The cardiovascular system is responsible for the delivery of oxygen and nutrients to the tissues and the removal of the end'products of catabolism. Disturbances in cardiovascular function can result from several different factors that derange the determinants of cardiovascular function including the filling volumes of the heart (prelaod), myocardial contractility, or vascular tone. Alterations of these parameters can significantly impair tissue perfusion, oxygen delivery, and the removal of catabolic products. Early and aggressive intervention with correction of these problems is required to restore perfusion before irreparable damage to end organs occurs. This article discusses basic cardiovascular physiology, the hemodynamic derangements that occur with the various types of shock, and the treatment of shock states including fluid resuscitation and the use of inotropic agents.
CARDIOVASCULAR PHYSIOLOGY: THE BASICS
One problem in treating abnormalities of cardiovascular function is the lack of a simple and quick clinical tool to measure cardiac output. Even in the intensive care unit, such measurements require placement of invasive vascular monitors or use of sophisticated equipment. The regulation of cardiovascular function is dependent on both cardiac output and vascular tone. This relationship implies that blood pressure is a poor reflection of cardiac output. Cardiac output can be four to five times normal and yet the patient is hypotensive or the cardiac output can be one fourth to one fifth normal and the blood pressure is normal. The regulation of vascular tone, either endogenously by the renin-angiotensin system or exogenously by vasoactive medications, controls blood pressure independent of cardiac output.1 Therefore, the clinician must use other signs to assess cardiac output. These may include peripheral perfusion and temperature, capillary refill, urine output, mentation, and acid-base status. The latter may be a particularly valuable in assessing the adequacy of resuscitation and treatment of shock. With inadequate tissue perfusion, anaerobic metabolism occurs with the accumulation of lactic acid leading to a base deficit. While many laboratories cannot quickly perform lactate assays, the base deficit on a routine arterial or venous blood gas analysis can be used to asses the adequacy of the ongoing resuscitation and the need for further base administration or volume resuscitation.
Two additional relationships are crucial in understanding the physiologic control of the cardiovascular and its subsequent pharmacologic manipulation. The first is: cardiac output=heart rateXstroke volume. The volume of blood leaving the heart every minute (cardiac output) is equal to the heart rate times the amount ejected with each beat (stroke volume). In the majority of patients, the primary determinant of cardiac output is stroke volume. If the heart rate drops, the stroke volume increases to maintain cardiac output. However, certain groups of patients may be unable to alter stroke volume and therefore their cardiac output is dependent on heart rate. If the ventricular muscle is noncompliant, the stroke volume cannot change and cardiac output falls when heart rate falls. Various disorders of the myocardium may lead to a noncompliant state. Examples include patients who have had multiple myocardial infarctions, patients with chronic cardiomyopathies, and neonates. The latter is especially important to remember because neonates do not tolerate bradycardia well since it results in a precipitous fall in cardiac output.
The second relationship to remember is there are three variables that control stroke volume: preload, after load, and myocardial contractility. The preload is the volume of blood in the left ventricle at the end of diastole (just prior to contraction) or left-ventricular end diastole volume (LVEDV). Preload is generally a reflection of the volume status of the patient. In the clinical arena, LVEDV is not measured, but rather inferred from measurements of filling pressures such as central venous pressure or pulmonary capillary wedge pressure.2
The LVEDV determines cardiac output according to the relationship originally described by Starling. Starling demonstrated that increasing the resting muscle strip length prior to excitation increases the tension that develops. This relationship holds true until the muscle fiber is overstretched, at which point, the tension or force of contraction decreases. In the clinical arena, increasing the precontraction muscle fiber length by increasing LVEDV through volume administration increases the force of contraction (cardiac output).
The second variable that regulates cardiac output is after load. Afterload can be thought of as the impedance or resistance to ventricular ejection. It is primarily determined by two variables: vascular tone and intrathoracic pressure changes. If contractility and preload are kept constant, cardiac output will decrease as the afterload increases. Increasing afterload can be thought of as an increased resistance or force inhibiting flow of blood out of the heart. In the normal state, the vascular resistance is the primary determinant of afterload; however, with patients in acute respiratory distress, large increases in the negative interpleural pressure can occur. The marked increases in interpleural pressures increase afterload and can affect cardiac output adversely, especially in patients with decreased preload or compromised myocardial contractility. This relationship is one of the reasons for early airway control and mechanical ventilation in patients with shock.
Cardiac output is determined by heart rate and stroke volume. Stroke volume, in turn, is controlled by preload, afterload, and myocardial contractility. The latter relationship is particularly important in the treatment of shock states and the use of fluid/inotropic agents. Identification of the cause of shock and the physiologic alterations related to it will help guide subsequent therapy and hopefully improve the eventual outcome.
CLASSIFICATION OF SHOCK STATES
Shock is an acute disruption of circulatory function leading to the inadequate delivery of nutrients to the tissue. Shock is not diagnosed based on blood pressure. As stated previously, the body's response to a drop in cardiac output is to activate the reninangiotensin and sympathetic nervous systems to increase vascular tone (systemic vascular resistance) to maintain blood pressure even as the cardiac output falls. Therefore, a patient in shock can have a low, normal, or even high blood pressure.
Shock is the end result of several different physiologic disturbances. The various etiologic factors responsible for the disruption of circulatory function leading to shock can have markedly different effects on the three determinants of cardiac output (preload, afterload, and myocardial contractility). Shock can be further classified according to its cardiovascular features as: cardiogenic, septic, hypovolemic, or distribufive. The classification is useful in that it may give some information on the physiologic alterations involved including the changes in preload, afterload, and contractility (Table 1). These cardiovascular changes should be kept in mind as one institutes therapy. The underlying etiology, when known, can be used to guide the appropriate therapy (fluid versus inotropic agent as well as which inotropic agent). Distributive shock describes a constellation of physiologic findings that occur with a long list of disorders (Table 2). The underlying cardiovascular alteration is a marked decrease in systemic vascular resistance resulting in hypotension and inadequate perfusion pressure. The drop in vascular tone also can affect the venous side leading to a decrease in venous return/preload. From looking at Table 1, it is apparent that the cardiovascular changes seen with early septic shock are the same as those of distributive shock, and in fact, early septic shock is the most common cause of distributive shock in children.
Cardiovascular Changes In Shock
Etiologies of Distributive Shock
The physiologic changes of septic shock are dependent on the stage of the disease. Early on, there is a marked vasodilatation with a drop in systemic vascular resistance and a drop in venous tone with a resultant decrease in preload. These changes result in hypotension with tachycardia, increased cardiac contractility, and increased cardiac output. Clinically, the patient is frequently febrile with a bounding and rapid pulse. Peripherally, the patient is warm and vasodilated. This can progress rapidly to late septic shock with myocardial failure. The hemodynamic changes of late septic shock are the same as those of cardiogenic shock. Late septic shock is one form of cardiogenic shock.
Cardiogenic shock is defined broadly as acute circulatory failure caused by inadequate myocardial function. In the pediatric age range, this occurs most commonly following cardiopulmonary bypass and surgery for congenital heart lesions. However, the etiologic classification is markedly different in the child who presents to the emergency department (Table 3). The most likely diagnoses include congestive heart failure from either a congenital cardiac lesion or idiopathic myocarditis.
Aside from the previously mentioned classification of shock, three additional enologie possibilities must be kept in mind when facing the neonate or young infant with shock. These include congenital adrenal hyperplasia, inherited metabolic disorders with hyperammonemia, and obstructive left-sided cardiac lesions. Infants with congenital adrenal hyperplasia may present in the neonatal period with profound alterations of cardiovascular function, shock, metabolic acidosis, and hyperkalemia. While some children in shock will have hyperkalemia related to ongoing acidosis and alterations in renal blood flow, die diagnosis of congenital adrenal hyperplasia should be considered in the seriously ill child with metabolic acidosis and hyperkalemia. If the appropriate assay to diagnosis congenital adrenal hyperplasia is not readily available, blood can be stored for later investigations and a corticosteroid administered (2 mg/kg methylprednisolone or 10 mg/kg hydrocortisone). While mild elevations of serum ammonia are sometimes seen with shock and acidosis, patients with inborn errors of metabolism (ie, uTea cycle defects, and organic acidemias) generally will have elevations of serum ammonia levels in excess of 1000.
The last of the triad of diseases that must be ruled out when faced with the neonate in shock is an obstructive left-sided cardiac lesion. A group of cardiac lesions including aortic stenosis, hypoplastic left heart syndrome, coarctation of the aorta, and interrupted aortic arch can present as shock in the neonatal period. Infants with these lesions are dependent on the ductus arteriosus for perfusion of all or part of the systemic circulation. Since blood cannot be ejected from the left side of the heart (aortic stenosis and hypoplastic left heart syndrome) or cannot reach the lower half of the body (coarctation of the aorta and interrupted aortic arch), blood flows from the pulmonary artery across the ductus arteriosus into the systemic circulation. Although this is deoxygenated blood, the oxygen content is sufficient to meet the metabolic needs of the tissues. As the duct closes, the flow ceases, and circulatory failure and tissue hypoxia occur. Treatment of these three conditions includes the basics of resuscitation, but also must include specific treatment of the underlying condition and the administration of prostaglandin E to maintain ductal patency. Without such treatment, the other resuscitative efforts will fail.
TREATMENT OF SHOCK
The approach to and treatment of shock in infants and children will vary somewhat based on the etiologic classification. However, regardless of the cause, the primary resuscitative efforts must include the basic ABC's (airway, breathing, and circulation). During the initial assessment, supplemental oxygen should be administered via a high flow, non-rebreathing system. Even if the patient is well saturated, supplemental oxygen should be administered until the initial assessment is completed. The initial physical examination should focus on the pertinent findings, which can be used to assess cardiovascular function, and attempt to determine the etiology oi the cardiovascular disturbance. These should include an initial set of vital signs, auscultation of the cardiorespiratory system, examination of peripheral perfusion/pulses/capillary refill, and an assessment of liver size. The physical examination combined with the history may give clues to the underlying etiology, which can be used to direct further therapy.
The importance of early airway management cannot be overemphasized. Early endotracheal intubation and control of ventilation may be indicated even in patients with a normal PaC02 and acceptable oxygen saturations. If there is any indication of impending respiratory failure or airway compromise, endotracheal intubation and controlled ventilation is suggested. Airway control should be based on the clinical state of the patient and not the numbers on the arterial blood gases. Early endotracheal intubation allows for control of ventilation with mild hyperventilation to partially compensate for metabolic acidosis. A decrease of PaCC>2 of 10 torr results in an increase in pH of 0.08 units. The administration of 100% oxygen improves oxygenation and maximizes the oxygen content of blood and oxygen delivery. In patients with severe respiratory distress, the increases in negative intrathoracic pressure that occur with breathing may significantly increase afterload and further compromise cardiovascular function. This effect is eliminated with controlled ventilation. Most important while the patient may look stable, patients with shock have decreased oxygen delivery to all muscles including the diaphragm, which can result in progressive respiratory fatigue and failure.3 It makes more sense to eleetively rather than emergently control the airway. The techniques for airway management are discussed elsewhere in this issue.
Etiologies of Cardiogenic Shock
Following the assessment and management of "airway and breathing," one's attention should next be focused on "circulation." The resuscitation of the cardiovascular system depends on the underlying etiology of shock. Treatment is based on the presumed alterations of preload, afterload, and myocardial contractility.
Before appropriate fluid resuscitation can be accomplished, vascular access must be established. The simplest, safest, and often the most rapid means of obtaining venous access is by percutaneous peripheral vein cannulation. Because of the smaller size of veins in children and the fact that veins usually collapse when a child is in shock, percutaneous peripheral cannulation may be difficult and time-consuming. If peripheral venous cannulation cannot be accomplished within 60 to 90 seconds, initial access to the circulation can be obtained rapidly by placement of an intraosseous cannula. The preferred site is the medial aspect of the tibia, 2 to 4 cm below the anterior tibial tuberosity. While several intraosseous needles are available commercially, a 16-or 18-ga spinal needle also can be used. Fluid and medications can be administered through the intraosseous needle. The intraosseous route provides rapid and direct access to the central circulation. Once appropriate fluid resuscitation has been carried out, cannulation of a peripheral vein is often possible.
Composition of Crystalloid Solutions*
One area of active debate in shock resuscitation is the type of fluid that should be used: crystalloid or colloid?4'5 Only 25% of the volume of crystalloid that is administered will remain in the intravascular compartment. The remainder will fill the interstitial and extracellular fluid compartments. The tendency for crystalloids to leave the vascular compartment along with the dilution of plasma proteins theoretically may predispose patients to the development of pathologic extravascular fluid such as pulmonary edema. While this makes sense theoretically based on the Starling forces that control fluid movements across the vascular compartment, clinical studies do not provide any evidence for the superiority of colloid over crystalloid for volume expansion in shock resuscitation. Additionally, there is a marked cost reduction when using crystalloids compared to colloids. The cost of 1 L of 5% albumin is as much as 50 times that of a vasoactively equivalent amount (4 L) of Ringer's lactate.
The commercially available colloid solutions include 5% albumin, 6% hydroxyethyl starch, and low molecular weight dextran (dextran 40). Adverse effects including platelet dysfunction, interference with crossmatching of blood, and renal failure limit the use of dextran 40. Albumin is a naturally occurring plasma protein that provides approximately 80% of the intravascular colloid oncotic pressure in normal subjects.6 The albumin molecule has a molecular weight of 69,000 and is relatively impermeable to the vascular membrane under normal conditions. The vascular membrane may be disrupted following sepsis and shock, thereby allowing albumin to pass into the interstitial spaces. The intravascular half-life of albumin is 24 hours, with hemodynamic improvement persisting for up to 36 hours after administration.7 As albumin is heat treated, there are no infectious disease risks with its use. Another protein product derived from blood (plasma protein fraction or Plasmanate) is not recommended for resuscitation in shock as it can occasionally cause hypotension due to the presence of activated mediators of the kininogen pathway that are present in the solution.
Hydroxyethyl starch is a synthetic colloid that consists of a hydroxyethyl-substituted, branchedchain amylopectin with a molecular weight similar to that of albumin. Although its elimination half-time is 17 days, its clinical effects generally persist for only 24 to 36 hours.8 Adverse effects include inhibition of platelet aggregation following the administration of more than 15 to 20 mL/kg.
There is also controversy as to which particular crystalloid is most appropriate for volume expansion (Table 4). Without a doubt, an isotonic fluid should be used: normal saline, Ringer's lactate, or Plasmalyte (Baxter, Deerfield, Illinois). Ringer's lactate has a chloride concentration (109 mEq/L) that is roughly equivalent to the plasma chloride while the lactate provides a source of buffer. The lactate of Ringer's lactate is converted by the liver (Cori cycle) into bicarbonate. One problem with Ringer's lactate is that the sodium concentration of 130 mEq/L is somewhat hypotonic compared with normal plasma.
In contrast, the infusion of large amounts of isotonic saline can result in a metabolic, hyperchloremia acidosis. While the sodium concentration of 154 mEq/L is isotonic with normal serum, the high chloride concentration of 154 mEq/L can lead to the development of hyperchloremic acidosis. A third alternative is Plasmalyte with a more physiologic concentration of sodium and chloride (Table 4). Its buffers include both gluconate and acetate.
Aside from the isotonic crystalloids, recent attention has shifted to the possible beneficial effects of hypertonic crystalloids with or without the addition of colloid. These agents were used in clinical practice as early as World War I. The principle behind their use is to restore effective circulating blood volume with a lower volume of fluid (4 to 5 mL/kg). This can be accomplished because the hypertonic saline increases serum osmolarity and promotes the movement of endogenous fluid from the extravascular space into the intravascular space. Additional effects demonstrated in laboratory animals include an increase in inotropic function of the heart, constriction of capacitance vessels, decrease in resistance vessels, and dilatation of precapillary sphincters.9'11 The initial clinical studies in humans have shown similar beneficial effects. Holcroft et al12 and Vassar et al13 have demonstrated successful resuscitation of trauma patients with hypertonic saline (250 mL of 7.5% sodiurn chloride) without adverse effects except for transient hypokalemia. These agents may have particular benefit for patients with associated closed head injuries or at risk for cerebral edema. The initial clinical studies in adult trauma victims have demonstrated improved survival following resuscitation with hypertonic saline compared with Ringer's lactate.14,15
Although the ideal resuscitation fluid has not yet been clearly identified, the initial studies in adults support the superiority of hypertonic saline solutions (ie, 7.5% NaCl). These solutions restore intravascular volume with rapid mobilization of endogenous fluid, reduce vascular resistance, and improve myocardial contractility. These agents may be particularly beneficial in the patient with associated closed head injury. As with other crystalloid solutions, hypertonic solutions are inexpensive and have a long shelf life. Studies are needed in the pediatric population to identify if similar beneficial effects will be seen in pediatric resuscitation.
For now, clinical studies do not support any advantage of colloids over crytalloids. Blood and blood products are administered only when replacement of hemoglobin or coagulation products is necessary. Appropriate fluids include normal saline, Ringer's lactate, and Plasmalyte. Dextrose-containing fluids should not be used for volume expansion. Based on its physiologic concentrations, the author prefers the Plasmalyte.
The second question concerning fluid resuscitation of shock is: How much fluid should be administered? This will depend on the type of shock. For cardiogenic shock, fluids may initially improve cardiac output and peripheral perfusion; however, the delayed effects may be deleterious with the accumulation of extravascular fluid and pulmonary edema. In the setting of cardiogenic shock, inotropic agents generally are required to improve the underlying problem: defective myocardial contractility and increased systemic vascular resistance.
In hypovolemic shock, the treatment is singular and straightforward: fluid. In this setting, fluid should be administered to restore cardiovascular function, peripheral perfusion, and urine output, and to correct metabolic abnormalities including lactic acidosis. Inotropic agents and vasoactive drugs should not be used to maintain blood pressure instead of appropriate fluid administration. In septic shock and distributive shock, the decrease in intravascular volume (preload) may be a direct problem related to fluid loss, but also may be an indirect effect due to venodilatation. Correcting these problems may require not only fluid, but also use of an inotropic agent with vasoconstricting properties to increase the vascular tone.
In sepsis, decreased intravascular volume may result from increased insensible losses (fever and tachypnea), decreased intake, and increased losses (vomiting and gastrointestinal losses). The increased loss may be compounded further by a breakdown in the normal integrity of the vascular wall, with the transudation of fluid from the intravascular to extravascular spaces further decreasing the functional intravascular volume. The initial fluid requirements in these patients may be quite large including up to 80 to 120 mL/kg during the initial resuscitative phase.
Cardilo et al16 examined the fluid requirements and eventual outcome including the subsequent development of adult respiratory distress syndrome in children. The patients were divided into three groups based on the amount of fluid administered during the initial 60 minutes of therapy: group 1 - 20 mL/kg, group 2 - 20 to 40 mL/kg, and group 3 - ≤40 mL/kg of fluid. Patients in group 3 received 69 ± 19 mL/kg of fluid at 1 hour and 117 ±29 mL/kg of fluid at 6 hours. They reported improved survival, decreased occurrence of persistent hypovolemia, and no increased incidence of cardiogenic or noncardiogenic pulmonary edema in group 3. The study demonstrates the large fluid requirements that may be present in patients with septic shock and the need to aggressively replete the intravascular volume to improve eventual outcome. The rapid repletion of the intravascular space does not increase the incidence of adult respiratory distress syndrome while the delayed or slow administration of fluid increases eventual mortality. While the use of inotropic agents is not suggested as a replacement for fluid therapy, agents that increase vascular tone are sometimes needed while restoration of the intravascular volume is provided.
Fluids and inotropic agents generally are used in the treatment of distributive shock. While the primary problem is a decrease in systemic vascular resistance, alterations in the integrity of the vascular endothelium can lead to a transudation of fluid from the intravascular to the extravascular space with a decrease in the effective intravascular volume. The decrease in intravascular volume is compounded further by the increase in the vascular space due to vasodilatation. The combination of these problems generally requires fluid plus an adrenergic agent with vasoconstrictor properties.
Regardless of the fluid chosen, an initial 20 to 30 mL/kg of an isotonic crystalloid solution is given as quickly as possible. Additional crystalloid is infused and titrated against urine output, skin perfusion, heart rate, and blood pressure.
Correction of Metabolic Abnormalities
Aside from fluid therapy, correction of the metabolic abnormalities may improve cardiac output and correct shock. With tissue hypoperfusion, metabolic acidosis frequently develops. This can be partially compensated for by endotracheal intubation and controlled ventilation. While fluid administration and cardiovascular resuscitation is mandatory to eliminate the ongoing anaerobic processes that lead to lactate production, buffer administration frequently is required to rapidly correct the problem. Persistent acidosis (pH <7.2) not only profoundly depresses myocardial contractility, but also impairs the effectiveness of exogenous catecholamines. The adverse effects of sodium bicarbonate must be weighed against the beneficial effects of restoring pH (Table 5). Bicarbonate administration, if decided on, should be administered slowly in a dose of 1 to 2 mEq/kg in a concentration of 0.5 to 1.0 mEq/L. An additional method of estimating the amount of sodium bicarbonate that should be administered (a half correction of pH) uses the formula: mEq sodium bicarbonate= 0.3 X weight (kg)Xbase deficit.
Adverse Effects of Sodium Bicarbonate
The rapid administration of sodium bicarbonate may abruptly increase pH and lower ionized calcium levels due to alterations in protein binding. Because many patients in shock may have low ionized calcium levels, measurement and correction of this cation may be indicated.17 Hypocalcemia impairs cardiac contractility and limits the pressor effect of catecholamines. Because the free or ionized fraction is the physiologic active moiety, measurement of ionized calcium is suggested. Hypocalcemia is treated by the administration of either calcium chloride or calcium gluconate. Calcium chloride is administered in a dose of 0.1 to 0.2 mL/kg of a 10% solution. Calcium chloride spontaneously dissociates in the serum to release the free calcium ion. Calcium gluconate is administered in a dose of 0.2 to 0.4 mL/kg of a 10% solution. The larger dose is required because on a milliliter per milliliter basis the gluconate solution contains less calcium since the gluconate molecule has a greater molecular weight. Calcium gluconate is degraded in the liver to release the calcium ion. When given in equivalent amounts based on the calcium ion, both agents result in an equivalent rise in the serum ionized calcium level. If these agents are administered via a peripheral infusion, the calcium gluconate solution is suggested since it may cause less tissue irritation should extravascular extravasation occur. Calcium solutions should be administered over 10 to 15 minutes to prevent bradycardia.
During the initial evaluation, a quick check of serum glucose is suggested with a rapid bedside analyzer. The value can be confirmed by formal laboratory evaluation of serum glucose. Children, especially toddlers and infants, have limited glycogen stores and rapidly develop hypoglycemia during periods of stress. Severe hypoglycemia with subsequent central nervous systme damage may occur if hypoglycemia is not identified and treated promptly. There is also some evidence to suggest that severe hypoglycemia may impair cardiovascular function. Serum glucose levels <60% should be treated promptly with 1 mL/kg of 25% glucose or 2 mL/kg of 10% glucose.
Additional initial laboratory evaluation should include serum electrolytes, especially looking for hyperkalemia, blood urea nitrogen and creatinine to evaluate renal function. While blood urea nitrogen generally rises out of proportion to creatinine with hypovolemia, significant elevations in creatinine may occur with isolated hypovolemia without underlying renal disease. Hemoglobin, hematocrit, and a platelet count also should be checked. Shock, regardless of the etiology, can lead to disseminated intravascular coagulation and thrombocytopenia. Repeat determinations of hemoglobin and hematocrit may be indicated as significant drops may occur after volume resuscitation.
Endogenous and exogenous adrenergic agents exert their effects by binding to specific cell membrane bound receptors. Several different subclasses of adrenergic receptors exist including alpha, betaj, and beta2- Binding of the catecholamine to the beta receptor activates a stimulatory G protein, which subsequently activates the enzyme adenylate cyclase. This leads to the conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP). Cyclic adenosine monophosphate is degraded by the enzyme phosphodiesterase. The increase of intracellular cAMP levels leads to the phosphorylation of intracellular enzymes that govern excitationcontraction coupling and intracellular calcium levels. Activation of the alpha-adrenergic receptor and its associated G protein activates the enzyme phospholipase C with the hydrolysis of membrane bound phospholipids with the release of inositol triphosphate and diacylglycerol. Inositol triphosphate stimulates the release of calcium from the sarcoplasmic reticulum. The increase in intracellular calcium increases excitation-contraction coupling with an increase in tone of the vascular smooth muscle (vasoconstriction) or an increase in contractility of myocardial cells (inotropy). The actual cardiovascular effects vary from inotrope to inotrope based on the dose used and their interaction with the various adrenergic receptors.
Dopamine is an intermediate product in the catecholamine pathway that leads to the production of epinephrine and norepinephrine. Its cardiovascular effects are dose dependent. In doses of 1 to 4 pg/kg/minute, renal dopaminergic receptors are activated with an increase in glomerular filtration rate, renal vasodilatation, and increased sodium excretion by the renal tubules. This effects leads to an increase in urine output. Doses ranging from 4 to 8 pg/kg/minute lead to predominantly betaj activation with increased inotropic function of the myocardium. Doses in excess of 8 to 10 pg/kg/minute activate alpha ? receptors with vasoconstriction. As it increases both inotropy and vascular tone, dopamine may be indicated in shock states with depressed inotropic function associated with decreased vascular tone such as early septic shock or distributive shock. Due to its beta ? effects, increased chronotropic function may occur, leading to tachycardia and increased arrhythmogenicity, which may limit its use in older patients. These latter effects are dose dependent and more common with doses > 8 to 10 pg/kg/minute.
Dobutamine is a synthetic catecholamine that exists as an enantiomeric mixture of the two optically active isomers. The - isomer is a potent alpha agonist resulting in vasoconstriction while the + isomer is a beta agonist resulting in increased inotropic effects as well as peripheral beta agonism with vasodilatation that antagonizes the alpha effects of the - isomer. Consequently, dobutamine results in an increase in inotropic function with a decrease in systemic vascular resistance, making it an appropriate agent for shock states that result in decreased inotropy and increased SVR (cardiogenic shock and late septic shock). Moderate tachycardia also may be seen with dobutamine although the increase in heart rate and the arrythmogenic potential are less than with dopamine. Doses range from 5 to 20 pg/kg/min.
Amrinone is a nonadrenergic agent that results in increased inotropy and peripheral vasodilatation. Amrinone inhibits phosphodiesterase III, the enzyme responsible for the degradation of cAMP. The resultant increase in intracellular cAMP leads to an increase in the intracellular calcium concentration and increased force of contraction. As amrinone has a significantly longer half-life than catecholamine agents such as dopamine, a loading dose is recommended prior to starting a continuous infusion. The recommended loading dose for adults is 0.75 mg/kg over 3 to 5 minute: However, the limited studies in pediatric patients have suggested that higher loading doses (2 to 4 mg/kg) are needed.18 While its cardiovascular actions are similar to those of dobutamine, amrinone tends to have a greater effect on the pulmonary vasculature and may be particularly beneficial in patients with increased pulmonary vascular resistance.
Other adrenergic agents used for the treatment of shock states include epinephrine, phenylephrine, and norepinephrine. Epinephrine's cardiovascular effects are dependent on the dose used. Lower infusion rates of 0.05 to 0.2 pg/kg/minute result in stimulation of primarily beta ? and beta? receptors with increased inotropy, chronotropy, and peripheral vasodilatation. Infusion rates >0.2 pg/kg/minute lead to increased peripheral resistance through alpha-adrenergic stimulation. Epinephrine's effects are also age dependent so that tachycardia is more common in older patients. Infusion rates of 0.01 to 0.05 pg/kg/minute may be effective in older patients. Norepinephrine stimulates only alpha and betaj receptors, leading to increased contractility and increased SVR. The increase in SVR limits the tachycardia that occurs via beta stimulation. Infusion rates vary from 0.05 to 0 pg/kg/minute. Phenylephrine is a pure alpha agonist that results in vasoconstriction. A significant problem with any agent that primarily results in increased SVR is that perfusion can be sacrificed at the expense of maintaining blood pressure. As mentioned previously, an adequate blood pressure does not ensure an adequate cardiac output. Monitoring of peripheral perfusion is mandatory when these agents are used. They should not be used at doses that result in peripheral vasoconstriction leading to cold extremities and decreased urine output.
Isoproterenol has limited utility in the treatment of shock states. It is a pure beta agonist with effects at both the betaj and beta2 receptors leading to increased heart rate, increased contractility, and peripheral vasodilatation. Its major role is for the treatment of refractory bradycardia that is unresponsive to anticholinergic agents such as atropine. Due to its beta2 effects with resultant bronchodilatation, it is also used for refractory status asthmaticus.
When selecting an inotropic agent for the treatment of shock, two important concepts should be kept in mind:
1. Inotropic agents should be not used instead of appropriate fluid resuscitation.
2. There is not a natural progression of one inotrope to another (ie, dopamine, dobutamine, and epinephrine) based on how sick the patient is. The inotropic agents have different cardiovascular actions, and different inotropic agents are used based on the type of shock and the underlying cardiovascular parameters (contractile state and systemic vascular resistance).
With early septic shock, the primary problems include decreased preload and decreased SVR. Initial therapy includes aggressive fluid management; however, an inotropic agent with vasoconstrictor properties also may be needed. These may include dopamine (doses of 8 to 20 pg/kg/minute), norepinephrine, or phenylephrine. The latter agents are not used instead of fluid, but to increase the pathologically low SVR to normal levels. The same pathologic process occurs in distributive shock with an abnormally low SVR. In that setting, vasoconstrictor agents are also indicated.
In patients with late septic shock or cardiogenic shock, there is decreased cardiac contractility with an increase in SVR. Inotropic agents to treat these problems must result in increased inotropy with vasodilatation. This may include dobutamine, arminone, or epinephrine for refractory cases. The latter agent is used in doses of 0.05 to 0.2 pg/kg/minute to provide pure beta receptor stimulation.
Significant morbidity and even mortality can result if early and aggressive resuscitation is not provided for children in shock. When faced with such patients, the initial therapy must include the basics of resuscitation including airway management and assisted ventilation when indicated. Correction of metabolic abnormalities such as hypoglycemia, hypocalcemia, and acidosis may partially correct the cardiovascular dysfunction. Fluids and inotropic agents are chosen based on the underlying pathology and the associated cardiovascular parameters.
1. Burnstock G. Integration of factors controlling vascular tone: overview. Anesthesiology. 1993;79:1363-1380.
2. Rahko PS- Comparative efficacy of three indexes of left ventricular performance derived from pressure-volume loops in heart failure induced by tachypacing. J Am Coll Cardiol. 1994;23:209-218.
3. Aubier M, Trippenback T, Roussos C. Respiratory muscle fatigue during cardiogenic shock. J Appl Physiol. 1981;51:499-508.
4. Shoemaker WC, Hauser CJ. Critique of crystalloid versus colloid therapy in shock and shock lung. Crit Care Mea 1979;7:117-121.
5. Skillman JJ. The role of albumin and oncotically active fluids in shock. Crit Care Med. 1976;4:55-58.
6. Tullis JL. Albumen. JAMA. 1977;237:355-362.
7. Rothschild MA, Bauman A, Yalow RS, Berson SA. Tissue distribution of 1-131 labeled human serum albumin following intravenous administration. J Clin Invest. 1955;34:1354-1358.
8. Metcalf W, Papadopoulos A, Tufaro R, Barth A. A clinical physiologic study of hydroxyethyl starch. Surg Gynecol Obstet. 1970;131:255-259.
9. Wildenthal K, Mieraqiak DS, Mitchell JH. Acute effects of increased serum osmolarity on left ventricular performance. Amc J Physiol. 1969;216:898-904.
10. Rowe GG, Mckenna DH, Corliss RJ, et al. Hemodynamic effects of hypertonic sodium chloride. J Appl Physiol. 1972;32:182-184.
11. Lundvall J, Mellander S, Whire T. Hyperosmolarity and vasodilation in human skeletal muscle. Acta Physiol Seeni. 1969;77:224-233.
12. Holcroft J, Vassar M, Perry C. et al. Use of a 7.5% NaCl/6% dextran 70 solution in the resuscitation of injured patients in the emergency room. Prog CIm Biol Res. 1989;299:331-338.
13. Vassar M, Perry C, Holcroft J. Analysis of potential risks associated with 7.5% sodium chloride resuscitation of traumatic shock. Arch Surg. 1990;125:1309-1315.
14. Holcroft J, Vassar M, Perry C, et al. 3% NaCl and 7.5% NaCl/dextran-70 in the resuscitation of severely injured patients. Ann Surg. 1987;206:279-288.
15. Holcroft J, Vassar M, Perry C, et al. Perspectives on clinical trials for hypertonic saline/dextran solutions for the treatment of traumatic shock. Braz J Med Biol Res. 1989;22:291-293.
16. Cardilo JA, Davis AL, Zaritsky A. Role of early fluid resuscitation in pediatric septic shock. JAMA. 1991;9:1242-1245.
17. Cardenas-Rivero N, Chemow B, Stoiko MA, Nussbaum SR, Todres ID. Hypocalcemia in critically ill children. J Pediatr. 1989;114:946-951.
18. Lawless S, Burckart G, Diven W, Thompson A, Siewers R. Attirinone in neonates and infants after cardiac surgery. Crit Care Med. 1989;17:751-754.
Cardiovascular Changes In Shock
Etiologies of Distributive Shock
Etiologies of Cardiogenic Shock
Composition of Crystalloid Solutions*
Adverse Effects of Sodium Bicarbonate