Didier Keh

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.

Hydrocortisone therapy for patients with septic shock.

BACKGROUND Hydrocortisone is widely used in patients with septic shock even though a survival benefit has been reported only in patients who remained hypotensive after fluid and vasopressor resuscitation and whose plasma cortisol levels did not rise appropriately after the administration of corticotropin. METHODS In this multicenter, randomized, double-blind, placebo-controlled trial, we assigned 251 patients to receive 50 mg of intravenous hydrocortisone and 248 patients to receive placebo every 6 hours for 5 days; the dose was then tapered during a 6-day period. At 28 days, the primary outcome was death among patients who did not have a response to a corticotropin test. RESULTS Of the 499 patients in the study, 233 (46.7%) did not have a response to corticotropin (125 in the hydrocortisone group and 108 in the placebo group). At 28 days, there was no significant difference in mortality between patients in the two study groups who did not have a response to corticotropin (39.2% in the hydrocortisone group and 36.1% in the placebo group, P=0.69) or between those who had a response to corticotropin (28.8% in the hydrocortisone group and 28.7% in the placebo group, P=1.00). At 28 days, 86 of 251 patients in the hydrocortisone group (34.3%) and 78 of 248 patients in the placebo group (31.5%) had died (P=0.51). In the hydrocortisone group, shock was reversed more quickly than in the placebo group. However, there were more episodes of superinfection, including new sepsis and septic shock. CONCLUSIONS Hydrocortisone did not improve survival or reversal of shock in patients with septic shock, either overall or in patients who did not have a response to corticotropin, although hydrocortisone hastened reversal of shock in patients in whom shock was reversed. (ClinicalTrials.gov number, NCT00147004.)

Corticosteroids for severe sepsis and septic shock: a systematic review and meta-analysis

Abstract Objective To assess the effects of corticosteroids on mortality in patients with severe sepsis and septic shock. Data sources Randomised and quasi-randomised trials of corticosteroids versus placebo (or supportive treatment alone) retrieved from the Cochrane infectious diseases groups trials register, the Cochrane central register of controlled trials, Medline, Embase, and LILACS. Review method Two pairs of reviewers agreed on eligibility of trials. One reviewer entered data on to the computer and four reviewers checked them. We obtained some missing data from authors of trials and assessed methodological quality of trials. Results 16/23 trials (n = 2063) were selected. Corticosteroids did not change 28 day mortality (15 trials, n = 2022; relative risk 0.92, 95% confidence interval 0.75 to 1.14) or hospital mortality (13 trials, n = 1418; 0.89, 0.71 to 1.11). There was significant heterogeneity. Subgroup analysis on long courses (≥ 5 days) with low dose (≤ 300 mg hydrocortisone or equivalent) corticosteroids showed no more heterogeneity. The relative risk for mortality was 0.80 at 28 days (five trials, n = 465; 0.67 to 0.95) and 0.83 at hospital discharge (five trials, n = 465, 0.71 to 0.97). Use of corticosteroids reduced mortality in intensive care units (four trials, n = 425, 0.83, 0.70 to 0.97), increased shock reversal at 7 days (four trials, n = 425; 1.60, 1.27 to 2.03) and 28 days (four trials, n = 425, 1.26, 1.04 to 1.52) without inducing side effects. Conclusions For all trials, regardless of duration of treatment and dose, use of corticosteroids did not significantly affect mortality. With long courses of low doses of corticosteroids, however, mortality at 28 days and hospital morality was reduced.

Adrenal function in sepsis: The retrospective Corticus cohort study

Objective:To refine the value of baseline and adrenocorticotropin hormone (ACTH)-stimulated cortisol levels in relation to mortality from severe sepsis or septic shock. Design:Retrospective multicenter cohort study. Setting:Twenty European intensive care units. Patients:Patients included 477 patients with severe sepsis and septic shock who had undergone an ACTH stimulation test on the day of the onset of severe sepsis. Interventions:None. Measurements and Main Results:Compared with survivors, nonsurvivors had higher baseline cortisol levels (29.5 ± 33.5 vs. 24.3 ± 16.5 &mgr;g/dL, p = .03) but similar peak cortisol values (37.6 ± 40.2 vs. 35.2 ± 22.9 &mgr;g/dL, p = .42). Thus, nonsurvivors had lower &Dgr;max (i.e., peak cortisol minus baseline cortisol) (6.4 ± 22.6 vs. 10.9 ± 12.9 &mgr;g/dL, p = .006). Patients with either baseline cortisol levels <15 &mgr;g/dL or a &Dgr;max ≤9 &mgr;g/dL had a likelihood ratio of dying of 1.26 (95% confidence interval, 1.11–1.44), a longer duration of shock, and a shorter survival time. Patients with a &Dgr;max ≤9 &mgr;g/dL but any baseline cortisol value had a likelihood ratio of dying of 1.38 (95% confidence interval, 1.18–1.61). Conclusions:Although delta cortisol and not basal cortisol level was associated with clinical outcome, further studies are still needed to optimize the diagnosis of adrenal insufficiency in critical illness. Etomidate influenced ACTH test results and was associated with a worse outcome.

Intraoperative thoracic epidural anaesthesia attenuates stress-induced immunosuppression in patients undergoing major abdominal surgery

BACKGROUND Intraoperative stress may suppress the adaptive immune system. Abolished proinflammatory lymphocyte function is associated with higher risk of infection and postoperative complications. We hypothesized that thoracic epidural anaesthesia (TEA) reduces intraoperative stress and thus attenuates lymphocyte decrease and impairment of proinflammatory lymphocyte function. METHODS Fifty-four patients undergoing major abdominal surgery who had a thoracic epidural catheter inserted were studied. In the TEA-I group, this catheter was used for intraoperative analgesia, whereas the TEA-P group received systemic opioids during surgery. In both groups, patient-controlled epidural analgesia was used for postoperative pain management. Blood samples for immune analyses were obtained before induction of anaesthesia, 2 h after skin incision, and at days 1 and 4 after surgery. Lymphocyte subpopulations, expression of human leucocyte antigen (HLA)-DR on monocytes, plasma concentrations of interleukin (IL)-10, interferon-gamma (IFN-gamma), and IL-12, and concanavalin-A-stimulated concentrations of IFN-gamma and IL-10 were measured. Intraoperative data including bispectral index and plasma concentrations of epinephrine/cortisol were analysed; APACHE-II, SAPS II, and additional postoperative data were documented. RESULTS Plasma concentrations of epinephrine and cortisol were significantly lower in the TEA-I patients during surgery. IFN-gamma/IL-10 ratio was significantly higher in the TEA-I group from 2 h after skin incision until day 1. Lymphocyte numbers and T-helper cells were significantly higher in the TEA-I group at day 1, whereas no significant differences were detected among IL-12, HLA-DR, and postoperative clinical course. CONCLUSIONS Intraoperative use of thoracic epidural catheter reduced stress response and prevented stress-induced perioperative impairment of proinflammatory lymphocyte function.

High-Protein Enteral Nutrition Enriched With Immune-Modulating Nutrients vs Standard High-Protein Enteral Nutrition and Nosocomial Infections in the ICU: A Randomized Clinical Trial

IMPORTANCE Enteral administration of immune-modulating nutrients (eg, glutamine, omega-3 fatty acids, selenium, and antioxidants) has been suggested to reduce infections and improve recovery from critical illness. However, controversy exists on the use of immune-modulating enteral nutrition, reflected by lack of consensus in guidelines. OBJECTIVE To determine whether high-protein enteral nutrition enriched with immune-modulating nutrients (IMHP) reduces the incidence of infections compared with standard high-protein enteral nutrition (HP) in mechanically ventilated critically ill patients. DESIGN, SETTING, AND PARTICIPANTS The MetaPlus study, a randomized, double-blind, multicenter trial, was conducted from February 2010 through April 2012 including a 6-month follow-up period in 14 intensive care units (ICUs) in the Netherlands, Germany, France, and Belgium. A total of 301 adult patients who were expected to be ventilated for more than 72 hours and to require enteral nutrition for more than 72 hours were randomized to the IMHP (n = 152) or HP (n = 149) group and included in an intention-to-treat analysis, performed for the total population as well as predefined medical, surgical, and trauma subpopulations. INTERVENTIONS High-protein enteral nutrition enriched with immune-modulating nutrients vs standard high-protein enteral nutrition, initiated within 48 hours of ICU admission and continued during the ICU stay for a maximum of 28 days. MAIN OUTCOMES AND MEASURES The primary outcome measure was incidence of new infections according to the Centers for Disease Control and Prevention (CDC) definitions. Secondary end points included mortality, Sequential Organ Failure Assessment (SOFA) scores, mechanical ventilation duration, ICU and hospital lengths of stay, and subtypes of infections according CDC definitions. RESULTS There were no statistically significant differences in incidence of new infections between the groups: 53% (95% CI, 44%-61%) in the IMHP group vs 52% (95% CI, 44%-61%) in the HP group (P = .96). No statistically significant differences were observed in other end points, except for a higher 6-month mortality rate in the medical subgroup: 54% (95% CI, 40%-67%) in the IMHP group vs 35% (95% CI, 22%-49%) in the HP group (P = .04), with a hazard ratio of 1.57 (95% CI, 1.03-2.39; P = .04) for 6-month mortality adjusted for age and Acute Physiology and Chronic Health Evaluation II score comparing the groups. CONCLUSIONS AND RELEVANCE Among adult patients breathing with the aid of mechanical ventilation in the ICU, IMHP compared with HP did not improve infectious complications or other clinical end points and may be harmful as suggested by increased adjusted mortality at 6 months. These findings do not support the use of IMHP nutrients in these patients. TRIAL REGISTRATION trialregister.nl Identifier: NTR2181.

Use of corticosteroid therapy in patients with sepsis and septic shock: An evidence-based review

Objective:In 2003, critical care and infectious disease experts representing 11 international organizations developed management guidelines for the use of corticosteroid therapy in patients with 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. Design:The 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. Methods: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 five levels to create recommendation grades from A to E, with A being the highest grade. Pediatric considerations to contrast adult and pediatric management are in the article by Parker et al. on p. S591. Conclusions:Low doses of corticosteroids are recommended in patients with septic shock. In the absence of vasopressor requirement, corticosteroids should not be used to treat sepsis. High-dose corticosteroids are not recommended in severe sepsis. The use of adrenal function tests to guide decisions on corticosteroid therapy, the weaning of steroids at the end of the treatment period, the decision to discontinue steroids earlier with resolution of shock, and the addition of oral fludrocortisone are considered optional approaches.

Multicenter comparison of cortisol as measured by different methods in samples of patients with septic shock

PurposeTo compare inter-laboratory and inter-assay measurements of total cortisol in patients with septic shock and to evaluate current recommendations for diagnosis of corticosteroid insufficiency in septic shock.MethodsIn the multinational CORTICUS study duplicate serum samples were taken before and after corticotropin stimulation tests in patients with septic shock. Serum cortisol was measured in paired samples, one being measured by the chemical laboratory of each participating site and the other by a central laboratory using an electrochemiluminescence immunoassay. Cortisol levels measured by tandem mass spectrometry were used as a ‘gold standard’ reference method in a subset of samples.ResultsA total of 425 corticotropin tests (850 cortisol samples) were available for comparison of local and central laboratory measurements. The concordance correlation coefficient between central laboratoty immunoassay and local hospital assays was 0.98 (CI 0.97–0.99) when the immunoassay of one manufacturer was used and 0.60 (CI 0.54–0.65) when immunoassays of different manufacturers were used. The comparison with the reference method of mass spectrometry showed concordance correlation coefficients ranging from 0.43 to 0.97 depending on the assay under study. Diagnosis of corticosteroid insufficiency was diverging due to inter-assay variations in up to 27% of cases.ConclusionIn samples taken from patients in septic shock, there was a high inter-assay variation of total serum cortisol. Comparisons with a reference method revealed both over- and underestimations of true cortisol levels. These inter-assay variations in samples of patients with septic shock complicate the diagnosis of corticosteroid insufficiency.

Risk factors in critical illness myopathy during the early course of critical illness: a prospective observational study

IntroductionNon-excitable muscle membrane indicates critical illness myopathy (CIM) during early critical illness. We investigated predisposing risk factors for non-excitable muscle membrane at onset of critical illness.MethodsWe performed sequential measurements of muscle membrane excitability after direct muscle stimulation (dmCMAP) in 40 intensive care unit (ICU) patients selected upon a simplified acute physiology (SAPS-II) score ≥ 20 on 3 successive days within 1 week after ICU admission. We then investigated predisposing risk factors, including the insulin-like growth factor (IGF)-system, inflammatory, metabolic and hemodynamic parameters, as well as suspected medical treatment prior to first occurrence of abnormal dmCMAP. Nonparametric analysis of two-factorial longitudinal data and multivariate analysis were used for statistical analysis.Results22 patients showed abnormal muscle membrane excitability during direct muscle stimulation within 7 (5 to 9.25) days after ICU admission. Significant risk factors for the development of impaired muscle membrane excitability in univariate analysis included inflammation, disease severity, catecholamine and sedation requirements, as well as IGF binding protein-1 (IGFBP-I), but did not include either adjunctive hydrocortisone treatment in septic shock, nor administration of neuromuscular blocking agents or aminoglycosides. In multivariate Cox regression analysis, interleukin-6 remained the significant risk factor for the development of impaired muscle membrane excitability (HR 1.006, 95%-CI (1.002 to 1.011), P = 0.002).ConclusionsSystemic inflammation during early critical illness was found to be the main risk factor for development of CIM during early critical illness. Inflammation-induced impairment of growth-factor mediated insulin sensitivity may be involved in the development of CIM.

Effect of Hydrocortisone on Development of Shock Among Patients With Severe Sepsis: The HYPRESS Randomized Clinical Trial

Importance Adjunctive hydrocortisone therapy is suggested by the Surviving Sepsis Campaign in refractory septic shock only. The efficacy of hydrocortisone in patients with severe sepsis without shock remains controversial. Objective To determine whether hydrocortisone therapy in patients with severe sepsis prevents the development of septic shock. Design, Setting, and Participants Double-blind, randomized clinical trial conducted from January 13, 2009, to August 27, 2013, with a follow-up of 180 days until February 23, 2014. The trial was performed in 34 intermediate or intensive care units of university and community hospitals in Germany, and it included 380 adult patients with severe sepsis who were not in septic shock. Interventions Patients were randomly allocated 1:1 either to receive a continuous infusion of 200 mg of hydrocortisone for 5 days followed by dose tapering until day 11 (n = 190) or to receive placebo (n = 190). Main Outcomes and Measures The primary outcome was development of septic shock within 14 days. Secondary outcomes were time until septic shock, mortality in the intensive care unit or hospital, survival up to 180 days, and assessment of secondary infections, weaning failure, muscle weakness, and hyperglycemia (blood glucose level >150 mg/dL [to convert to millimoles per liter, multiply by 0.0555]). Results The intention-to-treat population consisted of 353 patients (64.9% male; mean [SD] age, 65.0 [14.4] years). Septic shock occurred in 36 of 170 patients (21.2%) in the hydrocortisone group and 39 of 170 patients (22.9%) in the placebo group (difference, -1.8%; 95% CI, -10.7% to 7.2%; P = .70). No significant differences were observed between the hydrocortisone and placebo groups for time until septic shock; mortality in the intensive care unit or in the hospital; or mortality at 28 days (15 of 171 patients [8.8%] vs 14 of 170 patients [8.2%], respectively; difference, 0.5%; 95% CI, -5.6% to 6.7%; P = .86), 90 days (34 of 171 patients [19.9%] vs 28 of 168 patients [16.7%]; difference, 3.2%; 95% CI, -5.1% to 11.4%; P = .44), and 180 days (45 of 168 patients [26.8%] vs 37 of 167 patients [22.2%], respectively; difference, 4.6%; 95% CI, -4.6% to 13.7%; P = .32). In the hydrocortisone vs placebo groups, 21.5% vs 16.9% had secondary infections, 8.6% vs 8.5% had weaning failure, 30.7% vs 23.8% had muscle weakness, and 90.9% vs 81.5% had hyperglycemia. Conclusions and Relevance Among adults with severe sepsis not in septic shock, use of hydrocortisone compared with placebo did not reduce the risk of septic shock within 14 days. These findings do not support the use of hydrocortisone in these patients. Trial Registration clinicaltrials.gov Identifier: NCT00670254.