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.

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.

Calculation and Estimation of CO

CO can be calculated using a thermodilution catheter placed in the pulmonary artery. Injection of an iced quantity of fluid into the right atrium will produce a temperature change in the pulmonary artery that is inversely related to the CO. Such thermodilution CO calculations can be performed using a pulmonary artery catheter with thermistor or a separate thermistor placed into the pulmonary artery at the time of cardiac surgery. Additional information about thermodilution CO calculation can be found in Chapter 21.

The CO can be continuously evaluated if the pulmonary artery catheter contains an oximeter for continuous evaluation of pulmonary artery (mixed venous) oxyhemoglobin saturation. Pulmonary artery catheterization is not commonly performed in pediatric critical care, although it may be indicated in certain situations that complicate shock resuscitation.²⁷⁶

Pulse contour intermittent and continuous CO (PiCCO^®) monitoring is possible using a femoral or axillary arterial catheter and a central venous catheter. Algorithms use pulse contour analysis combined with intermittent thermodilution calculations. The arterial waveform contours are analyzed to assess SV and thereby cardiac index (CI). In a pediatric validation study, the PiCCO system provided continuous calculation of CI without the need to perform thermodilution injections with every calculation.⁹⁰

Esophageal Doppler studies of blood flow velocity in the descending aorta have been used in adults for many years, and pediatric probes are now available. In the past, the higher HRs in children compromised reliability of this technique of CO evaluation. Fairly reliable CO calculations have recently been reported in children,²⁷⁰ although this method of CO evaluation is very operator dependent.³

CO and blood volume can be calculated from a form of ultrasound dilution. This technology uses a computer and arterial and venous sensors attached to a specialized extracorporeal tubing loop that is placed between an indwelling central venous and arterial catheter. A small bolus (0.5 to 1.0 mL/kg) of isotonic saline is injected into the central venous catheter to create a dilution curve. The saline dilutes the total blood protein concentration and alters blood velocity detected by the arterial sensor in the extracorporeal loop. The change in blood velocity over time can be graphed, and results in a dilution curve that is similar to that created during thermodilution CO calculations. In addition to calculating the CO and index, the ultrasound dilution computer calculates SV index, active circulating volume, SVR, and ejection fraction. This technology has been validated in neonates and children.¹⁵⁷

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.

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).

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