Section 2: Shock and Cardiac Arrest

INTRODUCTION

Shock is the clinical condition of organ dysfunction resulting from an imbalance between cellular oxygen supply and demand. This life-threatening condition is common in the intensive care unit (ICU). There are a multitude of heterogeneous disease processes that can lead to shock. The organ dysfunction seen in early shock is reversible with restoration of adequate oxygen supply. Left untreated, shock transitions from this reversible phase to an irreversible phase and death from multisystem organ dysfunction (MSOF). The clinician is required to identify the patient with shock promptly, make a preliminary assessment of the type of shock present, and initiate therapy to prevent irreversible organ dysfunction and death. In this chapter, we review a commonly used classification system that organizes shock into four major types based on the underlying physiologic derangement. We discuss the initial assessment utilizing the history, physical examination, and initial diagnostic testing to confirm the presence of shock and determine the type of shock causing the organ dysfunction. Finally, we will discuss key principles of initial therapy with the aim of reducing the high morbidity and mortality associated with shock.

PATHOPHYSIOLOGY OF SHOCK

The cellular oxygen imbalance of shock is most commonly related to impaired oxygen delivery in the setting of circulatory failure. Shock can also develop during states of increased oxygen consumption or impaired oxygen utilization. An example of the impaired oxygen utilization is cyanide poisoning, which causes uncoupling of oxidative phosphorylation. This chapter will focus on the approach to the patient with shock related to inadequate oxygen delivery.

In the setting of insufficient oxygen supply, the cell is no longer able to support aerobic metabolism. With adequate oxygen, the cell metabolizes glucose to pyruvate, which then enters the mitochondria where ATP is generated via oxidative phosphorylation. Without sufficient oxygen supply, the cell is forced into anaerobic metabolism, in which pyruvate is metabolized to lactate with much less ATP generation (per mole of glucose). Maintenance of the homeostatic environment of the cell is dependent on an adequate supply of ATP. ATP-dependent ion pumping systems, such as the Na+/K+ ATPase, consume 20–80% of the cell’s energy. Inadequate oxygen delivery and subsequent decreased ATP disrupt the cell’s ability to maintain osmotic, ionic, and intracellular pH homeostasis. Influx of calcium can lead to activation of calcium-dependent phospholipases and proteases, causing cellular swelling and death. In addition to direct cell death, cellular hypoxia can cause damage at the organ system level via leakage of the intracellular contents into the extracellular space activating inflammatory cascades and altering the microvascular circulation.

DETERMINANTS OF OXYGEN DELIVERY

Since shock is the clinical manifestation of inadequate oxygen delivery compared to cellular needs, we will review determinants of oxygen delivery (DO₂). Disease processes affecting any of the components of oxygen delivery have the potential to lead to the development of shock. Disturbances to key determinants of oxygen delivery form the basis of the four major shock types described below.

The two major components of DO₂ are cardiac output (CO) and arterial oxygen content (CaO₂):

The two components of CO are heart rate (HR) and stroke volume (SV), which can be substituted in the above equation as

The major determinants of SV are preload, afterload (systemic vascular resistance, SVR), and cardiac contractility. The relationship can be represented as

In this equation, preload refers to the myocardial fiber length before contraction (the ventricular end-diastolic volume). Contractility refers to the ability of the ventricle to contract independent of preload and afterload. The SVR represents the afterload, or the force against which the ventricle must contract.

The CaO₂ is composed of oxygen carried by convection with hemoglobin and oxygen dissolved in blood, given as

A disease process that affects these variables (HR, preload, contractility, SVR, SaO₂, or Hb) has the potential to reduce oxygen delivery and cause cellular hypoxia. Each of the shock types described below has a distinctive physiologic hemodynamic profile corresponding with alterations in one of the variables affecting oxygen delivery described above.

CLASSIFICATION OF SHOCK

While there is a heterogeneous list of specific conditions that can cause shock, it is helpful to categorize these processes into four major shock types based on the primary physiologic derangement leading to reduced oxygen delivery and cellular hypoxia. The four major shock types are distributive, cardiogenic, hypovolemic, and obstructive. Table 296-1 outlines these major shock types as well as specific disease processes that can result in that physiologic derangement. Each shock type has a distinct hemodynamic profile (Table 296-2). Familiarity with the major shock types and their unique hemodynamic profile is essential so that when evaluating a patient presenting with shock, the clinician can use the history, physical examination, and laboratory testing to determine the type of shock present and promptly begin appropriate initial therapy to restore oxygen delivery.

Distributive Shock

Distributive shock is the condition of reduced oxygen delivery where the primary physiologic disturbance is a reduction in SVR. It is unique among the types of shock in that there is a compensatory increase in CO (Table 296-2). The central venous pressure (CVP) and pulmonary capillary wedge pressure (PCWP) are usually reduced. The most common cause of distributive shock is sepsis. Sepsis has recently been redefined as the dysregulated host response to infection resulting in life-threatening organ dysfunction. When this process is accompanied by persistent hypotension requiring vasopressor support, it is classified as septic shock. Other processes that are manifest as cellular hypoxia related to a primary reduction of SVR include pancreatitis, severe burns, and liver failure. Anaphylaxis is predominantly an IgE-mediated allergic reaction that can rapidly develop after exposure to an allergen (food, medication, or insect bite), in which there is a profound distributive type of shock possibly mediated through histamine release. In this setting, there is evidence of both venous and arterial vasodilation. Studies have demonstrated extravasation of up to 35% of the circulating blood volume within 10 min. Patients with severe brain or spinal cord injury may have a reduction of SVR related to disruption of the autonomic pathways that regulate vascular tone. In these patients, there is pooling of blood in the venous system with a resulting decreased venous return and decreased CO. A final category of patients who present with distributive shock are those with adrenal insufficiency. Adrenal insufficiency may be related to chronic steroid use, metastatic malignancy, adrenal hemorrhage, infection (tuberculosis, HIV), autoimmune adrenalitis, or amyloidosis. In conditions of stress (such as infection or surgery), the deficit may become apparent with an inability to increase cortisol leading to vasodilation as well as aldosterone deficiency-mediated hypovolemia.

Cardiogenic Shock

Cardiogenic shock is characterized by reduced oxygen delivery related to a reduction in CO owing to a primary cardiac problem. There is usually a compensatory increase in SVR in cardiogenic shock. When the cardiac process (e.g., myocardial infarction) affects the left ventricle (LV), there will be elevation of the PCWP and when it affects the right ventricle (RV), the CVP will be elevated. As detailed above, the CO (and accordingly the DO₂) can be reduced by alterations in the SV or HR. In cardiogenic shock, the SV may be reduced by processes that affect myocardial contractility (myocardial infarction, ischemic cardiomyopathies, and primary myocarditis) or mechanical valvular disease (acute mitral insufficiency or aortic insufficiency). Both bradyarrhythmias and tachyarrhythmias (from either an atrial or ventricular source) may have associated hemodynamic consequence with a reduction in CO.

Hypovolemic Shock

Hypovolemic shock encompasses disease processes that reduce CO (and oxygen delivery) via a reduction in preload. In addition to the reduced CO, this shock type is characterized by an elevated SVR and low CVP and PCWP related to decreased intravascular volume. Any process causing a reduction in intravascular volume can cause shock of this type. Hypovolemic shock most commonly is related to hemorrhage, that may be external (secondary to trauma) or internal (most commonly upper or lower gastrointestinal [GI]) bleeding. Hypovolemic shock can also be seen with nonhemorrhagic processes. Examples include GI illnesses causing profound emesis or diarrhea, renal losses (osmotic diuresis associated with diabetic ketoacidosis or diabetes insipidus), or skin loss (severe burns, inflammatory conditions such as Stevens-Johnson).

Obstructive Shock

Obstructive shock is also characterized by a reduction in oxygen delivery related to reduced CO, but in this case the etiology of the reduced CO is an extracardiac processes impairing blood flow. Processes that can impede venous return to the heart and reduce CO include tension pneumothorax (PTX), cardiac tamponade, and restrictive pericarditis. Similarly processes that obstruct cardiac outflow, such as pulmonary embolism (right heart) or aortic dissection (left heart), are included in this shock type category.

Mixed Shock

The types of shock outlined in this classification scheme are not mutually exclusive; not uncommonly, a patient will present with more than one type of shock. The initial physiologic disturbance leading to reduced perfusion and cellular hypoxia in sepsis is distributive shock. In this setting, a sepsis-induced cardiomyopathy can develop, which reduces myocardial contractility, thus producing a cardiogenic component to what now would be described as a mixed type of shock.

Undifferentiated Shock

Upon initial presentation, many patients have undifferentiated shock in which the shock type and specific disease process are not apparent. Using the history, physical examination, and initial diagnostic testing (including hemodynamic monitoring), the clinician attempts to classify a patient with one of the types of shock outlined above so that proper therapy can be initiated to restore tissue perfusion and oxygen delivery.

The type of shock seen most commonly is dependent upon the clinical area of practice. In the medical ICU, the largest number of patients have distributive shock related to sepsis. A cardiac ICU will have a population weighted toward cardiogenic or obstructive types of shock. The emergency department will see more of a mix of patients with trauma patients presenting with hypovolemic shock and septic patients having a distributive pathophysiology.

STAGES OF SHOCK

Regardless of type, shock progresses through a continuum of three stages. These stages are compensated shock (preshock), shock (decompensated shock), and irreversible shock. During compensated shock, the body utilizes a variety of physiologic responses to counteract the initial insult and attempts to reestablish the adequate perfusion and oxygen delivery. At this point, there are no overt signs of organ dysfunction. Laboratory evaluation may demonstrate mild organ dysfunction (i.e., elevated creatinine or troponin) or a mild elevation of lactate. The specific compensatory response is determined by the initial pathophysiologic defect. In early sepsis with reduction in SVR, there is a compensatory rise in HR (and CO). With early hemorrhagic volume loss, there will be a compensatory increase in SVR. As the host compensatory responses are overwhelmed, the patient transitions into true shock with evidence organ dysfunction. Appropriate interventions to restore perfusion and oxygen delivery during these initial two phases of shock can reverse the organ dysfunction. If untreated the patient will progress to the third phase of irreversible shock. At this point, the organ dysfunction is permanent and often the patient progresses to MSOF.

EVALUATION OF THE PATIENT WITH SHOCK

The evaluation of the patient with shock utilizes the history, physical examination, and diagnostic testing toward two specific aims. The first aim is confirmation of the presence of shock. Given the reversible nature of the organ dysfunction in early shock, it is important that the clinician has a high clinical suspicion for this condition. The possibility of shock should be considered all patients presenting with new organ dysfunction. This early recognition of the presence of shock is an essential tenet of shock care (Table 296-3). A second aim of the initial assessment (history, physical examination, and diagnostic testing) is to identify either a specific shock etiology or to determine the type of shock present. We will discuss the role of the history, physical examination, and diagnostic testing toward these specific aims. While the assessment of shock etiology is ongoing, the initiation of therapy should not be delayed until the final diagnosis is determined. Evaluation of shock etiology and initiation of therapy should be simultaneous.

History

Obtaining a concise, focused history is essential. If the patient is unable to provide a history, ancillary information from anyone accompanying the patient should be obtained, and a brief chart review should be performed. As the history is being obtained, the clinician must be attentive to any details indicating new organ dysfunction. The most easily identified new organ dysfunction from the history is the presence of a newly altered mental status or decrease in renal function (oliguria). In some cases, the type of shock (and the specific disease process) is apparent from the history. Patients with distributive shock from sepsis may present with fever and a history revealing of a focal site of infection. Anaphylactic distributive shock may be suggested by the onset of hives, dyspnea, and new facial edema after exposure to common allergens. Cardiogenic shock may be identified by the onset of exertional chest discomfort. The patient with significant arrhythmia may have an initial complaint of palpitations with syncope or presyncope. Hypovolemic shock may be identified in patients who present with a history of trauma (blunt or penetrating) or GI bleed (hematemesis, melena, or bright red blood per rectum). A patient with hypertension and tearing chest or back pain may be presenting with acute aortic dissection and obstructive type shock. Acute onset chest pain with dyspnea in the setting of immobility and or underlying malignancy raises concern for obstructive shock due to pulmonary embolism.

For most patients, the specific etiology will be less clear but the history can be helpful in raising the likelihood of a particular type of shock. As an example, a patient with a preexisting immune dysfunction or medication-induced neutropenia may present with hypoperfusion and new organ dysfunction, in which the clinician must have a high suspicion for septic shock. Similarly, a patient with extensive cardiac disease requires a higher suspicion for cardiogenic shock.

Physical Examination

The physical examination should be conducted with the aim of answering two questions. Is shock present (either in compensated stage prior to overt evidence of organ dysfunction or decompensated indicated by the presence of new organ dysfunction)? Secondly, what type of shock is present (distributive, cardiogenic, hypovolemic, or obstructive)?

The physical examination findings present during the compensated phase of shock tend to be nonspecific. These include an elevation of the HR (with the body’s attempt to increase CO) or tachypnea (to compensate for the developing metabolic acidosis). While nonspecific, the clinician should recognize these findings early as they may herald the development of end-organ dysfunction if perfusion and oxygen delivery are not restored. Shock is most commonly seen in the setting of circulatory failure. In most cases, this is manifest as hypotension (a mean arterial pressure [MAP] of <60 mmHg), but this finding is not always present. Many patients may have underlying conditions that cause longstanding low blood pressure without any evidence of organ dysfunction. Alternatively, patients with underlying hypertension may develop organ dysfunction at higher blood pressures.

The physical examination can confirm the presence of shock prior to the return of laboratory testing. The central nervous system (CNS), kidney, and skin are the organ systems most easily assessed for evidence of organ dysfunction. These organ systems are considered the “windows” through which we can identify organ dysfunction. Decreased oxygen delivery to the brain is manifest as confusion and encephalopathy. In the early stage of shock, the body will redirect blood flow to the CNS to maintain adequate perfusion. In the patient with shock and altered mental status, all the usual compensatory mechanisms have been outstripped by the magnitude of shock pathophysiology. New encephalopathy represents decompensated shock. To assess renal function during the physical examination, one should evaluate the patient’s urine output since the time of presentation. If not already present, a urinary catheter should be placed for accurate hourly assessment of urine output. In patients with normal baseline renal function, oliguria (<0.5 mL/kg per h) may indicate shock. Finally, decreased capillary refill and cold and clammy skin are signs of hypoperfusion and shock.

Many components of the examination provide insight into hemodynamics and assist in elucidating the type of shock present. Evaluation of jugular venous pressure (JVP) and peripheral edema can provide insight into right-sided cardiac pressures. Pulmonary auscultation can identify signs of left-sided cardiac dysfunction. The physical examination may be used to differentiate shock with high CO (distributive) from that with low CO (cardiogenic shock, hypovolemic shock, and obstructive shock). Examination findings suggestive of high output shock (distributive) include warm peripheral extremities, brisk capillary refill (<2 s), and bounding pulses. Alternatively, cool extremities, delayed poor capillary refill, or weak pulses would indicate low CO forms of shock. Among those with evidence of low CO, the examination can be used to distinguish between conditions with increased intravascular filling pressure (cardiogenic shock) and intravascular volume depletion (hypovolemic shock). The JVP may be elevated cardiogenic shock (with right-sided failure) and reduced (JVP <8 cm) in hypovolemic shock. The presence of cardiogenic shock would be further supported by an S3 gallop. One must remember, however, that it is well established that patients with chronic heart failure do not present with the classical findings of acute heart failure.

At times, the physical examination may identify the specific etiology of shock. This is particularly helpful in the patient who cannot provide a detailed history. The examination may demonstrate the site of an untreated infection (cellulitis, abscess, infected pressure injury, or focal). The examination may reveal a brady- or tachyarrhythmia leading to development of shock. Similarly, large ecchymosis may indicate a significant bleed related to trauma or spontaneous retroperitoneal bleeding. The rectal examination may reveal GI hemorrhage. Pulsus paradox and elevated JVP may suggest the presence of cardiac tamponade. Patients with a tension PTX may have a paucity of breath sounds over the affected side, deviation of the trachea away from the affected side, or subcutaneous emphysema.

Combinations of easily assessed examination components have been combined to create a scoring system to identify high risk patient populations. The shock index (SI) is defined as the HR/systolic blood pressure (SBP) with a normal SI being 0.5–0.7. An elevated SI (>0.9) has been proposed to be a more sensitive indicator of transfusion requirement and of patients with critical bleeding among those with hypovolemic (hemorrhagic) shock than either HR or BP alone. The SI may also identify patients at risk for postintubation hypotension. This concept of use of a clinical score to identify at-risk patients has been extended to patients with distributive shock from sepsis. The quick Sequential Organ Failure Assessment (qSOFA) score is a rapid assessment scale that assigns a point for SBP <100, respiratory rate >22, or altered mental status (Glasgow Coma Scale <15). A qSOFA ≥2 (with a concern for infection) is associated with a significantly greater risk of death or prolonged ICU stay. The Third International Consensus Definition of Sepsis has recommended the use of the qSOFA to identify the most acutely ill subset of patients with sepsis (longer length of stay, increased need for ICU admission, and higher in-hospital mortality).

Diagnostic Testing

Laboratory evaluation should be initiated promptly in all patients with suspected shock. The laboratory evaluation is directed toward the dual aim of assessing the extent of end-organ dysfunction and of gaining insight into the possible etiology of shock. Table 296-4 outlines the recommended initial laboratory evaluation of the patient with undifferentiated shock.

BLOOD TESTS

Evaluation of blood urea nitrogen (BUN), creatinine, and transaminases provide an assessment of the extent of end-organ dysfunction related to shock. Urine electrolytes with subsequent calculation of the fractional excretion of sodium (FENa) or fractional excretion of urea (FEUrea) may indicate states of hypovolemia or decreased effective circulating volume. Elevation of alkaline phosphatase may suggest biliary obstruction and may thereby identify a source of infection in patients with distributive shock. Elevation of cardiac enzymes can indicate a primary cardiac problem with myocyte damage related to ischemia, myocarditis, or a pulmonary embolism. An elevation of the white blood cell count may raise suspicion for an infective process, but this is certainly not diagnostic; an accompanying left shift may improve the sensitivity of this measure. While the extent of acidosis may be determined with a venous blood gas (VBG), if there is accompanying hypoxemia an arterial blood gas should be obtained. For patients with undifferentiated shock, there should always be a high index of suspicion for possible infection. Urinalysis and urine sediment should be sent to evaluate for pyuria. Blood cultures, urine cultures, and sputum cultures should be obtained. Radiographic evaluation should be directed to seek sources of infection suggested by the history and physical examination.

Lactate measurement has a role in the diagnosis, risk stratification, and, potentially, the treatment of shock. Increased lactate (hyperlactemia) and lactic acidosis (hyperlactemia and pH <7.35) are common in shock. Lactate is a product of anaerobic glucose metabolism. In glycolysis, the enzyme phosphofuctokinase metabolizes glucose to pyruvate. Under aerobic conditions, the pyruvate is then converted (in the mitochondria) to acetyl CoA and enters the Krebs cycle with resulting ATP generation through oxidative phosphorylation. In the setting of cellular hypoxia, the Krebs (tricarboxylic acid) cycle cannot oxidize the pyruvate, and thus, the pyruvate is converted to lactate by the enzyme lactate dehydrogenase. Under normal conditions, lactate is produced from skeletal muscle, brain, skin, and intestine. In the setting of reduced oxygen delivery and cellular hypoxia, the amount of lactate produced from these tissues increases (and other tissue can begin to produce lactate). While most of the studies have been performed in patients with septic shock, there is evidence that elevated lactate correlates with a worse outcome. A recent systematic literature review evaluating the role of lactate measurement in a variety of critically ill populations supported the value of serial lactate measurements in the evaluation of critically ill patients and their response to therapy.

ECG

The electrocardiogram (ECG) is an essential part of the evaluation of the patient with shock. There may be a bradycardia or tachycardic arrhythmia causing a reduction in CO. ST segment elevation myocardial infarction may be identified. The presence of the S1 Q3 T3 pattern would raise concerns for pulmonary embolism. Reduced voltage in the presence of electrical alternans raises the possibility of pericardial tamponade.

Echocardiography

Echocardiography is increasingly used as an essential tool to help categorize shock, and it provides an assessment that is both rapid and noninvasive. Familiarity with basic echocardiographic techniques and interpretation is now expected in the critical care setting. Accordingly, competency standards have been proposed for critical care providers in both basic and advanced echocardiographic techniques. The bedside echocardiogam performed by the ICU team does not replace a formal examination performed by the echocardiography service.

The basic echocardiographic assessment for the shock patient is transthoracic echocardiography (TTE) utilizing both the two-dimensional (2D) and M mode. Standardized, focused echocardiography protocols such as the RACE protocol (rapid assessment for cardiac echocardiography) have been introduced to facilitate the assessment of cardiac function. It focuses the examination on LV function, RV function, and pericardium. It also can assess volume, but the use of echocardiography for volume assessment will be discussed in the section below.

The 2D mode can evaluate LV size, wall thickness, and ventricular function. Ventricular size and thickness can suggest longer standing cardiac processes. Evaluation of LV function through estimation of left ventricular ejection fraction (LVEF), and can identify shock with globally reduced LV function or regional wall motion abnormalities. Similarly, the assessment of RV function also examines RV size and wall thickness (to identify conditions such as elevated pulmonary pressures or suggest pulmonary embolism), and also evaluate the patient for pericardial tamponade. Two-dimensional echocardiography can also be used to assess valve function, including acute processes, such as mitral valve rupture. Assessment of valvular function is often a process that requires a higher skilled practitioner. The performance of the bedside echocardiogram by the critical care practitioner does not replace formal assessment by a cardiologist.

INITIAL TREATMENT of SHOCK

Since shock can progress rapidly to an irreversible stage, a key principle in shock management is to initiate treatment for circulatory shock simultaneous with efforts to elucidate shock etiology (Table 296-3). If the initial history, physical examination, and laboratory evaluation have identified the shock type or the specific etiology, then therapy is directed to reverse the underlying physiologic abnormality causing the hypoperfusion and reduced oxygen delivery. Details of the optimal care for the specific disease processes leading to shock may be found in other chapters of this text. As many patients will present with undifferentiated shock, in this section we will discuss treatment directed at the patient with undifferentiated shock. At the conclusion of this section, we will highlight etiologies of shock that require initiation of lifesaving specific therapy.

The development of shock is a medical emergency, and optimal therapy involves the involvement of a multidisciplinary team to allow the evaluation and initiation of therapy to begin simultaneously. Patients must be treated in a setting where adequate resources are available to support frequent reassessments and invasive monitoring. Most patients with shock should be cared for in an ICU setting.

A key early consideration is to ensure adequate intravenous access. Placement of a peripheral venous catheter (16G or 18G) will provide initial access for the aggressive volume resuscitation that is required for patients with distributive or hypovolemic shock. If there is concern for distributive shock with sepsis, this IV access will also permit prompt antibiotic administration. For patients with ongoing hypotension despite adequate volume resuscitation, placement of a central venous catheter (CVC) is indicated to provide therapy with vasopressors and inotropes. The CVC will provide a mechanism for hemodynamic monitoring (CVP) as well as a means to obtain central venous oxygen saturations (ScvO₂). The ScvO₂ is a surrogate of mixed venous oxygen saturation, and, thus, can provide insight into the adequacy of oxygen delivery. Central venous access using a sheath will provide an access point for placement of a Swan Ganz catheter if more detailed assessment of hemodynamic measurements are required (PCWP, CO, and SVR). If the patient presents critically ill or in the midst of cardiopulmonary arrest, the quickest method of obtaining central access will be through the use of an intraosseous device. Placement of an arterial line allows for intravascular measurement of blood pressure and continuous determination of MAP. In addition, it can provide insight into the adequacy of volume resuscitation through the measurement of systolic or pulse pressure variation. The arterial line will provide access for determination of arterial oxygen tension, which is helpful since peripheral oximetry measurements (SpO₂) can be unreliable in states of tissue hypoperfusion. The arterial line facilitates repeated measures of acid base status or lactate to assess the impact of treatment. All patients with shock should have a urinary catheter placed to permit hourly assessment of renal function as another potential indication of the adequacy of resuscitation.

Volume Resuscitation

Initial volume resuscitation has the aim of restoring tissue perfusion and is crucial to optimal shock therapy. Assessment of current intravascular volume status and determination of the optimal amount of volume resuscitation are challenging. The physiologic goal of volume resuscitation is to move the patient to the nonpreload-dependent portion of the Starling curve. Most patients with any of the four shock types will benefit from an increase in intravascular volume. For patients with distributive shock, the need for early aggressive volume replacement is well established. In the past, the use of early goal-directed therapy (EGDT) in septic shock targeted specific measures of CVP, MAP, and SvO₂ to guide volume resuscitation (and initiation of vasopressors and inotropes). More recent studies have demonstrated that targeted resuscitation using invasive monitoring is not required, but in all of these studies patients in the “usual care” arms of the study received early initial volume resuscitation. For patients with suspected septic shock, a minimum of 30 mL/kg is recommended by the Surviving Sepsis Campaign. While the need for volume resuscitation is most apparent for patients with distributive or hypovolemic shock, even patients with cardiogenic shock may benefit by cautious volume replacement. In these patients, there should be a careful assessment of volume status prior to volume administration.

In general, volume replacement therapy should be given as a bolus with a predefined endpoint to assess the effect of the volume resuscitation. Most commonly, the volume resuscitation will begin with crystalloid. In patients with hypovolemic shock due to ongoing hemorrhage, volume replacement with packed red blood cells is warranted. In cases of massive transfusion, platelets and fresh frozen plasma should be provided to offset the dilution of these components during volume replacement. Since hemoglobin is a key determinant of CaCO₂ red cell administration may be a part of volume replacement even without hemorrhage if hemoglobin content is <7 g/dL in order to optimize oxygen delivery.

Assessment of intravascular volume status (and the adequacy of volume resuscitation) begins with the physical examination (described above). The passive leg raise (PLR) test can predict responsiveness to additional intravenous fluid (IVF) by providing the patient with an endogenous volume bolus. While the patient is resting in a semi-recumbent position at a 45-degree angle, the bed is placed in trendelenburg such that the patient’s head becomes horizontal and the legs are extended at a 45-degree angle. There is then an immediate (within 1 min) assessment of changes in CO (or pulse pressure variation as a surrogate). It is important to emphasize that one does not merely look for changes in blood pressure; if the shock patient is mechanically ventilated there is the option of looking at changes in SV variation (or pulse pressure variation) during the respiratory cycle to assess volume responsiveness. A >12% SV variation suggests a volume-responsive state. This measurement requires that the patient be in a volume cycle mode of ventilation, without breath-to-breath variations in intrathoracic pressure and without arrhythmias. A final caveat to the use of these parameters to assess volume status is that these studies are performed on patients being ventilated with tidal volumes larger than currently used to minimize ventilator-induced lung injury.

There is also increased use of echocardiography to assist in determination of intravascular fluid status, with a variety of static and dynamic variables that the trained operator can assess. The most commonly used parameters to assess adequacy of volume resuscitation are inferior vena cava (IVC) diameter and IVC collapse. Alternatively, serial assessments of LV function can be performed while volume is being administered. Placement of a pulmonary artery catheter (PAC) is another tool for assessment of volume status. This more invasive measure involves placement of the PAC into the central venous circulation and through the right heart. Ports in the PAC (Swan Ganz catheter) allow for direct measurement of CVP, pulmonary artery (PA), and PCWPs. The PCWP is used as a surrogate for LA pressure. While studies have not identified a mortality or length-of-stay benefit with routine use of PA catheterization, there are cases where it may be beneficial. Patients with mixed shock (distributive and cardiogenic) or those with ongoing shock of unclear etiology are examples of situations in which it should be considered.

The need for continued volume replacement must be frequently reassessed. As the patient continues to receive treatment for shock, the initial proper strategy regarding volume management may change in light of development of processes that independently require a different volume management strategy. For patients who initially present with shock but then develop failure related to acute respiratory distress syndrome (ARDS) or renal failure, it may be reasonable to begin volume removal.

Vasopressor and Inotropic Support

If intravascular volume status has been optimized with volume resuscitation but hypotension and inadequate tissue perfusion persist, then vasopressor and inotropic support should be initiated. The use of vasopressors and inotropes must be tailored to the primary physiologic disturbance. The clinician must understand the receptor selectivity of various agents and that for some agents the selectivity may be dose-dependent. In patients with distributive shock, the aim is to increase the SVR. Norepinephrine is the first choice vasopressor: with potent α₁ and β₁ adrenergic effects. The α₁ causes vasoconstriction while β₁ has positive inotropic and chronotropic effects. At high doses, epinephrine has a similar profile (at lower doses the β effects predominate), but is associated with tachyarrhythmia, myocardial ischemia, decreased splanchnic blood flow, pulmonary hypertension, and acidosis. In distributive shock, vasopressin deficiency may be present. Vasopressin acts on the vasopressin receptor to reverse vasodilation and redistribute flow to the splanchnic circulation. In a randomized trial in patients with septic shock, the addition of low-dose vasopressin did not reduce all-cause 28-day mortality compared to norepinephrine. Vasopressin is safe and has a role as a second agent for hypotension in septic shock. Dopamine does not have a role as a first line agent in distributive shock. A randomized control study in patients with all cause circulatory shock did not show a survival benefit, but did reveal an increase in adverse events (arrhythmia). In this study, the subgroup of patients with cardiogenic shock had increased mortality. For patients with cardiogenic shock, dobutamine is the first line agent; it is a synthetic catecholamine with primarily β-mediated effects and minimal α adrenergic effects. The β₁ effect is manifest in increased inotropy and the β₂ effect leads to vasodilation with decreased afterload; it can be used with norepinephrine in patients with mixed distributive and cardiogenic shock.

OXYGENATION AND VENTILATION SUPPORT

In addition to the cellular hypoxia caused by the circulatory failure, patients with shock may present with hypoxemia. For patients with distributive shock, this may be related to a primary pulmonary process (pneumonia in a patient with septic shock). For patients with cardiogenic or obstructive shock, the hypoxemia may be related to LV dysfunction and elevations of PCWP. For patients with all types of shock, there can be development of ARDS and subsequent V̇/Q̇ mismatch and shunt. Supplemental oxygen should be initiated and titrated to maintain SpO₂ of 92–95%. This may require intubation and initiation of mechanical ventilation. If the patient requires intubation and initiation of mechanical ventilation, this should be provided promptly so as to minimize the duration of tissue hypoxia. Patients with shock may have high minute ventilatory needs to compensate for metabolic acidosis. As shock progresses, they may not be able to maintain adequate respiratory compensation, which may be a second indication to initiate mechanical ventilator support. If mechanical support is initiated, it is important to provide ventilation with lung-protective strategies focused on low tidal volume ventilation and optimization of positive end-expiratory pressure to minimize ventilator-induced lung injury. In addition, there should be daily sedation cessation to assess underlying neurologic function and minimize time on mechanical ventilation. There are currently little data to support the use of noninvasive ventilation in the setting of shock.

Antibiotic Administration

Sepsis and septic shock are the most common cause of shock. For patients presenting with undifferentiated shock, if the diagnosis of septic shock is being entertained then broad spectrum antibiotics should be administered after obtaining appropriate cultures. For patients with sepsis, every hour delay in antibiotic administration is associated with an increase in mortality. While it is ideal to initiate antibiotics after appropriate cultures, the inability to obtain cultures should not delay the start of treatment. When sepsis is excluded as a cause of shock, an important aspect of antibiotic stewardship is to stop all antibiotics.

Specific Causes of Shock Requiring Tailored Intervention

The initial evaluation (history, physical examination, and diagnostic testing) may have identified an etiology of shock that requires urgent lifesaving intervention in addition to the initial treatment steps outlined above. Patients with distributive shock secondary to anaphylaxis require removal of the inciting allergen, administration of epinephrine, and vascular support with intravenous fluid resuscitation and vasopressors. Adrenal insufficiency requires replacement with intravenous stress dose steroids. Cardiogenic shock patients with arrhythmia may require treatment as outlined in advanced cardiac life support algorithms or placement of an artificial pacemaker. In cases of acute ischemic events, consideration must be given to revascularization and temporary mechanical supportive measures. In the case of valve dysfunction, emergency surgery may be considered. Patients with hypovolemic shock due to hemorrhage may require surgical intervention in the case of trauma or endoscopic or interventional radiology procedures in the case of a GI source of blood loss. Among patients with obstructive shock, a tension PTX would necessitate immediate decompression. Proximal pulmonary embolism requires evaluation for thrombolytic therapy or surgical removal of the clot. Dissection of the ascending aorta may require surgical intervention.

FURTHER READING

INTRODUCTION AND DEFINITIONS

Sepsis is a common and deadly disease. More than two millennia ago, Hippocrates wrote that sepsis was characterized by rotting flesh and festering wounds. Several centuries later, Galen described sepsis as a laudable event required for wound healing. Once the germ theory was proposed by Semmelweis, Pasteur, and others in the nineteenth century, sepsis was recast as a systemic infection referred to as “blood poisoning” and was thought to be due to pathogen invasion and spread in the bloodstream of the host. However, germ theory did not fully explain sepsis: many septic patients died despite successful removal of the inciting pathogen. In 1992, Bone and colleagues proposed that the host, not the germ, was responsible for the pathogenesis of sepsis. Specifically, they defined sepsis as a systemic inflammatory response to infection. Yet sepsis arose in response to many different pathogens, and septicemia was neither a necessary condition nor a helpful term. Thus, these investigators instead proposed the term severe sepsis to describe cases where sepsis was complicated by acute organ dysfunction and the term septic shock for a subset of sepsis cases that were complicated by hypotension despite adequate fluid resuscitation along with perfusion abnormalities.

In the past 20 years, research has revealed that many patients develop acute organ dysfunction in response to infection but without a measurable inflammatory excess (i.e., without the systemic inflammatory response syndrome [SIRS]). In fact, both pro- and anti-inflammatory responses are present along with significant changes in other pathways. To clarify terminology and reflect the current understanding of the pathobiology of sepsis, the Sepsis Definitions Task Force in 2016 proposed the Third International Consensus Definitions specifying that sepsis is a dysregulated host response to infection that leads to acute organ dysfunction. This definition distinguishes sepsis from uncomplicated infection that does not lead to organ dysfunction, a poor course, or death. In light of the wide variation in the ways that septic shock is identified in research, clinical, or surveillance settings, the Third International Consensus Definitions further specified that septic shock be defined as a subset of sepsis cases in which underlying circulatory and cellular/metabolic abnormalities are profound enough to substantially increase mortality risk.

To aid clinicians in identifying sepsis and septic shock at the bedside, new “Sepsis-3” clinical criteria for sepsis include (1) a suspected infection and (2) acute organ dysfunction, defined as an increase by two or more points from baseline (if known) on the sequential (or sepsis-related) organ failure assessment (SOFA) score (Table 297-1). Criteria for septic shock include sepsis plus the need for vasopressor therapy to elevate mean arterial pressure to ≥65 mmHg with a serum lactate concentration >2.0 mmol/L despite adequate fluid resuscitation.

ETIOLOGY

Sepsis can arise from both community-acquired and hospital-acquired infections. Of these infections, pneumonia is the most common source, accounting for about half of cases; next most common are intraabdominal and genitourinary infections. Blood cultures are typically positive in only one-third of cases, while many cases are culture negative at all sites. Staphylococcus aureus and Streptococcus pneumoniae are the most common gram-positive isolates, while Escherichia coli, Klebsiella species, and Pseudomonas aeruginosa are the most common gram-negative isolates. In recent years, gram-positive infections have been reported more often than gram-negative infections, yet a 75-country point-prevalence study of 14,000 patients on intensive care units (ICUs) found that 62% of positive isolates were gram-negative bacteria, 47% were gram-positive bacteria, and 19% were fungi.

The many risk factors for sepsis are related to both the predisposition to develop an infection and, once infection develops, the likelihood of developing acute organ dysfunction. Common risk factors for increased risk of infection include chronic diseases (e.g., HIV infection, chronic obstructive pulmonary disease, cancers) and immunosuppression. Risk factors for progression from infection to organ dysfunction are less well understood but may include underlying health status, preexisting organ function, and timeliness of treatment. Age, sex, and race/ethnicity all influence the incidence of sepsis, which is highest at the extremes of age, higher in males than in females, and higher in blacks than in whites. The differences in risk of sepsis by race are not fully explained by socioeconomic factors or access to care, raising the possibility that other factors, such as genetic differences in susceptibility to infection or in the expression of proteins critical to the host response, may play a role.

EPIDEMIOLOGY

The incidences of sepsis and septic shock depend on how acute organ dysfunction and infection are defined as well as on which data sources are studied. Disparate estimates come from administrative data, prospective cohorts with manual case identification, and large electronic health-record databases. Organ dysfunction is often defined by the provision of supportive therapy, in which case epidemiologic studies count the “treated,” rather than the actual, incidence. In the United States, recent cohort studies using administrative data suggest that upwards of 2 million cases of sepsis occur annually. Shock is present in ~30% of cases, resulting in an estimated 230,000 cases in a recent systematic review. An analysis of data (both clinical and administrative) from 300 hospitals in the United Healthcare Consortium estimated that septic shock occurred in 19 per 1000 hospitalized encounters. The incidences of sepsis and septic shock are also reported to be increasing (according to ICD9-CM diagnosis and procedure codes), with a rise of almost 50% in the past decade. However, the stability of objective clinical markers (e.g., provision of organ support, detection of bacteremia) over this period in a two-center validation study suggests that new ICD-9 coding rules, confusion over semantics (e.g., septicemia versus severe sepsis), rising capacity to provide intensive care, and increased case-finding confound the interpretation of serial trends. Studies from other high-income countries report rates of sepsis in the ICU similar to those in the United States.

While the data demonstrate that sepsis is a significant public-health burden in high-income countries, its impact on the populations of low- and middle-income countries is probably even more substantial because of the increased incidence of infectious diseases and the high prevalence of HIV in some parts of the developing world. Although there are fewer high-quality studies on sepsis in these countries, the available data support sepsis as a major public-health problem. For example, a study of one cohort in rural Uganda found an incidence of laboratory-confirmed sepsis tenfold that of current global sepsis estimates; as only a minority of patients with sepsis develop bacteremia, the incidence of sepsis in the cohort was probably even higher. Case–fatality rates in low- and middle-income countries are also higher than those in high-income countries, as exemplified by two observational cohorts in Brazil with mortality rates >40%.

PATHOGENESIS

For many years, the clinical features of sepsis were considered the result of an excessive inflammatory host response (SIRS). More recently, it has become apparent that infection triggers a much more complex, variable, and prolonged host response than was previously thought. The specific response of each patient depends on the pathogen (load and virulence) and the host (genetic composition and comorbidity), with different responses at local and systemic levels. The host response evolves over time with the patient’s clinical course. Generally, proinflammatory reactions (directed at eliminating pathogens) are responsible for “collateral” tissue damage in sepsis, whereas anti-inflammatory responses are implicated in the enhanced susceptibility to secondary infections that occurs later in the course. These mechanisms can be characterized as an interplay between two “fitness costs”: direct damage to organs by the pathogen and damage to organs stemming from the host’s immune response. The host’s ability to resist as well as tolerate both direct and immunopathologic damage will determine whether uncomplicated infection becomes sepsis.

Initiation of Inflammation

Over the past decade, our knowledge of pathogen recognition has increased tremendously. Pathogens activate immune cells by an interaction with pattern recognition receptors (Fig. 297-1), of which four main classes are prominent: Toll-like receptors (TLRs), RIG-I-like receptors, C-type lectin receptors, and NOD-like receptors; the activity of the last group occurs partially in protein complexes called inflammasomes. The recognition of structures conserved across microbial species—so-called pathogen-associated molecular patterns (PAMPs)—by all these receptors results in upregulation of inflammatory gene transcription and initiation of innate immunity. A common PAMP is the lipid A moiety of lipopolysaccharide (LPS or endotoxin), which attaches to the LPS-binding protein on the surface of monocytes, macrophages, and neutrophils. LPS is transferred to and signals via TLR4 to produce and release cytokines such as tumor necrosis factor that grow the signal and alert other cells and tissues. Up to 10 TLRs have been identified in humans.

At the same time, these receptors also sense endogenous molecules released from injured cells—so-called damage-associated molecular patterns (DAMPs), such as high-mobility group protein B1, S100 proteins, and extracellular RNA, DNA, and histones. The release of DAMPs during sterile injuries such as those incurred during trauma gives rise to the concept that the pathogenesis of multiple-organ failure may be similar in sepsis and noninfectious critical illness. In addition to activating the proinflammatory cytokines, the inflammatory responses implicated in the pathogenesis of sepsis also activate the complement system, platelet-activating factor, arachidonic acid metabolites, and nitric oxide.

Coagulation Abnormalities

Sepsis is commonly associated with coagulation disorders and frequently leads to disseminated intravascular coagulation. Abnormalities in coagulation are thought to isolate invading microorganisms and/or to prevent the spread of infection and inflammation to other tissues and organs. Excess fibrin deposition is driven by coagulation via tissue factor, a transmembrane glycoprotein expressed by various cell types; by impaired anticoagulant mechanisms, including the protein C system and antithrombin; and by compromised fibrin removal due to depression of the fibrinolytic system. Coagulation (and other) proteases further enhance inflammation via protease-activated receptors. In infections with endothelial predominance (e.g., meningococcemia), these mechanisms can be common and deadly.

Organ Dysfunction

Although the mechanisms that underlie organ failure in sepsis are only partially known, impaired tissue oxygenation plays a key role. Several factors contribute to reduced oxygen delivery in sepsis and septic shock, including hypotension, reduced red-cell deformability, and microvascular thrombosis. Inflammation can cause dysfunction of the vascular endothelium, accompanied by cell death and loss of barrier integrity, giving rise to subcutaneous and body-cavity edema. An excessive and uncontrolled release of nitric oxide causes vasomotor collapse, opening of arteriovenous shunts, and pathologic shunting of oxygenated blood from susceptible tissues. In addition, mitochondrial damage due to oxidative stress and other mechanisms impairs cellular oxygen utilization. The slowing of oxidative metabolism, in parallel with impaired oxygen delivery, reduces cellular O₂ extraction. Yet energy (i.e., ATP) is still needed to support basal, vital cellular function, which derives from glycolysis and fermentation and thus yields H⁺ and lactate. With severe or prolonged insult, ATP levels fall beneath a critical threshold, bioenergetic failure ensues, toxic reactive oxygen species are released, and apoptosis leads to irreversible cell death and organ failure. The actual morphologic changes in sepsis-induced organ failure are also complex. Generally, organs such as the lung undergo extensive microscopic changes, while other organs may undergo rather few histologic changes. In fact, some organs (e.g., the kidney) may lack significant structural damage while still having significant tubular-cell changes that impair function.

Anti-Inflammatory Mechanisms

The immune system harbors humoral, cellular, and neural mechanisms that may exacerbate the potentially harmful effects of the proinflammatory response. Phagocytes can switch to an anti-inflammatory phenotype that promotes tissue repair, while regulatory T cells and myeloid-derived suppressor cells further reduce inflammation. The so-called neuroinflammatory reflex may also contribute: sensory input is relayed through the afferent vagus nerve to the brainstem, from which the efferent vagus nerve activates the splenic nerve in the celiac plexus, with consequent norepinephrine release in the spleen and acetylcholine secretion by a subset of CD4+ T cells. The acetylcholine release targets α7 cholinergic receptors on macrophages, reducing proinflammatory cytokine release. Disruption of this neural-based system by vagotomy renders animals more vulnerable to endotoxin shock, while stimulation of the efferent vagus nerve or α7 cholinergic receptors attenuates systemic inflammation in experimental sepsis.

Immune Suppression

Patients who survive early sepsis but remain dependent on intensive care occasionally demonstrate evidence of a suppressed immune system. These patients may have ongoing infectious foci despite antimicrobial therapy or may experience the reactivation of latent viruses. Multiple investigations have documented reduced responsiveness of blood leukocytes to pathogens in patients with sepsis; these findings were recently corroborated by post-mortem studies revealing strong functional impairments of splenocytes harvested from ICU patients who died of sepsis. Immune suppression was evident in the lungs as well as the spleen; in both organs, the expression of ligands for T cell–inhibitory receptors on parenchymal cells was increased. Enhanced apoptotic cell death, especially of B cells, CD4+ T cells, and follicular dendritic cells, has been implicated in sepsis-associated immune suppression and death. In a cohort of >1000 ICU admissions for sepsis, secondary infections developed in 14% of patients, and the associated genomic response at the time of infection was consistent with immune suppression, including impaired glycolysis and cellular gluconeogenesis. The most common secondary infections included catheter-related bloodstream infections, ventilator-associated infections, and abdominal infections. What is not yet understood is the optimal way to identify those sepsis patients who have hyperinflamed rather than immunosuppressed phenotypes. Similarly, it is unknown whether the dysfunctional immune system is driving organ dysfunction and secondary infections or whether the immune system itself is just another dysfunctional organ.

APPROACH TO THE PATIENT

CLINICAL MANIFESTATIONS

The specific clinical manifestations of sepsis are quite variable, depending on the initial site of infection, the offending pathogen, the pattern of acute organ dysfunction, the underlying health of the patient, and the delay before initiation of treatment. The signs of both infection and organ dysfunction may be subtle. Guidelines provide a long list of potential warning signs of incipient sepsis (Table 297-1). Once sepsis has been established and the inciting infection is assumed to be under control, the temperature and white blood cell (WBC) count often return to normal. However, organ dysfunction typically persists.

Cardiorespiratory Failure

Two of the most commonly affected organ systems in sepsis are the respiratory and cardiovascular systems. Respiratory compromise classically manifests as acute respiratory distress syndrome (ARDS), defined as hypoxemia and bilateral infiltrates of noncardiac origin that arise within 7 days of the suspected infection. ARDS can be classified by Berlin criteria as mild (PaO₂/FiO₂, 201–300 mmHg), moderate (101–200 mmHg), or severe (≤100 mmHg). A common competing diagnosis is hydrostatic edema secondary to cardiac failure or volume overload. Although traditionally identified by elevated pulmonary capillary wedge measurements from a pulmonary artery catheter (>18 mmHg), cardiac failure can be objectively evaluated on the basis of clinical judgment or focused echocardiography.

Cardiovascular compromise typically presents as hypotension. The cause can be frank hypovolemia, maldistribution of blood flow and intravascular volume due to diffuse capillary leakage, reduced systemic vascular resistance, or depressed myocardial function. After adequate volume expansion, hypotension frequently persists, requiring the use of vasopressors. In early shock, when volume status is reduced, systemic vascular resistance may be quite high with low cardiac output; after volume repletion, however, this picture may rapidly change to low systemic vascular resistance and high cardiac output.

Kidney Injury

Acute kidney injury (AKI) is documented in >50% of septic patients, increasing the risk of in-hospital death by six- to eightfold. AKI manifests as oliguria, azotemia, and rising serum creatinine levels and frequently requires dialysis. The mechanisms of sepsis-induced AKI are incompletely understood. AKI may occur in up to 25% of patients in the absence of overt hypotension. Current mechanistic work suggests that a combination of diffuse microcirculatory blood-flow abnormalities, inflammation, and cellular bioenergetic responses to injury contribute to sepsis-induced AKI beyond just organ ischemia.

Neurologic Complications

Typical central nervous system dysfunction presents as coma or delirium. Imaging studies typically show no focal lesions, and electroencephalographic findings are usually consistent with nonfocal encephalopathy. Sepsis-associated delirium is considered a diffuse cerebral dysfunction caused by the inflammatory response to infection without evidence of a primary central nervous system infection. Consensus guidelines recommend delirium screening with valid and reliable tools such as the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) and the Intensive Care Delirium Screening Checklist (ICDSC). Critical-illness polyneuropathy and myopathy are also common, especially in patients with a prolonged course. For survivors of sepsis, neurologic complications can be severe. In a national (U.S.) representative prospective cohort of >1000 elderly patients with severe sepsis, moderate to severe cognitive impairment increased by 10.6 percentage points among patients who survived severe sepsis (odds ratio, 3.34; 95% confidence interval [CI], 1.53–7.25) over that among survivors of nonsepsis hospitalizations. Many of these limitations persisted for up to 8 years.

Additional Manifestations

Many other abnormalities occur in sepsis, including ileus, elevated aminotransferase levels, altered glycemic control, thrombocytopenia and disseminated intravascular coagulation, adrenal dysfunction, and sick euthyroid syndrome. Adrenal dysfunction in sepsis is widely studied and is thought to be related more to reversible dysfunction of the hypothalamic–pituitary axis or tissue glucocorticoid resistance than to direct damage to the adrenal gland. The diagnosis is difficult to establish. Recent clinical practice guidelines do not recommend use of the adrenocorticotropic hormone stimulation test or determination of the plasma cortisol level to detect relative glucocorticoid insufficiency.

DIAGNOSIS

Laboratory and Physiologic Findings

A variety of laboratory and physiologic changes are found in patients with suspected infection who are at risk for sepsis. In a 12-hospital cohort of electronic health records related to >70,000 encounters (Fig. 297-2), only tachycardia (heart rate, >90 beats per min) was present in >50% of encounters; the most common accompanying abnormalities were tachypnea (respiratory rate, >20 breaths per min), hypotension (systolic blood pressure, ≤100 mmHg), and hypoxia (SaO₂, ≤90%). Leukocytosis (WBC count, >12,000/μL) was present in fewer than one-third of patients and leukopenia (WBC count, <4000/μL) in fewer than 5%. Notably, many features that may identify acute organ dysfunction, such as platelet count, total bilirubin, or serum lactate level, are measured in only a small minority of at-risk encounters. If measured, metabolic acidosis with anion gap may be detected, as respiratory muscle fatigue occurs in sepsis-associated respiratory failure. Other, less common findings include serum hypoalbuminemia, troponin elevation, hypoglycemia, and hypofibrinogenemia.

Diagnostic Criteria

There is no specific test for sepsis, nor is there a gold-standard method for determining whether a patient is septic. In fact, the definition of sepsis can be written as a logic statement:

sepsis = f (threat to life | organ dysfunction | dysregulated host response | infection),

where sepsis is the dependent variable, which in turn is a function of four independent variables linked in a causal pathway, with—from left to right—one conditional upon the other. There may be uncertainty about whether each variable exists, whether it can be measured, and whether the causal and conditional relationships hold. If we assume that organ dysfunction exists and can be measured, then attributing the marginal degradation in function to a dysregulated host response is not simple and requires the ability to determine preexisting dysfunction, other noninfectious contributions to organ dysfunction, and—ideally—the mechanism by which the host response to an infection causes organ dysfunction.

In order to sort through these complex details, clinicians need simple bedside criteria to operationalize the logic statement (Fig. 297-3). With this mandate, the Sepsis Definitions Task Force recommended that, once infection is suspected, clinicians consider whether it has caused organ dysfunction by determining a SOFA score. The SOFA score ranges from 0 to 24 points, with up to 4 points accrued across six organ systems. The SOFA score is widely studied in the ICU among patients with infection, sepsis, and shock. With ≥2 new SOFA points, the infected patient is considered septic and may be at ≥10% risk of in-hospital death.

Because the SOFA score requires multiple laboratory tests and may be costly to measure repeatedly, the quick SOFA (qSOFA) score was proposed as a clinical prompt to identify patients at high risk of sepsis outside the ICU, whether on the medical ward or in the emergency department. The qSOFA score ranges from 0 to 3 points, with 1 point each for systolic hypotension (≤100 mmHg), tachypnea (≥22 breaths/min), or altered mentation. A qSOFA score of ≥2 points has a predictive value for sepsis similar to that of more complicated measures of organ dysfunction. The qSOFA score is undergoing broader evaluation in other cohorts, in low-and middle-income settings, and in algorithms linked to clinical decision-making. Recent work has also shown that, although SIRS criteria may be fulfilled in sepsis, they sometimes are not and do not meaningfully contribute to the identification of patients with suspected infection who are at greater risk of a poor course, ICU admission, or death—outcomes more common among patients with sepsis than among those without.

As stated above, recent definitions have specified that septic shock is a subset of sepsis in which circulatory and cellular/metabolic abnormalities are profound enough to substantially increase mortality risk, but the application of this definition as a criterion for enrollment of patients varies significantly in clinical trials, observational studies, and quality improvement work. For clarity, criteria are proposed for septic shock that include (1) sepsis plus (2) the need for vasopressor therapy to elevate mean arterial pressure to ≥65 mmHg, with (3) a serum lactate concentration >2.0 mmol/L after adequate fluid resuscitation.

The new definitions and diagnostic criteria were externally validated in >1 million encounters stored in electronic health records. Nevertheless, given the uncertainty around the diagnosis of sepsis, Sepsis-3 is undergoing both validation in prospective studies and incorporation into clinical practice and quality improvement initiatives.

Arterial lactate is a long-studied marker of tissue hypoperfusion, and hyperlactemia and delayed lactate clearance are associated with a greater incidence of organ failure and death in sepsis. In a study of >1200 patients with suspected infection, 262 (24%) of 1081 patients exhibited an elevated lactate concentration (≥2.5 mmol/L) even in the setting of normal systolic blood pressure (>90 mmHg) and were at elevated risk of 28-day in-hospital mortality. However, lactic acidosis may occur in the presence of alcohol intoxication, liver disease, diabetes mellitus, administration of total parenteral nutrition, or antiretroviral treatment, among other conditions. Furthermore, in sepsis, an elevated lactate concentration may simply be the manifestation of impaired clearance. These factors may confound the use of lactate as a stand-alone biomarker for the diagnosis of sepsis; thus it should be used in the context of other markers of infection and organ dysfunction.

TREATMENT

PROGNOSIS

Before modern intensive care, sepsis and septic shock were highly lethal, with infection leading to compromise of vital organs. Even with intensive care, nosocomial mortality rates for septic shock often exceeded 80% as recently as 30 years ago. Now, the U.S. Burden of Disease Collaborators report that the primary risk factor for sepsis and septic shock—i.e., infection—is the fifth leading cause of years of productive life lost because of premature death. More than half of sepsis cases require ICU admission, representing 10% of all ICU admissions. However, with advances in training, surveillance, monitoring, and prompt initiation of supportive care for organ dysfunction, the mortality rate from sepsis and septic shock is now closer to 20% in many series. Although some data suggest that mortality trends are even lower, attention has been focused on the trajectory of recovery among survivors. Patients who survive to hospital discharge after sepsis remain at increased risk of death in the following months and years. Those who survive often suffer from impaired physical or neurocognitive dysfunction, mood disorders, and low quality of life. In many studies, it is difficult to determine the causal role of sepsis. However, an analysis of the Health and Retirement Study—a large longitudinal cohort study of aging Americans—suggested that severe sepsis significantly accelerated physical and neurocognitive decline. Among survivors, the rate of hospital readmission within 90 days after sepsis exceeds 40%.

PREVENTION

In light of the persistently high mortality risk in sepsis and septic shock, prevention may be the best approach to reducing avoidable deaths, but preventing sepsis is a challenge. The aging of the population, the overuse of inappropriate antibiotics, the rising incidence of resistant microorganisms, and the use of indwelling devices and catheters contribute to a steady burden of sepsis cases. The number of cases could be reduced by avoiding unnecessary antibiotic use, limiting use of indwelling devices and catheters, minimizing immune suppression when it is not needed, and increasing adherence to infection control programs at hospitals and clinics. To facilitate earlier treatment, such pragmatic work could be complemented by research into the earliest pathophysiology of infection, even when symptoms of sepsis are nascent. In parallel, the field of implementation science could inform how best to increase adoption of infection control in high-risk settings and could guide appropriate care.

FURTHER READING

Additional Online References

INTRODUCTION

Cardiogenic shock (CS) and pulmonary edema are life-threatening high acuity conditions that require treatment as medical emergencies, usually in an intensive care unit (ICU) or cardiac intensive care unit (CICU). The most common joint etiology is severe left ventricular (LV) dysfunction from myocardial infarction (MI) that leads to pulmonary congestion and/or systemic hypoperfusion (Fig. 298-1). The pathophysiology of pulmonary edema and shock are discussed in Chaps. 33 and 296, respectively.

CARDIOGENIC SHOCK

CS is a low cardiac output state resulting in life-threatening end-organ hypoperfusion and hypoxia. The clinical presentation is typically characterized by persistent hypotension (<90 mmHg systolic blood pressure [BP]) unresponsive to volume replacement and is accompanied by clinical features of peripheral hypoperfusion, such as elevated arterial lactate (>2 mmol/L). Objective hemodynamic parameters such as cardiac index or pulmonary capillary wedge pressure can help confirm the diagnosis, but are not mandatory. The in-hospital mortality rates range from 40 to 60%, depending on shock severity and the associated underlying cause. Acute MI with LV dysfunction remains the most frequent cause of CS with other causes listed in Table 298-1. Circulatory failure based on cardiac dysfunction may be caused by primary myocardial failure, most commonly secondary to acute MI (Chap. 269), and less frequently by cardiomyopathy or myocarditis (Chap. 254), cardiac tamponade (Chap. 265), arrhythmias (Chap. 249), or critical valvular heart disease (Chap. 256).

Incidence

The incidence of CS complicating acute MI has decreased to 5–10%, largely due to increasing use of early mechanical reperfusion therapy for acute MI. Shock is more common with ST-elevation MI (STEMI) than with non-STEMI (Chap. 269).

LV failure accounts for ~80% of cases of CS complicating acute MI. Acute severe mitral regurgitation (MR), ventricular septal rupture (VSR), predominant right ventricular (RV) failure, and free wall rupture or tamponade account for the remainder. A recently recognized uncommon cause of transient CS is the Takotsubo syndrome.

Pathophysiology

The understanding of the complex pathophysiology of CS has evolved over the past decades. In general, a profound depression of myocardial contractility results in a deleterious spiral of reduced cardiac output, low blood pressure, and ongoing myocardial ischemia, followed by further contractility reduction (Fig. 298-1). This vicious cycle usually leads to death if not interrupted. CS can result in both acute and subacute derangements to the entire circulatory system. Hypoperfusion of vital organs and extremities remains a clinical hallmark. Although ineffective stroke volume is the inciting event, inadequate circulatory compensation also may contribute to shock. Initial peripheral vasoconstriction may improve coronary and peripheral perfusion at the cost of increased afterload. However, over the course of CS systemic inflammation response triggered by acute cardiac injury often induces pathologic vasodilatation. Inflammatory cytokines, endothelial and inducible nitric oxide synthase may augment NO production, accompanied by peroxynitrite, which has a negative inotropic effect and is cardiotoxic. Lactic acidosis and hypoxemia contribute to the vicious circle, as severe acidosis reduces the efficacy of endogenous and exogenous catecholamines. During ICU support bleeding and/or transfusions may trigger inflammation and are usually associated with higher mortality (Fig. 298-1).

Patient Profile

In patients with MI, older age, prior MI, diabetes mellitus, anterior MI location, and multivessel coronary artery disease with extensive coronary artery stenoses are associated with an increased risk of CS. Shock associated with a first inferior MI should prompt a search for a mechanical cause or RV involvement. CS may rarely occur in the absence of significant stenosis, as seen in Takotsubo syndrome or fulminant myocarditis.

Timing

Shock is present on admission in approximately one-quarter of MI patients who develop CS; one-quarter develop it rapidly thereafter, within 6 h of MI onset, and another quarter develop shock later on the first day. Later onset of CS may be due to reinfarction, marked infarct expansion, or mechanical complications.

Diagnosis

For these unstable patients, supportive therapy must be initiated simultaneously with diagnostic evaluation (Fig. 298-2). A focused history and physical examination should be performed along with an electrocardiogram (ECG), chest X-ray, arterial blood gas (ABG) analysis, lactate measurement, and blood specimens to the laboratory. Initial echocardiography is an invaluable tool to elucidate the underlying cause of CS.

CLINICAL FINDINGS

Most patients initially are dyspneic, appear pale, apprehensive, and diaphoretic, and mental status may be altered. The pulse is typically weak and rapid or occasionally severe bradycardia due to high-grade heart block may be present. BP is typically reduced (<90 mmHg; or catecholamines required to maintain blood pressure >90 mmHg), but occasionally BP may be maintained by very high systemic vascular resistance. Tachypnea and jugular venous distention may be present. Typically there is a weak apical pulse and soft S₁, and an S₃ gallop may be audible. Acute, severe MR and VSR usually are associated with characteristic systolic murmurs (Chap. 269). Crackles are audible in most patients with LV failure. Oliguria/anuria is common. Often CS patients require early mechanical ventilation (~80%) for management of acute hypoxemia, increased work of breathing, and hemodynamic instability; catecholamines often are required to maintain adequate blood pressure.

LABORATORY FINDINGS

The white blood cell count and C-reactive protein typically are elevated. Renal function often is progressively impaired. Newer renal function markers such as Cystatin C or Neutrophil gelatinase-associated lipocalin (NGAL) do not add prognostic information over creatinine. Hepatic transaminases are elevated due to liver hypoperfusion in ~20% of patients and may be very high. The arterial lactate level is usually elevated to >2 mmol/L. ABGs usually demonstrate hypoxemia and anion gap metabolic acidosis. Glucose levels at admission are often elevated, a strong independent predictor for mortality. Cardiac markers, creatine kinase and its MB fraction, and troponins I and T are typically markedly elevated in acute MI.

ELECTROCARDIOGRAM

In acute MI with CS, Q waves and/or ST elevation in multiple leads or left bundle branch block are usually present. Approximately one-half of MIs with CS are anterior infarctions. Global ischemia due to severe left main stenosis usually is accompanied by aVR lead ST segment elevation and ST depressions in multiple leads.

CHEST ROENTGENOGRAM

The chest x-ray typically shows pulmonary vascular congestion and often pulmonary edema, but may be normal in up to a third of patients. The heart size is usually normal when CS results from a first MI, but may be enlarged when it occurs in a patient with a previous MI.

ECHOCARDIOGRAM

An echocardiogram (Chap. 236) should be obtained promptly in patients with suspected/confirmed CS to help define its etiology. Echocardiography is able to delineate the extent of infarction/myocardium in jeopardy and the presence of mechanical complications such as VSR, MR, or cardiac tamponade. Furthermore, valvular obstruction or insufficiency, dynamic LV outflow tract obstruction, proximal aortic dissection with aortic regurgitation or tamponade may be seen, or indirect evidence for pulmonary embolism may be obtained (Chap. 273) (Table 298-2).

PULMONARY ARTERY CATHETERIZATION

The use of pulmonary artery catheter (PAC) hemodynamic monitoring is declining because clinical trials have shown no mortality benefit. However, hemodynamic data provided by a PAC can confirm the presence and severity of CS, involvement of the right ventricle, left-to-right shunting, pulmonary artery pressures and trans-pulmonary gradient, and the pulmonary and systemic vascular resistance. It can help in recognition of acute MR, decreased left atrial filling pressure, and secondary occult sepsis and to exclude left-to-right shunts. Equalization of diastolic pressures suggests cardiac tamponade, but echocardiogram is more definitive. The detailed hemodynamic profile can be used to individualize and monitor therapy and to provide prognostic information, such as cardiac index and cardiac power, can be obtained. The use of a PAC is currently recommended by the American Heart Association for potential utilization in cases of diagnostic or CS management uncertainty or in patients with severe CS who are unresponsive to initial therapy.

ADVANCED HEMODYNAMIC MONITORING

Recently new central venous catheter systems linked to computer-based algorithms provide continuous monitoring of a variety of derived hemodynamic parameters, including cardiac output, stroke volume, stroke volume variation, and systemic vascular resistance. When combined with a femoral arterial catheter, calculated extravascular lung water and pulmonary permeability index can be monitored. The information allows for more rational therapy and assessment, but has not yet shown improved clinical outcomes in patients with shock or pulmonary edema (Table 298-3).

CARDIAC CATHETERIZATION AND CORONARY ANGIOGRAPHY

The definition of the coronary anatomy provides useful information and is immediately indicated in all patients with CS complicating MI for further reperfusion treatment. Furthermore, cardiac catheterization should also be considered for resuscitated cardiac arrest survivors without ST-segment elevation because ~70% of these patients have relevant coronary artery disease.

TREATMENT

Prognosis

The expected death rates for patients with MI complicated by CS range widely based on age, severity of hemodynamic abnormalities, severity of clinical hypoperfusion (arterial lactate, renal function), and performance of early revascularization. The recently introduced IABP-SHOCK II score predicts prognosis based on six readily available variables: age >73 years; prior stroke; glucose at admission >10.6 mmol/L (191 mg/dL); creatinine at admission >132.6 μmol/L (1.5 mg/dL); thrombolysis in myocardial infarction flow grade after PCI <3; and arterial blood lactate at admission >5 mmol/L. It also may help guide treatment strategies.

SHOCK SECONDARY TO RIGHT VENTRICULAR INFARCTION

Persistent CS due to predominant RV failure accounts for only 5% of CS complicating MI. It often results from proximal right coronary artery occlusion. The salient features are relatively high right atrial pressures, RV dilation and dysfunction, and only mildly or moderately depressed LV function. High right-sided pressures may be absent without volume loading. However, CS often has overlap combinations of both RV and LV ischemia, given a shared septum and the effect of ventricular interdependence on RV function. Management of isolated RV CS includes fluid administration to optimize right atrial pressure (10–15 mmHg); avoidance of excess fluids, which shift the interventricular septum into the LV; catecholamines; early reestablishment of infarct-artery flow; and MCS.

MITRAL REGURGITATION

(See also Chap. 269) Acute severe MR due to papillary muscle dysfunction and/or rupture may complicate MI and result in CS and/or pulmonary edema. This complication most often occurs on the first day, with a second peak several days later. The diagnosis is confirmed by echocardiography (Table 298-2). Afterload reduction with IABP and, if tolerated, vasodilators to reduce pulmonary edema, is recommended as a bridge to surgery or interventional treatment. Mitral valve repair or reconstruction is the definitive therapy and should be performed early in the course in suitable candidates. Other options include percutaneous edge-to-edge repair which has been successful in small case series.

VENTRICULAR SEPTAL RUPTURE

(See also Chap. 269) VSR complicating MI is a relatively rare event associated with very high mortality if CS is present (>80%). The incidence of infarct-related VSR without reperfusion was 1–2% but has decreased to 0.2% in the era of reperfusion. VSR occurs a median of 24 h after infarction, but may occur up to 2 weeks later. Echocardiography demonstrates shunting of blood from the left to the right ventricle and may visualize the opening in the interventricular septum. Current guidelines recommend immediate surgical VSR closure, irrespective of the patient’s hemodynamic status, to avoid further hemodynamic deterioration. IABP support as bridge to surgery is recommended. Given high mortality, suboptimal surgical results and many patients not being eligible for surgery, interventional percutaneous VSR umbrella device closure has been developed. Results of interventional VSR closure suggest a similar outcome as surgery. How to close the VSR should be based on a heart team decision.

FREE WALL RUPTURE

Myocardial rupture is a dramatic complication of MI that is most likely to occur during the first week after the onset of symptoms. The clinical presentation typically is a sudden loss of pulse, blood pressure, and consciousness but sinus rhythm on ECG (pulseless electrical activity) due to cardiac tamponade (Chap. 265). Free wall rupture may also result in CS due to subacute tamponade when the pericardium temporarily seals the rupture sites. Definitive surgical repair is required.

ACUTE FULMINANT MYOCARDITIS

(See also Chap. 254) Myocarditis can mimic acute MI with ST abnormalities or bundle branch block on the ECG and marked elevation of cardiac markers. Acute myocarditis causes CS in a small proportion of cases. These patients are typically younger than those with CS due to acute MI and often do not have typical ischemic chest pain. Echocardiography usually shows global LV dysfunction. Initial management is the same as for CS complicating acute MI but does not involve revascularization. Endomyocardial biopsy is recommended to determine the diagnosis and need for immunosuppressives for entities such as giant cell myocarditis. Refractory CS can be managed with MCS.

PULMONARY EDEMA

The etiologies and pathophysiology of pulmonary edema are discussed in Chap. 33.

Diagnosis

Acute pulmonary edema usually presents with the rapid onset of dyspnea at rest, tachypnea, tachycardia, and severe hypoxemia. Crackles and wheezing due to alveolar flooding and airway compression from peribronchial cuffing may be audible. Release of endogenous catecholamines often causes hypertension.

It is often difficult to distinguish between cardiogenic and non-cardiogenic causes of acute pulmonary edema. Echocardiography may identify systolic and diastolic ventricular dysfunction and valvular lesions. Electrocardiographic ST elevation and evolving Q waves are usually diagnostic of acute MI and should prompt immediate institution of MI protocols and coronary artery revascularization therapy (Chap. 269). Brain natriuretic peptide levels, when substantially elevated, support heart failure as the etiology of acute dyspnea with pulmonary edema (Chap. 252).

The use of a Swan-Ganz catheter permits measurement of pulmonary capillary wedge pressure (PCWP) and helps differentiate high-pressure (cardiogenic) from normal-pressure (non-cardiogenic) causes of pulmonary edema. PAC is indicated when the etiology of the pulmonary edema is uncertain, when edema is refractory to therapy, or when it is accompanied by hypotension. Data derived from use of a catheter often alter the treatment plan, but no impact on mortality rates has been demonstrated.

TREATMENT

FURTHER READING

OVERVIEW AND DEFINITIONS

Cardiovascular collapse is severe hypotension from acute dysfunction of the heart or peripheral vasculature causing hypotension with resulting cerebral hypoperfusion and loss of consciousness that can be the result of a cardiac arrhythmia, severe myocardial or valvular dysfunction, loss of vascular tone, and/or acute disruption of venous return (see Table 299-1). When an effective circulation is restored spontaneously, patients present with syncope (see Chap. 18). If spontaneous resolution does not occur, then cardiac arrest occurs, ultimately resulting in death if resuscitation attempts are unsuccessful or not initiated. Underlying etiologies for cardiovascular collapse include benign conditions such as vasovagal syncope, but also life-threatening conditions, including: ventricular tachyarrhythmias, severe bradycardia, severely depressed myocardial contractility, as with massive acute myocardial infarction (MI) or pulmonary embolus, and other catastrophic events interfering with cardiac function such as myocardial rupture with cardiac tamponade or papillary muscle rupture with torrential mitral regurgitation.

Sudden cardiac arrest (SCA) refers to an abrupt loss of cardiac function resulting in complete cardiovascular collapse due either to an acute life-threatening cardiac arrhythmia or abrupt loss of myocardial pump function that requires emergency medical intervention for restoration of effective circulation. Most SCAs occur outside the hospital, and fewer than 10% of these victims survive to be discharged from the hospital despite undergoing attempted resuscitation by emergency medical services (EMS). For those that die prior to hospital admission, a cardiovascular cause for the arrest is often presumed based upon the absence of evidence for a traumatic or other non-cardiac cause at the time of the arrest. If the patient does not survive an SCA, the death is classified as a sudden cardiac death (SCD). Deaths that occur during hospitalization or within 30 days after resuscitated cardiac arrest are usually counted as SCDs in epidemiologic studies.

SCD also includes a broader category of unexplained rapid deaths thought to be due to cardiac causes where resuscitation was not attempted. In epidemiologic studies, SCD is usually defined as an unexpected death without obvious extra-cardiac cause that occurs in association with a witnessed rapid collapse or within 1 h of the onset of symptoms. This definition is based on the presumption that rapid deaths are often due to an arrhythmia, an assumption that cannot always be validated. Approximately half of all SCDs are not witnessed, and in the United States, few deaths undergo autopsies, and non-cardiac conditions that evolve rapidly such as acute cerebral hemorrhage, aortic rupture, and pulmonary embolism cannot be excluded without an autopsy. Therefore, definitive information necessary to establish the cause of death is usually not available. In unwitnessed cases, the definition is often further expanded to include unexpected deaths where the subject was documented to be well when last observed within the preceding 24 h. This expanded definition further decreases the certainty that the death was due to an arrhythmia or cardiac causes. The majority of countries, including the United States, do not have national surveillance systems or reporting requirements for SCD; thus the true incidence and frequency of SCD and its different mechanisms can only be estimated.

EPIDEMIOLOGY

DEMOGRAPHICS

SCA and SCD are major public health problems that account for 15% of all deaths and comprise 50% of all cardiac deaths. In the United States alone, there are an estimated 350,000 EMS-attended out-of-hospital cardiac arrests and 210,000 SCDs in the adult population. The estimated societal burden of premature death due to SCD is 2 million years of potential life lost for men and 1.3 million years of potential life lost for women, which is greater than most other leading causes of death. Although cardiac pathology, particularly coronary heart disease (CHD), underlies the majority of SCD, up to two-thirds of all SCD occur as the first clinical expression of previously undiagnosed heart disease. SCD rates have declined but not as steeply as rates for CHD in general. Age, gender, race, and geographic region all influence the incidence of SCD. Rates of out-of-hospital cardiac arrest are lower in Asia (52.5 per 100,000 person-years) than Europe (86.4 per 100,000 person-years), North America (98.1 per 100,000 person-years), or Australia (111.9 per 100,000 person-years); and also vary within geographic regions of the United States. SCD is rare in individuals of younger than 35 years of age (1–3 per 100,000 per year), and increases markedly with age as the incidence of coronary artery disease (CAD), heart failure (HF), and other predisposing conditions also increase. Although absolute SCD rates increase with age, the proportion of deaths that are due to SCD decreases markedly as other causes of death increase.

Women have a lower incidence of SCD and SCA than men, and women are more likely to present with pulseless electrical activity (PEA) and to have their SCD occur at home as compared to men. Possibly related to these factors, the SCD rate has not declined as much for younger women compared to men in recent years. Black as opposed to white Americans have higher rates of SCD, are more likely to have unwitnessed arrests, to be found with PEA, and have worse rates of survival. Socioeconomic disparities, with resuscitation being less likely in low income neighborhoods, is likely a contributing factor, but does not appear to account for the entirety of the elevated SCD rate in blacks. Alternatively, individuals of Hispanic ethnicity appear to have lower rates of SCD, despite having a higher prevalence of cardiac risk factors. It also appears that the incidence of SCD may be relatively low among Asian populations as well, both within the United States and globally. These gender and racial differences in SCD/SCA incidence and survival are poorly understood and warrant further research.

RISK FACTORS

The presence of overt structural heart disease and/or a certain types of inherited arrhythmia syndromes markedly elevates SCD risk (see Chaps. 249 and 250) (See Fig. 299-1). Preexisting CHD and HF are the most prevalent predisposing cardiac conditions and are associated with four- to tenfold increases in SCD risk. Correspondingly, SCD shares many of the same risk factors with CHD and HF, including: hypertension, diabetes, hypercholesterolemia, obesity, and smoking. Diabetes is a particularly strong risk factor for SCD even in patients with established CHD. Hypertension and resultant left ventricular hypertrophy (LVH) appear to be particularly important markers of SCD risk in blacks, in whom the prevalence of these conditions is greater. Smoking markedly elevates risk, and smoking cessation lowers risk particularly among individuals who have not yet developed overt CHD. Serum cholesterol appears to be more strongly related to SCD at younger ages, and the benefits of cholesterol lowering on SCD incidence have not been firmly established. There also appears to be a genetic component to SCD risk that is distinct from that associated with other manifestations of atherosclerosis. A history of SCD among a first-degree relative is associated with an increased risk for SCD, and with the occurrence of ventricular fibrillation (VF) during acute MI, but is not associated with an increased risk for acute MI. These data suggest that genetic factors may predispose to fatal ventricular arrhythmia in the setting of ischemia, rather than to CHD in general.

Obstructive sleep apnea and seizure disorders are also associated with increased SCD risk, and the underlying mechanism is not clear, but may be due to hypoxia and/or suffocation-induced cardiac arrest. Atrial fibrillation also appears to be associated with an increased risk of SCD, which is partly, but not entirely, accounted for by its association with underlying heart disease. Patients with chronic kidney disease are also at higher SCD risk with annualized SCD rates approaching 5.5% in patients undergoing dialysis. Electrolyte shifts and LVH, which are common in this population, have been suggested to play a role. There are also potential dietary influences on SCD risk. Individuals with higher intakes of polyunsaturated fatty acids, particularly n-3 fatty acids, and other components of a Mediterranean-style diet have lower SCD risks in observational studies, possibly due to antiarrhythmic effects of dietary components. Low levels of alcohol intake may be beneficial, but heavy intake (>3 drinks/day) appears to elevate risk.

PRECIPITATING FACTORS

SCD/SCA occurs with higher frequency at certain times, locations, and in association with certain activities and exposures. There are circadian variations in the incidence of SCD and cardiac arrest, with peaks in incidence in the morning hours and again in the later afternoon. There is also seasonal variability in SCD rates, which may be related to temperature and light exposure. Rates are highest during winter in the northern hemisphere and summer in the southern hemisphere. SCD rates also acutely peak during disasters such as earthquakes and terrorist attacks. SCA arrests are more likely to occur in certain locations as well, with notable clustering around train stations, airports, and other public places where there is significant population transit. SCD rates tend to be higher in urban areas and individuals that live near major roadways are at elevated SCD risk. There is also a well-recognized acute elevation in SCD risk that occurs during or shortly after bouts of vigorous exertion, and men appear to be more susceptible. Habitual exercise and training lowers this acute risk, but does not appear to eliminate it entirely. Exertion-associated SCDs are particularly tragic and highly publicized when they occur in highly trained athletes; however, the majority of such deaths actually occur in the general “non-athlete” population. The common thread amongst these precipitating factors is likely heightened autonomic tone, which can promote ischemia and has direct proarrhythmia and electrophysiologic actions that lower the threshold for VF.

CAUSES OF SUDDEN CARDIAC DEATH

UNDERLYING HEART DISEASE

Our understanding regarding the diseases which contribute to SCD is derived primarily from autopsy series and cardiac evaluations in cardiac arrest survivors, which are highly variable in level of detail (Fig. 299-1). Despite the limitations of these data, it is generally accepted that SCD is most commonly associated with underlying CAD, although the proportion due to CAD varies markedly by age, race, and sex. It is estimated that ~70–75% of SCDs in white men are due to CAD, as compared to only 40–50% in women and blacks. The proportion of SCDs with underlying CAD may be even lower in Asian ethnicities. Recent data suggest that the proportion of SCDs with CAD may be declining in some parts of Europe (Fig. 299-2A) and the United States, and, at the same time, increasing in parts of Japan and other parts of Asia. Beyond CAD, non-ischemic cardiomyopathies (hypertrophic, dilated, and infiltrative) are the second most frequent cause of SCD in the United States and European countries. Other less common causes include valvular heart disease, myocarditis, myocardial hypertrophy (often from hypertension), and rare primary electrical heart diseases such as the long QT and Brugada syndrome. On average, 5–10% of SCA victims do not have a significant cardiac abnormality at the time of autopsy or after extensive premortem cardiac evaluation, and this also varies by gender and race. Before 35 years of age, atherosclerotic CAD accounts for a much smaller proportion of deaths, with hypertrophic cardiomyopathy (HCM), coronary artery anomalies, myocarditis, arrhythmogenic right ventricular cardiomyopathy, and primary ion channelopathies accounting for a significant number of these deaths.

CARDIAC RHYTHMS AND SUDDEN DEATH

The initial rhythm found when EMS arrive at the scene of an out-of- hospital cardiac arrest is an important indication of the potential cause of the arrest and of the prognosis. In the early days of EMS systems, over half of victims were found in VF, giving rise to the hypothesis that ischmic VF or ventricular tachycardia (VT) degenerating to VF was the most common event. The proportion of cardiac arrests found in VF has decreased markedly since the 1970s, to only 20–25%, and PEA or asystole are now the most common scenarios (Fig. 299-2B). However, the vast majority of cardiac arrests are not monitored at the time of collapse, and since arrhythmias are inherently unstable once hemodynamic collapse occurs, the rhythm at the time of EMS arrival may not reflect the rhythm that initially precipitated the SCA. VF and primary bradycardias can degenerate quickly into asystole. VF as an initial rhythm still predominates in public locations or in other situations when there is a short time between collapse and arrival of EMS, suggesting that VF remains a common initial rhythm. However, there are also data to support an absolute decrease in VF incidence. Proposed explanations include decreases in underlying CHD incidence, increased used of beta blockers in CHD, and implantable cardioverter defibrillators (ICD) in high-risk patients. There also appears to be an increase of PEA incidence over the past several years, suggesting that the proportion of SCD due to abrupt hemodynamic collapse in the absence of preceding fatal arrhythmia may be increasing. Proposed explanations for these proportional changes in PEA versus VF include the aging of the population and the increased prevalence of end-stage cardiovascular disease and other severe comorbidities. These older, sicker patients may be more likely to have arrests in the home and to have acute precipitants leading to PEA (i.e., respiratory, metabolic, vascular), and/or be less likely to sustain VF up to the point of EMS arrival.

DISEASE SPECIFIC MECHANISMS

Coronary artery disease can cause SCD through a number of mechanisms (Table 299-2). The most common cause is acute MI or transient ischemia that leads to polymorphic VT and VF (see Chap. 250). Other primary mechanisms include severe bradyarrhythmias such as heart block with a slow escape rhythm, or PEA due to a massive MI or associated myocardial rupture. Areas of ventricular scar from prior infarcts increase the predisposition to reentrant VT, which often degenerates to VF. Once patients have suffered a MI, their risk of SCD elevates up to tenfold, with the highest absolute rates in the first 30 days after MI. The mechanisms underlying SCD vary at different time points after MI, with non-arrhythmic causes such as myocardial rupture and/or extensive reinfarction predominating early, within the first 1–2 months, and ischemic polymorphic VT and/or scar-related ventricular arrhythmias prevailing later. VT and sudden death can, and often does, occur years after an initial MI.

Cardiomyopathies and Other Forms of Structural Heart Disease

Scar-mediated reentrant VT can also occur in a host of nonischemic cardiomyopathies in which replacement fibrosis and/or inflammatory ventricular infiltrates occur Chap. 249. In congenital heart disease, surgical scars created during corrective surgery, such as those performed to correct ventricular septal defects in tetralogy of Fallot, can also serve as the substrate for ventricular re-entry. Other common predisposing processes such as LVH, ventricular stretch due to fluid overload, and cardiomyocyte dysfunction can result in electrical heterogeneity and other electrophysiologic changes that predispose to ventricular arrhythmias, including ion channel alterations that prolong action potential duration, impair cellular calcium handling, and diminished cellular coupling. These processes occur in a wide variety of diseases associated with depressed ventricular function and/or hypertrophy, including CAD, valvular heart disease, myocarditis, and non-ischemic cardiomyopathies.

Absence of Structural Heart Disease

In the absence of structural heart disease, VF can be due to an inherited ion channel abnormality, as in the long QT and Brugada syndromes (Chap. 250), rapid atrial fibrillation associated with the Wolff-Parkinson-White syndrome (Chap. 244), or drug toxicities, such as polymorphic VT due to drugs that prolong the QT interval (Chap. 250). PEA can result from pulmonary emboli, exsanguination, or the terminal phase of respiratory arrest.

MANAGEMENT OF CARDIAC ARREST

As the ability to predict SCA in the population is very limited, community approaches to reduce death focus on the rapid identification of victims and implementation of resuscitation measures by those who first encounter the victim, most likely the lay public, who ideally summon EMS and initiate basic life support measures with chest compressions. The approach is codified in the “out-of-hospital chain of survival” which includes (1) initial evaluation and recognition of the SCA; (2) rapid initiation of cardiopulmonary resuscitation (CPR) with an emphasis on chest compressions; (3) defibrillation as quickly as possible usually with an automatic external defibrillation applied by the lay rescuer or EMT; (4) basic and advanced EMS; and (5) advanced life support and postcardiac arrest care. There have been major advances in each of these areas and survival rates to hospital discharge have increased from about 6% in 2005 to 10% in 2012, but much more progress is needed (Fig. 299-2C).

The initial goal of resuscitation is to achieve the return of spontaneous circulation. Success is related to the time between collapse and initiation of resuscitation, decreasing markedly after 5 min, and the rhythm at the time of EMT arrival, being best for VT (25–30%), worse for VF and poor for PEA and asystole (<5%). Outcomes are also determined by the clinical state and comorbidities of the victim prior to the arrest, being worse for those with severe disease, such as cardiogenic shock, prior to arrest.

INITIAL EVALUATION AND INITIATION OF CPR

The rescuer should check for a response from the victim, shout for help, and call or ask someone else to call their local emergency number (e.g., 911), ideally on a cell phone that can be placed on speaker mode at the patient’s side such that the responding dispatcher can provide instructions and queries to the rescuer. Consideration of aspiration or airway obstruction is important and if suspected a Heimlich maneuver may dislodge the obstructing body. A trained healthcare provider would also check for a pulse (taking no longer than 10 s so as not to delay initiation of chest compressions) and assess breathing. Gasping respirations and brief seizure activity are common during SCA and may be misinterpreted as breathing and responsiveness. Chest compressions should be initiated without delay and administered at a rate of 100–120/min depressing the sternum by 5 cm (2 in.) and allowing full chest recoil between compressions. Chest compressions generate forward cardiac output with sequential filling and emptying of the cardiac chambers, with competent valves maintaining forward direction of flow. Interruption of chest compressions should be minimized to reduce end organ ischemia. Ventilation may be administered with two breaths for every 30 compressions if a trained rescuer is present, but for lay rescuers without training, chest compressions alone (“hands only CPR”) are more likely to be effectively applied and of similar benefit. If a second rescuer is present, they should be sent to seek out an automatic external defibrillator (AED), which are now widely available in many public areas.

RHYTHM-BASED MANAGEMENT

The rapidity with which defibrillation/cardioversion is achieved is an important predictor of outcome (Fig. 299-3). A defibrillator, most often an AED, should be applied as soon as available. AEDs are easily used by lay rescuers and trained first responders, such as police officers and trained security guards. When the arrest is witnessed, the use of AEDs by lay responders can improve cardiac arrest survival rates. Once patches are applied to the chest, a brief pause in chest compressions is required to allow the AED to record the rhythm. An AED will advise a shock if the recorded rhythm meets criteria for VF or VT. Chest compressions are continued 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 should be delivered. Chest compressions are resumed immediately and continue for 2 min until the next rhythm check. If VT/VF is still present, a second maximal energy shock is delivered. This sequence is continued until personnel to administer advanced life support are available, or return of spontaneous circulation is achieved. Electrocardiogram (ECG) rhythm strips produced by the AED should be retrieved, as the initial rhythm can be an important consideration in determining the cause of the arrest and to guide further therapy and evaluation if resuscitation is successful.

When advanced cardiac life support is available, an intravenous or intraosseous line is established for administration of medication and consideration given to placement of an advanced airway (endotracheal tube or supraglottic airway device). Epinephrine 1 mg every 3–5 min may be administered intravenously or intraosseously. If circulation is not restored or the patient is less than fully conscious despite return of circulation, confirmation that acidosis and hypoxia are adequately addressed should be assessed with arterial blood gas analysis. If metabolic acidosis persists after successful defibrillation and with adequate ventilation, 1 meq/kg NaHCO₃ may be administered.

The cardiac rhythm guides resuscitation when monitoring is available. VT is treated with external shocks synchronized to the QRS when VT is monomorphic, and asynchronous shocks for polymorphic VT or VF. If VT/VF recurs after one or more shocks, amiodarone 300 mg can be administered as a bolus via intravenous or intraosseous route in the hope that arrhythmia recurrence will be prevented after the next shock, followed by a 150 mg bolus if the arrhythmia recurs. If amiodarone fails, lidocaine can be administered.

Consideration of etiology should also guide therapy (Chaps. 249 and 250). Commonly encountered causes of recurrent VT/VF may be due to ongoing myocardial ischemia or infarction that would benefit from emergent coronary angiography and revascularization, or QT prolongation causing the polymorphic VT torsades des pointes that may respond to administration of magnesium. Hyperkalemia should respond to administration of calcium, while other measures are implemented to reduce serum K.

PEA/asystole should be managed with CPR, ventilation, and administration of epinephrine. Causes of PEA/asystole that require specific therapy should be considered including airway obstruction, hypoxia, hypovolemia, acidosis, hyperkalemia, hypothermia, toxins, cardiac tamponade, tension pneumothorax, pulmonary embolism, and MI. Naloxone should be administered if opiate overdose is suspected.

POSTCARDIAC ARREST ACUTE MANAGEMENT

Following restoration of effective circulation, the possibility of acute MI should be immediately assessed. More than 90% of patients who have ST elevation consistent with acute MI will be found to have a culprit coronary stenosis/occlusion and likely benefit from emergent coronary angiography with percutaneous angioplasty and stenting. Angiography should also be considered if an acute coronary syndrome is suspected, even if ST segment elevation is absent, as more than half of selected patients undergoing angiography for this concern are found to have a coronary lesion as a potential cause of the ACA. Decisions regarding which patients without ST segment elevation should undergo urgent angiography are complex and factors such as hemodynamic or electrical instability, evidence of ongoing ischemia, comorbidities, and overall prognosis are taken into consideration.

Hemodynamic instability is often present following resuscitation and further ischemic end organ damage is a major consideration. Optimizing ventilation with consideration of acidosis, hypoxemia, and electrolyte abnormalities is important. Maintaining systolic BP at >90 mmHg, mean BP >65 mmHg is desirable and may require administration of vasopressors and adjustment of volume status. Potentially treatable reversible causes including hyperkalemia, severe hypokalemia, and drug toxicity with QT prolongation causing torsades des pointes should be identified and treated Chap. 250.

After stable spontaneous circulation is achieved, brain injury due to ischemia and reperfusion is a major determinant of survival and accounts for over two-thirds of deaths. The probability of successful neurologic recovery decreases rapidly with time between collapse and restoration of circulation and is <30% at 5 min in the absence of bystander CPR. The time between collapse and restoration of circulation is generally imprecise and some patients have a period of hypotensive VT prior to complete collapse, such that a reported long period prior to arrival of rescuers does not always preclude a good recovery. Therapeutic hypothermia (targeted temperature management) has been shown to improve the likelihood of survival and neurologic recovery in patients who present with shockable (VT or VF) rhythms and is recommended for all cardiac arrest patients who remain comatose, regardless of presenting rhythm, who have lack of purposeful response to verbal commands following return of spontaneous circulation. A constant target temperature of 34–36°C for at least 24 h is recommended, although a recent trial failed to demonstrate benefit compared with a strategy of targeted normothermia with early and aggressive treatment of fever. Shivering suppression with analgesics and sedatives may be needed. Induction of hypothermia should be started in-hospital, as no benefit was shown for implementation before hospital arrival, and administration of large volumes of cold saline for this purpose increased the risk of pulmonary edema. Brain injury is often accompanied by seizures and status epilepticus that may have further deleterious effects, warranting periodic or continuous electroencephalography (EEG) monitoring and treatment. A number of other therapies hoped to improve postarrest outcomes have been assessed, but have not been shown to be beneficial, including administration of corticosteroids, hemofiltration, and efforts to tightly control blood glucose.

Hypothermia and sedation preclude reliable prognostication for neurologic recovery. Functional neurologic assessment for neurologic recovery is generally deferred for at least 72 h after return to normothermia, typically 4–5 days after the cardiac arrest. Features that predict poor outcome include absence of pupillary reflex to light, status myoclonus, absence of EEG reactivity to external stimuli, and persistent burst suppression on EEG.

LONG-TERM MANAGEMENT AFTER SURVIVAL OF OUT-OF-HOSPITAL CARDIAC ARREST

For patients who survive cardiac arrest and have neurologic recovery, the likely underlying cause of the arrest guides further treatment. For arrests not due to an obvious non-cardiac cause, a full evaluation for the forms of structural heart disease outlined in Fig. 299-1 and Table 299-2 should be performed including an assessment for underlying CAD and ischemia as well as echocardiography and/or cardiac MRI to look for evidence of prior MI, valvular disease, nonischemic cardiomyopathies and to provide an assessment of left ventricular ejection fraction (LVEF). If the initial evaluation is not definitive or is suggestive of an inflammatory cardiomyopathy (i.e., sarcoidosis, myocarditis), a cardiac PET-scan and/or endomyocardial biopsy may also be performed. Patients without obvious structural abnormalities should undergo an evaluation for primary electrical disease (long-QT syndrome [LQTS], Brugada syndrome, early repolarization syndrome, or WPW). In cases where a heritable syndrome is suspected, further genetic evaluation should be considered. Diagnostic electrophysiology studies are warranted in selected patients to assess inducible arrhythmias, or perform provocative testing, such as with epinephrine challenge for LQTS, or sodium channel blocker (e.g., procainamide) challenge for Brugada syndrome.

Patients with shockable rhythms at arrest (VF and VT) that are not deemed to have been due to a transient reversible cause and have reasonable life expectancy should undergo insertion of an ICD for secondary prevention of SCA/SCD. Most of these patients will be found to have CAD. Patients with a VF arrest that occurs within the first 48 h of a documented acute MI generally do not require an ICD since they have a similar risk of sudden death over the next 5 years as infarct survivors who did not have a cardiac arrest. However, patients who have a large infarction with acutely depressed LV ejection fraction (e.g., <35%) have an increased risk for future development of life-threatening ventricular arrhythmias related to reentry in the infarct scar Chap. 247. The percentage of patients with such large infarcts has been declining due to improved treatment strategies for acute MI (Fig. 299-2D). Implantation of an ICD early after MI in these patients does not, however, improve survival, in part because a significant number of sudden deaths in the first three months are due to recurrent myocardial ischemia or myocardial rupture, rather than arrhythmias. For patients with large infarcts a wearable defibrillator that will treat VT/VF if it occurs may be used, while left ventricular remodeling is taking place, followed by reevaluation of arrhythmia risk after the infarct is healed to determine if an ICD is warranted. Patients who experience VF in-hospital >48 h after MI or in the setting of myocardial ischemia without infarction may be at risk for recurrent VT/VF. These patients should be evaluated and optimally treated for ischemia. If there is evidence that clearly implicates ischemia immediately preceding the onset of VF without evidence of a prior MI, coronary revascularization may be adequate therapy. Others may warrant an ICD. When the cardiac arrest is due sustained monomorphic VT, a prior infarct scar is often present and the recurrence rate is significant regardless of whether the arrest occurred in association with elevated serum troponin. An ICD is usually warranted even if revascularization is also needed.

Patients who have cardiac arrest due to a treatable reversible cause, such as hyperkalemia, or drug toxicity with QT prolongation causing torsades des pointes Chap. 250, that can be adequately addressed and prevented by other means do not usually need an ICD. An ICD is usually recommended for cardiac arrest due to VT or VF without a clearly reversible cause, particularly when structural heart disease, such as hypertrophic or dilated cardiomyopathy, arrhythmogenic cardiomyopathy, cardiac sarcoidosis, or a cardiac syndrome associated with sudden death, including Brugada syndrome, or LQTS are present (Chaps. 249 and 250). In patients with structural heart disease, it is important to recognize that life-threatening arrhythmias can be an indication of terminal, end-stage heart disease with minimal prospect for meaningful survival despite successful resuscitation, and ICDs will not alter the course of these patients and should not be implanted in this situation, unless there is a prospect for cardiac replacement therapy with future cardiac transplantation or a ventricular assist device.

PREVENTION OF SCD

Although advances in CPR and postresuscitation care have improved survival rates after cardiac arrest, 90% of patients will not survive to be discharged from the hospital. Of those that do survive, a proportion (~20%) are left with severe neurologic and/or physical disability. The majority of cardiac arrests do not occur in public places where AEDs and rapid defibrillation have the greatest impact. Patients who suffer an arrest at home also have longer EMS response times and are much less likely to be found in VF. Finally, 50% of cardiac arrests are not witnessed precluding effective resuscitation efforts. Thus, preventive efforts are critical to reducing mortality from cardiac arrest.

SCD RISK STRATIFICATION

The presence of overt structural heart disease and/or primary electrical heart disease is associated with an increased risk of SCD that varies with the severity and type of disease. For patients with structural heart disease, depressed left ventricular function is the best validated marker for risk, and clinical HF elevates risk further. After MI, SCD risk increases gradually as the LVEF decreases to 40% and then exponentially thereafter. In addition to LVEF and CHF, other potential markers of increased SCD risk in the setting of structural heart disease include unexplained syncope, sustained VT induced at electrophysiology study (EP study), left ventricular scar size and heterogeneity on cardiac magnetic resonance, markers of altered autonomic function and altered repolarization, and QRS prolongation. The majority of these tests, with the exception of the EP study in post-MI patients, broadly predict death from cardiovascular causes and are not able to discriminate patients who will die suddenly from those who will die of other cardiac causes. For instance, patients with the greatest degree of systolic HF and/or lowest LVEF, although at elevated risk for SCD, are more likely to die from HF. Although sustained VT at EP study does identify individuals at a higher risk of SCA versus non-SCA in certain subsets of patients, the sensitivity of the test is generally inadequate when LV function is significantly reduced.

PREVENTIVE THERAPIES FOR SCD IN HIGH-RISK POPULATIONS

Therapy with beta-adrenergic blockers has been demonstrated to reduce SCD risk in a multitude of settings including after MI, among patients with ischemic and nonischemic cardiomyopathy, and in LQTS. Angiotensin-converting enzyme inhibitors, aldosterone antagonists, and most recently angiotensin-receptor/neprilysin inhibitors have been associated with reductions in SCD in subsets of patients with structural heart disease, primarily ischemic and non-ischemic cardiomyopathy accompanied by HF. Coronary artery bypass grafting has also been associated with reductions in SCD risk, and revascularization in general may lower SCD risk through reduction in ischemic events and resultant improvements in left ventricular systolic function by reducing areas of hibernating myocardium.

For patients whose disease continues to confer substantial risk of sustained VT or VF on optimal medical therapy, an ICD is recommended (Table 299-3). The ICD indication in these patients is referred to as “primary prevention of sudden death.” The indications for primary prevention ICDs vary depending on the type of underlying structural heart disease and its severity, and variable strength of evidence. In patients with a history of MI more than 40 days ago, primary prevention ICDs are indicated for those with Class II-III NYHA HF and LVEF <35%, and those who are NYHA functional Class I with LVEF <30%. Although, ICDs have not been found to be beneficial when implanted within 40 days of a MI, those with recent or old MI, nonsustained VT, LVEF <40% and inducible sustained VT at EP study also warrant an ICD. In general, these criteria are not applied to patients who are within 90 days of myocardial revascularization, since some will experience improvement in ventricular function and older trial data suggested there was no benefit with ICDs in these patents. High-risk patients with low LVEFs may be considered for a wearable defibrillator with later reassessment of ventricular function and ICD placement.

ICDs for primary prevention of sudden death are also recommended for patients with diseases other than CAD, that put them at risk for SCD. ICDs are recommended for those with nonischemic DCM who have an LVEF ≤ 35% and who are in NYHA functional Class II or III and receiving medical therapy. Benefit is more likely in patients aged <60 years, as non-arrhythmia causes of death increase with age. For patients with LVEF <35%, HF, and left bundle branch block (LBBB) with QRS duration >150 ms cardiac resynchronization therapy also offers protection against SCD, particularly in patients with nonischemic cardiomyopathy. Primary prevention ICDs are also recommended in select high-risk patients with HCM, arrhythmogenic right ventricular dysplasia, cardiac sarcoidosis, and Brugada syndrome and some patients with congenital LQTS with high-risk features or that have failed therapy with beta-adrenergic blocking agents. There are circumstances where an ICD is not indicated even if there is a significant sudden death risk (Table 299-4). Most notably, patients who do not have a reasonable expectation of survival with an acceptable functional status for at least 1 year, should not undergo ICD placement.

THE CHALLENGE OF SCD PREVENTION

(Fig. 299-4)

The Greatest Number of Sudden Deaths Occur in “Low Risk” Patients

While patients with reduced left ventricular function and HF are at substantially elevated SCD risk, only ~20% of all SCDs occur in patients with poor left ventricular function. Most SCDs occur in individuals with preserved ventricular function who would not qualify for a primary prevention ICD. Although SCD rates are elevated compared to the general population, the absolute SCD risk in patients with CHD or HF who have an LVEF >35% is not high enough to warrant consideration of ICD therapy. While the incidence of SCD is lower in patients with preserved LVEF, SCD accounts for a greater proportion of cardiac deaths, and active efforts are being made to advance SCD risk stratification in this segment of the population. However, at the present time, SCD prevention primarily involves cardiac risk factor modification and standard medical therapy for the underlying condition.

Preventing Sudden Death in the General Population

Only about half of men and a third of women who suffer SCA are recognized to have heart disease prior to the event, and only half have warning symptoms prior to the event. SCD often occurs without warning as the first manifestation of cardiac disease. In order to prevent these SCDs, preventive interventions would need to be employed broadly to the general population. Although several risk scores have recently been developed with the intent to stratify SCD risk in low-risk populations, the clinical utility to date is limited by the low absolute incidence of SCD which is estimated to be only 50–90 per 100,000 in the general adult population. Therefore, current efforts aimed at preventing SCD in general populations primarily focus on modification of the SCD risk factors outlined previously. Individuals who adhere to a low risk, healthy lifestyle that includes avoidance of smoking, maintaining a healthy body weight, participating in moderate exercise, and a Mediterranean-type dietary pattern have markedly lower rates of SCD. A substantial number of SCDs are likely to be preventable thorough lifestyle modifications and treatment of risk factors.

ACKNOWLEDGMENT

The authors gratefully acknowledge the prior contributions of Agustin Castellanos and Robert J. Myerburg.

FURTHER READING

Additional Online References