In 1895, John Collins Warren, who previously had demonstrated ether anaesthesia, described sepsis as a momentary pause in the act of death. Since that time, little progress has been made to decrease the nearly 40% mortality associated with sepsis syndrome and septic shock. Sepsis syndrome is an increasingly prevalent clinical problem, which faces intensivists and anaesthetists. Mortality associated with this syndrome is high, thought to be 4050%. There are approximately 1.5 million cases of sepsis each year in developed countries, with 750 000 cases per year in the USA alone.1 2 The increasing incidence of this syndrome results from a number of factors, including increased use of immunosuppressive agents, a larger elderly population undergoing surgical procedures, and the development of antibiotic resistance. Although many sepsis patients undergo surgical procedures, little is known about optimal intraoperative management. In this issue, Allaouchiche and colleagues found that sevoflurane MAC was significantly decreased in sepsis patients.3 This is an important contribution to the sparse anaesthesia literature that helps guide clinical management of septic patients when they come to the operating room. The findings of Allaouchiche and colleagues build on those of Gill and colleagues, who found a significant decrease in MAC for isoflurane in a rodent sepsis model.4 It appears clear that sepsis syndrome results in decreased MAC in experimental models, and it is likely that this finding will hold true in humans. Aside from moderating doses of inhaled anaesthetics, what else can be done to optimize management of septic patients?
Pathophysiology of sepsis
Sepsis syndrome covers a spectrum of disease states, ranging from mild physiological disturbances, such as tachypnoea, fever and tachycardia, up to irreversible septic shock. The pathophysiology of sepsis is best understood as a systemic inflammatory response syndrome (SIRS) mediated by circulating cytokines that is triggered by bacterial or fungal organisms. Although originally described with Gram-negative organisms, with the inciting agent identified as lipopolysaccharide (LPS, or endotoxin), recent studies have identified that the incidence of SIRS associated with Gram-positive organisms and fungi is increasing in incidence.5 Once an infectious agent triggers the inflammatory response, the syndrome that results is independent of the inciting organism. The physiological response is characterized by a state of overwhelming inflammation, which is soon followed by a state of relative immunosuppression.
Much has been made of the release of cytokines into the circulation with sepsis syndrome, and the majority of clinical trials have focused on neutralizing these proteins. The predominant cytokines found in the circulation early in sepsis syndrome are tumour necrosis factor alpha (TNF) and interleukin-1 beta (IL-1ß). TNF and IL-1 stimulate release of IL-6 and IL-8, both of which propagate the inflammatory cycle initiated by the infectious organism. Circulation of these cytokines results in widespread endothelial dysfunction, which underlies the multisystem organ failure (MSOF) that occurs, inevitably leading to death. Indeed, high levels of circulating cytokines correlate with mortality in sepsis syndrome.6
Clinical trials
In spite of promising laboratory studies, which showed that neutralization of cytokines significantly improves survival, clinical studies using this strategy have been uniformly unsuccessful.7 8 The failure of these trials is probably a result of both the heterogeneous nature of sepsis syndrome and the naïve view that high levels of cytokines are uniformly harmful and should be blocked. The same molecules that are pro-inflammatory and cause tissue damage are essential components of host defence against infection. A more sophisticated approach to cytokine blockade might customize therapy, with measurement of circulating cytokines and treatment based on their relative plasma concentrations and physiological effects. Although clinical trials of cytokine blockade continue, enthusiasm in the sepsis clinical trials community is waning.
Early investigations pursued the approach of increasing oxygen delivery in patients with septic shock. The foundation of this therapy was based on the work of Shoemaker and colleagues, who demonstrated that patients who survived septic shock tended to have higher oxygen delivery than those that died.9 Since then, dozens of studies have examined the efficacy of increasing oxygen delivery in septic patients through the use of inotropes. The controversy continues; in 1993, Boyd and colleagues demonstrated decreased mortality in high-risk surgical patients who were treated with dopexamine to increase oxygen delivery.10 Soon thereafter, Hayes and colleagues demonstrated increased mortality in patients treated with dobutamine to increase their oxygen delivery.11 Given these conflicting findings, and a more recent, large, multicentre trial showing no efficacy, this approach cannot be recommended at this time.12
Sepsis and the coagulation system
Whereas most clinical trials in sepsis syndrome have concentrated on blocking the inflammatory response, recent focus has been on the coagulation pathway. Severe sepsis is associated with microvascular coagulopathy, which is evident by elevated fibrin-degradation products and thrombocytopenia. Severe microvascular dysfunction presents clinically as disseminated intravascular coagulation (DIC). Recent investigations have identified endothelial dysfunction with resultant coagulation abnormalities as a possible cause of the propagation of organ dysfunction in patients with sepsis. The hypothesis is that diffuse microthrombosis occurs in organ system beds, triggered by elevated levels of thrombin and tissue factor, resulting in a diffuse inflammatory response with subsequent MSOF. Figure 1 demonstrates this process.
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Sepsis, the lung and mechanical ventilation
What else can be done to manage patients with sepsis when they come to the operating room? Since respiratory failure is the most common organ failure accompanying sepsis syndrome, much attention has been paid to preventing or limiting lung injury. The recognition that mechanical ventilation may injure the lungs has been recognized since the 1940s and the pioneering studies of Macklin and Macklin.16 More recently, it has been recognized that over-distension of the lung can cause not only volutrauma, but also biotrauma, with release of cytokines such as TNF and IL-1 into the circulation.17 A strategy known as lung-protective ventilation aims to avoid injury to the lung by limiting tidal volume and using increased levels of positive end-expiratory pressure (PEEP) to avoid cyclic alveolar collapse.18 A recent multicentre trial conducted in the USA compared low tidal volume ventilation (6 ml kg1) with higher tidal volume (12 ml kg1).19 This trial found a significant decrease in mortality (40% vs 31%) in patients ventilated with a low stretch strategy. Lower tidal volumes are thought to decrease the propagation of lung injury by decreasing inflammatory activation. Not only might high tidal volumes increase inflammatory activation and circulating cytokines, but also in an animal model of Pseudomonas aeruginosa pneumonia, high tidal volume ventilation led to increased translocation of bacteria across the lung and into the circulation.20
What can we do to optimize the care of septic patients undergoing anaesthesia and surgery? Until more clinical trials are completed, there are no specific pharmacological interventions indicated. In patients with normal lungs, high tidal volume and low PEEP do not appear to be injurious.21 However, low tidal volumes have been shown to decrease mortality in patients with acute lung injury and acute respiratory distress syndrome. Although most intensivists are familiar with protective ventilation strategies, anaesthetists also need to be aware of these data, and apply lung protective strategies to patients undergoing anaesthesia who are at risk for acute lung injury and sepsis.
M. A. Gropper
Anesthesia and Physiology
Critical Care Medicine and Cardiovascular Research Institute
San Francisco, CA
USA
Note added in proof
Bernard et al. recently published an important multi-centre, randomized, placebo-controlled trial of the efficacy of protein C in severe spesis. They found that protein C decreased the relative risk of death by nearly 20% in patients with severe sepsis. There was a slightly increased risk of significant bleeding in the treatment group, and therefore caution should be exercised in patients at high risk for bleeding. This is the first large clinical trial demonstrating efficacy in severe sepsis syndrome, and protein C will likely become standard therapy for these patients.
Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. New Engl J Med 2001; 344: 699709
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