Philipp Simon

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.

Hyperlactatemia is an independent predictor of mortality and denotes distinct subtypes of severe sepsis and septic shock.

PURPOSE Current guidelines and most trials do not consider elevated lactate (Lac) serum concentrations when grading sepsis severity. We therefore assessed the association of different types of circulatory dysfunction regarding presence of hyperlactatemia and need for vasopressor support with clinical presentation and outcome of sepsis. METHODS In a secondary analysis of a prospective observational multicenter cohort study, 988 patients with severe sepsis were investigated regarding vasopressor support, Lac levels, and outcome. RESULTS Twenty-eight-day mortality regarding shock or hyperlactatemia was as follows: hyperlactatemia more than 2.5 mmol/L and septic shock (tissue dysoxic shock): 451 patients with a mortality of 44.8%; hyperlactatemia without vasopressor need (cryptic shock): 72 patients, mortality 35.3%; no hyperlactatemia with vasopressor need (vasoplegic shock): 331 patients, mortality 27.7%; and absence of hyperlactemia or overt shock (severe sepsis): 134 patients, mortality 14.2% (P < .001). These groups showed differences in source and origin of infection. The influence of hyperlactatemia on 28-day mortality (P < .001) (odds ratio 3.0, 95% confidence interval 2.1-4.1 for Lac >4 mmol/L) was independent of vasopressor support (P < .001) (odds ratio 2.0, 95% confidence interval 1.3-3.0 for norepinephrine >0.1 μg/kg per minute) in logistic regression. CONCLUSIONS Hyperlactatemia increases risk of death independent of vasopressor need resulting in different phenotypes within the classic categories of severe sepsis and septic shock.

The effects of hemoglobin glutamer-200 and iNO on pulmonary vascular tone and arterial oxygenation in an experimental acute respiratory distress syndrome

INTRODUCTION Hemoglobin-based oxygen carriers (HBOC) have been developed as an alternative to blood transfusions. Their nitric-oxide-scavenging properties HBOC also induce vasoconstriction. In acute lung injury, an excess of nitric oxide results in a general vasodilation, reducing oxygenation by impairing the hypoxic pulmonary vasoconstriction. Inhaled nitric oxide (iNO) is used to correct the ventilation perfusion mismatch. We hypothesized that the additional use of HBOC might increase this effect. In a rodent model of ARDS we evaluated the combined effect of HBOC and iNO on vascular tone and gas exchange. METHODS ARDS was induced in anaesthetized Wistar rats by saline lavage and aggressive ventilation. Two groups received either hydroxyethylstarch 10% (HES; n = 10) or the HBOC hemoglobin glutamer-200 (HBOC-200; n = 10) via a central venous infusion. Additionally, both groups received iNO. Monitoring of the right ventricular pressure (RVP) and mean arterial pressure (MAP) was performed with microtip transducers. Arterial oxygenation was measured via arterial blood gas analyses. RESULTS Application of HBOC-200 led to a significant increase of MAP and RVP when compared to baseline and to the HES group. This effect was reversed by iNO. The application of HBOC and iNO had no effect on the arterial oxygenation over time. No difference in arterial oxygenation was found between the groups. CONCLUSION Application of HBOC led to an increase of systemic and pulmonary vascular resistance in this animal model of ARDS. The increase in RVP was reversed by iNO. Pulmonary vasoconstriction by hemoglobin glutamer-200 in combination with iNO did not improve arterial oxygenation in ARDS.