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.