Graham Ramsay

2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference.

ObjectiveIn 1991, the American College of Chest Physicians (ACCP) and the Society of Critical Care Medicine (SCCM) convened a “Consensus Conference,” the goals of which were “to provide a conceptual and a practical framework to define the systemic inflammatory response to infection, which is a progressive injurious process that falls under the generalized term ‘sepsis’ and includes sepsis-associated organ dysfunction as well.” The general definitions introduced as a result of that conference have been widely used in practice and have served as the foundation for inclusion criteria for numerous clinical trials of therapeutic interventions. Nevertheless, there has been an impetus from experts in the field to modify these definitions to reflect our current understanding of the pathophysiology of these syndromes. DesignSeveral North American and European intensive care societies agreed to revisit the definitions for sepsis and related conditions. This conference was sponsored by the SCCM, The European Society of Intensive Care Medicine (ESICM), The American College of Chest Physicians (ACCP), the American Thoracic Society (ATS), and the Surgical Infection Society (SIS). MethodsThe conference was attended by 29 participants from Europe and North America. In advance of the conference, five subgroups were formed to evaluate the following areas: signs and symptoms of sepsis, cell markers, cytokines, microbiologic data, and coagulation parameters. The subgroups corresponded electronically before the conference and met in person during the conference. A spokesperson for each group presented the deliberation of each group to all conference participants during a plenary session. A writing committee was formed at the conference and developed the current article based on executive summary documents generated by each group and the plenary group presentations. The present article serves as the final report of the 2001 International Sepsis Definitions Conference. ConclusionThis document reflects a process whereby a group of experts and opinion leaders revisited the 1992 sepsis guidelines and found that apart from expanding the list of signs and symptoms of sepsis to reflect clinical bedside experience, no evidence exists to support a change to the definitions. This lack of evidence serves to underscore the challenge still present in diagnosing sepsis in 2003 for clinicians and researchers and also provides the basis for introducing PIRO as a hypothesis-generating model for future research.

Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock

ObjectiveTo develop management guidelines for severe sepsis and septic shock that would be of practical use for the bedside clinician, under the auspices of the Surviving Sepsis Campaign, an international effort to increase awareness and improve outcome in severe sepsis.DesignThe process included a modified Delphi method, a consensus conference, several subsequent smaller meetings of subgroups and key individuals, teleconferences, and electronic-based discussion among subgroups and among the entire committee. The modified Delphi methodology used for grading recommendations built upon a 2001 publication sponsored by the International Sepsis Forum. We undertook a systematic review of the literature graded along 5 levels to create recommendation grades from A–E, with A being the highest grade. Pediatric considerations were provided to contrast adult and pediatric management.ParticipantsParticipants included 44 critical care and infectious disease experts representing 11 international organizations.ResultsA total of 46 recommendations plus pediatric management considerations.ConclusionsEvidence-based recommendations can be made regarding many aspects of the acute management of sepsis and septic shock that will hopefully translate into improved outcomes for the critically ill patient. The impact of these guidelines will be formally tested and guidelines updated annually, and even more rapidly when some important new knowledge becomes available.

The Surviving Sepsis Campaign: results of an international guideline-based performance improvement program targeting severe sepsis.

Objective: The Surviving Sepsis Campaign (SSC or “the Campaign”) developed guidelines for management of severe sepsis and septic shock. A performance improvement initiative targeted changing clinical behavior (process improvement) via bundles based on key SSC guideline recommendations. Design and Setting: A multifaceted intervention to facilitate compliance with selected guideline recommendations in the intensive care unit, emergency department, and wards of individual hospitals and regional hospital networks was implemented voluntarily in the United States, Europe, and South America. Elements of the guidelines were “bundled” into two sets of targets to be completed within 6 hrs and within 24 hrs. An analysis was conducted on data submitted from January 2005 through March 2008. Subjects: A total of 15,022 subjects. Measurements and Main Results: Data from 15,022 subjects at 165 sites were analyzed to determine the compliance with bundle targets and association with hospital mortality. Compliance with the entire resuscitation bundle increased linearly from 10.9% in the first site quarter to 31.3% by the end of 2 yrs (p < .0001). Compliance with the entire management bundle started at 18.4% in the first quarter and increased to 36.1% by the end of 2 yrs (p = .008). Compliance with all bundle elements increased significantly, except for inspiratory plateau pressure, which was high at baseline. Unadjusted hospital mortality decreased from 37% to 30.8% over 2 yrs (p = .001). The adjusted odds ratio for mortality improved the longer a site was in the Campaign, resulting in an adjusted absolute drop of 0.8% per quarter and 5.4% over 2 yrs (95% confidence interval, 2.5–8.4). Conclusions: The Campaign was associated with sustained, continuous quality improvement in sepsis care. Although not necessarily cause and effect, a reduction in reported hospital mortality rates was associated with participation. The implications of this study may serve as an impetus for similar improvement efforts.

Feasibility and effects of the semirecumbent position to prevent ventilator-associated pneumonia: a randomized study.

Context:Reducing aspiration of gastric contents by placing mechanically ventilated patients in a semirecumbent position has been associated with lower incidences of ventilator-associated pneumonia (VAP). The feasibility and efficacy of this intervention in a larger patient population, however, are unknown. Objective:Assessment of the feasibility of the semirecumbent position for intensive care unit patients and its influence on development of VAP. Design:In a prospective multicentered trial, critically ill patients undergoing mechanical ventilation were randomly assigned to the semirecumbent position, with a target backrest elevation of 45°, or standard care (i.e., supine position) with a backrest elevation of 10°. Main Outcome Measures:Backrest elevation was measured continuously during the first week of ventilation with a monitor-linked device. A deviation of position was defined as a change of the randomized position >5°. Diagnosis of VAP was made by quantitative cultures of samples obtained by bronchoscopic techniques. Results:One hundred nine patients were assigned to the supine group and 112 to the semirecumbent group. Baseline characteristics were comparable for both groups. Average elevations were 9.8° and 16.1° at day 1 and day 7, respectively, for the supine group and 28.1° and 22.6° at day 1 and day 7, respectively, for the semirecumbent group (p < .001). The target semirecumbent position of 45° was not achieved for 85% of the study time, and these patients more frequently changed position than supine-positioned patients. VAP was diagnosed in eight patients (6.5%) in the supine group and in 13 (10.7%) in the semirecumbent group (NS), after a mean of 6 (range, 3–9) and 7 (range, 3–12) days, respectively. There were no differences in numbers of patients undergoing enteral feeding, receiving stress ulcer prophylaxis, or developing pressure sores or in mortality rates or duration of ventilation and intensive care unit stay between the groups. Conclusions:The targeted backrest elevation of 45° for semirecumbent positioning was not reached in the conditions of the present randomized study. The achieved difference in treatment position (28° vs. 10°) did not prevent the development of VAP.

Sepsis change bundles: converting guidelines into meaningful change in behavior and clinical outcome.

The incidence of severe sepsis (sepsis with organ dysfunction) is increasing (1). Several recently published studies have demonstrated decreased mortality and morbidity as a result of interventions and therapeutics applied to patients with sepsis (2–5). These new data, resulting from rigorously perf

Reduced citrulline production in sepsis is related to diminished de novo arginine and nitric oxide production

BACKGROUND L-Arginine is an important precursor of nitric oxide (NO) and protein synthesis. Arginine is produced in the body (mainly kidney) by de novo production from citrulline and by protein breakdown. Arginine availability appears to be limited in sepsis. OBJECTIVE The objective was to compare arginine and citrulline metabolism in septic patients and nonseptic control patients in an intensive care unit (ICU) and in healthy control subjects. DESIGN Ten patients with septic shock, 7 critically ill control patients, and 16 healthy elderly subjects were studied. Metabolism was measured by using a primed continuous (2 h) stable-isotope infusion protocol. NO production was calculated as the conversion rate of arginine to citrulline; de novo arginine production was calculated as the conversion rate of citrulline to arginine. Arterial blood (arterialized venous blood in healthy subjects) was collected for the measurement of amino acid enrichment and concentrations. Data are reported as means +/- SDs. RESULTS Whole-body citrulline production was significantly lower in septic patients (4.5 +/- 2.1 micromol . kg(-1) . h(-1)) than in ICU control patients (10.1 +/- 2.9 micromol . kg(-1) . h(-1); P < 0.01) and in healthy control subjects (13.7 +/- 4.1 micromol . kg(-1) . h(-1); P < 0.001). Accordingly, de novo arginine production was lower in patients with sepsis (3.3 +/- 3.7 micromol . kg(-1) . h(-1)) than in healthy controls (11.9 +/- 6.6 micromol . kg(-1) . h(-1); P < 0.01) and tended to be lower in septic patients than in ICU control patients (10.9 +/- 9.4 micromol . kg(-1) . h(-1); P = 0.05). NO production was lower in septic patients than in healthy control subjects (P < 0.01), whereas a larger part of arginine was converted to urea in sepsis. CONCLUSIONS Citrulline production is severely low in patients with sepsis and is related to diminished de novo arginine and NO production. These metabolic alterations contribute to reduced citrulline and arginine availability, and these findings warrant further studies of therapeutic nutritional interventions to restore arginine metabolism in sepsis.

Sepsis: an arginine deficiency state?

Objective:Sepsis is a major health problem considering its significant morbidity and mortality rate. The amino acid l-arginine has recently received substantial attention in relation to human sepsis. However, knowledge of arginine metabolism during sepsis is limited. Therefore, we reviewed the current knowledge about arginine metabolism in sepsis. Data Source:This review summarizes the literature on arginine metabolism both in general and in relation to sepsis. Moreover, arginine-related therapies are reviewed and discussed, which includes therapies of both nitric oxide (NO) and arginine administration and therapies directed toward inhibition of NO. Data:In sepsis, protein breakdown is increased, which is a key process to maintain arginine delivery, because both endogenous de novo production from citrulline and food intake are reduced. Arginine catabolism, on the other hand, is markedly increased by enhanced use of arginine in the arginase and NO pathways. As a result, lowered plasma arginine levels are usually found. Clinical symptoms of sepsis that are related to changes in arginine metabolism are mainly related to hemodynamic alterations and diminished microcirculation. NO administration and arginine supplementation as a monotherapy demonstrated beneficial effects, whereas nonselective NO synthase inhibition seemed not to be beneficial, and selective NO synthase 2 inhibition was not beneficial overall. Conclusions:Because sepsis has all the characteristics of an arginine-deficiency state, we hypothesise that arginine supplementation is a logical option in the treatment of sepsis. This is supported by substantial experimental and clinical data on NO donors and NO inhibitors. However, further evidence is required to prove our hypothesis.

Meta-analysis of hemodynamic optimization: relationship to methodological quality

IntroductionTo review systematically the effect of interventions aimed at hemodynamic optimization and to relate this to the quality of individual published trials.MethodsA systematic, computerized bibliographic search of published studies and citation reviews of relevant studies was performed. All randomized clinical trials in which adult patients were included in a trial deliberately aiming at an optimized or maximized hemodynamic condition of the patients (with oxygen delivery, cardiac index, oxygen consumption, mixed venous oxygen saturation and/or stroke volume as end-points) were selected. A total of 30 studies were selected for independent review. Two reviewers extracted data on population, intervention, outcome and methodological quality. Agreement between reviewers was high: differences were eventually resolved by third-party decision. The methodological quality of the studies was moderate (mean 9.0, SD 1.7), and the outcomes of the randomized clinical trials were not related to their quality.ResultsEfforts to achieve an optimized hemodynamic condition resulted in a decreased mortality rate (relative risk ratio (RR) 0.75 (95% confidence interval (CI) 0.62 to 0.90) in all studies combined. This was due to a significantly decreased mortality in peri-operative intervention studies (RR 0.66 (95% CI 0.54 to 0.81). Overall, patients with sepsis and overt organ failure do not benefit from this method (RR 0.92 (95% CI 0.75 to 1.11)).ConclusionThis systematic review showed that interventions aimed at hemodynamic optimization reduced mortality. In particular, trials including peri-operative interventions aimed at the hemodynamic optimization of high-risk surgical patients reduce mortality. Overall, this effect was not related to the trial quality.

Predisposition, insult/infection, response, and organ dysfunction: A new model for staging severe sepsis.

Objective: To generate and validate an initial version of the predisposition, insult/infection, response, and organ dysfunction (PIRO) staging model for risk stratification in severe sepsis. The goal was to create distinct levels of mortality risk within each of the four categories (P, I, R, and O), and that these risk levels would be meaningful in terms of prediction independent of the other categories. Design: Retrospective analysis using a statistical model utilizing two large, global databases of patients with severe sepsis. Setting and Patients: Database #1: Placebo-treated patients from a phase III clinical trial of patients with severe sepsis (PROtein C Worldwide Evaluation in Severe Sepsis [PROWESS], 840 patients). Database #2: Global severe sepsis registry performed in 276 intensive care units in 37 countries (PROmoting Global Research Excellence in Severe Sepsis [PROGRESS], 10,610 patients). Interventions: None. Methods: Classification and regression trees were used to classify patients and derive a scoring system from the PROWESS and PROGRESS databases with internal validation. Regression tree parameters included Chi-square tests and a minimum of five patients per node. The risk levels were done in a stepwise manner, adjusting for the previous categories. Initially, the predisposition scoring was developed, and subsequently, the infection scoring was then developed after adjusting for the predisposition levels, and so on. Logistic regression analyses, odds ratios, and area under the receiver operator characteristic curve were used to evaluate the scoring systems. Measurements and Main Results: Each of the four PIRO components had similar odds ratios in multivariable logistic regressions. In PROWESS, the correlation of the PIRO total score and in-hospital mortality rates was 0.974 (p < 0.0001), and in PROGRESS, the correlation of the PIRO total score and hospital mortality rates was 0.998 (p < 0.0001). Conclusions: PIRO can develop into an effective model for staging severe sepsis, seems to be predictive of mortality, and may be useful in future sepsis research.

The Role of Arginine in Infection and Sepsis

Sepsis is a systemic response to an infection, with high morbidity and mortality rates. Metabolic changes during infection and sepsis could be related to changes in metabolism of the amino acid L-arginine. In sepsis, protein breakdown is increased, which is a key process to maintain arginine delivery because both endogenous de novo arginine production from citrulline and food intake are reduced. Arginine catabolism, on the other hand, is markedly increased by enhanced use of arginine via the arginase and nitric oxide pathways. As a result, lowered plasma arginine levels are usually found. Arginine may therefore be considered as an essential amino acid in sepsis, and supplementation could be beneficial in sepsis by improving microcirculation and protein anabolism. L-Arginine supplementation in a hyperdynamic pig model of sepsis prohibits the increase in pulmonary arterial blood pressure, improves muscle and liver protein metabolism, and restores the intestinal motility pattern. Arguments raised against arginine supplementation are mainly pointed at stimulating nitric oxide (NO) production, with concerns about toxicity of increased NO and hemodynamic instability with refractory hypotension. NO synthase inhibition, however, increased mortality. Arginine supplementation in septic patients has transient effects on hemodynamics when supplied as a bolus but seems without hemodynamic side effects when supplied continuously. In conclusion, arginine could have an essential role in infection and sepsis.