and no risk factor,* Warfarin, INR 2 to 3

Class III
1.Mechanical valve, no warfarin therapy.
2.Mechanical valve, aspirin therapy only.
3.Bioprosthesis, no warfarin and no aspirin therapy.

Symptom and Sign Diabetes

2008-07-10T06:23:00.000-07:00

SYMPTOMS AND SIGNS

Type 1 diabetes
Increased urination is a consequence of osmotic diuresis secondary to sustained hyperglycemia. This results in a loss of glucose as well as free water and electrolytes in the urine. Thirst is a consequence of the hyperosmolar state, as is blurred vision, which often develops as the lenses are exposed to hyperosmolar fluids.
Weight loss despite normal or increased appetite is a common feature of type 1 when it develops subacutely. The weight loss is initially due to depletion of water, glycogen, and triglycerides; thereafter, reduced muscle mass occurs as amino acids are diverted to form glucose and ketone bodies.
Lowered plasma volume produces symptoms of postural hypotension. Total body potassium loss and the general catabolism of muscle protein contribute to the weakness.
Paresthesias may be present at the time of diagnosis, particularly when the onset is subacute. They reflect a temporary dysfunction of peripheral sensory nerves, which clears as insulin replacement restores glycemic levels closer to normal, suggesting neurotoxicity from sustained hyperglycemia.
When absolute insulin deficiency is of acute onset, the above symptoms develop abruptly. Ketoacidosis exacerbates the dehydration and hyperosmolality by producing anorexia and nausea and vomiting, interfering with oral fluid replacement.
The patient's level of consciousness can vary depending on the degree of hyperosmolality. When insulin deficiency develops relatively slowly and sufficient water intake is maintained, patients remain relatively alert and physical findings may be minimal. When vomiting occurs in response to worsening ketoacidosis, dehydration progresses and compensatory mechanisms become inadequate to keep serum osmolality below 320â€“330 mosm/L. Under these circumstances, stupor or even coma may occur. The fruity breath odor of acetone further suggests the diagnosis of diabetic ketoacidosis.
Hypotension in the recumbent position is a serious prognostic sign. Loss of subcutaneous fat and muscle wasting are features of more slowly developing insulin deficiency. In occasional patients with slow, insidious onset of insulin deficiency, subcutaneous fat may be considerably depleted.

Type 2 diabetes
While many patients with type 2 diabetes present with increased urination and thirst, many others have an insidious onset of hyperglycemia and are asymptomatic initially. This is particularly true in obese patients, whose diabetes may be detected only after glycosuria or hyperglycemia is noted during routine laboratory studies. Occasionally, type 2 patients may present with evidence of neuropathic or cardiovascular complications because of occult disease present for some time prior to diagnosis. Chronic skin infections are common. Generalized pruritus and symptoms of vaginitis are frequently the initial complaints of women. Diabetes should be suspected in women with chronic candidal vulvovaginitis as well as in those who have delivered large babies (> 9 lb, or 4.1 kg) or have had polyhydramnios, preeclampsia, or unexplained fetal losses.
Obese diabetics may have any variety of fat distribution; however, diabetes seems to be more often associated in both men and women with localization of fat deposits on the upper segment of the body (particularly the abdomen, chest, neck, and face) and relatively less fat on the appendages, which may be quite muscular. Standardized tables of waist-to-hip ratio indicate that ratios of "greater than 0.9" in men and "greater than 0.8" in women are associated with an increased risk of diabetes in obese subjects. Mild hypertension is often present in obese diabetics. Eruptive xanthomas on the flexor surface of the limbs and on the buttocks and lipemia retinalis due to hyperchylomicronemia can occur in patients with uncontrolled type 2 diabetes who also have a familial form of hypertriglyceridemia.

PATHOLOGY OF ACUTE PANCREATITIS

2008-07-07T07:18:00.001-07:00

PATHOLOGY
Detailed histological studies of pancreatic tissue are available from a limited number of cases of human acute pancreatitis. A histological spectrum of acute pancreatitis is recognized ranging from mild, interstitial disease to coagulation necrosis. 3 Interstitial pancreatitis may lead to local and systemic complications but is rarely fatal; necrotizing pancreatitis may be fatal in up to 30% of cases.

Interstitial
In interstitial pancreatitis the gland is edematous, but its gross architecture is preserved. Parenchymal inflammatory cells are present together with interstitial edema. Disruption of the normal acinar cell architecture is common and may contribute to the reduced enzyme secretion characteristic of acute pancreatitis. Zymogen granules are displaced from their fusion site in the apical domain of the cell and become dispersed throughout the cell, and the apical membrane appears contracted and microvilli disappear. 4 Zymogen granules fuse with each other instead of the apical membrane. Similar to animal models of pancreatitis, a distinct form of cell necrosis is observed in which the apical domain of the acinar cell is shed into the lumen, resulting in intact zymogen granules within the lumen. This pattern of partial cell necrosis may allow the acinus to regenerate rapidly after injury.

Necrotizing
Macroscopically, marked tissue necrosis and hemorrhage are apparent. Surrounding areas of fat necrosis are also prominent. These chalky areas of dead adipose tissue are found within the peripancreatic tissue and throughout the abdomen. Large hematomas often are located in the retroperitoneal space. The microscopic appearance of the pancreas parallels the gross changes, with marked fat and pancreatic necrosis. Vascular inflammation and thrombosis are common.

TREATMENT OF ACUTE MYOCARD INFARCTION

2008-06-25T08:14:00.000-07:00

Treatment

Because myocardial damage progresses rapidly during the early hours, efforts during this critical period must be directed toward reducing myocardial oxygen demand and improving coronary blood supply to diminish the extent of myocardial damage. To be maximally effective, these interventions must be initiated as soon as possible: The reduction in benefit is very time-dependent, and patients who are treated within an hour fare significantly better than those treated later. Thus, prompt reperfusion therapy via primary angioplasty or thrombolytic therapy should be initiated in the absence of contraindications as early as possible in patients with ST elevation acute infarctions. It is now becoming clear that urgent treatment also reduces the morbidity associated with non-Q wave infarctions as well, especially if followed by definitive intervention on the infarct related artery.

A. EMERGENCY CARE AND PROTOCOLS

More than 85% of patients who present with ST elevation within 4 h of the onset of acute infarction have total thrombotic occlusion, thought to be caused by plaque rupture and subsequent development of an intramural coronary thrombus. The timely reestablishment of nutritive perfusion saves lives. This is best done, if possible, by primary angioplasty but if not available in <60 min (door to balloon time), thrombolytic agents should be used. The time window may not be the same for all patients, however. In some patients, collateral perfusion to the infarct zone extends this window; in others, there is only intermittent occlusion and transient recanalization prior to total occlusion, which may modify the time course of the infarction. It cannot be emphasized enough that the earlier treatment occurs the better (Figure 5–4). Although the magnitude of benefit varies for thrombolytic therapy, patients treated within 1 h of the onset of infarction (an impossibility if treatment requires 90 min to initiate) have up to a 50% reduction in mortality rates; those treated in the second hour have only half that benefit, and there is controversy about whether benefit occurs at all after 6 h. For primary angioplasty, this time dependence, especially after the first hour is less, but treatment during the initial 60–90 min is associated with profound benefit. The mortality rate for patients treated within 60–90 min of the onset of infarction in an outpatient trial of thrombolysis was 1%; for patients receiving identical treatment from 90 min to 3 h, the mortality rate was 10%. Emergency departments and hospitals must facilitate the way in which interventions aimed at coronary recanalization are implemented.

To this end, each hospital should have a plan that addresses each step in the identification, triage, and treatment of the patient who is a potential candidate for coronary recanalization.
It is starting to become clear that such a plan should be expanded, albeit with different therapies for patients with non-Q wave events as well. Such plans should include:
1. Activities that can be initiated by paramedics en route to the hospital— Paramedics can record and transmit 12-lead ECGs to the receiving facility; they can screen patients for indications for and contraindications to treatment with thrombolytic agents. In some emergency medical systems, thrombolytic therapy can safely be implemented by paramedics. Although the cost-effectiveness of initiating therapy in the field is unclear, screening by paramedics and the availability of a diagnostic ECG prior to arrival appear desirable.
2. Emergency room procedures— A triage plan should be developed to identify patients with chest discomfort compatible with ischemia and to facilitate rapid ECGs. Electrocardiograph machines should be available in all emergency facilities, with personnel trained to rapidly record 12-lead ECGs available at all times. The ECG must be read expeditiously by a physician. Although ECG screening by computer algorithms may be a reasonable adjunct, all computer systems do not perform equally well. The ultimate responsibility for interpretation of the ECG therefore resides with the physician. Emergency room physicians without a high level of expertise in this area should have readily available expert consultation (whether on-site or via electronic communications) to minimize delays in interpretation. This step should take no more than 5 min.
The first physician who sees the patient with chest discomfort and appropriate ECG changes should have both the responsibility and the authority to initiate treatment. If there is a prospective plan to use primary angioplasty in patients with ST elevation events, this is the therapy of choice. If not or if there is delay, thrombolytic therapy should be given. For patients with non-Q wave events (those with elevated troponins), treatment with antiischemic agents such as nitrates and b-blockers and the use of heparin (LMWH is better) is called for, and if intervention is likely, IIB/IIIA agents should be initiated. Each hospital should develop a protocol to address the following issues:

How many intravenous (IV) lines are necessary? One line must always be available in the event of an emergency and for infusion of medication to facilitate reperfusion (heparin, lytic agents, or IIB/IIIA agents). An additional line may be necessary for other medicines or for a heparin lock through which to draw blood.

How much oxygen should be used routinely? This should be defined; blood gases are relatively contraindicated in this situation, oximetry is preferred.

If primary angioplasty is the therapy of choice, prospectively detailed lines of communication must be established. If thrombolysis is the choice, the facility should know the thrombolytic agent of choice, and the dose for the routine patient. These should be decided by consensus. Instances in which an exception is necessary should be detailed, as should whom to call for consultation. The agent for routine use should, of course, be available in appropriate doses within the emergency department to facilitate rapid administration.

Which medicines should be used adjunctively? Aspirin, heparin, nitroglycerin, b-blockers, and IIB/IIIA agents for the routine patient should be specified in advance—and should be immediately available in the emergency department.

Which contraindications should preclude treatment?

How will patients be moved rapidly from the treatment area to their ultimate destination in an intensive care unit?
B. GENERAL PROCEDURES

1. Intravenous line— An intravenous line should be placed immediately in any patient who is seriously considered to have suffered acute ischemia; this will provide access for the administration of pharmacologic agents should they be necessary and for emergency treatment should the need arise. The IV line should be large (18 gauge or greater); its patency should be maintained with an infusion of 5% dextrose in water, one-half normal saline, or normal saline solution.
2. Oxygen— Oxygen is appropriate for all patients with suspected AMI. Given the current aggressive approach toward anticoagulation and reperfusion in treating coronary heart disease, which often entails the use of potent anticoagulants or thrombolytic agents, blood gas determinations are not appropriate as a routine measure; oximetry is preferred. The empiric use of oxygen, usually via nasal prongs at 2–4 L/min, is recommended for all patients except those who have both normal oxygen saturations by oximetry or some reason to withhold oxygen (eg, a history of CO2 retention). Even patients with severe chronic obstructive pulmonary disease who may be at risk for CO2 retention should receive oxygen if systemic oxygenation is inadequate. Although supported by experimental data, the concern that supraphysiologic doses of oxygen may induce vasoconstriction and adverse effects has never been convincingly documented clinically.
3. Relief of discomfort— Relief of discomfort is a high priority.
a. Sublingual nitroglycerin— Unless contraindicated by hemodynamic abnormalities, sublingual nitroglycerin can be used to try to relieve chest discomfort and reverse ECG changes. A reversal of ECG changes is found most often in patients with patent infarct-related coronary arteries; it suggests that ischemia rather than infarction is present. Nitroglycerin must be given cautiously, however, especially to patients with inferior MI who may have RV infarction and who are prone to hypotension in response to this agent. A small subset of patients without RV infarction will also develop hypotension and an inappropriately slow heart rate after nitroglycerin. This is a vagally mediated phenomenon that has also been reported with morphine sulfate. Atropine (0.5 mg) is the treatment of choice in such cases.
b. Intravenous nitroglycerin— If patients have a beneficial response to sublingual nitroglycerin, it is reasonable to initiate treatment with IV nitroglycerin at a low dose (5–10 µg/min). Although this may relieve some of the chest discomfort in patients with acute infarction, it does not reduce the need for treatment with analgesics. Furthermore, reductions in blood pressure by more than 10% in normotensive patients are likely to be detrimental. Keeping the dose low and not expecting it to provide total relief of discomfort is recommended. This approach reduces the incidence of tolerance to the agent, which occurs in up to 25% of patients. Some physicians also use more potent vasodilators such as sublingual nifedipine to assess whether chest pain can be relieved and ECG changes reversed. Although these agents are effective, there is an associated incidence of marked hypotension that can cause detrimental cardiovascular effects. Calcium channel blockers are not recommended for routine administration.
c. Morphine sulfate— If the patient does not have a prompt response to sublingual nitroglycerin, morphine sulfate is the drug of choice. An IV dose of 2–4 mg and repeated as necessary and tolerated until chest discomfort is relieved is recommended. In addition to relieving pain, morphine sulfate reduces anxiety and the catecholamine secretion that occurs across the myocardial vasculature during acute infarction. As noted earlier, there is a small incidence of hypotension with an inappropriate heart-rate response that responds to atropine. Other analgesic agents used for the treatment of pain include meperidine and pentazocine.
d. Beta-blockers— Beta-blockers are commonly used to treat the chest discomfort associated with AMI in countries outside the United States. They have been shown to be effective, apparently because of both their membrane-stabilizing effects and their beneficial effects on myocardial oxygen supply and demand. Small doses of metoprolol (generally 5 mg), propranolol (1–3 mg IV) or esmolol (a loading dose of 250 mg/kg followed by 25–50 mg/kg/min, up to a maximum dose of 300 mg/kg/min) can be given as long as hemodynamic and electrical stability can be maintained. Although esmolol’s efficacy in this area is not well established, it is rapidly metabolized by esterases in red cells and is the only agent with a brief duration of action. Beta-blockers may also be useful in reducing the extent of infarction and for secondary prevention (see section d. Adjunctive therapy).
e. Angiotensin-converting enzyme inhibitors— Patients with ST elevation infarction seem to benefit from the early initiation of treatment with angiotensin-converting enzyme inhibitors (ACEI) if blood pressure allows. This strategy improves ventricular remodeling acutely but is even more efficacious over the longer term
4. Activity— Bed rest, except for the patients who require the use of a bedside commode, is mandatory during the first 24 h; autonomic instability, hypotension, and arrhythmias are common. It was believed in years past that strict bed rest was appropriate for 7–10 days and that discharge should occur after approximately 2 weeks. It is now clear that it is less stressful and thus more beneficial medically if hemodynamically stable patients are allowed to sit in a chair and use a bedside commode after 24 h. In general, patients without complications remain in an intensive care unit for 2–3 days, during which time their activities are markedly restricted. On transfer out of the intensive care unit, they can gradually begin ambulation, and most patients without complications can be discharged as early as 4 days after infarction.
5. Diet— It generally has been recommended that patients with acute infarction avoid extremes of hot and cold, have no caffeine, and be maintained initially on a liquid diet. The rationale for this approach includes the presence of autonomic instability, concerns that caffeine might exacerbate arrhythmias, and fear that particulate matter could be aspirated in the event of cardiac arrest (which tends to occur early during the evolution of acute infarction). Although none of these concerns have been strictly validated, such restrictions are considered prudent. After the first day, if patients are stable, their diet can be advanced. Education to facilitate good eating habits and a reduction in fat intake can be initiated at that time.
6. Bowel care— Patients, especially those who are older and are put to bed-rest with a reduced oral intake, have a tendency to constipation. Given the autonomic instability indigenous to AMI, the reduction of straining when bowel movements occur is recommended. In general, the use of stool softeners such as docusate sodium in a once-a-day dose of 100 mg is adequate. Some degree of selection is appropriate; some patients are not in need of this treatment, whereas others require more potent treatment.
7. Sedation— If patients are excessively restless and no physical cause can be determined, sedation with small doses of a sedative-hypnotic agent such as diazepam is recommended. During the initial 24 h, the dosage should be the minimum required to relieve anxiety, and patients should be continually reassessed to ensure that what is being treated is anxiety and not an underlying complication of infarction.
8. Electrocardiographic monitoring— All patients with significant likelihood of AMI should be monitored electrocardiographically. Those with chest pain and ECG changes that are highly likely to be due to infarction should be hospitalized in an intensive care unit. Those deemed at less risk still require ECG monitoring in an environment where defibrillation is readily available. It is recommended that patients with uncomplicated acute infarction be monitored until discharge; patients with complications require longer periods of observation.
9. Heparin— Unless there are contraindications to its use or patients are receiving other anticoagulants, all patients should receive subcutaneous heparin, 5000 units every 12 h. This regimen has been shown to reduce the incidence of deep venous thrombi that occurs in as many as 24% of treated patients; it should reduce the frequency of pulmonary emboli as well. Although the studies documenting these effects were done at a time when long periods of bed rest were mandated, they are most likely still correct—at least in principle—and there is little morbidity associated with the relatively modest doses of heparin. Therefore, despite earlier ambulation, the use of subcutaneous heparin twice daily is still recommended. Most patients with ST segment elevation AMI or with non-Q wave AMI benefit from the use of therapeutic doses of heparin. Many still recommend unfractionated heparin to increase the activated partial thromboplastin time (aPTT) to 1½–2½ times. However, it is now clear that LMWH is mC. RECANALIZATION THERAPY

Prompt coronary recanalization clearly reduces infarct size and, in the long term, saves lives. The so-called open artery hypothesis also has additional benefits (see section 2. Implemantation of Reperfusion Strategies). At one time, there was legitimate controversy over whether coronary recanalization induced by mechanical means (angioplasty) was better, with lower mortality and morbidity rates, than that induced by thrombolysis in patients presenting with an ST elevation MI. Comparative studies indicate that the greater degree of coronary patency induced by angioplasty produces less residual ischemia and recurrent infarction. It is clear that patients whose vessels are open, with sluggish flow (TIMI II grade), have a substantially worse prognosis than do those whose vessels are widely patent with a normal (TIMI III grade) flow. Thus, because direct reperfusion of a coronary artery via mechanical means is more apt to induce TIMI grade III flow and, thus, better nutritive perfusion, it results in reduced mortality and morbidity. In general, patency rates with primary percutaneous coronary intervention (PCI) are in the range of 85–90%, whereas with thrombolysis, the rates are roughly 65% and recurrent events are more common. With modern advances, direct stenting appears to be by far the best approach. This is clearly the case for patients who present ³1–1½ h after the onset of symptoms. The results with thrombolysis in early (<90 min) patients probably match the results of PCI. If intervention is delayed for more than 60 min, results are far less positive. Thus, unless PCI can be done immediately, treatment with thrombolytic agents should be initiated.
Similar data concerning the advantages of recanalization therapy are starting to emerge for those with non-Q wave infarction as well although the data are still controversial. However, both the FRISC 2 and Tactics TIMI 18 studies strongly suggest that the aggressive use of newer anticoagulants such as IIB/IIIA agents and LMWH along with urgent recanalization improve prognosis. Additional trials in this important area are ongoing.
1. Subsets of patients—
a. Inferior versus anterior myocardial infarction— The mortality rates associated with anterior ST elevation MI are at least twice those for ST elevation inferior MI, and patients with the former should be treated more aggressively. Specifically, recanalization therapy should be considered appropriate for as long as 12 h in patients with anterior MI. This is particularly true when the ST segment elevation is greater than 2 mm or when more than two anterior precordial leads are involved. Data from patients with inferior infarction suggest that those with marked ST elevation and especially those with ST depression in the right-sided anterior precordial leads (V1–V3) are at greatest risk. Such changes are associated with a larger area at risk for infarction and subsequent morbidity and mortality. In addition, patients with RV involvement benefit substantially from recanalization. Therefore, the site of infarction and the ECG changes must be factored in with the patient’s age, hemodynamic stability, and other signs in determining the time during which treatment is appropriate.
b. Elderly patients— Elderly patients with acute ST elevation MI are at high risk for increased morbidity and mortality with thrombolytic agents. Indeed, some studies suggest that these agents have no benefit in this group. On the other hand, PCI is clearly beneficial. However, if PCI cannot be accomplished, individual decisions concerning the risk (which is substantial, especially in regard to intracranial bleeding) and the potential benefits must be balanced. Given the high (20–30%) mortality rate from ST elevation MI in the elderly, some increased risk may be reasonable.
c. Hypertension— Many studies of thrombolysis have been extremely cautious about enrolling patients with concurrent hypertension. In some studies, the presence of hypertension has been a demonstrable risk factor for bleeding; in others, this has not been the case. Although even patients with severe hypertension have been treated with beneficial results and no complications in some studies, definitive data are absent in this area. One important consideration is the ease with which blood pressure can be controlled. Transient hypertension that resolves quickly when pain is treated is less worrisome than that which requires treatment with vasodilators. The use of less aggressive dosing regimens and gentler anticoagulation may help to avoid morbidity when treating hypertensive patients. Again, PCI avoids many of these problems.
d. Prior cerebral vascular accidents— Initially, all patients with a history of cerebral vascular accidents were handled cautiously and were considered to have contraindications to the use of thrombolytic agents. It is now clear that this criterion is too rigid, and only cerebral vascular accidents that have occurred within the past 2 months and those associated with intracranial bleeding should be considered absolute contraindications.
2. Implementation of reperfusion strategies— Once the decision is made to treat a patient, treatment should be initiated promptly and the patient transferred to an intensive care unit. (Contraindications to the use of thrombolytic agents are contained in Table 5–2).

a. Urgent percutaneous coronary intervention— Recent data suggest that stenting with the use of clopidogrel for at least 4 weeks is the preferred modality of therapy. Although in one study, stenting appeared to present a possible initial early hazard, this was not observed in a subsequent study, and the frequency of subsequent ischemia and restenosis is clearly improved. The adjunctive use of LMWH is problematic because the only data concerning its use in this setting are preliminary. However, for enoxaparin, an initial IV dose of 30 mg appears optimal or dalteparin in a dose of 120 IU/kg subcutaneously.
b. Plasminogen activators— Plasmin, the key ingredient in the fibrinolytic system, degrades fibrin, fibrinogen, prothrombin, and a variety of other factors in the clotting and complement systems. This effect inhibits clot formation and can lead to bleeding. Patients with AMI and ST segment elevation have little evidence of spontaneous or intrinsic fibrinolysis, despite the intense thrombotic stimulus present. This may be due in part to increased levels of circulating PAI 1 in plasma or PAI-1 that is elaborated locally from platelets. The pharmacologic administration of plasminogen activators (Table 5–3) to such patients seems reasonable. Plasminogen activators can be administered intravenously or directly into the coronary artery. Although more rapid patency occurs with local administration, and lower doses can be used, given the need for early treatment, plasminogen activators are generally administered intravenously.

In addition to invoking fibrinolysis and inhibiting clotting by degrading clotting factors, all activators enhance clot formation. These effects seem greater with nonspecific activators such as streptokinase and urokinase and could partly explain why fibrin-specific activators such as t-PA open arteries more rapidly.
The enhancement of coagulation by plasminogen activators suggests an important role for the concomitant use of antithrombotic agents.
(1) Streptokinase— Streptokinase is derived from streptococcal bacteria and activates plasminogen indirectly, forming an activator complex with a slightly longer half-life than streptokinase alone (23 min versus 18 min after a bolus). Because it activates both circulating plasminogen and plasminogen bound to fibrin, both local and systemic effects occur; that is, circulating fibrinogen degrades substantially (fibrinogenolysis as well as fibrinolysis occurs).
Because antibodies to the streptococci exist in many patients, allergic reactions can occur; anaphylaxis is rare, however, and the use of steroids to avoid allergic reactions is no longer recommended. When streptokinase is administered intravenously, a large dose is necessary to overcome antibody resistance. Because a dose of 250,000 units will suffice in 90% of patients, the recommended dose of 1.5 million units over a 1-h period is generally more than adequate to overcome resistance. Patients who are known to have had a severe streptococcal infection or to have been treated with streptokinase within the preceding 5 or 6 months (or longer) should not receive the agent.
Rapid administration of streptokinase, even at the recommended dose, can cause a substantial reduction in blood pressure. Although this might be considered a potential benefit of the agent, it may also be detrimental. The rate of the infusion should therefore be reduced in response to significant hypotension, and the blood pressure should be monitored closely. Because streptokinase is more procoagulant than other thrombolytic agents, it should not be surprising that patients benefit to a greater extent from the concomitant use of potent antithrombins such as hirudin. However, in combination with IIB/IIIA agents, streptokinase seems to be associated with markedly increased bleeding rates.
(2) Urokinase— Urokinase is a direct activator of plasminogen. It has a shorter half-life than streptokinase (14 ± 6 min) and is not antigenic. Its effects on both circulating and bound-to-fibrin plasminogen are similar to those from streptokinase. It is therefore difficult to understand why IV doses of urokinase (2.0 million units as bolus or 3 million over 90 min) seem to induce coronary artery patency more rapidly than does streptokinase. There is substantial synergism between urokinase and t-PA.
(3) Tissue plasminogen activator— The initial human t-PA was made by recombinant DNA technology. The half-life in plasma was short (4 min) as a bolus but longer (46 min) with prolonged infusions. Despite the short half-life lytic activity persisted for many hours after clearance of the activator. Although t-Pas are considered “fibrin-specific,” no activator is totally fibrin-specific, and fibrin specificity is lost at higher doses. At clinical doses, however, less fibrinogen degradation took place than with nonspecific activators. Tissue plasminogen activator clearly opened coronary arteries more rapidly than nonspecific activators and this is likely why its use improved mortality rates. Bleeding was not less and there was a slight increase in the number of intracranial bleeds which was in part due to the need for dosage adjustment for lighter-weight patients.
The original regimen for the use of t-PA was 100 mg over 3 h: 10 mg as a bolus, followed by 50 mg over the first hour and 40 mg over the next 2 h. Patients who weighed less than 65 kg received 1.25 mg/kg over 3 h with 10% of the total dose given as a bolus. An alternative front-loaded regimen was found to be more effective and included an initial bolus of 15 mg, followed by 50 mg over 30 min and 35 mg over the next 60 min. Doses higher than 100 mg are associated with a higher incidence of intracranial bleeding.
(4) Reteplase— Over time a variety of t-PA variant molecules have been developed. This mutant, called reteplase, lacks several of the structural areas of the parent molecule (the finger domain, kringle 1, and the epidermal growth factor domain). It is less fibrin-specific (causes more systemic degradation of fibrinogen) than the parent molecule, and has a longer half-life. Accordingly, it is used as a double bolus of 10 units initially followed by a second bolus 30 min later. Initial studies suggested that such a regimen used with unfractionated heparin opened more coronary arteries faster than did t-PA. This led to a large trial (GUSTO III) that compared the activators and found no difference. If anything, the minor trends that were present, favored the parent molecule. Nonetheless, many have elected to use reteplase because of the convenience of the double bolus administration.
(5) Tenecteplase— Tenecteplase is also a mutant form of t-PA. It has substitutions in the kringle 1 and protease domains to increase its half-life, increase its fibrin specificity, and reduce its sensitivity to its native inhibitor (PAI-1). These effects were substantiated in clinical trials and initially it appeared that the agent might be substantially superior to the parent molecule. However, in a direct comparison trial (Assent 2), using a 40-mg dose of tenecteplase, no differences in patient outcomes were observed with the possible exception of the group treated more than 4 h after the onset of symptoms. Nonetheless, because of the convenience of a single bolus dose, this agent is generally being used in preference to the parent molecule.
c. Combined thrombolysis and percutaneous coronary intervention— This combination approach has substantial promise. The early experience with coronary interventions after thrombolysis suggested substantial morbidity. Recent data using a half dose of thrombolytic agent (PACT) and studies using IIB/IIIA agents have suggested that now rapid serial thrombolysis and PCI can be accomplished without detriment and may in the long run permit the benefits of both modalities to be combined. This may be an important strategy for those patients living in areas where transport times or logistics make timely PCI impossible. Trials are ongoing to further test these strategies.
d. Adjunctive therapy—
(1) Aspirin— The ISIS II study showed that the combination of aspirin and streptokinase produced a greater reduction in mortality rates than did streptokinase or aspirin alone. Aspirin alone, however, in a dose of 162.5 mg, reduced mortality from acute infarction to almost the same extent as did streptokinase alone. These impressive data have led to the use of aspirin in all patients with AMI. Such a posture is supported by strong experimental evidence that aspirin inhibits platelet aggregation and facilitates fibrinolysis. In general, chewable aspirin in a dose of 162.5–325 mg is recommended initially because its effects on platelets occur within 20 min.
(2) Heparin— Intravenous heparin, used with plasminogen activators, improves the rapidity with which patency is induced; it is essential for maintaining coronary patency, especially with t-PA type agents. Its use is less necessary after treatment with streptokinase, probably because of the anticoagulant effects of fibrinogen depletion and degradation products.
The standard dose of unfractionated heparin is usually a bolus of 5000 units, followed by a 1000-unit-per-hour infusion until the partial thromboplastin time (PTT) can be used to titrate a dose between 1.5 and 2 times the normal range. It has become clear that optimal titration of unfractionated heparin is problematic and that if the activated PTT is either too high or too low, some benefit is lost. For this reason, the use of LMWH is recommended. With the exception of patients with renal failure, a dose of 1 mg/kg for enoxaparin and 120 unit/kg for dalteparin provides for consistent reduction in anti-Xa levels and thus consistent anticoagulation. This is probably the reason that recent studies suggest it is more effective for the treatment of patients with AMI. In addition, because LMWH inhibits Xa activity predominantly, there is some suggestion that discontinuing it may be less problematic than is the case for unfractionated heparin, which has fewer effects on Xa and more direct effects (when combined with antithrombin 3) on thrombin itself. The ability to use the agent intravenously in the catheterization laboratory has not been a problem in regions where this strategy has been embraced.
(3) Beta-blockers— If given early, IV b-blockers have been shown to lower the risk of reinfarction in low-risk patients treated with thrombolytic agents. This provides a rationale for their use (metoprolol, 5 mg IV every 5 min for 3 doses, followed by 25–50 mg every 12 h orally; or propranolol, 0.1 mg/kg initially (IV), followed by 20–40 mg every 6 h) in patients receiving thrombolytic therapy. It is presumed but has not been proven that similar benefits accrue to patients treated with primary PCI. Contraindications to the use of b-blockers include rales more than one-third of the way up the posterior lung fields, systolic blood pressure of less than 100 mm Hg, a heart rate of less than 60 bpm, conduction disturbances, a history of chronic obstructive pulmonary disease or asthma, or a history of an adverse responses to b-blockers. Tachycardia should not be considered the result of increased adrenergic tone and should be treated with b-blockers until all possible physiologic causes can be excluded. This is particularly important with diabetic patients, in whom autonomic neuropathy can at times cause tachycardia. Once treatment with b-blockers has been initiated, there will be some reason to discontinue the drug during the first 2–3 days for 20–30% of patients. This may be due to the evolution of infarction with the development of heart failure or to unanticipated complications of the drug (Table 5–4).

Table 5–4. Standard intravenous doses of commonly used agents in patients with acute myocardial infarction.

In general, b-blockers appear to induce most benefit in patients who reduce their degree of ST segment elevation in response to treatment. This is thought to be the marker of a patent infarct-related vessel and probably permits the agent to reach the infarct zone.
(4) Nitroglycerin— Sublingual nitroglycerin is usually administered immediately to patients with suspected AMI to assess resolution of ST elevation and relief of pain (discussed earlier). Intravenous nitroglycerin has been shown to reduce infarct size in patients not receiving reperfusion and to improve survival in patients with infarction and CHF. Its use during thrombolysis was presumed to induce similar benefit; however, the ISIS 4 trial failed to show any effect on subsequent morbidity and mortality. Therefore, the routine use of IV nitroglycerin is not recommended.
(5) Intravenous magnesium— Several small studies have documented a reduction in mortality rates after administration of IV magnesium (1–2 g over 1 h, followed by 8 g over 24 h) to patients presenting during the initial 24 h of acute infarction. ISIS 4, however, failed to demonstrate any benefit in morbidity or mortality with the routine use of IV magnesium. Therefore, because IV magnesium induces mild hypotension and bradycardia, its use cannot be recommended unless serum magnesium levels are shown to be low or other indications, such as torsade de pointes, are present.
(6) Calcium channel blockers— Dihydropyridine calcium channel blockers have shown to be detrimental in patients with AMI, probably because of a small but important incidence of severe hypotension. The data are inadequate to assess the risk or benefit of other calcium channel blockers. Although it is hoped that IV preparations may avoid adverse effects, allowing achievement of some of the benefits seen in experimental models, the use of calcium channel blockers cannot be recommended at this time.
(7) Lidocaine— Lidocaine was initially administered to patients receiving thrombolytic agents because of concern that coronary recanalization might exacerbate arrhythmias; However, recanalization reduces the incidence of such arrhythmias. In addition, recent analyses suggest the routine use of lidocaine may actually increase mortality rates. Accordingly, the use of prophylactic lidocaine is not recommended. The agent should be used if ventricular tachycardia (VT) or ventricular fibrillation (VF) occurs.
(8) IIB/IIIA agents— These agents bind to the platelet fibrinogen receptor and prevent platelet aggregation and activation. The initial agent in this group was abciximab, which is a chimeric antibody fragment to the receptor. Now both small peptide and nonpeptide competitive inhibitors of the receptor are available. These agents markedly inhibit hemostasis by both inhibiting hemostatic plug formation and reducing subsequent coagulation. They have not as yet been shown to be of benefit in patients with ST elevation AMI but are clearly efficacious in patients with non-Q wave events, especially if they undergo PCI. This is a group with an adverse long-term prognosis without intervention.
e. Complications— The most serious complication of treatment with thrombolytic agents is bleeding, particularly intracranial hemorrhage. Reduction in this dreaded complication is one of the very substantial benefits of catheter-based interventions. The mechanism of bleeding with thrombolytic agents is unclear but has been related to the efficacy of the agent, the concomitant use of antithrombotic agents such as heparin and aspirin, and the degree of hemostatic perturbation induced by the plasminogen activators. In most studies, the incidence of stroke and intracerebral bleeding has been slightly higher with t-PA type activators. This may be in keeping with the greater efficacy and rapidity of their effects. Although most bleeding occurs early during treatment, some can occur 24–48 h later, and vigilance even after the first few hours is important.
Bleeding may be of several types. Intracranial bleeding is by far the most dangerous because it is often fatal. For most activators, the incidence of intracranial hemorrhage is less than 1%; it may be as high as 2–3% in elderly patients. Risk factors for intracranial bleeding include a history of cerebral vascular disease, hypertension, and age. These factors must be taken into account when determining whether a thrombolytic agent has an appropriate benefit-to-risk relationship. Changes in mental status require an immediate evaluation—clinical and computed tomography or magnetic resonance imaging. If bleeding is strongly suspected, heparin should be discontinued or reversed with protamine.
There also is a substantial incidence of nonhemorrhagic, probably thrombotic, stroke that may be partly due to dissolution of thrombus within the heart, followed by migration. The exact mechanisms of this phenomenon are unclear. In some studies, the excess of strokes with t-PA has been found to be related to this phenomenon and in others it has been due to an apparent increase in intracranial bleeding.
Bleeding outside the brain can occur in any organ bed and should be prevented whenever possible. The puncture of noncompressible arterial or venous vessels is relatively contraindicated in all cardiovascular patients: those with unstable angina one day may be candidates for thrombolytic treatment on the next. Blood gas determinations should therefore be avoided if possible and oximeters used instead in cardiovascular patients. It should be understood that central lines placed in cardiovascular patients pose a substantial risk should there be a subsequent need for a lytic agent. Foley catheters and endotracheal (especially nasotracheal) intubation can also predispose to significant hemorrhage. Bleeding should be watched for assiduously. If severe bleeding occurs while heparin is in use, it should be antagonized with protamine. In general, this and supportive measures are all that can be done. In some studies, there appears to be a slightly higher incidence of extracranial bleeding with nonspecific activators than with t-PA; this finding has not been consistent. In an occasional patient, who begins to bleed shortly after receiving the plasminogen activator, epsilon amino caproic acid, which changes the activation of plasminogen, may be useful. Otherwise, discontinuation of the drug and conservative local measures are all that can done. If volume repletion is necessary, red blood cells are preferred to whole blood, and cryoprecipitate is preferred to fresh frozen plasma because they do not replenish plasminogen.
Allergic reactions related to the use of streptokinase are unusual but should be identified when they occur. Mild reactions such as urticaria can be treated with antihistamines; more severe reactions such as broncho-spasm may require glucocorticoids or epinephrine.
Bleeding after primary PCI whether for ST elevation of non-Q wave AMI can also be substantial, particularly if IIB/IIIA agents are administered. The use of newer closure devices are touted by some but close observation is the key to minimizing bleeding from the catheter site. On occasion, platelet transfusions may be necessary.
3. Subsequent early management— Aggressive monitoring can help determine which patients have coronary recanalization in response to treatment and which do not. Conventional ECG monitoring for ST segments and arrhythmias and consideration of the presence or absence of chest pain are not particularly reliable for this purpose. In fact, increasing degrees of ST segment elevation during the first hour after treatment appear to be a sign of incipient recanalization.
Emergency cardiac catheterization and angioplasty are not indicated for the routine patient who has been successfully thrombolysed. However, patients with non-Q wave AMI who have been stabilized pharmacologically and who are candidates for intervention should have it performed promptly. Patients who suffer continuing or persistent chest discomfort, who have recurrent segment change, or who have difficult-to-treat hypotension and heart failure should be considered for cardiac catheterization.
D. OTHER INTERVENTIONS

A variety of other interventions have been suggested throughout the years. These include the use of glucose, insulin, potassium, and hyaluronidase. Intraaortic balloon pumps have also been suggested, especially in patients with anterior infarction who might be deemed at risk for the development of severe heart failure. In general, none of these are recommended as routine measures. Perhaps the most promising of these is in the area of tight glucose control in diabetes. The DIGAMI study suggested an impressive benefit in early and late mortality and morbidity. With the availability of accurate glucose monitoring for point of care use, implementation of a strategy using rapid adjustments of IV insulin guided by hourly glucose measurements is likely to emerge as an important additional strategy.

DIANNOSTIC ACUTE MYOCARD IINFARCTION

2008-06-25T08:08:00.000-07:00

Clinical Findings
The clinical presentations of patients with AMI vary. Although most patients have had chest discomfort prior to the onset of infarction, 20% or more have infarction as a first manifestation of ischemic heart disease; in 20–30% of patients, infarction may go unrecognized. Nonetheless, symptoms are generally present.
A. SYMPTOMS AND SIGNS

The most common and best symptom on which to base a consideration of MI is chest discomfort, usually described as “pressure,” “dull,” “squeezing,” “aching,” or “oppressive,” although it may be described differently because of individual variability, differences in articulation or verbal abilities, or concomitant disease processes. The discomfort is usually in the center of the chest and may radiate to the left arm or the neck. In general, patients with ischemic chest pain tend to be still, but patients with infarction can be restless as well. The nature of the pain may lead patients to place a hand over the sternum (Levine’s sign). These clinical signs and symptoms were originally defined in groups of males. It is now clear that women often have more disease symptoms or more atypical symptoms.
Patients with diabetes or hypertension also may have atypical presentations; a classic presentation in a diabetic is with abdominal pain that mimics the discomfort commonly associated with gallstones. Elderly patients often present with heart failure: by age 85, only 40% of patients will present with chest discomfort. Patients who present with symptoms compatible with ischemia, (paroxysms of dyspnea, for example) or atypical chest discomfort should have the diagnosis of MI considered. Patients can also present with discomfort that is sharper or that radiates to the back. These patients can have pericarditis alone, pericarditis induced by infarction, or a dissecting aortic aneurysm—with or without concomitant infarction.
Much has been made of the presence of associated symptoms and findings such as dyspnea, diaphoresis, nausea and vomiting, and the response of chest discomfort to antianginal agents. Although positive findings should evoke increased consideration of a diagnosis of ischemic heart disease, their absence is not definitive.
B. PHYSICAL EXAMINATION

The physical examination may vary tremendously, from markedly abnormal, with signs of severe congestive heart failure (CHF), to totally normal. In general, an S4 sound is heard in patients with ischemic heart disease. Dyskinesis can be palpated in patients with larger infarctions. Signs of heart failure, such as neck vein distention, S3 sounds, and rales, should be looked for specifically.
C. DIAGNOSTIC STUDIES

The diagnosis of infarction in patients with suspected acute ischemic heart disease requires evidence of myocardial necrosis. This finding usually depends on elevated molecular markers of cardiac injury.
1. Troponins are the markers of choice— They are significantly more sensitive than CK2, and now with second- and third-generation assays, they have nearly absolute cardiac specificity. Absent analytic false-positives, one can be sure that the release of troponin is indicative of cardiac injury. However, because they are so sensitive, they detect cardiac insults that are nonischemic in nature (Table 5–1). Thus, the diagnosis of AMI requires clinical, electrocardiographic (ECG), or other (eg, coronary angiographic) evidence of acute ischemia (see Table 5–1). Troponin is elevated between 4 and 6 h after onset of an AMI and remains elevated for 8–12 days. Thus, the late or retrospective diagnosis of AMI can be made with this marker, making the use of lactate dehydrogenase isoenzymes superfluous. Troponin elevations in patients with ST elevation at the time of admission presage a lower rate of recanalization regardless of reperfusion modality used and a worse prognosis. This may be, at least in part, because patients with elevations present later than those without elevations. Patients who present with ST depression also have a worse prognosis if troponin is elevated to any extent. Even minor elevations are of significance (Figure 5–2). This group also has a unique beneficial response to LMWH and IIb/IIIa agents. Patients at low risk for ischemic heart disease who present with chest pain have a high frequency of coronary artery disease if troponin is elevated. Because increases in troponin persist for up to 2 weeks after an acute event, if the initial troponin value is elevated, it may be of value to define a shorter-lived marker (eg, CK2) if the cardiac injury is acute or has occurred in the days or weeks prior to presentation.

Table 5–1. ESC/ACC definition of myocardial infarction.

Figure 5–2. Prognosis in patients with acute coronary syndrome (ACS), elevated troponin, and no elevation of CK2 (isoenzyme of creatinine kinase), Peto odds ratio (OR), and 95% confidence interval (fixed). Adapted, with permission, from Am Heart J 2000;140:917.

Coronary recanalization, whether spontaneous or induced pharmacologically or mechanically, alters the timing of all markers’ appearance in the circulation. Because it increases the rapidity with which the marker is washed out from the heart, leading to rapid increases in plasma, the diagnosis of infarction can be made much earlier—generally within 2 h of coronary recanalization. Although patency can be approximated from the marker rise, distinguishing between thrombolysis in myocardial infarction (TIMI) II and TIMI III flow is not highly accurate. It should also be understood that peak elevations are accentuated, which must be taken into account if one wants to use peak values as a surrogate for infarct size.
2. Other molecular markers— The diagnosis of infarction requires increases in molecular markers of myocardial injury. Myoglobin release from injured myocardium occurs quite early and is very sensitive for detecting infarction. Unfortunately, it is not very specific because minor skeletal muscle trauma also releases myoglobin. Myoglobin is cleared renally, so even minor decreases in glomerular filtration rate lead to elevation. The other early marker advocated by some are isoforms of CK2. This marker has comparable early sensitivity to myoglobin, but because it uses such sensitive criteria, it also has nearly similar specificity as well. The marker of choice in past years was the MB isoenzyme of creatine kinase (CK2). A typical rising-and-falling pattern of CK2 alone (in the proper clinical setting) was sufficient for the diagnosis of acute infarction. In the typical pattern of CK2 release after infarction, the enzyme marker level exceeds the upper bound of the reference range within 6–12 h after the onset of infarction. Peak levels occur by 18–24 h and generally return to baseline within no more than 48 h. However, elevations can occur due to release of the enzyme from skeletal muscle. The lack of a rising-and-falling pattern should raise the suspicion that the release is from skeletal muscle, which is usually due to a chronic skeletal muscle myopathy. Elevations of CK2 in patients with hypothyroidism (where clearance CK2 is retarded) and those with renal failure (where clearance is normal because CK2 is not cleared renally) have elevations caused, in part, by myopathy. The percentage of CK2 with respect to total CK2 is an unreliable criterion for the diagnosis of infarction.
3. Electrocardiography— Only a few ECG patterns have high specificity for infarction (Figure 5-3). In general, an upwardly concave elevation of the ST segment is considered diagnostic of acute myocardial injury, with a high degree of specificity. Patients with inferior infarction should all be evaluated with right-sided chest leads to determine if right ventricular (RV) infarction is present by detecting ST elevation in V3R or V4R. Patients with ST segment depression in V1 and V2 may have total circumflex occlusions, which can be unmasked by the findings of ST segment elevation in the so-called posterior leads (V7–V9). The Q waves that tend to develop mark these patients as potential candidates for strategies designed to reduce the extent of infarction (discussed in the section on Implementation Reperfusion Strategies). Reperfusion accelerates the appearance of the Q waves often associated with this type of infarction. The electrocardiogram may not show typical changes, however, because of concomitant conduction disturbances (eg, left bundle branch block [LBBB]) that may mask the findings or because only ST depression, which is considered more nonspecific, is present. Without acute ST segment elevation or the development of new Q waves, no other ECG changes can be considered highly specific—and even these findings are not 100% specific. The ECG can even be totally normal. In the absence of an old ECG for comparison, any changes present should be presumed to be new. Although persistent or fixed changes are more characteristic of infarction, labile changes have a greater predictive value for the presence of ischemia for patients with elevated biomarkers thought to have non-Q wave MI, the presence of ST depression is a negative prognostic sign.

Figure 5–3. Typical evolution of the electrocardiographic changes of acute myocardial infarction. A: Anterior infarction. B: Inferior infarction. Reproduced, with permission, from Lipman BS, Dunn MI, Massie E: Clinical Electrocardiography. St. Louis: Mosby, 1984.

4. Imaging— Imaging can also be used to confirm the presence or absence of acute infarction, but it is rarely used in modern practice. Infarct-avid imaging with technetium 99m pyrophosphate indium-111-labeled myosin or 99m sestamibi can be used. These techniques detect large AMIs well. With smaller infarctions, however, sensitivity is lost. In addition, with larger infarctions, a significant number (20–30%) of images will remain persistently positive for at least 6 months.
Echocardiography also may be helpful in detecting an AMI. Some researchers argue that the absence of regional abnormalities on the ECG is strong evidence against the presence of acute infarction. The sensitivity of echocardiography, however, is critically dependent on the quality of the views obtained; the absence of an abnormal ECG should not of itself be used to exclude the presence of ischemic heart disease. Furthermore, echocardiography cannot distinguish acute infarction from a persistent defect caused by an old myocardial injury. At present, therefore, it is diagnostically useful for AMI when the ECG and clinical history are equivocal. It is valuable in defining the presence of the complications of AMI.

PHATOPHYSIOLOGI ACUTE MYOCARD INFARCTION

2008-06-25T07:40:00.000-07:00

It is generally accepted that a prolonged imbalance between myocardial oxygen supply and demand leads to the death of myocardial tissue. Coronary atherosclerosis is an essential part of the process in most patients. Ischemic heart disease seems to progress through a process of plaque rupture that transiently increases the amount of luminal impingement by the stenotic lesion. Infarction may occur when the plaque ruptures and leads to thrombosis, erosion of the plaque causes thrombosis, or when cardiac work exceeds the ability of the narrowed coronary artery to supply nutritive perfusion. Recent work suggests that inflammation may play a pivotal role in the genesis of plaque rupture.
Greater numbers of acute infarctions occur during the early morning hours (from 6:00 AM to 12:00 noon) than any other time of the day, suggesting that perhaps the increased catecholamine secretion associated with awakening or circadian changes in coagulation common in the early morning (eg, increases in type-1 plasminogen activator inhibitor [PAI-1]) may induce platelet aggregation and lead to thrombus formation. Beta-blockers reduce this propensity and psychiatric depression shifts this pattern back 6 h—as it does with other circadian patterns. In keeping with this pattern, most infarctions do not appear to be induced by exertion. When severe exertion or severe emotional distress does occur, it appears to induce a window of vulnerability for roughly an hour or two after the acute event in susceptible individuals.
In general, patients with acute infarction tend to be males in their 50s and 60s, although infarction in elderly women in their 70s and older is now equally common. Indeed, acute infarction is now equal in incidence between women and men. Most often, those individuals have risk factors for the development of coronary artery disease, such as an increased cholesterol, diabetes, hypertension, cigarette smoking, a sedentary life-style, or a family history of early coronary artery disease. These risks are not present in all patients, however, and the absence of risk factors does not eliminate the possibility of infarction. This is especially true with the increasing prevalence of drug abuse. In patients who have AMI without apparent risk factors, an evaluation for the presence of novel risk factors, such as homocysteine, lipoprotein(a), small dense low-density lipoprotein (LDL), and markers of inflammation such as C-reactive protein and phospholipase A2 is warranted.
A. TOTAL THROMBOTIC OCCLUSION

In many patients (roughly 50%), total thrombotic occlusion is superimposed on the atherosclerotic plaque. The occlusion is thought to develop in response to plaque rupture when the luminal diameter of the coronary artery is sufficiently reduced to initiate clot formation or if erosion of the plaque causes exposure of procoagulant factors. Procoagulant factors (such as tissue factor) reside within the plaque itself and the absence of counterbalancing antithrombotic factors (eg, heparin, tissue-factor-inhibitor) and fibrinolytic activities (tissue plasminogen activator [t-PA] and single-chain urokinase-type plasminogen activator) within the endothelial cells of the coronary artery can cause thrombosis. Total thrombotic occlusion occurs most commonly in proximal coronary arteries; its presence has been documented during the first 4 h after infarction in more than 85% of patients who present with ST segment elevation (Figure 5–1). Most patients who present in this manner subsequently develop Q waves. A similar type of myocardial insult occurs occasionally despite angiographically normal coronary arteries and is caused by emboli (eg, in patients with prosthetic valves or those with endocarditis), dissection of the coronary artery (most commonly in pregnant women), or on rare occasions, coronary vasospasm. It can also be caused by thrombosis in situ, the probable mechanism by which patients who have variant angina or who abuse cocaine can suffer acute infarction. In these cases, vasoconstriction secondary to endothelial dysfunction and a propensity to thrombosis is of sufficient magnitude and duration to cause thrombus formation. Oxygen consumption and possibly direct myocyte toxicity also increase with cocaine use. In addition, thrombosis in situ can apparently cause infarction among women who take estrogens (especially if they smoke).

Figure 5–1. Incidence of total occlusion in patients with acute myocardial infarction. Reproduced, with permission, from DeWood MA, Spores J, Notske R et al: Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med 1980;303:897.

B. NON-Q WAVE INFARCTION

The remainder of infarctions occur generally in the absence of total thrombotic occlusion. The term non-Q wave infarction is used because the infarction is not associated with the development of new Q waves on the electrocardiogram. (This term is preferred to nontransmural infarction because no correlation has been found between Q waves and the presence of infarction through all levels of the ventricle). The frequency of this type of infarction is increasing because of the use of newer more sensitive and specific markers such as the troponins to detect small events.
Although, overall, the coronary anatomy of patients with non-Q wave infarctions is virtually identical to that of patients with Q wave infarctions, the incidence of documented total thrombotic occlusion during the initial 24 h after presentation with non-Q wave infarctions is only 29%.
Some clinicians believe that non-Q wave infarction is caused by small clots that dissolve prior to investigation, leaving only an open artery to be detected. Evidence for this includes an early rise in both the total and the MB isoenzyme of creatine kinase (CK2) and the finding of contraction-band necrosis (a sign of calcium overload commonly seen after reperfusion). The rapidity of the rise and fall of marker proteins and the presence of contraction bands are related to coronary blood flow, however, and continued antegrade flow could also be responsible. Because smaller infarctions also tend to have earlier times to peak CK concentrations, early enzyme peaking could represent a small infarction or the presence of antegrade coronary flow rather than spontaneous coronary recanalization.
Nonetheless, abundant data confirm that thrombosis is common in such patients if diagnosed by an elevated troponin level, especially if concomitant ST depression is present. There are other pathophysiologic possibilities for non-Q wave infarctions. An imbalance of myocardial oxygen supply and demand could be the result of a prolonged increase in myocardial work and oxygen consumption in the distribution of a coronary artery unable to increase its blood flow because of atherosclerosis or endothelial dysfunction. The coronary artery could also constrict abnormally and cause a similar imbalance. Small amounts of vasoconstriction can cause major changes in the cross-sectional area of a vessel since A = pr2.
Patients with non-Q wave infarction and partial coronary occlusion are at increased risk for subsequent total occlusion and recurrent infarction during the hospital course and in the weeks and months following the event. After the first few days, although these infarctions are smaller, mortality rates increase more rapidly than in patients with Q wave infarctions because of the greater number of recurrent events. By 6 months, mortality rates are similar to those for patients with Q wave infarctions. However, it is now clear that invasive interventions such as stenting with the assistance of potent anticoagulant modalities such as IIB/IIIA antiplatelet agents and low-molecular-weight heparins (LMWH) can reduce these subsequent events.
Non-Q wave infarction is often seen when other medical illnesses coexist with ischemic heart disease. Pulmonary embolism, septic shock, severe anemia, or even great emotional distress can increase myocardial oxygen demand, reduce coronary perfusion pressure, or evoke paradoxical coronary artery responses and lead to non-Q wave infarction.
Regardless of the cause, the process of myocyte death occurs as a wavefront. It is clear that by 20 min after occlusion (in animal models and likely in humans) some myocytes have died. Then the infarction spreads, usually from the subendocardium toward the epicardium. In experimental animals, infarction is complete in 3–4 h, and it is difficult to save myocardium after that time. In human patients, the time window for myocardial salvage is less clear because the time of onset is more difficult to delineate. Some antegrade flow may occur in many coronary arteries from subtotal occlusion or transient constriction and relaxation of the affected vessel, or myocyte viability may be sustained by collateral perfusion from other vessels. There appears to be some time (in general, perhaps as long as 12 h, and in some patients possibly even longer) during which it may be possible to modify the extent of the myocardial injury by increasing blood flow to the infarct area.

treatment chronic myiocard ischemic

2008-06-25T07:27:00.000-07:00

A. GENERAL APPROACH

Because myocardial ischemia is produced by an imbalance between myocardial oxygen supply and demand, in general, treatment consists of increasing supply or reducing demand—or both. Heart rate is a major determinant of myocardial oxygen demand, and attention to its control is imperative. Any treatment that accelerates heart rate is generally not going to be efficacious in preventing myocardial ischemia. Therefore, care must be taken with potent vasodilator drugs, which may lower blood pressure and induce reflex tachycardia. Furthermore, because most coronary blood flow occurs during diastole, the longer the diastole, the greater the coronary blood flow; and the faster the heart rate, the shorter the diastole.
Blood pressure is another important factor: Increases in blood pressure raise myocardial oxygen demand by elevating left ventricular wall tension, and blood pressure is the driving pressure for coronary perfusion. A critical blood pressure is required that does not excessively increase demand, yet keeps coronary perfusion pressure across stenotic lesions optimal. Unfortunately, it is difficult to tell in any given patient what this level of blood pressure should be, and a trial-and-error approach is often needed to achieve the right balance. Consequently, it is prudent to reduce blood pressure when it is very high, and it may be important to allow it to increase when it is very low. It is not uncommon to encounter patients whose myocardial ischemia has been so vigorously treated with a combination of pharmacologic agents that their blood pressure is too low to be compatible with adequate coronary perfusion. In such patients, withholding some of their medications may actually improve their symptoms. Although myocardial contractility and left ventricular volume also contribute to myocardial oxygen demand, they are less important than heart rate and blood pressure. Myocardial contractility usually parallels heart rate. Attention should be paid to reducing left ventricular volume in anyone with a dilated heart, but not at the expense of excessive hypotension or tachycardia because these factors are more important than volume for determining myocardial oxygen demand.
It is important to eliminate any aggravating factors that could increase myocardial oxygen demand or reduce coronary artery flow (Table 3–3). Hypertension and tachyarrhythmias are obvious factors that need to be controlled. Thyrotoxicosis leads to tachycardia and increases in myocardial oxygen demand. Anemia is a common problem that increases myocardial oxygen demand because of reflex tachycardia; it reduces oxygen supply by decreasing the oxygen-carrying capacity of the blood. Similarly, hypoxia from pulmonary disease reduces oxygen delivery to the heart. Heart failure increases angina because it often results in left ventricular dilatation, which increases wall stress, and in excess catecholamine tone, which increases contractility and produces tachycardia.

Table 3–3. Factors that can aggravate myocardial ischemia.

The long-term outlook for patients with coronary atherosclerosis must be addressed by reducing their risk factors for the disease. Once a patient is known to have atherosclerosis, risk-factor reduction should be fairly vigorous: If diet has not reduced serum cholesterol, strong consideration should be given to pharmacologic therapy because it has been shown to reduce cardiac events. Patients should be encouraged to exercise, lose weight, quit smoking, and try to reduce stress levels. Daily low-dose aspirin is important for preventing coronary thrombosis. The use of megadoses of vitamin E, b-carotene, and vitamin C should be discouraged in the patient with known coronary atherosclerosis because clinical trials have not demonstrated efficacy.
B. PHARMACOLOGIC THERAPY

1. Nitrates—Nitrates, which work on both sides of the supply-and-demand equation, are the oldest drugs used to treat angina pectoris (Table 3–4). These agents are now available in several formulations to fit the patient’s lifestyle and disease characteristics. Almost all patients with known coronary atherosclerosis should carry sublingual nitroglycerin to abort acute attacks of angina pectoris. Nitrates work principally by providing more nitrous oxide to the vascular endothelium and the arterial smooth muscle, resulting in vasodilation. This tends to ameliorate any increased coronary vasomotor tone and dilate coronary obstructions. As long as blood pressure does not fall excessively, nitrates increase coronary blood flow. Nitrates also cause venodilation, reducing preload and decreasing left ventricular end-diastolic volume. The reduced left ventricular volume decreases wall tension and myocardial oxygen demand.

Table 3–4. Common oral antianginal drugs.

Sublingual nitroglycerin takes 30–60 s to dissolve completely and begin to produce beneficial effects, which can last up to 30 min. Although most commonly used to abort acute attacks of angina, the drug can be used prophylactically if the patient can anticipate its need 30 min prior to a precipitating event. Prophylactic therapy is best accomplished, however, with longer acting nitrate preparations. Isosorbide dinitrate and mononitrate are available in oral formulations; each produces beneficial effects for several hours. Large doses of these agents must be taken orally to overcome nitrate reductases in the liver. Liver metabolism of the nitrates can also be avoided with cutaneous application. Nitroglycerin is available as a topical ointment that can be applied as a dressing; it is also available as a ready-made, self-adhesive patch that delivers accurate continuous dosing of the drug through a membrane. Although the paste and the patches produce similar effects, the patches are more convenient for patients to use.
Sublingual nitroglycerin tablets are extremely small and difficult for patients with arthritis to manipulate. A buccal preparation of nitroglycerin is available, which comes in a larger, more easily manipulable tablet that can be chewed and allowed to dissolve in the mouth, rather than being swallowed. This achieves nitrate effectiveness within 2–5 min and lasts about 30 min, as do the sublingual tablets. An oral nitroglycerin spray, which may be easier to manipulate and more convenient for some patients, is also available.
The major difficulty with all long-acting nitroglycerin preparations is the development of tolerance to their effects. The exact reason for tolerance development is not clearly understood, but it may involve liver enzyme induction or a lack of arterial responsiveness because of local adaptive factors. Regardless of the mechanism, however, round-the-clock nitrate administration will lead to progressively increasing tolerance to the drug after 24–48 h. Because of this, nitroglycerin is usually taken over the 16-h period each day that corresponds to the time period during which most of the ischemic episodes would be expected to occur. For most patients, this means not taking nitrate preparations before bed and allowing the ensuing 8 h for the effects to wear off and responsiveness to the drug to be regained. This timing would have to be adjusted for patients with nocturnal angina. The difficulty with the 8-h overnight hiatus in therapy, however, is that the patient has little protection during the critical early morning wakening period—when ischemic events are more likely to occur. Patients should therefore take the nitrate preparation as soon as they arise in the morning. For this reason, the nitroglycerin patches have a small amount of paste on the outside of the membrane that delivers a bolus of drug through the skin, which quickly elevates the patient’s blood level of the drug. It is important that the patient be careful not to wipe this paste off the patch before applying it.
Nitrates, which are effective in preventing the development of angina as well as aborting acute attacks, are helpful in both patients with fixed coronary artery occlusions and those with vasospastic angina. Their potency, compared with other agents, is limited, however, and patients with severe angina often must turn to other agents. In such patients, nitrates can be excellent adjunctive therapy.
2. Beta-blockers—Beta-adrenergic blocking agents are highly effective in the prophylactic therapy of angina pectoris. They have been shown to reduce or eliminate angina attacks and prolong exercise endurance time in double-blind, placebo-controlled studies. They can be used around the clock because no tachyphylaxis to their effects has been found. Beta-blockers mainly work by lowering myocardial oxygen demand through decreasing heart rate, blood pressure, and myocardial contractility. As mentioned earlier, however, they also increase myocardial oxygen supply by increasing the duration of diastole through heart rate reduction. Currently, several b-blocker preparations are available, with one or more features that may make them more—or less—attractive for a particular patient.
Among these features is the agent’s pharmacologic half-life, which ranges from 4 to 18 h. Various delivery systems have been developed to slow down the delivery of short-acting agents and prolong the duration of drug activity through sustained release or long-acting formulations. Note that the pharmacodynamic half-life of b-adrenergic blockers is often longer than their pharmacologic half-life, and drug effects can be detected for days after discontinuation of chronic b-blocker therapy.
Ideally, b-blockers should be titrated against the heart rate response to exercise because blunting of the exercise heart rate response is the hallmark of their efficacy. Adverse effects of b-blockers include such expected pharmacologic effects as excessive bradycardia, heart block, hypotension, and—in susceptible individuals—bronchospasm. This is less commonly found in the b1-selective agents. Blocking b2-peripheral vasodilatory actions may aggravate claudication in patients with severe peripheral vascular disease. Beta-adrenergic stimulation is also important for the gluconeogenic response to hyperglycemia in severely insulin-dependent diabetics. Although b-blockers may impair this response, the major problem with their use in insulin-dependent diabetics is that they block the warning signals of hypoglycemia (sweating, tachycardia, piloerection) to the patient. Because of their negative inotropic properties, b-blockers may also precipitate heart failure in patients with markedly reduced left ventricular performance.
Other side effects of b-blockers are less predictably related to their anti-b-adrenergic effects. Adverse central nervous system effects are especially troublesome and include fatigue, mental slowness, and impotence. These side effects are somewhat less common with agents that are less lipophilic, such as atenolol and nadolol. Unfortunately, it is these side effects that make many patients unable to tolerate b-blockers.
3. Calcium channel antagonists—Calcium channel antagonists theoretically work on both sides of the supply-and-demand equation. By blocking calcium access to smooth muscle cells, they produce peripheral vasodilatation and are effective antihypertensive agents. In the myocardium, they block sinus node and atrioventricular node function and reduce the inotropic state. They dilate the coronary arteries and increase myocardial blood flow. The calcium blockers available today produce a variable spectrum of these basic pharmacologic effects. The biggest group is the dihydroperidine calcium blockers, which are potent arterial dilators and thereby cause reflex sympathetic activation, which overshadows their negative chronotropic and inotropic effects.
A second major group of calcium blockers are the heart rate-lowering calcium blockers. Because these drugs have less peripheral vasodilatory action in individuals with normal blood pressure, they produce little reflex tachycardia. The average daily heart rate is usually reduced with these agents because their inherent negative chronotropic effects are not suppressed; negative inotropic effects are also more common with these agents. Hypertensive and normotensive individuals seem to have a different vascular responsiveness to calcium blockers; interestingly, in hypertensive individuals, they lower the blood pressure as well as do the dihydroperidine agents. The two most commonly used drugs in this class are diltiazem and verapamil. Diltiazem is more widely used because of its low side effect profile. Verapamil, which is an excellent treatment for patients with supraventricular arrhythmias, has potent effects on the arteriovenous (AV) node; this can cause excessive bradycardia and heart block in patients with angina pectoris. Verapamil is also more likely than diltiazem to precipitate heart failure, and it often produces troublesome constipation, especially in elderly individuals. All the calcium blockers can produce peripheral edema. This is due not to their negative inotropic effects but rather to an imbalance between the efferent and afferent peripheral arteriolar tone, which increases capillary hydrostatic pressure. Other adverse effects of these drugs are idiosyncratic and include gastrointestinal and dermatologic effects.
Calcium blockers are titrated to the patient’s symptomatology because no physiologic marker of their effect corresponds well to the heart rate response to exercise with b-blockers. This makes choosing the appropriate dosage difficult, and many physicians increase the dose until some side effect occurs, and then they reduce it. The most common side effects are related to the pharmacologic effects of the drugs. With the dihydroperidines, vasodilatory side effects such as orthostatic hypotension, flushing, and headache, occur. Hypotension is less common with the heart rate-lowering calcium blockers, and their side effects are more related to cardiac effects such as excessive bradycardia. These drugs are very useful because they are excellent for preventing angina pectoris, lowering high blood pressure, and, in the case of the heart rate-lowering agents, controlling supraventricular arrhythmias.
4. Combination therapy—Although monotherapy is desirable for patient convenience and cost considerations, many patients, especially those with severe inoperable coronary artery disease, require more than one antianginal agent to control their symptoms. Because all antianginal agents have a synergistic effect in preventing angina, the initial choices should be for agents with complementary pharmacologic effects. For example, nitrates can be added to b-blocker therapy: Nitrates have an effect on dilating coronary arteries and increasing coronary blood flow, and their peripheral effects may increase reflex sympathetic tone and counteract some of the negative inotropic and chronotropic effects of the b-blockers. This has proved to be a highly effective combination. Similarly, combining a b-blocker with dihydroperidine drugs, when the b-blockers suppress the reflex tachycardia produced by the dihydroperidine, has also proved to be highly effective. Combinations of the heart rate-lowering calcium blockers and nitrates have also proved efficacious. Extremely refractory patients may respond to the combination of a dihydroperidine calcium blocker and a heart rate-lowering calcium blocker.
Combining a dihydroperidine calcium blocker and nitrates makes little sense, however, because of the high likelihood of producing potent vasodilatory side effects. This combination may excessively lower blood pressure to the point that coronary perfusion pressure is compromised and the patient’s angina actually worsens. In fact, in as many as 10% of patients with moderately severe angina, both the nitrates and the dihydroperidine calcium blockers alone have been reported to aggravate angina. Although few corroborative data exist, this percentage is certainly higher with the combination of the two agents.
The most difficult cases often involve triple therapy, with a calcium blocker, a b-blocker, and a nitrate. Although there are few objective data on the benefits of this approach, it has proven efficacious in selected patients. The major problem with triple therapy is that side effects, such as hypotension, are increased, which often limits therapy.
Gibbons RJ, Chaterjee K, Daley J et al: ACC/AHA/ACP-ASIM Guidelines for the management of patients with chronic stable angina: A report of the American College of Cardiology/American Heart Association task force on practice guidelines (Committee on Management of Patients with Chronic Stable Angina). J Am Coll Cardiol 1999;3:2092.
Opie LH: Calcium channel antagonists in the treatment of coronary artery disease: fundamental pharmacological properties relevant to clinical use. Prog Cordiovasc Dis 1996;38:273.
Pitt B, Waters D, Brown WV et al. Aggressive lipid-lowering therapy compared with angioplasty in stable coronary artery disease. N Engl J Med 1999;341:70–76.
Thadani U: Management of stable angina pectoris. Prog Cardiovasc Dis1999;14:349–358.
C. REVASCULARIZATION

1. Catheter-based methods—The standard percutaneous coronary intervention (PCI) is balloon dilatation with placement of a metal stent. Such treatment is limited to the larger epicardial arteries and can be complicated by various types of acute vessel injury, which can result in myocardial infarction unless surgical revascularization is immediately employed. Smaller arteries may be amenable to plain old balloon angioplasty (POBA), and large arteries with complicated lesions may be candidates for other forms of PCI. PCI requires intense antiplatelet therapy usually with aspirin and clopidogrel for a month to prevent stent thrombosis. After the stent has been covered with endothelium this risk is much less.
In the absence of acute complications, initial success rates for significantly dilating the coronary artery are > 85%, and the technique can be of tremendous benefit to patients—without their undergoing the risk of cardiac surgery. The principal disadvantage to PCI is restenosis, which occurs in about one-fourth of patients during the first 6 months. Repeat PCI can be as effective as initial PCI, but, again, the restenosis rate remains around one fourth; however, a second PCI can result in a long-term success. Although many agents are under intense investigation, there is currently no pharmacologic approach to preventing restenosis.
PCI is ideal for symptomatic patients with one or two discrete lesions in one or two arteries. In patients with more complex lesions or those with three or more vessels involved bypass surgery is preferable for several reasons. First, the restenosis risk is the same for each lesion treated by PCI, so that if enough vessels are worked on the risk of restenosis in one of them will approach 100%. Second, the ability to completely revascularize patients with multivessel disease is less with PCI compared with bypass surgery. Finally, clinical trials have shown that diabetics have better outcomes after bypass surgery relative to PCI.
2. Coronary artery bypass graft surgery—Controlled clinical trials have shown that coronary artery bypass graft (CABG) surgery can successfully alleviate angina symptoms in up to 80% of patients. These results compare very favorably with pharmacologic therapy and catheter-based techniques and can be accomplished in selected patients with less than 2% operative mortality rates. Although the initial cost of surgery is high, studies have shown it can be competitive with repeated angioplasty and lifelong pharmacologic therapy in selected patients.
The standard surgical approach is to use the saphenous veins, which are sewn to the ascending aorta and then, distal to the obstruction, in the coronary artery, effectively bypassing the obstruction with blood from the aorta. Although single end-to-side saphenous-vein-to-coronary-artery grafts are preferred, occasionally surgeons will do side-to-side anastomoses in one coronary artery (or more) and then terminate the graft in an end-to-side anastomosis in the final coronary artery. There is some evidence that although these skip grafts are easier and quicker to place than multiple single saphenous grafts, they may not last as long. The major problem with saphenous vein grafts is recurrent atherosclerosis in the grafts, which is often quite bulky and friable, and ostial stenosis, probably from cicatrization at the anastomotic sites. Although these problems can be approached with PCI and other interventional devices, the success rate of catheter-delivered devices to open obstructed saphenous vein grafts is not as high as that seen with native coronary artery obstructions, and many patients require repeat saphenous vein grafting after an average of about 8 years. It is believed that meticulous attention to a low-fat diet, cessation of smoking, and the ingestion of one aspirin a day (80–325 mg) will retard the development of saphenous vein atherosclerosis; some patients do well for 20 years or more after CABG.
There is now considerable evidence that arterial conduits make better bypass graft materials. The difficulty is finding large enough arteries that are not essential to other parts of the body. The most popular arteries used today are the internal thoracic arteries. Their attachment to the subclavian artery is left intact, and the distal end is used as an end-to-side anastomosis into a single coronary artery. If a patient requires more than two grafts, some surgeons, rather than using a saphenous vein, have employed the radial artery or abdominal vessels, such as the gastroepiploic. There are less data on these alternative conduits, but theoretically they would have the same advantages as the internal thoracic arteries in terms of graft longevity. Efforts at preventing bypass graft failure are worthwhile because the risk of repeat surgery is usually higher than that of the initial surgery. There are several reasons for this, including the fact that the patient is older, the scar tissue from the first operation makes the second one more difficult, and finally, any progression of atherosclerosis in the coronary arteries makes finding good-quality insertion sites for the graft more difficult.
D. SELECTION OF THERAPY

Pharmacologic therapy is indicated when other conditions may be aggravating angina pectoris and can be successfully treated. For example, in the patient with coexistent hypertension and angina, it is often prudent to treat the hypertension and lower blood pressure to acceptable levels before pursuing revascularization for angina, because lowering the blood pressure will often eliminate the angina. For this purpose, it is wise to use antihypertensive medications that are also antianginal (eg, b-blockers, calcium channel blockers) rather than other agents with no antianginal effects (eg, angiotensin-converting enzyme (ACE) inhibitors, centrally acting agents). The presence of heart failure can also produce or aggravate angina, and this should be treated. Care must be taken in choosing antianginal drugs that they do not aggravate heart failure. For this reason, nitrates are frequently used in heart failure and angina because these drugs may actually benefit both conditions. Calcium channel blockers should be avoided if the left ventricular ejection fraction is below 35%, unless it is clear that the heart failure is episodic and is being produced by ischemia. In this situation, however, revascularization may be a more effective strategy. Beta-blockers can be effective, but they must be started at low doses and uptitrated carefully. Although beta blockers are now part of standard therapy for heart failure, there is little data on their use in patients with angina and reduced left ventricular performance. Finally, the presence of ventricular or supraventricular tachyarrhythmias may aggravate angina. Rhythm disorders also afford an opportunity for using dual-purpose drugs. The heart rate-lowering calcium blockers may effectively control supraventricular arrhythmias and also benefit angina. Beta-blockers can often be effective treatment for ventricular arrhythmias in patients with coronary artery disease and should be tried before other, more potent antiarrhythmics or devices are contemplated. Keep in mind that digoxin blood levels may be increased by concomitant treatment with calcium blockers. In addition, the combination of digoxin and either heart rate-lowering calcium blockers or b-blockers may cause synergistic effects on the AV node and lead to excessive bradycardia or heart block.
The major indication for revascularization of chronic ischemic heart disease is the failure of medications to control the patient’s symptoms. Drug-refractory angina pectoris is the major indication for revascularization. Note that myocardial ischemia should be established as the source of the patient’s symptoms before embarking on revascularization, lest one find out after revascularization that the symptoms were actually due to gastroesophageal reflux. Consequently, some form of stress testing that verifies the relationship between demonstrable ischemia and symptoms is advisable before performing any revascularization procedure.
In some other instances—patient preference, for example—revascularization therapy might be considered before even trying pharmacologic therapy. Some patients do not like the prospect of lifelong drug therapy and would rather have open arteries. Although this is a valid reason to perform revascularization, the physician must be careful that his or her own enthusiasm for revascularization as treatment does not pressure the patient into such a decision. Other candidates for direct revascularization are patients with high-risk occupations who cannot return to these occupations unless they are completely revascularized (eg, airline pilots).
Revascularization is preferred to medical therapy in managing certain types of coronary anatomy that are known (through clinical trials) to have a longer survival if treated with CABG rather than medically. Such lesions include left main obstructions of more than 50%, three-vessel disease, and two-vessel disease in which one of the vessels is the left anterior descending artery. Currently, left main stenoses are not effectively treated with catheter-based techniques, but two- and three-vessel coronary disease could potentially be treated by PCI. Clinical trials have shown equivalent long-term outcomes between PCI and CABG in patients with multivessel disease.
CABG is also recommended for patients with two- or three-vessel coronary artery disease and resultant heart failure from reduced left ventricular performance, especially if viable myocardium can be demonstrated. Because the tests for viable myocardium are not perfect, however, many physicians believe that all these patients should be revascularized in the hope that some myocardial function will return. This seems a prudent approach, given that donor hearts for cardiac transplantation are difficult to obtain—and many patients with heart failure and coronary artery disease improve following bypass surgery.
Surgery is also recommended when the patient has a concomitant disease that requires surgical therapy, such as significant valvular heart disease, heart failure in the presence of a large left ventricular aneurysm, or mechanical complications of myocardial infarction, such as a ventricular septal defect. In the presence of hemodynamic indications for repairing these problems, any significant coronary artery disease that is found should be corrected with bypass surgery at the same time.
The risk of bypass surgery in a given individual must also be considered because several factors can increase the risk significantly and might make catheter-based techniques or medical therapy more desirable. Age is always a risk factor for any major surgery, and CABG is no exception. Also, female gender tends to increase the risk of CABG, possibly because women are, on the average, smaller and have smaller arteries than men. Some data indicate that if size is the only factor considered, gender disappears as a risk predictor with CABG. Other medical conditions that may complicate the perioperative period (eg, obesity, lung disease, diabetes) also raise the risks of surgery. Another factor (discussed earlier) is whether this is a repeat bypass operation. The technical difficulties are especially troublesome when a prior internal thoracic artery graft has been placed because this artery lies right behind the sternum and can be easily compromised when opening the chest.
The choice between catheter-based techniques and CABG surgery is based on several considerations: Is it technically feasible to perform either technique with a good anticipated result? What does the patient wish to do? The patient may have a strong preference for one technique over the other. Again, the physician must be careful not to unduly influence the patient in this regard, lest it give the appearance of a conflict of interest. Consideration must also be given to factors that increase the risk of surgery. The most difficult decision involves the patient who is suitable for either surgery or a catheter-based technique. The few controlled, randomized clinical trials that have been done on such patients have shown equivalent clinical results with PCI and surgery in terms of mortality and symptom relief. Note that this is accomplished by PCI at the cost of repeated procedures in many patients. Despite the necessity for these repeated procedures, the overall cost of bypass surgery is higher over the short term. Unfortunately, the trials do not leave us with clear guidelines for choosing PCI or CABG in the patient who is a good candidate for either treatment; this continues to be a decision to be made by the physician and the patient on a case-by-case basis.

CHRONIC ISCHEMIC HEART DISEASE

2008-06-25T07:19:00.000-07:00

General Considerations
For clinical purposes, patients with chronic ischemic heart disease fall into two general categories: those with symptoms related to the disease, and those who are asymptomatic. Although the latter are probably more common than the former, physicians typically see symptomatic patients more frequently. The issue of asymptomatic patients becomes important clinically when physicians are faced with estimating the risk to a particular patient who is undergoing some stressful intervention, such as major noncardiac surgery. Another issue is the patient with known coronary artery disease who is currently asymptomatic. Such individuals, especially if they have objective evidence of myocardial ischemia, are known to have a higher incidence of future cardiovascular morbidity and mortality. There is, understandably, a strong temptation to treat such patients, despite the fact that it is difficult to make an asymptomatic patient feel better, and some of the treatment modalities have their own risks. In such cases, strong evidence that longevity will be positively influenced by the treatment must be present in order for its benefits to outweigh its risks.
Pathophysiology & Etiology
In the industrialized nations, most patients with chronic ischemic heart disease have coronary atherosclerosis. Consequently, it is easy to become complacent and ignore the fact that other diseases can cause lesions in the coronary arteries (Table 3–1). In young people, coronary artery anomalies should be kept in mind; in older individuals, systemic vasculitides are not uncommon. Today, collagen vascular diseases are the most common vasculitides leading to coronary artery disease, but in the past, infections such as syphilis were a common cause of coronary vasculitis. Diseases of the ascending aorta, such as aortic dissection, can lead to coronary ostial occlusion. Coronary artery emboli may occur as a result of infectious endocarditis or of atrial fibrillation with left atrial thrombus formation. Infiltrative diseases of the heart, such as tumor metastases, may also compromise coronary flow. It is therefore essential to keep in mind diagnostic possibilities other than atherosclerosis when managing chronic ischemic heart disease.

Table 3–1. Nonatherosclerotic causes of epicardial coronary artery obstruction.

Myocardial ischemia is the result of an imbalance between myocardial oxygen supply and demand. Coronary atherosclerosis and other diseases reduce the supply of oxygenated blood by obstructing the coronary arteries. Although the obstructions may not be enough to produce myocardial ischemia at rest, increases in myocardial oxygen demand during activities can precipitate myocardial ischemia. This is the basis for using stress testing to detect ischemic heart disease. Some patients may develop transient increases in the degree of coronary artery obstruction as a result of platelet and thrombus formation or through increased coronary vasomotor tone. Although it is rare in the United States, pure coronary vasospasm in the absence of atherosclerosis can occur and cause myocardial ischemia and even infarction. In addition, in the presence of other cardiac diseases, especially those that cause a pressure load on the left ventricle, myocardial oxygen demand may outstrip the ability of normal coronary arteries to provide oxygenated blood, resulting in myocardial ischemia or infarction. A good example would be the patient with severe aortic stenosis, considerable left ventricular hypertrophy, and severely elevated left ventricular pressures who tries to exercise. The manifestations of chronic ischemic heart disease thus have their basis in a complex pathophysiology of multiple factors that affect the myocardial oxygen supply and demand.
Clinical Findings
A. CLINICAL MILIEU

Coronary atherosclerosis is more likely to occur in patients with certain risk factors for this disease (Table 3–2). These include advanced age, male gender or the postmenopausal state in females, a family history of coronary atherosclerosis, diabetes mellitus, systemic hypertension, high serum cholesterol and other associated lipoprotein abnormalities, and tobacco smoking. Additional minor risk factors include a sedentary lifestyle, obesity, high psychologic stress levels, and such phenotypic characteristics as earlobe creases, auricular hirsutism, and a mesomorphic body type. The presence of other systemic diseases—hypothyroidism, pseudoxanthoma elasticum, and acromegaly, for example—can accelerate a propensity to coronary atherosclerosis. In the case of nonatherosclerotic coronary artery disease, evidence of such systemic vasculitides as lupus erythematosus, rheumatoid arthritis, and polyarthritis nodosa should be sought. Although none of these risk factors is in itself diagnostic of coronary artery disease, the more of them are present, the greater the likelihood of the diagnosis.

Table 3–2. Risk factors for coronary heart disease.

B. SYMPTOMS

The major symptom of chronic ischemic heart disease is angina pectoris, with a clinical diagnosis based on five features:

The character of the pain is a deep visceral pressure or squeezing sensation, rather than sharp or stabbing or pinprick-like pain.

The pain almost always has some substernal component, although some patients complain of pain only on the right or left, back, or epigastrium.

The pain may radiate from the thorax to the jaw, neck, or arm. Arm pain in angina pectoris typically involves the ulnar surface of the left arm. Occasionally, the radiated pain may be more noticeable to the patient than the origin of the pain, resulting in complaints of only jaw or arm pain. These considerations have led some physicians to suggest that any pain between the umbilicus and the eyebrows should be considered angina pectoris until proven otherwise.

Angina is usually precipitated by exertion, emotional upset, or other events that obviously increase myocardial oxygen demand, such as rapid tachyarrhythmias or extreme elevations in blood pressure.

Angina pectoris is transient, lasting between 2 and 30 min. It is relieved by cessation of the precipitating event, such as exercise, or by the administration of treatment, such as sublingual nitroglycerin. Chest pain that lasts longer than 30 min is more consistent with myocardial infarction; pain of less than 2 min is unlikely to be due to myocardial ischemia.
For reasons that are unclear, some patients with chronic ischemic heart disease do not manifest typical symptoms of angina pectoris but have other symptoms that are brought on by the same precipitating factors and are relieved in the same way as angina. Because myocardial ischemia can lead to transient left ventricular dysfunction, resulting in increased left ventricular end-diastolic pressure and consequent pulmonary capillary pressure, the sensation of dyspnea can occur during episodes of myocardial supply-and-demand imbalance. Dyspnea may be the patient’s only symptom during myocardial ischemia, or it may overshadow the chest pain in the patient’s mind. Therefore, dyspnea out of proportion to the degree of exercise or activity can be considered an angina equivalent. Severe myocardial ischemia may lead to ventricular tachyarrhythmias manifesting as palpitations or even frank syncope. Severe episodes of myocardial ischemia may also lead to transient pulmonary edema, especially if the papillary muscles are involved in the ischemic myocardium and moderately severe mitral regurgitation is produced. The most dramatic result of myocardial ischemia is sudden cardiac death.
Patients with chronic myocardial ischemia can also present with symptoms caused by the effects of repeated episodes of ischemia or infarction. Thus, patients may present with the manifestations of chronic cardiac rhythm disorders, especially ventricular arrhythmias. They may present with chronic congestive heart failure, or they may have symptoms related to atherosclerosis of other vascular systems. Patients with vascular disease in other organs are more likely to have coronary atherosclerosis. Those with prior cerebral vascular accidents or symptoms of peripheral vascular disease may be so disabled by these diseases that their ability to either perceive angina or generate enough myocardial oxygen demand to produce angina may be severely limited.
C. PHYSICAL EXAMINATION

The physical examination is often not helpful in the diagnosis of chronic ischemic heart disease. This is because many patients with chronic ischemic heart disease have no physical findings related to the disease, or if they do, the findings are not specific for coronary artery disease. For example, a fourth heart sound can be detected in patients with chronic ischemic heart disease, especially if they have had a prior myocardial infarction; however, fourth heart sounds are very common in hypertensive heart disease, valvular heart disease, and primary myocardial disease. Palpation of a systolic precordial bulge can occur in patients with prior myocardial infarction, but this sign is not specific and can occur in patients with left ventricular enlargement from any cause. Other signs can also be found in cases of chronic ischemic heart disease, such as those associated with congestive heart failure or mitral regurgitation. Again, these are nonspecific and can be caused by other disease processes. Because coronary atherosclerosis is the most common heart disease in industrialized nations, any physical findings suggestive of heart disease should raise the suspicion of chronic ischemic heart disease.
D. DIAGNOSTIC STUDIES

1. Stress tests—Because angina pectoris or other manifestations of myocardial ischemia often occur during the patient’s normal activities, it would be ideal to detect evidence of ischemia at that time. This can be done with ambulatory electrocardiogram (ECG). Under unusual circumstances, a patient may have spontaneous angina or ischemia in a medical facility, where it is possible to inject a radionuclide agent and immediately image the myocardium for perfusion defects. Detection of myocardial ischemia during a patient’s normal activities, however, does not have as high a diagnostic yield as exercise stress testing does.
Of the various forms of exercise stress that can be used, the most popular is treadmill exercise, for several reasons: It involves walking, a familiar activity that often provokes symptoms. Because of the gravitational effects of being upright, walking requires higher levels or myocardial oxygen demand than do many other forms of exercise. In addition, walking can be performed on an inexpensive treadmill device, which makes evaluating the patient easy and cost-effective. Bicycling is an alternative form of exercise that is preferred by exercise physiologists because it is easier to quantitate the amount of work the person is performing on a bicycle than on a treadmill. Unfortunately, bicycle exercise does not require as high a level of myocardial oxygen demand as does treadmill walking. Thus, a patient may become fatigued on the bicycle before myocardial ischemia is induced, resulting in lower diagnostic yields. On the other hand, bicycle exercise can be performed in the supine position, which facilitates some myocardial ischemia detection methods such as echocardiography. In patients with peripheral vascular disease or lower limb amputations, arm and upper trunk rowing or cranking exercises can be substituted for leg exercise. Arm exercise has a particularly low diagnostic yield because exercising with the small muscle mass of the arms does not increase myocardial oxygen demand by much. Rowing exercises that involve the arms and the trunk muscles produce higher levels of myocardial oxygen demand that can equal those achieved with bicycle exercise—but not quite the levels seen with treadmill exercise. For these reasons, patients who cannot perform leg exercises are usually evaluated using pharmacologic stress testing.
There are two basic kinds of pharmacologic stress tests. One uses drugs, such as the synthetic catecholamine dobutamine, that mimic exercise; the other uses vasodilator drugs, such as dipyridamole and adenosine, that, by producing profound vasodilatation, increase heart rate and stroke volume, thereby raising myocardial oxygen demand. In addition, vasodilators may dilate normal coronary arteries more than diseased coronary arteries, augmenting any differences in regional perfusion of the myocardium, which can be detected by perfusion scanning. In general, vasodilator stress is preferred for myocardial perfusion imaging, and synthetic catecholamine stress is preferred for wall motion imaging.
2. Electrocardiography—Electrocardiography (ECG) is the most frequently used method for detecting myocardial ischemia because of its ready availability, low cost, and ease of application. The usual criterion for diagnosing ischemia is horizontal or down-sloping ST segment depression, achieving at least 0.1 mV at 80 ms beyond the J point (junction of the QRS and the ST segment). This criterion provides the highest values of sensitivity and specificity. Sensitivity can be increased by using 0.5 mV, but at the expense of lower specificity; similarly, using 0.2 mV increases the specificity of the test at the expense of lower sensitivity. Furthermore, accuracy is highest when ECG changes in the lateral precordial leads (V4, V5, V6) are used instead of the inferior leads (II, III, aVF). In the usual middle-aged, predominantly male population of patients with chest pain syndromes, who have normal resting ECGs and can achieve more than 85% of their maximal predicted age-based heart rate during treadmill exercise, the preceding ECG criteria have a sensitivity and specificity of approximately 85%. If the resting ECG is abnormal, if the patient does not achieve 85% of maximum predicted heart rate, or if the patient is a woman, the sensitivity and specificity are lower and range from 70% to 80%. In an asymptomatic population with a low pretest likelihood of disease, sensitivity and specificity fall below 70%.
3. Myocardial perfusion scanning—This method detects differences in regional myocardial perfusion rather than ischemia per se; however, there is a high correlation between abnormal regional perfusion scans and the presence of significant coronary artery occlusive lesions. Thus, when coronary arteriography is used as the gold standard, the sensitivity and specificity of stress myocardial perfusion scanning in the typical middle-aged, predominantly male population with symptoms are approximately 85–95%. Testing an asymptomatic or predominantly female population would result in lower values. Failure to achieve more than 85% of the maximal predicted heart rate during exercise also results in lower diagnostic accuracy. Although treadmill exercise is the preferred stress modality for myocardial perfusion imaging, pharmacologically induced stress with dipyridamole or adenosine produces nearly as good results and is an acceptable alternative in the patient who cannot exercise. Position emission tomography with vasodilator stress also can be used to detect regional perfusion differences indicative of coronary artery disease.
4. Assessing wall motion abnormalities—Reduced myocardial oxygen supply results in diminishment and, if severe enough, failure of myocardial contraction. Using methods to visualize the left ventricular wall, a reduction in inward endocardial movement and systolic myocardial thickening is observed with ischemia. Echocardiography is an ideal detection system for wall motion abnormalities because it can examine the left ventricle from several imaging planes, maximizing the ability to detect subtle changes in wall motion. Five percent of the time (or less), the image may not be adequate to ensure a high degree of accuracy. In the 95% of patients who can be adequately imaged, however, the results with either exercise or pharmacologic stress are comparable to those of myocardial perfusion imaging and superior to the ECG stress test detection of ischemia. The preferred pharmacologic detection method with wall motion imaging is dobutamine because it directly stimulates the myocardium to increase contractility, as well as raising heart rate and blood pressure and increasing myocardial oxygen demand. In some laboratories, if the heart rate increase is not comparable to that usually achieved with exercise testing, atropine is added to further increase myocardial oxygen demand. Magnetic resonance imaging can also be used to assess left ventricular wall motion during pharmacologic stress, but there is relatively little experience with this technique.
5. Evaluating global left ventricular performance—Myocardial ischemia, if profound enough, results in a reduction in global left ventricular performance, which can be detected by either a decrease in left ventricular ejection fraction or a failure for it to increase during exercise; the latter is the normal response. Therefore, techniques such as radionuclide angiography, single-photon emission computed tomography (SPECT) left ventricular reconstruction, and echocardiography have been used for the detection of myocardial ischemia. Because fairly profound ischemia is required to depress global left ventricular function, this method has not been as sensitive as other techniques. Furthermore, myocardial disease can lead to an abnormal exercise ejection fraction response, which lowers the specificity of the test. In addition, age and female gender blunt the ejection fraction response to exercise, making the test less reliable in the elderly and in women. As a result, there is currently little enthusiasm for the use of exercise radionuclide angiography alone for detecting ischemic heart disease.
6. Evaluating coronary anatomy—
a. Coronary angiography—Coronary angiography is the standard for evaluating the anatomy of the coronary artery tree. It is best at evaluating the large epicardial coronary vessels that are most frequently diseased in coronary atherosclerosis. Experimental studies suggest that lesions that reduce the lumen of the coronary artery by 70% or more in area (50% in diameter) significantly limit flow, especially during periods of increased myocardial oxygen demand. If such lesions are detected, they are considered compatible with symptoms or other signs of myocardial ischemia. This assessment is known to be imprecise for several reasons, however. First, the actual cross-sectional area of the coronary artery at the point of an atherosclerotic lesion must be estimated from two-dimensional diameter measurements in several planes. When compared with autopsy findings, stenosis severity is usually found to have been underestimated by the coronary angiography. Second, the technique does not take into consideration that lesions in series in a coronary artery may incrementally reduce the flow to distal beds by more than is accounted for by any single lesion. Thus, a series of apparently insignificant lesions may actually reduce myocardial blood flow significantly. Third, the cross-sectional area is not actually measured routinely. It is instead referenced to a supposed normal segment of artery in terms of a percentage of stenosis or percentage of reduction in the normal luminal diameter or cross-sectional area. The problem with this type of estimate is that it is often difficult to determine what a normal segment of artery is, especially in patients with diffuse coronary atherosclerosis.
Quantitative coronary angiogram measurements are an improvement over this visual inspection technique, but they are not commonly used except in research projects. Epicardial coronary artery anatomy is a static representation at the time of the study. It does not take into consideration potential changes in coronary vasomotor tone that may occur under certain circumstances and further reduce coronary blood flow. In addition, coronary angiography does not adequately evaluate disease in the intramyocardial blood vessels; this may be important in some patients, especially insulin-dependent diabetics. In patients with pure vasospastic angina, the coronary arteries are usually normal or minimally diseased. To establish increased vasomotion as the cause of the angina, provocative tests have been used to induce coronary vasospasm in the cardiac catheterization laboratory. The most popular of these is an ergonovine infusion, which is reputed to produce focal vasospasm only in naturally susceptible arteries and not in normal coronary arteries, which usually exhibit only a uniform reduction in vessel diameter. Ergonovine infusion has some risks, however, in that the resultant coronary vasospasm may be difficult to alleviate and can be quite profound. In addition, not all patients with vasospastic angina may respond to this agent. Its use has diminished in favor of electrocardiographic monitoring during the patient’s normal daily activities.
b. Other techniques—ECG or imaging evidence of old myocardial infarction is often presumed to indicate that severe coronary artery stenoses are present in the involved vessel. Myocardial infarction, however, can occur as a result of thrombus on top of a minor plaque that has ruptured and occasionally from intense vasospasm or coronary emboli from the left heart. In these cases, coronary angiography would not detect significant (narrowing of more than 50% of the diameter) coronary lesions despite the evidence of an old myocardial infarction. Coronary artery imaging is therefore necessary because estimating the degree of stenosis from the presence of infarction is not accurate. The presence of inducible myocardial ischemia almost always correlates with significant coronary artery lesions. Under the right clinical circumstances, coronary angiography can often be avoided if noninvasive stress testing produces myocardial ischemia. Coronary angiography could then be reserved for patients who failed medical therapy and were being considered for revascularization, where visualizing the coronary anatomy is necessary.
Other imaging techniques have also had some success. Echocardiography, especially transesophageal, can often visualize the first few centimeters of the major epicardial coronary arteries, and magnetic resonance imaging (MRI) has also shown promise. At present, neither of these noninvasive imaging techniques has reached the degree of accuracy needed to replace contrast coronary angiography; however, technical improvements may change this in the future.
E. CHOOSING A DIAGNOSTIC APPROACH

Normally, noninvasive stress testing is performed first in the evaluation of suspected coronary atherosclerosis. There are several reasons for this: There is less risk with stress testing than with invasive coronary angiography. Mortality rates for stress testing average 1 per 10,000 patients, compared with 1 per 1000 for coronary angiography. The physiologic demonstration of myocardial ischemia and its extent forms the basis for the therapeutic approach irrespective of coronary anatomy. Mildly symptomatic patients who show small areas of ischemia at intense exercise levels have an excellent prognosis and are usually treated medically. Knowledge of the coronary anatomy is not necessary to make this therapeutic decision. In general, therefore, a noninvasive technique should be used to detect myocardial ischemia and its extent before considering coronary angiography, which is both riskier and more costly.
In patients whose profound symptoms with minimal exertion are almost certainly due to severe diffuse coronary atherosclerosis or left main obstruction and when the likelihood of needing revascularization is extremely high, it is prudent to proceed directly with coronary angiography. Anyone with severe unstable angina should receive coronary angiography because of the potential increased risk posed by stress testing. If this approach is not appropriate in a particular clinical setting, the physician might medicate the patient and perform careful stress testing after demonstrating a lack of symptoms on medical therapy. Patients with angina or evidence of ischemia in the early period after myocardial infarction are categorized as having unstable angina and probably should be taken directly to coronary angiography. The typical postinfarction patient who is not having recurrent ischemia, however, can usually be evaluated by stress testing and then a decision can be made about the advisability of coronary angiography. If the clinical situation is such that it is likely that noninvasive testing will be inaccurate or uninterpretable, coronary angiography should be performed. Left bundle branch block on the ECG, for example, not only renders the ECG useless for detecting myocardial ischemia but may also affect the results of myocardial perfusion imaging and wall motion studies. Noninvasive techniques have poor diagnostic accuracy in morbidly obese female patients who are unable to exercise. In general, patients whose medical conditions preclude accurate noninvasive testing are candidates for direct coronary angiography.
Which type of noninvasive testing to select is based on several factors. The most important of these is the type of information desired; second, certain characteristics of the patient, which may make one test more applicable than another. There is, for example, some evidence that wall motion imaging may be more accurate than perfusion scanning in women. On the other hand, perfusion scanning is more likely than echocardiographic imaging to provide adequate technical quality in obese individuals or those with chronic obstructive pulmonary disease. Cost is also an important consideration, and the ECG stress test is the least expensive. In most patients with a low-to-medium clinical pretest likelihood of disease, using the ECG stress test makes sense, especially because good exercise performance with a negative ECG response for ischemia indicates an excellent prognosis even if coronary artery disease is present. In the patient who is highly likely to have coronary artery disease, however, it is useful to not only confirm the presence of the disease but to document its extent. For this purpose, myocardial imaging techniques are better at determining the extent of coronary artery disease than is the ECG. It is also believed that myocardial perfusion scanning is somewhat better at identifying the coronary arteries involved in the production of ischemia than are techniques for detecting wall motion abnormalities.

UNSTABLE ANGINA

2008-06-25T07:16:00.000-07:00

General Considerations
A. BACKGROUND AND HISTORICAL PERSPECTIVE

Nearly 40 years ago, the term intermediate coronary syndrome was used to describe what is now known as the syndrome of unstable angina, which has also been given numerous other labels: preinfarction angina, status anginosus, crescendo angina, impending myocardial infarction (MI), coronary failure, acute coronary insufficiency, spasmodic angina, and atypical angina—all of which terms attest to the heterogeneity of its clinical presentation. In the current era, unstable angina is the admitting diagnosis for about 40–50% of all admissions to cardiac intensive care units.
B. CLINICAL SPECTRUM

Atherosclerotic coronary artery disease comprises a spectrum of conditions that ranges from a totally asymptomatic state at one end to sudden cardiac death at the other (Table 4–1). It is clear that coronary artery disease, the primary cause of mortality and morbidity in much of the industrialized world, takes its toll through such acute complications (unstable coronary syndromes) as unstable angina, myocardial infarction, acute congestive heart failure, and sudden cardiac death. Also known as acute ischemic syndromes, these are the first clinical expressions of atherosclerotic coronary artery disease in 30–40% of patients with coronary artery disease.

Table 4–1. Clinical spectrum of atherosclerotic coronary artery disease.

C. PATHOPHYSIOLOGY

Angina pectoris is the symptomatic equivalent of transient myocardial ischemia, which results from a temporary imbalance in the myocardial oxygen demand and supply. Most episodes of myocardial ischemia are generally believed to result from an absolute reduction in regional myocardial blood flow below basal levels, with the subendocardium carrying a greater burden of flow deficit relative to the epicardium, whether triggered by a primary reduction in coronary blood flow or an increase in oxygen demand. As shown in Figure 4–1, the various acute coronary syndromes share a more-or-less common pathophysiologic substrate. The differences in clinical presentation result largely from the differences in the magnitude of coronary occlusion, the duration of the occlusion, the modifying influence of local and systemic blood flow, and the adequacy of coronary collaterals.

Figure 4–1. Schematic summarizing the current view of the key pathophysiologic events in acute coronary syndromes.

In patients with unstable angina, most episodes of resting ischemia occur without antecedent changes in myocardial oxygen demand but are triggered by primary and episodic reductions in coronary blood flow.
Worsening of ischemic symptoms in patients with stable coronary artery disease may be triggered by such obvious extrinsic factors such as severe anemia, thyrotoxicosis, acute tachyarrhythmias, hypotension, and drugs capable of increasing myocardial oxygen demand or coronary steal; in most cases, however, no obvious external trigger can be identified. In these patients—who constitute the majority—the evolution of unstable angina and its clinical complications is the outcome of a complex interplay involving coronary atherosclerotic plaque and resultant stenosis, platelet-fibrin thrombus formation, and abnormal vascular tone.
1. Unstable plaque— Several studies have shown that the atherosclerotic plaque responsible for acute unstable coronary syndromes is characterized by a fissure or rupture in its fibrous cap, most frequently at the shoulder region (junction of the normal part of the arterial wall and the plaque-bearing segment). These plaques tend to have relatively thin acellular fibrous caps infiltrated with foam cells or macrophages and eccentric pools of soft and necrotic lipid core (fatty gruel or pultaceous debris). Many clinical and angiographic studies suggest that plaque fissure leading to unstable angina or acute myocardial infarction may occur not only at sites of severe atherosclerotic stenosis, but even more commonly at minimal coronary stenoses. Serial angiographic observations have shown that development from stable to unstable angina is associated with progression of atherosclerotic disease in 60–75% of patients. This may reflect ongoing episodes of mural thrombosis and incorporation into the underlying plaque. These and other studies have shown that coronary lesions initially occluding less than 75% of the coronary artery area are likely to progress and lead to unstable angina or myocardial infarction; lesions occluding more than 75% are likely to lead to total occlusion. The latter are less likely to lead to myocardial infarction, probably because of the possibility of collateral blood vessel development in more severely stenotic arteries. Furthermore, outward positive remodeling (Glagov effect) of coronary artery segments containing large atherosclerotic plaques may minimize luminal compromise and yet enhance vulnerability for plaque disruption.
Although the precise mechanisms are not known, several hypotheses explain the propensity of plaques to rupture. These include circumferential hemodynamic stresses related to arterial pulse and pressure, intraplaque hemorrhage from small intimal fissures, vasoconstriction, and the twisting and bending of arteries. Other possibilities are inflammatory processes that involve elaboration of matrix-degrading enzymes (collagenase, elastase, stromelysin) released by foam cells or macrophages and other mesenchymal cells in response to undefined stimuli (including, but not limited to, oxidized low-density lipoprotein [LDL]). An excess of matrix-degrading enzymatic activity may contribute to loss of collagen in the protective fibrous cap of the plaque, predisposing it to disruption. Similarly reduced synthesis of collagen, resulting from increased death of matrix-synthesizing smooth muscle cells by apoptosis (programmed cell death), may also contribute to plaque disruption. Intracellular pathogens, such as Chlamydia pneumoniae, Helicobacter pylori, cytomegalovirus (CMV), and immune activation have recently been shown to cause inflammatory responses in atherosclerotic plaques and are implicated as potential triggers for plaque rupture.
2. Dynamic obstruction—
a. Thrombosis— Plaque fissure or rupture initiates the process of mural—and eventually luminal—thrombosis by exposing platelets to the thrombogenic components of plaque (collagen, lipid gruel, and tissue factor, etc). This leads to platelet attachment, aggregation, platelet thrombus formation, and the exposure of tissue factor, an abundant procoagulant in the plaque, which interacts with clotting factor VII. The ensuing cascade of events results in the formation of thrombin, which contributes to further platelet aggregation, fibrin formation, and vasoconstriction; it may also play a role as a smooth muscle cell mitogen and chemoattractant for inflammatory cells. The magnitude of the thrombotic response may be further modulated by such local rheologic factors as the shear rate, as well as the status of local and circulating coagulability, platelet aggregability, and fibrinolysis. The superimposition of thrombus on a fissured atherosclerotic plaque can abruptly worsen the local coronary stenosis and lead to a sudden decrease in blood flow. In about 20% of acute coronary syndromes seen during autopsy, however, neither plaque fissure nor rupture can be found underlying thrombosis (plaque erosion). The mechanism of coronary thrombosis is unclear in these cases, but it might include severe stenosis and an enhanced prothrombic tendency of circulating blood.
b. Vasoconstriction— It has become increasingly clear that atherosclerosis is generally associated with a reduced vasodilator response, an increased vasoconstrictor response, or a paradoxical vasoconstrictor response to a variety of stimuli: flow changes, exercise, vasoactive substances (eg, acetylcholine, platelet aggregates, thrombin). This abnormal vasomotor response has been observed well before the development of full-blown atherosclerosis; it has also been seen in patients with risk factors for coronary artery disease but no overt atherosclerosis. The response has generally been attributed to endothelial dysfunction with enhanced inactivation or a reduction in the release of nitric oxide or related nitroso-vasodilators (eg, the relaxation factor produced by the normal endothelium). Some studies have also suggested other causes, such as enhanced sensitivity of the vascular smooth muscle, abnormal platelet function, and an increased release of endothelin (a vasoconstrictor peptide).
Braunwald E: Unstable angina, an etiologic approach to management. Circulation 1998;98:2219.
Ross R: Atherosclerosis—An inflammatory disease. N Engl J Med 1999;340:115.
Shah PK: Plaque disruption and thrombosis, potential role of inflammation and infection. Cardiol Clin 1999;17:271.
Clinical Findings
A. SYMPTOMS AND SIGNS

Unstable angina is a clinical syndrome characterized by symptoms of ischemia, which may include classic retrosternal chest pain or such pain surrogates as a burning sensation, feeling of indigestion, or dyspnea (Table 4–2). Anginal symptoms may also be felt primarily or as radiation in the neck, jaw, teeth, arms, back, or epigastrium. In some patients, particularly the elderly, dyspnea, fatigue, diaphoresis, light-headedness, a feeling of indigestion and the desire to burp or defecate, or nausea and emesis may accompany other symptoms—or may be the only symptoms. The pain of unstable angina typically lasts 15—30 min; it can last longer in some patients. The clinical presentation of unstable angina can take any one of several forms.

Table 4–2. Clinical presentation of unstable angina.

There may be an onset of ischemic symptoms in a patient who had been previously free of angina, with or without a history of coronary artery disease. If symptoms are effort-induced, they are often rapidly progressive, with more frequent, easily provoked, and prolonged episodes. Rest pain may follow a period of crescendo effort angina—or exist from the beginning.
Symptoms may intensify or change in a patient with antecedent angina. Pain may be provoked by less effort and be more frequent and prolonged than before. The response to nitrates may decrease and their consumption increase. The appearance of new pain at rest or with minimal exertion is particularly ominous. On the other hand, recurrent long-standing ischemic symptoms at rest do not necessarily constitute an acute ischemic syndrome.
Ischemic symptoms may recur shortly after (usually within 4 weeks) an acute myocardial infarction, coronary artery bypass surgery, or catheter-based coronary artery intervention.
In some patients, an acute unstable coronary syndrome may manifest itself as acute pulmonary edema or sudden cardiac death.
B. PHYSICAL EXAMINATION

No physical finding is specific for unstable angina, and when the patient is free of pain the examination may be entirely normal. During episodes of ischemia, a dyskinetic left ventricular apical impulse, a third or fourth heart sound, or a transient murmur of ischemic mitral regurgitation may be detected. Similarly, during episodes of prolonged or severe ischemia there may be transient evidence of left ventricular failure, such as pulmonary congestion or edema, diaphoresis, or hypotension. Arrhythmias and conduction disturbances may occur during episodes of myocardial ischemia.
C. DIAGNOSTIC STUDIES

Unstable angina is a common reason for admission to the hospital, and the diagnosis, in general, rests entirely on clinical grounds. In a patient with typical effort-induced chest discomfort that is new or rapidly progressive, the diagnosis is relatively straightforward, particularly (but not necessarily) when there are associated ECG changes. Often, however, the symptoms are less clear-cut. The pain may be atypical in terms of its location, radiation, character, and so on, or the patient may have had a single, prolonged episode of pain—which may or may not have resolved by the time of presentation. The physician should strongly suspect unstable angina, particularly in the presence of risk factors for or in the case of known coronary artery disease. When in doubt, it is safer to err on the side of caution and consider the diagnosis to be unstable angina until proven otherwise. Even though dynamic ST-T changes on the ECG make the diagnosis more certain, from 5% to 10% of patients with a compelling clinical history (especially middle-aged women) turn out to have angiographically normal coronary arteries. In general, the more profound the changes, the greater the likelihood of an ischemic origin for the pain and the worse the prognosis.
1. ECG and Holter monitoring— Electrocardiographic abnormalities are common in patients with unstable angina. In view of the episodic nature of ischemia, however, the changes may not be present if the ECG is recorded during an ischemia-free period or the ischemia involves the myocardial territories (eg, the circumflex coronary artery territory) that do not show well on the standard 12-lead ECG. It is therefore not surprising that 40–50% of patients admitted with a clinical diagnosis of unstable angina have no electrocardiographic abnormalities on initial presentation. The ECG abnormalities tend to be in the form of transient ST segment depression or elevation and, less frequently, T wave inversion, flattening, peaking or pseudo-normalization (ie, the T wave becomes transiently upright from a baseline state of inversion). It must be emphasized, however, that a normal or unremarkable ECG in a patient with a compelling clinical history and an appropriate risk-factor profile should never be used to disregard the diagnosis of unstable angina.
Continuous Holter ambulatory ECG recording reveals a much higher prevalence of transient ST-T wave abnormalities, of which 70–80% are not accompanied by symptoms (silent ischemia). These episodes, which may be associated with transient ventricular dysfunction and reduced myocardial perfusion, are much more prevalent in patients with ST-T changes on their admission tracings (up to 80%) than in subjects without such changes. Frequent and severe ECG changes on Holter monitoring, in general, indicate an increased risk of adverse clinical outcome.
2. Angiography— More than 90–95% of patients with a clinical syndrome of unstable angina have angiographically detectable atherosclerotic coronary artery disease of varying severity and extent. The prevalence of single-, two-, and three-vessel disease is roughly equal, especially in patients older than 55 and those with a past history of stable angina. In relatively younger patients and in those with no prior history of stable angina, the frequency of single-vessel disease is relatively higher (50–60%). Left mainstem disease is found in 10–15% of patients with unstable angina. The minority of patients (5–10%) with angiographically normal or near normal coronary arteries may have noncardiac symptoms masquerading as unstable angina, the clinical syndrome X (ischemic symptoms with angiographically normal arteries and possible microvascular dysfunction), or the rare primary vasospastic syndrome of Prinzmetal (variant) angina. It should be recognized, however, that the majority of patients (even those with Prinzmetal’s angina) tend to have a significant atherosclerotic lesion on which the spasm is superimposed. In general, the extent (number of vessels involved, location of lesions) and severity (the percentage of diameter-narrowing, the minimal luminal diameter, or the length of the lesion) of coronary artery disease and the prevalence of collateral circulation, as judged by traditional angiographic criteria, do not differ between patients with unstable angina and those with stable coronary artery disease. The morphologic features of the culprit lesions do tend to differ, however. The culprit lesion in patients with unstable angina tends to be more eccentric and irregular, with overhanging margins and filling defects or lucencies. These findings (on autopsy or in vivo angioscopy) represent a fissured plaque, with or without a superimposed thrombus. Such unstable features in the culprit lesion are detected more frequently when angiography is performed early in the clinical course.
3. Noninvasive tests— Any form of provocative testing (exercise or pharmacologic stress) is clearly contraindicated in the acute phase of the disease because of the inherent risk of provoking a serious complication. Several studies of patients who had been pain-free and clinically stable for more than 3–5 days, however, have shown that such testing, using electrocardiographic, scintigraphic, or echocardiographic evaluation may be safe. Provocative testing is used primarily to stratify patients into low- and high-risk subsets. Aggressive diagnostic and therapeutic interventions can then be selectively applied to the high-risk patients; the low-risk patients are treated more conservatively. In general, these studies have shown that patients who have good exercise duration and ventricular function, without significant inducible ischemia or ECG changes on admission, are at a very low risk and can be managed conservatively. On the other hand, patients with electrocardio- graphic changes on admission, a history of prior myocardial infarction, evidence of inducible ischemia, and ventricular dysfunction tend to be at a higher risk for adverse cardiac events and therefore in greater need of further and more invasive evaluation.
P>4. Other laboratory findings— Blood levels of myocardial enzymes are, by definition, not elevated in unstable angina; if they are elevated without evolution of Q waves, the diagnosis is generally a non-Q wave myocardial infarction (or non-ST elevation myocardial infarction, NSTEMI). This distinction is somewhat arbitrary, however.
There is evidence of elevated blood levels of biochemical inflammation markers (eg, C-reactive protein [CRP], serum amyloid A, fibrinogen) in patients presenting with USA/NSTEMI. An elevated blood level of CRP or serum amyloid A on admission is associated with a higher risk for early mortality, even in patients in whom classic myocardial damage marker (cardiac-specific troponins) is negative. Increased blood level of fibrinogen is also associated with increased rate of death or MI. The presence of such markers may be useful in risk stratification for clinical outcomes, however, their current roles in diagnosing USA/NSTEMI have not been established. It is also unclear whether treatment strategies based on these biochemical markers would alter clinical outcomes.
Morrow DA, Rafai N, Antman EM et al: C-reactive protein is a potent predictor of mortality independently of and in combination with troponin T in acute coronary syndromes: A TIMI 11A substudy. J Am Coll Cardiol 1998;31:1460.
Morrow DA, Rafai N, Antman EM et al: Serum amyloid A predicts early mortality in acute coronary syndromes: A TIMI 11A substudy. J Am Coll Cardiol 2000;35:358.
Toss H, Lindahl B, Siegbahn A et al: Prognostic influence of increased fibrinogen and C-reactive protein levels in unstable coronary artery disease. Circulation 1997;96:4204.
Differential Diagnosis
Conditions that simulate or masquerade as unstable angina include acute myocardial infarction, acute aortic dissection, acute pericarditis, pulmonary embolism, esophageal spasm, hiatal hernia, chest wall pain, and so on. Careful attention to the history, risk factors and objective findings of ischemia (transient ST-T changes and mild elevations of troponins in particular) remain the cornerstones for the diagnosis.
A. ACUTE MYOCARDIAL InFARCTION

Although myocardial infarction often produces more prolonged pain, the clinical presentation can be indistinguishable from that of unstable angina. As stated earlier, this distinction should be considered somewhat arbitrary because abnormal myocardial technetium-99m pyrophosphate uptake, mild creatine kinase elevations detected on very frequent blood sampling, and increases in troponin-T and I levels (released from necrotic myocytes) are observed in some patients with otherwise classic symptoms of unstable angina—which represents the severe end of the continuum of acute ischemic syndromes.
B. ACUTE AORTIC DISSECTION

The pain of aortic dissection is usually prolonged and severe. It frequently begins in or radiates to the back and tends to be relatively unrelenting and often tearing in nature; transient ST-T changes are rare. An abnormal chest x-ray film showing a widened mediastinum, accompanied by asymmetry in arterial pulses and blood pressure, can provide clues to the diagnosis of aortic dissection, which can be verified by bedside echocardiography (transesophageal, with or without transthoracic echocardiography), magnetic resonance imaging (MRI), computed tomography (CT) scanning, or aortography.
C. ACUTE PERICARDITIS

Acute pericarditis may be difficult to differentiate from unstable angina. A history of a febrile or respiratory illness suggests the former. The pain of pericarditis is classically pleuritic in nature and worsens with breathing, coughing, deglutition, truncal movement, and supine posture. A pericardial friction rub is diagnostic, but it is often evanescent, and frequent auscultation may be needed. Prolonged, diffuse ST elevation that is not accompanied by reciprocal ST depression or myocardial necrosis is typical of pericarditis. Leukocytosis and an elevated sedimentation rate are common in pericarditis but not in unstable angina. Echocardiography may detect pericardial effusion in patients with pericarditis; diffuse ventricular hypokinesis may imply associated myocarditis. Regional dysfunction, especially if transient, is more likely to reflect myocardial ischemia.
D. ACUTE PULMONARY EMBOLISM

Chest pain in acute pulmonary embolism is also pleuritic in nature and almost always accompanied by dyspnea. Arterial hypoxemia is common, and the ECG may show sinus tachycardia with a rightward axis shift. Precordial ST-T wave abnormalities may simulate patterns of anterior myocardial ischemia or infarction. A high index of suspicion, combined with a noninvasive assessment of pulmonary ventilation-perfusion mismatch, evidence of lower extremity deep vein thrombosis, and possibly pulmonary angiography, is necessary to exclude the diagnosis.
E. GASTROINTESTINAL CAUSES OF PAIN

Various gastrointestinal pathologies can mimic unstable angina. These include esophageal spasm, peptic ulcer, hiatal hernia, cholecystitis, and acute pancreatitis. A history compatible with those conditions, the response to specific therapy, and appropriate biochemical tests and imaging procedures should help clarify the situation. It should be noted that these abdominal conditions may produce ECG changes that simulate acute myocardial ischemia.
F. OTHER CAUSES OF CHEST PAIN

Many patients present with noncardiac chest pain that mimics unstable angina, and sometimes no specific diagnosis can be reached. The pain may be musculoskeletal or there may be nonspecific changes on the ECG that increase the diagnostic confusion. In these patients, a definite diagnosis often cannot be reached despite careful clinical observation. When the pain has abated and the patient is stable, a provocative test for myocardial ischemia may help rule out ischemic heart disease. Although coronary angiography may provide evidence of atherosclerotic coronary artery disease, anatomic evidence does not necessarily prove an ischemic cause for the symptoms. In some patients acute myocarditis may also produce chest pain syndromes simulating unstable angina and acute myocardial infarction. Recreational drug use (cocaine and amphetamine) may also produce clinical syndromes of chest pain, sometimes related to drug-induced acute coronary syndrome precipitated by the vasoconstrictor and prothrombic effects of drugs.
Management
In treating unstable angina, the initial objective is to stratify patients for their short-term morbidity and mortality risks based on their clinical presentations (Figure 4–2). Following risk stratification, management objectives include eliminating episodes of ischemia and preventing acute myocardial infarction and death.

In the very acute phase, it is preferable to use intravenous nitroglycerin to ensure adequate bioavailability, a rapid onset and cessation of action, and easy dose titratability. Oral, sublingual, transdermal, and transmucosal preparations are better suited for subacute and chronic use. To minimize the chances of abrupt hypotension, nitroglycerin infusion should be started at 20–30 µg/min and the infusion rate titrated according to symptoms and blood pressure. The goal is to use the lowest dose that will relieve ischemic symptoms without incurring side effects. The side effects of nitrates include hypotension, which should be meticulously avoided; reflex tachycardia associated with hypotension; occasional profound bradycardia, presumably related to vagal stimulation; headaches; and facial flushing. Rare side effects include methemoglobinemia, alcohol intoxication, and an increase in intraocular and intracranial pressure. Some studies have shown a nitroglycerin-induced decrease in the anticoagulant effect of heparin; these results have not been confirmed by others. More recent studies suggest that nitroglycerin may reduce the circulating levels of exogenously administered tissue plasminogen activator, possibly reducing its thrombolytic efficacy. Because the magnitude of reduced arterial pressure that a patient can tolerate without developing signs of organ hypoperfusion varies, it is difficult to define an absolute cut-off point. A reasonable approach in normotensive subjects without heart failure is to maintain the arterial systolic blood pressure no lower than 100–110 mm Hg; in hypertensive patients, reduction below 120–130 mm Hg may be unwise.
Continuous and prolonged administration of intravenous nitroglycerin for more than 24 h may lead to the attenuation of both its peripheral and coronary dilator actions. This effect is due to the development of tolerance in some patients, presumably from depletion of sulfhydryl groups. Some studies show that this attenuation diminishes when sulfhydryl donors such as N-acetylcysteine are administered. At the present time, however, there is no easy and practical way to avoid or overcome this problem other than escalating the dose to maintain reduction in measurable endpoints (eg, the arterial blood pressure).
Although nitrates may reduce the number of both symptomatic and asymptomatic episodes of myocardial ischemia in unstable angina, no effect has yet been demonstrated on the incidence of myocardial infarction.
b. Antiplatelet and anticoagulant therapy— Coronary thrombosis had long been suspected as a culprit in the pathophysiology of unstable angina, and several observational studies published in the 1950s and 1960s reported on the beneficial effects of anticoagulation. The protective effects of aspirin (including the fact that taking a single aspirin had the same benefit as taking more than one) in coronary-prone patients were also described in the 1950s. The unequivocal benefits of antiplatelet and anticoagulant therapy in unstable angina were established only in the past decade, however, when several placebo-controlled randomized trials were completed.
1. Aspirin— Aspirin has been shown to reduce the risk of developing myocardial infarction by about 50% in at least four randomized trials. The protective effect of aspirin in unstable angina has been comparable, in the dosage range of 75–1200 mg/day. Low doses of aspirin (75–81 mg/day) are preferable because the gastrointestinal side effects are clearly lessened with lower doses. A lower dose should be preceded by a loading dose of 160–325 mg on the first day in order to initiate the antiplatelet effect more rapidly.
2. Ticlopidine and Clopidogrel— These two drugs are adenosine diphosphate (ADP) antagonists that are approved for antiplatelet therapy. They have been shown to be comparable to aspirin in reducing the risk of developing acute myocardial infarction in unstable angina. Because they are more expensive than aspirin and carry a 1% risk of agranulocytosis and rarely thrombotic thrombocytopenia purpura, ticlopidine and clopidogrel should be used only when a patient cannot tolerate aspirin due to hypersensitivity or major gastro- intestinal side effects.
3. Unfractionated heparin and low-molecular-weight heparin— The protective effect of intravenous unfractionated heparin (UFH) in treating unstable angina has been demonstrated in randomized trials. During short-term use, the risk of myocardial infarction in unstable angina is reduced by about 90%, and ischemic episodes are reduced by about 70%.
Two studies have compared the relative benefits of intravenous heparin with those of aspirin alone or combined with heparin. Although both agents offer protection against the development of acute myocardial infarction in unstable angina, the studies show that heparin may be somewhat more effective in reducing both the risk of infarct development and the number of ischemic episodes. Aspirin and heparin together may not be superior to heparin alone, but aspirin does offer protection against rebound reactivation of acute ischemic syndromes shortly after short-term heparin therapy ends—a argument for their combined use in unstable angina. Because combined therapy may increase the risk of bleeding, only low-dose aspirin should be used.
Recently low-molecular-weight heparin (LMWH) was tested to examine its role as an alternative anticoagulation therapy to UFH in patients with USA/ NSTEMI. Low-molecular-weight heparin has certain pharmacologically superior features to UFH: longer half-life, weaker binding to plasma protein, higher bioavailability with subcutaneous injection, more predictable dose response, less incidence of heparin-induced thrombocytopenia. Dalteparin has been shown to be superior to placebo and equivalent to UFH for acute, short-term treatment of USA/NSTEMI in reducing composite end-points in FRISC and FRIC trials, respectively. In FRISC II trial, dalteparin also lowered the risk of death or MI in patients receiving invasive procedures, especially in high-risk patients. In ESSENCE and thrombolysis in myocardial infarction (TIMI) 11B trials, enoxaparin modestly but significantly reduced the combined incidence of death, MI, or recurrent angina over UFH. This reduction is mainly due to a decrease of recurrent angina. Taken together, acute treatment with LMWH is as effective or marginally superior to UFH in USA/NSTEMI patients receiving aspirin,. However because LMWH is easier to use and does not require PTT monitoring, it is being increasingly preferred over UFH.
4. Glycoprotein IIb/IIIa receptor inhibitor— Activation of glycoprotein IIb/IIIa (GP IIb/IIIa) receptors leads to interaction of receptors with ligands such as fibrinogen followed by platelet aggregation. Several GP IIb/IIIa receptor antagonists have been developed to inhibit this agonist-induced platelet aggregation and tested in clinical trials. Current available intravenous IIb/IIIa receptor inhibitors are abciximab, a monoclonal antibody against receptor; nonpeptidic inhibitors, lamifiban and tirofiban and a peptidic inhibitor eptifibatide.
Four major randomized clinical trials (PRISM, PRISM-PLUS, PURSUIT and PARAGON) evaluated the efficacy of intravenous GP IIb/IIIa receptor inhibitors in reducing clinical events (death, MI, or refractory angina) in patients with USA/NSTEMI. Different inhibitors were tested in the trials (tirofiban in PRISM and PRISM-PLUS, eptifibatide in PURSUIT and lamifiban in PARAGON). Although patient population, experimental designs, angiographic strategies, and end-point measurement in these trials were different, these trials showed consistent, though small, reduction of short-term composite event rates in the management of the acute phase of USA/NSTEMI. However, the efficacy of these IIb/IIIa inhibitors in reducing short-term mortality is not as consistent if only death is considered as the clinical end-point. Subgroup analysis of these trials indicated that patients with high-risk features would benefit more from the use of IIb/IIIa inhibitors.
The efficacy of intravenous IIb/IIIa inhibitors in reducing clinical events in patients with USA/NSTEMI undergoing percutaneous coronary intervention (PCI) was also tested—abciximab in EPILOG and CAPTURE, tirofiban in RESTORE. These trials consistently showed a reduction of short-term clinical events (composite end-point of death, MI, urgent or repeat revascularization). The major benefit appears to be in nonfatal adverse events rather than mortality At the present time there is no clinical role for oral GP IIb/IIIa antagonists such as xemilofiban, orbofiban, and sibrafiban because of lack of proven clinical benefit and increased risk of bleeding.
Thus, overall data suggest that intravenous GP IIb/IIIa inhibitor used judiciously, along with ASA and heparin, is beneficial in high-risk patients with UA/NSTEMI undergoing PCI,
c. Thrombolytic drugs— A number of trials have examined the role of thrombolytic therapy in unstable angina. Despite improved angiographic appearance of the culprit vessel following thrombolytic therapy, no clear-cut benefit over and above antiplatelet and anticoagulant therapy alone has been demonstrated. The precise reasons for this are unclear, especially because there is general agreement about the important pathophysiologic contribution of thrombus to unstable angina. It may well be that antiplatelet-anticoagulant therapy is so effective in itself that any additional benefits are difficult to demonstrate and adding thrombolytic therapy would reduce the risk-to-benefit ratio of the therapy. At this time, therefore, the routine use of thrombolytic therapy in unstable angina cannot be recommended.
d. Beta-blockers— Beta-blockers are commonly used in managing ischemic heart disease because they have been shown to reduce the frequency of both symptomatic and asymptomatic ischemic episodes in stable as well as unstable angina. The protective effects of b-blockers in ischemic heart disease are generally attributed to their negative chronotropic and inotropic effects, which reduce the imbalance of myocardial oxygen demand and supply. Their ability to reduce the risk of infarct development is less clear, but they do decrease reinfarction and mortality rates in postinfarction patients. The mechanism of their protective effect against reinfarction remains unexplained although it has been speculated that they reduce the risk of plaque rupture by reducing mechanical stress on the vulnerable plaque. It is also unclear whether b-blockers offer any additional benefit in unstable angina in patients who are already receiving nitrates and antiplatelet-anticoagulant therapy. At present, the use of b-blockers in patients with unstable angina should be considered an adjunctive therapy.
e. Calcium blockers— Calcium blockers are also frequently used in managing ischemic heart disease. Their beneficial effects in myocardial ischemia are generally attributed to their ability to improve myocardial blood flow by reducing coronary vascular tone and dilation of large epicardial vessels and coronary stenoses through an endothelium-independent action. They also reduce myocardial workload through their negative chronotropic and inotropic and peripheral vasodilator effects. Because exaggerated vasoconstriction may play a role in unstable angina, calcium blockers have been used in its management. In general, although calcium blockers have been shown to reduce the frequency of ischemic episodes in unstable angina, their protective effect against the development of acute myocardial infarction has not been definitively demonstrated. In fact, the use of such calcium blockers as nifedipine tends to increase the risk of ischemic complications in unstable angina. Such adverse effects may well be due to reflex tachycardia or coronary steal caused by the arteriole-dilating actions of some calcium blockers. The protective effects of the heart rate-slowing calcium blocker diltiazem have been reported in patients with a non-Q wave myocardial infarction and preserved ventricular function. As in the case of b-blockers, the additive benefits of calcium blockers in patients with unstable angina who are receiving nitrates and antithrombotic therapy have not been defined, and their use should also be considered an adjunct to such drugs.

CARDIOGENIC SHOCK

2008-06-25T07:10:00.000-07:00

The initial development of coronary care units and rapid cardioversion or defibrillation of life-threatening ventricular arrhythmias, followed by risk-factor modification and such major advances as thrombolytic therapy and emergency revascularization, have contributed significantly to the successful care of the acute myocardial infarction patient. To understand the reasons for the continued high mortality rates in cardiogenic shock patients, it is important to understand the pathophysiology of cardiogenic shock and to examine the optimal treatment strategies that may improve mortality rates. In a strict sense, cardiogenic shock syndrome develops as a result of cardiac muscle failure (either right or left ventricle) that causes inadequate cardiac output. The cardiovascular system can contribute in a number of other ways to the development of shock: hypovolemia, mechanical problems, nonischemic valve lesions, arrhythmias, and abnormalities of diastolic filling. Although the primary focus of this chapter is cardiogenic shock that is due to muscle failure, there is also some discussion of other mechanical causes associated with acute myocardial infarction.
A number of definitions have been proposed; although they differ in some ways, there is general agreement that both hemodynamic and clinical parameters should be included. The hemodynamic criteria include a systolic blood pressure less than 80 mm Hg (less than 90 mm Hg if the patient is on pressors, inotropic agents, or intraaortic balloon pumping) and cardiac index less than 2.2 L/min/m2. Clinical criteria require that signs of decreased peripheral perfusion be present, including cool clammy skin, cyanosis, altered mental status, and diminished urine output (less than 30 mL/h). The common denominator of the clinical findings is that they reflect a failure of tissue perfusion. Oxygen delivery is insufficient to sustain aerobic metabolism and therefore lactic acidosis is a metabolic consequence, regardless of the cause.
Using a combination of clinical and hemodynamic measurements means that fewer patients with only some symptoms (eg, low blood pressure but no signs of diminished tissue perfusion, or normal blood pressure with altered mental status or diminished urine output) are given an inappropriate diagnosis of shock.
Etiology
The most common cause of cardiogenic shock is acute myocardial infarction and is due to the loss of a large amount of myocardium. The incidence of shock in acute myocardial infarction is between 5% and 10%, and the mortality rate is extremely high in medically treated patients, ranging between 70% and 100%, a figure unchanged over the last several decades. Cardiogenic shock may occur in a patient with a massive first infarction, or it may occur with a smaller, recurrent infarction in a patient with an already substantially infarcted myocardium.
Mechanical complications of acute myocardial infarction can cause shock; ventricular septal rupture, papillary muscle rupture or dysfunction, and myocardial rupture are all associated with cardiogenic shock. Right ventricular infarction in the absence of significant left ventricular infarction or dysfunction can cause shock. Hypovolemia or hypovolemic shock, although distinct from cardiogenic shock by definition, may be an important contributor to the development of shock in acute myocardial infarction.
Refractory tachyarrhythmias or bradyarrhythmias, usually in the setting of left ventricular dysfunction, are occasionally a cause of shock, which can occur with either ventricular or supraventricular arrhythmias.
Cardiogenic shock may occur as the end-stage, final common pathway for any progressive myocardial dysfunction, including ischemic heart disease and idiopathic, hypertrophic, and restrictive cardiomyopathies.
Pathophysiology
In cardiogenic shock resulting from acute myocardial infarction, dysfunction of a large enough quantity of myocardium (if in the left ventricle, approximately 40% must be infarcted) occurs to prevent the heart from meeting its minimum work requirements as a pump. The initial event is obstruction of a coronary artery, usually the left anterior descending coronary artery in first infarctions, but it can be any artery when previous infarctions have caused significant cumulative myocardial damage. The obstruction decreases the oxygen supply, resulting in myocardial ischemia, which in turn leads to diminished myocardial contractility and impaired left ventricular function. The ensuing drop in cardiac output and blood pressure leads to decreased coronary perfusion, resulting in further ischemia and additional deterioration in left ventricular function. This process of ischemia leading to myocardial dysfunction leading to further ischemia and so on has been appropriately termed a vicious cycle. Prolonged serum enzyme elevations, rather than the characteristic rise and fall seen in acute myocardial infarction, also suggest a protracted, stuttering course. Evidence for this vicious cycle is also found in autopsy studies that show infarct extension at the edges of an infarct in addition to discrete, remote infarctions throughout the ventricle.
The majority of patients with shock in acute myocardial infarction have extensive coronary disease. In patients dying of cardiogenic shock, more than two thirds have severe three-vessel coronary artery disease.
Early studies of acute myocardial infarction identified clinical and hemodynamic subsets that had prognostic significance. The Killip classification is based on clinical subsets, as shown in Table 6–1. The Forrester classification uses hemodynamic instead of clinical subsets (Table 6–2). Although the Killip and Forrester subsets have somewhat different definitions, they very clearly establish the point that progressive worsening of left ventricular function, whether measured by clinical or by hemodynamic parameters, is associated with a poorer prognosis. The pathophysiology of cardiogenic shock in acute infarction complicated by mechanical problems is somewhat different. Acute severe mitral regurgitation from papillary muscle or chordal rupture markedly diminishes cardiac output, leading to pulmonary edema. The sympathetic nervous system response to cardiac failure results in increased afterload and a further increase in the regurgitant fraction, another example of a disastrous vicious cycle causing cardiogenic shock.

Table 6–1. Killip classification.

Table 6–2. Forrester classification.

Rupture of the myocardial free wall resulting in shock, a rare complication of acute myocardial infarction, generally occurs within 4–7 days and may account for 10–30% of all deaths from acute infarction. Acute bleeding into a relatively nondistendible pericardial space leads rapidly to pericardial tamponade and cardiovascular collapse.
Rupture of the ventricular septum with formation of a ventricular septal defect has an incidence of 2–4% in acute myocardial infarction. A large ventricular septal defect causes significant left-to-right shunting and right ventricular volume overload. As with acute mitral regurgitation, the sympathetic nervous system response results in increased afterload, thereby shunting a larger fraction of the cardiac output across the interventricular septum. Pulmonary congestion develops as a consequence of the right ventricular volume and pressure overload. Diminished forward cardiac output from the left ventricle leads to depression of blood pressure and the diminished tissue perfusion characteristic of shock.
Right ventricular infarction occurs in 10–20% of patients with inferior myocardial infarctions and may be a cause of cardiogenic shock. The degree of left ventricular function is variable and shock can occur even in the absence of left ventricular dysfunction. Failure of the right ventricle leads to diminished right ventricular stroke volume, which results in a decreased volume of blood returning to the left ventricle (preload). Markedly diminished left ventricular filling pressure, even with normal left ventricular contractility, causes decreased systemic cardiac output.
As noted earlier, a variety of arrhythmias can contribute to the development of shock. A sustained arrhythmia, that is, one that does not culminate in ventricular fibrillation and sudden death, is generally a cause of shock only in the already compromised ventricle. Atrial and ventricular tachyarrhythmias are associated with both a greatly diminished time for ventricular filling in diastole and loss of the atrial contribution to diastolic filling. The diminished preload causes decreased volume available for forward output and, by the Frank-Starling relationship for ventricular performance, diminished contractility. These factors, superimposed on an already impaired left ventricle, may be enough to result in cardiogenic shock.
Bradyarrhythmias do not generally result in diastolic filling abnormalities, although (as with tachyarrhythmias) loss of atrial systole may be a factor. The major problem here is diminished forward cardiac output caused by the slow heart rate. Because total cardiac output is a function of heart rate and stroke volume, a markedly decreased heart rate, especially with left ventricular dysfunction and reduced stroke volume, may result in shock.
Many forms of heart disease can result in an end-stage dilated and congested cardiomyopathy. These include hypertensive heart disease; ischemic heart disease; restrictive, idiopathic, and toxic cardiomyopathies; and cardiomyopathy secondary to endocrine disease. In all cases, the inexorable progression of myocardial disease, accompanied by the effects of volume and pressure overload, can ultimately lead to inadequate cardiac output and shock.
Chatterjee K: Pathogenesis of low output in right ventricular infarction. Chest 1992;102(Suppl 2):590S.
Hollenberg SM, Kavinsky CJ, Parrillo JE: Cardiogenic Shock. Ann Intern Med 1999;131(1):47.
Clinical Findings
Approximately half the patients destined to develop shock will present initially with shock; the other half will develop cardiogenic shock after admission to the hospital.
A. HISTORY

The symptoms and signs that precede the development of cardiogenic shock depend on the cause. Patients with acute myocardial infarction will generally have the typical history of acute-onset chest pain, possibly in the setting of known coronary artery disease. The mechanical complications of acute myocardial infarction all tend to occur several days to a week following the infarction. They may be heralded by chest pain, but they more commonly present abruptly as acute pulmonary edema or cardiac arrest. Patients with arrhythmias may have a history of symptoms, such as palpitations, presyncope, syncope, or a sensation of skipped beats, that suggest this cause. The patient may appear obtunded and lethargic as a result of decreased central nervous system perfusion. Regardless of the cause, however, by the time shock develops, the patient may be unable to give any useful history. Family members may be able to help by identifying any previous history of heart disease and providing the history of the present illness.
B. PHYSICAL EXAMINATION

1. Vital signs— Blood pressure is less than 90 mm Hg systolic in patients on pressors and less than 80 mm Hg in the untreated patient. Heart rate is commonly elevated from sympathetic stimulation, and the respiratory rate is generally increased as a result of pulmonary congestion.
2. Chest— The chest examination in most cases shows diffuse rales. Patients with right ventricular infarction or those who are hypovolemic may have less evidence of pulmonary congestion.
3. Cardiovascular system— Neck veins are commonly elevated, although they may be normal in hypovolemic patients. The apical impulse is displaced in patients with dilated cardiomyopathy, and the intensity of heart sounds is diminished in pericardial effusion or tamponade. A gallop rhythm, especially a third heart sound suggesting significant left ventricular dysfunction, may be present. A mitral regurgitation or ventricular septal defect murmur can help in establishing these causes. Patients with significant right heart failure may have such signs (on abdominal examination) as liver enlargement, a pulsatile liver in the presence of significant tricuspid regurgitation, or ascites in long-standing right heart failure.
4. Extremities— Peripheral pulses will be diminished, and peripheral edema may be present. Cyanosis and cool extremities are indicative of diminished tissue perfusion. Profound peripheral vasoconstriction can result in livido reticularis on the abdomen.
C. DIAGNOSTIC STUDIES

The diagnosis of cardiogenic shock is a clinical diagnosis based on hypotension and evidence of peripheral hypoperfusion. Information gathered from history, physical examination, and laboratory data—especially hemodynamic monitoring—will corroborate the diagnosis and give valuable information as to its cause. It must be stressed, however, that shock in general and cardiogenic shock in particular are clinical syndromes that are diagnosed by clinical criteria.
1. Electrocardiography— The electrocardiogram (ECG) is often helpful in distinguishing between causes of cardiogenic shock. Patients with coronary disease and acute myocardial infarction may show evidence of both old and new infarctions. Right-sided chest leads in patients with inferior myocardial infarctions can detect the presence of right ventricular infarction (ST elevation in V4R). Although the ECG readily aids in the diagnosis of arrhythmias contributing to cardiogenic shock, it is often not precise when shock is caused by problems other than acute infarction or arrhythmia.
2. Chest radiograph— The chest radiograph shows cardiomegaly and evidence of pulmonary congestion or edema in patients with severe left ventricular failure. Ventricular septal defect or mitral regurgitation associated with acute infarction will lead to pulmonary congestion but not necessarily cardiomegaly, however, particularly in patients suffering a first infarction. Findings of pulmonary congestion may be less prominent—or absent—in the case of predominantly right ventricular failure or hypovolemia.
3. Echocardiography— The noninvasive nature and ready availability of two-dimensional and Doppler echocardiography make these techniques suitable for immediate assessment of the patient in shock and a tremendous benefit in the bedside diagnosis and treatment of many types of heart disease. Information obtained by echocardiography includes assessment of right and left ventricular function (global as well as segmental), valvular function (stenosis or regurgitation), right ventricular pressures; and detection of shunts (eg, ventricular septal defect with left-to-right shunting), pericardial fluid, or tamponade. The echocardiogram is especially helpful in diagnosing the mechanical complications of myocardial infarction.
4. Hemodynamic monitoring— The use of Swan-Ganz catheters to measure pulmonary artery and pulmonary capillary wedge pressure (PCWP) is generally very useful, if not essential, in establishing the diagnosis and cause of cardiogenic shock and in planning and monitoring therapy. Patients with cardiogenic shock as a result of severe left ventricular failure have, by definition, elevation of the PCWP. The presence of a wedge pressure higher than 18 mm Hg in a patient with acute myocardial infarction indicates adequate intravascular volume. Patients with primarily right ventricular failure or significant hypovolemia may have normal or reduced PCWP. The presence of a large v wave on the PCWP tracing implies significant mitral regurgitation.
The value of hemodynamic monitoring lies in its ability to assist in optimizing the ventricular function and thereby tissue perfusion. The Frank-Starling relationship of cardiac performance (measured by cardiac output, stroke work, or stroke volume) as a function of filling pressure demonstrates that the performance of the heart will increase as filling pressure increases—up to a point. In the failing heart, this point is eventually reached where no further increases in performance are gained by additional increases in preload—the “flat” part of the curve. Serial measurements of cardiac performance and left ventricular filling pressure indicate the optimal preload (ie, the lowest preload at which cardiac work is optimized).
Monitoring of hemodynamic parameters also allows calculation of the afterload (systemic vascular resistance [SVR]), defined by the following equation:

Minimizing afterload is important because increasing afterload mimics the effect of decreased contractility, resulting in diminished cardiac output.
Right-side filling pressures (central venous or right atrial pressure) are commonly normal, except in the case of right ventricular infarction, pericardial tamponade, or preexisting pulmonary disease.
Hemodynamic definitions of cardiogenic shock, as noted previously, include a cardiac index less than 2.2 L/min/m2. Cardiac index is preferred to cardiac output as a measure because it normalizes the cardiac output for body size. Small patients may be incorrectly diagnosed with shock if cardiac output alone is used.
5. Oxygen saturation— Venous O2 saturation may be helpful in two ways. The arteriovenous difference in oxygen content, which is a useful indicator of cardiac output, increases as more oxygen is extracted from the blood in the setting of low cardiac output. Serial determinations are especially useful in monitoring a patient’s course and response to therapy.
Oxygen saturations obtained while placing the Swan-Ganz catheter may also be helpful in diagnosing a ventricular septal defect. The shunting of oxygenated blood from the left ventricle to the right ventricle results in an oxygen saturation step-up when comparing venous oxygen saturation from the venae cavae with that obtained in the pulmonary artery.
Treatment
A. GENERAL

Although some general therapeutic considerations are applicable to all patients in cardiogenic shock, treatment is most effective when the cause is identified. In many situations, this identification allows rapid correction of the underlying problem. In fact, survival in most forms of shock requires a quick, accurate diagnosis. The patient is so critically ill that only prompt, directed therapy can reverse the process. It is clear that the already high mortality rates in cardiogenic shock are even higher in patients for whom treatment is delayed. Therefore, although measures aimed at temporarily stabilizing the patient may provide enough time to start definitive therapy, potentially life-saving treatment can be carried out only when the cause is known (Table 6–3).

Table 6–3. Management of cardiogenic shock.

B. MECHANICAL COMPLICATIONS

Acute mitral regurgitation secondary to papillary muscle dysfunction or rupture or to ventricular septal defect is a true emergency when associated with cardiogenic shock. The only effective therapy for these catastrophes is surgical repair. If the patient is to survive, all efforts must be made to get the patient to the operating room as soon as possible after the diagnosis is made. Pharmacologic agents and intraaortic balloon pumping (see section “Circulatory support devices”) are useful as temporizing measures only and should not delay surgical treatment.
Patients with ventricular free-wall rupture rarely survive if the rupture is massive and results in shock and pericardial tamponade. As is true with the other major mechanical problems, emergency surgical correction is the only hope for survival.
C. RIGHT VENTRICULAR INFARCTION

Cardiogenic shock may occur with right ventricular infarction and no or only minimal left ventricular dysfunction. The probability for long-term survival is excellent if the diagnosis is made promptly and appropriate treatment instituted. Hemodynamic data suggesting right ventricular dysfunction out of proportion to left ventricular dysfunction and ST elevation in lead V4R are most helpful in establishing the diagnosis. Initial treatment is fluid resuscitation to increase right ventricular preload and output. Significant amounts of fluid (1–2 L or more) may be required to develop an adequate preload for the failing ventricle. Inotropic agents are usually necessary when the right ventricular failure is so profound that shock continues despite adequate volume administration. Vasodilators may be helpful in some circumstances, diminishing the right ventricular afterload, which would theoretically improve the cardiac output. Vasodilators such as nitroprusside, which affect both the arterial and venous systems, may actually decrease preload, however—to the point that right ventricular output is unchanged.
Patients with right ventricular infarction are dependent on atrial contraction. As a result, single-chamber ventricular pacing may be inadequate in patients who require pacing, and atrioventricular sequential pacing is required to improve cardiac output.
D. ARRHYTHMIAS

Arrhythmias contributing to cardiogenic shock are readily recognized with ECG monitoring and should be promptly treated. Tachyarrhythmias (ventricular tachycardia and supraventricular tachycardias) should be treated with electrical cardioversion. Bradyarrhythmias may respond to pharmacologic agents (atropine, isoproterenol) in some circumstances, but external or transvenous pacing may be required.
E. ACUTE MyOCARDIAL InFARCTION

In patients with cardiogenic shock caused by a large amount of infarcted or stunned myocardium, it has become increasingly clear that the only treatment that can decrease mortality is revascularization, with either coronary angioplasty or coronary artery bypass surgery (discussed later). A number of pharmacologic and nonpharmacologic measures may be helpful in stabilizing the patient prior to cardiac catheterization or surgery.
1. Ventilation-oxygenation— Because respiratory failure usually accompanies cardiogenic shock, every effort should be made to ensure adequate ventilation and oxygenation. Adequate oxygenation is essential to avoid hypoxia and further deterioration of oxygen delivery to tissues. The majority of patients with cardiogenic shock require mechanical ventilation with supplemental oxygen. Hypoventilation can lead to respiratory acidosis, which could exacerbate the metabolic acidosis caused by tissue hypoperfusion. Acidosis worsens cardiac function; it also makes the heart less responsive to inotropic agents.
2. Fluid resuscitation— Although hypovolemia is not the primary defect in cardiogenic shock, a number of patients may be relatively hypovolemic when shock develops following myocardial infarction. The causes of decreased intravascular volume include increased hydrostatic pressure and the increased permeability of blood vessels. Note that the physical examination may not always be helpful in determining the adequacy of left ventricular filling pressure. Furthermore, because the central venous pressure correlates poorly with PCWP in shock, it may not be useful, especially with a single reading. These facts underscore the importance of hemodynamic monitoring with a pulmonary artery catheter for an accurate assessment of left ventricular filling pressure. The optimal filling pressure is higher in patients with shock because the left ventricle is operating on a depressed function curve (less stroke volume for any given filling pressure). Generally, a PCWP of 18–22 mm Hg is considered adequate; further increases will lead to pulmonary congestion without a concomitant gain in cardiac output. Fluid resuscitation, when indicated by low or normal PCWPs, should be undertaken in boluses of 200–300 mL saline, followed by reassessment of hemodynamic parameters, especially cardiac output and PCWP.
3. Inotropic agents— A variety of drugs are available for intravenous administration to increase the contractility of the heart. Because the heart is operating on a markedly depressed Frank-Starling curve, a positive inotropic agent may improve the hemodynamic status significantly.
a. Digoxin— Although digoxin benefits patients with chronic congestive heart failure, it is of less benefit in cardiogenic shock because of its delayed onset of action and relatively mild potency (compared with other available agents).
b. Beta-adrenergic agonists— Dopamine is an endogenous catecholamine with qualitatively different effects at varying doses. At low doses (less than 4 µg/kg/ min) it predominantly stimulates dopaminergic receptors that dilate various arterial beds, the most important being the renal vasculature. Intermediate doses of 4–6 µg/kg/min cause b1-receptor stimulation and enhanced myocardial contractility. Further increases in dosage lead to prominent a-receptor stimulation (peripheral vasoconstriction) in addition to continued b1 stimulation. Dopamine improves cardiac output, and its combination of cardiac stimulation and peripheral vasoconstriction may be especially beneficial as initial treatment of hypotensive patients in cardiogenic shock.
Dobutamine is a synthetic sympathomimetic agent that differs from dopamine in two important ways: It does not cause renal vasodilation, and it has a much stronger b2 (arteriolar vasodilation) effect. The vasodilatory effect may be deleterious in the hypotensive patients because a further drop in blood pressure may occur. On the other hand, many patients with cardiogenic shock experience excessive vasoconstriction and inappropriately elevated afterload as a result of the natural sympathetic discharge or of treatment with inotropic agents, such as dopamine, that also have prominent vasoconstrictor effects. In such patients, the combination of cardiac stimulation and decreased afterload with dobutamine may improve cardiac output without a loss of arterial pressure.
Isoproterenol is also a synthetic sympathomimetic agent. It has very strong chronotropic and inotropic effects, resulting in a disproportionate increase in oxygen consumption and ischemia. It is therefore not generally recommended for cardiogenic shock except for bradyarrhythmias responsive to its chronotropic effect.
Norepinephrine has even stronger a and b1 effects than dopamine and may be beneficial when a patient continues to be hypotensive despite large doses of dopamine (more than 20 µg/kg/min). Because of the intense peripheral vasoconstriction that occurs, perfusion of other vascular beds such as the kidney, extremities, and mesentery may be compromised. Therefore, norepinephrine cannot be used for any extended time unless plans are made for definitive treatment. Beta-adrenergic agonists, which are extremely useful agents for improving the circulatory state of patients with cardiogenic shock, can also have adverse effects. Their ability to increase cardiac output is accompanied by an increased oxygen demand from enhanced contractility, a faster heart rate, and increased blood pressure—which can be harmful to the already ischemic myocardium. In addition, b-agonists can precipitate serious ventricular or atrial tachyarrhythmias.
c. Phosphodiesterase inhibitors— The intracellular mediator of b-adrenergic-receptor stimulation is cyclic adenosine monophosphate (cAMP), produced by adenylate cyclase after stimulation of the receptor. Cyclic-AMP in turn increases calcium influx into the cell, thereby increasing contractility. The phosphodiesterase inhibitors, such as milrinone and amrinone, inhibit the breakdown of cAMP by phosphodiesterase, prolonging its effect on cardiac contractility. These agents also act on cAMP produced at sites of b2 stimulation to prolong the vasodilatory effects. Phosphodiesterase inhibitors appear to have no advantage over the b-agonists in patients with cardiogenic shock.
4. Vasodilators— Vasodilation (especially of the arterioles to reduce afterload) is often necessary because of the increased levels of catecholamines and resultant peripheral vasoconstriction. Vasodilators are also useful in patients who require the enhanced contractility of b1 stimulation by an adrenergic agonist, even though the associated vasoconstriction (especially with dopamine) may inappropriately increase the afterload. In addition, the preload may be inappropriately high in many patients; here, a venodilator will be beneficial in reducing filling pressure (preload).
a. Nitroprusside— Nitroprusside is a direct-acting vascular smooth muscle relaxant, with a balanced effect (vasodilation of both the arterial and venous beds). It is commonly used in combination with an inotropic agent. Doses begin as low as 0.25–0.5 µg/kg/min and may go as high as 8–10 µg/kg/min. Even though nitroprusside is a very short-acting drug, hypotension is a common side effect, and close arterial pressure monitoring is required.
b. Phentolamine— Phentolamine is an a-antagonist that acts predominantly on arterial a receptors to produce vasodilation. It is not commonly used because of the tachycardia induced by the release of cardiac norepinephrine stores.
c. Nitroglycerin— Nitroglycerin is primarily a venodilator, although it may have some arterial effects at high doses. Its benefits arise from a decrease in pulmonary congestion and, through its coronary vasodilatory effects, a decrease in myocardial ischemia. It is not commonly used in cardiogenic shock, however, unless coronary vasospasm is thought to be contributing to myocardial ischemia.
5. Circulatory support devices— Among the mechanical devices developed to assist the left ventricle until more definitive therapy can be undertaken, the intraaortic balloon pump (IABP) has been in use the longest and is the most well studied.
The IABP is placed in the descending aorta via the femoral artery. Its inflation and deflation are timed to the cardiac cycle (generally synchronized with the ECG). The balloon inflates in diastole immediately following aortic valve closure. The augmentation of diastolic pressure (to a level higher than systolic pressure) increases coronary perfusion as well as that of other tissues. The balloon deflates at the end of diastole, immediately before left ventricular contraction, abruptly decreasing the afterload and improving left ventricular ejection.
Indications for use of the IABP include shock from severe ischemia, severe ventricular failure (especially when used as a bridge to cardiac transplant), ventricular septal rupture, and mitral regurgitation. In both ventricular septal rupture and mitral regurgitation, the principal benefit is caused by the decreased afterload as the balloon deflates. This results in a larger fraction of the left ventricular volume being ejected into the aorta rather than into the left atrium (mitral regurgitation) or the right ventricle (ventricular septal rupture).
The complication rate, especially vascular damage, is significant because of the large catheter size. As a result, the IABP is contraindicated in patients with significant peripheral vascular disease. In selected cases the balloon can be placed in the descending thoracic aorta from an axillary cut-down. It must be remembered that although these devices can clearly improve hemodynamics in the short term, they cannot improve survival by themselves, reaffirming the importance of definitive treatment.
A number of other circulatory support devices have been developed in recent years. A percutaneous cardiopulmonary bypass device with large-bore catheters placed in the right atrium and the femoral artery is capable of creating flow rates of 3–5 L/min. Prosthetic left ventricles and various surgically placed left ventricular assistance devices have also been used in patients with cardiogenic shock as a bridge to cardiac transplant. Although anecdotal reports of their benefits are encouraging, none has yet been subjected to controlled studies for comparison with IABP.
6. Revascularization— Revascularization is the only definitive therapy shown to decrease mortality in patients who develop cardiogenic shock following myocardial infarction. Early, primarily retrospective, studies of coronary angioplasty or coronary artery bypass graft surgery (CABG) reported survival rates of 60–80% in revascularized patients compared with 0–30% survival rate with medical therapy alone. More recently the multicenter, randomized SHOCK (Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock) trial showed a trend toward improved survival at 30 days in patients randomized to revascularization (either angioplasty or CABG). The survival benefit for revascularization became significant at 6 months, a benefit that persisted at 1 year. Of note, patients 75 years of age and older had worse survival rates with revascularization, a finding that was also seen in earlier nonrandomized studies. Many experts believe that the SHOCK trial was underpowered to show a mortality difference at 30 days and, based on the 6 month and 1 year data, now recommend emergency revascularization for patients with cardiogenic shock complicating acute myocardial infarction.
a. Coronary angioplasty— Studies of coronary angioplasty in cardiogenic shock have consistently found that older patients (65 years of age or older) do not appear to benefit from coronary angioplasty. It is also noteworthy that although the likelihood of survival appears to be much improved in patients with successful coronary angioplasty, it remains very low—around 20%—in those with failed angioplasty. Whether these patients should be offered any further CABG surgery is unclear at this time. Future research will be aimed at identifying patients at high risk for failed coronary angioplasty and determining any preferable alternatives.
b. Coronary artery bypass graft surgery— Emergency CABG has also been studied in patients with cardiogenic shock caused by acute myocardial infarction. As with coronary angioplasty, the studies are generally retrospective but also show an improved survival rate (60–80%) over patients treated medically. These benefits appear to be more consistent in trials reflecting post-1980 improvements in surgical techniques. Again, as in coronary angioplasty, elderly patients do not appear to benefit from CABG.
7. Thrombolytic therapy— Thrombolytic therapy is considered a reperfusion strategy comparable to coronary angioplasty for decreasing mortality rates in acute myocardial infarction patients without cardiogenic shock. It would seem logical that patients in cardiogenic shock might also benefit from thrombolytic therapy. This benefit, however, has not been realized. Analysis of survival data for thrombolytic trials of patients with cardiogenic shock have consistently shown mortality rates in the 70–80% range—no different from those treated conservatively. Thrombolysis has been less successful in patients with cardiogenic shock; the rates of reperfusion are lower. It has been suggested that the low flow state present in shock may explain this lack of benefit in that adequate cardiac output appears to be necessary for successful thrombolysis. If the patient is not a candidate for angioplasty or CABG, however, or if revascularization is not immediately available, there appears to be no harm from thrombolytic therapy—and it may succeed in some cardiogenic shock patients.
8. Other medical therapies— Platelet IIb/IIIa inhibitors have been studied extensively in recent years in the setting of acute coronary syndromes and with percutaneous coronary interventions. A retrospective analysis of one such trial showed that patients randomized to the IIb/IIIa inhibitor eptifibatide had a significant 50% absolute risk reduction for mortality at 30 days. This finding will need to be verified in future trials designed to prospectively evaluate the efficacy of IIb/IIIa inhibitors in cardiogenic shock.

Arrhytmia

2008-06-24T06:22:00.000-07:00

DIAGNOSTIC OF ARRHYTMIA
History
Begins with a careful history addressing specific questions regarding the presence of palpitations, syncope, spells of lightheadedness, chest pain, or symptoms of congestive heart failure. Palpitations,[1] an awareness of one’s heartbeat (see Chap. 3 ), may result from irregularities in cardiac rate or rhythm or a change in contractility of the heart. Some patients are able to reproduce this sensation by tapping their hand on their chest, knee, or a table top in a fashion similar to the perceived palpitation or may recognize a cadence tapped out by a physician. Such a maneuver can help establish the rate and rhythm of the arrhythmia by narrowing it to a particular rate range, a regular or irregular arrhythmia, or one in which a regular rhythm is interrupted by premature beats. The latter are often perceived only upon the contraction that ends the pause following the premature beat. The patient may feel as though the heart has stopped for a moment. Rapid, irregular tapping can suggest the ventricular response to atrial fibrillation, whereas rapid, regular tapping can suggest an atrioventricular (AV) nodal reentrant supraventricular tachycardia, particularly in a young person, or ventricular tachycardia (VT) in an older person. Information regarding the nature of the onset and termination of the rhythm disturbance is particularly important. Knowing the rate of the arrhythmia is crucial, and a brief demonstration by the physician of how to determine the heart rate can yield important dividends. The patient, and sometimes a close relative, should be instructed in how to count the pulse.
Answers by the patient to key questions can provide clues to the type of rhythm disturbance, particularly if the physician has additional information, such as physical findings and a 12-lead electrocardiogram (ECG). For example, a young adult with presyncope, normal physical findings, and ECG changes indicating Wolff-Parkinson-White (WPW) syndrome should be asked whether the palpitations are regular or irregular, how fast they are, and how they start and stop. If the tachycardia is regular, with a rate of approximately 200 beats/min, and of sudden onset and termination, it is likely that the patient is experiencing an AV reciprocating tachycardia; on the other hand, if the rhythm is irregular, the patient may have atrial fibrillation, a potentially more serious arrhythmia in the presence of WPW syndrome. In an older patient with presyncope, especially with a history of myocardial infarction, the physician should suspect VT if the ventricular rate is rapid and suspect AV heart block or sinus nodal disease if the rate is slow. The ventricular rhythm can be regular or irregular. Premature atrial or ventricular beats, perceived as dropped or skipped beats by the patient, are probably the most common cause of palpitations.
The physician should inquire about circumstances that can trigger the arrhythmia, such as emotionally upsetting events, ingestion of caffeine-containing beverages, cigarette smoking, exercise, excessive alcohol intake, or gastrointestinal problems (Fig. 25-1) . A careful diet and drug history can be useful, for example, in revealing that palpitations develop only after the use of a nasal decongestant that contains a sympathomimetic vasoconstrictor or in revealing that the patient has been exposed to "street" drugs such as cocaine. States conducive to the genesis of arrhythmias should be considered, such as thyrotoxicosis, pericarditis, mitral valve prolapse, hypokalemia secondary to diuretics, and so forth. The family history can be helpful. In addition to the congenital long QT syndrome, a variety of other familial disorders can result in arrhythmias, including myotonic dystrophy, Duchenne muscular dystrophy (see Chap. 71 ), and dilated cardiomyopathy (see Chap. 48 ). Congenital conduction system disorders can result in sudden death.
Physical Examination
In addition to recording the cardiac rate and rhythm, a number of physical findings can be helpful. For example, findings accompanying AV dissociation include variable peak systolic blood pressure as the atria alter their contribution to ventricular filling, variable intensity of the first heart sound as the PR interval changes despite a regular ventricular rhythm, intermittent cannon a waves in the jugular venous pulse as atrial contraction occurs against closed AV valves, and apparent "intermittent" gallop sounds when atrial systole occurs at various times of the cardiac cycle. The venous pulse provides a window through which to judge atrial and ventricular rates and relative timing relationships. It is of interest that Wenckebach first noted the two types of second-degree AV block that bear his name by recording the jugular phlebogram before the ECG was available.
to ventricular filling, variable intensity of the first heart sound as the PR interval changes despite a regular ventricular rhythm, intermittent cannon a waves in the jugular venous pulse as atrial contraction occurs against closed AV valves, and apparent "intermittent" gallop sounds when atrial systole occurs at various times of the cardiac cycle. The venous pulse provides a window through which to judge atrial and ventricular rates and relative timing relationships. It is of interest that Wenckebach first noted the two types of second-degree AV block that bear his name by recording the jugular phlebogram before the ECG was available.

Examining the second heart sound can be helpful (see Chap. 4 ). A paradoxically split second heart sound can occur during a QRS complex with a left bundle branch block contour that results from VT or supraventricular tachycardia with aberration. A widely split second heart sound that does not become single during expiration can accompany a right bundle branch block. Unfortunately, similar physical findings occur with different cardiac arrhythmias. For example, progressive diminution of the intensity of the first heart sound results as the PR interval lengthens, which can occur during AV dissociation when the atrial rate exceeds the ventricular rate or during a Wenckebach second-degree AV block. Similarly, constant cannon a waves can occur with 1:1 AV relationships during ventricular or supraventricular tachycardia. Since AV dissociation can occur (uncommonly) during supraventricular tachycardia and VA association can occur during VT, the clues provided by physical findings can be only suggestive.
Carotid Sinus Massage
The response to carotid sinus massage or the Valsalva maneuver provides important diagnostic information by increasing vagal tone and primarily slowing the rate of sinus nodal discharge and prolonging AV nodal conduction time and refractoriness. Sinus tachycardia slows gradually during carotid massage and then returns to the previous rate when the massage is discontinued; AV nodal reentry and AV reciprocating tachycardias that involve the AV node in one of its pathways can slow slightly, terminate abruptly, or not change, and the ventricular response to atrial flutter, atrial fibrillation, and some atrial tachycardias usually decreases (Table 25-1) . Rarely, carotid sinus massage terminates a VT.
To perform carotid massage, the patient is placed in a supine position with the neck hyperextended and the head turned away from the side being tested, the sternocleidomastoid muscles relaxed or gently pushed out of the way, and the carotid impulse felt at the angle of the jaw. The carotid bifurcation is touched gently initially with the palmar portion of the fingertips to detect hypersensitive responses. Then, if no change in cardiac rhythm occurs, pressure is applied more firmly for approximately 5 seconds, first on one side and then on the other (never on both sides simultaneously) with a gentle rotating massaging motion. External pressure stimulates baroreceptors in the carotid sinus to trigger a reflex increase in vagal activity and sympathetic withdrawal. Responses can occur with right-sided massage and not left, or vice versa, so each side should be tested separately. Generally, the maximal response occurs with the first massage if repeated attempts are performed at short intervals. Some risk is associated with carotid sinus massage, particularly in older patients, and cerebral emboli can occur.[2] Before massage, the carotid artery should be auscultated so that massage is not performed in patients who have carotid bruits indicative of carotid arterial disease.
Electrocardiography
The ECG remains the most important and definitive single noninvasive diagnostic test. Figure 25-2 depicts an algorithm for diagnosing specific tachyarrhythmias from the 12-lead ECG. Initially, a 12-lead ECG is recorded, and a long recording using the lead that shows distinct P waves is obtained for proper analysis. If P waves are not clearly visible, atrial activity can be recorded by placing the right and left arm leads in various chest positions to discern P waves (so-called Lewis leads) and applying esophageal electrodes or by using intracavitary right atrial leads. An echocardiogram showing atrial contraction can be helpful.
Each arrhythmia must be approached in a systematic manner to answer the following questions: Are P waves present? What are the atrial and ventricular rates? Are they identical? Are the P-P and R-R intervals regular or irregular? If irregular, is it a consistent, repeating irregularity? Is there a P wave related to each ventricular complex? Does the P wave precede or follow the QRS complex? Is the resultant PR or RP interval constant? Is the RP interval long and the PR interval short, or vice versa? Are all P waves and QRS complexes identical and normal in contour? To determine the significance of changes in P wave or QRS contour or amplitude, one must know the lead being recorded. Are P, PR, QRS, and QT durations normal? In view of the clinical setting, what is the significance of the arrhythmia? Should it be treated and, if so, how? For supraventricular tachycardias with a normal QRS complex, a branching decision tree may be useful.
The Ladder Diagram
The ladder diagram is used to depict depolarization and conduction schematically. Straight or slightly slanting lines drawn on a tiered framework beneath an ECG trace represent electrical events occurring in the various cardiac structures (Fig. 25-3 A and B). Since the ECG and therefore the ladder diagram represent electrical activity against a time base, conduction is indicated by the lines of the ladder diagram sloping in a left-to-right direction. A less steep line depicts slower conduction. A short bar drawn perpendicular to a sloping line represents blocked conduction (Fig. 25-3 C). Activity originating in an ectopic site such as the ventricle is indicated in another tier drawn beneath the ventricular tier. In general, atrial, AV junctional, or ventricular activity is diagrammed to begin in that particular tier. It is important to remember that sinus nodal discharge and conduction and, under certain circumstances, AV junctional discharge and conduction can only be assumed; their activity is not recorded on scalar ECG.
Electrophysiological Study
When an electrophysiological study is indicated, it is performed by introducing multipolar catheter electrodes into the vascular system and positioning them in various parts of the heart. The catheters are used to record local electrical activity and to stimulate the heart. Multiple leads are recorded simultaneously, usually at a paper speed of 50 to 200 mm/sec. (Standard ECGs are generally recorded at a paper speed of 25 mm/sec.) Because of the rapid recording speed, intervals or complexes of normal duration may appear prolonged. An electrode positioned across the septal leaflet of the tricuspid valve records His bundle activity, as well as low right atrial activity and high ventricular septal depolarization. Occasionally, a right bundle branch deflection
can also be recorded. Three basic measurements are made by using the ECG and the His bundle catheter recording: the PA, A-H, and H-V intervals (Fig. 25-3 D). The PA interval is the time between the onset of the P wave in the surface tracing (which generally slightly precedes the onset of the high right atrial recording) and the low right atrial deflection and is recorded in the His lead. This interval reflects intraatrial conduction and has not proved to be of much clinical value.
THE A-H INTERVAL.
The A-H interval is timed from the onset of the first rapid deflection recorded in the atrial electrogram (A) in the His bundle lead to the beginning of the His (H) deflection. Since the low right part of the atrium and the His bundle anatomically delineate the boundaries of the AV node, the A-H interval closely approximates AV nodal conduction time. The A-H interval is affected by various interventions: Atropine and isoproterenol shorten the A-H interval, whereas vagal maneuvers, digitalis, propranolol, verapamil, adenosine, and rapid or premature atrial pacing lengthen it. The normal range for the A-H interval is 55 to 130 milliseconds, depending on the heart rate, autonomic tone, and other factors.
THE H-V INTERVAL.
The H-V interval is the time from the beginning of the H deflection to the earliest onset of ventricular depolarization recorded in any lead. This interval represents conduction from the His bundle through the bundle branch-Purkinje system to the point of ventricular muscle activation and is usually constant--between 30 and 55 milliseconds--regardless of the heart rate or autonomic tone. Other intervals are discussed under the individual tachycardias.

Arrhytmia

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Arrhytmia

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