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Use of vasoactive drugs in sepsis and septic shock
12 Use of vasoactive drugs in sepsis and septic shock JEAN-LOUIS VINCENT GILBERTO FRIEDMAN STANISLAW JANKOWSKI HAIBO ZHANG
Septic shock is a distributive form of shock, associated with peripheral vasodilatation, pooling of blood and decreased venous return to the heart (Vincent, 1991a). Alterations in oxygen extraction are secondary to the alterations in vascular tone and endothelial cell function. The severity of the peripheral vasodilatation has been directly related to the severity of sepsis (Groeneveld et al, 1986; Parker et al, 1989; Vincent et al, 1992a). Myocardial depression can also occur relatively early and is related to decreased coronary perfusion, myocardial oedema and release of various myocardial depressant substances. The degree of myocardial depression has been also shown to be directly proportional to the severity of sepsis (McDonough et al, 1986; D'Orio et al, 1990; Vincent et al, 1992a). The peripheral and myocardial alterations seen in severe sepsis share some causative mechanisms. Both are associated with the release of various mediators, such as tumour necrosis factor and interleukin-1 (Vicaut et al, 1991; Hollenberg et al, 1992; Vincent et al, 1992b), and both exhibit a decreased response of adrenergic receptors to their stimulation (Silverman et al, 1993). Besides the removal of the septic focus and the administration of antibiotic agents, immediate therapy of severe sepsis requires the restoration of haemodynamic stability by the administration of fluids and adrenergic agents. It is essential to emphasize that vasoactive therapy is no substitute for fluid therapy. The clinician is often afraid that an excessive increase in the cardiac filling pressure may lead to the development of pulmonary oedema. However, fluid overload, although a source of considerable morbidity, is not likely to limit the chances of survival. On the other hand, the maintenance of any degree of hypovolaemia can lead to the persistence of tissue hypoxia and subsequent multiple organ failure. HAEMODYNAMIC PATTERNS OF SEVERE SEPSIS
There was a time when vasoactive treatment of severe sepsis was based primarily on the recognition of one of two typical haemodynamic patterns: Baillibre' s Clinical Anaesthesiology--
Vol. 8, No. 1, March 1994 ISBN 0-7020-1824-4
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(a) the hyperkinetic state, characterized by a high cardiac output and low systemic vascular resistance, in which vasopressors were thought to be particularly indicated; and (b) the less common hypokinetic state, due to profound myocardial depression, in which inotropic agents were thought to have a place. These schematic, and somewhat simplistic, views have been reevaluated in view of recent developments in the pathophysiology of septic shock. The haemodynamic presentation of severe sepsis corresponds to a spectrum of alterations, and the division into two subsets is arbitrary. In addition, the peripheral and the cardiac alterations coexist in all forms of septic shock. Myocardial depression can be present even when cardiac output is normal or high, as indicated by the analysis of ventricular function curves (D'Orio et al, 1990; Vincent et al, 1992a) or the determination of ventricular ejection fractions (Parker et al, 1989; Vincent et al, 1992a). An alteration in vascular tone can persist even when cardiac output is reduced. It is more appropriate to distinguish between the peripheral and the myocardial alterations associated with severe sepsis, and therefore to consider vasoactive therapy in septic shock as having two objectives. The first objective is to increase the vascular tone to restore adequate tissue perfusion pressure. The second is to increase myocardial contractility, not only to correct the myocardial depression as such, but also to use the heart as a pump to deliver more oxygen to the tissues.
R E S T O R A T I O N OF TISSUE PERFUSION P R E S S U R E
Vasopressor therapy is commonly required after initial resuscitation with fluids to restore a minimal tissue perfusion pressure. A systolic blood pressure above 90 mm Hg or a mean arterial pressure of 70 mm Hg is the usual goal. Dopamine is the drug of choice for its combined a, [3 and dopaminergic properties, resulting in combined increases in cardiac output and arterial pressure. The vasoconstrictive effects of dopamine become increasingly potent as the doses are increased by progressive a-adrenergic stimulation. Dopamine, the natural precursor of noradrenaline, is not as potent a vasoconstrictor, so that blood flow can be better maintained with dopamine than with noradrenaline. In addition, the dopaminergic effects can help to preserve blood flow in the renal and splanchnic beds. Dopamine is useful in controlling hypotension, but, if an adequate arterial pressure is not achieved with doses up to 20 to 25txgkg-1min -1, noradrenaline can be started (Vincent, 1991a). Recommended doses are not appropriate for the administration of noradrenaline. After restoring the cardiac filling pressure, the dose of noradrenaline must be titrated to maintain a systolic blood pressure of 90-100 mm Hg. Because of its strong a-stimulating effects, noradrenaline can effectively restore vascular tone. It also induces less tachyarrhythmia than dopamine and other adrenergic agents. For these reasons, some investigators have proposed using noradrenaline early in high-output states to increase
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vascular resistance (Des jars et al, 1987, 1989; Meadows et al, 1988; Fukuoka et al, 1989; Hesselvick and Brodin, 1989; Martin et al, 1990; Gregory et al, 1991). However, the use of stronger vasoconstrictors such as noradrenaline carries a risk of aggravating the perfusion failure by limiting the blood flow to the capillaries. Other vasoconstrictors, such as phenylephrine, metaraminol, mephentermine or methoxamine, were used in the past to increase blood pressure in patients with shock states, but have been virtually abandoned for their undesired effects on organ function. Noradrenaline decreases mesenteric blood flow, which can lead to splanchnic ischaemia and may facilitate bacterial translocation and endotoxin resorption from the gut. It increases renal vascular resistance and therefore has a potentially deleterious effect on renal function. Nevertheless, several studies have stressed that noradrenaline may sometimes have a positive rather than a negative effect on renal function. In all the studies in which a beneficial effect was found, the patients were initially very hypotensive, so that it is not clear whether increasing systemic vascular resistance as such can be beneficial (Desjars et al, 1987, 1989; Meadows et al, 1988; Fukuoka et al, 1989; Hesselvick and Brodin, 1989; Martin et al, 1990; Gregory et al, 1991; Redl-Wenzl et al, 1993). In these studies the pulmonary artery occlusion pressure was also low. Hence, the question was raised whether further fluid therapy could have corrected some degree of hypovolaemia and improved renal function. Fukuoka et al (1989) reported an increase in urine flow in nine patients with hypotension without circulatory failure, but a worsening of renal function in six other patients with established septic shock. Hence, the risk of alterations in renal function cannot be underestimated. An important question to answer is whether a low dose of dopamine should be maintained to attenuate the reduction in renal blood flow under the influence of noradrenaline. At low doses (< 5 Ixg kg -1 min -1) dopamine may increase renal blood flow by its dopaminergic properties, but at higher doses the s-stimulating effect becomes significant and the effect on renal blood flow is lost. Hence, it is doubtful that low doses of dopamine exert any protective effects on the renal vasculature in the presence of strong o~-adrenergic stimulation (Vincent, 1994). In dogs, Schaer et al (1985) studied the effects of incremental dosage of noradrenaline alone versus supplementation with 4 txgkg-amin -1 dopamine. Renal blood flow was increased only in the dopamine group, and no change was observed in the noradrenaline group. Interpretation of this experimental study is limited by the fact that, in these acute conditions, noradrenaline increased both arterial pressure and cardiac output but exerted hardly any effect on systemic vascular resistance. Hence, whether low doses of dopamine can exert a protective effect on renal function remains highly speculative. Adrenaline is the predominant circulating endogenous catecholamine in humans. Because it is a natural catecholamine available at low cost, adrenaline is regularly used in the treatment of septic shock in a number of centres. The physiological responses to exogenous adrenaline are dose dependent. At low doses, adrenaline is predominantly a balanced [3-adrenergic receptor stimulant through its action on [31- (inotropic and
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chronotropic effects) and [32-receptors (vasodilating effect). At higher doses the o>adrenergic effects become more prominent, with increases in both systolic and diastolic pressures and in systemic vascular resistance. Bollaert et al (1990) investigated the effects of adrenaline in 13 patients with septic shock who remained hypotensive despite a dose of dopamine > 15 p~gkg -1 min -1. In these patients the infusion of high doses of adrenaline, reaching 0.5-1 p~gkg-1 min-1, was associated with significant increases in arterial pressure, pulmonary artery pressure, systemic vascular resistance, cardiac index and stroke volume. However, as in other studies, the pulmonary artery occlusion pressure was low, averaging 9 mm Hg, so that further fluid therapy could be beneficial before the introduction of a vasoactive agent. Other studies have reported an increase in arterial pressure and cardiac output following administration of adrenaline in patients with septic shock (Lipman et al, 1991; Mackenzie et al, 1991; Wilson et al, 1992). More recently, a group of Australian investigators (Moran et al, 1993) reported their experience with adrenaline in 18 patients with septic shock who had received abundant fluid resuscitation up to a pulmonary artery occlusion pressure of 19 mm Hg. They observed a significant increase in arterial pressure and cardiac output. However, the increase in cardiac output rapidly reached a plateau, despite a further increase in heart rate, so that the stroke volume eventually declined. Specifically, increasing the dose of adrenaline from 3 to 18 ~g/min had no effect on cardiac index (from 4.2 to 4.31 min -1 m -z) or oxygen delivery (Do2) (from 547 to 531ml min -1m-z), but markedly increased mean arterial pressure (from 70 to 81 mm Hg) and heart rate (from 104 to 122 beats per rain) and reduced stroke volume (from 43 to 36 ml/m- 2 ). Arterial pH simultaneously declined, from 7.28 to 7.21. Hence, the effects of adrenaline at low doses are similar to those of dopamine. At higher doses, the effects are more comparable to those of noradrenaline. At any rate, the risk of tachyarrhythmia is greater with adrenaline than with other agents, so that it should not replace them. Phenylephrine is another vasoconstrictor agent that acts almost exclusively by stimulating the o~-adrenergic receptors, and thus has less effect on the heart rate than noradrenaline, which also has [3-adrenergic effects. Gregory et al (1991) reported their experience with the use of phenylephrine in patients with septic shock. The dosage of phenylephrine was titrated to maintain the mean arterial pressure above 70mmHg. Administration of phenylephrine was apparently associated with increases in Do2 and oxygen consumption (Vo2) and a reduction in blood lactate concentration. Phenylephrine may therefore be considered but should be reserved for extreme situations, when other vasoactive drugs have failed to correct the hypotension. An important issue is whether or not, by increasing vascular resistance, vasoconstrictors may improve tissue extraction capabilities. Studies reporting a beneficial effect of noradrenaline or adrenaline have usually failed to document an increase in Do~ and Vow,or have even reported an increase in blood lactate concentrations. In the studies using noradrenaline, cardiac output usually failed to increase (Desjars et al, 1987, 1989; Meadows et al,
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1988; Fukuoka et al, 1989; Redl-Wenzl et al, 1993), and the increases in Do2 and Vo2 were not consistent (Meadows et al, 1988; Hesselvik and Brodin, 1989; Redl-Wenzl et al, 1993). In some patients profound reductions in Do2 and increases in blood lactate concentrations were observed (Meadows et al, 1988; Hesselvik and Brodin, 1989). Similar observations have been made in studies using adrenaline. In the study by Bollaert et al (1990), despite increases in Do2 and Vo2 and a reduction in oxygen extraction, adrenaline infusion was associated with an increase in blood lactate concentrations. Mackenzie et al (1991) reported an increase in Do~, but a minimal increase in Vo2, and thus a reduction in oxygen extraction. Wilson et al (1992) also observed a rise in Do~ and no change in Vo2, and thus a reduction in oxygen extraction. In addition, in this study there was a concurrent increase in blood lactate levels. Taken together, these studies failed to indicate a significant improvement in cellular oxygenation under vasopressor therapy. Clearly, it is difficult to assess the effects of vasoactive agents on the oxygen extraction capabilities of acutely ill patients, so this needs to be studied experimentally. In the absence of sepsis, adrenergic agents such as noradrenaline and dobutamine do not increase the extraction capabilities when blood flow is reduced acutely (Cain and Chapter, 1981; Zhang et al, 1994). In endotoxic shock in pigs, Breslow et al (1987) studied the effects of dopamine, noradrenaline and phenylephrine on organ blood flow with radiolabelled microspheres. None of these agents influenced the blood flow distribution in this model, but noradrenaline increased left ventricular blood flow. In an endotoxic shock model in the dog, Hussain et al (1988) showed that noradrenaline had no beneficial effect on blood flow in comparison with fluid. In another dog model of endotoxic shock, Bakker and Vincent (1993) recently demonstrated that noradrenaline appears to increase Vo2 slightly more than dobutamine for a similar Do~. However, dobutamine increased Do~ more consistently than noradrenaline. Moreover, both agents induced a similar reduction in oxygen extraction for any given increase in Do~. Some recent studies have indicated that agents with vasodilator properties may improve the extraction capabilities in septic shock. For instance, prostaglandinE1 (PGE1) has recently been shown to improve the extraction capabilities when blood flow is acutely reduced with the use of positive end-expiratory pressure in pigs (Groeneveld et al, 1991). In a tamponade model, the alterations in oxygen extraction capabilities following endotoxin administration were reversed with PGE1 (Zhang et at, 1992) but not with sodium nitroprusside (personal observations). In the same model, pentoxiphyllin, a vasodilator with important anti-inflammatory effects (Zhang, 1992), or N-acetylcysteine, an antioxidant substance, also markedly improved the oxygen extraction (Zhang et al, 1993). These beneficial properties may in part be related to an interference with the inflammatory response, which is incriminated in these peripheral haemodynamic changes. Some of these effects may be due to microvascular dilatation, which results in a lesser distance for oxygen diffusion from the red blood cell to the cell mitochondria. In conclusion, vasoconstrictor agents can restore tissue perfusion
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pressure, but have little capacity to improve the peripheral blood distribution and cellular oxygen availability. Titration of the vasopressor therapy according to calculations of systemic vascular resistance carries the risk of limiting blood flow to the tissues. It is more advisable to titrate therapy according to the level of arterial pressure. After achieving adequate cardiac filling pressures with fluid therapy, most investigators recommend dopamine as the first agent to restore tissue perfusion pressure, adding noradrenaline if this goal is not achieved. INCREASE IN MYOCARDIAL CONTRACTILITY In the presence of reduced myocardial contractility, an agent with predominant inotropic properties without strong vasoconstrictor effects is preferred. Dobutamine has become the drug of choice to increase myocardial contractility. This drug increases cardiac output but has little effect on arterial pressure. With higher doses some reduction of arterial pressure can be observed secondary to some vasodilating effects. In any case, when a reduction in blood pressure occurs during dobutamine administration, unsuspected hypovolaemia must be considered (Shoemaker et al, 1986; Vincent et al, 1990). Vincent et al (1990) studied the effects of the addition of 5 txg kg -z min -1 dobutamine to a standard resuscitation regimen in 18 patients with septic shock. The resuscitation consisted of intravenous fluids and administration of dopamine and/or noradrenaline to maintain a systolic arterial pressure above 90mmHg. Dobutamine increased the cardiac index from 3.0 to 3.91 min -1 m -2 without influence on arterial or cardiac filling pressures. Dobutamine also has a potential beneficial effect on cardiac filling pressures. All catecholamines may increase cardiac filling pressures and limit fluid administration. Unlike dopamine, dobutamine either has no effect or reduces cardiac filling pressures. In a dog model of endotoxic shock, Vincent et al (1987) compared the effects of dopamine and dobutamine during fluid resuscitation. Fluid infusion was titrated to maintain cardiac filling pressures at constant level. The total amount of fluid was significantly greater with dobutamine, and the combination of dobutamine and fluids resulted in higher Do2 and Vo2values than in the dopamine group. The dose of dobutamine to be recommended is a difficult problem. Despite the well-documented decreased response to adrenergic stimulation in patients with septic shock, the response to dobutamine generally remains quite satisfactory, so that required dose seldom exceeds 10-15 txg kg -1 min -~. A dose of 5 p,g kg- 1min- ~usually suffices to increase cardiac output, Do2 and Vo2 (Vincent et al, 1990). The dobutamine infusion should be titrated according to the patient's needs. Clearly, repeated clinical assessments are important. As the Vo]Do2dependency phenomenon is associated with lactic acidosis, repeated measurement of blood lactate levels can provide an important clue. Repeated determinations of mixed venous oxygen saturation and oxygen extraction can also be helpful in the recognition of Vo]Do2 dependency (Vincent, 1991b).
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Dopexamine is a synthetic catecholamine with structural and pharmacological similarities to dopamine. Like dopamine, it stimulates the dopaminergic receptors, causing vasodilatation in the renal, splanchnic and coronary circulations (Bilski et al, 1983; Brown et al, 1983). Dopexamine has a potent [3-adrenergic receptor agonist effect, but no o~-adrenergic properties. It improves cardiac performance in septic shock but also increases the heart rate and decreases the systemic vascular resistance (Collardyn et al, 1989). Preiser et al (1989) compared the effects of dopexamine and dobutamine in endotoxic dogs and intravenous fluids; they observed that the left ventricular stroke index increased more with dobutamine and the systemic vascular resistance decreased more with dopexamine. With both drugs the cardiac output and the Do2 increased without adverse effects on tissue perfusion pressure. Dopexamine causes tachycardia that usually becomes clinically important at dosages exceeding 4 ~g kg -1 rain -1 (Dawson et al, 1985; Vincent et al, 1989). This effect can limit its use more than the potential decrease in arterial pressure resulting from a decrease in systemic vascular resistance. Hence, dopexamine administered at low doses can be seen as an adjunctive agent, as a substitute to low doses of dopamine to increase blood flow to the renal and splanchnic circulations. NON-ADRENERGIC AGENTS Other vasoconstrictive agents
Some investigators have used angiotensin II (Thomas and Nielsen, 1991) or vasopressin (unpublished data) to increase arterial pressure in extreme forms of cardiovascular collapse. These agents may have the attractive property of acting without stimulation of the adrenergic receptors. Although a-, like [3-, adrenergic receptors can be desensitized in patients with septic shock, requiring higher doses of adrenergic agents, unresponsiveness to adrenergic stimulation does not occur. Interference with nitric oxide
Endotoxin, like a number of mediators of sepsis (TNF, interleukin 1, interferon -/), can activate the inducible nitric oxide (NO) synthase, resulting in increased release of this vasodilating substance. Intuitively, blockade of the effects of NO may represent an effective way to increase arterial pressure. There have been some reports indicating that substances such as L-N-methylarginine can increase arterial pressure in septic shock. This form of therapy has not been shown to increase cardiac output. Similarly, blockade of the vasodilating effects of NO with methylene blue may not increase cellular oxygen availability (Preiser et al, 1993a). Some experimental studies have shown that blockade of NO release may increase the mortality rate in sepsis (Klabunde and Ritger, 1991; Cobb et al, 1992; Wright et al, 1992; Preiser et al, 1993b). Until further information is available, these forms of therapy remain experimental.
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Phosphodiesterase inhibitors These substances inhibit the phosphodiesterase (PDE) fraction III of the myocardium, which is specific for the degradation of cyclic AMP (Mancini et al, 1985). The inhibition of PDE results in an increased concentration of cyclic AMP that causes an increase in intracellular calcium levels as well an increase uptake of calcium by the sarcoplasmic reticulum. These effects result in improvement of myocardial contractility and a relaxation of the vascular smooth muscle with subsequent vasodilatation. Unfortunately, these compounds have a long half-life which limits their use in circulatory shock. The use of these agents is particularly attractive in combination with adrenergic agents to increase their effects on the cyclic AMP levels in the myocardium. Several investigators have stressed the interest of combining PDE inhibitors with adrenergic agents in patients with congestive heart failure (Gage et al, 1986) and even cardiogenic shock (Vincent et al, 1988). In endotoxic shock with dogs, De Boelpaepe et al (1989) studied the effects of the addition of amrinone to noradrenaline to test the hypothesis that the two agents could exert synergistic effects on myocardial function and opposite effects on the peripheral circulation. The combination of drugs resulted in a greater increase of cardiac output and Do2 than noradrenaline alone, without a significant reduction in arterial pressure. In human septic shock, the clinical application of this observation is made difficult by the underlying vasodilatation and the long half-life of these agents. Nevertheless, there are some observations that stress the value of PDE inhibitors in severe forms of myocardial depression associated with septic shock (Vincent et al, 1986). Calcium agonists and calcium entry blockers Calcium agonists can increase cardiac output and systemic vascular resistance. Preiser et al (1991) studied an experimental agent in a dog model of endotoxic shock that has strong vasopressor effects but similar inotropic effects as noradrenaline. However, these substances have limited use owing to a strong coronary vasoconstriction. It is also not clear whether increasing calcium availability to the cell can be deleterious in sepsis. A low ionized calcium concentration is related to mortality in critically ill patients (Zaloga, 1992). However, experimental studies have shown that calcium supplementation is associated with an increased mortality rate in sepsis (Zaloga et al, 1992). In addition, the use of calcium-entry blockers in endotoxic (Lee and Lum, 1986) or bacteraemic (Bosson et al, 1986) shock exerts protective effects and improved survival. Vasodilators Vasodilators are important in the treatment of heart failure, but they have a limited use in septic shock as they reduce arterial pressure. Nevertheless, Cerra et al (1978) suggested that the prudent use of nitrates may improve cardiovascular function in patients with septic shock and vasoconstriction
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associated with heart failure. As discussed above, some vasodilating agents may improve the oxygen extraction capabilities by improving blood flow in hypoxic regions. This was also the basis for the prostacyclin administration in critically ill patients by Bihari et al (1987). Recent developments related to the role of N O in septic shock may open a new field of opportunities. As mentioned above, blockade of the effects of N O may not improve the cellular oxygen availability in cardiovascular collapse due to sepsis (Preiser et al, 1993b). We may find out in the future that increasing N O availability may be beneficial in some forms of severe sepsis.
CONCLUSIONS The restoration of tissue perfusion pressure and restoration of sufficient Do2 should be complementary. Importantly, fluid therapy should remain the basis for the initial resuscitation of septic shock. If haemodynamic stability is not achieved, dopamine can be administered as the first vasopressor agent. Noradrenaline can be added if tissue perfusion pressure is not restored with high doses of dopamine. Once the perfusion pressure is restored, attention should focus on the improvement in blood flow and oxygen availability to the cells. For this purpose, the adjunction of dobutamine is often beneficial. It is important to base the vasoactive treatment of sepsis and septic shock on the pathophysiological alterations. The correction of severe hypotension is necessary, but not sufficient to prevent complications. The aim of the vasoactive treatment in severe sepsis is to restore sufficient oxygen availability to the cell. Nevertheless, vasoactive therapy alone is not life-saving if the septic source is not correctly managed.
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Preiser JC, Armistead CW, Le Minh T et al (1989) Increase in oxygen supply during experimental septic shock: the effects of dobutamine versus dopexamine. Journal of Critical Care 4: 40. Preiser JC, Moulart D, Cosyns B e t al (1991) Administration of the calcium antagonist BAY K 8644 in endotoxic shock. Circulatory Shock 35: 199-206. Preiser JC, Lejeune P, Roman A et al (1993a) Use of methylene blue in patients with refractory septic shock. Circulatory Shock $2:68 (abstract). Preiser JC, Zhang H, Wachel D et al (1993b) Is endotoxin-induced hypotension related to nitric oxide formation? European Surgical Research (in press). Redl-Wenzl EM, Armbruster C, Edelmann G e t al (1993) The effects of norepinephrine on hemodynamics and renal function in severe septic shock states. Intensive Care Medicine 19: 151-154. Schaer GL, Fink MP & Parrillo JE (1985) Norepinephrine alone versus norepinephrine plus low dose dopamine: enhanced renal blood flow with combination pressor therapy. Critical Care Medicine 13: 492. Shoemaker WC, Appel PL & Kram HB (1986) Hemodynamic and oxygen transport effects of dobutamine in critically ill general surgical patients. Critical Care Medicine 14: 10321037. Silverman HJU, Penaranda R, Orens JB et al (1993) Impaired beta-adrenergic stimulation of cyclic adenosine monophosphate in human septic shock: association with myocardial hyporesponsiveness to catecholamines. Critical Care Medicine 21: 31-39. Thomas VK & Nielsen MS (1991) Administration of angiotensin II in refractory septic shock. Critical Care Medicine 19: 1084-1086. Vicaut E, Hou X, Payen D et al (1991) Acute effects of tumor necrosis factor on the microcirculation in rat cremaster muscle. Journal o f Clinical Investigation 87: 1537-1540. Vincent JL (1991a) Diagnostic and medical management/supportive care of patients with Gram-negative bacteremia and septic shock. Infectious Disease Clinics o f North America 5: 807-816. Vincent JL (1991b) Advances in the concepts of intensive care. American Heart Journal 121: 1859-1865. Vincent 3L (1994) Renal effects of dopamine: may our dream ever come true? Critical Care Medicine (in press) (editorial). Vincent JL, Reeth VO, Bogaert VE et al (1986) Use of the new inotropic agent ARL-115 BS to treat severe myocardial depression in septic shock. Critical Care Medicine 14: 661-662. Vincent JL, Van der Linden P, Domb M e t al (1987) Dopamine compared with dobutamine in experimental septic shock: relevance to fluid administration. Anesthesia and Analgesia 66: 565-571. Vincent JL, Carlier E, Berre J e t al (1988) Administration of enoximone in cardiogenic shock. American Journal of Cardiology 62: 419-423. Vincent JL, Reuse C & Kahn RJ (1989) Administration of dopexamine, a new adrenergic agent, in cardiorespiratory failure. Chest 96: 1233-1236. Vincent JL, Roman A & Kahn RJ (1990) Dobutamine administration in septic shock: addition to a standard protocol. Critical Care Medicine 18: 689-693. Vincent JL, Gris P, Coffernils M e t al (1992a) Myocardial depression and decreased vascular tone characterized fatal course from septic shock. Surgery 111: 660-667. Vincent JL, Bakker J, Marecaux G et al (1992b) Anti-TNF antibodies administration increases myocardial contractility in septic shock patients. Chest 101: 810-815. Wilson W, Lipman J, Scribante J e t al (1992) Septic shock: does adrenaline have a role as a first-line inotropic agent? Anaesthesia and Intensive Care 20: 470-474. Wright CH, Rees DD & Moncada S (1992) Protective and pathological roles of nitric oxide in endotoxin shock. Cardiovascular Resuscitation 26: 48--57. Zaloga GP (1992) Hypocalcemia in critically ill patients. Critical Care Medicine 20: 251-262. Zaloga GP, Sager A, Black KW et al (1992) Low dose calcium administration increases the mortality during septic peritonitis in rats. Circulatory Shock 37: 226-229. Zhang H (1992) Pentoxifylline increases oxygen extraction during tamponade in an endotoxin shock model. Intensive Care Medicine 18: $231. Zhang H, Benlabed M, Dur Nam N & Vincent JL (1992) Effects of prostaglandin E1 on oxygen extraction in experimental cardiac tamponade associated with sepsis. American Review o f Respiratory Disease 145: A683.
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Zhang H, Spapen H, Nguyen DN et al (1993) N-acetylcysteine can improve O2 extraction following endotoxemia. American Review o f Respiratory Disease 147: A615. Zhang H, Spapen H & Vincent JL (1994) The effects of dobutamine and norepinephrine on oxygen availability in tamponade-induced stagnant hypoxia. Critical Care Medicine (in press).
Septic shock is a distributive form of shock, associated with peripheral vasodilatation, pooling of blood and decreased venous return to the heart (Vincent, 1991a). Alterations in oxygen extraction are secondary to the alterations in vascular tone and endothelial cell function. The severity of the peripheral vasodilatation has been directly related to the severity of sepsis (Groeneveld et al, 1986; Parker et al, 1989; Vincent et al, 1992a). Myocardial depression can also occur relatively early and is related to decreased coronary perfusion, myocardial oedema and release of various myocardial depressant substances. The degree of myocardial depression has been also shown to be directly proportional to the severity of sepsis (McDonough et al, 1986; D'Orio et al, 1990; Vincent et al, 1992a). The peripheral and myocardial alterations seen in severe sepsis share some causative mechanisms. Both are associated with the release of various mediators, such as tumour necrosis factor and interleukin-1 (Vicaut et al, 1991; Hollenberg et al, 1992; Vincent et al, 1992b), and both exhibit a decreased response of adrenergic receptors to their stimulation (Silverman et al, 1993). Besides the removal of the septic focus and the administration of antibiotic agents, immediate therapy of severe sepsis requires the restoration of haemodynamic stability by the administration of fluids and adrenergic agents. It is essential to emphasize that vasoactive therapy is no substitute for fluid therapy. The clinician is often afraid that an excessive increase in the cardiac filling pressure may lead to the development of pulmonary oedema. However, fluid overload, although a source of considerable morbidity, is not likely to limit the chances of survival. On the other hand, the maintenance of any degree of hypovolaemia can lead to the persistence of tissue hypoxia and subsequent multiple organ failure. HAEMODYNAMIC PATTERNS OF SEVERE SEPSIS
There was a time when vasoactive treatment of severe sepsis was based primarily on the recognition of one of two typical haemodynamic patterns: Baillibre' s Clinical Anaesthesiology--
Vol. 8, No. 1, March 1994 ISBN 0-7020-1824-4
265 Copyright 9 1994, by Bailli~re Tindall All rights of reproduction in any form reserved
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(a) the hyperkinetic state, characterized by a high cardiac output and low systemic vascular resistance, in which vasopressors were thought to be particularly indicated; and (b) the less common hypokinetic state, due to profound myocardial depression, in which inotropic agents were thought to have a place. These schematic, and somewhat simplistic, views have been reevaluated in view of recent developments in the pathophysiology of septic shock. The haemodynamic presentation of severe sepsis corresponds to a spectrum of alterations, and the division into two subsets is arbitrary. In addition, the peripheral and the cardiac alterations coexist in all forms of septic shock. Myocardial depression can be present even when cardiac output is normal or high, as indicated by the analysis of ventricular function curves (D'Orio et al, 1990; Vincent et al, 1992a) or the determination of ventricular ejection fractions (Parker et al, 1989; Vincent et al, 1992a). An alteration in vascular tone can persist even when cardiac output is reduced. It is more appropriate to distinguish between the peripheral and the myocardial alterations associated with severe sepsis, and therefore to consider vasoactive therapy in septic shock as having two objectives. The first objective is to increase the vascular tone to restore adequate tissue perfusion pressure. The second is to increase myocardial contractility, not only to correct the myocardial depression as such, but also to use the heart as a pump to deliver more oxygen to the tissues.
R E S T O R A T I O N OF TISSUE PERFUSION P R E S S U R E
Vasopressor therapy is commonly required after initial resuscitation with fluids to restore a minimal tissue perfusion pressure. A systolic blood pressure above 90 mm Hg or a mean arterial pressure of 70 mm Hg is the usual goal. Dopamine is the drug of choice for its combined a, [3 and dopaminergic properties, resulting in combined increases in cardiac output and arterial pressure. The vasoconstrictive effects of dopamine become increasingly potent as the doses are increased by progressive a-adrenergic stimulation. Dopamine, the natural precursor of noradrenaline, is not as potent a vasoconstrictor, so that blood flow can be better maintained with dopamine than with noradrenaline. In addition, the dopaminergic effects can help to preserve blood flow in the renal and splanchnic beds. Dopamine is useful in controlling hypotension, but, if an adequate arterial pressure is not achieved with doses up to 20 to 25txgkg-1min -1, noradrenaline can be started (Vincent, 1991a). Recommended doses are not appropriate for the administration of noradrenaline. After restoring the cardiac filling pressure, the dose of noradrenaline must be titrated to maintain a systolic blood pressure of 90-100 mm Hg. Because of its strong a-stimulating effects, noradrenaline can effectively restore vascular tone. It also induces less tachyarrhythmia than dopamine and other adrenergic agents. For these reasons, some investigators have proposed using noradrenaline early in high-output states to increase
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vascular resistance (Des jars et al, 1987, 1989; Meadows et al, 1988; Fukuoka et al, 1989; Hesselvick and Brodin, 1989; Martin et al, 1990; Gregory et al, 1991). However, the use of stronger vasoconstrictors such as noradrenaline carries a risk of aggravating the perfusion failure by limiting the blood flow to the capillaries. Other vasoconstrictors, such as phenylephrine, metaraminol, mephentermine or methoxamine, were used in the past to increase blood pressure in patients with shock states, but have been virtually abandoned for their undesired effects on organ function. Noradrenaline decreases mesenteric blood flow, which can lead to splanchnic ischaemia and may facilitate bacterial translocation and endotoxin resorption from the gut. It increases renal vascular resistance and therefore has a potentially deleterious effect on renal function. Nevertheless, several studies have stressed that noradrenaline may sometimes have a positive rather than a negative effect on renal function. In all the studies in which a beneficial effect was found, the patients were initially very hypotensive, so that it is not clear whether increasing systemic vascular resistance as such can be beneficial (Desjars et al, 1987, 1989; Meadows et al, 1988; Fukuoka et al, 1989; Hesselvick and Brodin, 1989; Martin et al, 1990; Gregory et al, 1991; Redl-Wenzl et al, 1993). In these studies the pulmonary artery occlusion pressure was also low. Hence, the question was raised whether further fluid therapy could have corrected some degree of hypovolaemia and improved renal function. Fukuoka et al (1989) reported an increase in urine flow in nine patients with hypotension without circulatory failure, but a worsening of renal function in six other patients with established septic shock. Hence, the risk of alterations in renal function cannot be underestimated. An important question to answer is whether a low dose of dopamine should be maintained to attenuate the reduction in renal blood flow under the influence of noradrenaline. At low doses (< 5 Ixg kg -1 min -1) dopamine may increase renal blood flow by its dopaminergic properties, but at higher doses the s-stimulating effect becomes significant and the effect on renal blood flow is lost. Hence, it is doubtful that low doses of dopamine exert any protective effects on the renal vasculature in the presence of strong o~-adrenergic stimulation (Vincent, 1994). In dogs, Schaer et al (1985) studied the effects of incremental dosage of noradrenaline alone versus supplementation with 4 txgkg-amin -1 dopamine. Renal blood flow was increased only in the dopamine group, and no change was observed in the noradrenaline group. Interpretation of this experimental study is limited by the fact that, in these acute conditions, noradrenaline increased both arterial pressure and cardiac output but exerted hardly any effect on systemic vascular resistance. Hence, whether low doses of dopamine can exert a protective effect on renal function remains highly speculative. Adrenaline is the predominant circulating endogenous catecholamine in humans. Because it is a natural catecholamine available at low cost, adrenaline is regularly used in the treatment of septic shock in a number of centres. The physiological responses to exogenous adrenaline are dose dependent. At low doses, adrenaline is predominantly a balanced [3-adrenergic receptor stimulant through its action on [31- (inotropic and
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chronotropic effects) and [32-receptors (vasodilating effect). At higher doses the o>adrenergic effects become more prominent, with increases in both systolic and diastolic pressures and in systemic vascular resistance. Bollaert et al (1990) investigated the effects of adrenaline in 13 patients with septic shock who remained hypotensive despite a dose of dopamine > 15 p~gkg -1 min -1. In these patients the infusion of high doses of adrenaline, reaching 0.5-1 p~gkg-1 min-1, was associated with significant increases in arterial pressure, pulmonary artery pressure, systemic vascular resistance, cardiac index and stroke volume. However, as in other studies, the pulmonary artery occlusion pressure was low, averaging 9 mm Hg, so that further fluid therapy could be beneficial before the introduction of a vasoactive agent. Other studies have reported an increase in arterial pressure and cardiac output following administration of adrenaline in patients with septic shock (Lipman et al, 1991; Mackenzie et al, 1991; Wilson et al, 1992). More recently, a group of Australian investigators (Moran et al, 1993) reported their experience with adrenaline in 18 patients with septic shock who had received abundant fluid resuscitation up to a pulmonary artery occlusion pressure of 19 mm Hg. They observed a significant increase in arterial pressure and cardiac output. However, the increase in cardiac output rapidly reached a plateau, despite a further increase in heart rate, so that the stroke volume eventually declined. Specifically, increasing the dose of adrenaline from 3 to 18 ~g/min had no effect on cardiac index (from 4.2 to 4.31 min -1 m -z) or oxygen delivery (Do2) (from 547 to 531ml min -1m-z), but markedly increased mean arterial pressure (from 70 to 81 mm Hg) and heart rate (from 104 to 122 beats per rain) and reduced stroke volume (from 43 to 36 ml/m- 2 ). Arterial pH simultaneously declined, from 7.28 to 7.21. Hence, the effects of adrenaline at low doses are similar to those of dopamine. At higher doses, the effects are more comparable to those of noradrenaline. At any rate, the risk of tachyarrhythmia is greater with adrenaline than with other agents, so that it should not replace them. Phenylephrine is another vasoconstrictor agent that acts almost exclusively by stimulating the o~-adrenergic receptors, and thus has less effect on the heart rate than noradrenaline, which also has [3-adrenergic effects. Gregory et al (1991) reported their experience with the use of phenylephrine in patients with septic shock. The dosage of phenylephrine was titrated to maintain the mean arterial pressure above 70mmHg. Administration of phenylephrine was apparently associated with increases in Do2 and oxygen consumption (Vo2) and a reduction in blood lactate concentration. Phenylephrine may therefore be considered but should be reserved for extreme situations, when other vasoactive drugs have failed to correct the hypotension. An important issue is whether or not, by increasing vascular resistance, vasoconstrictors may improve tissue extraction capabilities. Studies reporting a beneficial effect of noradrenaline or adrenaline have usually failed to document an increase in Do~ and Vow,or have even reported an increase in blood lactate concentrations. In the studies using noradrenaline, cardiac output usually failed to increase (Desjars et al, 1987, 1989; Meadows et al,
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1988; Fukuoka et al, 1989; Redl-Wenzl et al, 1993), and the increases in Do2 and Vo2 were not consistent (Meadows et al, 1988; Hesselvik and Brodin, 1989; Redl-Wenzl et al, 1993). In some patients profound reductions in Do2 and increases in blood lactate concentrations were observed (Meadows et al, 1988; Hesselvik and Brodin, 1989). Similar observations have been made in studies using adrenaline. In the study by Bollaert et al (1990), despite increases in Do2 and Vo2 and a reduction in oxygen extraction, adrenaline infusion was associated with an increase in blood lactate concentrations. Mackenzie et al (1991) reported an increase in Do~, but a minimal increase in Vo2, and thus a reduction in oxygen extraction. Wilson et al (1992) also observed a rise in Do~ and no change in Vo2, and thus a reduction in oxygen extraction. In addition, in this study there was a concurrent increase in blood lactate levels. Taken together, these studies failed to indicate a significant improvement in cellular oxygenation under vasopressor therapy. Clearly, it is difficult to assess the effects of vasoactive agents on the oxygen extraction capabilities of acutely ill patients, so this needs to be studied experimentally. In the absence of sepsis, adrenergic agents such as noradrenaline and dobutamine do not increase the extraction capabilities when blood flow is reduced acutely (Cain and Chapter, 1981; Zhang et al, 1994). In endotoxic shock in pigs, Breslow et al (1987) studied the effects of dopamine, noradrenaline and phenylephrine on organ blood flow with radiolabelled microspheres. None of these agents influenced the blood flow distribution in this model, but noradrenaline increased left ventricular blood flow. In an endotoxic shock model in the dog, Hussain et al (1988) showed that noradrenaline had no beneficial effect on blood flow in comparison with fluid. In another dog model of endotoxic shock, Bakker and Vincent (1993) recently demonstrated that noradrenaline appears to increase Vo2 slightly more than dobutamine for a similar Do~. However, dobutamine increased Do~ more consistently than noradrenaline. Moreover, both agents induced a similar reduction in oxygen extraction for any given increase in Do~. Some recent studies have indicated that agents with vasodilator properties may improve the extraction capabilities in septic shock. For instance, prostaglandinE1 (PGE1) has recently been shown to improve the extraction capabilities when blood flow is acutely reduced with the use of positive end-expiratory pressure in pigs (Groeneveld et al, 1991). In a tamponade model, the alterations in oxygen extraction capabilities following endotoxin administration were reversed with PGE1 (Zhang et at, 1992) but not with sodium nitroprusside (personal observations). In the same model, pentoxiphyllin, a vasodilator with important anti-inflammatory effects (Zhang, 1992), or N-acetylcysteine, an antioxidant substance, also markedly improved the oxygen extraction (Zhang et al, 1993). These beneficial properties may in part be related to an interference with the inflammatory response, which is incriminated in these peripheral haemodynamic changes. Some of these effects may be due to microvascular dilatation, which results in a lesser distance for oxygen diffusion from the red blood cell to the cell mitochondria. In conclusion, vasoconstrictor agents can restore tissue perfusion
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pressure, but have little capacity to improve the peripheral blood distribution and cellular oxygen availability. Titration of the vasopressor therapy according to calculations of systemic vascular resistance carries the risk of limiting blood flow to the tissues. It is more advisable to titrate therapy according to the level of arterial pressure. After achieving adequate cardiac filling pressures with fluid therapy, most investigators recommend dopamine as the first agent to restore tissue perfusion pressure, adding noradrenaline if this goal is not achieved. INCREASE IN MYOCARDIAL CONTRACTILITY In the presence of reduced myocardial contractility, an agent with predominant inotropic properties without strong vasoconstrictor effects is preferred. Dobutamine has become the drug of choice to increase myocardial contractility. This drug increases cardiac output but has little effect on arterial pressure. With higher doses some reduction of arterial pressure can be observed secondary to some vasodilating effects. In any case, when a reduction in blood pressure occurs during dobutamine administration, unsuspected hypovolaemia must be considered (Shoemaker et al, 1986; Vincent et al, 1990). Vincent et al (1990) studied the effects of the addition of 5 txg kg -z min -1 dobutamine to a standard resuscitation regimen in 18 patients with septic shock. The resuscitation consisted of intravenous fluids and administration of dopamine and/or noradrenaline to maintain a systolic arterial pressure above 90mmHg. Dobutamine increased the cardiac index from 3.0 to 3.91 min -1 m -2 without influence on arterial or cardiac filling pressures. Dobutamine also has a potential beneficial effect on cardiac filling pressures. All catecholamines may increase cardiac filling pressures and limit fluid administration. Unlike dopamine, dobutamine either has no effect or reduces cardiac filling pressures. In a dog model of endotoxic shock, Vincent et al (1987) compared the effects of dopamine and dobutamine during fluid resuscitation. Fluid infusion was titrated to maintain cardiac filling pressures at constant level. The total amount of fluid was significantly greater with dobutamine, and the combination of dobutamine and fluids resulted in higher Do2 and Vo2values than in the dopamine group. The dose of dobutamine to be recommended is a difficult problem. Despite the well-documented decreased response to adrenergic stimulation in patients with septic shock, the response to dobutamine generally remains quite satisfactory, so that required dose seldom exceeds 10-15 txg kg -1 min -~. A dose of 5 p,g kg- 1min- ~usually suffices to increase cardiac output, Do2 and Vo2 (Vincent et al, 1990). The dobutamine infusion should be titrated according to the patient's needs. Clearly, repeated clinical assessments are important. As the Vo]Do2dependency phenomenon is associated with lactic acidosis, repeated measurement of blood lactate levels can provide an important clue. Repeated determinations of mixed venous oxygen saturation and oxygen extraction can also be helpful in the recognition of Vo]Do2 dependency (Vincent, 1991b).
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Dopexamine is a synthetic catecholamine with structural and pharmacological similarities to dopamine. Like dopamine, it stimulates the dopaminergic receptors, causing vasodilatation in the renal, splanchnic and coronary circulations (Bilski et al, 1983; Brown et al, 1983). Dopexamine has a potent [3-adrenergic receptor agonist effect, but no o~-adrenergic properties. It improves cardiac performance in septic shock but also increases the heart rate and decreases the systemic vascular resistance (Collardyn et al, 1989). Preiser et al (1989) compared the effects of dopexamine and dobutamine in endotoxic dogs and intravenous fluids; they observed that the left ventricular stroke index increased more with dobutamine and the systemic vascular resistance decreased more with dopexamine. With both drugs the cardiac output and the Do2 increased without adverse effects on tissue perfusion pressure. Dopexamine causes tachycardia that usually becomes clinically important at dosages exceeding 4 ~g kg -1 rain -1 (Dawson et al, 1985; Vincent et al, 1989). This effect can limit its use more than the potential decrease in arterial pressure resulting from a decrease in systemic vascular resistance. Hence, dopexamine administered at low doses can be seen as an adjunctive agent, as a substitute to low doses of dopamine to increase blood flow to the renal and splanchnic circulations. NON-ADRENERGIC AGENTS Other vasoconstrictive agents
Some investigators have used angiotensin II (Thomas and Nielsen, 1991) or vasopressin (unpublished data) to increase arterial pressure in extreme forms of cardiovascular collapse. These agents may have the attractive property of acting without stimulation of the adrenergic receptors. Although a-, like [3-, adrenergic receptors can be desensitized in patients with septic shock, requiring higher doses of adrenergic agents, unresponsiveness to adrenergic stimulation does not occur. Interference with nitric oxide
Endotoxin, like a number of mediators of sepsis (TNF, interleukin 1, interferon -/), can activate the inducible nitric oxide (NO) synthase, resulting in increased release of this vasodilating substance. Intuitively, blockade of the effects of NO may represent an effective way to increase arterial pressure. There have been some reports indicating that substances such as L-N-methylarginine can increase arterial pressure in septic shock. This form of therapy has not been shown to increase cardiac output. Similarly, blockade of the vasodilating effects of NO with methylene blue may not increase cellular oxygen availability (Preiser et al, 1993a). Some experimental studies have shown that blockade of NO release may increase the mortality rate in sepsis (Klabunde and Ritger, 1991; Cobb et al, 1992; Wright et al, 1992; Preiser et al, 1993b). Until further information is available, these forms of therapy remain experimental.
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Phosphodiesterase inhibitors These substances inhibit the phosphodiesterase (PDE) fraction III of the myocardium, which is specific for the degradation of cyclic AMP (Mancini et al, 1985). The inhibition of PDE results in an increased concentration of cyclic AMP that causes an increase in intracellular calcium levels as well an increase uptake of calcium by the sarcoplasmic reticulum. These effects result in improvement of myocardial contractility and a relaxation of the vascular smooth muscle with subsequent vasodilatation. Unfortunately, these compounds have a long half-life which limits their use in circulatory shock. The use of these agents is particularly attractive in combination with adrenergic agents to increase their effects on the cyclic AMP levels in the myocardium. Several investigators have stressed the interest of combining PDE inhibitors with adrenergic agents in patients with congestive heart failure (Gage et al, 1986) and even cardiogenic shock (Vincent et al, 1988). In endotoxic shock with dogs, De Boelpaepe et al (1989) studied the effects of the addition of amrinone to noradrenaline to test the hypothesis that the two agents could exert synergistic effects on myocardial function and opposite effects on the peripheral circulation. The combination of drugs resulted in a greater increase of cardiac output and Do2 than noradrenaline alone, without a significant reduction in arterial pressure. In human septic shock, the clinical application of this observation is made difficult by the underlying vasodilatation and the long half-life of these agents. Nevertheless, there are some observations that stress the value of PDE inhibitors in severe forms of myocardial depression associated with septic shock (Vincent et al, 1986). Calcium agonists and calcium entry blockers Calcium agonists can increase cardiac output and systemic vascular resistance. Preiser et al (1991) studied an experimental agent in a dog model of endotoxic shock that has strong vasopressor effects but similar inotropic effects as noradrenaline. However, these substances have limited use owing to a strong coronary vasoconstriction. It is also not clear whether increasing calcium availability to the cell can be deleterious in sepsis. A low ionized calcium concentration is related to mortality in critically ill patients (Zaloga, 1992). However, experimental studies have shown that calcium supplementation is associated with an increased mortality rate in sepsis (Zaloga et al, 1992). In addition, the use of calcium-entry blockers in endotoxic (Lee and Lum, 1986) or bacteraemic (Bosson et al, 1986) shock exerts protective effects and improved survival. Vasodilators Vasodilators are important in the treatment of heart failure, but they have a limited use in septic shock as they reduce arterial pressure. Nevertheless, Cerra et al (1978) suggested that the prudent use of nitrates may improve cardiovascular function in patients with septic shock and vasoconstriction
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associated with heart failure. As discussed above, some vasodilating agents may improve the oxygen extraction capabilities by improving blood flow in hypoxic regions. This was also the basis for the prostacyclin administration in critically ill patients by Bihari et al (1987). Recent developments related to the role of N O in septic shock may open a new field of opportunities. As mentioned above, blockade of the effects of N O may not improve the cellular oxygen availability in cardiovascular collapse due to sepsis (Preiser et al, 1993b). We may find out in the future that increasing N O availability may be beneficial in some forms of severe sepsis.
CONCLUSIONS The restoration of tissue perfusion pressure and restoration of sufficient Do2 should be complementary. Importantly, fluid therapy should remain the basis for the initial resuscitation of septic shock. If haemodynamic stability is not achieved, dopamine can be administered as the first vasopressor agent. Noradrenaline can be added if tissue perfusion pressure is not restored with high doses of dopamine. Once the perfusion pressure is restored, attention should focus on the improvement in blood flow and oxygen availability to the cells. For this purpose, the adjunction of dobutamine is often beneficial. It is important to base the vasoactive treatment of sepsis and septic shock on the pathophysiological alterations. The correction of severe hypotension is necessary, but not sufficient to prevent complications. The aim of the vasoactive treatment in severe sepsis is to restore sufficient oxygen availability to the cell. Nevertheless, vasoactive therapy alone is not life-saving if the septic source is not correctly managed.
REFERENCES Bakker J & Vincent JL (1993) Effects of norepinephrine and dobutamine on oxygentransport and consumptionin a dog model of endotoxicshock. Critical Care Medicine 21: 425-432. Bihari D, Smithies M, Gimson A et al (1987) The effects of vasodilation with prostacyclinon oxygendeliveryand uptake in criticallyill patients. New England Journal of Medicine 317: 397-403. Bilski AJ, Halliday SE, Fitzgerald JD et al (1983) The pharmacologyof a beta2-selective adrenoreceptor antagonist. Journal of Cardiovascular Pharmacology 5: 430-435. De Boelpaepe C, Vincent JL, Contempre Bet al (1989) Combination of norepinephrine and amrinone in the treatment of endotoxin shock. Journal of Critical Care 4: 202-207. Bollaert PE, Bauer PH, Audibert G etal (1990) Effects of epinephrine on hemodynamicsand oxygen metabolism in dopamine resistant shock. Chest 98: 949-953. Bosson S, Kuenzig M & Schwartz SI (1986) Increased survival with calcium antagonists in antibiotic-treated bacteremia. Circulatory Shock 19: 69-74. Breslow MJ, Miller CF, Parker SD et al (1987) Effect of vasopressors on organ blood flow during endotoxin shock in pigs. American Journal of Physiology 252: H291-H300. Brown RA, Dixon J, Farmer JB et al (1983) Dopexamine: a novel agonist at peripheral dopamine receptors and beta-2 adrenoreceptors. British Journal of Pharmacology 5: 430--434. Cain SM & Chapler CK (1981) Effects of norepinephrine and alpha-blockon 02 uptake and blood flowin dog hindlimb. Journal of Applied Physiology 51: 1245-1250.
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