Severe Sepsis and Septic Shock in 2012: What Have We Learned?
By David J. Pierson, MD, Editor, Professor Emeritus, Pulmonary and Critical Care Medicine, University of Washington, Seattle, is Editor for Critical Care Alert.
When I was a medicine resident 40 years ago just as the first ICUs were being introduced, treatment for life-threatening bacterial infections consisted of antibiotics, control or removal of the primary source, intravenous fluids, and vasopressors. The intervening decades have brought unimaginable technical advances in critical care, as well as the ability to cure some conditions that were once uniformly fatal and to greatly extend survival in many incurable but now-treatable diseases. Since I trained, we have refined our concepts and clinical classification of sepsis, with gradations of severity from SIRS (the systemic inflammatory response syndrome), to sepsis, to severe sepsis, to septic shock. In North America, the last two of these sepsis categories develop in some 750,000 patients each year, and one-third of them die. What progress have we made in their treatment? I will briefly consider several aspects of this question, a number of which are discussed in more detail by Suffredini and Munford in a recent review.1
THE RISE AND FALL OF XIGRIS
On October 25, 2011, Eli Lilly and Company announced a worldwide voluntary market withdrawal of Xigris (drotrecogin alfa [activated]),2,3 bringing to a close a decade of contention and controversy since that drug was first introduced in critical care. The Xigris story illustrates several aspects of the challenges facing attempts to improve care for patients with severe sepsis and septic shock.
Drotrecogin alfa (activated), also known as activated protein C (APC), represents an attempt to target an aspect of the sepsis process itself rather than the causative microorganism. It is a recombinant anticoagulant protein intended to inhibit the widespread thrombosis that occurs in sepsis, and thus to ameliorate at the tissue level the multiple organ dysfunctions that lead to morbidity and mortality in this condition. The initial clinical trial of APC in severe sepsis and septic shock (the PROWESS trial)4 was stopped early because an interim data analysis showed a 6.1% decrease in 28-day mortality among patients who received the new agent, and it was promptly approved by the Food and Drug Administration (FDA) for use in patients with sepsis and APACHE II scores > 25, indicating a high risk of death.
From the beginning, APC was controversial, not only with respect to its clinical effectiveness and adverse effects (primarily hemorrhage, sometimes fatal) but also because of its manufacturer's marketing and alleged role in the promulgation of worldwide practice guidelines and clinical bundles for sepsis management. Studies subsequent to the PROWESS trial were generally unable to confirm its positive results. A trial of APC in patients with severe sepsis who were less severely ill (with APACHE II scores < 25) was stopped early because of futility,5 as was a trial in pediatric patients.6 A clinical trial of APC vs placebo in acute lung injury and the acute respiratory distress syndrome in patients who did not have severe sepsis and APACHE II scores > 25 also showed no survival benefit.7
Because of growing concern about the efficacy of APC, even in its original high-risk patient population, in 2007 the European Medicines Agency asked Eli Lilly to essentially repeat the original PROWESS study.8 The results of this second trial (PROWESS-SHOCK)9 have recently been made public. Data from the company, subsequently submitted to the FDA, showed a 28-day, all-cause mortality rate of 26.4% (223/846) in APC-treated patients as compared to 24.2% (202/834) in the placebo group (relative risk, 1.09; 95% confidence interval, 0.92-1.28), with a non-significant P value of 0.31.3 Because of this, and in keeping with the findings of a recent Cochrane Review that recommended APC not be used because of lack of evidence of efficacy and substantial risk for adverse effects,10 the company withdrew the drug from the market worldwide.
EFFECTIVENESS OF OTHER NEW AGENTS FOR SEPSIS
Numerous other new agents have been studied in treating patients with severe sepsis and septic shock.1 Because multi-organ dysfunction is both a primary manifestation of severe sepsis and a main determinant of overall patient outcome, much investigation has focused on interfering with systemic inflammation and its mediators. After an initial positive report of the use of anti-endotoxin serum in sepsis, subsequent trials of anti-endotoxin monoclonal antibodies showed no benefit. Studies of polyclonal immunoglobulin, also aimed at neutralizing endotoxin and preventing its adverse effects, have been disappointing. Clinical trials of agents targeting individual pro-inflammatory mediators, such as tumor necrosis factor, platelet-activating factor, bradykinin, and others, have been negative despite favorable preliminary reports.
Examination of multiple such studies suggests that failure to demonstrate overall survival benefits may be due in part to divergent effects of at least some of these agents in different patients.1 For example, because the studied therapies have their own risks, positive effects on survival in the most severely ill patients may be masked by worse outcomes due to adverse effects in patients with milder illness. This remains speculative, although it is a point in favor of careful stratification of illness severity and other factors potentially related to outcome in such trials.
OTHER ASPECTS OF SEPSIS MANAGEMENT
The use of high-dose corticosteroids in patients with severe sepsis and septic shock goes back five decades, but analysis of the numerous clinical trials conducted into the late 1980s showed that this actually worsened survival, and it was abandoned. By the turn of the century, though, there had been an upsurge of interest in the use of steroids in lower, "replacement" doses, for longer courses than had been given earlier, which was associated in multiple relatively small studies with both decreased vasopressor use and improved survival. The administration of low-dose corticosteroids is a feature in many current guidelines, although the clinical benefit of this and how steroids should best be used remain to be established definitively.
Because of associations of infection and other adverse outcomes with hyperglycemia in critically ill patients, its avoidance has emerged during the last decade as an important topic in sepsis management. An initial study showed improved survival in ICU patients with intensive insulin therapy and careful control of serum glucose levels, and so-called "tight glucose control" was both widely embraced in clinical practice and incorporated into practice guidelines. However, subsequent studies in other patient populations and practice settings have demonstrated increased hypoglycemia-related complications and less clear outcome benefits. Again, although the control of glucose levels continues to be included in many current guidelines for managing sepsis and other critical illness, it is doubtful that we have heard the final word in this area.
A facet of sepsis management that has profoundly influenced both clinical practice guidelines and institutional policies is what has come to be known as early goal-directed therapy (EGDT). This is a package of assessments and interventions aimed at identifying the presence of sepsis, assessing its severity in terms of adequacy of tissue perfusion, and initiating therapy as quickly as possible — within 6 hours in all cases. Although the EGDT approach is only 10 years old, and essentially based on the results of one single-center clinical trial,11 current evidence and clinical consensus support the concept that this may be the most important innovation in recent decades for improving outcomes in severe sepsis and septic shock.
WHAT HAVE WE LEARNED?
Progress in the management of sepsis, like that in mechanical ventilation for severe respiratory failure and in numerous other aspects of critical care, proceeds in identifiable cycles. One such cycle, particularly when potential innovations have commercial implications, is illustrated in the Figure.
A new therapy or approach, typically with a sound pathophysiologic rationale, is introduced on the basis of initial reports of benefit. In the case of pharmaceutical agents like APC, this requires preliminary clinical studies to meet FDA requirements, although with novel ventilator approaches and new medical devices much less preliminary investigation is usually carried out. Because of promotion by advocates and/or corporate marketing efforts, the new therapy becomes well known and is put into wide clinical use, perhaps even finding its way into institutional protocols and guidelines issued by professional groups. It is typically only after this point that more extensive studies are undertaken. These further studies, frequently larger and better controlled for bias and confounding than the initial reports, typically demonstrate that the new therapy or approach is less effective than initially hoped — or no better than previous therapies, or even worse. There are many examples of this in critical care.
The construct shown in the Figure is a gross oversimplification of the challenges to innovation in the complex environment of the ICU, and it is not meant as a condemnation of the system. For clinicians confronted by high-mortality illnesses and imperfect therapies, motivation to embrace new interventions with the potential for better patient outcomes is to be expected and hard to criticize. And the fact is that most of what we do in the ICU — including the management of severe sepsis and septic shock — rests on a foundation that is much less than completely solid.
Prompt initiation of antibiotic therapy, after appropriate cultures are obtained, has stood the test of time as perhaps the most important aspect of sepsis management. There seems little doubt that antibiotic therapy should be tailored to the patient and the clinical context, including:
- The patient's underlying health and immune status
- Whether the infection is community- or health care-associated
- Recent antibiotic treatment
- Local organism prevalence and antibiotic resistance patterns
- Available specific microbiological data, such as Gram stain findings and previous culture results
Antibiotic therapy, source control, supplemental oxygen, protection of the airway, and mechanical ventilation if needed remain clear requirements for managing severe sepsis and septic shock. Beyond these, however, the clinician faces many uncertainties. A few of the latter are the following:
- Assessment and monitoring of the adequacy of tissue perfusion — physical exam vs serum lactate vs central venous oxygen saturation vs gastric tonometry
- Intravenous fluids — how much; what kind
- Vasopressors — which one(s); optimal usage
- Inotropes — whether to use; if so, which one(s)
- Red blood cell transfusion — when; how much
- Serum glucose — desirable ranges; how to control most effectively and safely
- Corticosteroids — whether to use, how to assess, which one, how much, and how long
- Procalcitonin and other potential indicators of inflammation and response — clinical value; whether and how to use
Severe sepsis and septic shock are among the most common and vexing challenges confronting the intensivist. Although critical care now deals with different types of patients and takes place in a far different environment than was the case four decades ago, many of the most important aspects of managing these conditions have not changed very much. Sepsis remains one of the most active and important areas of critical care research, and help with the controversies and unknowns described above is to be hoped for — and expected — in the future.
- Suffredini AD, Munford RS. Novel therapies for septic shock over the past 4 decades. JAMA 2011;306:194-199.
- Bernard GR, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344: 699-709.
- Abraham E, et al. Administration of Drotrecogin Alfa (activated) in Early Stage Severe Sepsis (ADDRESS) Study Group. Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med 2005;353:1332-1341.
- Nadel S, et al. REsearching severe Sepsis and Organ dysfunction in children: A gLobal perspective (RESOLVE) study group. Drotrecogin alfa (activated) in children with severe sepsis: A multicentre phase III randomised controlled trial. Lancet 2007;369:836-843.
- Liu KD, et al. Randomized clinical trial of activated protein C for the treatment of acute lung injury. Am J Respir Crit Care Med 2008;178:618-623.
- PROWESS SHOCK Steering Committee. Statistical analysis plan of PROWESS SHOCK study. Intensive Care Med 2010;36: 1972-1973.
- Martí-Carvajal AJ, et al. Human recombinant activated protein C for severe sepsis. Cochrane Database Syst Rev 2011 Apr 13;4: CD004388.
- Rivers E, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001;345:1368-1377.