Shock in the pediatric patient. Part I

T H E J O U R N A L OF

P E DI ATRIC S A U GU S T 198 2

V o l u m e I01

Number 2

M E D I C A L PROGRESS

Shock in the pediatric patient. Part I Ronald M. Perkin, M.D., and Daniel L. Levin, M.D.,* Dallas, Texas

TFII S REV1EW encompasses the definition, etiology, pathophysiology, and monitoring of shock. Current recommendations for management of pediatric patients in shock will appear in Part II. ~ A brief review of terminology is presented in the Appendix.z Oxygen capacity is the maximal amount of oxygen that can be taken up by hemoglobin in blood. The oxygen capacity ean be derived by multiplying the hemoglobin concentration by 1.36 which is the amount (in milliliters per gram) of oxygen that can be bound to one gram of hemoglobin. Oxygen content is the amount of oxygen present in any blood sample; it is the total quantity of oxygen both combined with hemoglobin and dissolved in plasma. At 37 oC 0.00003 ml of 02 will be dissolved in 1 ml of plasma when the partial pressure of oxygen is 1 mm Hg. Therefore at 37~ at a partial pressure of 100 mm Hg, 0.00003 ml • 100 = 0.003 ml 02 will be dissolved in each milliliter of plasma: Oxygen saturation is a ratio: oxygen combined with hemoglobin/the amount of oxygen that can be taken up by hemoglobin in a blood sample. The oxygen dissociation curve (Fig. 1) shows the relationship between the Po2 to which a hemoglobin solution or blood is exposed and the degree of saturation of hemoglobin. Abnormal hemoglobins may also affect the oxygen content of blood. Oxygen delivery is the product of oxygen content and cardiac output. From the Children's Medical Center and Department o f Pediatrics, University of Texas Health Science Center. *Reprint address: 1935 Amelia, Dallas, TX 75235. Part H will appear in the September, 1982, issue of THe JOURNAL.

0022-3476/82/080163+07500.70/0 9 1982 The C. V. Mosby Co.

Cardiac output is the product of heart rate and stroke volume. Stroke volume is dependent upon three factors: the preload (myocardial end diastolic fiber length) or filling volume of the ventricle, the contractility of the myocardium, and the afterload (ventrieular wall tension during systole) or resistance to emptying of the ventricle. Cardiac output is measured by the use of indicators in the blood. If Abbreviations used P02: partial pressure of oxygen CO: cardiac output Cao2: oxygencontent of arterial blood Cvo2: oxygencontent of venous blood V02: oxygenconsumption the concentration of the indicator (I) in volume (V) of blood is known before (C~) and after (C~2) the indicator is added, then the volume can be calculated: V C~2- V C~ = I V-

1 C~2- C~1"

If the fluid is constantly flowing, then the volume of flow per unit time (Q) can be calculated

1 Q = ~Cl2_ " Cl The Fiek principle uses the natural marker of oxygen consumption and the oxygen content of arterial versus mixed venous blood, so that cardiac output can be calculated (see Appendix). Cardiac index relates the cardiac output to body surface area. When there are no shunts the output of the right ventricle equals that of the left Vol. 101, No. 2, pp. 163-169

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Perkin and Levin

The Journal of Pediatrics August 1982

100

atrial pressure (Pra), and dividing it by the blood flow through the circuit. This is indexed by dividing by body surface area so that

-,I.,1 80

t Temperature/

_ ,Pacoz /

/

/

Rs =

60-

/ I

~

/ / /

_

/

,' Paeo,

20--

0

-

~11 0

I 20

I

Qs

+ M2.

The principle is the same for the pulmonary circuit:

T 7 /

4o-

P,~ (mean) - Pr~ (mean)

I

I

I

40 60 Pa02 (mm Fig)

I

1 80

I 1O0

Fig. l. Oxygen-hemoglobinsaturation curve. Normal, B. Abnormalities that result in an increased, A, or a decreased, C, affinity of the hemoglobin moleculefor oxygenare shown beside the outer curves. The curve is shifted to the left (greater affinity of hemoglobin for oxygen) by decreases in hydrogen ion concentration, the partial pressure of carbon dioxide in blood, temperature, and 2,3 DPG. The curve is shifted to the right (a lesser affinity of hemoglobin for oxygen) by increases in tile same factors. 2,3-Diphosphoglycerate is an organophosphate in red blood cells which interacts with hemoglobin and shifts the oxygen dissociation curve. A horizontal dash (Ps0) indicates that Po2 at which hemoglobinis 50% saturated. The higher the Ps0value the greater the shift to the right and the less the affinity of hemoglobin for oxygen. (From Levin DL, Morriss FC, and Moore GC: A pediatric guide to pediatric intensive care, St. Louis, 1979, The CV Mosby Co.)

ventricle. Cardiac output can also be determined by adding cardiogreen dye or cold (or room temperature) fluid (saline) to the blood. The latter technique using a SwanGanz thermodilution catheter and a bedside cardiac output computer is the most practical for patients in the intensive care unit. The preload (myocardial end diastolic fiber length) is related to the filling pressures of the left and right ventricles and is therefore related to the pulmonary and systemic venous returns, respectively. In the intensive care setting these are estimated by measuring the left atrial pressure and right atrial pressure, respectively. When direct left atrial pressure measurement is not possible it can be estimated by the pulmonary capillary wedge pressure using the Swan-Ganz catheter. Left and right ventricular afterload are related to the ventricular wall tension during systole and are estimated by calculating the systemic and pulmonary vascular resistances, respectively. Vascular resistance (Rs) is derived by measuring the pressure differences across the circuit, the mean systemic arterial pressure (Psi) minus the mean right

Rp =

Pp~ (mean) - Ppv or la (mean) Qp + M~,

where Ppa is pulmonary arterial pressure, Ppv is mean pulmonary venous pressure, P~ais mean left atrial pressure, and Qp is pulmonary blood flow. It can be converted from resistance units to standard units (dyne sec/cm 5 M 2) a more physiologic measurement by multiplying • 80. Preload is best related to stroke volume by the FrankStarling curve (Fig 2). The two curves depict normal versus decreased contractility. When a volume challenge is given the preload increases (moving from A to B or C to D) and stroke volume increases, w h e n volume is diminished, for example with diuretics, preload decreases (E to D) and stroke volume decreases. When ionotropes are given and contractility improves (D to B) stroke volume increases. When vasodilators are given, and afterload is reduced (D to F) stroke volume increases. Shock is inadequate delivery of oxygen to the tissues and the objective in treating shock is to improve oxygen delivery primarily by increasing stroke volume. This is accomplished by optimizing oxygen content, preload, myocardial contractility, a n d afterload. DEFINITION Shock is an acute, complex pathophysiologic state of circulatory dysfunction which results in a failure of the organism to deliver sufficient amounts of oxygen and other nutrients to satisfy the requirements of the tissue beds) Consequences of severe shock are altered cellular metabolism and energy production which lead to alterations in cellular function and structure: Eventually, cells die, and release proteolytic enzymes and other toxic products which further alter cellular function and structure in adjoining and distant tissue beds: Because of its progressive nature, shock may be divided into three phases: compensated, uncompensated, and irreversible. In compensated shock, vital organ function is maintained by intrinsic compensatory mechanisms: The common demoninator in this early stage is not low blood flow; flow is usually normal or increased unless limited by pre-existing hypovolemia or myocardial dysfunction) More often blood flow is uneven or maldistributed in the microcirculation) Nonspecific measurements such as systemic arterial blood pressure, pulse rate, and cardiac

Volume 101 Number 2

Shock in the pediatric patient. Part I

16 5

Table I. Common causes of hypovolemia in children F

Stroke Volume

B

0 ~

I c

E

Normal Contractility Decreased Contractility Ii

Preload Fig. 2. Frank-Starling curve. See text. output do not differentiate between the normal state and compensated shock states with their important underlying physiologic derangements? As shock progresses to an uncompensated state, efficiency of the cardiovascular system is gradually undermined and microvascular perfusion becomes marginal despite compensatory adjustments. 7 Eventually, circulatory impairment becomes self-sustained and compensatory mechanisms may then contribute to progression and perpetuation of the shock state? Toxic materials are elaborated which interfere with cardiac function and vasomotor adjustment? Arterioles may no longer control flow through the capillary system, allowing vasodilation in some vessels; blood may have difficulty in leaving others, resulting in pooling in the capillary beds. 7 The vascular pooling reduces the circulating blood volume and allows platelet adhesion, coalescence of red blood cells, and, together with the high level of circulating catecholamines, may produce dangerous chain reactions in the coagulation and kinin systems? Cellular function deteriorates and disturbances in function becomes sequentially demonstrable in all organ systems. Terminal or irreversible shock implies damage to key organs such as heart or brain which is of such magnitude that the entire organism will be disrupted regardless of therapeutic intervention?'5 Death occurs even if therapy returns cardiovascular measurements to normal levels. The exact cardiorespiratory pattern manifested during shock depends on the complex interaction of host and illness. The precipitating event initiates a state of cardiovascular dysfunction and these circulatory problems are modified or augmented by complex neuroendocrine activity, products of cellular breakdown, altered metabolism, and individua! host factors such as blood volume status, nutritional state, and myocardial competence? Because of the multiple factors involved, the cardiorespiratory pattern will vary considerably as the shock state evolves. ETIOLOGY

OF SHOCK SYNDROMES

Hypovolemicshock. The most common cause of shock in pediatric patients is acute hypovolemia which follows a

Whole blood loss Hemorrhage External Internal (e.g., gastrointestinal bleeding, hepatic or splenic rupture, fractures, major vessel injury, intracranial bleeding, surgical complications) Relative loss Vasodilating drugs (e.g., phentolamine), anesthestic agents (e.g., morphine) Positive pressure ventilation Sepsis Plasma loss Burns Inflammation/sepsis (capillary leak syndrome) Nephrotic syndrome Intestinal obstruction Hypoproteinemia Fluid and electrolyte loss Vomiting and diarrhea Excessive sweating Pathologic renal loss Altered intrinsic renal function Endocrine causes (e.g., adrenal insufficiency, diabetes insipidus, diabetes mellitus)

reduction in circulating blood volume (Table I). Loss of circulating blood volume is followed by a series of cardiac and peripheral homeostatic adjustments which restore the systemic arterial blood pressure and perfusion pressure in critical organs such as the heart and brain. 9 Whether these adjustments are adequate to maintain cardiovascular homeostasis is determined by the patient's pre-existing status and the amount and rate of blood volume loss. 1~ Cardiogenic shock. Cardiogenic shock is the state in which an abnormality of cardiac function is responsible for the failure of the cardiovascular system to meet metabolic needs. 11 The common denominator is depressed cardiac output and, in most instances, is the result of decreased myocardial contractility. A common cause of cardiogenic shock in children is impaired cardiac performance following intracardiac surgery and is associated with significant mortality and morbidity in the early postoperative period? 2 Other clinically important causes of cardiogenic shock in children are dysrhythmias, drug intoxication, hypoxic/ischemic episodes, acidemia, hypothermia, metabolic derangement (hypoglycemia, myopathies), extrinsic inflow or outflow obstructions (tension pneumothorax-pneumopericardium, pericardial effusion), and severe congestive heart failure secondary to congenital heart disease. TM14Also, myocardial dysfunction is frequently a late manifestation of shock of any etiology?,8 Although the etiology is not completely understood, the following mechanisms have been proposed:

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Perkin and Levin

The Journal of Pediatrics August 1982

I Left Ventricular ~

Dysfunction

,

t \

[

§ Central-m------_..__

Mechanisms

---I 7:::::'1 I

Sodiumand water

blood volume

+ Afterload

§ Contractility -+

t ventricular

9

'

+ Heart rate - -

oxygenconsumption

pressure and volume I -- Hypoxemia,Acidosis ~

~

~ Impaireddiastolic subendocardialperf " I "~

I OXYGENSUPPLY<'OXYGENDEMAND 1

Fig. 3. Self-perpetuating pathways in cardiogenic shock. See text.

specific toxic substances released during the course of shock cause a direct cardiac depressant effect4; cardiac depression is secondary to exhaustion of myocardial contractility as a consequence of nonspecific shock metabolismT; or reduced coronary blood flow results in focal areas of myocardial ischemia and necrosis.4 Distributive shock. Abnormalities in the distribution of blood flow may lead to profound inadequacies in tissue perfusion. 6 This may occur as a result of vasomotor paralysis, increased venous capacitance, or physiologic shunting past capillary beds. Etiologies of distributive shock in children include anaphylaxis, sepsis, central nervous system injury, and drug intoxication (barbiturates, smooth muscle relaxants, antihypertensive medications, and tranquilizers). 6 Septic shock is frequent and is associated with high mortality in children as well as adults. 15Sepsis is a systemic disease caused by microorganisms or their products in the blood. When sepsis leads to circulatory insufficiency and inadequate tissue perfusion, shock is present. The most common offending organisms are gram~negative bacteria; however, septic shock may occur after infection with gram-positive bacteria, fungi, rickettsiae, and viruses. 15,16 Regardless of the offending organism, there are similar cardio-respiratory responses which appear to be host dependenC 6 Sepsis, with consequent shock, often complicates other forms of shock. Moreover, lesions in the heart

or intestines in septic shock may be sufficiently severe to induce fatal cardiogenic or hypovolemic shock even though the infection is controlled. PATHOPHYSIOLOGY

Hypovolemic shock. Cardiac and peripheral compensatory adjustments may suffice to restore cardiac output, systemic arterial blood pressure, and organ perfusion to normal or near normal levels, although they do so at the expense of altered intracardiac and systemic venous blood pressures and changes in blood flow to various regional circulations.4.7 Compensated phases of hypovolemic shock are characterized by decreases in central venous blood pressure, stroke volume, and urine output, with increases in heart rate, systemic vascular resistance, and myocardial contractility2 Systemic arterial blood pressure is frequently normal, the result of increased systemic vascular resistance. Neurologie status is normal or only minimally impaired. The extremities are pale and cool. With continued loss of blood volume or with delayed or inadequate replacement, the intravascular fluid losses surpass the compensatory abilities and decompensated phases appearr The pronounced systemic vasoconstriction and hypovolemia produce ischemic and stagnant hypoxia in the visceral and cutaneous circulations. Altered cellular metabolism and function occur in these areas resulting in

Volume 101 Number 2

Shock in the pediatric patient. Part I

16 7

Table II. Stages of septic shock Early: Hyperdynamic

Beside observations Tachycardia Tachypnea Fever Warm extremities Bounding pulses Normal capillary refill Normal or elevated systemic systolic blood pressure Wide pulse pressure Elevated cardiac index Decreased systemic vascular resistance Adequate urine output or polyuria Mild mental confusion, occasional hallucinations Laboratory measurements Hypoxemia Respiratory alkalosis Metabolic acidosis (not always present in early phase) Marked pulmonary shunt Narrow arterio-venous oxygen saturation difference Hyperglycemia Mild coagulation abnormalities Normal or mild elevation of blood lactate

damage to vessels, kidneys, liver, pancreas, and bowel. 7 The patients are hypotensive, acidotic, lethargic, or comatose, and oliguric or anuric. Stroke volume and cardiac output are further decreased. Terminal phases of shock are characterized by myocardial dysfunction and widespread cell death. 4,7 Cardiogenic shock. As opposed to hypovolemic shock, intrinsic compensatory responses can have deleterious effects in patients with cardiogenic shock?" Compensatory responses are nonspecific, not precisely set, and in patients with cardiogenic shock they may contribute to the progression of shock by further depressing cardiac function and accelerating tissue injury (Fig 3). 17 Compensatory mechanisms for the decreased stroke volume in cardiogenic shock can eventually further depress cardiac function. Increased arteriolar and venous resistance will help maintain an adequate blood pressure in the central circulation and vital organs (heart, brain) but will also increase left ventricular afterload and therefore increase the left ventricular work and oxygen requirements at a time when oxygen supply is diminished. This causes myocardial ischemia which further depresses cardiac function. Another compensatory mechanism for decreased stroke volume is sodium and water retention which will increase central blood volume and thereby increase left ventricular pressure and volume. Unfortunately, this impairs subendocardial blood flow, reduces oxygen supply to the muscle, and causes ischemia, further diminishing ventricular function. The increased left ventricular pres-

Late: Cardiogenic

Tachycardia Respiratory depression Hypothermia Cool, pale extremities Decreased pulses Prolonged capillary refill Hypotension Narrow pulse pressure Depressed cardiac index Increased systemic vascular resistance Oliguria Lethargy or coma Hypoxemia Respiratory acidosis Metabolic acidosis Minimal pulmonary shunt Wide arteriovenous 02 saturation difference Hypoglycemia Marked coagulopathy Markedly elevated blood lactate

sure and volume also cause pulmonary edema, resulting in hypoxia and acidosis, and thereby diminishes cardiac function further. Because of this self-perpetuating cycle, compensated phases of cardiogenic shock are rarely observed and frequently only one cardiorespiratory pattern, in varying degrees of severity, is observed. The patients are tachycardic, hypotensive, oliguric, and acidotic. Extremities are cool and mental status is altered. Cardiac output is depressed and elevations of central venous blood pressure, pulmonary wedge pressure, and systemic vascular resistance are observed. 13 Distributive shock. The precise mechanisms causing circulatory dysfunction in septic shock are not clear. It appears to be the result of many interrelated factors including: (1) derangements of intermediary metabolism18; (2) direct effect of the infecting organism or its byproducts on the cardiovascular system~5; (3) cardiovascular effects of secondary products including the products of activated protein cascade systems (complement, coagulation, kallikrein) and the toxic myocardial factors tS,16; (4) liberation of other vasoactive agents (serotonin, endorphins, prostaglandins, histamine) ~5,~8; (5) failure of oxygen extraction at the cellular level~9; (6) host compensatory mechanisms~8,19 and; (7) underlying host factors such as pre-existing cardiovascular, nutritional, and immunologic status. 5.20 It is impossible to predict the effect, at the microcirculatory level, of these factors, which cause and perpetuate uneven flow and inadequate tissue oxygenation which

16 8

Perkin and Levin

results in progressive decompensation of the capillary circulation and the cells it supports. In spite of these difficulties, definite patterns have emerged, allowing clinical classification and staging. Three stages can be recognized: hyperdynamic-compensated, hyperdynamic-uncompensated, and cardiogenic (Table II). is, 21 The early stages are characterized by vascular tone abnormalities and hyperdynamic compensatory responses. TM The late or cardiogenic stage is manifested by a hypodynamic cardiovascular picture, because cardiac insufficiency is the rule. 2~ In this stage, the classic signs of circulatory collapse are indistinguishable from late shock of any etiology. All aspects of cardiac performance rapidly deteriorate even with aggressive support. Cellular dysfunction, originating in the early hyperdynamic phases, prevent survival despite efforts to return circulatory function to normal. 2~ SEQUELAE OF SHOCK Although circulatory failure is often amenable to intervention by resuscitation and support of the circulation, many patients may die because of multiple organ failure, z2 Thus, circulatory failure is not the limiting factor, but even brief periods of inadequate tissue perfusion may result in damage to several organ systems and failure in one organ system may contribute to the failure of others. 23 Although wide-spread tissue damage depends on the duration and magnitude of circulatory dysfunction, it is also influenced by the initial resuscitative measures. The manifestations of cellular injury in each organ system must be considered when planning resuscitation if wide-spread damage is to be prevented or minimized. Preservation of the central nervous system, myocardium, and renal tissue should be considered in that order as the primary objectives of resuscitation efforts. Multiple organ failure, progressive organ failure, or sequential organ failure are terms used to describe problems which may develop after a period of circulatory dysfunetionY Common sequelae include: acute renal failure, so-called shock lung, hepatic dysfunction, pancreatic ischemia, and gastrointestinal bleeding. Central nervous system injury often becomes the limiting factor that prevents survival. MONITORING Adequate monitoring generates information which serves the following purposes: (1) it allows definition of the exact cardiorespiratory pattern which is helpful in diagnosis, prognosis, and treatment; (2) it permits continuous assessment of vital organ function; (3) it provides a means of assessing the response to therapeutic interventions; and (4) it minimizes the frequency of complications by detect-

The Journal of Pediatrics August 1982

ing correctable problems early, thereby facilitating rapid resolution. Occasionally, in patients with clearly definable courses of shock, which are rapidly corrected and do not recur rapidly (e.g., paroxysmal atrial tachycardia converted by cardioversion; hypovolemia due to diarrhea which responds rapidly to fluid administration) the only requirements for effective patient monitoring include the accurate measurement and recording of vital signs including heart rate, respiratory rate, temperature, and systemic arterial blood pressure (by cuff) together with observation of the patient's color, activity, and peripheral perfusion. More aggressive monitoring .is required for critically ill children with shock and multisystem dysfunction which is more complex, which does not respond rapidly to the initial therapeutic measures (septic shock), or which is likely to put the patient at risk for many hours or days (postoperative patient with tetralogy of Fallot). Many invasive and noninvasive bedside monitoring devices are now available, and are complemented by an ever-widening range of laboratory measurements. 24-26 In addition to obtaining a detailed history and performing thorough and repeated physical examinations, the physician should consider the following. All patients in shock should have continuous electrocardiographic display and heart rate monitoring, skin or core temperature (or both) recorded, continuous intra-arterial systemic blood pressure and pulse wave displays, continuous central venous blood pressure and wave form displayed, fluid intake recorded and urine output measured using a bladder catheter, and an initial chest roentgenogram which is either repeated daily, or when the patient's condition deteriorates, or after procedures such as intubation, placement of central catheters, or chest tubes. Patients who have elevated systemic vascular resistance, pulmonary edema, pulmonary hypertension, eardiogenic shock requiring intravenous ionotropic agents for therapy, or who have undergone cardiac surgery requiring the use of cardiopulmonary bypass should have central venous filling pressures, pulmonary artery pressure, and cardiac output measured using a Swan-Ganz thermodilution catheter. Measurement of these variables will allow the physician to make accurate diagnoses, choose the proper therapeutic agents, and rapidly, repeatedly, and objectively assess the results of therapy. For example, measurement of wedge pressure in a patient with severe pulmonary edema can help differentiate between edema due to shock lung versus that of cardiogenic failure. Calculation of an elevated systemic vascular resistance would suggest the use of an afterload reducing agent in a patient with decreased peripheral perfusion; the measurement of cardiac index

Volume 101 Number 2

S h o c k in the pediatric patient. Part 1

would aid in assessing the response to such a n agent. Patients in septic shock often do not respond to a specific ionotropic a g e n t and m a y need different agents or a c o m b i n a t i o n of ionotropic and vasoactive agents in order to achieve a n a d e q u a t e cardiac index a n d vascular resistances. Objective m a n i p u l a t i o n of these agents is impossible without m e a s u r e m e n t of preload, arterial blood pressure, and cardiac index along with calculation of pulmonary and systemic vascular resistances.

8. 9. 10.

APPENDIX Cardiovascular terminology. Oxygen capacity (ml O J d l ) = Hgb (gm/dl) • 1.36 (ml OJgm). Oxygen content (ml Oz/dl) = Oxygen capacity (ml O J d l ) + dissolved 02 (ml O2/dl). Oxygen content (ml O J d l ) Oxygen dissolved O~ (ml O J d l ) saturation (%) = Oxygen capacity (ml O2/dl) Oxygen delivery = Oxygen content (ml O J d l ) x cardiac output (L/min). Cardiac output (ml/min) = Heart rate (beat/min) • stroke volume (ml/beat). Stroke volume (ml/beat) is dependent on preload, contractility, and afterload. Cardiac output (L/rain) 902 (ml/min) (Fick determination) = Cao2 (ml/L) - CVo2 (ml/L) ' Cardiac index ( L / m i n / M ~) =

7.

11.

12.

i3.

14. 15. 16.

17.

CO (L/min)

Body surface area (M s) Preload = Myocardial end diastolic fiber length. Afterload = Tension of ventricular wall during systole.

18.

19. REFERENCES I. Perkin RM, and Levin DL: Shock in the pediatric patient. Part If, J PEOIATR (in press) 2. Rudolph AM: Cardiac catheterization and angiography, in Congenital diseases of the heart, Chicago, 1974, Year Book Medical Publishers, Inc., pp 49-162. 3. Glenn T: Cellular response to shock, in Skjoldborg H, editor: Scanticon shock seminar, Amsterdam, 1978, Excerpta Medica, pp 95-126. 4. Lefer AM, and Spath JA: Pharmacologic basis of the treatment of circulatory shock, in Antonaccio M, editor: Cardiovascular pharmacology, New York, 1977, Raven Press, pp 377-428. 5. Shoemaker WC: Cardiorespiratory patterns in various types of shock and their therapeutic implications, in Skjoldborg H, editor: Scanticon shock seminar, Amsterdam, 1978, Exeerpta Medica, pp 127-144. 6. Weil MH, Shubin H, and Carlson RW: Sympathomimetic

20.

21. 22. 23. 24.

25. 26.

16 9

and related vasoactive agents for treatment of circulatory shock, in Weil MH, and Shubin H, editors: Critical care medicine---current principles and practices, New York, p 76, Harper & Row, Publishers, pp 99-108. Zeifach BW, and Bronek A: The interplay of central and peripheral factors in irreversible hemorrhagic shock, Prog Cardiovasc Dis 18:147, 1975. Tarazi RC: Sympathomimetic agents in the treatment of shock, Ann Intern Med 81:364, 1974. Lucas CE: Resuscitation of the injured patient: The three phases of treatment, Surg Clin North Am 57:3, 1977. Hauser C J, and Shoemaker WC: Volume therapy~iagnosis of hypovolemia, Hosp Phys 16:38, 1980. Lucehesi BR: Inotropic agents and drugs used to support the failing heart, in Antonaccio M editor: Cardiovascular pharmacology, New York, 1977, Raven Press, pp 337-376. Kouchoukos NT, and Kurp RB: Management of the postoperative cardiovascular surgical patient, Am Heart J 92:513, 1976. Lappas DB, PowelI WMJ, and Daggett WM: Cardiac dysfunction in the perioperative period: pathophysiology, diagnosis, and treatment, Anesthesiology 47:117, 1977. Mason DT: Afterload reduction and cardiac performance, Am J Med 65:106, 1978. Hierro FR, Palomeque A, Calvo M, and Torralba A: Septic shock in pediatrics, Paediatrician 8:93, t979. Wiles JB, Cerra FB, Siegel JH, and Border JR: The systemic septic response: does the organism matter? Crit Care Med 8:55, 1980. Mason DT, Awan NA, Joye JA, Lee G, Demaria AN, and Amsterdam EA: Treatment of acute and chronic congestive heart failure by vasodilator-afterload reduction, Arch Intern Med 140:1577, 1980. Siegel JH, Cei-ra FB, Coleman B, Giovannini 1, Shetye M, Border JR, and McMenamy RH: Physiological and metabolic correlations in human sepsis, Surgery 86:163, 1979. Duff JF: Cardiovascular and metabolic changes in shock and sepsis, Eur Surg Res 9:155, 1977. MacLean LD, Mulligan WG, McLean APH, and Duff JH: Patterns of septic shock in a m a n - - a detailed study of 56 patients, Ann Surg 166:543, 1967. Weft MH, and Nishijima H: Cardiac output in bacterial shock, Am J Med 64:920, 1978. Fry DE, Pearlstein L, Fulton RL, and Polk HC: Multiple system organ failure, Arch Surg 115:136, 1980. Bave AE: Multiple, progressive, or sequential systemic failUre, Arch Surg 110:779, 1975. Edmonds JF, Barker GA, and Conn AW: Current concepts in cardiovascular monitoring in children, Crit Care Med 8:548, 1980. Bachbinder N, and Ganz W: Hemodynamic monitoring: invasive techniques, Anesthesiology 45:146, 1976. Wetzel RC, and Rodgers MC: Pediatric hemodynamic monitoring in critical care the state of the art, in Shoemaker and Thompson, editors: Fullerton, Calif., 1981, The Society of Critical Care Medicine, pp lI(L):I-II(L):78.