Adenosine triphosphate (ATP) is the energy currency of the cell. Shock is a state of acute energy failure in which there is insufficient ATP production to support systemic cellular function.⁵³ During stress and periods of increased energy demand, glucose is produced from glycogenolysis and gluconeogenesis. Fat metabolism is the secondary source of energy in this state. Long-chain fatty acids are oxidized, and carnitine is used to shuttle acetyl coenzyme A (CoA) into mitochondria. Protein catabolism can also contribute acetyl CoA to the Krebs cycle for energy production. However, this method of energy production is inefficient; aerobic metabolism provides 20-fold the energy produced by anaerobic metabolism. Glucose is oxidized to pyruvate via glycolysis (also called the Embden-Meyerhof pathway), generating only two molecules of ATP in the process.

When oxygen supply is adequate, pyruvate enters the mitochondria and is converted to acetyl CoA by the pyruvate dehydrogenase enzyme complex; it is then completely oxidized to CO₂ and H₂O via the Krebs cycle (also known as the tricarboxylic acid or citric acid cycle) and oxidative phosphorylation, generating a net total of 36 to 38 moles of ATP for every mole of glucose. Conversely, when oxygen supply is inadequate, pyruvate is reduced by nicotinamide adenine dinucleotide and lactate dehydrogenase to lactate, a relatively inefficient process that generates considerably less ATP.

Cells do not have the means to store oxygen and are therefore dependent on a continuous supply that closely matches the changing metabolic needs during normal metabolism and cellular function. If the oxygen supply is not sufficient for metabolic requirements, hypoxia will ensue, eventually resulting in cellular injury or death. As defined previously, shock is a state characterized by an inadequate delivery of oxygen and substrates to meet the metabolic demands of the cells and tissues of the body. Alterations in cellular function and structure result directly from the consequent derangements in cellular metabolism and energy production. Eventually, these derangements lead to cellular necrosis, with subsequent release of proteolytic enzymes and other toxic products that produce a systemic inflammatory response.

In practical terms, using this operational definition, a state of shock may result from inadequate substrate delivery (glycopenia) or mitochondrial dysfunction (cellular dysoxia).⁵³ Oxygen delivery to the cells and tissues depends primarily on three factors: hemoglobin (Hb) concentration, cardiac output (CO), and the relative proportion of oxygenated hemoglobin (i.e., percent saturation [SaO₂]). Oxygen is transported in the blood combined with hemoglobin, although a relatively small amount is freely dissolved in the plasma fraction of the blood. When fully saturated at normal body temperature, each gram of hemoglobin can carry about 1.34 to 1.36 mL of oxygen. The normal arterial oxygen content is calculated as follows:

Oxygen delivery (DO₂) is a product of arterial oxygen content and CO:

Generally, more oxygen is delivered to the cells of the body than the cells actually require for normal metabolism. However, a low CO (stagnant hypoxia), low hemoglobin concentration (anemic hypoxia), or low hemoglobin saturation (hypoxic hypoxia) will result in inadequate delivery of oxygen unless the other factors can increase commensurately.

Adequate glucose delivery depends on the presence of adequate blood glucose concentration, normal blood flow (or CO), and an adequate concentration of insulin for cells with insulin-responsive glucose transporters (e.g., cardiomyocytes). Glycopenic shock can be caused by hypoglycemia and by extreme insulin resistance.⁵³ Finally, even when oxygen delivery and glucose delivery are adequate, shock may occur as a result of mitochondrial dysfunction. For example, cyanide poisons the oxidative phosphorylation chain, preventing production of ATP. Cellular dysoxia (also known as cytopathic hypoxia) may theoretically occur from one or a combination of several mechanisms, including diminished delivery of a key substrate (e.g., pyruvate) to the Krebs cycle of the electron transport chain or uncoupling of oxidative phosphorylation.

Determinants of Oxygen Delivery

Normal CO

As defined previously, oxygen delivery is the product of CO and arterial oxygen content (CaO₂). CO is the product of heart rate (HR) and stroke volume (SV; Fig. 6-1). SV, in turn, is dependent on preload, afterload, and contractility. Furthermore, blood pressure (BP) is determined by the product of CO and systemic vascular resistance (SVR).

Fig. 6-1 A, Relationships of factors determining cardiac output and systemic perfusion. B, Relationships of factors determining systemic oxygen delivery.

Myocardial performance can be affected by changes in oxygenation, perfusion, serum ionized calcium concentration, acid-base, and electrolyte balance, sympathetic or vagal stimulation, and drugs.²⁴⁴ These factors can affect CO by altering either HR or SV.

Sympathetic nervous system β-adrenergic stimulation increases myocardial calcium release and influx, enhancing myocardial contraction. In addition, because calcium reuptake is more rapid, the ventricular systolic time is shorter. Shortening of ventricular systolic time results in prolongation of the diastolic filling time at the same HR, so SV improves. Many of these effects are mediated by cyclic adenosine monophosphate (cAMP), an intracellular messenger that promotes phosphorylation of sarcolemmal proteins and increases the opening of calcium channels in myocardial cell membranes. Phosphodiesterase then converts the cAMP to an inactive compound, ending the cAMP and sympathetic effects. Phosphodiesterase inhibitors (such as milrinone) prevent the inactivation of cAMP; therefore they prolong any adrenergic effects that are mediated by cAMP.

Contractility is enhanced by any conditions or factors that increase intracellular calcium. Alpha-adrenergic stimulation and cardiac glycosides all increase intracellular ionized calcium. The intracellular sodium concentration can influence the free calcium levels in the myocyte, because sodium and calcium ions share storage sites and compete for space in the sodium-potassium pump. When the intracellular sodium concentration is increased (e.g., during digitalis therapy), sodium occupies space in the exchange pump. As a result, calcium ions accumulate in the myocardial cell, and myocardial contractility increases.

Factors Influencing SV

Three terms first defined in the physiology laboratory are used clinically to describe several important factors influencing myocardial function. These terms—preload, contractility, and afterload—can be defined precisely in the physiology laboratory using isolated normal myocardial preparations. Their application to the clinical setting, however, where it may be impossible to separate the effects of each factor, has been less precise. The common usage and clinical application of these terms are provided here.

Ventricular Preload

Preload is the amount of myocardial fiber stretch that is present before contraction. The significance of ventricular preload was first appreciated by Howell (in 1894), Frank (in 1894), and Starling (in 1914)²⁴² in a series of experiments performed on isolated normal myocardial muscle preparations. Howell, Frank, and Starling observed that normal myocardium generates greater tension during contraction if it is stretched before contraction. This increase in the force of contraction occurs as a result of optimization of overlap between actin and myosin filaments in the sarcomere. These observations became known as the Frank-Starling law of the heart, which states that an increase in ventricular work, systolic tension, and SV results from an increase in presystolic stretch (preload). The graphic representation of the relationship between ventricular end-diastolic myocardial fiber length (usually approximated by ventricular end-diastolic pressure [VEDP]) and SV is the Frank-Starling curve, which is a ventricular (myocardial) function curve (Fig. 6-2).

Fig. 6-2 Frank-Starling curve. In the laboratory description of the Frank-Starling law (using isolated normal myocardial fibers), an increase in the end-diastolic myocardial fiber length increased the tension generated by the myocardial fiber. In the clinical setting, measurement of end-diastolic fiber length is impossible, so the ventricular end-diastolic pressure (VEDP) is increased to produce improvement in SV or cardiac output. To a point, an increase in VEDP will produce an improvement in cardiac output. (A → B), This increase in VEDP is accomplished through judicious titration of intravenous fluid. The clinician must also recognize that a family of myocardial function curves exist. The patient’s myocardial function can be characterized as normal, dysfunctional, or hyperdynamic. If the myocardium is dysfunctional, it generally requires a higher VEDP than the normal myocardium to maximize cardiac output. In addition, excessive volume administration can produce a decrease in cardiac output and myocardial performance if the ventricle is dysfunctional (B → D). In this case, administration of a diuretic or vasodilator may improve cardiac output (D → B). Correction of acid-base imbalances, reduction in afterload, or administration of inotropic medications may improve myocardial function so that cardiac output increases without need for further increase in VEDP (B → C). If the patient’s myocardial function is hyperdynamic, cardiac output will be high even at low VEDP.

(Courtesy William Banner, Jr.)

The Frank-Starling law of the heart applies to dysfunctional and normal myocardium, although the appearance (i.e., the position and slope) of each function curve will differ. Optimal stretch of any myocardial fiber should improve myocardial performance, but it will be necessary to tailor the approach to the patient with shock to attempt to identify the optimal preload that yields the best CO and systemic perfusion.

Myocardial fiber length is not readily measured in the clinical setting; therefore VEDP is monitored as an indirect measure of the stretch placed on the myocardial fibers before contraction. VEDP is increased by intravenous volume administration. The relationship between ventricular end-diastolic volume (and fiber length) and VEDP is not a linear one, however. The rise in VEDP that occurs as end-diastolic volume is increased is determined by ventricular compliance (see “Ventricular Compliance”) and by venous return; both of these factors may be altered by disease or therapy.

To a point, as VEDP is increased, the force of contraction and myocardial fiber shortening should increase, and SV should rise.⁹⁸ If, however, the ventricle is filled beyond a critical point, overlap of actin and myosin filaments is no longer optimal; ventricular dilation can result, and stroke volume decreases.⁴⁷ Extremely high VEDPs (higher than approximately 25 cm H₂O pressure when capillary permeability is normal, and lower pressures when capillary permeability is increased) result in pulmonary and systemic edema, and high pressures will compromise coronary and subendocardial blood flow.

If SV or CO can be estimated reliably (e.g., using Doppler, Fick, or thermodilution calculations) a ventricular function curve can be constructed for any patient. CO or SV (CO divided by HR) are plotted on the vertical axis of the graph, and VEDP is plotted on the horizontal axis. As fluid administration is titrated and the SV is determined at various VEDPs, the optimal VEDP is identified as the peak point on the curve.

A family of ventricular function curves can be constructed to illustrate the response of normal, depressed, or enhanced myocardial response to increased VEDP (see Fig. 6-2). If the patient demonstrates poor myocardial function, the ventricular function curve will be relatively flat, and a high VEDP will be required to produce even a modest improvement in myocardial function. If myocardial function is normal, a small increase in VEDP can produce a significant rise in SV or CO. If ventricular function is hyperdynamic, even nominal increases in VEDP will produce significant increases in SV or CO.

A goal of the treatment of any patient with cardiovascular dysfunction is to maximize SV and CO while minimizing adverse effects of fluid administration, such as pulmonary edema. An increase in SV and CO can be achieved by moving the patient to the highest point of an individual ventricular function curve (see Fig. 6-2) through judicious fluid administration. Improvement in SV and CO also can be achieved by altering the ventricular compliance, using vasodilator therapy. Further increase in SV and CO also can be achieved through improvement in cardiac contractility; this raises the ventricular function curve (see Fig. 6-2). Such an improvement can be attained by eliminating factors that normally depress myocardial function or by administering inotropic agents or vasodilators (discussed under Afterload).

In the clinical setting, VEDP can be measured to evaluate ventricular preload. In addition, ventricular end-diastolic volume can be estimated through the use of echocardiography or nuclear imaging.

Right VEDP (RVEDP) is equal to right atrial pressure unless tricuspid valve stenosis is present. Central venous pressure (CVP) equals right atrial and right VEDP, unless central venous obstruction is present.

RVEDP and CVP often can be estimated with careful clinical assessment of the level of hydration, liver size, palpation of the infant’s fontanelle, determination of presence (or absence) of systemic edema, and evaluation of the cardiac size on chest radiograph.²⁷⁵ Dry mucous membranes, a sunken fontanelle, and the absence of hepatomegaly are findings consistent with a normal or low central venous pressure. Hepatomegaly and periorbital edema usually are present once the CVP is elevated significantly. Systemic edema also may be noted despite a normal or low CVP if capillary leak or hypoalbuminemia is present. A high RVEDP and heart failure is often associated with cardiac enlargement on chest radiograph.

Left VEDP (LVEDP) is equal to left atrial pressure unless mitral valve disease is present. Reliable estimation of LVEDP is not possible through clinical assessment alone.²⁷⁵ Although the presence of pulmonary edema frequently is assumed to indicate the presence of a high LVEDP (exceeding 20 to 25 mm Hg), pulmonary edema may be observed at any (even a low) LVEDP if capillary leak is present.

A left atrial catheter or pulmonary artery catheter must be inserted to measure LVEDP, because this pressure cannot be estimated from clinical examination. In the absence of pulmonary venous constriction or obstruction, a pulmonary artery wedge pressure will approximate left atrial pressure. In the absence of mitral valve disease or extreme tachycardia, left atrial pressure should reflect LVEDP. However, the pulmonary artery catheter must be placed appropriately and the transducer must be zeroed, leveled, and calibrated correctly.

VEDP directly affects the resting length of the ventricular myocardial cells before contraction. Although VEDP is increased through the administration of intravenous fluids, VEDP is not related linearly to fluid volume administered. VEDP also will be affected by ventricular compliance. Ventricular compliance is in turn affected by ventricular function, ventricular relaxation, wall thickness, ventricular size, pericardial pressures, and HR.

Ventricular Compliance

Ventricular compliance refers to the distensibility of the ventricle. It is defined as the change in ventricular volume (in milliliters) for a given change in pressure (in millimeters of mercury), or ΔV/ΔP, and can be depicted graphically by a ventricular compliance curve (Fig. 6-3). The opposite of compliance is stiffness (ΔP/ΔV).

Fig. 6-3 Ventricular compliance is illustrated by a ventricular end-diastolic pressure (VEDP)-volume curve. The slope of a tangent to the curve (arrows) indicates the change in pressure/change in volume (ΔP/ΔV), representing the stiffness of the ventricle at a given filling pressure. Ventricular compliance changes with age (compliance is lower, or the compliance curve is shifted to the left in the fetus or young infant), cardiovascular disease, and drug therapy. In the normal ventricle (curve A), a low ventricular end-diastolic volume is associated with a low VEDP. As the ventricle is filled, smaller changes in volume produce exponentially greater rises in end-diastolic pressure. When the ventricle is dysfunctional or hypertrophied (curve C), ventricular compliance is reduced, and even a small increase in ventricular end-diastolic volume will produce a rise in VEDP. Vasodilator therapy can increase ventricular compliance (curve B), so that greater ventricular volume can be tolerated without a rise in VEDP. In this manner, the stroke volume can be increased without increasing the VEDP.

(Courtesy William Banner, Jr.)

If the ventricle is extremely compliant, a large volume of fluid may be administered without producing a significant increase in VEDP (see Fig. 6-3, curve B). If the ventricle is dysfunctional (as occurs with restrictive cardiomyopathy) or hypertrophied, ventricular compliance usually is reduced (see Fig. 6-3, curve C). In this case, even a small volume of administered intravenous fluids will produce a significant rise in VEDP.²⁶⁸ The more dysfunctional and noncompliant the ventricle, the higher the resting VEDP and the VEDP needed to optimize SV and ventricular performance (see Fig. 6-2).

Ventricular compliance is not constant over all ranges of VEDP. Any ventricle is maximally compliant at low filling pressures. As the ventricle is filled, compliance is reduced because ventricular stretch may be maximal.⁵⁵ ^,169 Rapid volume infusion tends to raise VEDP more rapidly than gradual volume infusion. Compliant ventricles usually demonstrate a substantial improvement in SV when an intravenous fluid bolus is administered.

Vasodilator therapy will improve ventricular compliance. When these drugs are administered the compliance curve is altered, so a greater end-diastolic volume may be present without a substantial increase in VEDP (see Fig. 6-3). SV may then be increased without a rise in VEDP.

Compliance also is affected by ventricular size, pericardial space, and HR.⁵⁵ Infants have small and relatively noncompliant ventricles, so the infant’s VEDP may rise sharply with minimal fluid volume administration. If the same volume (on a per-kilogram basis) is administered to an older child, a smaller change in VEDP will result because the ventricles are larger and more compliant in older children.

Constrictive pericarditis and tamponade will decrease ventricular compliance, because ventricular expansion cannot occur in response to volume administration. Diastolic filling will be impaired and SV often is reduced. As a result, if pericarditis or tamponade is present, VEDP usually will be elevated and will rise significantly with even modest fluid volume infusion. SV and CO may not improve despite the rise in VEDP.

Extreme tachycardia (such as supraventricular tachycardia, SVT) can produce a rise in VEDP. A rapid HR is associated with reduced ventricular diastolic time and incomplete relaxation. As a result the VEDP rises.

Because VEDP is affected by a variety of factors, it is important to attempt to determine the VEDP associated with optimal systemic perfusion for each patient on each day. Obviously this optimal pressure can change frequently during the patient’s clinical course. Throughout therapy, evidence of systemic perfusion always should be assessed as VEDP is manipulated.

Ventricular Contractility

The term contractility refers to the strength and efficiency of contraction; it is the force generated by the myocardium, independent of preload and afterload. Contractility is estimated by velocity of fiber shortening; this can be determined using echocardiography. If myocardial function is good, the ventricular fibers shorten rapidly. As a result, at the same HR, systole requires less time, leaving more time for diastole (filling time). SV will increase if circulating blood volume is adequate and ventricular afterload is unchanged.

Although contractility can be measured in the laboratory, it is not easily isolated and measured in the clinical setting. The most common method of evaluating contractility at the bedside is echocardiographic evaluation of fiber-shortening times and measurement of the shortening fraction of left ventricular diameter. Shortening fraction is calculated by determining the difference between the end-diastolic and end-systolic dimensions. Normal shortening fraction is approximately 28% to 44%.²⁰⁶

If a thermodilution CO pulmonary artery catheter is in place, or if reliable Doppler CO estimations can be obtained, the nurse can create a ventricular function curve (see Fig. 6-2). If CO improves with no change in VEDP or HR, ventricular contractility or compliance has probably improved.

Although evaluation of contractility considers the effectiveness of ventricular systolic function, ventricular filling, SV, and CO may also be impaired by a compromise in ventricular diastolic function. Diastolic function can be evaluated by echocardiography, but this evaluation will also be influenced by HR, ventricular preload, and ventricular systolic function.

Afterload

Afterload is any impediment to ventricular ejection; it is the sum of all forces opposing ventricular emptying and is described as ventricular wall stress. If ventricular wall stress is increased, there will be a significant impediment to ventricular ejection, and the ventricle will be required to generate higher pressure to eject the same amount of blood. If the higher pressure cannot be generated, the amount of blood ejected by the ventricle will fall. With any increase in afterload, oxygen consumption and the work of the ventricle increase. Even a normal afterload may be excessive when myocardial function is poor.

The major determinants of ventricular afterload or wall stress are: ventricular lumen radius, ventricular wall thickness (note that hypertrophy decreases afterload), and the ventricular intracavitary ejection pressure (Fig. 6-4). In the absence of left ventricular outflow tract obstruction (e.g., aortic stenosis), left ventricular ejection pressure will equal aortic and systemic arterial pressure. In the absence of right ventricular outflow tract obstruction (e.g., pulmonary stenosis), right ventricular ejection pressure will equal pulmonary arterial pressure. Systemic and pulmonary artery pressures in turn are determined by blood flow and resistance. Therefore in the absence of ventricular outflow tract obstruction or significant alterations in ventricular size or wall thickness, ventricular afterload is related primarily to the impedance provided by the pulmonary and systemic arterial circulations.

Fig. 6-4 Factors influencing ventricular wall stress. According to Laplace’s law, Wall stress = (Ventricular pressure × Ventricular radius) ÷ (2 × Ventricular wall thickness). R, Radius.

The ventricle of the infant or child can usually adapt to increases in ventricular afterload, provided that the increases are neither severe nor acute. For example, if the left ventricular muscle thickness increases and the diameter of the left ventricular chamber is reduced, wall stress (afterload) may be normalized. If, however, afterload increases severely or acutely—such as occurs with acute, reactive pulmonary vasoconstriction in response to severe alveolar hypoxia—CO may fall.

Afterload cannot be measured in the clinical setting. Resistances in the pulmonary and systemic circulations can be calculated using a thermodilution pulmonary artery catheter. SVR can also be calculated using estimations of CO obtained by Doppler calculations, and PVR can be estimated using echocardiography. It is important to note that, at best, SVR and PVR are calculated or estimated numbers, not measurements.

Oxygen Delivery

The ultimate function of the heart and lungs is to deliver oxygenated blood to the tissues. Systemic DO₂ is the volume of oxygen (in milliliters) delivered to the tissues per minute. DO₂(I) is the volume of oxygen delivered to the tissues per minute, indexed to body surface area (BSA), so that the units are milliliters per minute per square meter. DO₂ is the product of arterial oxygen content (the amount of oxygen in arterial blood in milliliters per deciliter) the CO (in liters per minute), and a factor of 10. DO₂(I) is the product of arterial oxygen content (in milliliters per deciliter), the cardiac index (in liters per minute per square meter), and a factor of 10 (see Fig. 6-1).

Under resting conditions with normal distribution of CO, oxygen delivery is more than adequate to meet the total oxygen requirements the tissues need to maintain aerobic metabolism, which is referred to as oxygen consumption (VO₂). Excess oxygen delivery or oxygen reserve serves as a buffer, so a modest reduction in oxygen delivery will be more than adequately compensated by increased extraction of the delivered oxygen, without any significant reduction in oxygen consumption. During stress or vigorous exercise, oxygen consumption markedly increases, as does oxygen delivery. Therefore, under most conditions, the metabolic demands of the cells and tissues of the body dictate the level of oxygen delivery. However, little oxygen is stored in the cells and tissues of the body; therefore as oxygen delivery falls with critical illness, oxygen extraction must necessarily increase to meet metabolic demands, and oxygen consumption remains relatively constant (i.e., it is delivery independent; Fig. 6-5). However, there is a critical level of oxygen delivery at which the body’s compensatory mechanisms are no longer able to meet metabolic needs (i.e., the point at which oxygen extraction is maximal). Once oxygen delivery falls below this level, oxygen consumption must also fall and is said to become delivery dependent (see Fig. 6-5, Normal critical delivery threshold).

Fig. 6-5 Theoretical relationship between oxygen delivery and oxygen consumption. In normal tissues (horizontal portion of solid line, labeled supply-independent), oxygen delivery far exceeds oxygen consumption, so a significant fall in systemic oxygen delivery can be tolerated without any change in oxygen consumption (tissue oxygen extraction merely increases). However, eventually a profound fall in oxygen delivery will reach a critical delivery threshold. Further compromise in oxygen delivery will then result in a proportional fall in oxygen consumption (slope of solid line, labeled supply-dependent); the oxygen consumption is supply-dependent. In patients with adult respiratory distress syndrome and patients with sepsis (broken line), oxygen consumption is thought to be far more supply dependent than in the normal population (dotted arrow indicates critical delivery threshold for patients with acute respiratory distress syndrome [ARDS] and sepsis—note that oxygen consumption becomes supply dependent at a much higher level of oxygen delivery than in normal patients). In these patients, even a small reduction in oxygen delivery can force a fall in oxygen consumption. For this reason, medical therapy may target increasing oxygen delivery to ranges above normal during the treatment of ARDS or sepsis.

(Modified with permission from Schumaker PT, Samuel RW: Oxygen delivery and uptake by peripheral tissues. Crit Care Clin 5:255, 1989.)

If either arterial oxygen content or CO falls without a commensurate and compensatory increase in the other component, oxygen delivery will fall (Fig. 6-6, A–H). For example, if arterial oxygen content falls (e.g., caused by a fall in hemoglobin concentration or its saturation), oxygen delivery can be maintained by a commensurate rise in CO. If CO falls, however, oxygen delivery will fall in direct correlation, because there is no way for arterial oxygen content to increase when CO falls.

Fig. 6-6 Oxygen delivery and balance. A, Normal. B, Compensated anemia (increased cardiac index/output). C, Uncompensated anemia (normal index/cardiac output). D, Compensated hypoxemia (increased cardiac index/output). E, Uncompensated hypoxemia (normal cardiac index/output). F, Shock with low cardiac index/output. G, Sepsis with low oxygen extraction (high oxygen delivery). H, Sepsis with improved oxygen extraction (treated sepsis with high oxygen delivery).

If oxygen delivery falls significantly, the sympathetic nervous system attempts to redistribute blood flow to vital organs. In addition, tissue oxygen extraction increases. If these compensatory mechanisms fail to maintain adequate blood flow or oxygen delivery, anaerobic metabolism will result in lactic acidosis.

Oxygen Content

Oxygen content is the total amount of oxygen (in milliliters) carried in each deciliter of blood. Because oxygen is carried primarily in the form of oxyhemoglobin, the arterial oxygen content essentially is determined by the hemoglobin concentration and its saturation, although a small amount of oxygen is carried dissolved in the blood.

Arterial oxygen content will be decreased by anemia or a fall in the oxyhemoglobin saturation. For this reason, anemia should be avoided in patients with compromised cardiorespiratory function, and transfusion therapy should be considered if anemia develops.

There is no “magic” hemoglobin concentration that is perfect for all patients. A low hemoglobin value decreases the oxygen-carrying capacity of the blood. An extremely high hemoglobin value is also undesirable, because it increases blood viscosity and resistance to blood flow in small vessels. In the presence of sluggish systemic, pulmonary, or cerebral perfusion, the hemoglobin may be maintained at 10 to 11 g/dL, despite the fall in oxygen content that results.

The optimal hemoglobin threshold for erythrocyte (red blood cell) transfusion in critically ill children is unknown.¹⁶⁰ Whereas transfusion is indicated in conditions of hemodynamic instability and anemia (hemoglobin <10 g/dL), once stability is achieved the threshold hemoglobin level for transfusion may need to be lowered. A recent multicenter trial demonstrated that in stable, critically ill children a hemoglobin threshold of 7 g/dL for red blood cell transfusion decreased transfusion requirements without increasing adverse outcome.¹⁶⁰

The oxyhemoglobin saturation will fall in the presence of an intrapulmonary shunt or a right-to-left intracardiac shunt (cyanotic congenital heart disease [CHD]). If an intrapulmonary shunt is causing the hypoxemia, the oxyhemoglobin saturation and the arterial oxygen content can usually be increased through the administration of supplementary inspired oxygen. It may be necessary to provide mechanical ventilation with positive end-expiratory pressure to maximize oxyhemoglobin saturation.

The child with cyanotic CHD is always hypoxemic (i.e., has low arterial oxyhemoglobin saturation). As a compensatory mechanism, these children develop polycythemia; this maintains their arterial oxygen content at near normal levels despite oxyhemoglobin desaturation. These children cannot tolerate a fall in hemoglobin concentration, such as can occur after a minor surgical procedure, because it will result in a significant fall in oxygen content. If possible, in these children the hemoglobin concentration should be maintained at approximately 15 to 16 g/dL. The child with cyanotic CHD and polycythemia cannot be allowed to become dehydrated and hemoconcentrated. Once the hemoglobin concentration exceeds 20 to 25 g/dL and the hematocrit exceeds 60% to 70%, the blood becomes too viscous, and the risk of thromboembolic complications is high. Pheresis (removal of whole blood and replacement of the volume with plasma, albumin, or normal saline) is generally recommended at this point.

As noted previously, arterial oxygen content can be calculated by multiplying the hemoglobin concentration (in grams per deciliter) by 1.34 mL O₂/g and the arterial oxyhemoglobin saturation. The resulting number is added to the dissolved oxygen, calculated by the product of 0.003 and the arterial oxygen tension:

The arterial oxyhemoglobin saturation can be evaluated using arterial blood gas analysis, and it can be monitored noninvasively using pulse oximetry.

If the patient’s hemoglobin concentration is stable (e.g., hemorrhage or other sources of blood loss have been ruled out, volume resuscitation is not producing a hemodilution), trends in the pulse oximeter readings of oxyhemoglobin saturation will reflect trends in the arterial oxygen content. Pulse oximetry will not accurately reflect hemoglobin saturation in the presence of methemoglobinemia or carbon monoxide poisoning, and it is important to note that in the presence of severe anemia, oxygen delivery will be inadequate despite a normal oxyhemoglobin saturation.

Noninvasive measurement of CO in children is novel and evolving.¹²⁸ Doppler ultrasonography is a simple, noninvasive method of assessing blood flow and is an accepted noninvasive method of deriving CO.¹¹⁸ Data obtained with Doppler ultrasonography correlate well with accepted standard hemodynamic methods in animal studies, adults, and neonates; formal validation is underway in children.³⁷ ^,65 ^,128

Because adequate organ perfusion is the goal of supportive and therapeutic critical care, monitors that directly assess organ oxygenation offer the best possibility of improved recognition and treatment of circulatory abnormalities to reduce multiorgan dysfunction and related morbidity and mortality.²⁶⁰ Some of these monitors are presented in the next several sections

Relationship of Mixed Venous Oxygen Saturation to CO

A true mixed venous oxygen saturation is evaluated from blood in the pulmonary artery, because it includes a true mixed sample of systemic venous blood from the superior vena cava, inferior vena cava, and coronary circulations. The mixed venous oxygen saturation can be continuously monitored through the use of a pulmonary artery catheter that contains a pulmonary artery oximeter. If hemoglobin concentration and saturation and oxygen consumption or extraction are stable (these assumptions often cannot be made about the critically ill patient), the mixed venous oxygen saturation will vary directly with the CO (see Fig. 6-6).

When oxygen delivery falls, tissues compensate by increasing the amount of oxygen extraction from circulating blood.¹⁹⁶ Mixed venous oxygen saturation is thus used as a measure of the balance between oxygen delivery and oxygen demand, and it will fall as the result of either decreased oxygen delivery (i.e., decreased arterial oxygen content; decreased CO, index, or both) or increased oxygen extraction (from increased demand, decreased delivery, or both). The normal mixed venous oxygen saturation is greater than 70%.¹⁹⁶ Mixed venous oxygen saturation levels between 50% and 75% reflect compensatory increased extraction in cases of increased oxygen demand or decreased oxygen delivery, whereas levels between 30% and 50% reflect the beginning of lactic acidosis indicating exhaustion of compensatory extraction. A further decline to levels between 25% and 30% is indicative of severe lactic acidosis, and levels less than 25% probably reflect cellular death.¹⁹⁶

The mixed venous oxygen saturation has been shown to be an effective indicator of the balance between oxygen supply and demand, and it is a useful guide for management in adults. However, its use is limited in pediatrics by the need for a pulmonary artery or central venous catheter for intermittent or continuous measurement; this is often not feasible, especially early in resuscitation.¹⁸³

Use of Central Venous Oxygen Saturation Monitoring

The desire for easier venous oxygen saturation measurement has led to an assessment of central venous oxygen saturation (ScvO₂). Unlike the pulmonary artery catheter samples that are composed of blood from all parts of the systemic venous circulation, including blood from the coronary sinus, ScvO₂ is obtained from the superior vena cava, so it assesses only the oxygen delivery-oxygen consumption balance in the upper body.¹⁹⁶ Many studies have examined how the two are related. Oxygen saturation of superior vena cava blood is approximately 70%, which is slightly lower than the saturation of blood in the inferior vena cava (75%). Coronary sinus blood, with an oxygen saturation of approximately 30% to 40%, is then added to the combined superior vena cava and inferior vena cava blood, so that a true mixed venous sample in the pulmonary artery (after mixing is complete) averages approximately 70% to 75% and corresponds to a mixed venous oxygen tension of 38 to 40 mm Hg. Thus the ScvO₂ is normally approximately 2% to 3% higher than mixed venous oxygen saturation in healthy individuals.¹⁸³ In shock states, however, the difference can range from 5% to 18%.³⁷ ^,183 Some studies have shown that although the two are not interchangeable, there is a good correlation in the trending of one to the other, and the ScvO₂ correlates well with changes in systemic perfusion.⁸¹ ^,132 ^,183

Limitations of continuous ScvO₂ monitoring are significant. Because sympathetic tone raises vascular resistance in splanchnic-mesenteric beds as CO falls, in shock states the effects of desaturated blood from those regions on ScvO₂ may be blunted. As an extreme example, the renal blood flow may fall to 20% of its normal value because of intense renal vasoconstriction, with renal vein saturation falling from 85% to 25% while the ScvO₂ remains above 60%.¹³²

Near-Infrared Spectroscopy (NIRS)

NIRS is relatively new technology that is used to access regional tissue oxygenation as an indicator of tissue perfusion. Near-infrared light (700 to 1000 nm bandwidth) is transmitted through muscle, bone, tissue, and skin, and reflected light is then read by a sensor.¹⁸³ The technology is similar to that used for pulse oximetry and continuous monitoring of ScvO₂. This technology uses the difference in light absorption between deoxygenated hemoglobin versus oxygenated hemoglobin to calculate a percent saturation level. Because most blood is not in arteries but in capillaries and veins, the greatest quantitative contribution to the calculated light absorption of hemoglobin is from venous and capillary blood. Pulse oximeters attempt to subtract the nonpulsatile component of the light signal (i.e., contributed from veins and capillaries) to examine the absorption spectrum of arterial blood, whereas NIRS technology focuses on the total light signal. An NIRS device approved by the U.S. Food and Drug Administration (INVOS; Somanetics, Troy, MI) uses a dual-detector system to subtract a shallow light path from a deep light path, theoretically allowing the derivation of the average oxyhemoglobin saturation in a volume of tissue approximately 2.5 to 3.0 cm deep under the skin and the sensor. The device displays an approximation of venous-weighted hemoglobin saturation in tissue deep below the sensor. The parameter is displayed as a relative number from 0% to 100% using an algorithm calibrated from in vivo and in vitro cerebral models, and is termed regional oxygen saturation (rSO₂).¹³²

Because venous-weighted capillary blood represents the limiting oxygen tension for diffusion, NIRS provides a window to evaluate the oxygen economy in the monitored tissue bed or regional tissue oxyhemoglobin saturation.⁹¹ ^,132 The use of NIRS technology to monitor oxygenation in the brain, muscle, liver, and kidney has been extensively described.⁹¹ ^,132 ^,133 ^,228 Changes in tissue oxygen tension monitored by NIRS are sensitive indicators of perfusion-metabolism coupling, and regional NIRS monitoring can guide resuscitation from shock.⁶⁶ ^,132

The indication approved by the U.S. Food and Drug Administration for the INVOS device is for trend monitoring of regional saturation in the cerebral circulation, which has been widely modeled as a compartment with 75% venous blood, thus allowing validation of the device in an accepted clinical model. In animal models, brain rSO₂ less than 40% is associated with intracellular anaerobic metabolism and depletion of high-energy phosphates.¹⁵⁸ Clinical data in children and adults support the hypothesis that cerebral rSO₂ less than 40% to 50%, or a change in baseline of more than 20%, is associated with hypoxic-ischemic neural injury.¹³² ^,133 ^,228

Blood Pressure

Arterial BP may be the most widely used and most widely misinterpreted parameter related to CO. Arterial BP is generated by the kinetic energy imparted by the heart and the interaction of blood flow, viscosity, systemic vascular tone, and downstream (venous) pressure. The major determinants of mean arterial BP are the SVR and CO. Peripheral and central arterial pressure differences result from differential impedances in the vascular system and are increased with nonuniform vasoconstriction. Noninvasive BP measurement by auscultation using a cuff and sphygmomanometer (mercury manometer) and noninvasive oscillometric BP measurements correlate well with indwelling intraarterial measurements under conditions of normal vascular resistance and blood flow, but “cuff” and invasive pressures frequently diverge under conditions of low and high SVR.¹³² Automated determination by cuff oscillometry shows good reproducibility and allows for determination of the mean pressure.

Although BP is rapidly and routinely measured, its relationship to CO or systemic perfusion is confounded by simultaneous changes in SVR. SVR tends to change in the opposite direction from CO; the sympathetic nervous system is activated by a falling BP, and sympathetic outflow is reduced and the parasympathetic system is activated with a rising BP. These responses are designed to minimize the variability in BP, making this parameter a late indicator of failing circulation. Similarly, resuscitation to a BP end point is often incomplete if the goal is to restore adequate CO and perfusion.²⁷⁶

Blood flow through a regional vascular bed is directly proportional to the organ perfusion pressure (ΔP), which is calculated as the difference between the arterial inflow pressure (P_a) and the venous outflow pressure (P_v): ΔP = P_a − P_v.⁵³ With reasonable approximation and ignoring local extravascular effects, the inflow arterial pressure can be estimated to be the mean arterial pressure (MAP), and the outflow venous pressure can be estimated to be CVP:

For any given ΔP, the blood flow is determined by the resistance to blood flow according to the following equation, analogous to Ohm’s law, where Q is arterial blood flow and R is vascular resistance:

Under ideal laminar flow conditions, vascular resistance is independent of flow and pressure; therefore an increase in vascular resistance will decrease blood flow, and a decrease in vascular resistance will increase blood flow for any given ΔP. Control mechanisms in the body generally maintain arterial and venous BPs within a narrow range; therefore changes in organ and tissue blood flow are primarily regulated by changes in vascular resistance. Resistance to blood flow within a vascular network is determined by the size of the vessels, the organization of the vascular network, physical characteristics of the blood, and extravascular forces acting on the vasculature.⁵³

The relationship between flow (i.e., CO), perfusion pressure (i.e., MAP − CVP), and SVR is vital to the understanding of the pathophysiologic principles of shock. The perfusion pressure may be more important than BP alone. According to the equation, a patient can theoretically have a normal MAP but no forward flow (i.e., CO)—for example, if CVP is equal to MAP. Importantly, when fluid resuscitation is used to improve BP, the increase in MAP must be greater than the increase in CVP. If the increase in MAP is less than the increase in CVP, then the perfusion pressure is actually reduced, and CO is reduced. Inotropic agents, and not additional fluid resuscitation, are indicated to improve CO in this scenario.

Understanding the perfusion pressure helps guide the management of blood flow reflected as CO. CO can be decreased when perfusion pressure (MAP − CVP) is decreased, but it can also be decreased when the perfusion pressure is normal and vascular resistance is increased. Therefore children with normal BP can have inadequate CO, because systemic vascular tone is too high. CO can be improved in this scenario with the use of inotropes, vasodilators, and volume loading. The cardiovascular pathophysiology of shock can therefore be attributed to reduced CO, reduced perfusion pressure, or both. Reduced CO is caused by either reduced HR or reduced SV caused by hypovolemia (inadequate preload), decreased contractility (insufficient inotropy), or excess vascular resistance (increased afterload). Reduced perfusion pressure can be caused by reduced MAP or increased CVP.

Shock states

Shock is a progressive condition of circulatory failure that results in inadequate CO and oxygen and substrate delivery to the tissues. Shock may be present in the patient with a low, normal, or high CO or index.²⁴⁵

Shock frequently is classified according to its cause. The four major types of shock are hypovolemic, cardiogenic, septic (or distributive), and obstructive. Hypovolemic shock results from inadequate intravascular volume relative to the vascular space. Cardiogenic shock results from myocardial dysfunction. Septic shock is the most common form of distributive shock; it is induced by infectious agents or their by-products with resultant myocardial dysfunction and aspects of cardiogenic shock. Obstructive shock results from severe obstruction to ventricular filling or outflow, such as results from cardiac tamponade, tension pneumothorax, ductal-dependent congenital heart disease (when ductus begins to close), or pulmonary embolus.

Although the patient may demonstrate one type of shock, many patients have combined causes of shock. For example, the patient in early septic shock may demonstrate elements of hypovolemic and cardiogenic shock. A relative hypovolemia is present, and myocardial depression develops rapidly and is associated with maldistribution of blood flow. Therefore it is important to access and support all aspects of cardiovascular function when caring for the patient in shock.

Hypovolemic Shock

Etiology

Hypovolemia is the most common cause of shock in infants and children.²⁴⁵ Hypovolemic shock is best defined as a sudden decrease in the intravascular (blood) volume, relative to vascular capacity (i.e., inadequate intravascular volume relative to the vascular space), to such an extent that effective tissue perfusion cannot be maintained. Causes include hemorrhage from gastrointestinal disease or trauma, fluid and electrolyte loss, endocrine disease, and plasma loss.

Intravascular volume loss can also result from a shift of fluid into a third space. Third space fluid comprises a pool of water, electrolytes, and protein that is not available for incorporation into the intravascular space. Examples include fluids found in pleural effusions, ascites, and intraluminal fluid in the gastrointestinal tract. Surgical bowel manipulation or trauma can produce a shift of fluid into this potential fluid space. When the fluid shift is substantial, it can contribute to the development of hypovolemic shock.

Pathophysiology

Hypovolemia causes a decrease in preload that reduces SV and CO. Activation of peripheral and central baroreceptors produces an outpouring of catecholamines; the resulting tachycardia and peripheral vasoconstriction are usually initially adequate to support the BP, with little or no evidence of hypotension. Another aspect of the body’s compensatory mechanism for dealing with hypovolemia is through the activation of the renin-angiotensin-aldosterone system. Angiotensin (a potent vasoconstrictor) promotes the release of aldosterone, which increases the kidney’s sodium resorption; this, combined with an increase in antidiuretic hormone secretion, results in increased water resorption in the kidney.

Clinical Signs and Symptoms

Reliable indicators of early, compensated hypovolemic shock in children are persistent tachycardia, cutaneous vasoconstriction, and diminution of the pulse pressure (difference between systolic and diastolic BPs). Clinical evidence of decreased tissue perfusion includes skin mottling, prolonged capillary refill, and cool extremities. Systemic arterial BP is frequently normal, which is the result of increased SVR, making BP monitoring of limited value in managing the patient with compensated hypovolemic shock.¹³² ^,245 Neurologic status is initially normal or only minimally impaired.

Although capillary refill has long been advocated as an important means of quickly and reliably assessing the level of hydration and circulatory status of acutely ill or injured children, there are several important limitations to the use of capillary refill in the assessment of circulatory status in children.²³ ^,112 ^,297 It is necessary to account for the ambient temperature, in addition to the site of measurement, when interpreting the results.

On rare occasions, BP may be paradoxically elevated in children with hypovolemia.³³ Recognition of this phenomenon is extremely important because some healthcare providers may be reluctant to provide appropriate fluid resuscitation for these patients because of fear of exacerbating the hypertension. Treatment of the hypertension, especially with β-blockers or calcium channel antagonists, may precipitate hypotension. Dehydrated, volume-depleted children with paradoxic hypertension should be given a trial of volume expansion; such therapy will cause little harm and could ameliorate the hypertension.

With continued loss of intravascular volume or with delayed or inadequate intravascular volume replacement, the intravascular fluid losses surpass the body’s compensatory abilities, causing circulatory failure and organ dysfunction. Pronounced systemic vasoconstriction and hypovolemia produce ischemia and hypoxia in the visceral and cutaneous circulations. Cellular metabolism and function are altered in these areas, resulting in damage to the blood vessels, kidneys, liver, pancreas, and bowel. SV and CO are decreased. The patient ultimately becomes hypotensive, acidotic, lethargic, or comatose, and oliguric or anuric. It is important to emphasize that arterial BP falls only after compensatory mechanisms are exhausted; this may be long after the precipitating event and only after a severe reduction in CO.²⁴³ Terminal phases of hypovolemic shock are characterized by myocardial dysfunction and widespread cell death.

Ischemia can develop in nonvital organs as a result of reduced circulating blood volume and preferential vasoconstriction. In skeletal muscle during shock, the normal intermittent perfusion pattern in capillary networks has been observed to transform to a marked maldistribution of flow, with cessation of blood flow in most capillaries.¹⁹⁸ ^,199 In addition to a low and irregular flow state in capillaries, recent findings have demonstrated a progressive narrowing of the capillary lumen during shock. The nearly 25% decrease in lumen diameter after 1 hour of shock principally results from swelling of endothelial cells; this significantly increases the capillary resistance to flow and contributes to further flow retardation.¹⁹⁸ ^,199 In addition, in a variety of organs impaired microcirculatory blood flow has been observed with reperfusion after a period of ischemia (no reflow or slow reflow). The causes of no reflow include red blood cell aggregation, leukocyte trapping, and edema of tissue and capillary endothelial cells.¹⁹⁹

In any form of shock, including hypovolemic shock, the end result of hypoperfusion and tissue ischemia is cellular oxygen and nutrient deficiency that can affect the integrity of cell function and structure. Anaerobic metabolism results from the decrease in oxygen delivery, leading to glycogen depletion and lactate production. An increase in cytosolic calcium is also evident, which leads to an increase in membrane phospholipid hydrolysis and lysosomal membrane damage.²⁹⁵ This process eventually progresses to irreversible cellular injury and a host of inflammatory responses, which stimulate further tissue inflammation and injury. Ischemia or reperfusion can also induce expression of inflammatory genes in endothelial cells. In some hypovolemic animal models, fluid resuscitation leads to a decrease in the inflammatory cascade that was triggered by organ ischemia secondary to hypoperfusion.²⁹⁵ Because this inflammatory response is not likely to protect or repair organs from hypovolemic insult, downregulation of this inflammation seen with fluid resuscitation is likely to be beneficial.

Serum tonicity is important in both the presentation and the management of dehydration. In approximately 80% of cases of dehydration, patients have normal serum osmolality; 15% are hyperosmolar, and 5% are hypoosmolar.²⁴³ The serum sodium concentration can be used as a rough estimate of serum osmolality and dehydration, which is classified as hyponatremic, isonatremic, or hypernatremic (Box 6-1).

Box 6-1 Classification of Hypovolemic Shock Based on Serum Sodium

Hyponatremic: serum sodium <130 mEq/dL

Isonatremic: serum sodium 130-150 mEq/dL

Hypernatremic: serum sodium >150 mEq/dL

Hyponatremic dehydration occurs secondary to a disproportionate loss of solute to fluid (i.e., proportionately more sodium lost than water). There is depletion of extracellular (including intravascular and interstitial) fluid volume relative to intracellular fluid volume, producing characteristic physical findings of dry mucous membranes, reduced skin turgor, cool extremities, compromised perfusion, and in severe cases, hemodynamic collapse.

Hypernatremic dehydration is the result of fluid loss out of proportion to solute loss (i.e., proportionately more water lost than sodium). There is relative preservation of the extracellular volume, but at the expense of water drawn into the extracellular (including vascular space) compartment from the intracellular compartment. Physical findings include a doughy consistency of the skin and subcutaneous tissues and the apparent maintenance of good hemodynamic function and BP, even in the face of large volume losses.

The approach for infants or children with diarrheal dehydration can be organized using the five-point assessment ¹⁴¹ ^,243 (Table 6-2). Initial management is guided by a simple history and physical examination, followed by assignment of the patient to one of three groups based on severity of illness.

Table 6-2 Rapid Assessment of Dehydration

Point of Assessment	Method
Volume deficit	History and physical
Osmolar disturbance	Serum sodium
Acid-base disturbance	Serum pH, PCO₂, bicarbonate
Potassium disturbance	Serum potassium
Renal function	Serum blood urea nitrogen, creatinine
Renal function	Urine analysis, specific gravity, sodium

Adapted from Kallen RJ: The management of diarrheal dehydration in infants using parenteral fluids. Pediatr Clin North Am 37:265, 1990.

Table 6-3 lists the signs and symptoms that can be used to group patients by severity of dehydration. Of the 10 findings listed, none is sufficiently accurate to be used in isolation.¹¹³ The presence of fewer than three signs corresponds with a fluid deficit of less than 5%, whereas children with a deficit of 5% to 9% generally have three or more clinical findings. At least six or seven findings should be present to diagnose a deficit of 10% or more.

Table 6-3 Severity of Dehydration Based on History and Physical Examination

A recent study has suggested that it may be possible to rely on a relatively restricted subset of clinical indicators: general appearance, capillary refill, mucous membranes, and tears. Of these four findings, the presence of any two indicates a deficit of 5% or more, and three or more findings indicates a deficit of at least 10%.¹¹³

Children usually have healthy compensatory mechanisms that initially maintain peripheral perfusion and BP despite volume loss. HR increases to maintain CO despite deceased SV (see table of Normal Blood Pressures in Children on pages inside front cover). For this reason, tachycardia is an early sign of acute blood loss with impending shock. Total blood volume in children is generally estimated as 7% to 8% of body weight or 70 to 80 mL/kg. With blood loss of 10% to 15% (class I hemorrhage as defined by Advanced Trauma Life Support), the injured child easily compensates with a 10% to 20% increase in HR (Table 6-4). BP and peripheral capillary refill are usually unchanged. Even with a 20% to 25% loss of blood volume (class II hemorrhage), there is often little change in the systolic BP as increasing tachycardia and peripheral vasoconstriction mediated through the sympathetic nervous system and other mechanisms serve to maintain perfusion pressure. It is for this reason that one must avoid the tendency to equate hypotension with shock in the pediatric trauma patient. Hypotension is a late finding with ongoing hemorrhage and often signals that the child is near the point of complete decompensation.²⁴³ Furthermore, studies in adults and children with trauma showed that systolic BP is a predictor of mortality and that prehospital hypotension is associated with an increased risk of mortality.¹²⁰ ^,185 ^,274 There is a need for studies to validate the appropriate BP target and to better define hypotension in critically ill children.¹²⁰

Table 6-4 Classification of Hemorrhage by Blood Volume Lost

Degree of Hemorrhage	Blood Volume Lost (%)	Signs
Class I	<15	Minimal tachycardia; normal respiration, BP, capillary refill
Class II	15-30	Tachycardia; tachypnea; diminished pulse pressure; systolic BP unchanged; prolonged capillary refill; minimal decrease in urine output; anxiety
Class III	30-40	Tachycardia; tachypnea; decreased BP; decreased urine output; mental status changes
Class IV	>40	Hypotension; anuria; loss of consciousness

BP, Blood pressure.

Adapted from Morgan WM 3rd, O’Neill JA Jr: Hemorrhagic and obstructive shock in pediatric patients. New Horiz 6:150−154, 1998.

Management

Initial treatment of the child in hypovolemic shock is the same, regardless of the cause. Therapy begins with establishing adequate oxygenation and ventilation. Oxygen should always be the first drug administered. Once a patent airway is ensured or established (intubation may be required) and ventilation is adequate, measures to restore an effective circulating blood volume should begin. The most important therapeutic maneuvers are establishing adequate intravenous or intraosseous access and rapid volume replacement.

Vascular access is achieved using the largest, most easily accessible vein. Peripheral venotomy can be performed in the veins of the hand, foot, arm, leg, or scalp, but these vessels tend to be small and difficult to cannulate in the hypovolemic child, so attempts to achieve vascular access should be limited before attempting intraosseous access.²⁴³ If peripheral access is difficult and vascular access is critical, early intraosseous access is encouraged.^57a ^,259

If time allows and clinical experts are available, vascular access can be obtained by central venous cannulation or saphenous cutdown; however, the latter route is less frequently used because intraosseous access is so readily available. The femoral vein is often the most easily accessible in an emergency situation.²⁴³

The amount of volume required to resuscitate a child in hypovolemic shock is variable. However, the most common error made in resuscitation of a child in hypovolemic shock is inadequate or delayed volume administration.¹¹⁹ ^,271 The variance in disease processes that lead to hypovolemic shock may require different treatment and will be discussed separately.

Fluid Therapy: Diarrhea and Dehydration

Diarrhea can severely disrupt the balance of fluids and electrolytes, and it is a leading cause of infant mortality worldwide.²⁹⁰ Dehydration and shock as a consequence of diarrhea are more likely to occur in infants or small children than in adults.

Isotonic crystalloid (20 mL/kg), delivered as a rapid infusion, is effective in the resuscitation of all children with shock secondary to dehydration, regardless of the serum osmolality or osmolarity. The use of hypotonic solutions is ineffective (it is distributed in both the intracellular and extracellular—including intravascular—spaces) and can be harmful in hypernatremic dehydration, because it can reduce serum sodium concentration too quickly.

Administering large volumes of isotonic saline (0.9% sodium chloride) frequently can cause the development of hyperchloremic acidosis; this occurs because isotonic saline contains 154 mEq/L of chloride, and its administration results in a dilutional decrease of serum bicarbonate and an increase in serum chloride concentration. Both of these changes will produce metabolic acidosis. Resuscitation with lactated Ringer’s solution provides a more balanced electrolyte replacement and is less likely to produce metabolic acidosis. The infusion of lactated Ringer’s solution in general does not influence the circulating serum lactate concentration.⁷⁴

The use of colloid is not indicated in the initial resuscitation of the patient with shock secondary to dehydration. Albumin and other colloids have been used effectively for volume replacement in patients who have large volumes of nonfunctional extracellular or third space fluid loss or low albumin states.¹²³

The first fluid infusion (20 mL/kg) should be administered rapidly and the HR, pulse pressure, BP, peripheral perfusion, quality of mentation, and volume of urine output should be monitored closely for signs of improvement. Improvement in these measurements suggests that maintenance fluid administration can then be initiated and vital signs can be monitored. The appropriate maintenance fluid to be used is determined by the child’s serum electrolyte balance.

The end point of fluid resuscitation should be normalization of HR and respiratory rate, an increase in arterial BP, an increase in pulse pressure and peripheral perfusion, establishing adequate urine output, and a decrease in the metabolic acidosis. However, if shock persists after the first fluid infusion is completed, a second infusion of 20 mL/kg should be started. If the patient does not improve after two or three infusions of isotonic crystalloid solution (40 to 60 mL/kg), more aggressive monitoring and therapy are clearly required and the child must be evaluated for complicating factors. Causes of unresponsive shock in a patient with adequate oxygenation include unrecognized pneumothorax or pericardial effusion, intestinal ischemia (e.g., volvulus, intussusception, necrotizing enterocolitis), sepsis, myocardial dysfunction, adrenocortical insufficiency, pulmonary hypertension, and potential occult bleeding caused by inflicted trauma.²⁴³

While the initial 60 mL/kg of fluid is infusing, some children require inotropic or vasopressor support to maintain adequate end-organ perfusion. This subset of patients, said to have fluid-refractory shock, may require a combination of fluid resuscitation and catecholamine support. It is important to confirm the diagnosis in these cases, because the clinical signs of different types of shock frequently overlap. In addition, it is important to reassess the patient frequently and thoroughly during the resuscitation to guide additional therapy. For example, if the child with hypovolemic shock secondary to diarrhea does not improve despite significant volume administration, the child may have unrecognized ongoing gastrointestinal losses, requiring further volume administration to keep pace with ongoing output. An analogous situation is the child with diabetic ketoacidosis who continues to lose large amounts of fluid in the urine that, if inadequately replaced, will lead to a further decrease in intravascular volume.

Children with dehydration secondary to burns or septic shock frequently require large amounts of fluid administration, because they have ongoing capillary leak; they often require concurrent inotropic support, vasopressor support, or both.⁵⁰ To guide therapy, it is important to determine whether these children have failure of the vasculature, cardiac function, or a combination, leading to requirements for support in addition to volume administration. The cardiac failure seen with thermal injuries, trauma, or sepsis must be evaluated further to distinguish cardiac dysfunction from decreased CO resulting from external compression or obstruction (e.g., pericarditis, tamponade).⁹²

Children who have fluid-refractory shock may also have adrenal insufficiency. With the increased use of long-term steroid therapy in children (e.g., transplantation, malignancy, asthma), a relative adrenal insufficiency may be contributing to the patient’s fluid-refractory shock state, and exogenous steroid therapy may have a role in treatment of these patients (see the discussion under the section, Septic Shock).

Fluid Therapy in Traumatic or Hemorrhagic Shock

Shock in the injured child is almost always secondary to hypovolemia, so acute blood loss must always be considered first. With hemorrhagic shock, the source of blood loss may be external and readily apparent, such as the laceration of a major vessel in an extremity or a large scalp laceration. The scalp is often a source of significant blood loss in infants and children, because of its inherent vascularity and because the head is relatively large (with a relatively large percentage of the child’s BSA) in young children. More commonly, however, the source of blood loss is internal and therefore less apparent. Extremity (i.e., femur fracture) and intraabdominal injuries are common after blunt trauma in children, especially with motor vehicle crashes,²⁴³ and can result in significant occult blood loss.

Intraabdominal solid organ injury is a common cause of occult blood loss, and such injuries are probably the most common cause of traumatic shock in children.⁹⁹ ^,152 Single or complex fractures of the liver and spleen often result in significant hemorrhage. Associated injury to the inferior vena cava is rare, but if present it usually leads to life-threatening hemorrhage. Mesenteric injury is often seen as part of the “lap belt syndrome,” but does not usually result in sufficient blood loss to cause shock. Blunt injury of the kidney can also cause significant blood loss into a retroperitoneal hematoma. Fracture of the bony pelvis is relatively common in older children and may lead to massive hemorrhage, at times requiring urgent stabilization.

Occult blood loss may occur in the chest as well, with laceration of the lung or an intercostal vessel. Great vessel injury secondary to blunt trauma in children is, fortunately, rare.

With any signs of hypovolemic shock (e.g., tachycardia), a fluid bolus of 20 mL/kg of isotonic crystalloid solution should be given. Transfusion of packed red blood cells or whole blood is indicated for the patient with hemorrhagic shock who shows signs of persistent intravascular volume depletion despite the rapid administration of 60 mL/kg (three boluses) of crystalloid. Packed red blood cells should be given in boluses of 10 mL/kg. Type-specific blood is used if available, but typing should not delay resuscitation. Un–cross-matched O-negative universal donor blood should be immediately available. Aggressive fluid resuscitation is paramount, even when there is associated closed-head injury, because ongoing hypoperfusion leads to secondary hypoxic end-organ injury, especially in the brain.⁵ ^,14 ^,54 ^,60 ^,302

Although hypovolemia is the most frequent cause of shock, occasionally other causes of hemodynamic compromise may be present. Obstructive shock owing to tension pneumothorax or pericardial tamponade, myocardial confusion, and spinal shock can complicate the management of pediatric trauma.²⁴³ Blunt cardiac injury can cause myocardial contusion, myocardial concussion, aneurysm, septal defects, chamber rupture, valvular rupture, and damage to the pericardium.⁴⁰ ^,78 ^,249 Each of these entities has separate presentations, although the lesions are often concurrent. The majority of blunt injuries to the heart are myocardial contusions; devastating events such as ventricular rupture are rare.⁷⁸ ^,249

There are important clinical considerations in the management of children with blunt cardiac injury:

• If a child with a suspected blunt cardiac injury is hemodynamically stable and has a normal sinus rhythm, then the development of serious arrhythmia or cardiac failure is not likely. In other words, high risk for a patient is usually evident immediately.⁷⁸

• Trauma patients with a suspected cardiac injury should receive prompt evaluation of cardiac function with echocardiography.⁴⁰ ^,78 Any patient with unexplained hypotension or diminished peripheral perfusion should be studied using echocardiography.

• Elevated cardiac isoenzyme values and electrocardiography are nonspecific for clinically significant myocardial injury.⁷⁸

Crystalloid Versus Colloid

Volume resuscitation can include the use of crystalloid, colloid, or blood products, or all three. Crystalloids are electrolyte-containing solutions distributed through the body according to their chemical composition and tonicity. Isotonic crystalloid solutions (lactated Ringer’s solution, 0.9% sodium chloride) are distributed throughout the extracellular compartment (i.e., the vascular and interstitial spaces). Hypotonic solutions have a proportion of water not associated with sodium and are therefore distributed throughout the entire body water. Hypertonic solutions (sodium concentrations in excess of 180 mEq/L) increase serum osmolality and therefore induce movement of water from the intracellular space to the extracellular space.

Colloids used in the treatment of patients in shock include plasma, prepared plasma fractions, and synthetic plasma substitutes. Colloids consist of large molecules that are generally restricted to the intravascular compartment, exerting an oncotic effect on the distribution of water. In doing so, isooncotic solutions (5% albumin, fresh frozen plasma) result in a greater expansion of the intravascular volume than that achieved with isotonic crystalloid solutions when the same volume is infused. Hyperoncotic solutions, such as 25% albumin, move fluid into the vascular compartment from the interstitial space.

Plasma expanders, such as the dextrans and hydroxyethyl starch, are also available for intravascular volume replacement. The dextrans, dextran-40 and dextran-70, are available as either 0.9% sodium chloride solutions or 5% dextrose solutions. Hetastarch is amylopectin in which hydroxyethyl starch groups are substituted. It is available as a 6% solution in 0.9% sodium chloride. Use may be limited by hypersensitivity reactions; experience with use of dextrans and hetastarch in pediatrics is limited.

There continues to be an ongoing debate as to the most suitable type of fluid to use for resuscitation. Both choices, crystalloid solutions and colloid solutions, have their own advantages and disadvantages.

The advantages of using crystalloids for resuscitation are their ready availability and their cost effectiveness. The cost of 5% albumin is manyfold that of the common crystalloid solutions. The main disadvantage is that crystalloids reduce colloid oncotic pressure and can predispose to pulmonary and peripheral edema.⁶¹

Colloid solutions are useful because they contain relatively large molecules that are impermeable to the capillary membrane, leading to increased volume remaining in the intravascular space. Disadvantages of colloid infusions are chiefly related to cost and the potential exposure to blood products.

There is now a reasonable evidence base to support the use of isotonic crystalloids (e.g., normal saline) as the best initial choice of fluid for intravenous resuscitation of shock. Two randomized controlled studies of fluid resuscitation in pediatric septic shock failed to demonstrate any difference in outcome, regardless of whether crystalloid or colloid (i.e., albumin) fluid therapy was used in initial resuscitation.³⁰³ ^,319 A well-powered study investigating fluid resuscitation of adults in shock has also failed to show benefit of the use of colloids over crystalloids. Subgroups of patients in the adult study (e.g., patients with traumatic brain injuries) had a better outcome with the use of crystalloids instead of colloids.⁹⁶ A physiology-based argument has existed for many years that whereas crystalloids may be clinically effective for fluid resuscitation, their reduced osmolar drag relative to colloid therapy leads to increased capillary leak and movement of water extravascularly. As a result, the “3:1 rule” suggests that a significantly greater volume of crystalloid than colloid would be necessary to replace the depleted intravascular compartment. A consistent finding from all three of the previously cited studies is that there is no difference between the volume of crystalloid and colloid necessary to resuscitate the patient in shock. This is not to say that there is no role for colloids in fluid resuscitation. Children with advanced septic shock might still benefit from colloid therapy, and those with advanced hemorrhagic shock will ultimately require the use of blood products to replace both blood cells and coagulation factors.

Distributive Shock: Definitions

Distributive shock, as the name implies, results from abnormalities in vasomotor tone that lead to the maldistribution of a normally effective blood volume and flow. Peripheral vasodilation and shunting can lead to a state of relative hypovolemia. Distributive shock arises from a variety of disorders and encompasses various states of shock arising from anaphylaxis (anaphylactic shock), central nervous system injury (which includes neurogenic and spinal shock), and sepsis.

Anaphylaxis refers to a systemic, immediate hypersensitivity reaction that is potentially life threatening and characterized by the onset of signs and symptoms within seconds to minutes after exposure to the offending agent (e.g., insect envenomation, medication, food), involvement of multiple organ systems, and involvement of systems distant from the site of exposure. Although the true incidence of anaphylaxis is difficult to define, it is certainly not uncommon, and the most frequent causes of anaphylaxis are foods, hymenoptera stings, and medications.

Anaphylaxis is caused by the release of mediators from mast cells and basophils. Antigen bridging of immunoglobulin (Ig) E antibodies bound to high-affinity IgE receptors on the cell surface leads to the aggregation of the receptors and activation of an enzymatic cascade initiating mediator release. Mast cells and basophils are concentrated near exposed mucosal surfaces, such as the lung and the gastrointestinal tract, and children with anaphylaxis will typically have signs and symptoms affecting these organ systems (e.g., wheezing, respiratory distress, vomiting, hives). Although several mediators are released from the mast cell and basophil, including histamine, platelet activating factor, and the leukotrienes (the so-called slow-reacting substances of anaphylaxis), histamine is the most important mediator of anaphylaxis. Intramuscular administration of epinephrine is the mainstay of the treatment of anaphylaxis. Additional adjunctive therapies include the administration of systemic corticosteroids and parenteral antihistamines.

Neurogenic shock results from autonomic dysfunction occurring secondary to injury to the spinal cord. Loss of peripheral vascular tone and subsequent increased venous capacitance lead to a relative hypovolemia caused by expansion of the vascular space. Children with neurogenic shock often fail to improve with fluid resuscitation, but instead respond to treatment with selective α-adrenergic vasoactive infusions (Table 6-5; see discussion under Cardiogenic Shock, Treatment, later in this chapter).

Table 6-5 Pediatric Vasoactive Drugs for the Treatment of Shock *^†

Dose	Effects	Cautions
Sympathomimetics
Dobutamine, 2-20 mcg/kg per min	Selective β-adrenergic effects; increases cardiac contractility and also increases heart rate (this latter effect is variable); β₂ effects produce peripheral vasodilatation; no dopaminergic or α-adrenergic effects	Extreme tachyarrhythmias have been reported, particularly in infants; hypotension may develop; may produce pulmonary venoconstriction
Dopamine, 1-5 mcg/kg per min	Dopaminergic effects predominate, including increase in glomerular filtration rate and urine volume	Can produce extreme tachyarrhythmias; can result in increase in pulmonary artery pressure; inhibits thyroid-stimulating hormone and aldosterone secretion
Dopamine, 2-10 mcg/kg per min	Dopaminergic effects persist and β₁ effects are seen, especially an increase in heart rate	As above
Dopamine, 8-20 mcg/kg per min	α-Adrenergic effects dominate	As above
Epinephrine, 0.05-0.15 mcg/kg per min	Endogenous catecholamine, which produces α, β₁, and β₂ adrenergic effects; at low doses, β₁ effects dominate	Will increase myocardial work and oxygen consumption at any dose; splanchnic constriction will occur at even low doses
Epinephrine, 0.2-0.3 mcg/kg per min	α-Adrenergic (vasoconstrictive) effects dominate	As above
Isoproterenol, 0.05-0.1 mcg/kg per min	β-Adrenergic effects; β₁ effects may result in rapid increase in heart rate; β₂ effects may produce peripheral vasodilatation and also may effectively treat bronchoconstriction	Monitor for tachyarrhythmias, hypotension; will increase myocardial oxygen consumption
Norepinephrine, 0.05-1.0 mcg/kg per min	Endogenous catecholamine with α- and β-adrenergic effects; produces potent peripheral and renal vasoconstriction; can increase blood pressure	May produce tachyarrhythmias, increased myocardial work, and increased oxygen consumption; may result in hepatic and mesenteric ischemia
Vasopressin
Vasopressin, 0.2 to 2 milliunits/kg per min (0.0002 to 0.002 unit/kg per min)	Antidiuretic hormone analogue that acts on vasopressin receptors; produces peripheral and splanchnic vasoconstriction; also used to treat GI hemorrhage for this reason	May cause hypertension, bradycardia
Phosphodiesterase inhibitors and inodilators
Inamrinone, Loading dose: 0.075 to 0.1 mg/kg (75 to 100 mcg/kg) slowly, Infusion: 5-10 mcg/kg per min	Nonadrenergic inotropic agent that produces phosphodiesterase inhibition and increase in intracellular cyclic-adenosine monophosphate cAMP intracellular calcium uptake also is delayed; these effects result in improved cardiac contractility and vasodilatation	Monitor for arrhythmias (especially accelerated junctional rhythm, junctional tachycardia, and ventricular ectopy); may produce hypotension (especially if patient is hypovolemic), liver and gastrointestinal dysfunction, thrombocytopenia, and abdominal pain; experience in children is limited and recent
Milrinone, Loading Dose: 0.05 mg/kg (50 mcg/kg) over 10-60 min, Infusion: 0.25-0.75 mcg/kg per min	As above	Reduce dose when renal dysfunction present
Vasodilators
Nitroglycerin, 0.25-0.5 mcg/kg per min; increase as tolerated to maximum 10 mcg/kg per min (adolescents, 5 mcg/min; note, not per kg per min)	Arterial and venodilator	Is adsorbed by polyvinylchloride tubing; use special infusion set
Nitroprusside, 0.3-0.5 mcg/kg per min; titrate up to 8 mcg/kg per min	Arterial and venodilator	Light-sensitive; use specialized infusion set or cover tubing when infusion slow; may produce thiocyanate and cyanide toxicity, particularly for higher doses or prolonged infusion

GI, Gastrointestinal; IV, intravenous.

* Infusion rate = mL/hr = [Weight (kg) × Dose (mcg/kg per min) × 60 min/h] ÷ Concentration (mcg/mL).

† For additional information, see Cardiogenic Shock, Treatment in this chapter.

Septic Shock

Etiology and Definitions

Septic shock is the most complex and controversial type of shock. Septic shock comprises a cascade of metabolic, hemodynamic, and clinical changes resulting from invasive infection and the release of microbial toxins into the bloodstream. Historically, a distinction was made between the clinical findings and the type of invading microorganism (e.g., gram-positive versus gram-negative shock). However, on closer analysis, it became apparent that the systemic response was independent of the type of invading organism (e.g., bacteria, virus, fungus, rickettsia), rather it was a host-dependent response.⁵¹ ^,243 The morbidity and mortality are primarily the result of endogenous proteins and phospholipids synthesized by the patient.⁵¹ Sepsis is the culmination of complex interactions between the infecting microorganism and the host immune, inflammatory, and coagulation responses.¹¹ ^,46 ^,265

One of the factors hampering progress in the understanding of sepsis and septic shock has been the variability of definitions used and patient populations studied. As an approach to standardizing the definitions of sepsis and organ failure, the American College of Chest Physicians and the Society of Critical Care Medicine held a consensus conference to define sepsis and organ failure more precisely.⁹ This group proposed the term systemic inflammatory response syndrome (SIRS), recognizing that the inflammatory response can be precipitated by processes other than infection. The group included in the definition of SIRS abnormalities of temperature, HR, respiratory rate, and white blood cell count. Whereas the definitions used were applied to adults, age-appropriate values must be used to apply the same descriptions to children.

Recently, consensus definitions for the pediatric sepsis continuum were developed and published.¹⁰⁹ The pediatric sepsis continuum includes SIRS, infection, sepsis, severe sepsis, septic shock, and multiple organ dysfunction syndrome.

Initial definitions for these points on the sepsis continuum have been proposed and are listed in Box 6-2. A few comments need to be made concerning the use of these definitions. First, it is important to realize that the definitions are sensitive but not specific screening tools to be used primarily for research purposes, and any direct application to the clinical setting must take into account the dynamic and continuous nature of the sepsis disease process and the static and categorical nature of the definitions.³⁹

Box 6-2 International Consensus Definitions of Systemic Inflammatory Response Syndrome, Sepsis, Severe Sepsis, and Septic Shock in Children

Systemic Inflammatory Response Syndrome

The presence of at least two of the following four large bulleted criteria, one of which must be abnormal temperature or leukocyte count:

• ALTERATION IN TEMPERATURE: Core body temperature of >38.5°C or <36°C.

• ALTERATION IN HEART RATE (characterized by any of the three open bullets, below):

Tachycardia in the absence of external stimulus, chronic drugs, or painful stimuli, defined as follows:

– Newborn to 1 year: HR >180/minute

– 2-5 years: >140/minute

– 6-12 years: >130/minute

– 13 to <18 years: >110/minute

Otherwise unexplained persistent elevation in heart rate over a 0.5- to 4-hr time period

For children under 1 yr: bradycardia, in the absence of external vagal stimulus, β-blocker drugs, or congenital heart disease, defined by one of the three dashes below:

– Newborn to 1 month: <100/minute

– 1 month to 1 year: <90/minute

– otherwise unexplained persistent depression over a 30-minute time period.

• ALTERATION IN RESPIRATORY RATE (characterized by either of the open bullets, below):

Mean respiratory rate >95th percentile normal for age, defined as follows:

– Newborn-1 week: >50/minute

– 1 week-1 month: >40/minute

– 1 month to 1 year: >34/minute

– 2-5 years: >22/minute

– 6-12 years: >18/minute

– 13 to <18 years: >14/minute

Mechanical ventilation for an acute process not related to underlying neuromuscular disease or the receipt of general anesthesia.

• ALTERATION IN WHITE BLOOD CELL COUNT: Leukocyte count elevated or depressed for age (not secondary to chemotherapy-induced leukopenia) or >10% immature neutrophils.

Infection (one of the following)

• A suspected or proven (by positive culture, tissue stain, or polymerase chain reaction test) infection caused by any pathogen

• A clinical syndrome associated with a high probability of infection.

Note: Evidence of infection includes positive findings on clinical examination, imaging, or laboratory tests (e.g., white blood cells in a normally sterile body fluid, perforated viscus, chest radiograph consistent with pneumonia, petechial or purpuric rash, purpura fulminans)

Sepsis

• SIRS in the presence of or as a result of suspected or proven infection

Severe Sepsis

Sepsis plus one of the following:

• Cardiovascular organ dysfunction

• Acute respiratory distress syndrome

• Two or more other organ dysfunctions; organ dysfunctions are defined in Box 6-3

Septic Shock

• Sepsis and cardiovascular organ dysfunction as defined in Box 6-3

Modified from Goldstein B, et al: International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med 6:2−8, 2005.

Second, the definitions of severe sepsis and septic shock in children create challenges. Unlike adults, children may clearly be in a shock state without the presence of systemic hypotension. Thus, the delineation between severe sepsis and septic shock in children may be artificial, and these two definitions may be describing the same clinical syndrome when applied to children.

Third, the clinical parameters used to define SIRS and organ dysfunction are greatly affected by the normal physiologic changes that occur as children develop,³⁹ ^,109 and the baseline organ function of children with chronic diseases must be considered. The consensus definitions propose six age groups for age-specific vital signs and laboratory parameters: newborn (0 to 7 days), neonate (1 week to 1 month), infant (1 month to 1 year), toddler and preschooler (2 to 5 years), school-aged child (6 to 12 years), and adolescent and young adult (13 to 18 years). The age groups were determined by a combination of age-specific risks for invasive infections, age-specific antibiotic treatment recommendations, and developmental cardiorespiratory physiologic changes.³⁹ ^,109 Evidence-based data combined both physiologic and laboratory normative information to support these age groupings. Furthermore, most of the normative data were reported to identify the 5th and 95th percentile ranges. The relationship between values and ranges obtained in normal children and appropriate values and ranges in critically ill children with sepsis is unclear.

Finally, the panel chose not to advocate for the use of a single multiple-organ dysfunction score, but developed criteria for organ dysfunction based on those used in the Pediatric Logistic Organ Dysfunction score or the pediatric multiple organ dysfunction syndrome ³⁹ ^,159 ^,239 (Box 6-3).

Box 6-3 Criteria for Organ Dysfunction in Children with Severe Sepsis or Septic Shock

Cardiovascular dysfunction

Despite administration of isotonic intravenous fluid boluses of more than 40 mL/kg in 1 hour, is described by the characteristics in one or more of the three bullets below:

Respiratory * (one of the following four bulleted conditions)

• PaCO₂/FiO₂ < 300 in absence of cyanotic heart disease or preexisting lung disease

• PaCO₂ > 65 torr or 20 mm Hg over baseline PaCO₂

• Proven need ^† or >50% inspired oxygen to maintain saturation >92%

• Need for nonelective invasive or noninvasive mechanical ventilation ^‡

Neurologic (either of the following)

• Glasgow Coma Score ≤11

• Acute change in mental status with a decrease in Glasgow Coma Score ≥3 points from abnormal baseline

Hematologic (one of the following three bulleted conditions)

• Platelet count <80,000/mm³

• A decline of 50% in platelet count from highest value recorded over the past 3 days (for chronic hematology/oncology)

• International normalized ratio >2

Renal

• Serum creatinine ≥twofold upper limit of normal for age or twofold increase in baseline creatinine

Hepatic (either of the following)

• Total bilirubin ≥4 mg/dL (not applicable for newborn)

• ALT twofold upper limit of normal for age

ALT, Alanine transaminase; BP, blood pressure.

Modified from Goldstein B, et al: International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med 6:2−8, 2005.

^* Acute respiratory distress syndrome must include a PaO₂/FiO₂ ratio ≤200 mm Hg, bilateral infiltrates, acute onset, and no evidence of left heart failure. Acute lung injury is defined identically except the PaO₂/FiO₂ ratio must be ≤300 mm Hg.

^† Proven need assumes oxygen requirement was tested by decreasing flow with subsequent increase in flow if required.

^‡ In postoperative patients, this requirement can be met if the patient has developed an acute inflammatory or infectious process in the lungs that prevents them from being extubated.

These definitions for pediatric sepsis are a significant step forward in facilitating clinical trials in pediatric sepsis, but the definitions go beyond use for research; they can facilitate earlier clinical recognition and treatment of sepsis in children.²³⁹ Further refinements may allow differentiation between morbidity arising from infection and morbidity caused by the host response to infection. The PIRO system stratifies patients on the basis of their predisposing conditions (P), the nature and extent of the infection (I), the nature and magnitude of the host response (R), and the degree of concomitant organ dysfunction (O)¹⁶⁴ ^,231 (Table 6-6).

Table 6-6 Basic Elements of PIRO Stratification of Patients with Sepsis

P	Predisposing factors	Innate: Genetic polymorphisms and deficiencies of immune response genes affecting innate immune response, coagulation system complement receptors, Toll-like receptors, and intracellular signaling. Acquired: Burns, trauma, acquired immune deficiencies
I	Infection	Site, quantity, intrinsic virulence, and local versus systemic infection caused by specific microbial pathogens
R	Response	Differential responses based on hyperresponsiveness versus hyporesponsiveness-immunosuppression; response modifiers such as age, sex, nutritional status, diabetes, other preexisting diseases, and physiologic status of host
O	Organ dysfunction	Number, severity, and pattern of organ dysfunction in response to systemic infection; primary versus secondary organ injury; and organ injury owing to sepsis versus preexisting organ dysfunction

Modified from Opal SM: Concept of PIRO as a new conceptual framework to understand sepsis. Pediatr Crit Care Med 6(3):S55–S60, 2005.

Pathophysiology

The pathophysiology of septic shock is not completely understood. A combination of the direct effects of microbial agents, microbiological toxins, and the patient’s inflammatory response to infection results in the cardiovascular instability and multisystem organ failure seen in septic shock.

Organ dysfunction is the final tissue sequelae in response to severe sepsis and is the ultimate determinant of survival. Mortality is much higher in patients with sepsis who develop progressive multiple organ failure than in those who develop a single or no organ dysfunction in response to sepsis.¹⁶⁴ ^,231 What remains unclear is why some patients develop one type of organ dysfunction and others develop another organ dysfunction, despite seemingly similar septic stimuli. Some patients develop profound coagulation abnormalities in the early phases of sepsis, whereas others develop severe acute respiratory dysfunction syndrome, and others experience acute renal failure. The sequence and pattern of organ dysfunction after severe sepsis can also vary between patients and provide some insights into the likelihood of survival and response to therapy.

The host inflammatory response to systemic infection is perhaps the key element to understanding severe sepsis and septic shock. The complexities of the host response and the variations between patients in response to microbial challenge present the major hurdle to a comprehensive understanding of the pathophysiology of septic shock. Although there is better understanding of many of the essential cellular and humoral elements that contribute to septic shock than in years past, integration of these disparate processes into a clearly defined and recognizable system has proved to be extremely difficult.

It is now recognized that multiple clinical and laboratory variables have the capacity to alter the host response to infection. Many of these are rather simple and straightforward. The patient’s age, nutritional status, sex, genetic background, and underlying disease processes may affect the host innate immune and acquired immune response to invasive infection. The complexity arises from the redundancy of inflammatory networks and the fact that there are many nonlinear, competing negative feedback loops and amplification pathways that occur simultaneously in the septic host. There is also evidence of compartmentalization at the immune response where cellular elements in the systemic circulation can express a different series of immune responses when compared with cells residing in the liver, spleen, lung, or other host tissues.

Some patients have a marked systemic response, often referred to as hyperinflammation, induced by certain microbial pathogens.²³¹ The clearest examples of this occur in previously healthy children who develop meningococcal sepsis or in patients with streptococcal toxic shock syndrome after a relatively mild soft-tissue injury.²³² ^,241 The other extreme exists in febrile, neutropenic patients with cancer or in bone marrow transplant patients who have a markedly impaired systemic host response to microbial infection and often die of overwhelming infection with an inadequate host response.¹¹ ^,135 ^,231 There are numerous gradations in the spectrum between these two extremes, yet it is often difficult to clinically distinguish between patients with hyperinflammation and those with inadequate inflammatory responses.

A key element in the pathogenesis of sepsis is activation of the cytokine network. Cytokines are host produced, pleomorphic immunoregulatory peptides.³⁰⁵ ^,316 The most widely investigated cytokines are tumor necrosis factor, interleukin-1, and interleukin-8, which are generally proinflammatory, and interleukin-6 and interleukin-10, which tend to be antiinflammatory. A trigger, such as a microbial toxin, stimulates the production of tumor necrosis factor and interleukin-1, which in turn promote endothelial cell-leukocyte adhesion, release of proteases and arachidonic acid metabolites, and activation of clotting.⁵¹ ^,316 Interleukin-1 and tumor necrosis factor are synergistic, share many biologic functions, and interact to promote positive feedback cascades that result in fever, vasodilation, cardiovascular failure, and lactic acidosis (see Septic Mediators in the Chapter 6 Supplement on the Evolve Website).⁵¹

The cytokines stimulate the production of many important effector molecules, including proinflammatory cytokines, antiinflammatory cytokines, and nitric oxide. Increased pro-inflammatory cytokines, antiinflammatory cytokines, and nitric oxide correlate with outcome and the development of multiple organ failure in pediatric sepsis and septic shock.⁵¹ ^,289 ^,320

It is now clear that inflammation is just one of the many contributors to septic physiology. Other factors include enhanced coagulation and impaired fibrinolysis (Table 6-7).⁸ ^,135 ^,194 Because of the multiple factors involved, the clinical pattern and presentation of septic shock can vary a great deal and depend on the dynamic interplay of the invading organism, elapsing time, and host response.

Table 6-7 Mediators of and Immunotherapy for Sepsis

Agent	Site of Action
Antiendotoxin antibodies	Neutralize endotoxin
E5 (murine)
HA-1A (human)
Bactericidal permeability-increasing protein	Neutralize endotoxin
TNF antibodies	Block TNF
IL-1 receptor antagonists	Inhibit action of IL-1 on cellular receptors
IL-1 antibodies	Block IL-1 receptor interaction
IL-6 and IL-8 antibodies	Block IL-6, IL-8 receptor interaction
Bradykinin-receptor antagonists	Prevent vasoactive effects of bradykinin
Platelet activating factor antagonist	Block platelet activation and platelet aggregation
Cyclooxygenase inhibitors (ibuprofen)	Block pyrogen, thromboxane, and prostaglandin production
NO synthase inhibitors	Block production of NO, restore vascular tone
Inhibitors of leukocyte-adhesion molecules	Prevent endothelium-leukocyte interaction
Corticosteroids	Promote and antiinflammatory response
Antiinflammatory cytokines (IL-6, IL-10)	Inhibit inflammatory response; reduce production of proinflammatory cytokines

IL, Interleukin; NO, nitric oxide; TNF, tumor-necrosis factor.

Clinical Signs and Symptoms

Abnormal hemodynamic responses are the hallmarks of septic shock. The clinical cascade may unfold over several days or a few hours. In many patients, the early stages consist of a hyperdynamic state with an elevated CO, decreased SVR, and a widened pulse pressure, with episodic hypotension and warm extremities with brisk capillary refill.³⁵ ^,37 ^,51 ^,52 In this hyperdynamic stage, the patient may also demonstrate high fever, mental confusion, and hyperventilation. Although these patients are typically tachycardic and tachypneic, the vital signs and clinical examination may not reflect the severity of disease. Mental status changes, a sensitive indicator of hypoperfusion, may present in a clinical spectrum that begins with fussiness, irritability, or hallucinations and, if untreated, evolves to lack of response to parents or noxious stimuli, and eventual coma.²⁴³

If sepsis is unchecked and uncorrected, cardiovascular function steadily deteriorates, which is characterized by a decline in CO, hypotension, and worsening metabolic acidosis. Paradoxically, hypotension may develop in the presence of normal or elevated CO. One fundamental abnormality in patients with septic shock is an altered relationship of SVR and CO.²⁹² The patient’s status deteriorates when cardiac compensation for falling SVR is lost. Some patients die of refractory hypotension associated with extremely low SVR.¹⁹¹ ^,292

A progression from high to low CO can occur over any time period.³⁵ As CO falls, tissue perfusion worsens, leading to anaerobic metabolism and accumulation of lactic acid.¹⁹⁵ Progressive lactic acidemia can be a sign of impending death.²¹ ^,22 ^,292 Infants or children with heart disease and any other patients with limited cardiac reserve can progress rapidly to this hypodynamic picture.

Survival following septic shock has been related to the host’s ability to establish and maintain a hyperdynamic cardiovascular state.⁴⁴ ^,253 ^,254 In this hyperdynamic shock, CO is increased and the SVR is low. Clinical studies of adults with septic shock have documented both right and left ventricular dilation with decreased contractility and reduced ejection fraction.⁴⁴ ^,238 In these patients, CO is maintained only through ventricular dilation (an increase in end-diastolic volume maintains SV at near-normal levels despite the fall in ejection fraction) and tachycardia (see Fig. 6-6). These septic shock studies in adults have not been replicated in children. Infants and children may not be fully capable of using or maintaining the same compensatory physiologic mechanisms. For example, infants and children have higher resting HRs, which can limit the efficiency of a chronotropic protective response. Because the pediatric ventricle is less compliant than the adult ventricle, the pediatric ventricle may be less able to dilate.

In the early stages of septic shock, hypovolemia or myocardial dysfunction (resulting from preexisting or intercurrent ventricular disease) can blunt or eliminate the hyperdynamic response to sepsis.¹⁹¹ ^,292 Several factors can contribute to the relative hypovolemia that commonly develops during septic shock. Increased capillary permeability, dilation of arteries and veins with subsequent peripheral pooling of intravascular blood volume, inappropriate polyuria, and poor oral intake all combine to reduce the effective blood volume (i.e., inadequate intravascular volume relative to the vascular space).²⁴³ Fluid loss secondary to fever, diarrhea, vomiting, or sequestered third space fluid also contributes to the relative hypovolemia.

In some patients without complicating preexisting heart disease, a relative depression in left ventricular contractility exists even in early stages.⁴⁴ ^,153 ^,238 ^,264 ^,291 Myocardial contractility is most likely depressed because of the inhibitory effects of one or more circulating substances (so-called myocardial depressant factor or factors). In patients who survive, this myocardial depression is transient.

Contrary to adult experience, low CO—not low SVR—is associated with mortality in pediatric septic shock.⁵¹ ^,254 Ceneviva et al.⁵⁶ reported outcome data associated with aggressive volume resuscitation and goal-directed therapies in children with septic shock. In this study, 50 children with fluid refractory septic shock were hemodynamically characterized using measurements and calculations obtained through use of pulmonary artery catheters. The majority of children (58%) in septic shock showed a low CO and high SVR state (group I); 20% showed the classic adult high CO and low SVR state (group II); and 22% had decreased CO and SVR (group III).

Patients in group I responded to inotropic therapy with or without a vasodilator. Patients in group II responded to vasopressor therapy, but some needed the addition of an inotrope for evolving myocardial dysfunction. Patients in group III responded to combined vasopressor and inotropic therapy. The overall 28-day survival rate was 80% (group I, 72%; group II, 90%; group III, 91%). This study demonstrates that therapies directed at cardiac dysfunction and systemic vasoconstriction (i.e., vasodilators) are likely to be needed more in pediatric than in adult septic shock.⁵⁶

Cardiovascular abnormalities described in sepsis include alterations of both systolic and diastolic ventricular function.²¹² ^,291 Although diastolic performance in sepsis has been less characterized, echocardiographic studies have demonstrated a pattern of abnormal left ventricular relaxation, which is more severe in nonsurvivors.

Septic shock is also characterized by abnormal utilization of oxygen.¹²² ^,124 ^,254 Although sepsis causes a hypermetabolic stress associated with increased oxygen demand, deterioration characteristically occurs when oxygen consumption falls during a period of increased cardiovascular function and oxygen delivery. This fall in oxygen consumption is the result of decreased oxygen extraction and reflects a severe impairment of oxidative metabolism at a time of major metabolic and physiologic stress. The pathophysiology of inadequate oxygen consumption in septic shock remains unclear. The most widely accepted theories to account for this oxygen debt are the redistribution of blood flow, with a consequent decrease in nutrient capillary flow, and the development of a cellular metabolic blockade at the mitochondrial level such that delivered oxygen cannot be used. Progressive deterioration in oxygen consumption and oxygen extraction portends a poor prognosis for patients in septic shock.¹²⁴

Management

Primary therapeutic goals for the initial treatment of septic shock are identification and control of the infection and rapid reversal of cardiovascular dysfunction.

Antibiotic Treatment

The removal or control of microorganisms by surgical debridement or drainage and antibiotic therapy is a crucial component of the treatment of septic shock. Antibiotic treatment is appropriate in patients with circulatory shock whenever an infectious etiology is suspected. Antimicrobial drugs are necessary but not sufficient for the treatment of sepsis, and paradoxically, they may precipitate septic changes by liberating microbial products (e.g., release of endotoxin following lysis of gram-negative bacteria).³¹⁶

Airway and Ventilation

The primary goal in the initial management of septic shock is to restore hemodynamic stability. Fundamental aspects of management include increasing the oxygen delivery by maximizing CO and arterial oxygen content while minimizing oxygen requirements.

Detection of septic shock is facilitated by the nearly universal presence of tachypnea.³¹⁶ Sepsis places extreme demands on the cardiopulmonary system, requiring a high-minute ventilation precisely when the compliance of the respiratory system is diminished, airway resistance is increased, and muscle efficiency is impaired. Timely intubation and mechanical ventilation reduce respiratory muscle oxygen demand and the risk of aspiration and cerebral anoxia from catastrophic respiratory arrest.

Volume Resuscitation

Restoration of preload by volume resuscitation is the first therapeutic measure for a decreased CO.^38,⁵⁰^–⁵² ^,72 ^,119 Early and effective expansion of the circulating blood volume may enhance oxygen delivery and prevent progression of the septic shock state. The American College of Critical Care Medicine-Pediatric Advanced Life Support guidelines recommend rapid, stepwise interventions with the following therapeutic end points in the first hour: reduction in extreme tachycardia, capillary refill of less than 2 s, normal pulses with no differential between peripheral and central pulses, warm extremities, urine output greater than 1 mL/kg per hour, and normal mental status.³⁸ ^,72 Further hemodynamic optimization using metabolic endpoints to treat global tissue hypoxia include an ScvO₂ obtained from the superior vena cava greater than or equal to 70%, a cardiac index greater than 3.3, and less than 6.0 L/min per m² BSA with normal perfusion pressure for age.³⁸ ^,52 ^,72

Studies in children have shown that early aggressive volume repletion, even without addressing myocardial dysfunction, significantly improves outcome.⁷² ^,119 ^,227 More importantly, when resuscitation was inadequate and shock persisted, the odds of mortality doubled with each hour of persistent shock.¹³⁷ Goal-directed hemodynamic optimization represents an organized approach to volume repletion, attainment of a target BP (vascular tone) and a more definitive resolution of a pathologic oxygen supply dependency or global tissue hypoxia through the normalization of ScvO₂ as a surrogate end point.⁷²

A study in adult patients with severe sepsis and septic shock confirmed that global tissue hypoxia, defined by an ScvO₂ less than 70%, can still be present even if physical examination, vital signs, central venous pressure, and urinary output are considered adequate.²⁶² In addressing this global tissue hypoxia using an early goal-directed approach, further reductions in the inflammatory response, morbidity, and mortality were achieved compared with conventional therapy.²⁶² Whereas the early goal-directed therapy patients received more fluids, red blood cell transfusions, and inotropes over the first 6 hours for a higher rate of attaining an ScvO₂ greater than or equal to 70%, there was essentially no difference in these therapies after the first 72 hours. Because of this early hemodynamic optimization, significant reductions in vasopressor, mechanical ventilation, and pulmonary artery catheter use were also realized.²⁶² Similarly, a pediatric study using a goal-directed approach demonstrated more fluid, more red blood cell transfusion, and more inotropic support in the first 6 hours of treatment in the group using ScvO₂ ≥70% as an end point.⁷² After 72 hours the amount of crystalloid administered and the percentage of red blood cells in transfusion were not different between the two groups. These observations were similar to those found in adults. These studies support the concept that early resuscitation rather than later resuscitation is beneficial.⁵² ^,56 ^,227 In addition, there was a statistically significant reduction in the number of children with ScvO₂ less than 70% at 72 hours in the intervention group (i.e., early and aggressive fluid resuscitation produced better oxygen delivery to utilization ratio). This finding supports the concept that goal-directed therapy can reduce global oxygen debt over the long term and the short term in patients with septic shock. In addition to the favorable reduction in mortality, a decrease in pulmonary (increased number of ventilator-free days), neurologic, and renal dysfunction was also seen.

Isotonic crystalloid solutions can be used initially to restore intravascular volume in the presence of septic shock if they increase the blood volume and CO. Debate over the relative advantages and disadvantages of crystalloid and colloid fluids for the treatment of sepsis and septic shock continues.⁵² A metaanalysis has shown no difference in mortality between patients resuscitated with normal saline or albumin, and a multidisciplinary consensus statement concluded that crystalloid is the preferred solution in patients with sepsis.⁸⁹ Three randomized controlled trials compared the use of colloid to crystalloid resuscitation in children with dengue shock.⁸² ^,220 ^,319 No difference in mortality between the colloid or crystalloid resuscitation groups was shown.

Theoretically, transfusion of packed red blood cells to maintain a normal hemoglobin concentration is the most effective means of increasing arterial oxygen content and systemic oxygen availability. Initial guidelines in patients with severe sepsis target a hemoglobin concentration greater than or equal to 10 g/dL.⁵²

The optimal hemoglobin for a critically ill child with severe sepsis is not known.⁷¹ A recent multicenter trial reported similar outcomes in stable, critically ill children managed with a transfusion threshold of 7.0 g/dL and those with a threshold of 9.5 g/dL; however, the study excluded children with congenital heart disease or hemodynamic instability.¹⁶⁰ Whether a lower transfusion trigger is safe or appropriate in the initial resuscitation has not been determined.⁷¹

Excessive tachycardia, severe mixed venous desaturation, cardiac systolic dysfunction, and failure to resolve lactic acidosis or failure to improve gastric intramucosal pH may indicate the need to increase hemoglobin concentration to levels of 10 g/dL.⁷² ^,180 ^,243 ^,292

Although fluid administration and antimicrobial therapy remain the cornerstones of the therapeutic approach to sepsis and septic shock, patients often require therapy with inotropic agents, vasoactive drugs, or both.³⁸ ^,51 Children can have predominant cardiac failure, predominant vascular failure, or a combination of cardiac and vascular failure.³⁵ ^,37 ^,52 ^,56 ^,72 Therapeutic approaches differ with each condition.

Myocardial depression complicates septic shock and can prevent the development of optimal CO despite adequate intravascular volume. The catecholamine and noncatecholamine inotropes may both be effective in reversing myocardial depression and improving contractility (see Table 6-5; Figs. 6-7 and 6-8).³⁸

Fig. 6-7 Potential mechanism for maintenance of near-normal stroke volume in septic shock, despite fall in ejection fraction (EF). When ejection fraction falls during septic shock, stroke volume can be maintained at normal or near-normal levels if ventricular dilation results in an increase in ventricular end-diastolic volume. For ease of calculations, simple numbers are used in this illustration. A, In the healthy patient with an ejection fraction of 50% and an end-diastolic volume of 100 mL, stroke volume is 50 mL. B, If ejection fraction falls to 25% and ventricular dilation results in an increase in ventricular end-diastolic volume of 200 mL, the stroke volume can remain at 50 mL. If the patient then has an increased heart rate, cardiac output and index may be higher than normal. C, If the SVR is extremely low, EF and stroke volume may be maintained during septic shock, but hypotension is likely to be present.

Fig. 6-8 Suggestions for hemodynamic support in pediatric septic shock.

Based on recommendations of Brierley J, Carcillo JA, Choong K, Cornell T, et al: Clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock: 2007 update from the American College of Critical Care Medicine. Crit Care Med 37:666–688, 2009. BP, Blood pressure; CI, cardiac index; SVRI, systemic vascular resistance index.

Inotropic Support

Children in a normotensive, hypodynamic state after volume resuscitation require an inotrope to increase CO and to reverse shock. Dobutamine or moderate-dose dopamine can be used as the first line of inotropic support. Patients with dobutamine-resistant septic shock often respond to the addition of epinephrine with or without vasodilators. When patients remain in a normotensive low CO state, despite adequate volume resuscitation and epinephrine and vasodilator therapy, then the use of milrinone should be considered.²⁵ ^,174

Catecholamines exert their β-adrenergic receptor effects by elevating intracellular calcium transit through increasing production of intracellular cAMP. However, benefits from the application of catecholamines in septic shock may not be sufficient. Myocardial hyporesponsiveness to catecholamine administration during septic shock has been documented by several investigators.⁵² ^,247 ^,291 This hyporesponsivity of the myocardium to catecholamines may be due to cytokine-induced uncoupling of the β-adrenergic receptor system or due to deranged intracellular calcium metabolism.²⁵

The bipyridines (milrinone, inamrinone) have no interaction with the adrenergic receptors, but exert their effects through the inhibition of phosphodiesterases, which degrade cAMP. Milrinone has been shown to improve cardiovascular function in pediatric patients with hypodynamic septic shock who are adequately volume resuscitated and are being treated with catecholamines.²⁵ ^,174

Vasopressors

Vasopressor therapy is commonly required in children with fluid refractory shock and hypotension. Choices for vasopressor effect include dopamine in a dose range of 10-20 mcg/kg per minute, norepinephrine, and epinephrine. Alpha-adrenergic agonists are vasoconstricting drugs that can boost SVR. All the drugs mentioned have marked β-adrenergic properties as well, increasing the HR and myocardial contractility.

Dopamine is an α-adrenergic agonist at higher concentrations. It mediates vasoconstriction indirectly by causing the release of norepinephrine from sympathetic vesicles.²⁷²

Norephinephrine often reverses dopamine-refractory septic shock.²⁰² Norephinephrine can also improve urine output and renal function by increasing perfusion pressure in hypotensive patients.

Both high-dose dopamine and norepinephrine have been recommended as the first-line vasopressor agents in the treatment of refractory shock. There is controversy about whether one agent is superior to the other.⁷⁰ Dopamine and norepinephrine have different effects on the kidney, the splanchnic region, and the pituitary axis, but the clinical implications of these differences are uncertain. Consensus guidelines and expert recommendations suggest that either agent may be used as a first-choice vasopressor in patients with shock.⁷¹

Recently, a multicenter, randomized trial assigned adult patients with shock to receive either dopamine or norepinephrine as first-line vasopressor therapy to restore and maintain BP.⁷⁰ The type of shock present most frequently was septic shock (62.2%), followed by cardiogenic shock (16.7%) and hypovolemic shock (15.7%). The primary outcome was mortality at 28 days after randomization; secondary end points included adverse events and number of days without the need for organ support. Although the mortality did not differ significantly between the group of patients treated with dopamine and the group treated with norepinephrine, this study raises serious concerns about the safety of dopamine therapy, because dopamine, as compared with norepinephrine, was associated with more arrhythmias and with an increased rate of death in the subgroup of patients with cardiogenic shock.⁷⁰

Although epinephrine is used for resuscitation and to treat anaphylaxis, its β₂-adrenergic effects can cause hyperglycemia, acidosis, and other adverse effects; therefore it may not be ideal for treating shock.¹⁷⁰ However, a recent study reported no difference in clinical in-patient outcomes or safety in a prospective comparison of norepinephrine with or without dobutamine to epinephrine for septic shock.¹²

In children with a warm vasodilated state after volume resuscitation, norepinephrine can be used to increase diastolic BP while maintaining good perfusion.⁵¹ ^,202 However, these cases of vasodilatory shock are characterized by hypotension caused by peripheral vasodilation and by a poor response to therapy with vasopressor drugs.¹⁶² Vasodilatory shock is caused by the inappropriate activation of vasodilator mechanisms and the failure of vasoconstrictor mechanisms. Unregulated nitric oxide synthesis through activation of soluble guanylate cyclase and generation of cyclic guanosine monophosphate (cGMP) causes dephosphorylation of myosin and hence vasorelaxation. In addition, nitric oxide synthesis and metabolic acidosis activate the potassium channels in the plasma membrane of vascular smooth muscle. The resulting hyperpolarization of the membrane prevents the calcium that mediates norepinephrine- and angiotensin II–induced vasoconstriction from entering the cell. As a result, hypotension and vasodilation persist, despite high plasma concentrations of these hormones. In marked contrast, the plasma concentrations of vasopressin are low, despite the presence of hypotension. This finding is unexpected, because plasma vasopressin concentrations are markedly elevated early in septic shock and hemorrhagic shock. However, the initial massive release of hormone may result in subsequent depletion, such that plasma concentrations of vasopressin are eventually too low to maintain arterial pressure. Although the pressor response to exogenous vasopressin in vasodilatory shock may be due to several different mechanisms, the ability of this hormone to block potassium channels in vascular smooth muscle and interfere with nitric oxide signaling are probably important contributors.

Elucidation of key components of the pathogenesis of vasodilatory shock—potassium channel activation, an increase in nitric oxide synthesis, and vasopressin deficiency—has suggested new possibilities for therapy. Unfortunately, a recent phase-three trial of a nonselective inhibitor of nitric oxide synthase in patients with septic shock was halted because of side effects.⁶³

In recent years, vasopressin has been increasingly used to treat the hypotension associated with shock.²⁴ ^,162 ^,170 Vasopressin can be particularly effective in reversing mediator-induced vasodilatory shock in patients with sepsis or anaphylaxis.¹⁷⁰ ^,173 ^,323

The use of vasopressin for hypotension in the setting of vasodilatory shock (warm shock) seems appropriate, and the limited use of vasopressin in this setting appears to be safe. However, for both adults and children, the appropriate patient population and dose regimen have not yet been determined.¹⁷³

In a recent report, admission and serial plasma vasopressin levels were appropriately elevated in children with septic shock.¹⁷⁶ These findings are in contrast with those reported in adults, suggesting that the role of vasopressin administration in children with septic shock is limited until prospective studies are performed. Although the addition of vasopressin to norepinephrine therapy in adult patients with septic shock appears to produce mortality rates similar to those of mortality with norepinephrine alone and it is safe, there is no compelling advantage to using vasopressin rather than norephinephrine.²⁴⁰ ^,266

Vasopressin could have variable effects depending on the cardiovascular profile of shock in any given patient. For example, vasopressin could produce favorable effects in a high CO and low SVR shock state, but could be deleterious if used alone in a patient with severe left ventricular dysfunction. Other reported adverse effects of vasopressin and norepinephrine include decreased CO,¹⁸¹ ^,266 mesenteric ischemia,¹⁵¹ ^,266 ^,306 hyponatremia, skin necrosis, and digital ischemia.⁸³ ^,125 ^,140

The use of vasopressors should be titrated to end points of normal perfusion pressure or SVR. Strict end-point measures should be used to avoid unnecessary vasoconstriction to key organs. A frequent adverse affect of α-agonist treatment is localized severe vasoconstriction after extravasation of the infusion; therefore these infusions are best administered into central venous or intraosseous catheters.²⁷²

When any patient in circulatory shock fails to respond to initial therapy, reversible causes should always be considered. These causes include pneumothorax, pericardial tamponade, and adrenal insufficiency.

Corticosteroid Therapy

Corticosteroid therapy has been used in varied doses for sepsis and related syndromes for more than 50 years, with no clear benefits on mortality.¹³ Since 1998, studies in adults have consistently used prolonged low-dose corticosteroid therapy, and analysis of this subgroup suggests a beneficial drug effect on short-term mortality.¹³ The Corticosteroid Therapy of Septic Shock (CORTICUS) study group found that hydrocortisone did not improve survival or reversal of shock in patients with septic shock, either overall or in patients who did not have a response to corticotrophin, although hydrocortisone hastened reversal of shock but not survival in those patients in whom shock was ultimately reversed.²⁸³

Over the past decade the concept of relative adrenal insufficiency has been proposed in the critical care unit (PCCU) setting and generally refers to patients with vasopressor-resistant hypotension.²⁷⁷ In critically ill adults who had a normal baseline cortisol level (≥20 mcg/dL) and incremental rise of cortisol of less than or equal to 9 mcg/dL after administration of 250 mcg of intravenous adrenocorticotropic hormone (ACTH), treatment with stress doses of hydrocortisone was associated with improved survival.¹⁰

Pizarro et al.²⁵² studied the baseline and peak incremental response (increase above baseline) to 250 mcg of ACTH in critically ill children with septic shock to learn whether this test would predict shock resistant to vasopressor in the pediatric setting. All children (18%) with a basal serum cortisol of less than 20 mcg/dL had catecholamine-resistant shock. Eighty percent of those with a low incremental cortisol response to ACTH (≤9 mcg/dL at 30 or 60 min) compared with 20% who had “normal” incremental cortisol response had catecholamine-resistant shock. The study concludes that absolute and relative adrenal insufficiency is common in children with septic shock and may contribute to the development of catecholamine-resistant shock—that is, it is associated with an increased vasopressor requirement.²⁵² However, doubts still persist regarding the efficacy of replacement therapy with low-dose steroids in children with catecholamine-resistant septic shock, and further study is needed to determine whether treatment of such patients changes morbidity, mortality, or both.²⁵² ^,327

The most recent consensus guidelines for treatment of pediatric septic shock suggest that hydrocortisone therapy should be reserved for use in children with catecholamine resistance and suspected or proven adrenal insufficiency.³⁸ Patients at risk for adrenal insufficiency include children with severe septic shock and purpura, children who have previously received steroid therapies for chronic illness, and children with pituitary or adrenal abnormalities.⁷¹ ^,252 ^,261 ^,327 Children who have clear risk factors for adrenal insufficiency should be treated with stress-dose steroids (hydrocortisone, 50 mg/m² BSA per 24 hours).⁷¹

Children who have received etomidate or ketoconazole may also be at risk for adrenal insufficiency.³²⁷ The use of etomidate as an anesthetic induction agent in critically ill patients is controversial, because this drug inhibits the 11β-hydroxylase enzyme that converts 11β-deoxycortisol into cortisol in the adrenal gland.¹⁹⁰ A single dose of etomidate has been demonstrated to inhibit cortisol production for up to 48 hours, prompting the suggestion of steroid supplementation during this period.²⁰⁴ ^,307

Adrenal insufficiency in severe pediatric sepsis is associated with a poor prognosis.⁶⁸ ^,71 No strict definitions exist, but absolute adrenal insufficiency in the case of catecholamine-resistant septic shock is assumed at a random total cortisol concentration of less than 18 mcg/dL.⁷¹ Relative adrenal insufficiency has been defined as a peak serum cortisol level increase of 9 mcg/dL or less above baseline, evaluated 30- or 60-minutes after administration of 250 mcg of corticotrophin (a 30- to 60-minutes post-ACTH stimulation test).⁷¹ The treatment of relative adrenal insufficiency in children with septic shock is controversial.⁷¹ ^,327 A retrospective study from a large administrative database recently reported that the use of any corticosteroid in children with severe sepsis was associated with increased mortality.¹⁹² Given the lack of data in children and the potential risk, steroids should not be used in children who do not have risk factors or who do not meet minimal criteria for adrenal insufficiency. A randomized, controlled trial in children is eagerly awaited.

There are potential complications to glucocorticoid administration in critically ill children, including antianabolic effects, attenuated immunity, depressed wound healing, calcium mobilization, impaired insulin action, and hyperglycemia.³²⁷ Although adjunctive corticosteroids for severe sepsis may hasten resolution of unstable hemodynamics, this may occur at the metabolic risk of hyperglycemia.³²⁷ Risk of hyperglycemia and associated increased mortality secondary to the gluconeogenic effects of cortisol deserve close scrutiny in children.⁹³ ^,284 ^,327

Immunotherapy

Because septic shock can result from endogenous proteins and phospholipids synthesized by the patient, it has been hypothesized that diminution or elimination of the host response will lessen morbidity and mortality.²⁴³ Although this hypothesis continues to be explored, the results of immunotherapy have, in general, been discouraging.¹⁹³ ^,243 ^,258 Some experimental therapies and their targets are listed in Table 6-7.

Administration of polyvalent intravenous immunoglobulin was recently shown to have no effect on outcome in an international, multicenter study of proven or suspected neonatal sepsis.^39a In a recent randomized controlled study, administration of polyclonal immunoglobulin in pediatric patients with sepsis syndrome (n = 100) significantly reduced mortality and length of stay, also resulting in fewer complications, especially disseminated intravascular coagulation.⁸⁷

Treatment of Coagulation Dysfunction

In patients diagnosed with sepsis, severe sepsis, or septic shock, cytokine-mediated endothelial injury and tissue factor activation initiate a cascade of events that culminate in the development of coagulation dysfunction characterized as procoagulant and antifibrinolytic.²²⁶ This abnormal state predisposes the patient to develop microvascular thrombosis, tissue ischemia, and organ hypoperfusion. Multiple organ dysfunction syndrome may be a product of this perturbation in coagulation regulation. Treatments aimed at correcting this coagulation dysfunction have met with limited success.²²⁶

Coagulation proteases and their cofactors modify the outcome of severe inflammation by engaging signaling-competent cell surface receptors. The central effector protease of the protein C pathway, activated protein C, interacts with the endothelial cell protein C receptor, protease-activated receptors, and other receptors to affect hemostasis and immune cell function.³¹¹ The immune regulatory capacity of the protein C pathway and its individual components might be at least as important as its well-documented effects on coagulation.³¹¹

The use of recombinant human activated protein C, although indicated in some adults with sepsis-induced organ dysfunction, is not recommended for use in children with septic shock.⁷¹ A randomized clinical trial of recombinant human activated protein C in pediatric severe sepsis patients was stopped by recommendation of the Data Monitoring Committee for futility, with evidence of increased bleeding complications.⁷¹ ^,213

The keystone of the treatment of hemostatic abnormalities in patients with sepsis is to treat the underlying infection using appropriate antibiotics and source control.¹⁶⁵ ^,166 However, additional supportive treatment, specifically aimed at the coagulation abnormalities, may be required.

Low levels of platelets and coagulation factors may increase the risk of bleeding. However, plasma or platelet substitution therapy should not be instituted on the basis of laboratory results alone and is indicated only in patients with active bleeding and in those requiring an invasive procedure or otherwise at risk for bleeding complications.¹⁶⁵ The use of agents that are capable of restoring the dysfunctional anticoagulation pathways in patients with disseminated intravascular coagulation has been studied.¹⁶⁵ The use of antithrombin concentrate, activated protein C, and recombinant factor VIIa are not currently recommended for use in pediatric septic shock.¹¹⁰ ^,200

Systemic inflammation will invariably lead to activation of the coagulation system, but components of the coagulation system may markedly modulate the inflammatory response. Increasing evidence points to extensive cross-talk between the coagulation and inflammation systems at various points, with tissue factor, thrombin, components of the protein C pathway and fibrinolytic activators, and inhibitors playing pivotal roles. Increased insight into the molecular mechanisms that play a role in the close relationship between inflammation and coagulation could lead to the identification of new targets for therapies that can modify excessive activation or dysregulation of these systems.¹⁶⁶

Extracorporeal Membrane Oxygenation (ECMO)

ECMO is used in septic shock in children but its effect is not clear. Survival from refractory shock or respiratory failure associated with sepsis is 80% in neonates and 50% in children.⁷¹ In one study of 12 ECMO patients with meningococcal sepsis, 8 of 12 patients survived, with six functionally normal at a median of 1 year of follow-up.¹⁰⁸ One multivariate analysis of long-term survivors of ECMO found no significant difference between the performance of children with sepsis and those treated for other causes (i.e., without sepsis).²⁰⁵

Cardiogenic Shock

Etiology and Definition

Cardiac shock is the pathophysiologic state in which an abnormality of cardiac function is responsible for failure to maintain adequate tissue oxygenation.⁵⁸ ^,245 The final common pathway is depressed CO, which in most instances results from decreased myocardial contractility. Cardiogenic shock or severe congestive heart failure (CHF) during infancy and childhood represents a diagnostic and therapeutic challenge because of its myriad etiologies (Box 6-4). In the following section, the abbreviation CHF is used for severe CHF or cardiogenic shock.

Box 6-4 Etiologies of Cardiogenic Shock in Infants and Children

Conduction Abnormalities

Supraventricular tachycardia

Ventricular arrhythmias

Bradycardia

Cardiomyopathy

Hypoxic/Ischemic Events

Cardiac arrest

Prolonged shock

Head injury

Anomalous origin of the coronary arteries

Excessive catecholamine state

Cardiopulmonary bypass

Acute myocardial infarction

Hypothyroid/hyperthyroid

Hypoglycemia

Pheochromocytoma

Glycogen storage disease

Mucopolysaccharidoses

Nutritional deficiencies (thiamine, selenium, carnitine)

Disorders of fatty acid metabolism

Acidosis

Hypothermia

Hypocalcemia, hypophosphatemia

Connective Tissue or Inflammatory Diseases

Systemic lupus erythematous

Juvenile rheumatoid arthritis

Polyarteritis nodosa

Kawasaki disease

Acute rheumatic fever

Neuromuscular Disorders

Duchenne’s muscular dystrophy

Myotonic dystrophy

Limb-Girdle

Spinal muscular atrophy

Friedreich’s ataxia

Toxin Hypersensitivity

Familial dilated cardiomyopathy

Congenital Heart Disease

Trauma

Pathophysiology

In contrast to hypovolemic shock, compensatory responses can have deleterious effects in patients with cardiogenic shock.⁴⁵ ^,58 ^,269 ^,273 Compensatory responses are nonspecific and imprecise, and in patients with cardiogenic shock these responses may contribute to the progression of shock by further depressing cardiac function.

The Sympathetic Nervous System

The baroreceptor-mediated increase in sympathetic tone that occurs with ventricular dysfunction has several consequences, including increased myocardial contractility, tachycardia, and arterial vasoconstriction, and it can produce increased cardiac afterload as well as venoconstriction and increased cardiac preload.²⁶⁹

Increased local and circulating concentrations of norepinephrine can contribute to myocyte hypertrophy; this can occur directly through stimulation of α1- and β-adrenergic receptors or secondarily by activating the renin-angiotensin-aldosterone system. Norepinephrine is directly toxic to myocardial cells, an effect mediated through calcium overload, the induction of apoptosis, or both.²¹⁶ ^,269 Norepinephrine-induced death of myocytes can be prevented by concomitant, nonselective β-adrenergic blockade or combined β- and α-adrenergic blockade. In the past, β-adrenergic blockade was thought to be contraindicated in patients with heart failure. However, if patients can tolerate short-term β-adrenergic blockade, ventricular function subsequently improves.⁵⁸ ^,229 ^,273 ^,315 There are few data on the use of β-blockers in children with heart failure.²⁷³

Renin-Angiotensin-Aldosterone System

The activity of the renin-angiotensin-aldosterone system is increased in most patients with heart failure.²⁶⁹ ^,273 As with plasma norepinephrine, the degree of increase in plasma renin activity provides a prognostic index in these patients.²⁶⁹ Patients with mild heart failure may have little or no increase in either plasma renin activity or the plasma aldosterone concentration. However, normal plasma renin and aldosterone values would be inappropriate in these patients because of their increased intracellular fluid and total blood volumes.²⁵¹ ^,310 Among patients with severe heart failure, the concentrations of plasma renin and aldosterone are high.

Through renal vasoconstriction, stimulation of the renin-angiotensin-system, and direct effects on the proximal convoluted tubule, increased renal adrenergic activity contributes to the avid renal sodium and water retention that occurs in patients with heart failure. The kidneys become adversaries of the heart, lungs, and liver.

Aldosterone has an important role in the pathophysiology of heart failure. Aldosterone promotes the retention of sodium, loss of magnesium and potassium, sympathetic activation, parasympathetic inhibition, myocardial and vascular fibrosis, baroreceptor dysfunction, vascular damage, and impaired arterial compliance.²⁵¹ ^,310 Many physicians have assumed that inhibition of the renin-angiotensin-aldosterone system by an angiotensin converting enzyme (ACE) inhibitor will adequately suppress the formation of aldosterone. In addition, treatment with an aldosterone-receptor blocker in conjunction with an ACE inhibitor has been considered relatively contraindicated because of the potential for serious hyperkalemia. However, there is increasing evidence to suggest that ACE inhibitors only transiently suppress the production of aldosterone.²⁵¹ ^,310 Furthermore, treatment with the aldosterone-receptor blocker spironolactone, in conjunction with an ACE inhibitor, is effective and well tolerated and it does not lead to serious hyperkalemia.⁷ ^,251

Other adverse consequences of long-term activation of the renin-angiotensin-aldosterone system in patients with CHF include a progressive remodeling of the heart and vasculature, which is mediated in part by the induction of various cytokines and growth factors.³¹⁰ Most of these actions support or increase arterial BP and maintain glomerular filtration. Vasoconstriction and the release of aldosterone in response to angiotensin occur in seconds or minutes, in keeping with their roles of supporting the circulation after hemorrhage, dehydration, or postural change. Other actions, such as vascular growth and ventricular hypertrophy, require days or weeks.¹¹¹

An ACE inhibitor is now considered first-line therapy for patients with heart failure.³¹⁵ These drugs have improved survival in patients with chronic heart failure and all degrees of severity. Moreover, ACE inhibition reverses left ventricular hypertrophy, a common harbinger of heart failure.⁴³ ^,250 The role of angiotensin-converting enzyme inhibitors in the treatment of heart failure in children is much less clear.²⁷³

The amino acid sequence of angiotensin II has long been known, and compounds that competitively inhibit its action have been studied almost as long. The recently released angiotensin-receptor antagonist losartan appears to be beneficial in some patients with heart disease.¹¹¹

Nonosmotic Release of Arginine Vasopressin

Water retention in excess of sodium retention can occur in patients with heart failure and lead to hyponatremia. In fact, hyponatremia is an ominous prognostic indicator in patients with heart failure.²⁶⁹ Hyponatremia may be partly due to the increased water intake caused by the increased thirst associated with heart failure. However, increased water intake alone rarely causes hyponatremia. In patients with heart failure and hyponatremia, hypoosmolality, which inhibits the release of arginine vasopressin in normal subjects, is associated with persistently high plasma concentrations of arginine vasopressin. This observation suggests a pivotal role for arginine vasopressin in hyponatremia. In preliminary studies of patients with heart failure, a nonpeptide, orally active antagonist of arginine vasopressin proved effective in reversing impaired urinary diluting capacity, increasing solute-free water excretion, and correcting hyponatremia.²⁶⁹

Natriuretic Hormone System

The natriuretic hormone system participates in the regulation of fluid balance and vascular resistance in healthy humans and in those afflicted with a variety of disease states.⁶⁴ The natriuretic hormone system is composed of several structurally and functionally related peptides, primarily produced by the myocardium, vascular endothelium, and kidneys; they influence volume homeostasis and vascular tone by binding to dedicated receptors throughout the cardiovascular and renal system.⁶⁴ These peptides induce natriuresis, diuresis, and vasodilation and specifically act to counter the effects of the renin-angiotensin-aldosterone system.²¹⁷

The cardiac members of these peptides are the atrial or A-type natriuretic peptide (ANP) and the B-type natriuretic peptide (BNP). ANP is secreted primarily from the cardiac atria in response to increased left and right atrial pressures as well as volume loads, and BNP is secreted primarily from the ventricles in response to increased left and right ventricular pressures and volume loads.

The physiologic properties of the natriuretic peptides made them attractive candidates for heart failure therapy. Indeed, BNP (nesiritide) was found to be beneficial, and it was approved for treatment of acute decompensated CHF in the United States in 2001. However, responsiveness to natriuretic peptides decreases as heart failure worsens, even as the plasma concentrations of the peptides rise.¹⁶⁸

Soon after the discovery of the physiologic role of these peptides, it became clear that the natriuretic peptides serve as biochemical markers for heart disease or shock.³⁰ ^,75 ^,97 ^,168 ^,186 ^,201 ^,217 In comparative studies, BNP and its terminal prohormone fragment, N-terminal pro-BNP, were found to be superior to ANP as markers in heart failure and myocardial infarction.²¹⁷

Endothelial Hormones

A crucial vascular structure is the endothelium, because it is strategically located between the circulating blood and the vascular smooth muscle and it is a source of a variety of mediators regulating vascular tone and growth as well as platelet function and coagulation.¹⁸² The endothelium is both a target for and a mediator of cardiovascular disease.

Prostacyclin and prostaglandin E are vasodilating hormones produced from arachidonic acid in many cells (see Septic Shock, Mediators of the Septic Cascade, and Evolve Fig. 6-1 in the Chapter 6 Supplement on the Evolve Website). Angiotensin II, norepinephrine, and renal nerve stimulation increase the synthesis of these vasodilating prostaglandins, which then attenuate the vasoconstrictor effects of these three stimuli.⁵⁸ These vasodilatory prostaglandins may thus counterbalance the neurohormone-induced renal vasoconstriction that occurs in heart failure.

Nitric oxide is an even more potent vasodilator than prostacyclin and prostaglandin E. Endothelial cells contain a constitutive nitric oxide synthase, the activity of which may be blunted in heart failure.¹⁸² ^,210 Thus, the constrictor action of the endogenous vasoconstrictors whose concentrations are elevated in heart failure—including angiotensin II, norepinephrine, and arginine vasopressin—may be enhanced by a concomitant decrease in nitric oxide synthesis in endothelial cells.

The endothelins are peptides of 21 amino acids that are produced in a wide variety of cells. Endothelin-1 is the only member produced in endothelial cells, and it is also produced in vascular smooth muscle cells.¹⁶⁷ Hypoxia, shear stress, and hormones associated with the development of CHF stimulate the production of endothelin-1.¹⁶⁷

Endothelin-1 can stimulate aldosterone secretion and decrease kidney perfusion and function, both of which contribute to the retention of sodium and water and increased intravascular volume. Endothelin-1 also stimulates hypertrophy of the ventricles and increases sympathetic activity and arterial vasoconstriction. Endothelin-1 is one of the most potent vasoconstrictors, and plasma endothelin concentrations are increased in some patients with heart failure.¹⁶⁷ ^,235 High plasma endothelin-1 concentrations are associated with a poor prognosis in patients with heart failure.²³⁵

Locally produced endothelin-1 has been implicated in closure of the ductus arteriosus at birth.¹⁶⁷ Inhibition of the production and action of endothelin-1 by prostacyclin or prostaglandin E may prevent closure of the ductus.

Cytokines

It is becoming increasingly apparent that proinflammatory cytokines play an important role in modulating the structure and function of the diseased heart.⁵⁹ The plasma concentrations of some cytokines, such as tumor necrosis factor alpha (TNF-α), are increased in patients with heart failure.⁵⁹ TNF-α, which is produced under a variety of stresses, exerts negative inotropic effects, and can produce left ventricular remodeling, pulmonary edema, cardiomyopathy, and is a major mediator of apoptosis (cell death).⁵⁹ ^,318 Various cytokines and TNF-α, in particular, represent new targets for therapeutic intervention in patients with heart failure.

Ventricular Dilation and Hypertrophy

The ventricle responds to abnormal loading conditions by chamber dilation and hypertrophy. Ventricular dilation causes an increase in end-diastolic ventricular volume, which results in an increased SV and an improvement in CO. Another compensatory mechanism is hypertrophy of the myocardium.¹⁰⁰ However, both these mechanisms increase oxygen requirements and make the heart more susceptible to ischemia.

Myocardial hypertrophy is an early milestone during the clinical course of heart failure and is an important risk factor for subsequent cardiac morbidity and mortality.¹³⁶ In response to a variety of mechanical, hemodynamic, hormonal, and pathologic stimuli, the heart adapts to increased demands of cardiac work by increasing muscle mass through the initiation of a hypertrophic response. However, initiation of this hypertrophic response can result in heart muscle failure and the loss of myocytes as a result of programmed cell death (apoptosis).⁵⁸ ^,318

Downward Spiral in Cardiogenic Shock

Diminished CO initiates baroreceptor-mediated neurohumoral events, particularly the activation of the sympathetic nervous system, the activation of the renin-angiotensin-aldosterone system, and the nonosmotic release of vasopressin, all of which attempt to maintain arterial perfusion to vital organs. However, over time, these neurohumoral events may have deleterious effects that include pulmonary edema, hyponatremia, increased cardiac afterload and preload, and cardiac remodeling.

As myocardial contractility deteriorates and CO decreases, SVR increases in response to neurohumoral mediators to maintain circulatory stability. However, this increase in afterload adds to the heart’s workload and further decreases pump function. Therefore in cardiogenic shock, a vicious cycle is established: ventricular dysfunction is exacerbated by neurohumoral vasoconstriction, which contributes to further ventricular dysfunction.

Because of the self-perpetuating cycle, compensated phases of cardiogenic shock may not be observed; patients are tachycardic, hypotensive, diaphoretic, oliguric, and acidotic. Extremities are cool and mental status is altered. Hepatomegaly, jugular venous distension, rales, and peripheral edema may be observed. CO is depressed, and central venous pressure, pulmonary wedge pressure, and SVR are all elevated.

Diastolic Heart Failure

Another form of CHF and cardiogenic shock (see Fig. 6-3) is caused by diastolic dysfunction.¹⁶ ^,115 ^,312 Impaired myocardial relaxation changes the pressure-to-volume relationship during diastole and increases ventricular pressure at any volume. This lack of myocardial relaxation is hemodynamically unfavorable because increased left VEDP will be transmitted to the lungs and result in pulmonary edema and dyspnea. Such patients exhibit heart failure, but have normal left ventricular systolic function.¹⁰⁰ Heart failure in the presence of a normal cardiac silhouette on the chest radiograph should suggest the possibility of diastolic dysfunction.

Diastolic heart failure is an insidious disease. Insults to the myocardium are followed by a series of compensatory changes that are beneficial in the short run, but have long-term deleterious effects. Structured remodeling and other factors, including myocardial ischemia, left ventricular hypertrophy, increased HR, and abnormal calcium flux can impair diastolic function and cause an increase in left ventricular filling pressure.¹⁶ ^,115 ^,312

Both ischemia and hypertrophy impair relaxation in early diastole. Ischemia reduces the supply of high-energy phosphates required for rapid removal of calcium from the cytoplasm and hypertrophy slows the rate of actin-myosin dissociation.³¹² Hypertrophy also decreases left ventricular compliance in all phases of diastole.³¹²

When approaching a patient with cardiogenic shock, it is important to characterize both systolic and diastolic function. Therapy designed to improve systolic function may impair myocardial diastolic function.³¹²

Right Ventricular Failure

Right ventricular (RV) failure can be defined as the inability of the right ventricle to provide adequate blood flow through the pulmonary circulation at a normal central venous pressure.¹¹⁴ RV failure may complicate the management of many pediatric critical care unit (PCCU) patients. Respiratory failure causing hypoxic pulmonary vasoconstriction, pulmonary hypertension, and consequent RV dysfunction is often seen in critically ill patients. Sepsis can cause right-sided heart failure directly by inducing RV dysfunction.¹⁶¹ Pulmonary embolism (PE) can result in RV failure. RV failure may be an independent risk factor for morbidity and mortality in patients with left ventricular failure.¹¹⁴ Finally, pulmonary arterial hypertension in children contributes significantly to morbidity and mortality in diverse pediatric cardiac, lung, hematologic, and other diseases.² Without therapy, high pulmonary vascular resistance contributes to progressive RV failure, low CO, and death.² ^,41 Fundamental management strategies for pulmonary hypertension are listed in Box 6-5 (see also Chapter 8).²²⁵ ^,293