Sepsis and the systemic inflammatory response syndrome (SIRS)

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1 Sepsis and the systemic inflammatory response syndrome (SIRS) R.C. Bone Medical College of Ohio, Toledo, Ohio, USA Confusion existed for many years over the use of proper terms and definitions to describe the systemic manifestations of infection. Terms such as Bacteremia, Septicemia, Sepsis, Sepsis Syndrome, and Septic Shock were used interchangeably to indicate the degree of sepsis. This led to much confusion and imprecise understanding of sepsis and related disorders. I During this period of confusion, the ACCP/SCCM Consensus Conference was held to determine the proper usage of terms and definitions for sepsis and its sequelae. The members of the Consensus Conference agreed to a new set of definitions which could be readily applied to patients with sepsis. The new terms became Infection, Bacteremia, Systemic Inflammatory Response Syndrome (SIRS), Sepsis, Severe Sepsis, Septic Shock, and Multiple Organ Dysfunction Syndrome (MODS). 2 PATHOGENESIS The systemic response to an infection, which is now termed sepsis, is characterized by a hyperdynamic and hypermetabolic state in which the inflammatory response is mediated via the macrophage derived cytokines which target end-organ receptors in response to injury. Cytokines are a group of mediators that includes TNFa, IL-1, IL-6, and IL-8. These mediators are among the first to be released in this cascade. They are produced by mononuclear phagocytes and other inflammatory cells as a result of contact with bacterial products (e.g. endotoxin) or other activating agents. These compounds stimulate release of secondary Roger C. Bone MD FCCM, President and Chief Executive Officer, Professor of Medicine, Medical College of Ohio, Toledo, OH 43614, USA. mediators including arachidonic acid-derived PGI2, thromboxane A2, PGE2, and platelet activating factor; vasoactive peptides, such as bradykinin, angiotensin, and vasoactive intestinal peptide; and amines, such as histamine and serotonin and a variety of complementderived products. They help to promote wound healing and combat pathogenic organisms. Under normal circumstances this cytokine response is regulated by an intricate network of mediators which keep the initial inflammatory response in check both by downregulating production and counteracting the effects of cytokines already produced. Sometimes these mediators are capable of feedback on the release of themselves and other mediators and the subsequent runaway inflammation may be capable of sustaining its own existence. It is at this stage that all control is lost and a massive systemic reaction begins and the body finds it impossible to reestablish homeostasis. These mediators initiate overlapping processes which directly influence the endothelium, cardiovascular, hemodynamic, and coagulation mechanisms. While it may be possible to determine how a particular inflammatory response begins, there are several conditions under which sepsis is likely to be initiated. The release of many of these vasoregulators is often local and excessive amounts of vasodilators and vasoconstrictors at the could be produced in different parts of the body same time, resulting in local abnormalities in blood flow. The deleterious effects caused by these mediators may involve a variety of mechanisms. The most damaging effect in this inflammatory response involves destruction of the vascular endothelium at various sites throughout the host circulatory system. Neutrophils may be activated causing them to adhere to the vascular endothelium and release oxygen-derived free radicals. 151

2 Risk 152 Fig. 1- Risk distribution of 519 sepsis patients who either met (n = 308) or did not meet (n = 211) the criteria for sepsis syndrome. Reprinted with permission from Chest. 2 These highly reactive compounds are normally used to kill bacteria, but when released in the œgion of the endothelium they are believed to cause damage to the vascular endothelial cells,3,4 Since most of the mediators have direct influence on the endothelium, the damage caused by these mediators, which is potentially lifethreatening, makes the blood vessels porous to water and solutes. Thus the patients are pre-disposed to pulmonary and peripheral oedema, weight gain, and the development of shock. Endotoxins can bring about changes that can affect the clotting response. They also have other effects on the coagulation cascade. These effects inciude activation of factor XII (Hageman factor), which initiates the intrinsic clotting sequence and to fibrin. The continued activity of endotoxin can lead to thrombosis and reduction in the levels of platelets and coagulation factors II, V, and VII, a situation associated with coagulopathy or disseminated intravascular coagulation (DIC). 5 These mediators also affect the heart by releasing the myocardial depressant substance which produces reversible myocardial depression, ventricular dilatation, causes the conversion of fibrinogen Fig. 2 - distribution of the same 519 sepsis patients as in Figure 1 according to whether they met criteria for SIRS. Reprinted with permission from Chest. 2

3 153 - Fig. 3 Risk distribution of 503 septic patients who met the criteria for SIRS. This demonstrates the relationship risk of hospital mortality, calculated on the first day of the ICU stay and actual hospital mortality rates. Reprinted with permission from Chest. 2 and decreased left ventricular ejection fraction. Unless the inflammatory reaction is brought back under control, multiple organ dysfunction may ensue with a greater risk of mortality.6 It is very important to diagnose sepsis early in its course. In cases where bacterial etiology is present, prompt treatment with appropriate antibiotics has been shown to be effective in decreasing mortality and morbidity resulting from sepsis by about 50%.1 The phase characterized by systemic inflammatory response to an infectious or non-infectious insult is termed the Systemic Inflammatory Response Syndrome or SIRS. SIRS can be identified by the presence of the following manifestations: 1. A body temperature of over 38 C or under 36 C; 2. Heart rate greater than 90 beats/min; 3. Tachypnoea (respiratory rate more than 20 breaths/min or PaC02 less than 32 mmhg); 4. Alterations in white blood cell counts (more than 12,000 cells/mm, less than 4,000 cells/mm3, or the presence of more than 10% immature neutrophils [bands]). 2 The new definition of SIRS proved to be highly sensitive in identifying patients with SIRS compared to sepsis syndrome (Figs 1 & 2). The broader definition tended to include patients with milder diseases; therefore, the committee recommended the concomitant use of a severity of illness scoring system in assessing patients to make an early bed-side detection of the disease possible (Fig. 3) and to start therapeutic intervention for a favorable outcome. SIRS is a continuous process and is characterized by an abnormal host response of a generalized activation of the inflammatory reaction in organs remote from the initial insult. When the process is due to an infection, the term sepsis is used. If SIRS is not diagnosed and treated early, SIRS may progress to MODS. The nature of disease presentation is changing and patient or host response is exemplified by the proposed introduction of new definitions/terms such as SIRS and MODS. 2,8 In a recent prospective study, 3,708 patients were studied out of which 2,527 met the Consensus Conference criteria for SIRS. The progression of SIRS to sepsis was examined by stratifying these patients into three groups: patients who met only two of the four criteria; those who met three of the four criteria; and those who met all four criteria. The median interval from SIRS to sepsis was inversely correlated with the number of SIRS criteria that the patients met. As the patients progressed from SIRS to septic shock, an increasing number of patients had adult respiratory distress syndrome, disseminated intravascular coagulation, acute renal failure, and shock. Mortality rates were seen to increase in a stepwise fashion. An equal number of patients who appeared to have sepsis, severe sepsis, and septic shock but had negative cultures were also observed. They were prescribed empirical antibiotics for a median of 3 days. The cause of the systemic inflammatory response in these patients is unknown. 9 With our current level of understanding, we determine the course of SIRS by relying primarily on sequential measurements of physiologic changes which correlate with the subsequent outcome. Priority should

4 154 be given based on the severity-of-illness scoring and other predictive methods so as to allow the development of a comprehensive model of the disease progression from SIRS to MODS. Researchers have made a tremendous effort with a variety of innovative therapies aimed at mediators and inflammation. Some of these therapies have undergone clinical trials while some trials may start in the near future. The use of established terminology may make it possible to competently compare the results of efficacy trials for innovative agents in the treatment of sepsis.2 Listed below are suggestions for future clinical trials,: 10 Trials should not start with humans. Possible reasons why there is a disparity between animal and human studies: Species variability (the usually quoted reason). Underlying health (animals are healthy but humans usually have underlying disease). Time of insult (animals often have an isolated insult but humans may have many). Dose and timing of experimental agent are often different. Variability of clinical sepsis site (systemic infection may differ in pathogenesis from a localized site such as peritonitis). Appropriate patient population must be better defined as there is a major problem in defining a homogeneous patient population for treatment of sepsis Standardize care for trials should be considered (antibiotic policy, fluid resuscitation, vasoactive drug therapy and nutritional therapy).19>20 Full and rapid reporting of all clinical trials in sepsis, regardless of results (withdrawals, dropouts, cross-overs, success, and failures), should be mandatory to avoid publication bias and to inform the ICU community about this rapidly growing literature. 2,19,20 Accrual at each center should be of sufficient size so as to allow the interpretation of the direction and marginal significance of the results at individual centers. Future studies should include a breakdown of the number of patients accrued at, and mortality rates experienced by, and the patient characteristics at each individual center. Pivotal trials should be preceded by sufficient pilot or phase II studies. 20 Correct drug dosage and appropriate dosage timing should be delineated in pilot studies.8 Large, multicenter, double-blind, placebo-controlled randomized trials of sufficient power should be used to maximize internal validity, minimize random error, avoid type II error and enhance the generalizability of trial results. 2,19 Analyses should be planned a priori, and include, at a minimum, an intention-to-treat analysis and a power calculation Definitions for the target population should be explicit, reproducible, and include illness severity scores. 2,18,19 Outcomes should be clinically relevant, reproducible, specified a priori, and include both measures of benefit and harem. 19 MODS and its reversal should be considered as an end point in addition to mortality.15,17,18 Quality of life should be considered as an endpoint. 8 19,22 The estimators of overall treatment effects should be controlled for base-line prognostic factors that qualify as potential confounders and subgroup analysis should only be used for hypothesis generation and not to modify the overall conclusion of the trial.21. Economic analysis should be included as part of clinical design. 820,22 Formal evaluation of the adequacy of source control should be a critical component of any study to evaluate new strategies for the treatment of sepsis.16 Standardized clinical mediator assays should be pursued.2o Monitor 02 metabolism and/or related variables should be considered (blood lactate, gastric intramucosal ph).20 Placebo patients of clinical trials should be studied for a better understanding of the pathogenesis and epidemiology of SIRS.I.18 Evidence based medication should be used to evaluate the validity of clinical evidence. It is possible many of the trials that showed negative results with innovative agents would have been positive if repeated with the principles enumerated above.

5 155 References 1. Bone RC. Sepsis, the sepsis syndrome, multi-organ failure: a plea for comparable definitions. Ann Intern Med 1991; 114: Bone RC, Balk RA, Cerra FB et al. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest 1992; 101: Bone RC. The pathogenesis of sepsis. Ann Intern Med 1991; 115: Bone RC. Gram-negative sepsis: background, clinical features, and intervention. Chest 1991; 101: Nies AS, Forsyth RP, Williams HE et al. Contribution of kinines to endotoxin shock in unanesthetized rhesus monkeys. Circ Res 1968; 22: Bone RC. Sepsis syndrome: new insights into its pathogenesis and treatment. Infect Dis Clin North Am 1991; 5: Kreger BE, Carven DE, McCabe WR. Gram-negative bacteremia. IV. Re-evaluation of clinical features and treatment in 612 patients. Am J Med 1980; 68: Bone RC. Sepsis and controlled clinical trials: the odyssey. Crit Care Med 1995: In press. 9. Rangel-Frausto SM, Pittet D, Costigan M et al. The natural history of Systemic Inflammatory Response Syndrome (SIRS) - a prospective study. JAMA 1995; 273: Bone RC. Sepsis and controlled clinical trials: the odyssey continues. Crit Care Med 1995: In press. 11. Wolff SM. Biological effects of bacterial endotoxins in man. J Infect Dis 1973; 128 (Suppl): Elias JA, Freundlich B, Kern JA, Rosenbloom J. Cytokine networks in the regulation of inflammation and fibrosis in the lung. Chest 1990; 97: Bone RC. The pathogenesis of sepsis. Ann Intern Med 1991; 115: Bone RC, Balk RA, Slotman G et al. Adult respiratory distress syndrome sequence and importance of development of multiple organ failure. The prostaglandin E1 study group. Chest 1992; 101: Schwartz DB, Bone RC, Balk RA et al. Hepatic dysfunction in the adult respiratory distress syndrome. Chest 1989; 95: Marshall JC, Lowry SF. In: Sibbald WJ, Vincent JL, eds. Clinical 1995: Bone RC. Gulliver s travels: sepsis, sepsis syndrome, and the systemic inflammatory response syndrome (SIRS). JAMA 1995; 273: Balk RA, Bone RC. Methodological issues in the design and implications of controlled clinical trials in severe sepsis and septic shock. Theor Surg 1994; 9: Fisher CJ. Cook DJ. In: Sibbald WJ, Vincent JL, eds. Clinical 1995: Sibbald WJ, Vincent JL. Roundtable conference on clinical trials for the treatment of sepsis: Brussels, March 12-14, Chest 1995: 102: Doig GS, Rochon J. In: Sibbald WJ, Vincent JL, eds. Clinical 1995: Cook DJ. In: Sibbald WJ, Vincent JL, eds. Clinical Trials for the Treatment of Sepsis. Heidelberg: Springer-Verlag, 1995: