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Intensive Care Med (2001) 27: S 80S 92

Jean-Louis Vincent

Hemodynamic support in septic shock

J.-L. Vincent ( ) Department of Intensive Care, Erasme University Hospital, Brussels, Belgium E-mail: jlvincen@ulb.ac.be Phone: +32-2-5 55 33 80 Fax: +32-2-5 55 45 55

Methods
This review of the literature enables recommendations to be established and graded according to the strength of the available evidence.

Introduction
Shock, defined as an imbalance between oxygen demand and oxygen supply, results in alterations in tissue perfusion, with reduction in delivery of oxygen and other nutrients to tissues, causing cellular, and then organ, dysfunction. The ultimate goals of hemodynamic therapy in shock are to restore effective tissue perfusion and to normalize cellular metabolism. In hypovolemic, cardiogenic, and obstructive shock, hypotension occurs as the result of a decrease in cardiac output, with consequent anaerobic tissue metabolism. Septic shock, however, typically results from distributive alterations, so that alterations in tissue perfusion result from abnormal control of the microvasculature with abnormal distribution of a normal or increased cardiac output. Cellular alterations in sepsis also result from the important inflammatory response, with the involvement of many mediators, including nitric oxide. Hence the endpoints of therapy are much more difficult to define with certainty than in other forms of shock in which a reduction in blood flow is the dominant problem. The complex nature of the pathophysiology of sepsis has led to considerable confusion and controversy regarding optimal patient management. Nevertheless, it is possible to develop a basic approach to the hemodynamic support of sepsis, which will almost certainly change as our understanding of sepsis improves further.

Altered tissue perfusion in septic shock


Septic shock is characterized by hypotension, which in adults generally refers to a mean arterial pressure below 6570 mmHg. Hypotension is usually accompanied by signs of altered tissue perfusion, for example, oliguria, reduced capillary refill, and altered sensorium. Some caution is necessary in interpreting these signs in septic patients, however, since signs of peripheral vasoconstriction may be remarkably absent; even oliguria is not always present. The adequacy of regional perfusion is usually assessed clinically by evaluating indices of organ function, although none of these parameters alone has been validated as a reliable indicator of adequate resuscitation. These parameters include: coagulation abnormalities (disseminated intravascular coagulation); altered renal function with increased blood urea nitrogen and creatinine; central nervous system dysfunction indicated by a clouded sensorium; altered liver parenchymal function with increased serum levels of transaminases, lactic dehydrogenase, and bilirubin; and altered gut perfusion, manifest by ileus and malabsorption.

Mixed venous oxygen saturation


Mixed venous oxygen saturation (SvO2) can be measured in patients with a Swan-Ganz catheter in place. SvO2 is dependent on cardiac output, oxygen demand, hemoglobin, and arterial oxygen saturation. The normal SvO2 value is 7075 % in critically ill patients but can be elevated in septic patients due to maldistribution of

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blood flow. Nevertheless, it is useful to measure SvO2 because if cardiac output becomes inadequate, SvO2 decreases. Ronco and colleagues [1] studied terminally ill patients in whom treatment was withdrawn; SvO2 decreased dramatically before oxygen consumption started to fall, indicating that oxygen extraction capabilities are not necessarily profoundly altered even in patients with terminal stages of the disease process. Hence SvO2, if normal or high does not necessarily indicate that everything is alright, while a low SvO2 should prompt rapid intervention to increase oxygen delivery to the tissues.

Blood lactate levels


Hyperlactatemia (> 2 mEq/l) is typically present and may be secondary to anaerobic metabolism due to hypoperfusion. However, the interpretation of blood lactate levels in septic patients is not always straightforward. Experimental studies have not always been able to show a reduction in high-energy phosphate levels in animal models of sepsis [2]. The differences between studies may be related to the severity of the septic model, with more severe sepsis being associated with depletion of ATP despite maintenance of systemic oxygen delivery and tissue oxygenation. Also, measurements of tissue PO2 in septic patients have not demonstrated tissue hypoxia in the presence of lactic acidosis [3]. However, if inhomogeneity in blood flow distribution is a real phenomenon, it is likely that cell hypoperfusion also exists with ischemia/reperfusion. A number of studies have suggested that elevated lactate levels may result from cellular metabolic failure rather than from global hypoperfusion in sepsis. Some organs may produce more lactate than others, in particular, the lungs in acute lung injury or acute respiratory distress syndrome [4, 5]. Elevated lactate levels can also result from decreased clearance by the liver. Nonetheless, the prognostic value of raised blood lactate levels has been well established in septic shock patients [6], particularly if the high levels persist [7, 8]. It is also of interest to note that blood lactate levels are of greater prognostic value than oxygenderived variables [9].

the serosa and muscularis [10], resulting in mucosal hypoxia. Any further reduction in splanchnic flow has a correspondingly greater effect on gut hypoxia. Second, the gut may have a higher critical oxygen delivery threshold than other organs [11]. Third, the tip of the villus is supplied by a central arteriole and drained by venules passing away from the tip. A countercurrent exchange mechanism operates in the villus, whereby a base to tip PO2 gradient exists, making the tip particularly sensitive to changes in regional flow and oxygenation. Fourth, constriction of the villus arteriole occurs during sepsis [12], rendering the villus even more sensitive to reductions in blood flow. Fifth, the capillary density at the villus tip is reduced during sepsis [13], impeding the transfer of oxygen. Finally, gut ischemia increases intestinal permeability, which may increase bacterial translocation, a suggested trigger or motor of the sepsis response and multiple organ failure. Gastric tonometry has been proposed as a method to assess regional perfusion in the gut by measuring DPCO2. Calculations of gastric intramucosal pH (pHi) have become obsolete as bicarbonate is global, nonspecific, and measured only intermittently. For these reasons gastric mucosal PCO2 may be more accurate than pHi because this measure is not confounded by arterial bicarbonate. Gastric mucosal PCO2 is influenced directly by systemic arterial PCO2, and some clinicians have proposed using the gastric-arterial PCO2 difference as the primary tonometric variable of interest [14]. Even this measure is not a simple measure of gastric mucosal hypoxia because either anaerobic metabolism decreased gastric blood flow in the absence of anaerobic metabolism, or a combination of the two can increase gastric mucosal PCO2 [14]. An early trial suggested that tonometry derived parameters may be useful in guiding therapy [15], but these findings were not confirmed recently [16], and many investigators have emphasized the limited sensitivity, and especially specificity, of these measurements. Various vasoactive agents have been shown to have divergent effects on PgCO2 and pHi that are neither consistent nor predictable [17]. In summary, each endpoint parameter should be considered in the appropriate context, and the combination of clinical parameters (mean arterial pressure, urine flow, skin perfusion, level of consciousness) with blood lactate levels is most useful.

Gut tonometry
The measurement of regional perfusion as a means of detecting inadequate tissue oxygenation has focused on the splanchnic circulation, as the hepatosplanchnic circulation is particularly sensitive to changes in blood flow and oxygenation for several reasons. First, under normal conditions the gut mucosa receives the majority of total intestinal blood flow. However, in sepsis there is a redistribution of flow away from the mucosa toward

Fluid resuscitation in septic shock


What is the endpoint of fluid resuscitation in septic shock? Answer: (a) adequate tissue perfusion, grade E.

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Recommendation The goal of fluid resuscitation in septic shock is restoration of tissue perfusion and normalization of cellular metabolism. Does fluid resuscitation increase cardiac output in septic shock patients? Answer: yes, grade C. Recommendation Volume repletion in patients with septic shock produces significant increases in cardiac output and systemic oxygen delivery [18, 19], and fluids alone are sometimes sufficient to reverse hypotension and restore hemodynamic stability [20]. Should fluid infusion be the initial step in the cardiovascular support of septic shock patients? Answer: yes, grade D. Recommendation Requirements for fluid infusion are not easily determined, and therefore the fluid challenge should be titrated to the clinical endpoints of blood pressure, heart rate, and urine output. Central venous pressure is initially required to evaluate the complex relationship between intravascular blood volume and cardiac function. It is difficult to give optimal values for cardiac filling pressures. Rationale Septic shock can be associated with either absolute or relative hypovolemia. Large fluid deficits can exist, as a consequence of external (e.g., diarrhea, sweating) or internal (e.g., peritonitis) losses. Relative hypovolemia is related to the maldistributive defect with vasodilation and peripheral blood pooling. The initial phases of experimental and clinical septic shock present as a low cardiac output syndrome with low filling pressures. Failure to appreciate the degree of underlying hypovolemia may result in a low cardiac output. The hyperdynamic state is apparent only after volume repletion [21, 22]. Increased blood and plasma volumes are associated with increased cardiac output and enhanced survival from septic shock [23].

Can the use of pulmonary artery catheter guided therapy improve outcome from septic shock? Answer: uncertain, grade D. Recommendation When central venous pressure increases, a pulmonary artery catheter is probably required, although its role has recently been questioned [24]. Rationale When pulmonary artery catheter measurements of cardiac output and SvO2 are available, filling pressures should be increased to a level associated with maximal cardiac output. In most patients with septic shock quite high pulmonary artery occluded pressures are required, despite the risk of pulmonary edema.

Choice of fluid
Patients with septic shock can be successfully resuscitated with crystalloid or colloid, although the choice of fluid continues to be a matter of debate, with colloids usually preferred in Europe, and crystalloids more widely used in North America. There are many different colloid solutions available including natural solutions (albumin, plasma protein fraction) and artificial solutions (gelatins, dextrans and hydroxyethyl starch). The most commonly used solutions are albumin and hetastarch. Is resuscitation with colloids or crystalloids associated with similar outcomes in septic shock? Answer: uncertain, grade C. Recommendation Increases in cardiac output and systemic oxygen delivery are proportional to the degree of intravascular volume expansion achieved. Rationale When crystalloids and colloids are titrated to the same level of filling pressure, they restore tissue perfusion to the same degree [25], but for the same effect, two to four times more volume of crystalloid is required than colloid, and slightly longer infusion periods may be nec-

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essary to achieve desired hemodynamic endpoints. Colloid solutions are, however, much more expensive than crystalloid solutions. Should albumin be avoided in resuscitation from septic shock? Answer: uncertain, grade C. Albumin is a naturally occurring plasma protein accounting for approximately 80 % of the plasma colloid osmotic pressure in normal subjects. In the presence of peripheral edema, mobilization of extravascular volume can be achieved by using hyperoncotic (20 or 25 %) albumin. Hydroxyethyl starch (HES, hetastarch) is a synthetic colloid available in a 6 % solution of normal saline. HES molecules may also affect endothelial cell function and reduce endothelial cell activation and injury [26], which could account in part for the preservation of microvascular structures with reduced leakage seen with HES in experimental sepsis models [27]. HES solutions can decrease factor VIII activity and prolong prothrombin time, so that the total amount of starch infused should be limited. The possibility that the long-term deposition of higher molecular weight hetastarch particles in the reticuloendothelial system could have immunosuppressive effects has caused some concern. However, in experimental studies, macrophage function and reticuloendothelial function were not altered by HES [28]. Gelatin solutions are cheaper but also less efficacious. They are not currently available in the United States, although they may soon become available there.

Rationale Excessive tachycardia, very low SvO2, or electrocardiographic signs of myocardial ischemia may suggest the need for higher hemoglobin levels to be maintained. A large study by Hebert et al. [29] in a mixed group of ICU patients showed no benefit of transfusion to a hemoglobin level of 10 vs. 7 g/dl. Indeed, this trial found that use of the lower hemoglobin level trigger for transfusion, 7 g/dl, resulted in improved survival. When considering blood transfusion to improve oxygenation in critically ill patients, stored blood may be less effective than fresh blood [30].

Vasopressor therapy in septic shock


Does adrenergic support improve outcome from septic shock? Answer: yes, grade E. Recommendation When fluid challenge fails to restore an adequate arterial pressure and organ perfusion, therapy with vasopressor agents should be started. Vasopressor therapy may also be required transiently to sustain life and maintain perfusion in the face of life-threatening hypotension, even when cardiac filling pressures are not elevated. Rationale In shock states the measurement of blood pressure using a cuff is often unreliable and inaccurate, and patients should have an arterial catheter in place for continuous blood pressure monitoring. This is even more the case in patients receiving vasopressor therapy for shock, as restoration of an adequate blood pressure is the required endpoint and measure of effectiveness. The precise level of mean arterial pressure to aim for is, however, not entirely certain and is likely to vary among patients. In animal studies a mean arterial pressure of less than 60 mmHg is associated with compromised autoregulation in the coronary, renal, and central nervous system vascular beds, and blood flow may be reduced. Some patients, however, especially the elderly, may require higher blood pressures to maintain adequate perfusion. Assessment of regional and global perfusion by a combination of the methods outlined previously is advisable.

Blood transfusion
Can one recommend a minimum hemoglobin concentration in severe sepsis? Answer: yes, 78 g/dl, grade B. Can one recommend a minimum hemoglobin concentration in septic shock? Answer: uncertain, grade E. Recommendation The optimal hemoglobin and hematocrit for patients with septic shock is unclear. Most experts recommend hemoglobin levels of 910 gm/dl in patients with septic shock. This degree of anemia is usually well tolerated in most patients, even with cardiac impairment.

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Effects of vasopressors on renal perfusion


Although no prospective randomized studies have demonstrated a significant improvement in renal function with vasopressors, a number of open-label clinical series support an increase in renal perfusion pressure [31, 32, 33, 34, 35, 36, 37, 38, 39]. Excessive doses of vasopressors may shift the renal autoregulation curve to the right, necessitating a greater perfusion pressure for a specified renal blood flow. The precise target mean blood pressure level depends on the premorbid blood pressure but can be as high as 75 mmHg [31, 33, 34, 35, 36, 37, 38, 39]. However, individual levels should be kept at the minimum needed to reestablish urine flow, and in some patients this can be achieved with a mean arterial pressure of 60 or 65 mmHg. Certain patients may remain oliguric despite normalization of systemic hemodynamic variables [32, 33, 34, 37, 39]. This may be due to the absence of an increase in renal blood flow, a decrease in glomerular perfusion pressure, or irreversible ischemic renal lesions. Although in nonseptic conditions combination therapy with the use of low-dose dopamine (14 mg kg1 min1) in addition to norepinephrine in an anesthetized dog model and healthy volunteers resulted in significantly higher renal blood flow and lower renal vascular resistance [40, 41], such effects have not been conclusively demonstrated in septic shock, and there is no information available on the effects of such therapy on patient survival.

blood flow, increases PgCO2 production, and decreases pHi, suggesting that the drug alters oxygen supply in the splanchnic circulation [42]. At low doses dopamine increases splanchnic oxygen delivery by 65 % but splanchnic oxygen consumption by only 16 %. Despite this, dopamine may decrease pHi, perhaps by a direct effect on the gastric mucosal cell. The effects of dopamine on cellular oxygen supply in the gut remain incompletely defined. The effects of norepinephrine on splanchnic circulation are hardly predictable. The combination of norepinephrine and dobutamine appears to be more predictable and more appropriate to the goals of septic shock therapy than the effects of epinephrine alone.

Individual vasopressor agents


Among adrenergic agents, are dopamine or norepinephrine the first line agents to correct hypotension in septic shock? Answer: yes, grade E. Should low-dose dopamine be routinely administered for renal protection? Answer: no, grade D. Dopamine

Effects of vasopressors on the splanchnic circulation


Is the combination of norepinephrine and dobutamine superior to dopamine in the treatment of septic shock? Answer: uncertain, grade C. Recommendation The effects of dopamine on cellular oxygen supply in the gut remain incompletely defined. The effects of norepinephrine on splanchnic circulation are hardly predictable. The combination of norepinephrine and dobutamine appears to be more predictable and more appropriate to the goals of septic shock therapy than the effects of epinephrine alone. Rationale Splanchnic perfusion and the integrity of the gut mucosa may play an important role in the pathogenesis of multiple organ failure. Epinephrine decreases splanchnic

Recommendation The hemodynamic effects of dopamine in patients with septic shock are well established. Dopamine increases mean arterial pressure primarily by increasing cardiac index with minimal effects on systemic vascular resistance. The increase in cardiac index is due to an increase in stroke volume, and to a lesser extent, to increased heart rate [43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54]. Patients receiving dopamine at rates greater than 20 mg kg1 min1 show increases in right heart pressures as well as in heart rate, and therefore doses should not usually exceed 20 mg kg1 min1, at least not without adequate hemodynamic monitoring. Rationale Dopamine is the natural precursor of norepinephrine and epinephrine, and possesses several dose-dependent pharmacological effects. Generally, at doses less than 5 mg kg1 min1 dopamine stimulates dopaminergic DA1 receptors in the renal, mesenteric, and coronary beds,

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resulting in vasodilation. Infusion of low doses of dopamine causes an increase in glomerular filtration rate, renal blood flow, and sodium excretion. At doses of 510 mg kg1 min1, 1-adrenergic effects become predominant, resulting in an increase in cardiac contractility and heart rate. Dopamine also causes the release of norepinephrine from nerve terminals, contributing to its cardiac effects. At higher doses (above 10 mg kg1 min1), 1-adrenergic effects predominate, leading to arterial vasoconstriction and an increase in blood pressure. Dopamine's effect on gastric tonometric parameters has been evaluated with mixed results. Roukonen et al. [51] and Meier-Hellmann et al. [54] have documented that dopamine increases splanchnic blood flow. Neviere and colleagues [55] reported that dopamine is associated with a reduction in gastric mucosal blood flow; there were changes in gastric PCO2, gastric-arterial PCO2 difference, and calculated intramucosal pH. They [55] concluded that they could not determine whether the reduction in gastric mucosal blood flow was critical because there were no changes in the acid-base parameters of the patients. Recent studies have shown that dopamine may alter the inflammatory response in septic shock by decreasing the release of a number of hormones, including prolactin [56]. Norepinephrine Recommendation Summarizing the results of studies of norepinephrine, it can be concluded that norepinephrine markedly improves mean arterial pressure and glomerular filtration. This is particularly true in the high output-low resistance state of many septic shock patients. After restoration of systemic hemodynamics, urine flow reappears in most patients and renal function improves without the use of low-dose dopamine or furosemide. This fact supports the hypothesis that renal ischemia observed during hyperdynamic septic shock is not worsened by norepinephrine infusion and even suggests that this drug may effectively optimize renal blood flow and renal vascular resistance. Rationale Norepinephrine is a potent -adrenergic agonist with some -adrenergic agonist effects. The effects of norepinephrine have been studied in a number of studies on patients with septic shock. In open label trials norepinephrine has been shown to increase mean arterial pressure in patients with hypotension resistant to fluid resus-

citation and dopamine. The potential that norepinephrine may have negative vasoconstrictive effects on regional vascular beds such as the liver and the kidney, with resultant regional ischemia, has meant that norepinephrine has commonly been reserved for use as a last resort, with predictably poor results. However, recent experience with the use of norepinephrine in patients with septic shock suggests that it can successfully increase blood pressure without causing the feared deterioration in organ function. Most studies have given septic patients fluid to correct hypovolemia before dopamine, with or without dobutamine, titrated to doses of 725 mg kg1 min1 to achieve the target blood pressure. Only if this regime failed was norepinephrine added [31, 32, 35, 39, 42, 51, 57, 58]. In older studies norepinephrine was added after the use of metaraminol, methoxamine, or isoproterenol [43, 59]. A few studies have used norepinephrine as the only adrenergic agent to correct sepsis-induced hemodynamic abnormalities [34, 37, 50, 51, 53]. In most studies the mean dose of norepinephrine was 0.21.3 mg kg1 min1, although the initial dose can be as low as 0.01 mg kg1 min1 [32], and the highest reported norepinephrine dose was 3.3 mg kg1 min1 [58]. Thus, large doses of the drug can be required in some patients with septic shock, which may be due to -receptor down-regulation in sepsis [60]. Norepinephrine therapy usually causes a statistically and clinically significant increase in mean arterial pressure due to its vasoconstrictive effects, with little change in heart rate or cardiac output, leading to increased systemic vascular resistance. Several studies have demonstrated increases in cardiac output ranging from 10 % to 20 % and increases in stroke volume index of 1015 % [39, 43, 53]; other studies, however, have observed no significant changes in either cardiac output or stroke volume index after the use of norepinephrine in the presence of a significant increase in vascular resistance, suggesting that norepinephrine is exerting 1receptor agonist effects [31, 32, 33, 35, 58, 61]. Obviously, since cardiac index is either increased or unchanged, and mean arterial pressure is consistently increased, left ventricular stroke work index is always statistically increased with norepinephrine. With regards to pulmonary capillary wedge pressure, no clinically significant changes are reported. Norepinephrine should be used only to restore normal values (or values in the lower part of the normal range) of mean arterial blood pressure and systemic vascular resistance. Higher values should be avoided during norepinephrine therapy, since elevated cardiac afterload could be deleterious in cases of severe underlying cardiac dysfunction. Due to methodological problems with the use of systemic vascular resistance as the sole measurement of peripheral resistance, the use of mean arterial pressure is more advisable, although, as men-

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tioned above, the optimal target mean arterial pressure is not known, and depends on many factors including age and premorbid condition. Norepinephrine is probably more effective than dopamine at reversing hypotension in septic shock patients. Martin et al. [50] carried out a study with the most striking findings. They prospectively randomized 32 volume-resuscitated patients with hyperdynamic sepsis syndrome to receive either dopamine (2.525 mg kg1 min1) or norepinephrine (0.55.0 mg kg1 min1) to achieve and maintain normal hemodynamic and oxygen transport parameters for at least 6 h. If the goals were not achieved with one agent, the other was added. The groups were similar at baseline. Dopamine administration (1025 mg kg1 min1) was successful in only 31 % (5 of 16) of patients whereas norepinephrine (1.5  1.2 mg kg1 min1) resulted in success in 93 % (15 of 16) of patients (p < 0.001). Of the 11 patients who did not respond to dopamine 10 responded when norepinephrine was added. In contrast, the one patient who did not respond to norepinephrine failed to respond to dopamine. The survival rate differed between the two groups (59 % norepinephrine vs. 17 % dopamine) although the study was not statistically designed to examine this issue. In patients with hypotension and hypovolemia, for example, during hemorrhagic shock, norepinephrine and other vasoconstrictor agents have severe detrimental effects on renal hemodynamics. Despite the constant improvement in blood pressure, renal blood flow does not increase, and renal vascular resistance continues to rise [62]. Renal tissue oxygen tension can decrease markedly, worsening renal ischemia [63]. Indeed, norepinephrine has been demonstrated to cause ischemia-induced acute renal failure in rats [64]. In nonseptic shock patients norepinephrine has a marked vasoconstrictive effect in most vascular beds, reducing blood flow to the liver, skeletal muscle, and kidneys [65]. When used in normotensive and hypertensive patients, norepinephrine can decrease renal blood flow and increase renal vascular resistance [66]. However, in hyperdynamic septic shock, during which urine flow is believed to decrease mainly as a result of lowered renal glomerular perfusion pressure, the situation is different. Since norepinephrine has a greater effect on efferent arteriolar resistance and increases the filtration fraction, normalization of renal vascular resistance could effectively reestablish urine flow. The importance of this during norepinephrine infusion was shown by Schaer et al. [40], who demonstrated that while renal vascular resistance increased during norepinephrine infusion; renal blood flow remained stable or even slightly increased because the drug enhanced cardiac output and renal perfusion pressure. The effects of norepinephrine on renal function in sepsis have been evaluated in four studies. Desjars

et al. [33] studied 22 septic shock patients treated with norepinephrine (0.51.5 mg kg1 min1) and dopamine (23 mg kg1 min1). Serum creatinine, blood urea nitrogen, free water clearance, and fractional excretion of sodium decreased significantly, while urine output, creatinine clearance, and osmolar clearance increased significantly. In this study [33] six of seven patients considered at risk for developing acute renal failure had improved renal function during norepinephrine treatment, and only one developed nonoliguric acute renal failure requiring dialysis. Martin et al. [37] studied 24 septic shock patients (treated with norepinephrine (1.1 mg kg1 min1 + dobutamine at 814 mg kg1 min1 + dopamine at 617 mg kg1 min1). No patient received low-dose dopamine or furosemide. Normalization of systemic hemodynamics was followed by reestablishment of urine flow, decrease in serum creatinine, and increase in creatinine clearance. Fukuoka et al. [34] studied 15 patients with septic shock treated with norepinephrine (0.050.24 mg kg1 min1), dopamine (9 mg kg1 min1) and dobutamine (5 mg kg1 min1). Only patients with a normal serum lactate concentration had an increase in systemic vascular resistance, and an increase in urine flow. Creatinine clearance was not affected (18.8+5.5 ml/min before and 20.1+6.6 ml/min after norepinephrine). Patients with elevated serum lactate concentrations had no change in vascular resistance, a decrease in creatinine clearance (32.6  6.4 to 11.9  4.9 ml/min), and required higher doses of furosemide. The authors concluded that the serum lactate concentration may predict which patients will experience potentially adverse renal effects with norepinephrine. However, this study included only a very limited number of patients and is at variance with the findings of other studies [39, 43, 50, 53, 57] in which vascular resistance and urine flow were increased in patients with elevated lactate concentrations (as high as 4.8  1.6 mmol/l [50]). Redl-Wenzel et al. [39] studied 56 patients with septic shock treated with norepinephrine (0.12.0 mg kg1 min1) and dopamine (2.5 mg kg1 min1). During norepinephrine infusion creatinine clearance increased significantly from 75  37 to 102  43 ml/ min after 48 h of treatment. The authors concluded that mean arterial pressure could be increased by norepinephrine with a positive effect on organ perfusion and oxygenation. The effects of norepinephrine on serum lactate concentrations have been assessed in five studies. Four studies assessed changes in serum lactate concentrations over a relatively short period of time, i.e., 13 h. Hesselvik et al. [35] reported unchanged lactate levels during norepinephrine therapy, but the actual values were not given. In the other three studies [51, 53, 57] mean values of serum lactate concentrations did not change over the 1- to 3-h study period. It should be noted that initial values were not very high (1.82.3 mmol/l). Since blood

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flow tended to significantly improve and lactic acid concentrations decreased (but not significantly) in one study, it is unclear whether sufficient time elapsed between measurements to see a significant norepinephrine-induced change in serum lactate concentrations. In the last study [50] initial lactate concentrations were elevated (4.8  1.6 mmol/l), and a statistically and clinically significant decrease in lactate levels was observed at the end of the 6-h study period. Norepinephrine thus does not worsen, and may even improve, tissue oxygenation, as assessed by serum lactate levels, in patients with septic shock. Ruokonen et al. [51] measured splanchnic blood flow and splanchnic oxygen consumption in septic shock patients receiving either norepinephrine (0.070.23 mg kg1 min1) or dopamine (7.633.8 mg kg1 min1) to correct hypotension. With norepinephrine no overall changes in splanchnic blood flow and splanchnic oxygen consumption or extraction were noted, and in individual patients its effects on splanchnic blood flow were unpredictable (increased in three patients, decreased in two). Dopamine caused a consistent and statistically significant increase in splanchnic blood flow. Meier-Hellman et al. [54] studied patients changed from dobutamine to norepinephrine. They observed a significant decrease in hepatic venous oxygen saturation. In another group of patients, they studied the effects of switching from dobutamine plus norepinephrine to the latter drug alone. They observed the previously reported changes in hepatic venous oxygen saturation together with a decrease in splanchnic blood flow (green dye dilution technique) and in cardiac output. Splanchnic oxygen consumption remained unchanged due to a regional increase in oxygen extraction. The decrease in splanchnic blood flow paralleled the decrease in cardiac output. The authors concluded that as long as cardiac output is maintained treatment with norepinephrine alone has no negative effects on splanchnic tissue oxygenation. This finding was confirmed by Marik and Mohedin [53] who observed a significant increase in pHi (from 7.16  0.07 to 7.23  0.07) over 3 h of norepinephrine treatment. During treatment with dopamine pHi decreased significantly (7.24  0.04 to 7.18  0.05). Reinelt et al. [67] tested the hypothesis that when dobutamine is added to norepinephrine to obtain a 20 % increase in cardiac index in septic shock patients, splanchnic blood flow and oxygen consumption increases and hepatic metabolic activity (hepatic glucose production) improves. Splanchnic blood flow and cardiac index increased in parallel, but there was no effect on splanchnic oxygen consumption and hepatic glucose production decreased. The conclusion of the authors was that splanchnic oxygen consumption was not dependent on delivery in septic shock patients well resuscitated with norepinephrine. Levy et al. [42] studied the effects of the combination of norepinephrine and dob-

utamine on gastric tonometric variables in 30 septic shock patients. pHi and gastric PCO2 gap were normalized within 6 h, while in epinephrine-treated patients pHi decreased and gastric PCO2 gap increased. Changes in the epinephrine group were only transient and were corrected within 24 h but could potentially have caused splanchnic ischemia. The authors concluded that the combination of norepinephrine with dobutamine was more predictable than epinephrine. Clinical experience with norepinephrine in septic shock patients suggests that this drug can successfully increase blood pressure without causing deterioration in cardiac index or organ function. Norepinephrine (at doses of 0.013 mg kg1 min1), consistently improves hemodynamic variables in the large majority of patients with septic shock. The effects of norepinephrine on oxygen transport variables remain undefined from the available data, but most studies find other clinical parameters of peripheral perfusion to be significantly improved. Unfortunately only one published study was controlled [50] and a prospective, randomized clinical trial is still required to assess whether the use of norepinephrine in septic shock patients affects mortality compared to other vasopressors. The data are sufficiently strong to suggest that when contemplated in the treatment of septic shock patients, norepinephrine should be used early and not merely as a last resort. Epinephrine In patients who fail to respond to fluid administration or other vasopressors epinephrine can increase arterial pressure primarily by increasing cardiac index and stroke volume [38, 68, 69, 70]. Moran et al. [70] reported a linear relationship between epinephrine dose and heart rate, mean arterial pressure, cardiac index, left ventricular stroke work index, and oxygen delivery, and consumption. Epinephrine, however, has detrimental effects on splanchnic blood flow and causes transient decreases in pHi and increases in the PCO2 gap [42, 71]. Epinephrine administration has been associated with increases in systemic and regional lactate concentrations [42, 69, 72], although the cause of these increases is unclear. As the monitoring periods in all these studies were short, it is unclear whether these increases are a transient phenomenon. Other adverse effects of epinephrine include tachyarrhythmias. In summary, epinephrine clearly increases blood pressure in patients unresponsive to other agents. However, because of its negative effects on gastric blood flow and blood lactate concentrations its use should be limited.

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Other vasoconstricting agents Phenylephrine, a selective-1-adrenergic agonist, has been used in septic shock patients, although there are concerns about its potential to reduce cardiac output and lower heart rate in these patients. Doses of phenylephrine start at 0.5 mg kg1 min1 and reach a maximum dose of 58 mg kg1 min1. A few studies have evaluated the clinical use of phenylephrine in septic shock [73, 74, 75]. Reinelt et al. [75] reported reduced splanchnic blood flow and oxygen delivery in six septic shock patients treated with phenylephrine compared to norepinephrine.

Dobutamine Dobutamine is an adrenergic agonist that stimulates b1-, b2-, and b1-adrenergic receptors. A number of studies have investigated the effect of dobutamine on cardiac function during sepsis or septic shock [82, 83, 84, 85, 86]. The doses utilized ranged from 2 to 28 mg kg1 min1. The majority of these studies found increases in cardiac index combined with increases in stroke volume and heart rate. Epinephrine See individual vasopressor agents, above.

Inotropic therapy in septic shock


Although the cardiac index is usually maintained in the volume resuscitated septic shock patient, cardiac function is impaired [76]. Characterized by ventricular dilatation, a decreased ejection fraction an impaired contractile response to volume loading, and a low peak systolic pressure/end-systolic volume [77, 78], the mechanism of the myocardial dysfunction is complex. Coronary blood flow is usually normal and there is no net lactate production across the coronary vascular bed, so myocardial ischemia is not implicated. Alterations in intracellular calcium homeostasis and in - -adrenergic signal transduction may be contributory factors. Several inflammatory mediators have been shown to cause myocardial depression in various animal models, including cytokines [79], platelet-activating factor, and nitric oxide [80]. Inotropic therapy in septic shock is thus not straightforward. Cardiac output is usually not decreased, and multiple factors may be involved in the depressed cardiac function. In patients with decreased cardiac output the goals of therapy are relatively clear and are aimed at restoring normal physiology. Because of the complexity of assessment of clinical parameters in septic patients, direct measurement of cardiac output by invasive hemodynamic monitoring is advisable, but other endpoints of global perfusion should be followed as well. When global hypoperfusion is manifest by a decreased SvO2, monitoring of SvO2 can be helpful to guide response to therapy. Similarly, although lactate production in sepsis is complex, a fall in blood lactate levels during inotropic therapy is a good prognostic sign [81]. Dopexamine Dopexamine is a dopamine analog that stimulates b2adrenergic and dopamine 1 and 2 receptors. It is not approved for use in the United States. Several studies have evaluated short-term infusions of dopexamine in sepsis or septic shock and demonstrated significant improvements in cardiac index and left ventricular stroke work index [87, 88, 89]. In addition, mesenteric perfusion, as assessed by gastric tonometry, were improved compared to baseline values in initial studies [88], but this has not been confirmed in subsequent studies [90]. Phosphodiesterase inhibitors Phosphodiesterase inhibitors alone, such as amrinone and milrinone, have little place in the treatment of septic shock. They may be considered in combination with adrenergic agents. One study evaluating milrinone in pediatric patients with sepsis observed that cardiac index and right and left ventricular stroke work indices improved significantly, with little change in heart rate [91]. Other agents Calcium supplementation has been proposed in the management of myocardial dysfunction in septic shock. However, no consistent beneficial hemodynamic effect of calcium administration in septic patients has been reported [92], and increased mortality has been reported in animal models [93, 94]. Digoxin has been reported significantly to improve cardiac performance in hypodynamic septic patients [95].

Individual inotropic agents


Is dobutamine the pharmacological agent of choice to increase cardiac output in the treatment of septic shock? Answer: yes, grade D.

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The supranormal approach


Are hyperkinetic patterns associated with better outcome in septic shock patients? Answer: yes, grade C. Systemic alterations occurring in sepsis including an increased oxygen demand, altered oxygen extraction, and myocardial depression, can explain how circulatory failure may persist despite a normal or high cardiac output (see alterations in distribution above). Hence, it may be valuable to further increase cardiac index (to 'supranormal' values) despite the fact that it is not typically decreased. This remains a controversial issue. Initial studies by Shoemaker et al. [96] seemed to support this approach, but in order to correlate with improved survival, the cardiac index needed to be greater than 4.5 l m2 min1, oxygen delivery greater than 600 ml m2 min1, and oxygen consumption greater than 170 ml m2 min1. Randomized studies [97, 98] to test this hypothesis in all critically ill patients have produced rather negative results, with increased mortality rates in the study by Hayes et al. [97] which sometimes involved

the administration of very high doses of dobutamine. Moreover, it is possible that increases in cardiac index and oxygen delivery may simply reflect higher underlying physiological reserve of the patients, associated with an increased chance of survival. The main problem with studying this approach in a typical ICU population is the heterogeneity of the patients included. What may be beneficial in certain groups of patients could potentially be harmful in others, thus giving an overall negative result. Tuchschmidt et al. [99] included only patients with septic shock and obtained more positive results. However, the strategy of increasing oxygen delivery to predetermined elevated endpoints of cardiac index and oxygen delivery cannot be recommended routinely. Different interventions to increase oxygen delivery, such as fluid resuscitation, blood transfusion, or infusion of vasoactive agents, can have different effects on regional perfusion. This is an area of controversy and ongoing research; randomized controlled trials, with clear, reproducible treatment algorithms and use of defined measures of regional perfusion are necessary. In the meanwhile, one should define the goals and desired endpoints of inotropic therapy in septic patients and use these endpoints to monitor and titrate therapy.

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