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(Chest. 2003;123:451S-459S.)
© 2003 American College of Chest Physicians

The Problems and Challenges of Immunotherapy in Sepsis*

Stanley A. Nasraway, MD, FCCP

* From the Department of Surgery and Section of Critical Care Research, Tufts-New England Medical Center, Tufts University School of Medicine, Boston, MA.

Correspondence to: Stanley A. Nasraway, MD, FCCP, Department of Surgery, Tufts-New England Medical Center, 750 Washington St, Box 4630, Boston, MA 02111; e-mail: Snasraway{at}lifespan.org


   Abstract
TOP
 Abstract
Introduction
 Is Research Striking Out?
 The Flaws in Sepsis...
 The Way Forward
 Conclusions
 References
 
Despite decades of research, the morbidity and mortality of sepsis and septic shock remain very high. To further compound the problem, results from all investigative trials (with one exception) have shown that tested immunotherapies aimed at modulating the excessive expression of key cytokines, such as the interleukins and tumor necrosis factor, have been either equivalent or inferior to placebo. While controversy prevails in terms of continuing such investigative trials, study designs can be held accountable for inherent flaws. Testing for the wrong hypothesis, errant study design, using the wrong agent, focusing on an inappropriate target group, excessive expectations, and uncontrolled variables have potentially obscured the real efficacy such agents might have to offer. By standardizing protocols and reducing uncontrolled variables, research can be more precisely targeted so as to unmask the real benefits to the patient.

Key Words: cytokines • immunomodulators • sepsis • sepsis trials • septic shock


   Introduction
TOP
 Abstract
 Introduction
Is Research Striking Out?
 The Flaws in Sepsis...
 The Way Forward
 Conclusions
 References
 
Sepsis and septic shock are significant causes of patient morbidity and mortality.1 Approximately 750,000 cases of severe sepsis occur in the United States each year, secondary to bacterial and fungal infections.2 In half of these patients, shock develops that is refractory to fluid resuscitation.1 Thirty years ago, mortality from septic or cardiogenic shock exceeded 70%3 ; today, the rate for septic shock is still high, at 50%, despite the availability of potent antibiotics and intensive supportive care.4 5

Overall, the incidence of sepsis and septic shock is escalating. From 1979 to 1987, the percentage of infectious disease diagnoses that included sepsis rose from 9 to 25%.6 This upsurge has been attributed to a host of factors, including the increased use of cytotoxic and immunosuppressive therapies, the aging of the population, a heightened frequency of infection from antimicrobial-resistant pathogens, and the increased use of invasive devices, such as intravascular catheters.7


   Is Research Striking Out?
TOP
 Abstract
 Introduction
 Is Research Striking Out?
The Flaws in Sepsis...
 The Way Forward
 Conclusions
 References
 
Sepsis treatment consists of appropriate antibiotic therapy and effective surgical eradication of the septic sources whenever possible. Yet, mortality rates remain high—why? The past decade has been a time of greater understanding of the inflammatory response and of organ dysfunction during overwhelming infection; however, this enhanced knowledge at the research level has not generally translated into clinical success. Trial results of immunotherapies for severe sepsis or septic shock, up to the spring of 2000, have been dismal. Three major trials of septic shock—the Immunex (Immunex Corporation; Seattle, WA) phase II study of the p80 soluble receptor to tumor necrosis factor (TNF),8 the Glaxo-sponsored (Glaxo SmithKline; Research Triangle Park, NC) study of nitric oxide (NO) synthase inhibition,9 and the Centocor (Centocor; Malvern, PA) phase IIIb anti-endotoxin trial of human monoclonal antibody (MAb) HA-1A10 —have culminated in excess mortality in patients receiving the experimental agent. A meta-analysis11 of 15 clinical trials12 13 14 15 16 17 18 19 20 21 22 23 24 25 that used nonglucocorticoid anti-inflammatory agents demonstrated no statistical benefit of immunomodulation, although a modest positive outcome may exist (odds ratio, 1.11; 95% confidence interval [CI], 0.99 to 1.23; p = 0.07). Since the publication of this meta-analysis, the results of other phase III trials have been reported, including anti-TNF studies.5 26 These also failed to demonstrate any clinical benefit.

In 1998, Glaxo Wellcome terminated its international trial of L-NG-methylarginine hydrochloride, a nonselective NO synthase inhibitor, for the treatment of patients with septic shock. The agent simulates a vasopressor by restoring vasomotor tone. An interim analysis in this trial of the first 522 patients who received this experimental agent demonstrated a significant increase in mortality.27

In addition to the Centocor phase IIIb trial of HA-1A,10 four other anti-endotoxin studies28 29 30 31 have produced disappointing results. For example, in the study by Bone and colleagues28 that evaluated the safety and efficacy of E5, a murine MAb directed against endotoxin, no significant improvement in survival after 30 days was observed in patients who received the agent as compared with those who received placebo (p = 0.21). The same lack of significant response was noted in a study by Ziegler and colleagues30 of HA-1A in Gram-negative sepsis in which the mortality rate was 43% and 39%, respectively, in the placebo and the human monoclonal IgM antibody groups (p = 0.24). More recently, a phase IIIc trial31 examining the use of E5 in 915 patients with confirmed severe Gram-negative sepsis once again demonstrated no appreciable survival benefit. These disheartening investigational outcomes that showed no benefit and, in some cases, an increase in mortality in patients with sepsis raise serious questions about the path of future clinical investigations.

The Immunomechanisms of Sepsis
Sepsis involves a complex interaction of proinflammatory and anti-inflammatory mediators (Table 1 ). The net effect of a given mediator can vary depending on the state of activation of the target cell, the presence of other mediators, and the ability of the target cell to release mediators that can augment or inhibit the primary mediator.32 Although the actions of many cytokines and cells are involved, TNF-{alpha} is considered the primary mediator of sepsis.32 Evidence supporting an important role for TNF-{alpha} includes the observations that endotoxin injected in healthy humans results in the detection of free TNF-{alpha} in plasma and the development of many signs and symptoms associated with Gram-negative infection. TNF-{alpha} release leads to activation of other cytokines, such as interleukin (IL)-1ß and IL-6, that are associated with cellular damage.32 33 TNF-{alpha} has received much attention because it is elevated in most patients with sepsis; however, TNF-{alpha} levels are also amplified in many healthy people as well as patients with sepsis, and those with a variety of diseases.32 IL-6 may be a more consistent predictor of sepsis because it remains elevated for a longer period of time than TNF-{alpha}, and it appears to better correlate with sepsis severity and mortality.34 35 Circulating concentrations of IL-8 also correlate with severity of sepsis and mortality.36


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  		Table 1. Pro-inflammatory and Anti-inflammatory Mediators in Sepsis

 
Through the actions of these aforementioned mediators, a variety of cells become activated, initiating cascades believed to be detrimental to the host (Fig 1 ). A long list of strategies has been developed to reverse or control the inflammatory processes initiated with sepsis, including antibody against lipopolysaccharide (endotoxin), IL-1 receptor antagonist, platelet activating factor (PAF) antagonist, anti-TNF-{alpha} antibody, and polyclonal Ig.28 37 38 One of the first interventions to gain attention was direct inhibition of the effects of endotoxin using specific MAbs; however, as mentioned, studies28 30 conducted with MAbs such as HA-1A and E5, which bind to the lipid A portion of the endotoxin molecule, have failed to demonstrate positive clinical outcomes in patients with sepsis, perhaps suggesting that the time window to reduce the endotoxin-initiated sepsis cascades had passed by the time treatment was started. Research in sepsis immunotherapy continues (Table 2 ).32 33 39 40 The question remains—at what cost?



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  		Figure 1. The cytokine cascade. G-CSF = granulocyte colony-stimulating factor.

 

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  		Table 2. Therapeutic Sepsis Interventions in Clinical Trials

 

   The Flaws in Sepsis Investigations
TOP
 Abstract
 Introduction
 Is Research Striking Out?
 The Flaws in Sepsis...
The Way Forward
 Conclusions
 References
 
While inadequate outcomes with respect to human sepsis research have been demonstrated in the past, such research should continue; however, substantial changes must be made in the way we study new inflammatory modulators to sidestep the flaws in the study designs of the past decade (Table 1) . Reasons abound to explain the failures of previous clinical sepsis studies.9 28 41

The Wrong Hypothesis
Perhaps the hypothesis that excessive and poorly regulated intravascular inflammation is causal for shock, multiple organ failure, and death in the septic host is wrong. Anti-TNF strategies have been successful in animal models of severe infection induced by endotoxin.42 43 In the study by Opal and colleagues,43 mice were given cyclophosphamide, rendered neutropenic, injected with a lethal dose of Pseudomonas aeruginosa, and denied antibiotics. The mice were then placed in four groups: those receiving an irrelevant MAb (placebo), those receiving anti-TNF MAb, those receiving MAb directed against P aeruginosa lipopolysaccharide, and those given a combination of anti-TNF and anti-lipopolysaccharide MAb (group 4). The mice given the placebo quickly died, while those given either the anti-TNF or anti-lipopolysaccharide had approximately a 40% survival rate. Those mice given the combination had an approximate 75% survival rate. The results were encouraging enough to attempt to treat humans in the same manner.

However, the primary hypothesis might be wrong. Runaway inflammation may not be responsible for the morbidity and mortality related to sepsis; in this case, immunotherapy alone would not be expected to reverse shock. Rather, the combination of antimicrobial therapy, fluid therapy, inotrope and vasoactive drug support, and ventilatory support in conjunction with immunotherapy would be considered equally vital as a therapeutic strategy. In addition, preclinical investigations supporting the underlying hypothesis or study agents may have been insufficient. Animal models of sepsis have limited applicability and may not properly replicate human sepsis.

Right Question, Wrong Study Design
Flaws in experimental design are undoubtedly partly responsible for many of the failures of past sepsis trials. Studies examining the role of recombinant human IL-1 receptor antagonist (rhIL-1ra) may be an example of this.

A phase IIIa study by Fisher and colleagues13 attempted to define the efficacy of rhIL-1ra in the treatment of sepsis syndrome. The study was designed to give the 893 patients with sepsis syndrome an IV loading dose of rhIL-1ra, 100 mg, or placebo followed by a continuous 72-h IV infusion of rhIL-1ra (1.0 mg/kg/h or 2.0 mg/kg/h) or placebo. The results of the trial showed no statistical benefit of giving the agent over the placebo (Fig 2 ); however, a subgroup analysis suggested that sicker patients did, in fact, respond to the continuous rhIL-1ra infusion. The study was subsequently redesigned for a IIIb phase. Investigators wanted to enroll patients who were more ill in an attempt to take advantage of the previous findings; however, the phase IIIb enrollment criteria in the subsequent study for sepsis and severity were almost identical to the criteria used in the phase IIIa study. Investigators also wanted to enroll patients who were more likely to sustain hypotension. Unfortunately, the definition of hypotension as a mean arterial pressure of < 70 mm Hg was lowered only to 65 mm Hg. These sorts of subtle changes in the study undermined the likelihood of finding a meaningful difference. The results of the phase IIIb trial were identical to those of the failed phase IIIa trial.12



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  		Figure 2. The results of a study by Fisher and colleagues13 using recombinant human interleukin-1 receptor antagonist for the treatment of sepsis syndrome. IL-1ra = IL-1 receptor antagonist.

 
Right Question, Wrong Agent
Clinical investigation is arguably premature, given the extreme complexity of the inflammation cascade and the current limitations in our understanding of the underlying fundamental biology. As investigators, we have to be careful about interpreting the information presented to us from animal and early clinical trials. Companies fueled by venture capital and eager to turn a profit try to put the best face on their data to sustain themselves. A small phase II trial funded by Immunex tested a P-80 TNF receptor, a recombinant, soluble fusion protein that is a dimer of an extracellular portion of TNF receptor and the Fc portion of Ig G1, and which binds and neutralizes TNF-{alpha}, preventing death in animal models of bacteremia and endotoxemia.8 The results in humans were devastating. Basically, in dose-related fashion, the higher the dose of the P-80 receptor, the higher the mortality rate. There was a 30% mortality among the 30 patients receiving the low dose, a 48% mortality among the 29 patients receiving the middle dose, and 53% mortality among the 49 patients receiving the high dose (p = 0.02). Baseline differences in the severity of illness did not account for the increased mortality in the groups receiving the higher doses of the P-80 receptor. The efforts of Immunex efforts to use the P-80 TNF receptor to treat sepsis were abandoned after this trial; however, when the same drug was used in rheumatoid arthritis, another inflammatory disease but one with greater chronicity as compared with severe sepsis, the results were astoundingly positive.

Right Question, Wrong Target Group
The enrollment criteria of the premier sepsis studies in the past decade have been exclusively dependent on overly sensitive, nonspecific clinical signs. Rather than the entire sepsis population, perhaps the focus should be on a narrower cohort of severely ill patients with reversible physiology. A 1991 study29 using E5 anti-endotoxin in patients with septic shock demonstrated that the agent also appeared to be beneficial when used in patients with nonseptic shock. The cohort became too broad to prove the worth of this agent when compared to placebo. Inclusion criteria were few in number and incorporated virtually omnipresent and nonspecific signs/symptoms such as altered mental status and a respiratory rate > 20 breaths/min. A study31 designed to again prove the efficacy of E5 in patients with either septic or nonseptic shock also failed, due to targeting a very heterogeneous patient population. Studies such as these have been driven by premature and spurious findings from post hoc, subgroup analyses. This case represents > 20 years of anti-endotoxin research and has not provided definitive answers about mortality reduction.

Excessive Expectations
In the 1990s, researchers hoped to dramatically increase survival in patients with septic shock and sepsis by as much as 50%. Such expectations of "hitting a home run" were built into the early studies. An animal study by Hinshaw and colleagues44 determined the efficacy of treatment with anti-TNF MAb in preventing the deleterious effects of sepsis in a nonhuman primate. Experiments were carried out using baboons IV infused with a lethal dose of Escherichia coli. Twelve baboons (6 control and 6 experimental) received infusions of E coli. The experimental group was administered a bolus of anti-TNF antibody 30 min after the E coli infusion. Control baboons lived an average of 19 h, while the MAb-treated baboons survived > 7 days with a significantly improved quality of life compared to the control group. The results of this study launched tremendous interest in TNF as a molecule that could be immunomodulated.

The next step was to try the agent on humans. Abraham and colleagues20 conducted a multicenter, placebo-controlled trial that tested TNF-{alpha} in > 900 patients with severe sepsis. Patients were administered placebo, low-dose TNF-{alpha}, or high-dose TNF-{alpha}. The outcome measure was 28-day mortality. At day 28, the reduction in mortality for all severely septic patients was not significantly different for either dose of TNF-{alpha} relative to placebo; however, a substantial trend in increased survival was evident in the subset of patients with septic shock receiving either dose of the TNF antibody, and this improvement was sustained throughout the 28-day period. This triggered a second trial that precisely reproduced the first study design in the hope of amplifying the survival rates for strict septic shock seen in the original study.5 Surprisingly, despite an identical experimental design and a much larger sample size, the results were not positive: 40.3% of the 948 patients who received TNF and 42.8% of 930 who received placebo had died by day 28 (95% CI, 0.02 to 0.07; p = 0.27). Thus, no association was seen between therapy with TNF and increased rapidity in reversal of initial shock or prevention of subsequent shock.

Studying the use of TNF in sepsis continued, but with a change in perspective. In septic shock patients, high amounts of circulating TNF-{alpha} and IL-6 were found to correlate with fatal outcome45 ; however, in trauma patients, and even those patients resuscitated from hemorrhagic shock, much less increased concentrations of IL-6 were detected while normal TNF-{alpha} circulating concentrations were measured. In these patients, cytokine concentrations did not correlate with outcome. This finding suggests a much higher degree of activation of the immunoinflammatory cascade in septic shock than in patients with multiple trauma. Increased IL-6 levels are now considered an indicator of the development of a nosocomial infection in trauma patients (Fig 3 . )



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  		Figure 3. Serum TNF-{alpha} and IL-6 in septic shock.45

 
Recently, Knoll Pharmaceuticals (Mount Olive, NJ) completed its North American study of anti-TNF for patients with severe sepsis; at the time of this writing, the results have been presented but not published.46 The Knoll Pharmaceutical approach differs from the earlier studies in that it looks not just at clinical signs of sepsis, but also at levels of inflammatory cytokines, specifically IL-6. Knoll Pharmaceuticals integrated an IL-6 semiquantitative assay with its MAb study because it found in phase II trials that patients whose IL-6 levels are < 1,000 pg/mL are less likely to benefit from receiving anti-TNF-{alpha}, whereas those patients with severe sepsis who have IL-6 levels > 1000 pg/mL do appear to benefit from anti-TNF.18 The final results of this phase III trial demonstrated a significant reduction in mortality, more so in that subset of patients with very high IL-6 concentrations at study enrollment. Absolute mortality was reduced by 3.6% (p < 0.05). In association with this, multiple organ dysfunction was similarly decreased during the first week in patients receiving anti-TNF. The decrease in mortality may not be clinically striking enough for US Food and Drug Administration (FDA) approval, which remains tenuous at best for this agent.

Too Many Uncontrolled Variables
Unlike animal studies, researchers investigating immunotherapy for clinical septic shock have not controlled for all the variables. The best example is the Glaxo Wellcome study that aimed to nonselectively inhibit the synthesis of NO. NO is a short-acting, potent vasodilator derived from the enzymatic oxidation of arginine. Under pathophysiologic conditions, stimulated by cytokines, the inducible form of NO becomes diffusely expressed, producing large amounts of NO. This has been implicated, for example, in the cardiovascular failure of septic shock.47 48

Pharmacologic inhibition of NO production has been investigated as an adjunct to standard therapies of septic shock.48 49 Glaxo Wellcome tested its NO synthase inhibitor, 1-n-methyl arginine, in a multicenter international study that was expected to be the largest trial ever in septic shock, with almost 5,000 patients. The end points were 14-day and 28-day mortality, as well as 7-day resolution of shock because of the vasopressor action associated with NO synthase inhibition; however, a key flaw in the experimental design was the wide and high range of mean arterial pressures to which vasopressors and the experimental agent were titrated: 70 to 90 mm Hg. Usual practice in North America would be to titrate BP to a minimum mean arterial pressure of 60 to 70 mm Hg; however, in other parts of the world, mean arterial pressures are maintained at 80 to 90 mm Hg in the severely septic patient, a level that can be deleterious given the need for vasopressors.50 There is no clinical evidence to support this practice. The Glaxo Wellcome trial was stopped after interim analysis when an increase in mortality in the group of patients receiving the experimental agent was observed. This mortality was due to hemodynamic compromise: pulmonary hypertension, right-heart failure, and a low cardiac index (S. Grossman; personal communication; April 1998). The increasing doses of the vasopressor caused a subsequent increase in afterload that aggravated cardiac failure in those patients already in circulatory shock.51 Also, other variables were noted. For example, patients were recruited from around the world: from Chile to Poland, from Canada to Singapore. This sort of widespread enrollment necessarily incorporated into the trial differences in physician practice and in the types of patients studied; variability related to physician and patient heterogeneity was uncontrolled and unaccounted for. Enrolled patients had to have been too diverse, with differences in comorbidities, severities of illness, types of infecting pathogens and sources of infection. Conventional management was variable and uncontrolled. Variability in investigator sites, country/cultural differences, and dissimilarities in the time to patient randomization from sepsis onset were also differences that confounded the results.


   The Way Forward
TOP
 Abstract
 Introduction
 Is Research Striking Out?
 The Flaws in Sepsis...
 The Way Forward
Conclusions
 References
 
Standardizing conventional practice is one way to sidestep the uncontrolled variables and heterogeneity of patient populations. Enrollment criteria for sepsis studies have been largely based on uniform definitions for sepsis, severe sepsis, and septic shock developed by the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference.52 Some studies and commentaries53 54 55 56 have critiqued these criteria as too sensitive, failing to target selectively the patient subgroup that is more likely to benefit from the experimental therapy. Lack of selectivity, as previously discussed, also aggravates the problem of patient heterogeneity.

Future studies will fail if based on the same old methods. Future studies that propose to modulate inflammation should not use enrollment criteria that rely exclusively on clinical signs of inflammation. Heterogeneity must be reduced. Sample sizes in much of the earlier research were too small, mainly as a result of overestimation of mortality risks and overly enthusiastic expectations in the potential benefits of immunomodulation. Larger sample sizes are therefore needed to unmask the relatively small beneficial effects of immunomodulation. Dosing is important; previously, the interventions tested were often ineffective in that doses studied were too high, too low, or too few. Also, the 28-day mortality end point mandated by the FDA may be too rigid or too crude, and may represent the wrong end point, in any event. Instead, the reversibility of organ failure or circulatory shock should be the focus. The severity of disease in many trials has been too low or too high. In some studies, patients were not stratified for illness severity. Finally, inadequate monitoring or quality control of investigation sites, in conjunction with lucrative per capita reimbursement, encourages enrollment of inappropriate patients.

Patient enrollment should be more selective, using scoring systems for illness severity, focusing on specific infection sources,57 and documenting biochemical inflammatory excess. Treatment protocols should be employed to reduce uncontrolled variables in physician practice that can alter cytokine expression.9 In addition to reducing the mortality in patients receiving the experimental agent, the use of standardized protocols can reduce mortality in patients randomized to the control group, since setting the rules for the process of care tends to decrease variability and errors, while improving quality.58 59

Attention to detail and revision of prior hypotheses led to two successful trials of immunotherapy. Investigators for Eli Lilly and Company (Indianapolis, IN) completed a phase III trial of 1,690 patients with severe sepsis or septic shock (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis [PROWESS]) showing that administration of human recombinant activated protein-C decreased 28-day mortality.60 The hypothesis for which this agent was studied is novel, and states that during severe sepsis, clinically undetectable microthromboses develop, occlude capillary flow, and result in organ ischemia and multiple organ dysfunction. In fact, animal and human studies have shown that protein-C concentrations are dramatically reduced in patients and, further, that protein-C concentrations correlate inversely with death.61 In the PROWESS study, administration of activated protein-C continuously for 96 h yielded an absolute mortality reduction of 6.1% (p = 0.005); however, this study was highly selective, in that many patients who might be prone to bleeding from a naturally occurring anticoagulant such as activated protein-C were excluded, such as those with hepatic or renal failure, a history of recent bleeding, or recent surgery. A separate monitoring group was responsible for ensuring purity of enrollment and screened and approved patients for study entry. Interestingly, initial review of the data from the PROWESS study did not clearly show a reduction in multiple organ dysfunction. Also, it appears, based on the FDA review, which is documented in the product label, that the sickest half of patients are the more likely subcohort to benefit. Activated protein-C may benefit patients by a multipronged action, in that it is an anti-inflammatory agent and also attenuates cellular death, ie, apoptosis.62

The second, and equally compelling trial, was French Steroids in Septic Shock Trial, the results of which were reported at the 30th International Educational and Scientific Symposium of the Society of Critical Care Medicine in February of 2001 and recently published.63 Prior efforts at using pharmacologic doses of glucocorticoids for septic shock had decisively failed to show benefit.64 65 Based on the numerous observations that as many as half to two thirds of patients in septic shock may sustain relative adrenal insufficiency, French investigators at 19 ICUs tested the hypothesis that giving physiologic doses of glucocorticoids and mineralocorticoids would improve adrenergic responsiveness, resulting in reversal of circulatory failure and improved survival.63 This prospective randomized trial in 299 patients in septic shock decreased mortality by 16% (absolute reduction 10%) for patients with adrenal insufficiency (229 of 299 studied patients), as determined by a short adrenocorticotropic hormone stimulation test (Table 3 ). There was no benefit evident for corticosteroid administration to those patients who were adrenocorticotropic hormone responders.


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  		Table 3. Comparison of Mortality Reductions Among the Successful Trials for Immunomodulation

 

   Conclusions
TOP
 Abstract
 Introduction
 Is Research Striking Out?
 The Flaws in Sepsis...
 The Way Forward
 Conclusions
References
 
Sepsis and septic shock continue to cause high rates of morbidity and mortality. Although our understanding of the role of inflammation in these conditions is increasing, 10 years of intense clinical research with immunotherapy has not yet yielded a successful treatment adjunct. More attention must be paid to study design in terms of eliminating variability in end points, focusing on the appropriate target groups, standardizing care, and having more realistic expectations. Research in this field must and will continue, necessitated by the high mortality seen in septic shock. One can expect that with continuous improvements in experimental design, more extensive preclinical research, and investigative tenacity, it is inevitable that immunotherapeutic adjuncts will be proven useful.


   Footnotes
 
Abbreviations: CI = confidence interval; FDA = US Food and Drug Administration; IL = interleukin; MAb = monoclonal antibody; NO = nitric oxide; PAF = platelet activating factor; PROWESS = Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis; rhIL-1a = recombinant human IL-1 receptor antagonist; TNF = tumor necrosis factor


   References
TOP
 Abstract
 Introduction
 Is Research Striking Out?
 The Flaws in Sepsis...
 The Way Forward
 Conclusions
 References
 

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