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Circulatory Failure/Shock

CHAPTER 26

LEARNING OBJECTIVES Defi ne shock. ■

Describe the pathophysiologic changes that occur with ■

the different classifi cations of shock. Understand the molecules that mediate the changes ■

in the cardiovascular system in children with shock. Recognize the role of cardiovascular monitoring in ■

circulatory failure. Understand the mechanistic principles of goal-directed ■

therapies (including use of lactate levels and venous saturations) aimed at improving outcome in children with circulatory failure. Defi ne and understand the pathophysiology of multiple ■

organ dysfunction syndrome.

CHAPTER OUTLINELearning ObjectivesIntroductionShock Classifi cationsDeterminants of Oxygen DeliveryCardiogenic ShockHypovolemic ShockDistributive ShockSeptic ShockShock at the Cellular LevelClinical Monitoring of ShockTherapy for ShockReview QuestionsAnswersSuggested Readings

INTRODUCTION

Shock is a common manifestation of many forms of critical illness. Although a patient with hypotension can have shock, shock is not necessarily defi ned by hypotension. That is, a patient can have a “normal” blood pressure and have shock concurrently. Accordingly, the defi nition of shock is based upon the concepts of oxygen delivery, the circulation-related factors that govern oxygen delivery, and tissue oxygen requirements. When tissue oxygen requirements are not met by the circulatory system, be it due to poor myocardial function, hypovolemia, and/or hypotension, a patient is said to be in shock.

SHOCK CLASSIFICATIONS

There are several classifi cation schemes for shock, but a useful classifi cation scheme is based on four broad forms of shock: cardiogenic shock, hypovolemic shock, distributive shock, and septic shock. Table 26-1 outlines the various sub-classifi cations/etiologies that fall into

HECTOR R. WONG

536 H. R. WONG

these broad categories. Cardiogenic shock implies primary myocardial failure such that there is an impaired ability of the heart to generate an adequate cardiac output to meet the tissue oxygen requirements. Hypovolemic shock implies that the intravascular volume has been decreased to a level that reduces cardiac output, reduces tissue perfusion pressure, and/or reduces oxygen carrying capacity to levels that cannot meet the tissue oxygen requirements. Distributive shock can also be thought of as pathological vasodilatation. This implies a con-dition in which cardiac output and intravascular volume status may be adequate to meet tissue oxygen requirements, but blood fl ow is distributed in an aberrant manner (secondary to pathological vasodilatation) such that the effective tissue perfusion is inadequate to meet the tissue oxygen requirements. Septic shock merits a separate classifi cation in that it can have concomitant manifestations of cardiogenic shock, hypovolemic shock, and distributive shock to varying degrees.

DETERMINANTS OF OXYGEN DELIVERY

In order to understand and treat shock in terms of oxygen delivery, it becomes imperative to understand the determinants of oxygen delivery. Oxygen delivery is globally defi ned by the following equation:

Oxygen Delivery Cardiac Output Arterial Oxygen Content= ×

The two major determinants of cardiac output are heart rate and stroke volume. Heart rate is a particularly important variable in the pediatric population due to age-dependent varia-tions in heart rate (i.e. the newborn requires a higher heart rate for normal cardiac output than a 12 year old child) and the remarkable capacity of the developing host to increase heart rate as a primary mechanism to compensate for shock. The three major determinants of stroke volume are preload, afterload, and contractility. With these concepts in mind it can be seen how hypovolemia (abnormal preload), pathological vasodilatation (abnormal afterload), and myocardial failure (abnormal contractility) can independently lead to decreased effective cardiac output, and hence shock.

Arterial oxygen content (Cao 2 ) is determined by the hemoglobin concentration (Hgb), the arterial hemoglobin saturation (Sao 2 ), and the arterial partial pressure of oxygen (Pao 2 ):

2 2 2Cao (1.34 Hgb Sao ) (0.003 Pao )= × × + ×

MAJOR SHOCK CLASSIFICATION SUB-CLASSIFICATION/ETIOLOGY

Hypovolemic shock Hemorrhagic shock Dehydration secondary to GI disorders Post-operative “third-spacing” Fluid loss from surgical wounds or burns

Distributive shock Anaphylactic shock Spinal shock secondary to spinal cord injury Unbalanced single ventricle physiology

Cardiogenic shock Cardiomyopathy: dilated or restrictive myocarditis Post-operative low cardiac output syndrome Left ventricular outfl ow obstruction Cardiac tamponade Pulmonary hypertension Valve disease: regurgitant or stenotic Bradycardia and tachyarrhythmia

Septic shock Bacterial Viral Fungal

TABLE 26-1

MAJOR CLASSIFICATIONS OF SHOCK AND THEIR SUB-CLASSIFICATIONS/ETIOLOGIES

537 C HAPTER 26 • C I RC U LATORY FAI LU R E/S HOC K

The factor of 1.34 refers to the oxygen carrying capacity of hemoglobin in mL O 2 /g, whereas

the factor of 0.003 refers to the solubility coeffi cient of oxygen in blood at 37°C. From this equation it can be seen that hemoglobin saturation and hemoglobin concentration are the most important factors in determining arterial oxygen content and the latter accounts, in large part, for the pathophysiology of hemorrhagic shock from the standpoint of oxygen delivery (see also Chap. 2 , Oxygen Delivery and Consumption ).

CARDIOGENIC SHOCK

As stated previously, cardiogenic shock implies that there is primary failure of the myocardium such that the heart cannot generate a suffi cient cardiac output to meet the tissue oxygen require-ments. The most common form of cardiogenic shock results from systolic dysfunction as seen in myocarditis, cardiomyopathy, and low cardiac output syndrome following cardiac surgery with cardiopulmonary bypass and aortic cross-clamping. In this condition there is decreased contractility leading to decreased stroke volume despite adequate preload and afterload.

Although systolic dysfunction is the more common cause of cardiogenic shock, abnor-malities of heart rate and diastolic dysfunction, in the setting of normal systolic function, can also lead to cardiogenic shock. Thus, signifi cant bradycardia can lead to low cardiac output and shock despite a normal stroke volume. Conversely, tachyarrhythmias can lead to cardio-genic shock secondary to compromise of diastolic fi lling time and/or eventual systolic dys-function from excessive myocardial oxygen demand. Diastolic dysfunction occurs when there is decreased myocardial compliance such that ventricular fi lling during diastole is inadequate to generate a normal stroke volume during the subsequent systolic component of the cardiac cycle. A common clinical scenario in which diastolic dysfunction is encountered is in the post-operative patient who has undergone repair for Tetrology of Fallot. Many of these patients will have low cardiac output secondary to diastolic dysfunction during the immediate post-operative period until the hypertrophied right ventricle is able to “relax” and accommodate a normal systemic venous return (preload) in the setting of a closed ventricu-lar septal defect. Other conditions that lead to low cardiac output and shock secondary to diastolic dysfunction include restrictive cardiomyopathies and cardiac tamponade.

HYPOVOLEMIC SHOCK

Any clinical condition that leads to a substantial net loss of intravascular fl uid can lead to hypovolemic shock. For example, gastrointestinal diseases associated with vomiting and/or diarrhea are leading causes of death from hypovolemic shock in children worldwide, par-ticularly in underdeveloped countries. Another example is the patient who has undergone an extensive surgical procedure and develops capillary leak syndrome during the post-operative period. These patients are prone to “third space” fl uid in the extravascular compartment dur-ing the post-operative period. Although these patients can have a net positive fl uid balance, they are at risk for developing hypovolemic shock, irrespective of post-operative bleeding, because the effective intravascular volume is inadequate to maintain a normal cardiac out-put. Thus, hypovolemic shock can be thought of as a preload abnormality. As intravascular fl uid volume is decreased, the heart has less venous return during diastole (preload) and the resulting stroke volume is decreased, leading to shock. Shock secondary to hypovolemia typically implies a substantial net loss of intravascular volume given the compensatory mechanisms that can be activated in response to fl uid loss. Children in particular are able to substantially increase their heart rate and thus maintain an adequate cardiac output despite a low intravascular volume/low stroke volume. Other compensatory mechanisms include reabsorbtion of fl uid at the level of the kidneys by complex humoral mechanisms and shunt-ing of blood to “more vital organs” (i.e. brain and heart) by complex vascular mechanisms involving the sympathetic and parasympathetic nervous systems.

Hemorrhagic shock is a more complex and somewhat unique form of hypovolemic shock for two broad reasons. First is the added and sometimes devastating component of decreased

538 H. R. WONG

oxygen carrying capacity secondary to reductions in red blood cell mass. Thus, the patient with hemorrhagic shock is affected by both the aforementioned problems associated with a net decrease of intravascular volume (decreased cardiac output), as well as a reduced oxygen carrying capacity. The second factor is that patients with hemorrhagic shock will often develop multiple organ dysfunction syndrome (MODS) several days after their initial event. This syndrome can occur despite adequate surgical control of blood loss sources and seem-ingly adequate restoration of intravascular vascular volume and red cell mass. It appears that massive blood loss activates a systemic reaction in the host, which causes tissue injury dis-proportionate to the initial insult of decreased intravascular volume and decreased red blood cell mass. This tissue and organ injury is also a manifestation of complex host mechanisms including activation of neutrophils, activation of endothelial cells, and oxidant injury related to the phenomenon of ischemia-reperfusion injury. In addition, massive requirement for transfusion of packed red blood cells, particularly red blood cells that have been in storage for several weeks, is associated with the development of transfusion-related acute lung injury.

DISTRIBUTIVE SHOCK

Distributive shock typically results from profound abnormalities in vascular motor tone, otherwise known as pathologic vasodilatation. On the arterial side of the circulation patho-logic vasodilatation leads to profound hypotension, leading to decreased tissue perfusion pressure. Although in pure distributive shock cardiac output is typically normal to supernor-mal, profound decreases in perfusion pressure can eventually lead to decreased coronary artery perfusion pressure and eventual myocardial dysfunction. In addition, pathologic arte-rial dilation can lead to a misdistribution of blood fl ow such that arterial blood is shunted away from the vascular beds of vital organs to less vital regions such as the skin and muscle. The classic example of distributive shock that is seen in the clinical setting is anaphylaxis. Other conditions that can lead to distributive shock include spinal cord injuries, spinal or epidural anesthesia, and overdoses of medications with vasodilator properties.

Children with single ventricle physiology, particularly in the pre-operative period and following a fi rst stage Norwood operation, can also manifest a form of shock that can be considered for classifi cation as distributive shock. In this scenario, however, the manifesta-tion of distributive shock is not secondary to pathologic vasodilatation per se . Rather, it is due to the fact that the pulmonary and vascular circulations have parallel connections (as opposed to the serial connection that is seen in normal physiology) supplied by a single ventricle (Fig. 26-1 ). In this condition blood exits the single ventricle and can enter either the pulmonary circulation or the systemic circulation. The physical laws of fl uid mechanics dictate that blood will preferentially fl ow along the path of least resistance. Thus, if the pul-monary vascular resistance is low and/or the source of pulmonary blood fl ow is not suffi -ciently restrictive, blood will preferentially fl ow into the pulmonary vasculature at the expense of the systemic vasculature. This results in a form of distributive shock because of decreased systemic blood fl ow (decreased systemic oxygen delivery), while the pulmonary vasculature is said to be “over circulated” relative to the systemic vasculature.

SEPTIC SHOCK

Septic shock is one of the most common conditions seen in pediatric critical care medicine. It is a manifestation of systemic infection as well as the host response to the infection. There are over 42,000 cases per year of pediatric septic shock in the United States, with a mortality rate of approximately 10%. Management of a patient with septic shock embodies the disci-pline of pediatric critical care medicine. The typical patient with septic shock has simultane-ous derangements of cardiovascular function, intravascular volume status, respiratory function, immune/infl ammatory regulation, renal function, coagulation, hepatic function, and/or metabolic function. The degree to which any of these derangements are manifest in a given patient is highly variable and infl uenced by multiple host and non-host factors including,

539 C HAPTER 26 • C I RC U LATORY FAI LU R E/S HOC K

developmental stage, the presence or absence of co-morbidities, the causative agent of septic shock, the host’s immune/infl ammatory state, and the host’s genetic background. These fac-tors combine, in turn, to profoundly infl uence the ultimate outcome of septic shock.

As stated previously, septic shock can be classifi ed as a unique entity because it has mani-festations of all three aforementioned major classifi cations of shock: cardiogenic shock, dis-tributive shock, and hypovolemic shock. Which of the three components predominates or is present in any given individual patient is highly variable, thereby presenting a signifi cant therapeutic challenge. The cardiogenic shock component of septic shock is manifested as a profound decrease in myocardial systolic function. Primary myocardial dysfunction is well documented in the setting of septic shock and is thought to be due to a “myocardial depres-sant factor” in the serum of patients with septic shock. Compelling data suggest that tumor necrosis factor- a , interleukin-1 b , and nitric oxide may all be responsible for this depressant activity. In addition, it has been suggested that primary myocardial dysfunction is a more common clinical scenario in the pediatric patient with septic shock compared to the adult patient with septic shock.

The distributive shock component of septic shock is similar to that previously described. That is, septic shock can be characterized by pathologic vasodilatation leading to profound hypotension and maldistribution of blood fl ow. The patient with septic shock that is primar-ily distributive is said to be in “warm shock” and is characterized by a vasodilated (warm/red skin and brisk pulses/capillary refi ll) and high cardiac output state. It has been suggested that this type of presentation of septic shock is much less common in the pediatric patient with septic shock compared to the adult patient with septic shock.

The hypovolemic shock component of septic shock is multifactorial. Many patients with septic shock have a net decrease of intravascular volume secondary to increased fl uid losses (i.e. fever, vomiting, and diarrhea) and decreased fl uid intake (i.e. transient anorexia). In addi-tion, patients with septic shock can develop a profound capillary leak syndrome secondary to the generation of vasoactive mediators, which leads to “third spacing” of fl uid into the extravascular space with a decreased effective intravascular volume. Finally, septic shock leads to pathologic venous and arterial dilation, as described above. Venodilation leads to decreased venous return. The consequence of this is increased intravascular capacitance such that the intravascular space is effectively increased relative to normal, thus creating a relative form of hypovolemia independent of fl uid losses or the phenomenon of “third spacing.”

Pulmonarycirculation

Single Ventricle

Systemic circulation

Pulmonarycirculation

Single Ventricle

Systemic circulation

FIGURE 26-1

Box diagram depicting single ventricle physiology in which one ventricle supplies pulmonary and systemic blood fl ow in a parallel circuit. In panel A the resistances of the pulmonary and systemic circuits are well-matched such that blood fl ow distribution is well-balanced between the pulmonary and systemic vasculature. In panel B the resis-tances of the pulmonary and systemic circuits are poorly balanced (decreased resistance in the pulmonary circuit and/or increased resistance in the systemic circuit) such that pulmonary blood fl ow is substantially increased at the expense of the systemic circula-tion. This situation can be considered as a form of distributive shock

540 H. R. WONG

SHOCK AT THE CELLULAR LEVEL

The cellular manifestations of shock are erratic. At the most fundamental level, however, shock results in oxygen debt at the cellular level. This oxygen debt leads to interruption of oxidative phosphorylation, reliance on ineffi cient anaerobic metabolism, and subsequent depletion of ATP. If shock is suffi ciently profound, ATP depletion leads to complete energy failure and necrotic cell death. If a signifi cant number of cells undergo necrotic cell death, then whole organs begin to irreversibly fail leading to death of the patient secondary to MODS.

It is now well recognized that MODS occurs in patients with shock despite seemingly adequate reversal of the shock state (i.e. normal cardiac output, normal intravascular volume status, normal blood pressure, and/or normal red blood cell mass). This realization has given rise to a large investigative discipline focused on the cellular responses that occur in the set-ting of shock. These investigations have provided substantial insight into the cellular and molecular mechanisms that lead to cell injury and death following shock. Some of these mechanisms will be discussed in the sections below.

Apoptosis : Apoptosis, or programmed cell death, refers to a form of cell death that is dis-tinct from necrotic cell death. Although there are important overlaps and a continuum between these two forms of cell death, for purposes of discussion the respective characteris-tics of apoptotic cell death and necrotic cell death are highlighted in Table 26-2 . An impor-tant feature of apoptosis, from a therapeutic standpoint, is that it is an active and regulated process that requires energy and the coordinated expression and repression of pro-apoptotic genes (“cell suicide” genes) and anti-apoptotic genes. In fetal biology, apoptosis is a normal occurrence that is crucial to normal organ and limb development. Apoptosis is also important in normal cell turnover (e.g. the gut epithelium) and in removal of potentially deleterious cell types (e.g. cancer). Thus, apoptosis can be viewed as being “benefi cial” to the host. It has become increasingly recognized, however, that apoptosis also occurs in response to shock and in this setting apoptosis may be “detrimental” to the host. Evidence for widespread apop-tosis abounds in animal models of shock as well as in humans with shock, and is generally believed to be a maladaptive response that accounts, in part, for shock-associated MODS. One notable exception is apoptosis of neutrophils, which is thought to be an important mech-anism for resolution of tissue infl ammation. It has been suggested that failure of neutrophil apoptosis accounts, in part, for the prolonged tissue infl ammation (and consequent tissue damage) that can occur during shock states. Nevertheless, shock-associated apoptosis has become an attractive therapeutic target because it is an active and regulated process, and as such is potentially reversible through pharmacologic or genetic intervention.

Nitric oxide : Nitric oxide (NO) is a gaseous molecule that is produced endogenously by a broad variety of cell types. It is produced during the conversion of arginine to citrulline by the enzyme nitric oxide synthetase (NOS). There are three broad isoforms of NOS. The constitutive human isoforms, formerly referred to as neuronal NOS (nNOS) and endothelial NOS (eNOS), are now known as NOS 1 and NOS 3, respectively, based on the order in which they were cloned. Generally speaking, the constitutive isoforms are responsible for production of low levels of NO that are highly important in the regulation of various

APOPTOSIS NECROSIS

Single cells die Groups of neighboring cells die Cellular shrinkage and fragmentation Cellular swelling Plasma membranes intact Cellular lysis Mitochondria swell and release contents Mitochondria swell; disordered structure Organelles contract Organelles swell; organelle disruption Nuclear clumping and fragmentation Nuclear membrane disruption Internucleosomal DNA fragmentation Diffuse and random DNA fragmentation Phagocytosis of apoptotic cells with no

infl ammation Infl ammation; macrophage infi ltration

TABLE 26-2

CHARACTERISTICS OF APOPTOSIS AND NECROSIS

541 C HAPTER 26 • C I RC U LATORY FAI LU R E/S HOC K

homeostatic processes including vascular tone, signal transduction, and neuro-transmission. NOS 2 is an inducible isoform (formerly known as inducible NOS or iNOS) and is respon-sible for high and prolonged output of NO during various normal and pathologic biological conditions. High production of NO is thought to mediate pathologic vasodilatation, myocar-dial suppression, and direct cellular toxicity.

Because NO has such a broad variety of biological functions, the exact role of NO in shock states remains controversial. This is particularly true in septic shock, where experi-mental evidence indicates that NO has both detrimental and benefi cial effects in the setting of septic shock. For example, over production of NO has been clearly demonstrated in both adults and children with septic shock. In children, the amount of NO production has been correlated with non-survival and with vascular hypo-responsiveness to vasoconstrictors. Despite this evidence, as well as compelling pre-clinical data, therapeutic strategies target-ing inhibition of NO production in human septic shock have not been of benefi t.

PARP - 1 : Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear protein that senses and repairs DNA strand breaks that occur during various forms of cellular stress. In this capacity, PARP-1 is thought to play a benefi cial role in shock states. In certain shock states, however, PARP-1 is thought to be over activated and leads to cellular injury. This occurs because high level PARP-1 activity consumes NAD(+) and can consequently deplete ATP, thereby leading to cellular death secondary to energy failure. In addition, PARP-1 activation plays a role in the apoptosis pathway. Accordingly, there is a great deal of ongoing research focused on inhibition of PARP-1 activity in shock states.

NF - k B : As previously mentioned, many shock states are characterized by a highly acti-vated infl ammatory response. Many of these infl ammatory responses are centrally regulated by nuclear factor- k B (NF- k B). NF- k B is a transcription factor that regulates the expression of many genes involved in the innate immune response and infl ammation. These include cytokines, chemokines, and NOS II. In addition, NF- k B has both pro- and anti-apoptotic activity. Because NF- k B is a central regulator of infl ammation, there has been considerable interest in elucidating the role of NF- k B in shock states. These studies have clearly demon-strated increased activation of NF- k B in shock states and inhibition of NF- k B activation has been demonstrated to be benefi cial in various animal models of shock. In humans with septic shock, the degree and duration of NF- k B activation has been correlated with mortality. In this regard, it is interesting to note that corticosteroids are potent inhibitors of NF- k B activation.

HIF - 1 : Hypoxia inducible factor-1 (HIF-1) is also a transcription factor, but functions as a cellular-level “sensor” of hypoxia, a common manifestation of all shock states. Active HIF-1 is composed of two subunits: HIF-1 a and HIF-1 b . Both subunits are constitutively present in the cytoplasm, but under conditions of normoxia the HIF-1 a subunit is degraded by the ubiquitin-proteasome pathway. Under conditions of hypoxia, however, the degrada-tion of HIF-1 a is terminated, thus allowing for the formation of HIF-1 a /HIF-1 b heterodim-ers, which are active and can translocate to the nucleus to increase the expression of various genes required for adaptation to hypoxia. These include erythropoietin, vascular endothelial growth factor, heme oxygenase, NOS II, and various genes related to glucose metabolism. Thus, HIF-1 activation is potentially an important compensatory/adaptive mechanism dur-ing shock and its regulation during shock states is a fruitful area of investigation.

Ischemia - reperfusion / oxidant injury : All forms of shock have the potential to lead to ischemia-reperfusion injury. As the term for this form of injury implies, cellular injury is a manifestation of both the period of low blood fl ow/low oxygen delivery (ischemia) and the restoration of normal blood fl ow/normal oxygen delivery (reperfusion). Thus, while the lat-ter process is an obvious therapeutic goal in the clinical setting, paradoxically, when blood blow and oxygen delivery are restored to normal (sometimes supernormal) levels, this pro-cess can itself exacerbate cellular and tissue injury. The process of reperfusion injury is highly complex, but seems to be mediated in large part by the generation of free radical oxygen species during restoration of normal blood fl ow and oxygenation. The oxygen free radicals are intrinsically injurious to cells and tissues by damaging intracellular proteins and cellular membranes. In addition, these oxygen free radicals can act as signaling molecules that can lead to various potentially cytotoxic events such as neutrophil and endothelial acti-vation, cytokine production, activation of apoptosis, complement activation, expression of

542 H. R. WONG

NOS II, and PARP-1 activation. Accordingly, another important investigative effort is focused on ameliorating the potentially deleterious effects of reperfusion injury by free-radical scavenging strategies.

Toll - like receptors : Toll-like receptors (TLRs) are central to the cellular response to shock, particularly septic shock. TLRs are molecules that recognize pathogen associated molecular patterns (PAMPS). Well described PAMPS include lipopolysaccharide (gram-negative bacte-ria), peptidoglycan and lipoteichoic acid (gram-positive bacteria), double stranded RNA (viruses), bacterial DNA, and fl agellin (bacteria that possess fl agella). TLRs are membrane-associated receptors that allow cells of the innate immune system to detect the presence of pathogens associated with septic shock. While pathogen recognition is vital for host defense mechanisms, TLR activation can also lead to the initiation of the various infl ammatory cas-cades that contribute to the pathophysiology of septic shock. This has led to some investigation in targeting TLRs (specifi cally TLR4) as therapeutic targets in sepsis. Some of the more well-studied TLRs and the specifi c PAMPS that are recognized by them are listed in Table 26-3 .

Heat shock proteins : Heat shock proteins (HSPs) are a broad group of intracellular pro-teins that serve as molecular chaperones. In this capacity, HSPs serve to stabilize, transport, and refold damaged intracellular proteins. HSP expression was fi rst described in response to hyperthermia, hence the term “heat shock proteins.” It is now known, however, that HSPs are also highly expressed in various forms of cellular stress, including shock. In this capac-ity, HSPs confer cellular protection against various forms of cellular injury including isch-emia-reperfusion, hypoxia, and oxidant stress. Much of these cytoprotective effects appear to be mediated by the inducible isoform of HSP70. Apart from their molecular chaperone properties, activation of heat shock proteins also appears to have an inhibitory effect on activation of the NF k B pathway described above. Extracellular levels of both HSP70 and HSP60 were found to be elevated in children with septic shock. Accordingly, there is a great deal of interest in developing novel therapeutic strategies to safely induce HSP expression in various forms of shock.

CLINICAL MONITORING OF SHOCK

Clinical : Despite technological advances in critical care medicine, physical exams and basic clinical parameters continue to be important “monitors” of shock. The following are key physical signs and basic clinical parameters that can assist in both detecting shock states and for gauging the patient’s response to therapy. Low blood pressure is highly suggestive of shock, but it must always kept in mind that shock can be present in the setting of a normal blood pressure. Thus, restoration of a normal blood pressure should not be the only endpoint for shock-related therapy. Tachycardia is a fundamental compensation for shock and resolu-tion of tachycardia, particularly in hypovolemic shock, can be a good indicator that the appropriate therapeutic endpoint (i.e. volume restoration) has been reached. Decreases in pulse amplitude and/or perfusion are also good clinical indicators of shock and are often evident before the onset of hypotension. The pulse pressure can also be highly informative. For example, a narrow pulse pressure can be seen in the setting of hypovolemic or cardio-genic shock. Alternatively, a wide pulse pressure (manifested as bounding pulses and very

RECEPTOR LIGAND

TLR1 Lipopeptides (bacteria) TLR2 Peptidoglycan and lipoteichoic acid (gram-positive bacteria),

HSP70 TLR3 Double stranded RNA (viruses) TLR4 Lipopolysaccharide (gram-negative bacteria), several HSPs TLR5 Flagellin (fl agella-bearing bacteria) TLR6 Lipopeptides (mycoplasma) TLR9 Bacterial DNA

TABLE 26-3

SELECTED TOLL-LIKE RECEPTORS (TLR) AND THEIR RESPECTIVE PATHOGEN LIGANDS

543 C HAPTER 26 • C I RC U LATORY FAI LU R E/S HOC K

brisk perfusion) can be seen in distributive shock and some forms of septic shock. Heart auscultation can reveal an S 3 or S 4 sound (“gallop” rhythm) indicative of myocardial dys-function. Alterations in mental status can also be a manifestation of shock, but it should be remembered that this is a relatively late sign of shock due to the various compensatory mechanisms that maintain cerebral blood fl ow. Thus, other clinical signs of shock are likely to be present before alterations in mental status are clinically evident. Finally, adequate urine output remains a valuable indicator of shock or shock resolution. Interpretation of urine output, however, must be made in the context of various confounding factors such as con-comitant use of diuretics and/or intrinsic renal disease.

Acid - base status : Since shock is defi ned by an insuffi cient delivery of oxygen to meet tissue oxygen demands, it would be expected that shock states lead to abnormalities in acid-base status. Specifi cally, shock can lead to increased dependence on anaerobic metabolism, which results in overproduction of lactate. The classic scenario in shock states is that of an increased anion gap metabolic acidosis secondary to increased lactate production. Thus, serial measurement of arterial blood gases and lactate can serve as a guide for the severity, evolution, and resolution of shock. It should be stressed that serial measurements are of more practical value than isolated measurements.

It should also be stressed that multiple factors, other than insuffi cient oxygen delivery, can affect acid-base status and lactate level. For example, liver dysfunction is associated with decreased metabolism of lactate, which can in turn lead to increased serum lactate levels that do not necessarily refl ect increased lactate production. Another notable exam-ple is loss of bicarbonate in the setting of severe diarrhea (hypovolemic shock). In this setting patients can have a mixed source of metabolic acidosis: normal anion gap meta-bolic acidosis secondary to bicarbonate loss plus an anion gap acidosis (lactic acidosis) secondary to hypovolemic shock. Infusion of large amounts of fl uid with high chloride content (e.g. normal saline) can also lead to a non-anion gap metabolic acidosis. Co-morbid conditions also need to be considered when assessing acid-base status in the setting of shock. For example, a patient that has been on chronic, high dose diuretic therapy, or a patient that has chronic respiratory failure (hypercarbia) is likely to have a high baseline bicarbonate level. When these patients develop metabolic acidosis secondary to shock, the serum bicarbonate level may be in a normal range, but it should be recognized that their bicarbonate level has decreased signifi cantly from the higher pre-shock level. Thus, is it imperative that serial measurements of arterial blood gases and lactate, in the setting of shock, be interpreted within the context of the multiple factors that can affect acid-base status independently of shock.

Pulmonary artery catheter : The pulmonary artery catheter (PAC) remains as the gold standard for objectively assessing oxygen delivery in the critically ill patient. Table 26-4 provides a condensed list of the variables that can be directly measured by a PAC and the variables that can be derived from these measurements. In this context, the PAC would seem to be an indispensable tool for the management of shock. Indeed, for many years PAC’s were placed routinely in adults for a broad arrange of clinical conditions. Insertion of a PAC, however, carries important risks to the patient that are likely to be exacerbated in the smaller pediatric patient. Importantly, the utility and appropriateness of routine PAC insertion have come under very strong criticism, with some leaders in the fi eld going as far as proposing a ban on the use of PACs. As this debate continues with considerable intensity, it is diffi cult to advocate for the routine use of PACs in pediatric patients with shock. It seems reasonable, however, to consider insertion of a PAC in pediatric patients with severe and complex forms of shock. As always, this consideration must be taken in the context of the potential iatro-genic complications that can occur with PAC placement.

Mixed venous saturation : Mixed venous oxygen saturation (S mv O 2 ), measured in the pul-monary artery after complete mixing of the venous return upon crossing the tricuspid and pulmonic valves, can serve as a valuable objective measurement of oxygen delivery in shock states. The relationship between oxygen delivery and S mv O 2 can be understood by the Fick principle:

2 2Oxygen Consumption Cardiac Output (Arterial O content Venous O content)= × −

544 H. R. WONG

This equation can be solved for cardiac output as follows:

2 2Cardiac Output Oxygen Consumption (Arterial O content Venous O content)-= ÷

The equation can be further modifi ed by changing arterial O 2 content to arterial saturation (S a O 2 ) and venous O 2 content to S mv O 2 .

a 2 mv 2Cardiac Output Oxygen Consumption (S O S O )= ÷ −

From this last equation, it can be seen that decreases of S mv O 2 yield a larger number in the denominator of the equation. If oxygen consumption and arterial oxygen content are con-stant, then a lower S mv O 2 would refl ect a lower cardiac output. Thus, decreases of S mv O 2 can suggest a decrease of oxygen delivery secondary to decreased cardiac output. The variables in this equation, however, are not always constant in the critically ill patient. For example, hypoxia and/or anemia would lead to decreased arterial oxygen content. If the cardiac output and oxygen consumption are relatively constant in this context, then the S mv O 2 would have to be lower based on this equation. In a similar manner, if oxygen consumption is increased, and cardiac output and arterial oxygen content are constant, then the S mv O 2 would also have to decrease based on this equation.

In the absence of a pulmonary artery catheter, the oxy-hemoglobin saturation of central venous blood sampled from the high right atrium (S v O 2 ) has become a widely accepted esti-mate of the mixed venous oxy-hemoglobin saturation (S mv O 2 ). Serial measurements of S v O 2 can serve as objective, indirect measurements of global oxygen delivery. Relatively recent technology based on near infrared and visible light spectroscopy provide non-invasive and clinically feasible estimates of S v O 2 . Decreased S v O 2 can be indicative of inadequate oxygen delivery, while increases of S v O 2 in response to therapy can be indicative of effective therapy for shock. As stated above, however, changes in S v O 2 can also be indicative of changes in oxygen consumption or changes in arterial oxygen content. The latter can be readily esti-mated at the bedside (i.e. hemoglobin and pulse oximetry) thus leaving oxygen consumption as the only other “unknown” variable. This is important because it can not be assumed that oxygen consumption is constant in the critically ill patient. For example, signifi cant fever can increase oxygen consumption and lead to decreased S v O 2 . Alternatively, some patients with shock (particularly septic shock) are unable to adequately consume oxygen. This would be refl ected as a high or normal S v O 2 that could be inappropriately interpreted as a sign of adequate oxygen delivery.

Variables that can affect S mv O 2 include intracardiac shunts (left to right) and catheter tip placement. As stated above, the ideal catheter tip placement for measuring S mv O 2 is the pulmo-nary artery since this site would represent the most complete mixing of venous blood return. It has been demonstrated, however, that placement of a catheter tip at the junction of the superior vena cava and the right atrium (S v O 2 ) can provide a clinically reasonable estimate of S mv O 2 .

The value of superior vena cava-derived S v O 2 data was demonstrated in a randomized trial involving adult patients with septic shock. Patients were randomized to one of two treat-ment protocols and importantly, protocol-based therapy was instituted during the fi rst 6 h of presentation to the emergency room, prior to transfer to the intensive care unit. In one

Direct measurements Cardiac output Central venous pressure Pulmonary artery pressure Pulmonary capillary wedge pressure Derived measurements Oxygen delivery Oxygen consumption Oxygen extraction ratio Systemic vascular resistance Pulmonary vascular resistance

TABLE 26-4

SELECTED VARIABLES MEASURED BY PULMONARY ARTERY CATHETERS

545 C HAPTER 26 • C I RC U LATORY FAI LU R E/S HOC K

protocol patients received therapy targeting “traditional” endpoints such as central venous pressure, blood pressure, and urine output (standard therapy group). The other protocol used similar therapies, but used S v O 2 measurements ( ³ 70%) as the goal endpoint for therapy (goal-directed therapy group). S v O 2 measurements were taken from central venous catheters placed in the superior vena cava. The standard therapy group had a 28 day mortality of 49%, whereas the goal-directed therapy group had a 28 day mortality of 33%.

This single center trial has subsequently come under some criticism and the protocol is being re-tested in a confi rmatory multi-center trial. In addition, a recent trial indicates that goal directed therapy based on serial lactate measurements is equally effi cacious to goal directed therapy based on S v O 2 . While not studied extensively in the pediatric patient in shock, in the pediatric intensive care unit, there are some data suggesting that this therapeu-tic strategy can improve outcomes in the setting of pediatric shock.

THERAPY FOR SHOCK

For all forms of shock there are two equally important levels of therapy: etiology-specifi c therapy and supportive therapy. In all cases of shock the direct cause of shock should be addressed if possible. For example, in hemorrhagic shock there often needs to be surgical intervention to curtail ongoing blood loss. In septic shock antibiotics and source removal con-tinue to be mainstays of therapy. In anaphylactic shock it is crucial to discontinue and avoid further contact with the antigenic stimulus, when known. In cardiogenic shock anatomic causes of myocardial failure (e.g. coarctation of the aorta) need to be addresses surgically.

Often, however, there are no specifi c therapeutic strategies to address the underlying cause of shock. In this scenario, supportive therapy becomes the mainstay of therapy. These supportive therapies will be the focus of the subsequent sections and will not include mechanical approaches such as extracorporeal membrane oxygenation, ventricular assist devices, and intra-aortic balloon pumps. The need to address the specifi c cause of shock, when feasible, cannot be overstated but will not be repeated in each of the following sec-tions. The therapeutic endpoints discussed in the previous section are potentially applicable for all of the following supportive therapies.

Hypovolemic shock : The primary supportive therapy for hypovolemic shock is restoration of intravascular volume. The type of intravenous fl uid that is used for volume restoration will vary depending on the cause of hypovolemia. In hypovolemic shock secondary to vomiting and diarrhea, crystalloid replacement is usually suffi cient. The type of crystalloid will depend on the presence or absence of associated electrolyte disturbances (e.g. hypo- or hyperna-tremia). The use of albumin as the replacement fl uid for hypovolemic shock is probably best reserved for situations associated with direct loss of albumin (e.g. burns, open wounds, pro-tein losing enteropathies). In cases of hemorrhagic shock volume replacement with crystalloid or albumin can be appropriate, but with signifi cant blood loss replacement of red blood cell mass will eventually become a necessity. In the setting of large volume red blood cell transfu-sion requirements, consideration also needs to be given to replacement of other blood compo-nents such as platelets and plasma. Ongoing work in the adult trauma literature, including literature related to battlefi eld casualties, indicates that the ratio of red blood cells to other blood components (i.e. plasma and platelets) is a critical outcome factor for patients with mas-sive hemorrhage, and that the ratio may be lower than advocated by traditional practice.

While most patients with hypovolemic shock will tolerate relatively rapid correction of intravascular volume depletion, there are some notable exceptions that may require less rapid correction. For example, in cases of hypovolemic shock that are accompanied by sig-nifi cant metabolic/electrolyte derangements (e.g. hypernatremia or diabetic ketoacidosis) volume defi cit correction must be tempered so as to not correct the accompanying metabolic/electrolyte abnormalities too rapidly. In patients with underlying myocardial dysfunction, correction of hypovolemic shock must be done more judiciously than that of a patient with normal myocardial function so as to not further compromise myocardial function. Finally, there may be trauma-specifi c situations in which very aggressive volume resuscitation for hemorrhagic shock is not appropriate until surgical control of hemorrhage is achieved.

546 H. R. WONG

Cardiogenic shock : Assuming that heart rate is appropriate, the therapeutic strategies for cardiogenic shock are focused on optimizing stroke volume. This entails optimization of the three aforementioned components of stroke volume: preload, afterload, and contractility.

Optimization of preload can consist of either administration of volume to increase pre-load, or administration of diuretics to decrease preload. The physiologic principle for basing this decision is depicted in Fig. 26-2 , a theoretical Starling curve. Admittedly it is sometimes diffi cult to correctly assess clinically where on the Starling curve a particular patient is func-tioning. Helpful adjuncts include central venous pressure (CVP), responses to fl uid chal-lenge, and chest radiographs. The optimal CVP will vary from patient to patient, because CVP is infl uenced by factors other than intravascular volume including myocardial compli-ance, intrathoracic pressure, and catheter tip placement. All of these factors must be taken into consideration when interpreting and optimizing CVP. There is, in fact, a degree of “trial and error” that must sometimes occur in order to optimize CVP at the bedside. For example, a fl uid challenge that does not change CVP, but leads to a decrease of heart rate and an improvement in perfusion and urine output, likely means that the patient needs further, judi-cious administration of fl uid to optimize preload. Conversely, a fl uid challenge that leads to a large change in CVP with increased heart size and pulmonary edema on chest radiograph, but no concomitant improvement in urine output or perfusion, likely means that the patient needs diuretics to optimize preload.

Afterload reduction (reduction of systemic vascular resistance) can be a very effective approach to optimizing stroke volume. The rationale for afterload reduction is based on the equation describing systemic vascular resistance (SVR):

SVR Mean Arterial Pressure Central Venous Pressure) Cardiac Output-= ( ÷ Solving this equation for cardiac output yields the following equation:

Cardiac Output Mean Arterial Pressure Central Venous Pressure) SVR-= ( ÷

From this equation it can be seen that if mean arterial pressure and central venous pres-sure remain relatively constant, then a reduction in SVR is accompanied by an increase in cardiac output (stroke volume). Measuring SVR requires direct measurement of cardiac out-put (i.e. pulmonary artery catheter). It is clinically feasible and appropriate, however, to

Str

oke

Vol

ume

Preload

A

B

C

FIGURE 26-2

Theoretical Starling curve in which stroke volume (y-axis) is dependent on preload (x-axis) with the assumption that myocardial contractility and afterload are constant. Point B is the ideal preload at which stroke volume is maximal for a given state of contractility and afterload. Point A depicts a condition in which additional preload (i.e. intravascular volume) is necessary to optimize stroke volume. Point C depicts a condition in which less preload (i.e. diuretic administration) is necessary to optimize stroke volume

547 C HAPTER 26 • C I RC U LATORY FAI LU R E/S HOC K

manipulate SVR without the use of invasive monitoring. In this more common scenario, medications for afterload reduction are titrated to clinical improvements in cardiac output (described previously) with the limiting factor being hypotension. Common medications for afterload reduction include sodium nitroprusside, milrinone, angiotensin converting enzyme inhibitors, and nicardipine. An important caveat to optimal afterload reduction is that the patient fi rst needs to have an optimal preload.

Contractility is manipulated through the use of inotropic medications. These include direct b -agonists (epinephrine and dobutamine) and phosphodiesterase inhibitors (milri-none). Calcium chloride infusions may also be of benefi t in cardiogenic shock, particularly in younger children who seem to derive a substantial contractility benefi t from increased exra-cellular calcium levels. Similar to afterload reduction, these medications can be titrated to invasive measurements of cardiac output or clinical improvements in cardiac output. Limiting factors for b -agonists include increased myocardial oxygen consumption, tachy-cardia and other arrhythmias, and undesired increases of SVR. Limiting factors for phospho-diesterase inhibitors include hypotension (i.e. excessive afterload reduction) and increased drug accumulation in the setting of renal dysfunction.

A more recent trend in the management of patients with established cardiomyopathies (i.e. chronically compensated cardiogenic shock) de-emphasizes the use of b -agonists due to obligate increases of myocardial oxygen consumption and cellular level changes leading to further cardiomyocyte dysfunction. In fact, some of these patients benefi t from long term use of highly selective b -antagonists in combination with afterload reduction and diuretics, once they are no longer in acute cardiogenic shock.

Distributive shock : Treatment for pure distributive shock includes restoration of vascular tone and intravascular volume expansion. Since the primary cardiovascular mechanism in distributive shock is pathologic vasodilatation, the use of vasoactive medications that restore vascular tone is appropriate as a primary supportive therapy. These include norepinephrine and phenylephrine infusions. Epinephrine infusions can also be used, but its b –agonist effect on the myocardium may not be necessary and could be detrimental. Subcutaneous epineph-rine injections are typically used at the onset of anaphylactic shock. The need for intravas-cular volume expansion is predicated on the concept that pathologic vasodilatation leads to increase vascular capacitance leading to a relative hypovolemia with decreased venous return. Adjunctive therapies for distributive shock secondary to anaphylaxis include corti-costeroids and anti-histamines.

Septic shock : As mentioned earlier in this chapter, septic shock is characterized by all three major classifi cations of shock: hypovolemic shock, cardiogenic shock, and distributive shock. Accordingly, all of the aforementioned supportive therapies and therapeutic endpoints are potentially applicable to the management of septic shock. The clinical challenge lies in the recognition that the degree to which any one of these three forms of shock is present in a given patient can be highly variable. Aggressive intravascular support, however, is univer-sally accepted as a primary supportive therapy for all patients with septic shock. This recom-mendation is supported by historical data demonstrating improved outcomes for children with septic shock that received >40 mL/kg of fl uid administration during the fi rst hour of presentation. In the setting of aggressive fl uid management, the clinical challenge then becomes whether the patient should be supported primarily for cardiogenic shock, distribu-tive shock, or some combination of the two. Physical exam in combination with CVP response and echocardiography are typically suffi cient data to make this decision. For cer-tain patients insertion of a PAC may provide further useful information on which to base therapeutic decisions. Specifi c recommendations and guidelines for supportive cardiovascu-lar therapy in pediatric septic shock were published by a task force composed of pediatric critical care practitioners and sponsored by the American College of Critical Care Medicine and the Society of Critical Care Medicine. The recommendations include serial examination for signs of intravascular fl uid overload during volume loading in order to avoid iatrogenic injury from volume overload.

Two other therapies for septic shock deserve specifi c mention: corticosteroids and acti-vated protein C. Historically, high dose, short term corticosteroids were used for patients with septic shock, but when this approach was subjected to formal, randomized trials they

548 H. R. WONG

were proven to not be of benefi t, and perhaps be detrimental. However, the use of corticos-teroids in septic shock has been reconsidered and coupled with the concepts of longer term therapy, lower steroid doses, and “relative adrenal insuffi ciency.” The latter is based on an ACTH stimulation test followed by serial measurements of serum cortisol levels. Based on current data a patient is said to have relative adrenal insuffi ciency if they have an increase of serum cortisol <9 m g/dL following ACTH stimulation. Using these criteria for initiation of corticosteroid replacement therapy, a signifi cant survival benefi t was demonstrated in adult patients treated with a combination of hydrocortisone and fl udrocortisone. However, a sub-sequent trial based on a similar strategy failed to show a survival benefi t secondary to adjunc-tive hydrocortisone. Pending randomized trials in children, it is reasonable to conduct ACTH stimulation tests in children with septic shock and consider replacement therapy if they are deemed to have relative adrenal insuffi ciency. Apart from the criteria described above, it has also been suggested that a baseline cortisol level (prior to ACTH stimulation) <15 m g/dL is consistent with relative adrenal insuffi ciency in the setting of “refractory” septic shock. Others advocate the use of physiologic doses of corticosteroids for patients who are fl uid unresponsive and poorly responsive to inotropes.

Coagulation abnormalities are known to occur in the setting of septic shock. Specifi cally, the balance of anti- and pro-coagulant activity seems to be altered toward a pro-coagulant state, and much of this alteration involves decreased levels of endogenous anti-coagulant proteins such as anti thrombin III, tissue factor pathway inhibitor, and protein C. Logically, clinical investigations have been directed toward replacement of these factors with recombi-nant forms of these specifi c proteins. Large randomized trials in adults with septic shock have been carried out with both anti thrombin III and tissue factor pathway inhibitor, but with negative results. A similar trial, involving activated protein C, yielded a survival benefi t in the activated protein C group and led to Food and Drug Administration approval of acti-vated protein C for sub-groups of adults with severe sepsis. However, a randomized trial of activated protein C in children with sepsis was terminated early due to futility. Thus, current therapy for pediatric septic shock is limited to intensive care unit support, antibiotics, pre-vention (i.e. vaccines), and possibly hydrocortisone.

Ultimate progress in further advancing therapeutic strategies in both adults and children with septic shock may be predicated on the development of stratifi cation strategies. Because septic shock is a heterogeneous syndrome, rather than a distinct disease, several sub-classes of patients with septic shock are likely to exist based on the host response to an infectious challenge. Unfortunately, clinical trials for septic shock fail to address this heterogeneity. Current translational research efforts in pediatric septic shock are directly addressing this challenge of heterogeneity by systematically deriving septic shock stratifi cation tools based on biomarkers and gene expression signatures. The ultimate goals of these stratifi cation strategies is to more rationally conduct clinical trials in more biologically homogeneous populations and to better inform individual patient management.

1. The statement that best describes physiologic alterations observed in shock is: A. cardiogenic shock is more often the result of diastolic dys-

function than systolic dysfunction. B. distributive shock is characterized by reduced cardiac output

and pathologic vasodilation. C. hemorrhagic shock produces an acute reduction in oxygen

carrying capacity and may be complicated by multiple organ dysfunction syndrome.

D. increasing the partial pressure of oxygen often results in the greatest increase in oxygen carrying capacity.

E. septic shock often displays a predictable hemodynamic pro-fi le across multiple hosts.

2. Shock at the cellular level may be characterized by; A. compromised oxidative phosphorylation and rapid accumu-

lation of cytosolic ATP. B. decreased activation of nuclear factor-κB activation. C. failure of neutrophil apoptosis causing prolonged tissue

infl ammation. D. low levels of poly(ADP-ribose) polymerase-1 activity lead-

ing to ATP depletion. E. overproduction of nitric oxide leading to pathologic

vasoconstriction.

REVIEW QUESTIONS

549 C HAPTER 26 • C I RC U LATORY FAI LU R E/S HOC K

3. The most correct statement regarding the monitoring of ther-apeutic interventions during shock is that: A. decreased S c v O 2 can be indicative of inadequate oxygen

delivery or decreased oxygen consumption, while increases of S cv O 2 in response to therapy can be indicative of effective therapy for shock.

B. due to the variable clinical examination fi ndings in shock, serial examinations have been supplanted by more objective measures of shock such as lactate and mixed venous oxygen saturation determinations.

C. insertion of a pulmonary artery catheter is often necessary early in the treatment of septic shock.

D. mixed venous oxygen saturation is best measured from a pul-monary artery catheter with the tip in the pulmonary artery or alternatively by a central venous line with the tip at the infe-rior portion of the right atrium.

E. serial examinations and serial measurements of mixed venous oxygen saturation and lactate can serve as a guide for the severity, evolution, and resolution of shock.

4. A 6 year old, 20 kg boy recently diagnosed with acute lymphocytic leukemia is undergoing induction chemotherapy. He develops fever and is found to be neutropenic (absolute neutrophil count 410 cells / m L), anemic (hemoglobin 8.1 gm/dL) and thrombocy-topenic (platelet count 108,000 / m L). In clinic, he is cool distally, has poor pulses and a delayed capillary refi ll of 5 seconds. He develops sustained tachycardia to 180 beats per minute and has a blood pressure of 85/67 mm Hg. He is given a 500 mL bolus of normal saline and is transferred to the PICU. Upon arrival to the PICU, he is agitated, poorly perfused and remains tachycardic (167 beats per minute). His blood pressure is 94/78 mm Hg. Central venous blood obtained from a broviac catheter (tip lo-cated at the superior portion of the right atrium) reveals a mixed venous oxygen saturation of 55% and a lactate of 3.4 mmol/L. He has made minimal urine since his admission. The most correct statement regarding his management is which of the following? A. An additional 20 mL/kg normal saline should be adminis-

tered while awaiting the arrival of packed red blood cells for transfusion.

B. Further volume resuscitation should be withheld pending results of a STAT echocardiogram.

C. No further volume resuscitation is required. He requires rapid initiation of inotropic support.

D. No further volume resuscitation is required. He requires rapid initiation of vasopressor support.

E. No further volume resuscitation is required. He requires rapid initiation of afterload reduction.

5. A 17 year old adolescent boy is transferred from an outlying facility to the PICU for treatment of refractory pneumonia. He had a 10 day viral prodrome consisting of low grade fe-ver, progressive fatigue and dyspnea. His initial chest radio-graph revealed bilateral basilar infi ltrates. His current exam reveals tachypnea (34 breaths per minute), tachycardia (132 beats per minute) and blood pressure 110/91 mm Hg. He is cold distally and has a capillary refi ll time of 5 seconds. He is anxious and complains of chest pain. Repeat chest radiograph reveals diffuse bilateral infi ltrates and cardiomegaly. Bedside

ultrasound demonstrates no pericardial or pleural effusion. His oxygen saturation is 98% on 2 liters oxygen via nasal can-nula. An arterial lactate is 7.8 mmol/L. Which of the following statements best describes the etiology and treatment of this patient? A. He has become fl uid overloaded from overzealous fl uid

administration and requires aggressive diuresis. B. His pneumonia is now complicated by ARDS and septic

shock. He requires endotracheal intubation and initiation of epinephrine at 0.1 mcg/kg/minute.

C. Myocarditis should be strongly suspected. He should undergo rapid endotracheal intubation and have an epinephrine infu-sion initiated at 0.5 mcg/kg/minute.

D. Myocarditis should be strongly suspected. Furosemide should be administered and a dopamine infusion initiated at 20 mcg/kg/minute.

E. Myocarditis should be strongly suspected. Milrinone should be initiated at 0.5 mcg/kg/minute while awaiting echocardiography.

6. A 16 year old female develops fever, rigors, diffuse erythema and syncope. In the emergency department, she is found to have tachycardia (162 beats per minute) and blood pressure 98/35 mm Hg. She is warm distally and has a capillary refi ll time of less than 1 second. She is anxious and complains of diffuse myal-gias. She again becomes syncopal when sitting up. She is placed in the Trendelenburg position and is given three 20 mL/kg nor-mal saline boluses over 1 hour. Her perfusion is unchanged and repeat blood pressure is 100/22 mm Hg. She is given an addi-tional 20 mL/kg fl uid bolus upon arrival to the PICU and has a central venous catheter placed. ST changes are noted on the bedside cardiac monitor. Which of the following statements best describes the etiology and treatment of this patient? A. She has cardiogenic shock complicating sepsis and requires

the institution of a milrinone infusion. B. She has a distributive type of septic shock and requires more

fl uid resuscitation. C. She has a distributive type of septic shock and requires the

initiation of a high dose dopamine infusion. D. She has a distributive type of septic shock and requires the

rapid institution of a vasopressor such as norepinephrine. E. She has overwhelming hypodynamic sepsis and requires the

institution of an epinephrine infusion.

7. The correct statement regarding acid-base status and shock is that: A. a bicarbonate infusion following volume resuscitation is

often necessary to correct systemic acidosis. B. increased anion gap metabolic acidosis is often due to bicar-

bonate loss. C. initial measurements of arterial blood gases and lactate, in

the setting of shock, are highly predictive of outcome. D. multiple factors, other than insuffi cient oxygen delivery, can

affect acid-base status and include liver dysfunction and infusions of normal saline.

E. shock can lead to increased dependence on aerobic metabo-lism, which results in overproduction of pyruvate.

550 H. R. WONG

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SUGGESTED READINGS

1. C 2. C 3. E 4. A

5. E 6. D 7. D

ANSWERS

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