OVERVIEW AND DEFINITIONS
Sudden cardiac death (SCD) is defined as natural death due to cardiac causes in a person who may or may not have previously recognized heart disease but in whom the time and mode of death are unexpected. The term “sudden,” in the context of SCD, is defined for most clinical and epidemiologic purposes as 1 h or less between a change in clinical status heralding the onset of the terminal clinical event and the cardiac arrest itself. One exception is unwitnessed deaths, in which pathologists may expand the temporal definition to 24 h after the victim was last seen to be alive and stable.
Another exception is the variable interval between cardiac arrest and biological death that results from community-based interventions, following which victims may remain biologically alive for days or even weeks after a cardiac arrest that has resulted in irreversible central nervous system damage. Confusion in terms can be avoided by adhering strictly to definitions of cardiovascular collapse, cardiac arrest, and death (Table 327-1). Although cardiac arrest is often potentially reversible by appropriate and timely interventions, death is biologically, legally, and literally an absolute and irreversible event. Biological death may be delayed by interventions, but the relevant pathophysiologic event remains the sudden and unexpected cardiac arrest. Accordingly, for statistical purposes, deaths that occur during hospitalization or within 30 days after resuscitated cardiac arrest are counted as sudden deaths.
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DISTINCTION BETWEEN CARDIOVASCULAR COLLAPSE, CARDIAC ARREST, AND DEATH |
The majority of natural deaths are caused by cardiac disorders. However, it is common for underlying heart diseases—often far advanced—to go unrecognized before the fatal event. As a result, up to two-thirds of all SCDs occur as the first clinical expression of previously undiagnosed disease or in patients with known heart disease, the extent of which suggests low individual risk. The magnitude of sudden cardiac death as a public health problem is highlighted by the estimate that ~50% of all cardiac deaths are sudden and unexpected, accounting for a total SCD burden estimated to range from <200,000 to >450,000 deaths each year in the United States. SCD is a direct consequence of cardiac arrest, which may be reversible if addressed promptly. Because resuscitation techniques and emergency rescue systems are available to respond to victims of out-of-hospital cardiac arrest, which was uniformly fatal in the past, understanding the SCD problem has practical clinical importance.
CLINICAL DEFINITION OF FORMS OF CARDIOVASCULAR COLLAPSE
Cardiovascular collapse is a general term connoting loss of sufficient cerebral blood flow to maintain consciousness due to acute dysfunction of the heart and/or peripheral vasculature. It may be caused by vasodepressor syncope (vasovagal syncope, postural hypotension with syncope, neurocardiogenic syncope; Chap. 27), a transient severe bradycardia, or cardiac arrest. The latter is distinguished from the transient forms of cardiovascular collapse in that it usually requires an active intervention to restore spontaneous blood flow. In contrast, vasodepressor syncope and other primary bradyarrhythmic syncopal events are transient and non-life-threatening, with spontaneous return of consciousness.
In the past, the most common electrical mechanism for cardiac arrest was ventricular fibrillation (VF) or pulseless sustained ventricular tachycardia (PVT). These were the initial rhythms recorded in 60–80% of cardiac arrests, with VF being the far more common of the two. Severe persistent bradyarrhythmias, asystole, and pulseless electrical activity (PEA; organized electrical activity, unusually slow, without mechanical response, formerly called electromechanical dissociation [EMD]) caused another 20–30%. Currently, asystole has emerged as the most common mechanism recorded at initial contact (45–50% of cases). PEA accounts for 20–25%, and VF is now present on initial contact in 25–35%. Undoubtedly, a significant proportion of the asystole cases began as VF and deteriorated to asystole because of long response times, but there are data suggesting an absolute reduction in VF as well. Acute low cardiac output states, having a precipitous onset, also may present clinically as a cardiac arrest. These hemodynamic causes include massive acute pulmonary emboli, internal blood loss from a ruptured aortic aneurysm, intense anaphylaxis, and cardiac rupture with tamponade after myocardial infarction (MI).
ETIOLOGY, INITIATING EVENTS, AND CLINICAL EPIDEMIOLOGY
Clinical, epidemiologic, and pathologic studies have provided information on the underlying structural substrates in victims of SCD and identified subgroups at high risk for SCD. In addition, studies of clinical physiology have begun to identify transient functional factors that may convert a long-standing underlying structural abnormality from a stable to an unstable state, leading to the onset of cardiac arrest (Table 327-2).
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CARDIAC ARREST AND SUDDEN CARDIAC DEATH |
Cardiac disorders constitute the most common causes of sudden natural death. After an initial peak incidence of sudden death between birth and 6 months of age (sudden infant death syndrome [SIDS]), the incidence of sudden death declines sharply and remains low through childhood and adolescence. Among adolescents and young adults, the incidence of SCD is approximately 1 per 100,000 population per year. The incidence begins to increase in adults over age 30 years, reaching a second peak in the age range of 45–75 years, when it approximates 1–2 per 1000 per year among the unselected adult population. Increasing age within this range is associated with increasing risk for sudden cardiac death (Fig. 327-1A). From 1 to 13 years of age, only one of five sudden natural deaths is due to cardiac causes. Between 14 and 21 years of age, the proportion increases to 30%, and it rises to 88% in the middle-aged and elderly.
FIGURE 327-1 Panel A demonstrates age-related risk for sudden cardiac death (SCD). For the general population age 35 years and older, SCD risk is 0.1–0.2% per year (1 per 500–1000 population). Among the general population of adolescents and adults younger than age 30 years, the overall risk of SCD is 1 per 100,000 population, or 0.001% per year. The risk of SCD increases dramatically beyond age 35 years. The greatest rate of increase is between 40 and 65 years (vertical axis is discontinuous). Among patients older than 30 years of age, with advanced structural heart disease and markers of high risk for cardiac arrest, the event rate may exceed 25% per year, and age-related risk attenuates. (Modified from RJ Myerburg, A Castellanos: Cardiac arrest and sudden cardiac death, in P Libby et al [eds]: Braunwald’s Heart Disease, 8th ed. Philadelphia, Saunders, 2008.) Panel B demonstrates the incidence of SCD in population subgroups and the relation of total number of events per year to incidence figures. Approximations of subgroup incidence figures and the related population pool from which they are derived are presented. Approximately 50% of all cardiac deaths are sudden and unexpected. The incidence bars on the left (percent/year) indicate the approximate percentage of sudden and nonsudden deaths in each of the population subgroups indicated, ranging from the lowest percentage in unselected adult populations (0.1–2% per year) to the highest percentage in patients with severe left ventricular dysfunction and heart failure (approximately 25% per year). The bars on the right indicate the total number of events per year in each of these groups with the population impact size of each of the subgroups. The highest risk categories identify the smallest number of total annual events, and the lowest incidence category accounts for the largest number of events per year. CHF, congestive heart failure; EF, ejection fraction; MI, myocardial infarction; VT, ventricular tachycardia. (After RJ Myerburg et al: Circulation 85:2, 1992.)
Young and middle-aged men and women have different susceptibilities to SCD, but the sex differences decrease and ultimately disappear with advancing age. The difference in risk for SCD parallels the differences in age-related risks for other manifestations of coronary heart disease (CHD) between men and women. As the gender gap for manifestations of CHD closes in the sixth to eighth decades of life, the excess risk of SCD in males progressively narrows. Despite the lower incidence among younger women, coronary risk factors such as cigarette smoking, diabetes, hyperlipidemia, and hypertension are highly influential, and SCD remains an important clinical and epidemiologic problem. The incidence of SCD among the African-American population appears to be higher than it is among the white population; the reasons remain uncertain.
Genetic factors contribute to the risk of acquiring CHD, and a genetic basis for its expression as SCD is being explored. A genetic hypothesis for at least part of the SCD risk is supported by data suggesting a familial predisposition to SCD as a specific form of expression of CHD. A parental history of SCD as a first cardiac event increases the probability that an acute coronary event in the offspring will express similarly. In a number of less common syndromes, such as hypertrophic cardiomyopathy, congenital long QT interval syndromes, right ventricular dysplasia, and the syndrome of right bundle branch block and nonischemic ST-segment elevations (Brugada syndrome), and other more rare syndromes, there is a specific inherited risk of ventricular arrhythmias and SCD (Chap. 277).
The etiologic structural substrates and functional factors contributing to expression of the SCD syndrome are listed in Table 327-2. Worldwide, and especially in Western cultures, coronary atherosclerotic heart disease is the most common structural abnormality associated with SCD in middle-aged and older adults. Up to 80% of all SCDs in the United States are due to the consequences of coronary atherosclerosis. The nonischemic cardiomyopathies (dilated and hypertrophic, collectively; Chap. 273e) account for another 10–15% of SCDs, and all the remaining diverse etiologies cause only 5–10% of all SCDs. The inherited arrhythmia syndromes (see above and Table 327-2) are proportionally more common causes in adolescents and young adults. For some of these syndromes, such as hypertrophic cardiomyopathy (Chap. 287), the risk of SCD increases significantly after the onset of puberty.
Transient ischemia in a previously scarred or hypertrophied heart, hemodynamic and fluid and electrolyte disturbances, fluctuations in autonomic nervous system activity, and transient electrophysiologic changes caused by drugs or other chemicals (e.g., proarrhythmia) have all been implicated as mechanisms responsible for the transition from electrophysiologic stability to instability. In addition, reperfusion of ischemic myocardium may cause transient electrophysiologic instability and arrhythmias.
PATHOLOGY
Data from postmortem examinations of SCD victims parallel the clinical observations on the prevalence of CHD as the major structural etiologic factor. More than 80% of SCD victims have pathologic findings of CHD. The pathologic description often includes a combination of long-standing, extensive atherosclerosis of the epicardial coronary arteries and unstable coronary artery lesions, which include various permutations of eroded, fissured, or ruptured plaques; platelet aggregates; hemorrhage; and/or thrombosis. As many as 70–75% of males who die suddenly have preexisting healed MIs, whereas only 20–30% have recent acute MIs, despite the prevalence of unstable plaques and thrombi. The latter suggests transient ischemia as the mechanism of onset. Regional or global left ventricular (LV) hypertrophy often coexists with prior MIs.
PREDICTION AND PREVENTION OF CARDIAC ARREST AND SUDDEN CARDIAC DEATH
SCD accounts for approximately one-half the total number of cardiovascular deaths. As shown in Fig. 327-1B, the very-high-risk subgroups consist of more focused populations at higher risk of cardiac arrest or SCD, with better individual prediction, but the representation of such subgroups within the overall population burden of SCD is small. This is indicated by the absolute number of events (“events per year”), in contrast to the percentage per year in the subgroup. To achieve a major population impact, effective prevention of underlying diseases and the development of new epidemiologic and clinical probes that will allow better individual risk prediction by identifying specific high-risk subgroups within the large general populations are needed.
Strategies for predicting and preventing SCD are classified as primary and secondary. Primary prevention refers to the attempt to identify individual patients at specific risk for SCD and institute preventive strategies. Secondary prevention refers to measures taken to prevent recurrent cardiac arrest or death in individuals who have survived a prior cardiac arrest.
The effectiveness of the prevention strategies currently used depends on the magnitude of risk among the various population subgroups. Because the annual incidence of SCD among the unselected adult population is limited to approximately 1 per 1000 population per year (Fig. 327-1) and ~50% of all SCDs due to coronary artery disease occur as the first clinical manifestation of the disease (Fig. 327-2A), the only currently practical strategies are profiling for risk of developing CHD and risk factor control (Fig. 327-2B). The most powerful long-term risk factors include age, cigarette smoking, elevated serum cholesterol, diabetes mellitus, elevated blood pressure, LV hypertrophy, and nonspecific electrocardiographic abnormalities. Markers of inflammation (e.g., levels of C-reactive protein) that may predict plaque destabilization have been added to risk classifications. The presence of multiple risk factors progressively increases incidence, but not sufficiently or specifically enough to warrant therapies targeted to potentially fatal arrhythmias (Fig. 327-1A). However, recent studies suggesting familial clustering of SCD associated with a first acute coronary syndrome offer hope that genetic markers for specific risk may be forthcoming.
FIGURE 327-2 Population subsets, risk predictors, and distribution of sudden cardiac deaths (SCDs) according to clinical circumstances. A. The population subset with high-risk arrhythmia markers in conjunction with low ejection fraction is a group at high risk of SCD but accounts for <10% of the total SCD burden attributable to coronary artery disease. In contrast, 50% of all SCD victims present with SCD as the first and only manifestation of underlying disease, and up to 30% have known disease but are considered relatively low risk because of the absence of high-risk markers. B. Profiling for individual prediction and prevention of SCD is difficult. The highest absolute numbers of events occur among the general population who may have risk factors for coronary heart disease or expressions of disease that do not predict high risk. This results in a low sensitivity for predicting and preventing SCD. New approaches that include epidemiologic modeling of transient risk factors and genetic predictors of individual patient risk offer hope for greater sensitivity in the future. AM, ambulatory monitoring; AP, angina pectoris; ASHD, arteriosclerotic heart disease; CAD, coronary artery disease; CT, computed tomography; EF, ejection fraction; EP, electrophysiologic; EPS, electrophysiologic study; MI, myocardial infarction. (Modified from RJ Myerburg: J Cardiovasc Electrophysiol 12:369–381, 2001.)
After coronary artery disease has been identified in a patient, additional strategies for risk profiling become available (Fig. 327-2B), but the majority of SCDs occur among the large unselected groups rather than in the specific high-risk subgroups that become evident among populations with established disease (compare events per year with percentage per year in Fig. 327-1B). After a major cardiovascular event, such as acute MI, recent onset of heart failure, or survival after out-of-hospital cardiac arrest, the highest risk of death occurs during the initial 6–18 months after the event and then plateaus toward the baseline risk associated with the extent of underlying disease. However, many of the early deaths are nonsudden, diluting the potential benefit of strategies targeted specifically to SCD. Thus, although post-MI beta blocker therapy has an identifiable benefit for both early SCD and nonsudden mortality risk, a total mortality benefit for implantable cardioverter-defibrillator (ICD) therapy early after MI has not been observed.
Among patients in the acute, convalescent, and chronic phases of MI (Chap. 295), subgroups at high absolute risk of SCD can be identified. During the acute phase, the potential risk of cardiac arrest from onset through the first 48 h used to be as high as 15%, but is now reported in the range of 2.3–4.4% because of early patient awareness of the significance of symptoms and the availability of emergency revascularization strategies. Those who survive acute-phase VF are not at continuing risk for recurrent cardiac arrest indexed to that event. During the convalescent phase after MI (3 days to ~6 weeks), an episode of sustained ventricular tachycardia (VT) or VF, which is usually associated with a large infarct, predicts a natural history mortality risk of >25% at 12 months. At least one-half of the deaths are sudden. Aggressive intervention techniques may reduce this incidence.
During the chronic phase after MI, the longer-term risk for total mortality and SCD mortality is predicted by a number of factors (Fig. 327-2B). The most important for both SCD and nonsudden death is the extent of myocardial damage sustained as a result of the acute MI. This is measured by the magnitude of reduction of the ejection fraction (EF) and/or the occurrence of heart failure. Various studies have demonstrated that ventricular arrhythmias identified by ambulatory monitoring contribute significantly to this risk, especially in patients with an EF <40%. In addition, inducibility of VT or VF during electrophysiologic testing of patients who have ambient ventricular arrhythmias (premature ventricular contractions [PVCs] and nonsustained VT) and an EF <35% is a strong predictor of SCD risk. Patients in this subgroup are now considered candidates for ICDs (see below). Risk falls off sharply with EFs >35% and the absence of ambient arrhythmias after MI, and conversely is high with EFs <30% even without the ambient arrhythmia markers.
The cardiomyopathies (dilated and hypertrophic, Chap. 287) are the second most common category of diseases associated with risk of SCD (Table 327-2). Some risk factors have been identified, largely related to extent of disease, presence of heart failure, documented ventricular arrhythmias, and syncope thought to be due to arrhythmias. The less common causes of SCD include valvular heart disease (primarily aortic) and inflammatory and infiltrative disorders of the myocardium. The latter include viral myocarditis, sarcoidosis, and amyloidosis.
Among adolescents and young adults, rare inherited disorders such as hypertrophic cardiomyopathy, the long QT interval syndromes, right ventricular dysplasia, and the Brugada syndrome have received attention as important causes of SCD, as has acute myocarditis and other less common acquired diseases. Among the subgroup of young competitive athletes, the incidence of SCD may be higher than it is for the general adolescent and young adult population, perhaps up to 1 in 75,000–100,000. Hypertrophic cardiomyopathy (Chap. 287) is the most common cause in the United States.
Secondary prevention strategies should be applied to survivors of cardiac arrest that was not associated with an acute MI or other controllable transient risk factors, such as certain drug exposures and correctable electrolyte imbalances. Multivessel coronary artery disease and dilated cardiomyopathy, especially with markedly reduced left ventricular EF, predict a high risk of recurrence of cardiac arrest or SCD and are indications for specific interventions, such as ICDs (see below). The occurrence of otherwise unexplained syncope or documented life-threatening arrhythmias in patients with long QT syndromes or right ventricular dysplasia are also associated with increased risk of SCD.
CLINICAL CHARACTERISTICS OF CARDIAC ARREST
PRODROME, ONSET, ARREST, DEATH
SCD may be presaged by days to months of increasing angina, dyspnea, palpitations, easy fatigability, and other nonspecific complaints. However, these prodromal symptoms are generally predictive of any major cardiac event; they are not specific for predicting SCD.
The onset of the clinical transition, leading to cardiac arrest, is defined as an acute change in cardiovascular status preceding cardiac arrest by up to 1 h. When the onset is instantaneous or abrupt, the probability that the arrest is cardiac in origin is >95%. Continuous electrocardiogram (ECG) recordings fortuitously obtained at the onset of a cardiac arrest commonly demonstrate a tendency for the heart rate to increase and for advanced grades of PVCs to evolve during the minutes or hours before the event.
The probability of achieving successful resuscitation from cardiac arrest is related to the interval from onset of loss of circulation to return of spontaneous circulation (ROSC), the setting in which the event occurs, the mechanism (VF, VT, PEA, asystole), and the clinical status of the patient before the cardiac arrest. ROSC and survival rates as a result of defibrillation decrease almost linearly from the first minute to 10 min. After 4-5 min, survival rates are no better than 25–30% in out-of-hospital settings without bystander cardiopulmonary resuscitation (CPR). Those settings in which it is possible to institute prompt CPR followed by prompt defibrillation provide a better chance of a successful outcome. The outcome in intensive care units and other in-hospital environments is heavily influenced by the patient’s preceding clinical status. The immediate outcome is good for cardiac arrest occurring in the intensive care unit in the presence of an acute cardiac event or transient metabolic disturbance, but survival among patients with far-advanced chronic cardiac disease or advanced noncardiac diseases (e.g., renal failure, pneumonia, sepsis, diabetes, cancer) is low and not much better in the in-hospital setting. Survival rates after unexpected cardiac arrest in unmonitored areas in a hospital do not differ from witnessed out-of-hospital arrests. Since implementation of community response systems, survival from out-of-hospital cardiac arrest has improved, although it still remains low, under most circumstances. Survival probabilities in public sites exceed those in the home environment, where the majority of cardiac arrests occur.
The success rate for initial resuscitation and survival to hospital discharge after an out-of-hospital cardiac arrest depends heavily on the mechanism of the event. When the mechanism is pulseless VT, the outcome is best; VF is the next most successful; and asystole and PEA, now the most common mechanisms, generate dismal outcome statistics. Advanced age also adversely influences the chances of successful resuscitation.
The probability of progression to biologic death is a function of the mechanism of cardiac arrest and the length of the delay before interventions. VF without CPR within the first 4–6 min has a poor outcome even if defibrillation is successful because of secondary brain damage; the prompt interposition of bystander CPR (basic life support; see below) improves outcome at any point along the time scale, especially when followed by early successful defibrillation. However, there are few survivors among patients who had no life support activities for the first 8 min after onset. Evaluations of deployment of automatic external defibrillators (AEDs) in communities (e.g., police vehicles, large buildings, airports, and stadiums) are beginning to generate encouraging data, but the data for home deployment has been have been less impressive.
Death during the hospitalization after a successfully resuscitated cardiac arrest relates closely to the severity of central nervous system injury. Anoxic encephalopathy and infections subsequent to prolonged respirator dependence account for 60% of the deaths. Another 30% occur as a consequence of low cardiac output states that fail to respond to interventions. Recurrent arrhythmias are the least common cause of death, accounting for only 10% of in-hospital deaths.
In the setting of acute MI (Chap. 295), it is important to distinguish between primary and secondary cardiac arrests. Primary cardiac arrests are those that occur in the absence of hemodynamic instability, and secondary cardiac arrests are those that occur in patients in whom abnormal hemodynamics dominate the clinical picture before cardiac arrest. The success rate for immediate resuscitation in primary cardiac arrest during acute MI in a monitored setting should exceed 90%. In contrast, as many as 70% of patients with secondary cardiac arrest succumb immediately or during the same hospitalization.
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TREATMENT |
CARDIAC ARREST |
An individual who collapses suddenly is managed in five stages: (1) initial evaluation and basic life support if cardiac arrest is confirmed, (2) public access defibrillation (when available), (3) advanced life support, (4) postresuscitation care, and (5) long-term management. The initial response, including confirmation of loss of circulation, followed by basic life support and public access defibrillation, can be carried out by physicians, nurses, paramedical personnel, and trained laypersons.
INITIAL EVALUATION AND BASIC LIFE SUPPORT
Confirmation that a sudden collapse with loss of consciousness (LOC) is due to a cardiac arrest includes prompt observations of the state of consciousness, respiratory movements, skin color, and the presence or absence of pulses in the carotid or femoral arteries. For lay responders, the pulse check is no longer recommended because it is unreliable. As soon as a cardiac arrest is suspected, confirmed, or even considered to be impending, calling an emergency rescue system (e.g., 911) is the immediate priority. With the development of AEDs that are easily used by nonconventional emergency responders, an additional layer for response has evolved (see below).
Careful attention to the respiratory status after abrupt LOC is important. Although normal breathing or tachypnea after LOC makes cardiac arrest less likely, gasping respiratory movements may persist during a true cardiac arrest, and their presence should not deter appropriate responses. In fact, continued gasping is considered a good prognostic sign for successful outcome. It is also important to observe for severe stridor with a persistent pulse as a clue to aspiration of a foreign body or food. If this is suspected, a Heimlich maneuver (see below) may dislodge the obstructing body. A precordial blow, or “thump,” delivered firmly with a clenched fist to the junction of the middle and lower thirds of the sternum may occasionally revert VT or VF, but there is concern about converting VT to VF. Therefore, it is recommended to use precordial thumps as a life support technique only when monitoring and defibrillation are available. This conservative application of the technique remains controversial.
The third action during the initial response is to clear the airway. The head is tilted back and the chin lifted so that the oropharynx can be explored to clear the airway. Dentures or foreign bodies are removed, and the Heimlich maneuver is performed if there is reason to suspect that a foreign body is lodged in the oropharynx. If respiratory arrest precipitating cardiac arrest is suspected, a second precordial thump is delivered after the airway is cleared.
Basic life support, more popularly known as CPR, is intended to maintain organ perfusion until definitive interventions can be instituted. The initial and primary element of CPR is maintenance of perfusion until spontaneous circulation can be restored. Closed chest cardiac compression maintains a pump function by sequential filling and emptying of the chambers, with competent valves maintaining forward direction of flow. The palm of one hand is placed over the lower sternum, with the heel of the other resting on the dorsum of the lower hand. The sternum is depressed, with the arms remaining straight, at a rate of 100 per minute. Sufficient force is applied to depress the sternum 4–5 cm, and relaxation is abrupt.
Until recently, providing ventilation of the lungs by mouth-to-mouth respiration was used if no specific rescue equipment was immediately available (e.g., plastic oropharyngeal airways, esophageal obturators, masked Ambu bag). However, ventilatory support during CPR has yielded to evidence that continuous chest compressions (“hands only” CPR) results in better outcomes. Compressions are interrupted only for single shocks from an AED when available, with 2 min of CPR between each single shock.
AUTOMATED EXTERNAL DEFIBRILLATION (AED)
AEDs that are easily used by nonconventional responders, such as nonparamedic firefighters, police officers, ambulance drivers, trained security guards, and minimally trained or untrained laypersons, have been developed. This advance has inserted another level of response into the cardiac arrest paradigm. A number of studies have demonstrated that AED use by nonconventional responders in strategic response systems and public access lay responders can improve cardiac arrest survival rates. The rapidity with which defibrillation/cardioversion is achieved is an important element for successful resuscitation, both for ROSC and for protection of the central nervous system. Chest compressions should be carried out while the defibrillator is being charged. As soon as a diagnosis of VF or VT is established, a biphasic waveform shock of 150–200 J (360 J if a monophasic waveform device is used) should be delivered. If 5 min has elapsed between collapse and first contact with the victim, there is some evidence that 60–90 s of CPR before the first shock may improve probability of survival without neurologic damage. If the initial shock does not successfully revert VT or VF, chest compression at a rate of 100 per minute is resumed for 2 min, and then a second shock is delivered. Multiple shocks given in sequence are no longer recommended, in order to minimize interruptions of chest compressions. This sequence is continued until personnel capable of, and equipped for, advanced life support are available, although not much data support the notion that shocks and chest compressions alone will revert VF after three shocks have failed.
ADVANCED CARDIAC LIFE SUPPORT (ACLS)
ACLS is intended to achieve and maintain organ perfusion and adequate ventilation, control cardiac arrhythmias, and stabilize blood pressure and cardiac output. The activities carried out to achieve these goals include (1) defibrillation/cardioversion and/or pacing, (2) intubation with an endotracheal tube, and (3) insertion of an intravenous line.
As in basic life support, the major emphasis during ACLS is minimizing interruptions of chest compressions until ROSC is achieved. After two or three unsuccessful defibrillation attempts, epinephrine, 1 mg IV, is given and attempts to defibrillate are repeated. The dose of epinephrine may be repeated after intervals of 3–5 min (Fig. 327-3A). Vasopressin (a single 40-unit dose given IV) has been suggested as an alternative to epinephrine.
FIGURE 327-3 A. The algorithm of ventricular fibrillation or pulseless ventricular tachycardia begins with and initial defibrillate on attempt. If a single shock fails to restore a pulse, it is followed by 2 min of cardiopulmonary resuscitation (CPR; chest compressions), followed by another single shock. After three such sequences, epinephrine and then antiarrhythmic drugs are added to the protocol. See text for details. B. The algorithms for bradyarrhythmia/asystole (left) or pulseless electrical activity (right) are dominated first by continued life support and a search for reversible causes. Subsequent therapy is nonspecific and is accompanied by a low success rate. See text for details. MI, myocardial infarction; VT, ventricular tachycardia.
If the patient is less than fully conscious upon reversion or if two or three attempts fail, prompt intubation, ventilation, and arterial blood gas analysis should be carried out. Ventilation with O2 (room air if O2 is not immediately available) may promptly reverse hypoxemia and acidosis. Quantitative waveform capnography is now recommended for confirmation and monitoring of endotracheal tube placement. A patient who is persistently acidotic after successful defibrillation and intubation or had acidosis prior to arrest, may be given 1 meq/kg NaHCO3 initially and an additional 50% of the dose repeated every 10–15 min. However, it should not be used routinely.
After initial unsuccessful defibrillation attempts or with persistent/recurrent electrical instability, antiarrhythmic therapy should be instituted. Intravenous amiodarone has emerged as the initial treatment of choice (150 mg over 10 min, followed by 1 mg/min for up to 6 h and 0.5 mg/min thereafter) (Fig. 327-3A). For cardiac arrest due to VF in the early phase of an acute coronary syndrome, a bolus of 1 mg/kg of lidocaine may be given intravenously as an alternative, and the dose may be repeated in 2 min. It also may be tried in patients in whom amiodarone is unsuccessful. Intravenous procainamide (loading infusion of 100 mg/5 min to a total dose of 500–800 mg, followed by continuous infusion at 2–5 mg/min) is now rarely used in this setting but may be tried for persisting, hemodynamically stable arrhythmias. Intravenous calcium gluconate is no longer considered safe or necessary for routine administration. It is used only in patients in whom acute hyperkalemia is known to be the triggering event for resistant VF, in the presence of known hypocalcemia, or in patients who have received toxic doses of calcium channel antagonists.
Cardiac arrest due to bradyarrhythmias or asystole (B/A cardiac arrest) is managed differently (Fig. 327-3B). The patient is promptly intubated, CPR is continued, and an attempt is made to control hypoxemia and acidosis and identify other reversible causes. Epinephrine may be given intravenously or by an intraosseous route. Atropine is no longer considered effective for asystole or PEA, but can be used for bradyarrhythmias. External pacing devices are used to attempt to establish a regular rhythm when atropine fails for a bradyarrhythmia, but chronotropic agents given intravenously are now recognized as an equally effective alternative.
The success rate may be good when B/A arrest is due to acute inferior wall MI or to correctable airway obstruction or drug-induced respiratory depression or with prompt resuscitation efforts. For acute airway obstruction, prompt removal of foreign bodies by the Heimlich maneuver or, in hospitalized patients, by intubation and suctioning of obstructing secretions in the airway is often successful. The prognosis is generally very poor in other causes of this form of cardiac arrest, such as end-stage cardiac or noncardiac diseases. Treatment of PEA is similar to that for bradyarrhythmias, but its outcome is also dismal.
POST-CARDIAC ARREST SYNDROME AND POSTRESUSCITATION CARE
After return of spontaneous or stable assisted circulation, attention shifts to the diagnostic and therapeutic elements of the post-cardiac arrest syndrome. This recently developed clinical classification emerged from the organization of the elements of injury following cardiac arrest into a multidisciplinary continuum. The four components of post-cardiac arrest syndrome include brain injury, myocardial dysfunction, systemic ischemia/reperfusion responses, and control of persistent precipitating factors. The therapeutic goal is to maintain a stable electrical, hemodynamic, and central nervous system status.
Postresuscitation care is determined by the specific clinical circumstances. The most pressing is the presence of anoxic encephalopathy, which is a strong predictor of in-hospital death and postarrest disability. Mild therapeutic hypothermia is indicated for resuscitated cardiac arrest victims who are hemodynamically stable, but remain comatose. Core body temperature is decreased to 32–34°C, by several available techniques (external and/or internal [core]), as soon as practical after resuscitation and maintained for a minimum of 12–24 h. By reducing metabolic demands and cerebral edema, this intervention improves probability of survival with better neurologic outcome.
Primary VF in acute MI (not accompanied by low-output states) (Chap. 295) is generally very responsive to life support techniques and easily controlled after the initial event. In the in-hospital setting, respirator support is usually not necessary or is needed for only a short time, and hemodynamics stabilize promptly after defibrillation or cardioversion. In secondary VF in acute MI (those events in which hemodynamic abnormalities predispose to the potentially fatal arrhythmia), resuscitative efforts are less often successful, and in patients who are successfully resuscitated, the recurrence rate is high. The clinical picture and outcome are dominated by hemodynamic instability and the ability to control hemodynamic dysfunction. Bradyarrhythmias, asystole, and PEA are commonly secondary events in hemodynamically unstable patients.
The outcome after in-hospital cardiac arrest associated with noncardiac diseases is poor, and in the few successfully resuscitated patients, the postresuscitation course is dominated by the nature of the underlying disease. Patients with end-stage cancer, renal failure, acute central nervous system disease, and uncontrolled infections, as a group, have a survival rate of <10% after in-hospital cardiac arrest. Some major exceptions are patients with transient airway obstruction, electrolyte disturbances, proarrhythmic effects of drugs, and severe metabolic abnormalities, most of whom may have a good chance of survival if they can be resuscitated promptly and stabilized while the transient abnormalities are being corrected.
LONG-TERM MANAGEMENT AFTER SURVIVAL OF OUT-OF-HOSPITAL CARDIAC ARREST
Patients who survive cardiac arrest without irreversible damage to the central nervous system and who achieve hemodynamic stability should have diagnostic testing to define appropriate therapeutic interventions for their long-term management. This approach is driven by the fact that survival after out-of-hospital cardiac arrest is followed by a 10–25% mortality rate during the first 2 years after the event, and there are data suggesting that significant survival benefits can be achieved by prescription of an ICD.
Among patients in whom an acute ST elevation MI or transient and reversible myocardial ischemia is identified as the specific mechanism triggering an out-of-hospital cardiac arrest, the management is dictated in part by the transient nature of life-threatening arrhythmia risk during the acute coronary syndrome (ACS) and in part by the extent of permanent myocardial damage that results. Cardiac arrest during the acute ischemic phase is not an ICD indication, but survivors of cardiac arrest not associated with an ACS do benefit. In addition, patients who survive MI with an EF less than 30–35% appear to benefit from ICDs.
For patients with cardiac arrest determined to be due to a treatable transient ischemic mechanism, particularly with higher EFs, catheter interventional, surgical, and/or pharmacologic anti-ischemic therapy is generally accepted for long-term management.
Survivors of cardiac arrest due to other categories of disease, such as the hypertrophic or dilated cardiomyopathies and the various rare inherited disorders (e.g., right ventricular dysplasia, long QT syndrome, Brugada syndrome, catecholaminergic polymorphic VT, and so-called idiopathic VF), are all considered ICD candidates.
PREVENTION OF SCD IN HIGH-RISK INDIVIDUALS WITHOUT PRIOR CARDIAC ARREST
Post-MI patients with EFs <35% and other markers of risk such as ambient ventricular arrhythmias, inducible ventricular tachyarrhythmias in the electrophysiology laboratory, and a history of heart failure are considered candidates for ICDs 40 days or more after the MI. Total mortality benefits in the range of a 20–35% reduction over 2–5 years have been observed in a series of clinical trials. One study suggested that an EF <30% was a sufficient marker of risk to indicate ICD benefit, and another demonstrated benefit for patients with Functional Class 2 or 3 heart failure and EFs ≤35%, regardless of etiology (ischemic or nonischemic) or the presence of ambient or induced arrhythmias (Chaps. 277 and 279). For patients with newly diagnosed heart failure and an EF <35%, the required delay between diagnosis and institution of medical therapy, and subsequent implantation of an ICD, is 90 days. In general, there appears to be a gradient of increasing ICD benefit with EFs ranging lower than the threshold indications. However, patients with very low EFs (e.g., <20%) may receive less benefit.
Decision making for primary prevention in disorders other than coronary artery disease and dilated cardiomyopathy is generally driven by observational data and judgment based on clinical observations. Controlled clinical trials providing evidence-based indicators for ICDs are lacking for these smaller population subgroups. In general, for the rare disorders listed above, indicators of arrhythmic risk such as syncope, documented ventricular tachyarrhythmias, aborted cardiac arrest, or a family history of premature SCD in some conditions, and a number of other clinical or ECG markers, may be used as indicators for ICDs.
SECTION 3 |
NEUROLOGIC CRITICAL CARE |
328 |
Coma |
Coma is among the most common and striking problems in general medicine. It accounts for a substantial portion of admissions to emergency wards and occurs on all hospital services. It demands immediate attention and requires an organized approach.
There is a continuum of states of reduced alertness, the most severe form being coma, defined as a deep sleeplike state from which the patient cannot be aroused. Stupor refers to a higher degree of arousability in which the patient can be transiently awakened by vigorous stimuli, accompanied by motor behavior that leads to avoidance of uncomfortable or aggravating stimuli. Drowsiness, which is familiar to all persons, simulates light sleep and is characterized by easy arousal and the persistence of alertness for brief periods. Drowsiness and stupor are usually accompanied by some degree of confusion (Chap. 34). A precise narrative description of the level of arousal and of the type of responses evoked by various stimuli as observed at the bedside is preferable to ambiguous terms such as lethargy, semicoma, or obtundation.
Several conditions that render patients unresponsive and simulate coma are considered separately because of their special significance. The vegetative state signifies an awake-appearing but nonresponsive state in a patient who has emerged from coma. In the vegetative state, the eyelids may open, giving the appearance of wakefulness. Respiratory and autonomic functions are retained. Yawning, coughing, swallowing, and limb and head movements persist, and the patient may follow visually presented objects, but there are few, if any, meaningful responses to the external and internal environment—in essence, an “awake coma.” The term vegetative is unfortunate because it is subject to misinterpretation. There are always accompanying signs that indicate extensive damage in both cerebral hemispheres, e.g., decerebrate or decorticate limb posturing and absent responses to visual stimuli (see below). In the closely related but less severe minimally conscious state, the patient displays rudimentary vocal or motor behaviors, often spontaneous, but some in response to touch, visual stimuli, or command. Cardiac arrest with cerebral hypoperfusion and head injuries are the most common causes of the vegetative and minimally conscious states (Chaps. 327 and 330). The prognosis for regaining mental faculties once the vegetative state has supervened for several months is very poor, and after a year, almost nil; hence the term persistent vegetative state. Most reports of dramatic recovery, when investigated carefully, are found to yield to the usual rules for prognosis, but there have been rare instances in which recovery has occurred to a severely disabled condition and, in rare childhood cases, to an even better state. The possibility of incorrectly attributing meaningful behavior to patients in the vegetative and minimally conscious states creates inordinate problems and anguish. On the other hand, the question of whether these patients lack any capability for cognition has been reopened by functional imaging studies that have demonstrated, in a small proportion of posttraumatic cases, meaningful cerebral activation in response to verbal and other stimuli.
Apart from the above conditions, several syndromes that affect alertness are prone to be misinterpreted as stupor or coma. Akinetic mutism refers to a partially or fully awake state in which the patient is able to form impressions and think, as demonstrated by later recounting of events, but remains virtually immobile and mute. The condition results from damage in the regions of the medial thalamic nuclei or the frontal lobes (particularly lesions situated deeply or on the orbitofrontal surfaces) or from extreme hydrocephalus. The term abulia describes a milder form of akinetic mutism characterized by mental and physical slowness and diminished ability to initiate activity. It is also usually the result of damage to the frontal lobes and its connections (Chap. 36).
Catatonia is a curious hypomobile and mute syndrome that occurs as part of a major psychosis, usually schizophrenia or major depression. Catatonic patients make few voluntary or responsive movements, although they blink, swallow, and may not appear distressed. There are nonetheless signs that the patient is responsive, although it may take ingenuity on the part of the examiner to demonstrate them. For example, eyelid elevation is actively resisted, blinking occurs in response to a visual threat, and the eyes move concomitantly with head rotation, all of which are inconsistent with the presence of a brain lesion causing unresponsiveness. It is characteristic but not invariable in catatonia for the limbs to retain the postures in which they have been placed by the examiner (“waxy flexibility,” or catalepsy). With recovery, patients often have some memory of events that occurred during their catatonic stupor. Catatonia is superficially similar to akinetic mutism, but clinical evidence of cerebral damage such as Babinski signs and hypertonicity of the limbs is lacking. The special problem of coma in brain death is discussed below.
The locked-in state describes yet another type of pseudocoma in which an awake patient has no means of producing speech or volitional movement but retains voluntary vertical eye movements and lid elevation, thus allowing the patient to signal with a clear mind. The pupils are normally reactive. Such individuals have written entire treatises using Morse code. The usual cause is an infarction or hemorrhage of the ventral pons that transects all descending motor (corticospinal and corticobulbar) pathways. A similar awake but de-efferented state occurs as a result of total paralysis of the musculature in severe cases of Guillain-Barré syndrome (Chap. 460), critical illness neuropathy (Chap. 330), and pharmacologic neuromuscular blockade.
THE ANATOMY AND PHYSIOLOGY OF COMA
Almost all instances of diminished alertness can be traced to widespread abnormalities of the cerebral hemispheres or to reduced activity of a special thalamocortical alerting system termed the reticular activating system (RAS). The proper functioning of this system, its ascending projections to the cortex, and the cortex itself are required to maintain alertness and coherence of thought. It follows that the principal causes of coma are (1) lesions that damage the RAS in the upper midbrain or its projections; (2) destruction of large portions of both cerebral hemispheres; or (3) suppression of reticulocerebral function by drugs, toxins, or metabolic derangements such as hypoglycemia, anoxia, uremia, and hepatic failure.
The proximity of the RAS to midbrain structures that control pupillary function and eye movements permits clinical localization of the cause of coma in many cases. Pupillary enlargement with loss of light reaction and loss of vertical and adduction movements of the eyes suggests that the lesion is in the upper brainstem where the nuclei subserving these functions reside. Conversely, preservation of pupillary light reactivity and of eye movements absolves the upper brainstem and indicates that widespread structural lesions or metabolic suppression of the cerebral hemispheres is responsible for coma.
Coma Due to Cerebral Mass Lesions and Herniations In addition to the fixed restriction of the skull, the cranial cavity is separated into compartments by infoldings of the dura. The two cerebral hemispheres are separated by the falx, and the anterior and posterior fossae by the tentorium. Herniation refers to displacement of brain tissue by an overlying or adjacent mass into a contiguous compartment that it normally does not occupy. Coma and many of its associated signs can be attributed to these tissue shifts, and certain clinical features are characteristic of specific configurations of herniation (Fig. 328-1). They are in essence “false localizing” signs because they derive from compression of brain structures at a distance from the mass.
FIGURE 328-1 Types of cerebral herniation: (A) uncal; (B) central; (C) transfalcial; and (D) foraminal.
In the most common form of herniation, brain tissue is displaced from the supratentorial to the infratentorial compartment through the tentorial opening; this is referred to as transtentorial herniation. Uncal transtentorial herniation refers to impaction of the anterior medial temporal gyrus (the uncus) into the tentorial opening just anterior to and adjacent to the midbrain (Fig. 328-1A). The uncus compresses the third nerve as the nerve traverses the subarachnoid space, causing enlargement of the ipsilateral pupil (the fibers subserving parasympathetic pupillary function are located peripherally in the nerve). The coma that follows is due to compression of the midbrain against the opposite tentorial edge by the displaced parahippocampal gyrus (Fig. 328-2). Lateral displacement of the midbrain may compress the opposite cerebral peduncle against the tentorial edge, producing a Babinski sign and hemiparesis contralateral to the hemiparesis that resulted from the mass (the Kernohan-Woltman sign). Herniation may also compress the anterior and posterior cerebral arteries as they pass over the tentorial reflections, with resultant brain infarction. The distortions may also entrap portions of the ventricular system, resulting in hydrocephalus.
FIGURE 328-2 Coronal (A) and axial (B) magnetic resonance images from a stuporous patient with a left third nerve palsy as a result of a large left-sided subdural hematoma (seen as a gray-white rim). The upper midbrain and lower thalamic regions are compressed and displaced horizontally away from the mass, and there is transtentorial herniation of the medial temporal lobe structures, including the uncus anteriorly. The lateral ventricle opposite to the hematoma has become enlarged as a result of compression of the third ventricle.
Central transtentorial herniation denotes a symmetric downward movement of the thalamic structures through the tentorial opening with compression of the upper midbrain (Fig. 328-1B). Miotic pupils and drowsiness are the heralding signs, in contrast to a unilaterally enlarged pupil of the uncal syndrome. Both uncal and central transtentorial herniations cause progressive compression of the brainstem, with initial damage to the midbrain, then the pons, and finally the medulla. The result is an approximate sequence of neurologic signs that corresponds to each affected level. Other forms of herniation are transfalcial herniation (displacement of the cingulate gyrus under the falx and across the midline, Fig. 328-1C) and foraminal herniation (downward forcing of the cerebellar tonsils into the foramen magnum, Fig. 328-1D), which causes compression of the medulla, respiratory arrest, and death.
A direct relationship between the various configurations of transtentorial herniation and coma is not always found. Drowsiness and stupor can occur with moderate horizontal displacement of the diencephalon (thalamus), before transtentorial herniation is evident. This lateral shift may be quantified on axial images of computed tomography (CT) and magnetic resonance imaging (MRI) scans (Fig. 328-2). In cases of acutely enlarging masses, horizontal displacement of the pineal calcification of 3–5 mm is generally associated with drowsiness, 6–8 mm with stupor, and >9 mm with coma. Intrusion of the medial temporal lobe into the tentorial opening is also apparent on MRI and CT scans as obliteration of the cisterna that surrounds the upper brainstem.
Coma due to Metabolic Disorders Many systemic metabolic abnormalities cause coma by interrupting the delivery of energy substrates (e.g., oxygen, glucose) or by altering neuronal excitability (drugs and alcohol, anesthesia, and epilepsy). The metabolic abnormalities that produce coma may, in milder forms, induce an acute confusional state. Thus, in metabolic encephalopathies, clouded consciousness and coma are in a continuum.
Cerebral neurons are fully dependent on cerebral blood flow (CBF) and the delivery of oxygen and glucose. CBF is ~75 mL per 100 g/min in gray matter and 30 mL per 100 g/min in white matter (mean ~55 mL per 100 g/min); oxygen consumption is 3.5 mL per 100 g/min, and glucose utilization is 5 mg per 100 g/min. Brain stores of glucose are able to provide energy for ~2 min after blood flow is interrupted, and oxygen stores last 8–10 s after the cessation of blood flow. Simultaneous hypoxia and ischemia exhaust glucose more rapidly. The electroencephalogram (EEG) rhythm in these circumstances becomes diffusely slowed, typical of metabolic encephalopathies, and as substrate delivery worsens, eventually brain electrical activity ceases.
Unlike hypoxia-ischemia, which causes neuronal destruction, most metabolic disorders such as hypoglycemia, hyponatremia, hyperosmolarity, hypercapnia, hypercalcemia, and hepatic and renal failure cause only minor neuropathologic changes. The reversible effects of these conditions on the brain are not understood but may result from impaired energy supplies, changes in ion fluxes across neuronal membranes, and neurotransmitter abnormalities. For example, the high ammonia concentration of hepatic coma interferes with cerebral energy metabolism and with the Na+, K+-ATPase pump, increases the number and size of astrocytes, and causes increased concentrations of potentially toxic products of ammonia metabolism; it may also affect neurotransmitters, including the production of putative “false” neurotransmitters that are active at receptor sites. Apart from hyperammonemia, which of these mechanisms is of critical importance is not clear. The mechanism of the encephalopathy of renal failure is also not known. Unlike ammonia, urea does not produce central nervous system (CNS) toxicity, and a multifactorial causation has been proposed for the encephalopathy, including increased permeability of the blood-brain barrier to toxic substances such as organic acids and an increase in brain calcium and cerebrospinal fluid (CSF) phosphate content.
Coma and seizures are common accompaniments of large shifts in sodium and water balance in the brain. These changes in osmolarity arise from systemic medical disorders, including diabetic ketoacidosis, the nonketotic hyperosmolar state, and hyponatremia from any cause (e.g., water intoxication, excessive secretion of antidiuretic hormone, or atrial natriuretic peptides). Sodium levels <125 mmol/L induce confusion, and levels <115 mmol/L are typically associated with coma and convulsions. In hyperosmolar coma, the serum osmolarity is generally >350 mosmol/L. Hypercapnia depresses the level of consciousness in proportion to the rise in carbon dioxide (CO2) tension in the blood. In all of these metabolic encephalopathies, the degree of neurologic change depends to a large extent on the rapidity with which the serum changes occur. The pathophysiology of other metabolic encephalopathies such as those due to hypercalcemia, hypothyroidism, vitamin B12 deficiency, and hypothermia are incompletely understood but must reflect derangements of CNS biochemistry, membrane function, or neurotransmitters.
Epileptic Coma Generalized electrical seizures are associated with coma, even in the absence of motor convulsions (nonconvulsive status epilepticus). The self-limited coma that follows a seizure, the postictal state, may be due to exhaustion of energy reserves or effects of locally toxic molecules that are the by-product of seizures. The postictal state produces continuous, generalized slowing of the background EEG activity similar to that of metabolic encephalopathies.
Toxic (Including Drug-Induced) Coma This common class of encephalopathy is in large measure reversible and leaves no residual damage provided there has not been cardiorespiratory failure. Many drugs and toxins are capable of depressing nervous system function. Some produce coma by affecting both the brainstem nuclei, including the RAS, and the cerebral cortex. The combination of cortical and brainstem signs, which occurs in certain drug overdoses, may lead to an incorrect diagnosis of structural brainstem disease. Overdose of medications that have atropinic actions produces signs such as dilated pupils, tachycardia, and dry skin; opiate overdose produces pinpoint pupils <1 mm in diameter.
Coma due to Widespread Damage to the Cerebral Hemispheres This category, comprising a number of unrelated disorders, results from widespread structural cerebral damage that simulates a metabolic disorder of the cortex. Hypoxia-ischemia is perhaps the best characterized and one in which it is not possible initially to distinguish the acute reversible effects of oxygen deprivation of the brain from the subsequent effects of anoxic neuronal damage. Similar widespread cerebral damage may be produced by disorders that occlude small blood vessels throughout the brain; examples include cerebral malaria, thrombotic thrombocytopenic purpura, and hyperviscosity. Diffuse white matter damage from cranial trauma or inflammatory demyelinating diseases can cause a similar coma syndrome.
APPROACH TO THE PATIENT:
Coma
A video examination of the comatose patient is shown in Chap. 329e.
Acute respiratory and cardiovascular problems should be attended to prior to neurologic assessment. In most instances, a complete medical evaluation, except for vital signs, funduscopy, and examination for nuchal rigidity, may be deferred until the neurologic evaluation has established the severity and nature of coma. The approach to the patient with coma from cranial trauma is discussed in Chap. 457e.
HISTORY
The cause of coma may be immediately evident as in cases of trauma, cardiac arrest, or observed drug ingestion. In the remainder, certain points are useful: (1) the circumstances and rapidity with which neurologic symptoms developed; (2) the antecedent symptoms (confusion, weakness, headache, fever, seizures, dizziness, double vision, or vomiting); (3) the use of medications, drugs, or alcohol; and (4) chronic liver, kidney, lung, heart, or other medical disease. Direct interrogation of family, observers, and ambulance technicians on the scene, in person or by telephone, is an important part of the evaluation when possible.
GENERAL PHYSICAL EXAMINATION
Fever suggests a systemic infection, bacterial meningitis, encephalitis, heat stroke, neuroleptic malignant syndrome, malignant hyperthermia due to anesthetics, or anticholinergic drug intoxication. Only rarely is fever attributable to a lesion that has disturbed hypothalamic temperature-regulating centers (“central fever”). A slight elevation in temperature may follow vigorous convulsions. Hypothermia is observed with exposure that attends alcohol, barbiturate, sedative, or phenothiazine intoxication; hypoglycemia; peripheral circulatory failure; or extreme hypothyroidism. Hypothermia itself causes coma when the temperature is <31°C (87.8°F). Tachypnea may indicate systemic acidosis or pneumonia or, rarely, infiltration of the brain with lymphoma. Aberrant respiratory patterns that reflect brainstem disorders are discussed below. Marked hypertension suggests hypertensive encephalopathy or cerebral hemorrhage or head injury. Hypotension is characteristic of coma from alcohol or barbiturate intoxication, internal hemorrhage, myocardial infarction, sepsis, profound hypothyroidism, or Addisonian crisis. The funduscopic examination can detect subarachnoid hemorrhage (subhyaloid hemorrhages), hypertensive encephalopathy (exudates, hemorrhages, vessel-crossing changes, papilledema), and increased intracranial pressure (ICP) (papilledema). Cutaneous petechiae suggest thrombotic thrombocytopenic purpura, meningococcemia, or a bleeding diathesis associated with an intracerebral hemorrhage. Cyanosis and reddish or anemic skin coloration are other indications of an underlying systemic disease or carbon monoxide as responsible for the coma.
NEUROLOGIC EXAMINATION
The patient should be observed without intervention by the examiner. Tossing about in the bed, reaching up toward the face, crossing legs, yawning, swallowing, coughing, or moaning reflect a drowsy state that is close to normal awakeness. Lack of restless movements on one side or an outturned leg suggests a hemiplegia. Intermittent twitching movements of a foot, finger, or facial muscle may be the only sign of seizures. Multifocal myoclonus almost always indicates a metabolic disorder, particularly uremia, anoxia, drug intoxication (especially with lithium or haloperidol), or a prion disease (Chap. 453e). In a drowsy and confused patient, bilateral asterixis is a certain sign of metabolic encephalopathy or drug intoxication.
Decorticate rigidity and decerebrate rigidity, or “posturing,” describe stereotyped arm and leg movements occurring spontaneously or elicited by sensory stimulation. Flexion of the elbows and wrists and supination of the arm (decorticate posturing) suggests bilateral damage rostral to the midbrain, whereas extension of the elbows and wrists with pronation (decerebrate posturing) indicates damage to motor tracts in the midbrain or caudal diencephalon. The less frequent combination of arm extension with leg flexion or flaccid legs is associated with lesions in the pons. These concepts have been adapted from animal work and cannot be applied with precision to coma in humans. In fact, acute and widespread disorders of any type, regardless of location, frequently cause limb extension, and almost all extensor posturing becomes predominantly flexor as time passes.
LEVEL OF AROUSAL
A sequence of increasingly intense stimuli is used to determine the threshold for arousal and the motor response of each side of the body. The results of testing may vary from minute to minute, and serial examinations are useful. Tickling the nostrils with a cotton wisp is a moderate stimulus to arousal—all but deeply stuporous and comatose patients will move the head away and arouse to some degree. An even greater degree of responsiveness is present if the patient uses his hand to remove an offending stimulus. Pressure on the knuckles or bony prominences and pinprick stimulation are humane forms of noxious stimuli; pinching the skin causes unsightly ecchymoses and is generally not necessary but may be useful in eliciting abduction withdrawal movements of the limbs. Posturing in response to noxious stimuli indicates severe damage to the corticospinal system, whereas abduction-avoidance movement of a limb is usually purposeful and denotes an intact corticospinal system. Posturing may also be unilateral and coexist with purposeful limb movements, reflecting incomplete damage to the motor system.
BRAINSTEM REFLEXES
Assessment of brainstem function is essential to localization of the lesion in coma (Fig. 328-3). The brainstem reflexes that are examined are pupillary size and reaction to light, spontaneous and elicited eye movements, corneal responses, and the respiratory pattern. As a rule, coma due to bilateral hemispheral disease preserves these brainstem activities, particularly the pupillary reactions and eye movements. However, the presence of abnormal brainstem signs does not always indicate that the primary lesion is in the brainstem because hemispheral masses can cause secondary brainstem damage by the earlier described transtentorial herniations.
FIGURE 328-3 Examination of brainstem reflexes in coma. Midbrain and third nerve function are tested by pupillary reaction to light, pontine function by spontaneous and reflex eye movements and corneal responses, and medullary function by respiratory and pharyngeal responses. Reflex conjugate, horizontal eye movements are dependent on the medial longitudinal fasciculus (MLF) interconnecting the sixth and contralateral third nerve nuclei. Head rotation (oculocephalic reflex) or caloric stimulation of the labyrinths (oculovestibular reflex) elicits contraversive eye movements (for details see text).
Pupillary Signs Pupillary reactions are examined with a bright, diffuse light (preferably not an ophthalmoscope, which illuminates only a limited part of the retina). Reactive and round pupils of midsize (2.5–5 mm) essentially exclude midbrain damage, either primary or secondary to compression. A response to light may be difficult to appreciate in pupils <2 mm in diameter, and bright room lighting mutes pupillary reactivity. One enlarged and poorly reactive pupil (>6 mm) signifies compression or stretching of the third nerve from the effects of a cerebral mass above. Enlargement of the pupil contralateral to a hemispheral mass may occur but is infrequent. An oval and slightly eccentric pupil is a transitional sign that accompanies early midbrain–third nerve compression. The most extreme pupillary sign, bilaterally dilated and unreactive pupils, indicates severe midbrain damage, usually from compression by a supratentorial mass. Ingestion of drugs with anticholinergic activity, the use of mydriatic eye drops, and direct ocular trauma are among the causes of misleading pupillary enlargement.
Unilateral miosis in coma has been attributed to dysfunction of sympathetic efferents originating in the posterior hypothalamus and descending in the tegmentum of the brainstem to the cervical cord. It is therefore of limited localizing value but is an occasional finding in patients with a large cerebral hemorrhage that affects the thalamus. Reactive and bilaterally small (1–2.5 mm) but not pinpoint pupils are seen in metabolic encephalopathies or in deep bilateral hemispheral lesions such as hydrocephalus or thalamic hemorrhage. Even smaller reactive pupils (<1 mm) characterize narcotic or barbiturate overdoses but also occur with extensive pontine hemorrhage. The response to naloxone and the presence of reflex eye movements (see below) assist in distinguishing between these.
Ocular Movements The eyes are first observed by elevating the lids and observing the resting position and spontaneous movements of the globes. Lid tone, tested by lifting the eyelids and noting their resistance to opening and the speed of closure, is progressively reduced as unresponsiveness progresses. Horizontal divergence of the eyes at rest is normal in drowsiness. As coma deepens, the ocular axes may become parallel again.
Spontaneous eye movements in coma often take the form of conjugate horizontal roving. This finding alone exonerates damage in the midbrain and pons and has the same significance as normal reflex eye movements (see below). Conjugate horizontal ocular deviation to one side indicates damage to the pons on the opposite side or, alternatively, to the frontal lobe on the same side. This phenomenon is summarized by the following maxim: The eyes look toward a hemispheral lesion and away from a brainstem lesion. Seizures also drive the eyes to one side but usually with superimposed clonic movements of the globes. The eyes may occasionally turn paradoxically away from the side of a deep hemispheral lesion (“wrong-way eyes”). The eyes turn down and inward with thalamic and upper midbrain lesions, typically thalamic hemorrhage. “Ocular bobbing” describes brisk downward and slow upward movements of the eyes associated with loss of horizontal eye movements and is diagnostic of bilateral pontine damage, usually from thrombosis of the basilar artery. “Ocular dipping” is a slower, arrhythmic downward movement followed by a faster upward movement in patients with normal reflex horizontal gaze; it usually indicates diffuse cortical anoxic damage.
The oculocephalic reflexes, elicited by moving the head from side to side or vertically and observing eye movements in the direction opposite to the head movement, depend on the integrity of the ocular motor nuclei and their interconnecting tracts that extend from the midbrain to the pons and medulla (Fig. 328-3). The movements, called somewhat inappropriately “doll’s eyes” (which refers more accurately to the reflex elevation of the eyelids with flexion of the neck), are normally suppressed in the awake patient. The ability to elicit them therefore reflects both reduced cortical influence on the brainstem and intact brainstem pathways, indicating that coma is caused by a lesion or dysfunction in the cerebral hemispheres. The opposite, an absence of reflex eye movements, usually signifies damage within the brainstem but can result from overdoses of certain drugs. In this circumstance, normal pupillary size and light reaction distinguishes most drug-induced comas from structural brainstem damage.
Thermal, or “caloric,” stimulation of the vestibular apparatus (oculovestibular response) provides a more intense stimulus for the oculocephalic reflex but provides essentially the same information. The test is performed by irrigating the external auditory canal with cool water in order to induce convection currents in the labyrinths. After a brief latency, the result is tonic deviation of both eyes to the side of cool-water irrigation and nystagmus in the opposite direction. (The acronym “COWS” has been used to remind generations of medical students of the direction of nystagmus—“cold water opposite, warm water same.”) The loss of induced conjugate ocular movements indicates brainstem damage. The presence of corrective nystagmus indicates that the frontal lobes are functioning and connected to the brainstem; thus catatonia or hysterical coma is likely.
By touching the cornea with a wisp of cotton, a response consisting of brief bilateral lid closure is normally observed. The corneal reflex depends on the integrity of pontine pathways between the fifth (afferent) and both seventh (efferent) cranial nerves; in conjunction with reflex eye movements, it is a useful test of pontine function. CNS-depressant drugs diminish or eliminate the corneal responses soon after reflex eye movements are paralyzed but before the pupils become unreactive to light. The corneal (and pharyngeal) response may be lost for a time on the side of an acute hemiplegia.
Respiratory Patterns These are of less localizing value in comparison to other brainstem signs. Shallow, slow, but regular breathing suggests metabolic or drug depression. Cheyne-Stokes respiration in its typical cyclic form, ending with a brief apneic period, signifies bihemispheral damage or metabolic suppression and commonly accompanies light coma. Rapid, deep (Kussmaul) breathing usually implies metabolic acidosis but may also occur with pontomesencephalic lesions. Agonal gasps are the result of lower brainstem (medullary) damage and are recognized as the terminal respiratory pattern of severe brain damage. A number of other cyclic breathing variations have been described but are of lesser significance.
LABORATORY STUDIES AND IMAGING
The studies that are most useful in the diagnosis of coma are chemical-toxicologic analysis of blood and urine, cranial CT or MRI, EEG, and CSF examination. Arterial blood gas analysis is helpful in patients with lung disease and acid-base disorders. The metabolic aberrations commonly encountered in clinical practice are usually exposed by measurement of electrolytes, glucose, calcium, osmolarity, and renal (blood urea nitrogen) and hepatic (NH3) function. Toxicologic analysis may be necessary in any case of acute coma where the diagnosis is not immediately clear. However, the presence of exogenous drugs or toxins, especially alcohol, does not exclude the possibility that other factors, particularly head trauma, are also contributing to the clinical state. An ethanol level of 43 mmol/L (0.2 g/dL) in nonhabituated patients generally causes impaired mental activity; a level of >65 mmol/L (0.3 g/dL) is associated with stupor. The development of tolerance may allow the chronic alcoholic to remain awake at levels >87 mmol/L (0.4 g/dL).
The availability of CT and MRI has focused attention on causes of coma that are detectable by imaging (e.g., hemorrhage, tumor, or hydrocephalus). Resorting primarily to this approach, although at times expedient, is imprudent because most cases of coma (and confusion) are metabolic or toxic in origin. Furthermore, the notion that a normal CT scan excludes an anatomic lesion as the cause of coma is erroneous. Bilateral hemisphere infarction, acute brainstem infarction, encephalitis, meningitis, mechanical shearing of axons as a result of closed head trauma, sagittal sinus thrombosis, and subdural hematoma isodense to adjacent brain are some of the disorders that may not be detected. Nevertheless, if the source of coma remains unknown, a scan should be obtained.
The EEG (Chap. 442e) is useful in metabolic or drug-induced states but is rarely diagnostic. However, it is the essential test to reveal coma that is due to clinically unrecognized, nonconvulsive seizures, and shows fairly characteristic patterns in herpesvirus encephalitis and prion (Creutzfeldt-Jakob) disease. The EEG may be further helpful in disclosing generalized slowing of the background activity, a reflection of the severity of an encephalopathy. Predominant high-voltage slowing (δ or triphasic waves) in the frontal regions is typical of metabolic coma, as from hepatic failure, and widespread fast (β) activity implicates sedative drugs (e.g., benzodiazepines). A special pattern of “alpha coma,” defined by widespread, variable 8- to 12-Hz activity, superficially resembles the normal α rhythm of waking but, unlike normal α activity, is not altered by environmental stimuli. Alpha coma results from pontine or diffuse cortical damage and is associated with a poor prognosis. Normal α activity on the EEG, which is suppressed by stimulating the patient, also alerts the clinician to the locked-in syndrome or to hysteria or catatonia. Still, the most important use of EEG recordings in coma is to reveal clinically inapparent epileptic discharges.
Lumbar puncture is performed less frequently than in the past for coma diagnosis because neuroimaging effectively excludes intracerebral and extensive subarachnoid hemorrhage. However, examination of the CSF remains indispensable in the diagnosis of meningitis and encephalitis. For patients with an altered level of consciousness, it is generally recommended that an imaging study be performed prior to lumbar puncture to exclude a large intracranial mass lesion. Blood culture and antibiotic administration usually precede the imaging study if meningitis is suspected (Chap. 164).
