Sepsis—Definitions, Pathophysiology, and Treatment
treatment update
Source: J Antimicrob Chemother 1998;41:Supplement A.
The clinical features and sequelae traditionally associated with sepsis are more correctly termed the systemic inflammatory response syndrome (SIRS). Although infection is assumed the principle cause of SIRS, there has been increasing recognition that other processes and conditions also elicit SIRS, including burns, trauma, surgery, and acute pancreatitis.
Macrophages, polymorphonuclear leucocytes, and endothelial cells play a pivotal role in the systemic inflammatory response by initiating the release of cytokines, complement, and nitric oxide which can culminate in cardiovascular complications and multiple organ dysfunction syndrome (MODS). Yet, despite the greater understanding and recognition of SIRS as a clinical entity, experimental treatments have failed to produce favorable outcomes when tested in clinical trials. These and other aspects of sepsis are covered in this supplement, which provides the reader with a clear and comprehensive illustration of the state of the art.
The Systemic Inflammatory Response Syndrome (SIRS)
The definitions and etiology of SIRS are described by Nyström in The Systemic Inflammatory Response Syndrome: Definitions and Aetiology.
SIRS is defined as the "clinical expression of the action of complex intrinsic mediators of the acute phase reactions" and occupies one end of the spectrum that encompasses septic shock and MODS. The principle motivation for coining the term SIRS was to clarify the pathophysiology of this manifestation of disease as well as to foster better understanding of the problem by ensuring common usage of the term. That there is confusion can be easily confirmed by a perusal of the literature where "septicemia" and "bacteremia" are used interchangeably and sepsis may be confined to a local region or entail the response to fulminant, disseminated infection. The term SIRS was agreed upon by a consensus meeting of the American College of Chest Physicians and the Society of Critical Care Medicine and was defined as the response to a variety of severe clinical insults manifest by at least two of the following:
• rectal temperature less than 36°C or greater than 38°C
• heart rate greater than 90 beats/min
• respiratory rate greater than 20 breaths/min or PaCO2 less than 32 torr (< 43 kPa)
• leucocyte count less than 4.0 ´ 109 cells/L (< 4000 cells/mm3) or greater than 12 ´ 106 cells/L (> 12,000 cells /mm3) or greater than 10% immature (band) forms.
This was later modified to the definitions shown in the Table.
| Table |
| The modified definition of sepsis syndrome |
| • Clinical evidence of infection |
| • Core temperature < 36°C or > 38°C |
| • Tachycardia (> 90 beats/min) |
| • Tachypnea (> 20 breaths/min while breathing spontaneously) |
| • At least one of the following manifestations of inadequate
organ function of perfusion: altered mental status hypoxemia (P2O2
< 72 torr breathing ambient air)
oliguria (urinary output < 30 mL or < 0.5 mL/kg for at least 1 hour) |
|
Adapted from Bone, et al. Crit Care Med 1989;17:389-393. |
| _______________________________________________________ |
Unlike the normal host response to tissue injury, which is confined to the affected part by the localization of pro-inflammatory mediators and the production of various inhibitors, SIRS arises when this process is uncontrolled and the pro-inflammatory substances spread to other distant sites leading to multiple organ dysfunction. Sepsis is defined as SIRS that results from infection, and is considered "severe" when there is also evidence of organ dysfunction, hypotension, or perfusion abnormalities that include, but are not limited to, lactic acidosis, oligouria, or an acute alteration in mental status. Hypotension is only considered to have been induced by sepsis when the systolic blood pressure is less than 90 mmHg or has dropped by at least 40 mmHg in the absence of an alternative explanation; septic shock is only considered present when there is sepsis with hypotension despite adequate resuscitation with fluids.
The SIRS criteria are a crude means of classifying patients and are not a diagnostic tool. (See Figure.) Moreover, the notion that sepsis is always triggered by infection is so ingrained that such patients are treated with antibiotics empirically even if, after extensive investigation, no evidence of infection is found. This is not an unreasonable assumption to make since an infective process, particularly involving the release of the very potent gram-negative bacterial endotoxin, is known to induce the release of TNF-a followed by the pro-inflammatory interleukins IL-1, IL-6, and IL-8—setting the sepsis cascade in motion. However, as this and other contributors to the supplement point out, the sepsis syndromes are not always the result of infection and can be brought about by non-infective tissue injury. Indeed, SIRS also arises through mechanisms other than inflammation, including the acute phase response, metabolic dysfunction, shock, hypoxia, and organ system failure.
The utility of SIRS as defined derives from the fact that they imply a level of risk depending upon the degree of pathophysiological disturbance. If SIRS is the result of inflammation, the latter will also result in the elaboration of anti-inflammatory substances that will arrest the SIRS and restore homeostasis, provided that the underlying cause is dealt with appropriately by surgery, intensive care treatment, or antibiotic therapy if infection is the trigger. Clearly, if something other than infection is involved, anti-infective interventions will fail. SIRS and MODS are graded expressions of the inflammation associated with acute illness. Mild forms of these syndromes are encountered in general medical and surgical wards, but severe forms require intensive care. Clinicians, therefore, need to be able to identify patients with SIRS at an early stage to determine the underlying cause and select the most appropriate treatment before it progresses to a more severe form.
Some clinical aspects of sepsis are then considered further. In "Cardiovascular alterations in septic shock," Vincent addresses the decrease in vascular tone and impairment of mycardial contractility that accompanies sepsis, both of which are largely the result of the release and action of the mediators of the sepsis cascade, as well as secondary mediators such as nitric oxide and oxygen free radicals. Administering fluids and erythrocyte transfusions, if necessary, improve patient outcome; once minimal tissue perfusion pressure has been restored, an additional rise in systemic vascular resistance can further increase blood pressure and cardiac afterload, or it can limit blood flow and oxygen delivery. Inotropic therapy can improve myocardial function in sepsis, enhancing cardiac output and oxygen delivery, but repeated hemodynamic evaluation is necessary to guide treatment, and serial measurements of blood lactate will assist in assessing the adequacy of tissue oxygenation.
The issue of nitric oxide synthase (NOS) inhibitors is addressed in "Nitric oxide in sepsis and endotoxemia." Parrat describes two NOS that are produced constitutively (cNOS), namely eNOS and nNOS, produced by endothelial cells and neurones, respectively. A third NOS enzyme (iNOS) is induced in a variety of cells including macrophages, hepatocytes, vascular smooth muscle, and cardiac mycocytes by exposure to endotoxin and other bacterial products. It is suggested that therapy of patients in shock should be selective and directed against induction of iNOS and not cNOS, since non-specific inhibition of the L-arginine-nitric oxide pathway can lead to increased systemic vascular resistance, elevated pulmonary artery pressure, reduced cardiac output, and oxygen delivery and increased platelet accumulation. However, if patients are to benefit, it is also necessary to determine precisely at which point during sepsis such selective inhibitors should be administered. In "The hematological manifestations of sepsis," Mammen describes the hematological changes associated with sepsis that primarily involve the leucocytes (neutrophilia or neutropenia), platelets, and alterations in the hemostasis system, especially disseminated intravascular coagulation (DIC), which is characterised by the production of more thrombin than fibrinolysis, leading to microvascular thrombosis.
TNF-a activates the clotting system, and, fibrinolysis is initially activated but then later inhibited as plasminogen-activator inhibitor is released, resulting in the accumulation of undissolved thrombin in the microcirculation and leading to multiple organ failure. Management of DIC must address the underlying disease, arrest the activated hemostasis system, and replace consumed coagulation constituents. Septic patients are treated with heparin in some countries, but this is not safe when patients are already bleeding. Animal studies have shown that antithrombin III (in reality a broad-spectrum inhibitor of serine proteases and clotting related enzymes) shortens the duration of DIC and reduces the incidence of multiple organ failure. However, since DIC develops at the SIRS stage, antithrombin substitution should be considered early for patients with SIRS and one or two failed organs but not for those already in septic shock.
The role of complement activation in mediating inflammation and in contributing to septic shock is discussed by Haeney. Bacteria that release endotoxin activate the alternative pathway, but patients often have pre-formed antibodies to these bacteria, allowing complement to be activated by the classical pathway. The anaphylotoxins C3a and C5a further enhance the sepsis cascade. The cytokines released act synergistically with complement activation products in activating granulocytes and in contributing toward the typical hemodynamic and metabolic changes seen in sepsis. C reactive protein is induced and, when bound to phosphocholine on damaged cell membranes, leads to induction of the classical complement pathway. There are two recombinant soluble substances, complement regulatory protein CR1 and decay accelerating factor (DAF), that inhibit C3 convertase and hence modulate the classical complement pathway, but their potential for treating human sepsis is not known.
Models of Sepsis
In "The value of animal models in the development of new drugs for the treatment of the sepsis syndrome," Michie reminds us that animal models of sepsis have been used extensively to select potential therapies for sepsis and to explore the pathophysiology. However, immunomodulatory agents shown to control endotoxemia or bacteremia in animal models have not proved effective in septic patients. This is partly because mice and other rodents are not as susceptible as man to many of the triggers of the inflammatory response, including endotoxin. Animals are also healthy before being challenged with a trigger such as live bacteria or endotoxin intended to be lethal and are treated before or shortly after the lethal challenge, whereas patients are unwell and have a variable history before becoming septic. Anti-cytokine agents also protect animals against death from hypotension and coagulopathy, whereas patients seldom die from these but usually from multiple organ failure, which occurs later. Sepsis is also "a classical example of a disease that is greater than the sum of its parts; it is a complex process in which intervention in one area may have only a modest effect on the final outcome." Nonetheless, the paper "Cytokines involved in human septic shock—the model of the Jarisch-Herxheimer reaction" by Griffin explores the potential of the Jarisch-Herxheimer (JH) reaction as a model for sepsis. This reaction was first seen in patients treated for syphilis with mercurial compounds and has also been described after treatment of spirochete infections with penicillin. The JH reaction is characterized by a rise in body temperature of 1°C or more, accompanied by rigors within two hours after administering penicillin and a temporary fall in leucocytes and arterial blood pressure. As this is paralleled by increase and fall in TNF-a, IL-6, and IL-8 levels, the JH reaction is therefore the archetype for the sepsis cascade and, as such, provides a model for investigating blocking agents. Wilson et al, in "Acute pancreatitis as a model of sepsis," propose acute pancreatitis as a model of sepsis because both syndromes result in cardiovascular instability, reduced ejection fraction, and decreased vascular resistance; the same cytokines are involved; and evidence also suggests that endotoxin, platelet activating factor, and phospholipase A2 are implicated in both syndromes.
Experimental Therapies for Sepsis
In "Experimental therapies for sepsis directed against tumor necrosis factor," Read points out that studies of experimental therapies with monoclonal antibodies against TNF and soluble TNF receptor (sTNFR) have been disappointing because the hypothesis that TNF is the central mediator of sepsis is incorrect. Not only is TNF only one of the mediators of the sepsis cascade, but other cytokines ( IL-4, IL-10, IL-11, IL-13, sTNFR, IL-1 r antagonists and transforming growth factor-b) control inflammation and restore homeostasis. Nevertheless, TNF is clearly important in the pathogenesis of sepsis since antibody does prevent the JH-reaction from developing in patients treated with antibiotics for infection due to Borrelia recurrentis and a phase II trial of the recombinant human TNF p55 receptor construct showed the substance led to a lower 28-day mortality rate and to less organ dysfunction.
Similarly, in "Anti-endotoxin therapeutic options for the treatment of sepsis," Lynn shows that, despite the interest in developing effective anti-lipopolysaccharide (LPS) binding protein such as those aimed at neutralizing circulating endotoxin (e.g., the anti-LPS monoclonal antibody HA-1A human anti-lipid A mAb and the LPS neutralizing protein bactericidal/permeability -increasing protein [BPI]) and those that antagonize the effects of endotoxin on human cells (e.g., the lipid A analogue monophosphoryl lipid A), the results are not convincing.
Therapeutic Options Directed Against Platelet Activating Factor, Eicosanoids, and Bradykinin in Sepsis
Fink also discussed some promising substances that block both the cyclo-oxygenase and lipoxygenase pathways that respectively lead, ultimately, to the production of thromboxane A2, prostaglandin E2, and prostacyclin, which have yet to proceed into clinical trials. Studies in patients and animal models have implicated bradykinin and the eicosanoids (lipid mediators that includes platelet activating factor [PAF] and the derivatives of the 20-carbon polyunsaturated fatty acid, arachidonic acid phospholipases A2 and C, cyclo-oxygenases, thromboxane A2, prostaglandin E2, prostacyclin and the leukotrienes C4, D4 and E4) in the pathogenesis of endotoxemic and septic shock, adult respiratory distress syndrome (ARDS), and multiple organ failure. However, clinical trials of cyclo-oxygenase inhibitors, thromboxane receptor antagonists, and bradykinin receptor antagonists have shown negative results largely because of insufficient sample size, inadequate length of treatment, and the heterogeneity of subjects.
Design of Clinical Trials in Sepsis
In "Design of clinical trials in sepsis: Problems and pitfalls," Finch looks specifically for reasons why clinical studies failed to fulfill the promise shown by animal studies. As suggested by the other authors, subjects were too heterogeneous. For instance, patients admitted to intensive care units in the United Kingdom were likely to be sicker than those admitted to similar units elsewhere simply because there are proportionally fewer ICU beds in the United Kingdom, and admission is limited to the severely ill patients. Another problem arose from the variability in withdrawing life support, which is determined very much by non-medical considerations such as local attitudes and politics and resource allocation. The type of antibiotic regimen used varied widely, whereas this should be the same for everyone, especially as some drugs, particularly the b-lactam antibiotics, vary in their causing release of endotoxin from gram-negative bacilli. Too great a reliance has also been placed upon clinical end points that are not capable of measuring a biological response. Finally, a variety of different end points were used for determining efficacy, including 28- or 30-day survival, shock reversal, reduction in APACHE score, the duration of hospital stay, and the occurrence of serious adverse events, to name but a few. Finch argues for 28- or 30-day mortality as the primary end point, since too short a period would lead to an underestimation of the side effects associated with treatment, and patients are at risk of dying for at least a month regardless of the underlying disease. Also, a scientific extramural review committee (SERC), composed of experts who are not themselves investigators in the particular study, should be established to: 1) ensure adherence to the protocol; 2) provide an independent assessment of important factors such as the underlying diseases of the study population, the nature and site of infection, the quality of the diagnostic microbiology, the appropriateness of antimicrobial treatment, the standard of care; and 3) deal with unforeseen confounding factors. This would result in a valid population for assessing efficacy and safety.
In the last article, "Management of multiple organ failure: Guidelines but no hard-and-fast rules," Singer concludes that, despite considerable efforts to find the magic bullet,’ no definitive treatment exists for multiple organ failure. Some studies on inhibiting nitric oxide synthesis or its action on organs are progressing. There are ongoing trials of enteral and parenteral nutrition as a means of immunomodulation, and phase III studies of perfluorocarbon ventilation to improve gas exchange are underway. But, in the meantime, management is more prosaic and revolves around support of organs by maintaining tissue oxygenation, and in preventing iatrogenic complications while recovery is awaited. This means maintaining intravascular volume and adequate nutrition and, importantly, employing rigorous infection control measures such as handwashing, changing catheters only when necessary and never routinely, and discontinuing antibiotic therapy when infection has resolved clinically or no benefit has resulted.
Comment by J. Peter Donnelly, PhD
The sepsis syndromes are clinically defined entities and reflect the perspectives of those involved in intensive care. By contrast, infection is defined as an inflammatory response to the presence of micro-organisms at a body site or invasion by such organisms of normally sterile host tissue, a definition familiar to surgeons. The bloodstream infections perceived by infectious disease physicians now become "bacteremia," "fungemia," or "viremia," all of which could be encompassed by the term "microbemia" and are defined by the presence of viable organism in the bloodstream. SIRS is also a means of recognizing patients at potential risk of developing septic shock and multiple organ failure. That such patients should be assumed to have an uncontrolled infection and, therefore, require empirical antimicrobial therapy is perfectly reasonable. However, if microbiological investigation fails to confirm an infective etiology, it is questionable whether such treatment should be continued, especially if there has been no measurable benefit after a reasonable length of time. And, there’s the rub. The translation of "measurable benefit" and "reasonable length of time" into practice is invariably a matter of judgment and, therefore, subject to considerable variation. It was a repeated theme of the papers that even though there was ample biological justification for selecting a specific intervention against sepsis for evaluation in the setting of a controlled, clinical trial, the results invariably fell below expectations and were not good enough to warrant approval by registration authorities. Almost every author emphasized the importance of selecting appropriate subjects, and those familiar with animal models all pointed out that the experimental therapies that worked did so most effectively during the early SIRS. This has important implications for investigating the utility of any therapy for SIRS. If the "right" mix of patients is selected to allow efficacy to be determined with sufficient scientific rigor, the resultant population may not reflect the full range of patients who might actually benefit from such treatment. Moreover, should a set of diagnostic tests ever be constructed for detecting and monitoring SIRS in trial patients, it remains to be seen whether it would ever be used in practice. In fact, with sepsis, scientific medicine seems to have gottten as good as it gets, and yet all the efforts expended and advances made have failed to produce any evidence that would satisfy the clinician, let alone the Cochrane Group. Even when a drug is proven effective in ameliorating the sepsis cascade, the enterprise involved in its licensure is so costly that the final product may prove prohibitively expensive, especially if its use requires the repeated ordering of specialized laboratory tests such as the measurement of cytokines. Inevitably, the worldwide drive toward containing the costs of health care may force the additional burden of proving the drug to be economical; however, that is defined, before any potential therapy for sepsis can be brought onto the market. In the meantime, the pragmatic approach of the last author in making fluid replacement, good nutritional support, and sound rigorous infection control measures the order of the day seems the best hope for patients fortunate enough to still be at the early stages of sepsis syndrome.
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