F. BLOOS, K. REINHART Dep. of Anaesthesiology and Intensive Care Medicine, Klinikum der Friedrich-Schiller-Universität Jena, Jena, Germany

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1 European Society of Anaesthesiologists Refresher Course MANAGEMENT OF SEPSIS 12 RC 5 F. BLOOS, K. REINHART Dep. of Anaesthesiology and Intensive Care Medicine, Klinikum der Friedrich-Schiller-Universität Jena, Jena, Germany Sunday June 1, 2003 Euroanaesthesia Glasgow DEFINITION OF SEPSIS Sepsis is defined as a systemic inflammatory reaction (Systemic Inflammatory Response Syndrome SIRS) caused by an infectious focus. This definition was laid down by a consensus conference of the American College of Chest Physicians and the Society of Critical Care Medicine [1] and is summarised in table 1. TABLE 1: DEFINITION OF SEVERE SEPSIS AND SEPTIC SHOCK [1]. SEVERE SEPSIS I. Infectious aetiology of inflammation Microbiological proof of infection, infection suspected by clinical examination II. Severe inflammatory host response (at least 2 criteria) Fever: body temperature 38 oc or hypothermia: body temperature 36 oc Tachycardia: heart rate 90 beats per minute Tachypnoea: 20 breaths/min or hyperventilation: PaCO2 4,3 kpa ( 33 mmhg) Leucocytosis 12 G/l or leucopenia 4 G/l or 10% immature neutrophils in the differential white blood cell count III. Signs of an uncontrolled inflammation: acute organ dysfunction remote from the site of infection At least 1 of the following criteria Acute encephalopathy: reduced vigilance, disorientation, anxiety, delirium without previous psychotropic medication, endocrine or metabolic causes. Arterial hypotension: systolic blood pressure 90 mmhg or mean arterial blood pressure 70 mmhg for at least 1 hour despite adequate fluid loading; other causes of shock excluded. Relative or absolute thrombocytopenia: drop of platelet count by more than 30% within 24 hours or platelet count <100 G/l without bleeding as cause of thrombocytopenia. Arterial hypoxaemia: PaO 2 10 kpa(75 mmhg) when breathing room air or PaO 2 /FIO 2 33 kpa (250 mmhg) when breathing oxygen without acute pulmonary or cardiac disorder as cause of hypoxaemia. Renal dysfunction: urine output 0.5 ml/kg for at least 2 hours despite adequate fluid loading and/or increase of serum creatinine levels >2 above the reference range. Metaboliic acidosis: base excess -5 mmol/l or serum lactate concentration >1,5 upper value of the reference range. SEPTIC SHOCK Criteria I and II Systolic blood pressure 90 mmhg or mean arterial blood pressure 70 mmhg for at least 2 hours or administration of vasopressors 1 to achieve a systolic blood pressure 90 mmhg or a mean arterial blood pressure 70 mmhg. Hypotension exists despite adequate fluid loading and cannot be explained by other causes of shock. 1 Dopamine 5 µgkg -1 min -1 or norepinephrine, epinephrine, phenylepinephrine, vasopressin at any dosage. 135

2 SIRS is caused by cellular and humoral responses of the immune system. Activation of monocytes release primary mediators such as tumor necrosis factor α (TNFa) and interleukin 1β (IL-1β). These then cause the release of additional mediators such as thrombocyte activating factor (PAF), interleukins IL-6 and IL-8 and products of the arachidonic acid metabolism. These primary and secondary mediators lead to the physiological changes of sepsis. Profound systemic vasodilation from activation of the NO-synthase and arterial hypotension is one of the characteristic clinical symptoms of sepsis. Activation of the immune system also causes generalised activation of the coagulation system. The resulting disseminated intravascular coagulation in combination with endothelial damage leads to severe alteration of the microcirculation. Impairment of tissue oxygen supply and direct tissue damage by oxygen radicals released by activated leukocytes trigger a multiorgan dysfunction syndrome (MODS) which is the most frequent cause of death in patients with sepsis. TREATMENTS Evidence exists for: Effective strategies for the management of the patient with sepsis are available and have been successfully tested in large studies. These strategies include: Early diagnosis Early and effective treatment of the infections focus Haemodynamic support Adjunctive therapy Low-pressure ventilation Glycaemic control Appropriate nutrition Early treatment is important. Most of the following strategies need to be used early in the course of the disease. FOCUS CONTROL Obviously, no prospective studies can compare early and delayed control of the focus of infection in patients with sepsis. Therefore, treatment of infection rely on retrospective studies and expert opinions eg exact opinion that patients with inappropriate antibiotic therapy or inadequate surgical management were confounded in such a way that another treatment would be unable to achieve a therapeutic effect [2]. A retrospective study showed that appropriate antibiotic therapy improves outcome in Gram-negative rod bacteraemia [3]. However, early surgical intervention may interfere with haemodynamic stabilisation since surgery and general anaesthesia may disturb the circulation and increase risk. Thus, surgery should be as soon as possible after stabilisation of the circulation [4]. HAEMODYNAMIC SUPPORT Sepsis causes loss of intravascular fluid into the extravascular space because of capillary leakage. Peripheral blood pooling from arterial vasodilation decreases cardiac preload. Thus, intravenous fluid must be given to maintain the circulation. It is clear that fluid resuscitation is a fundamental part of resuscitation; it remains controversial whether colloid or crystalloid solutions should be preferred. Several small studies had conflicting results. A meta-analysis suggested that the choice of solution did not affect survival [5]. It is also controversial whether the administration of albumin to patients with sepsis is harmful [6, 7]. Fluid administration alone is often not sufficient to achieve haemodynamic stabilization. However, there is no large study that shows one single catecholamine is better than any of the others. The International Sepsis Forum (ISF) has recommendations for the catecholamine treatment in sepsis [8]. Vasopressor therapy is often necessary to maintain a mean arterial pressure for adequate tissue perfusion. Norepinephrine or dopamine are catecholamines of first choice to achieve blood pressure control. However, we believe that norepinephrine is preferable since dopamine acts on multiple catecholamine receptors and may also affect the patient s endocrinological status. Cardiac dysfunction also occurs in sepsis. The ISF recommends dobutamine as the first choice inotropic agent since epinephrine limits mesenteric perfusion in this disease. There is no indication for low-dose dopamine to give renal protection. In case reports, vasopressin could maintain blood pressure in patients unresponsive to catecholamines. However, vasopressin has never been investigated in a controlled trial and should not be used in the routine management of patients with septic shock. 136

3 In the treatment of sepsis, patient management should aim to obtain rapid haemodynamic resuscitation, which is crucial for the survival of the patient with sepsis [9]. Continuous measurement of the central venous oxygen saturation (SvO 2 ) was an effective measure to guide haemodynamic therapy. A control group was treated to achieve a central venous pressure of 8 to 12 mmhg, a mean arterial blood pressure of 65 mmhg, and a urine output above 0.5 ml/kg/h. An Early Goal Directed Therapy (EGDT) group was treated using the algorithm in figure 1 where a SvO 2 of at least 70% was one of the most important goals. 28-days mortality was 46.5% in the control group versus 30.5% in the EGDT group (p <0.009). Patients of the EGDT group received more fluids, more dobutamine and more blood transfusions within the first 6 hours than the control group. In contrast, patients of the standard therapy group received more fluids, more catecholamines, and more blood transfusions than the EGDT group after 6 hours. Thus, adequate haemodynamic resuscitation was more rapid in the EGDT group than in the control group. This study shows that in severe sepsis or septic shock, early and aggressive treatment of the circulation improves outcome. FIGURE 1 Figure 1. - The haemodynamic treatment of patients with severe sepsis or septic shock; modified from [9]. CVP: central venous pressure, MAP: mean arterial pressure, SvO 2 : central venous oxygen saturation. ADJUNCTIVE THERAPY In the last decade, several treatments have been studied that affect the systemic immune response in sepsis. Two are available today for the immunological therapy of sepsis: low-dose hydrocortisone and activated protein C. In a recent study, patients with septic shock were either treated with 200 mg hydrocortisone pro day or with placebo [10]. When the patients were separated retrospectively according to the results of the corticotropin stimulation test, only patients unresponsive to this test showed a better outcome when treated with low-dose hydrocortisone. These results suggest that low-dose hydrocortisone should be administered to patients with septic shock and negative corticotropin stimulation test. It remains unclear whether low-dose hydrocortisone should be administered without performing such a test since adrenal insufficiency was diagnosed in about 70% 137

4 of patients with septic shock [10]. Furthermore, the accuracy of the corticotropin stimulation in the critically ill is unknown. Further investigation is needed to clarify the role of low-dose hydrocortisone in the treatment of sepsis. Higher doses of corticosteroids do not play a role in the therapy of sepsis as their administration might be harmful [11, 12]. The activated form of protein C has antithrombotic effects since it inactivates the factors Va and VIIIa by using protein S as a cofactor. Patients with sepsis have low levels of protein C and these low levels are associated with a poor outcome [13]. Drotrecogin alfa (activated) is a human recombinant activated protein C, tested in a large multicenter trial on patients with severe sepsis or septic shock [14]. A dose of 24 µg/kg/min of drotrecogin alfa (activated) for 96 hours reduced mortality from 30.8% to 24.7% (p = 0.005). In the United States, the FDA limited the use of this substance to patients with an APACHE II score >25 since subgroup analysis did not indicate improved survival in less sick patients. This limitation was not adopted in Europe. However, European certification confines the indication of drotrecogin alfa (activated) to patients with severe sepsis and two organ dysfunction. The antithrombotic actions of drotrecogin alfa (activated) increase the risk of bleeding. Severe bleeding occurred more frequently after treatment (3.5% vs. 2.1%, p = 0.06). Therefore, drotrecogin alfa (activated) should not be given to patients with a high risk of bleeding (i.e. within 12 hours after surgery, abnormal coagulation tests, heparin treatment etc.). LOW-PRESSURE VENTILATION Respiratory dysfunction is common in patients with sepsis and the acute respiratory distress syndrome (ARDS) complicates sepsis in about 25 42% of the patients. A multicenter study by the ARDS-network showed that mortality could be reduced if patients were ventilated with low tidal volumes (6 ml/kg, mortality rate 31.0%) compared with higher tidal volumes (12 ml/kg, mortality rate 38.9%, p = 0.007) [15]. Ventilation of ARDS patients with low tidal volumes is now widely accepted to reduce pulmonary injury. GLYCAEMIC CONTROL Patients, who developed hyperglycaemia during intensive care, had greater mortality than patients whose glucose remained normal [16]. Intensive treatment with insulin in critically ill patients, keeping glucose between mg/dl, gave a mortality of 4.6% compared with a rate of 8% in patients where glucose levels below 215 mg/dl were tolerated [17]. Patients with intensive insulin therapy had less frequent acute renal failure, episodes of septicaemia, critical illness polyneuropathy, and requirement for mechanical ventilation than the control group. Strict glycaemic is needed in critically ill patients. Whether patients with severe sepsis or septic shock benefit from intensive insulin therapy has not yet been investigated. APPROPRIATE NUTRITION Early enteral feeding is the basic concept of nutrition for patients with sepsis. A meta-analysis of studies comparing early versus delayed enteral feeding concluded that early enteral nutrition reduced incidence of infections and decreased the duration of hospital stay [18]. Some studies have addressed the concept of immune enhanced enteral nutrition solutions. A North American consensus conference had insufficient data to recommend these solutions for patients with sepsis [19]. CONCLUSION No single drug or intervention can save a patient with severe sepsis or septic shock. Managing such patients requires combined treatments. Successful haemodynamic stabilisation will not improve outcome if control of the focus of infection is neglected. In the same way, immunological treatments will not succeed without proper haemodynamic support or focus control. Early treatment is crucial in the management of patients with sepsis, as shown by the early goal directed therapy regarding haemodynamic support. 138

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