Update on the Management of Sepsis
By James E. McFeely, MD, Medical Director Critical Care Units, Alta Bates Summit Medical Center, Berkeley, CA, is Associate Editor for Critical Care Alert.
Dr. McFeely reports no financial relationship to this field of study.
Severe sepsis with organ failure has one of the highest mortality rates of any diagnosis commonly treated in the Intensive Care Unit. Recent clinical trials have provided some positive results with reductions in overall mortality from sepsis. This is a welcome change from the recent past when all clinical trials were negative. As a result, we now have some interventions that can be applied at the bedside with proven efficacy in this group of patients.
Eleven of the relevant medical societies have reviewed the most recent set of data and developed guidelines for the management of sepsis as part of a joint undertaking called the Surviving Sepsis Campaign.1 However, Eli Lilly's sponsorship has generated controversy about the guidelines, given that the company has the only drug approved for this indication and provided over 90% of the funding and supportive development of the project.2 In addition, Eli Lilly has recently begun awarding unrestricted grants for an "Implementing the Surviving Sepsis Campaign" program, the main goal of which is the creation of performance bundles based on recommendations from the campaign guidelines.
This article includes a summary of the primary research on which the guidelines are based, to facilitate review of the guidelines as submitted and to provide supporting evidence should local modification of those guidelines seem appropriate.
The Magnitude of the Problem
Sepsis is a common problem in the United States, with an estimated 750,000 cases per year and an overall mortality rate of 30-50%, depending on the number of organs involved and previous conditions existing in the patients. Sepsis is difficult to study because it is a complex response to infection involving a number of different pathways, including the patient's immune, coagulation, and inflammatory responses to the initial insult. Organ failures can occur due to a failure of a host response as well as from an over-reaction of the host response system. Over the years numerous trials attempting to manipulate each of these pathways have turned out to be negative for a variety of reasons, some having to do with underlying physiology and others related to clinical trial design.
More recently, various therapies have had positive clinical trials and these can be grouped into broad categories. Some of these interventions have been clearly shown to work; others have suggestive data that they might work with varying levels of risk (see Table). Other therapies have clearly been shown not to be effective and should not be implemented.
Early Goal-Directed Therapy
Early identification and resuscitation of patients with suspected sepsis and shock, as performed by Rivers and colleagues,3 was shown to be at least as effective as activated protein-C (absolute risk reduction, 16% vs 6%) in reducing mortality from sepsis. Early goal-directed therapy requires implementation in the emergency room and involves 6-hour resuscitation through administration of fluids, vasopressors, inotropes, and transfusion to preset end points that include a mean arterial pressure greater than 65 mm Hg, central venous pressure of 8-12 mm Hg, hematocrit greater than or equal to 30%, and central venous oxygen saturation greater than 70%.
For most hospitals, this therapy requires a change in practice in the emergency room setting, with an increase in utilization of central venous catheters, measurement of serum lactate level, and frequent reassessment and adjustments in fluid and vasopressor therapy. When these procedures were implemented as a group, Rivers et al were able to show a reduction in mortality from 49 to 33%, the highest overall mortality reduction of any sepsis intervention to date.3
Rapid Antibiotic Administration
No placebo-control trials have been performed to date to document the role of antibiotic administration in treatment of sepsis due to a lack of clinical equipoise in the control group. Common sense suggests the administration of appropriate antibiotic therapy as a cornerstone of treatment of sepsis. A recent retrospective cohort study showed that rapid treatment with appropriate antibiotics (within the first hour of identification of septic shock) does result in a significant reduction in overall mortality.4 Delays in antibiotic administration of even one hour resulted in a significant increase in mortality.
Low Tidal-Volume Ventilation
Use of a low-tidal-volume ("lung-protective") ventilation strategy for patients with acute respiratory failure in a setting of sepsis has also been shown to reduce mortality.5 The magnitude of the mortality reduction is slightly less than that seen with early goal-directed therapy, but greater than with activated protein C administration. Use of a "ventilator bundle" in this setting, including prophylaxis against deep-venous thrombosis and peptic ulcer, elevation of the head of the bed, and scheduled interruptions of sedative drugs ("sedation vacations"), would also be appropriate.
The use of corticosteroids in patients with severe sepsis and organ failure continues to be controversial. What is known is that early short courses of high-dose steroids failed to improve mortality in sepsis.6,7 Two small randomized trials of low-dose steroids have shown a decreased need for vasopressor support in patients with sepsis, but these studies did not show a reduction in overall mortality. Only one trial has shown a survival benefit in patients who failed to respond to an ACTH stimulation test and were treated with low-dose corticosteroids.8 Problems with implementation include variability in cortisol assays from hospital to hospital, as well as frequent lack of correlation between a total serum cortisol level and serum free cortisol levels, which can be affected by serum albumen. Well-known complications of the use of corticosteroids include development of hyperglycemia, myopathy, and immunosuppressive effects, some of which can be mitigated by use of low-dose hydrocortisone. The current trend is toward use of low-dose hydrocortisone in patients with refractory shock, at least until the results of a random serum cortisol or ACTH-stimulated cortisol level can be obtained.
Tight Glycemic Control
To date, no randomized control trials have been conducted of tight glycemic control in patients with sepsis, despite a recent resurgence and interest in this therapy. The most frequently cited research involved critically ill surgical patients and showed that tight glycemic control decreases mortality in patients staying in the ICU for at least five days.9 A subsequent trial by the same group in medical ICU patients showed an increased mortality rate among patients with an ICU stay of less than 3 days, but improvement in mortality rates for patients staying longer.10 There are theoretical reasons why intensive insulin therapy might be beneficial, including the known complications of hyperglycemia such as impairment in neutrophil function with increased risk of infection, decreased wound healing, and pro-coagulant effects. Initial concerns about increased risk of hypoglycemia have eased primarily through use of continuous glucose infusions and frequent rechecking of blood glucose values. Clearly, a randomized control trial of tight glycemic control in sepsis is badly needed.
Activated Protein C
The role of activated protein-C in treatment of sepsis with organ failure continues to evolve. After the initial positive results of the PROWESS trial, a series of negative trials with the same compound have raised questions about the appropriate use of the drug and the subset of patients for which it is indicated.11,12 For safety reasons, the PROWESS trial did not include several subsets of patients who become septic, including dialysis patients, those with liver failure, children, and transplant recipients.
Subsequent to the somewhat controversial approval of activated protein-C by the FDA, the manufacturer, Eli Lilly, conducted a trial on pediatric patients with severe sepsis with organ failure that failed to show a mortality benefit.13 In addition, a large trial in patients with single-organ failure and sepsis was stopped, again because of a lack of mortality benefit.14 A study of tissue factor pathway inhibitor (TFPI), an additional coagulant pathway inhibitor, was also negative.15 These negative results have raised questions within the medical community about the results of the initial PROWESS trial and have prompted calls for that trial to be repeated. For now, use of activated protein-C should be strictly limited to patients who meet the inclusion and exclusion criteria of the original PROWESS trial (eg, patients at a high risk of death with at least two organ failures), and should not be extrapolated to any other patient population without further supporting data.
A number of other compounds have been tested in sepsis and have failed to show any benefit. Most of these never came to market. Commonly utilized agents shown not to work include 'renal dose' dopamine and sodium bicarbonate for treatment of lactic acidosis.16,17 Neither of these has a place in current practice guidelines for treatment of sepsis—a fact that may require some re-education of the more senior members of the treatment team.
Management of sepsis continues to be an active area of investigation and over the last few years positive clinical trials have resulted in some real improvements in patient outcomes. Your development of local guidelines and goals for therapy should be based strictly on the data that is available in the medical literature and should be constantly revised as new information becomes available.
- Dellinger RP, et al. Surviving Sepsis Campaign Management Guidelines Committee. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med. 2004;32:858-873; Erratum in: Crit Care Med. 2004;32:1448; Correction of dosage error in text: Crit Care Med. 2004;32:2169-2170.
- Eichacker PQ, et al. Surviving sepsis—practice guidelines, marketing campaigns, and Eli Lilly. N Engl J Med. 2006;355:1640-1642.
- Rivers E, et al. Early Goal-Directed Therapy Collaborative Group. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345:1368-1377.
- Kumar A, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006;34:1589-1596.
- The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med. 2000;342:1301-1308.
- Bone RC, et al. A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. N Engl J Med. 1987;317:653-658.
- Sprung CL, et al. The effects of high-dose corticosteroids in patients with septic shock. A prospective, controlled study. N Engl J Med. 1984;311:1137-1143.
- Annane D, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA. 2002;288:862-871.
- van den Berghe G, et al. Intensive insulin therapy in the critically ill patients. N Engl J Med. 2001;345:1359-1367.
- van den Berghe G, et al. Intensive insulin therapy in the medical ICU. N Engl J Med. 2006;354:449-461.
- Bernard GR, et al. Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001;344:699-709.
- Deans KJ, et al. Substantiating the concerns about recombinant human activated protein C use in sepsis. Crit Care Med. 2004;32:2542-2543.
- Goldstein B, et al. ENHANCE: results of a global open-label trial of drotrecogin alfa (activated) in children with severe sepsis. Pediatr Crit Care Med. 2006;7:200-211.
- 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.
- Abraham E, et al. OPTIMIST Trial Study Group. Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial. JAMA. 2003;290:238-247.
- Jones D, Bellomo R. Renal-dose dopamine: from hypothesis to paradigm to dogma to myth and, finally, superstition? J Intensive Care Med. 2005;20:199-211.
- Cooper DJ, et al. Bicarbonate does not improve hemodynamics in critically ill patients who have lactic acidosis. A prospective, controlled clinical study. Ann Intern Med. 1990;112:492-498.