12RC3 Martin. Haemodynamic Management of Septic Shock. Claude Martin, Introduction. Objectives in the initial resuscitation of septic shock - 1 -

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1 12C3 Martin Haemodynamic Management of Septic Shock Claude Martin, Département d nesthésie et de éanimation et Centre de Traumatologie, Hôpital Nord, ssistance Publique-Hôpitaux de Marseille, Marseille Cedex 20, France Introduction Several factors contribute to organ dysfunction in patients who have developed septic shock. nce the inflammatory response has been activated, many organ systems can be adversely affected. marked fall in systemic vascular resistance results from arterial and venous dilatation. This is accompanied by leakage of plasma into the extravascular space, leading to relative hypovolaemia. The microcirculation is adversely affected, with impairment of blood flow. Importantly, oxygen neither reaches nor is effectively extracted by cells, probably because of arteriovenous shunting or abnormalities in cellular metabolism. t the organ level, blood flow and perfusion pressure is regulated by two control mechanisms. The first, extrinsic mechanism, involves a complex interaction of vasomotor effects between opposing neurohormonal systems. The second, intrinsic mechanism is organ autoregulation. This depends on changes in afferent arteriolar tone in response to organ perfusion pressure itself. In healthy subjects, below the autoregulation threshold, organ blood flow behaves in a linear manner which is dependent on perfusion pressure (Figure 1). In patients with septic shock, the autoregulation system is again disturbed resulting in a linear relation between organ blood flow and perfusion pressure. Haemodynamic factors such as volume depletion, low cardiac output or inappropriate vasodilation resulting in systemic hypotension may directly produce organ hypoperfusion through a reduction in organ perfusion pressure. Therefore, one goal of haemodynamic resuscitation in septic shock should be to restore adequate organ perfusion pressure without impairing blood flow to the organ. Figure 1. Theoretical organ pressure-flow relationship. Below ± 70 mmhg there is a linear dependence of organ blood flow on perfusion pressure (subautoregulatory slope). The intercept of the autoregulated zone (horizontal line) and the subautoregulatory slope is the autoregulatory threshold (± 70 mmhg in this particular case). bjectives in the initial resuscitation of septic shock From the Surviving Sepsis Campaign guidelines, the end-points for initial resuscitation (in the first six hours) are: central venous pressure (CVP) between 8 and 12 mmhg, mean arterial pressure (MP) > 65 mmhg, urine output > 0.5 ml/kg/h, and central venous (superior vena cava) oxygen saturation (Scv 2 ) > 70% [1]. Several limitations related to these guidelines need to be stressed: Specific end-points remain undetermined for the resuscitation of late septic shock. The use of CVP measurement to assess preload responsiveness is controversial because of its poor predictive value. Measurement of dynamic parameters could be used in preference to static parameters to predict fluid responsiveness in septic patients

2 The optimum level of MP is still unknown, although a target of 65 mmhg seems equivalent to higher pressures. bnormalities of oxygen distribution in patients with septic shock can occur despite a normal blood pressure. normal or elevated Scv 2 associated with an increased lactic acidaemia can act as surrogate measures of a reduction in peripheral oxygen utilization. prominent feature of sepsis is disruption to the microcirculation, with impaired perfusion and regional tissue oxygenation causing a deficit in oxygen extraction. Vasopressors Vasopressor agents should be used in patients with septic shock according to practical considerations (Table 1). The basic catecholamine structure is a phenylethylamine with three hydroxyl groups. The effects of catecholamines range from pure α-agonist to pure β-agonist (Table 2). Briefly, α-agonist stimulation produces a vasoconstriction, whereas β-agonist stimulation increases cardiac performance. Pure β-agonist will be not considered hereafter. Criteria for prescribing a vasopressor agent No response to fluid infusion Mean arterial pressure 60 mmhg (emergently if 40 mmhg) liguria High lactate level Criteria of effectiveness Mean arterial pressure > mmhg No decrease in cardiac index or Scv2* eestablishment of urine output Decrease in blood lactate level dequate skin perfusion dequate level of consciousness Criteria for modulating the dose Decrease (15-20 %) in cardiac index or Scv 2 * (<70%)* (consider using dobutamine) Mean blood pressure mmhg Table 1. Use of vasopressor agents in septic shock (Scv2: central venous blood oxygen saturation) Table 2. drenergic receptor effects of catecholamines Dopamine is the immediate precursor of norepinephrine. t low doses D 1 receptors are activated causing vasodilatation of the renal and mesenteric circulation. t doses of 2-10 µg/kg/min, β-adrenergic stimulation has positive inotropic and chronotropic effects, while at higher doses, α-adrenergic stimulation results in peripheral vasoconstriction. Norepinephrine is the endogenous mediator of sympathetic nervous system and has both α- and β-adrenergic dose dependent effects. arge doses increase blood pressure via an α-adrenergic mediated vasoconstriction. Norepinephrine induces vasoconstriction visibly in many vascular beds (e.g. the skin and muscles), and could therefore alter visceral blood flow and, more especially, renal blood flow, impairing organ function. In experimental rat models, norepinephrine caused ischemia-induced acute renal failure [2]. However, it is - 2 -

3 not clear whether the same scenario of vasopressor-induced visceral hypoperfusion actually occurs in sepsis, which is characterized by marked vasodilation related to muscle α-adrenergic receptor hyporesponsiveness or massive quantities of nitric oxide production. When normal haemodynamic parameters exist, administration of norepinephrine in order to raise MP by 20% will not affect glomerular filtration. In contrast, when severe vasodilation (i.e. low systemic vascular resistance and high cardiac index) affects the systemic circulation, the infusion of norepinephrine, in order to restore tissue perfusion pressure, is accompanied by a restoration of urine filtration, a decrease in serum creatinine level, and an increase in creatinine clearance in septic patients. The beneficial effect of norepinephrine in septic patients is in agreement with the conclusions of several clinical reports [3-4]. pinephrine is synthesized, stored and released from the chromaffin cells of the adrenal medulla. t low doses, stimulation of β 1 - and β 2 -adrenergic receptors predominates while at higher dose ( µg/kg/min) α-adrenergic receptors are activated with resultant potent vasoconstriction (Table 2). pinephrine increases oxygen delivery in septic shock by increasing cardiac index without an effect on systemic vascular resistance index or pulmonary artery occlusion pressure [5]. It has been associated with an impaired effect at the level of splanchnic circulation. The decrease in splanchnic blood flow with epinephrine can be observed in the presence of three measures of deteriorating tissue oxygenation: a decrease in splanchnic bed oxygen consumption, a decrease in mucosal ph (phi), and an increase in lactic acidaemia [6]. Clinical studies Martin et al. compared the ability of dopamine and norepinephrine to reverse hemodynamic and metabolic abnormalities of human hyperdynamic septic shock [7]. t the doses tested in this study, norepinephrine was found to be more effective and reliable than dopamine to reverse the abnormalities of hyperdynamic septic shock. In the great majority of the patients studied, norepinephrine was able to increase mean perfusion pressure without apparent adverse effect on peripheral blood flow or on renal blood flow. t the same time, oxygen uptake was increased. In a non-randomized study, the same group found better survival in patients treated with norepinephrine than in those treated with dopamine or epinephrine [8]. Two studies seem to confirm that administration of dopamine can be associated with increased mortality in septic shock patients [9,10]. In a population of 110 septic shock patients, resistance to dopamine was associated with an increased risk of death (odds ratio, 9.5; 95% confidence interval, 3-25) [9]. The dopamine group of an observational study including 1058 patients with shock had higher hospital mortality rate (42.9% vs. 35.7%, P = 0.02) [10], while this effect was not found with other vasopressor agents. The stimulation of a-adrenoreceptors, by inducing contraction of mesenteric vascular smooth muscle, can result in gut ischemia. The effects of dopamine, norepinephrine, and epinephrine on the splanchnic circulation have been compared in patients with septic shock [11]. Dopamine was progressively withdrawn and replaced successively by norepinephrine and then epinephrine to maintain mean arterial pressure constant (moderate shock) or to increase mean arterial pressure above 65 mmhg (severe shock). This study showed that dopamine and norepinephrine have similar haemodynamic effects, while epinephrine can impair splanchnic circulation in severe septic shock. ecent randomized studies showed that this splanchnic effect does not appear to have an impact on the patient outcome. In a French study aimed to compare the efficacy and safety in 330 patients with septic shock who were randomised to receive norepinephrine plus dobutamine with those who received epinephrine alone, there was no significant difference between the two groups mortality rates [12]. nother large randomized trial compared dopamine and norepinephrine in 1679 patients. mong these patients 1044 had septic shock [13]. lthough there was no significant difference in death, the use of dopamine was associated with a greater number of adverse events. meta-analysis was conducted in patients with septic shock treated with either dopamine or norepinephrine. Six randomized studies were retrieved that included a total of 2769 patients [14]. The conclusion is clear: dopamine administration is associated with greater mortality and higher incidence of arrhythmic events, making norepinephrine the first choice for the treatment of septic shock

4 role for vasopressin? ver time, vascular responsiveness to catecholamines diminishes. This vascular hyporeactivity to catecholamines is most likely to be due to excessive nitric oxide formation associated with an activation of TP-sensitive potassium channels and reduction in calcium entry through voltage-gated calcium channels. Thus, the search for alternative vasopressors, used alone or in combination with standard therapies is of great interest. Vasopressin mediates vasoconstriction via V1-receptors, coupled to phospholipase C, and increases intracellular calcium concentration. The plasma vasopressin levels of septic shock patients are almost always increased at the initial phase of septic shock and decrease afterward [15]. large randomized clinical trial entitled the VSST study compared the survival of 778 patients with septic shock treated with vasopressin (up to 0.03 IU/min) or norepinephrine [16]. The inclusion criterion was septic shock requiring at least 5 µg/min of norepinephrine for at least six hours during the preceding 12 hours. Mean arterial pressure was targeted between 65 and 75 mmhg. The mortality was similar in both groups (35.4% versus 39.3%, P = 0.26). actic acidaemia and renal function were unaffected by the two treatments. The survival of patients with greater forms of shock, defined by an entry dosage of norepinephrine ranging from 5 to 14 µg/min, was increased in the group treated with vasopressin (26.5% versus 35.7%, P = 0.05). Three hypotheses may explain this result. First, the significance may be due the 5% probability that the statistical tests infer a positive outcome when none exists. Second, vasopressin may confer beneficial hormonal activity, independent of its vasopressor effect. Third, the addition of vasopressin may be inefficient in the patients treated with high doses of norepinephrine. In a recent meta-analysis, the potential role of vasopressin or terlipressin was evaluated. verall these drugs do not provide any survival benefit [17]. They have a sparing effect on norepinephrine requirements. They can be considered as rescue therapy when catecholamines fail to improve blood pressure. Conclusion Vasopressor agents are required to maintain a minimal level of blood pressure in septic shock patients. ecent evidence suggests norepinephrine is probably the drug of first choice. In several studies, dopamine is associated with a poor outcome, and more side-effects. Vasopressin improves the norepinephrine-mediated smooth vessel muscle contraction. Use of vasopressin can be associated with a decrease in output, which can be detrimental to certain patients. However, its use does not affect the outcome in patients with septic shock. arly recourse to combination therapy with norepinephrine and vasopressin in septic shock should be the subject of future studies. summary of the suggested haemodynamic management of patients with septic shock is presented in figure Urgent treatment excluding life-threatening sepsis 90 minutes 60 minutes Minimum monitoring 2 to achieve Sp 2 95% Fluid loading : Crystalloids : 500 ml/15 min to achieve MP > 65 mmhg or cf. age Volume : 60 ml/kg/1 h Start norepinephrine outine sampling ppropriate antibiotics Haemodynamic parameters normal? No comorbidities? Infection with good prognosis? actate < 4 mmol/l? YS N Intermediate care unit goals: MP > 65 mmhg or cf. age Urine output > 0.5 ml/kg/h N 2. Intensive care: goals and treatment strategies 6 hours Central venous catheter rterial catheter Septic focus treatment Microbiological samples G S N T C H D V U T I N Blood tests (lactate) Mechanical ventilation Treatment by steroids Continue fluid loading and norepinephrine? Goals No clinical signs of hypoperfusion MP > 65 mmhg or normal range for age Urine output > 0.5 ml/kg/h Scv 2 > 70% Transfusion target: Hb > 8g/dl Fluid loading if preload dependence Dobutamine (adrenaline) as directed by haemodynamic monitoring 3. Treatment adjustments Continue with goals educe treatment as stabilization occurs Consider vasopressin if norepinephrine is ineffective G S C H D Figure 2. Summary of haemodynamic management - 4 -

5 Key learning points Fluid resuscitation is always the first step of the haemodynamic management in patients with septic shock The use of norepinephrine or epinephrine can be left to the discretion of the treating physician, but norepinephrine is probably the first choice. ow-dose vasopressin administration remains an option for catecholamine-refractory septic shock. The potential benefit arising from the early use of vasopressin in combination with moderate dose of norepinephrine remains to be determined. The place that remains for dopamine has yet to be determined eferences 1. Dellinger P, Carlet JM, Masur H, et al. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Critical Care Medicine 2008; 36: Cronin, rickson M, De Torrente, et al. Norepinephrine-induced acute renal failure: a reversible ischemic model of acute renal failure. Kidney International 1978; 14: lbanese J, leone M, Garnier F, et al. enal effects of norepinephrine in septic and nonseptic patients. Chest 2004; 126: Martin, C, on, B, Saux, P, et al. enal effects of norepinephrine used to treat septic shock patients. Critical Care Medicine 1990; 18: Moran J, Fathartaigh MS, Peisach, et al. pinephrine as an inotropic agent in septic shock: a dose-profile analysis. Critical Care Medicine 1993; 21: Meier-Hellmann, einhart K, Bredle D, et al. pinephrine impairs splanchnic perfusion in septic shock. Critical Care Medicine 1997; 25: Martin C, Papazian, Perrin G, et al. Norepinephrine or dopamine for the treatment of hyperdynamic septic shock? Chest 1993; 103: Martin C, Viviand X, eone M, Thirion X. ffect of norepinephrine on the outcome of septic shock. Critical Care Medicine 2000; 28: evy B, Dusang B, nnane D, et al. Cardiovascular response to dopamine and early prediction of outcome in septic shock: a prospective multiple-center study. Critical Care Medicine 2005; 33: Sakr Y, heinart K, Vincent J, et al. Does dopamine administration in shock influence outcome? esults of the Sepsis ccurrence in cutely Ill Patients. Critical Care Medicine 2006; 34: De Backer D, Creteur J, Silva, et al. ffects of dopamine, norepinephrine, and epinephrine on the splanchnic circulation in septic shock: which is best? Critical Care Medicine 2003; 31: nnane D, Vignon P, enault, et al. Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock: a randomised trial. ancet 2007; 370: De Backer D, Biston P, Devriendt J, Madl C. Comparison of dopamine and norepinephrine in the treatment of shock. New ngland Journal of Medicine 2010; 362: De Backer D, ldecoa C, Njimi H, Vincent J. Dopamine versus norepinephrine in the treatment of septic shock. Critical Care Medicine 2012; 40: andry DW, evin H, Gallant M, et al. Vasopressin deficiency contributes to the vasodilation of septic shock. Circulation 1997; 95: ussel J, Walley K, Singer J, Gordon C. Vasopressin versus norepinephrine infusion in patients with septic shock. New ngland Journal of Medicine 2008; 358: Polito, Parisini, icci Z, Picardo S, nnane D. Vasopressin for treatment of vasodilatory shock : an SICM systematic review and meta-analysis. Intensive Care Medicine 2012; 38: