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35th Critical Care Congress of the Society of Critical Care Medicine (SCCM)
San Francisco, CA, USA, January 7–11, 2006
James M O’Brien Jr, and Elliott D Crouser
Ohio State University Medical Center and Dorothy M Davis Heart and Lung Research Institute, Columbus, OH, USA
Due to the massive destruction and human tragedy inflicted by hurricane Katrina in August 2005, the Society of Critical Care Medicine’s 35th Critical Care Congress was relocated from New Orleans, LA, to San Francisco, CA, USA. Despite the abrupt change of venue, a record-breaking 5221 critical care specialists, including nurses, respiratory therapists, pharmacists, physicians, and basic scientists, participated in this exciting event. Scholarly input from the congress faculty, who represented academic institutions, government agencies, and industry, created an atmosphere conducive to intellectual discussion and scientific collaboration. Many of the scientific presentations and sessions were related to sepsis. This meeting report highlights a few of the many excellent presentations at the meeting.
Implementing best practice for sepsis
A pervasive theme at the congress was the implementation of best practice in the prevention and treatment of sepsis. Several studies reported that the Surviving Sepsis Campaign (SSC) guidelines and early goal-directed resuscitation can easily be implemented in a variety of settings [1–3]. Point-of-care testing of lactate levels may facilitate early identification of sepsis-induced lactic acidosis [4,5]. Other investigators reported efforts to prevent sepsis among the critically ill. For example, investigators at Ohio State University, Columbus, OH, USA, showed that assigning a nurse to assess compliance with protocols that aim to reduce the incidence of ventilator-associated pneumonia led to better adherence than provision of the protocol alone [6].
Prior to the congress, the SSC guidelines committee convened to consider revisions to the established best-practice recommendations for sepsis. R Phillip Dellinger (Cooper University Hospital, Camden, NJ, USA) outlined some of the draft changes to the guidelines, the final version of which will be published in the latter part of 2006. Among the changes is the adoption of a grading system to indicate the supporting evidence for each guideline. This approach would combine a level of recommendation in terms of perceived benefit to the patient (e.g. level 1: "we recommend" or level 2: "we suggest") with the level of supporting evidence (graded A–D, with A indicating the strongest evidence). In this way, a strategy for care that is supported by little evidence, but that is suspected to be highly beneficial and have few side effects, may be recommended. Other revisions to the SSC guidelines included strategies for the use of selective gut decontamination and administration of intravenous immunoglobulin.
Therapeutic trials in sepsis
The results of two multicenter studies of drotrecogin alfa (activated) were described. The first study was RESOLVE (Resolution of Organ Failure in Pediatric Patients with Severe Sepsis), a double-blind, placebo-controlled trial of drotrecogin alfa (activated) in pediatric severe sepsis, conducted at 104 sites in 18 countries [7]. Subjects (aged from 38 weeks to 18 years) with infection, signs of systemic inflammation, and a requirement for mechanical ventilation and/or vasopressors received drotrecogin alfa (activated) or placebo. The primary outcome was the time to complete resolution of organ failure. The data safety monitoring board stopped the study at the second interim analysis, as there were no differences in the average time to organ failure resolution or the number of serious adverse events in the two groups.
The second study discussed was the Phase IV XPRESS (Xigris [drotrecogin alfa (activated)] and Prophylactic Heparin in Severe Sepsis) investigation, which was presented by Derek Angus and colleagues (University of Pittsburgh Medical Center, Pittsburgh, PA, USA). XPRESS studied efficacy and risk of thrombosis in 1935 severe sepsis patients treated with drotrecogin alfa (activated) who received either concurrent thromboembolism prophylaxis (unfractionated heparin [UFH] or low-molecular-weight heparin [LMWH]) or placebo. There was a trend towards a lower 28-day mortality rate when drotrecogin alfa (activated) was administered in combination with UFH (29.3% of patients) or LMWH (27.3%) compared with co-administration with placebo (31.9%). This refutes the suggestion made by prior studies that co-administration of heparin with drotrecogin alfa (activated) has an adverse effect. There was no statistically significant difference in the rates of venous thromboembolism between the groups, but the incidence of ischemic stroke was higher in the placebo group. Rates of any bleeding event were higher during drotrecogin alfa (activated) infusion in the heparin groups, but the incidence of serious bleeding events was not increased by concomitant administration of heparin.
Medical practitioners can look forward to more information regarding the management of relative adrenal insufficiency in severe sepsis. As reported by Charles Sprung (Hadassah Medical Center, Jerusalem, Israel), the multicenter CORTICUS (Corticosteroid Therapy of Septic Shock) study has completed its enrollment of 500 patients. Compared with the recent French study of corticosteroids in sepsis [8], preliminary data from the CORTICUS study indicate a much lower prevalence of "non-responders" to adrenocorticotropic hormone (ACTH) and a lower overall mortality rate (33% vs. 58% in the French study). The benefit of adrenal replacement therapy on survival of ACTH non-responders will be determined at the conclusion of this study.
In addition to these large trials, preliminary clinical studies provide optimism for future treatments of sepsis. For example, a single-center study from Brazil suggested that early administration of an enteral formula rich in fish oil, borage oil, and antioxidants might reduce mortality rates in septic patients with respiratory failure [9]. A study from Japan showed that the administration of synbiotics to replenish the endogenous flora of the gut reduced infectious complications in patients with systemic inflammatory response syndrome compared with untreated controls [10].
The glycemic control controversy
The use of strict glycemic control as a potential sepsis therapy in surgical critical care patients has generated much interest and controversy [11]. Konrad Reinhart (University Hospital, Jena, Germany) presented data from a multicenter study that applied tight glycemic control to patients with severe sepsis or septic shock. Professor Reinhart’s results showed no benefit on mortality rate, and highlighted a concerning increase in hypoglycemia, in patients assigned to tight blood glucose control. Hypoglycemic episodes appeared to be associated with increased mortality. These findings are in keeping with a recent publication suggesting that stringent glucose control in septic patients should be approached with caution [12]. Further clarification of the role of glycemic control in the context of critical illness will be provided by the ongoing NICE-SUGAR (Normoglycaemia in Intensive Care Evaluation and Survival Using Glucose Algorithm Regulation) study, which plans to enroll 5000 subjects in Australia, New Zealand, and Canada.
In addition to the controversial clinical data, the mechanisms by which strict glycemic control might confer benefit remain unclear. Data presented at the congress suggested that insulin resistance may in part be due to decreased expression of cellular glucose transporters [13]. Another study observed attenuation of nuclear peroxisome proliferator-activated receptor-γ (PPARγ) translocation during sepsis [14]. PPARγ is a primary effector of insulin at the level of gene transcription, with effects including blood glucose regulation and inhibition of inflammatory pathways. Thus, enhanced activation of PPARγ, either by insulin or pharmacological agents, may be beneficial in septic patients. However, further investigation is needed to determine whether tight glucose regulation is beneficial in human sepsis.
Pathogenesis of sepsis-induced organ failures
The pathogenesis of organ failure, which is the usual cause of sepsis-related death, was a major topic of interest at the conference. In response to the controversy surrounding the design of the ARDSNet (Acute Respiratory Distress Syndrome Network) low tidal volume trial, plenary speaker Gordon Bernard (Vanderbilt University, Nashville, TN, USA) provided compelling evidence that progressively lower tidal volume, at least to a lower limit of 6 mL/kg predicted body weight, was associated with improved outcomes in ARDS patients. In approximately 70% of these, ARDS was caused by sepsis. The underlying mechanism of protection was explained by Arthur Slutsky (St Michael’s Hospital, Toronto, ON, Canada), who reviewed the experimental data supporting a protective role of low tidal volume ventilation. The data indicate that the protective effect is mediated by reduced ventilator-associated tissue damage, which ameliorates the systemic release of inflammatory mediators and attendant distal organ injury.
The fundamental cause of sepsis-induced organ failures remains unclear, but support for a tissue hypoxia paradigm was provided by Jean-Louis Vincent (Erasme University Hospital, Brussels, Belgium). Using a device that visualizes microvascular blood flow in mucosal membranes, Professor Vincent’s group documented altered blood flow in the oral mucosa of septic shock patients. Animal models confirmed that altered oral mucosal perfusion correlates with altered gut perfusion and with mortality during sepsis. Moreover, tissue perfusion was enhanced by vasodilators and by pharmacological agents promoting enhanced cardiac output. However, it remains unclear if improvement in microvascular perfusion actually influences sepsis outcomes. At the very least, detection of impaired microvascular perfusion may serve as a prognostic tool in sepsis.
Evidence for fundamental alterations in cell metabolism as a mechanism of organ failure is accumulating. The sepsis syndrome is associated with oxidative modification of proteins, lipids, and DNA, which has important implications for cell and organ function. For instance, cytochrome c, a metal-containing component of the mitochondrial electron transport chain, undergoes oxidative modification during sepsis, resulting in inhibition of electron transport [15]. Likewise, in a murine peritonitis model, Elliott Crouser (Ohio State University) reported sequential oxidative modification of liver mitochondrial proteins followed by mitochondrial clearance, resulting in mitochondrial depletion and suppression of liver oxygen consumption within 48 h. Mitochondrial biogenesis restores mitochondrial populations within 6 days in sepsis survivors. In related studies, Checchia et al. observed altered expression of genes that regulate ion transport and energy metabolism in the hearts of elderly septic animals [16]. This corroborates existing data demonstrating widespread suppression of metabolic pathways in a variety of tissues during sepsis.
Sepsis biomarkers
The search for a single, sensitive, and specific predictor of sepsis outcome continues, but new evidence presented at this meeting identified several promising candidates. Procalcitonin has many of the features of an effective biomarker, including innate proinflammatory activity, the availability of rapid and accurate detection techniques, and a clear association with sepsis outcome in both children [17] and adults (Kenneth Becker, George Washington University, Washington, DC, USA). In an analysis of 28 candidate genes in peripheral blood monocytes from pediatric sepsis patients, Hall et al. found that increased expression of pyrin, an anti-inflammatory mediator, and interleukin-10 (IL-10) correlates most strongly with mortality [18]. Conversely, overexpression of IL-10 in the gut and the attendant suppression of the immune response confers protection in an animal sepsis model [19]. Thus, tissue-specific expression of IL-10 may be an important determinant and predictor of sepsis outcomes.
Addressing clinical indices of sepsis, Mitchell Levy (Rhode Island Hospital, Providence, RI, USA) explored the characterization of sepsis using the proposed PIRO (Predisposition, Infection, Response, Organ Dysfunction) model. This framework takes into account an individual’s predisposition to sepsis (including comorbidities and genetic and epigenetic variations), the infectious agent and site of infection, the host response to infection (such as levels of specific cytokines), and organ dysfunction. An observational study to verify PIRO is ongoing that aims to enroll 1000 septic patients at 10 centers and collect a wide range of information from time of presentation in the emergency department to recovery. The PIRO system allows for integration of clinical, translational, and basic scientific discoveries and promises to more accurately predict outcomes and responses to therapy for individual patients.
Conclusion
The 35th Critical Care Congress left participants feeling optimistic that the conundrum of sepsis will soon be solved. From the selected highlights presented in this report, it can be seen that advances are being made on all fronts, including better diagnostic tools, establishment of best-practice processes for the intensive care unit, improved understanding of host–pathogen interactions, and new insights into the mechanisms of organ injury in the context of sepsis. These advances promise to deliver therapeutic breakthroughs for this deadly syndrome. The 36th Critical Care Congress will be held on 17–21 February 2007 in Orlando, FL, USA, where attendees are sure to gain a full appreciation of the latest progress in the field of sepsis.
Disclosures
The authors have no relevant financial interests to disclose.
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