Conservative vs liberal fluid therapy in septic shock (CLASSIC) trial-Protocol and statistical analysis plan

Introduction Intravenous (IV) fluid is a key intervention in the management of septic shock. The benefits and harms of lower versus higher fluid volumes are unknown and thus clinical equipoise exists. We describe the protocol and detailed statistical analysis plan for the conservative versus liberal approach to fluid therapy of septic shock in the Intensive Care (CLASSIC) trial. The aim of the CLASSIC trial is to assess benefits and harms of IV fluid restriction versus standard care in adult intensive care unit (ICU) patients with septic shock. Methods CLASSIC trial is an investigator-initiated, international, randomised, stratified, and analyst-blinded trial. We will allocate 1554 adult patients with septic shock, who are planned to be or are admitted to an ICU, to IV fluid restriction versus standard care. The primary outcome is mortality at day 90. Secondary outcomes are serious adverse events (SAEs), serious adverse reactions (SARs), days alive at day 90 without life support, days alive and out of the hospital at day 90 and mortality, health-related quality of life (HRQoL), and cognitive function at 1 year. We will conduct the statistical analyses according to a pre-defined statistical analysis plan, including three interim analyses. For the primary analysis, we will use logistic regression adjusted for the stratification variables comparing the two interventions in the intention-to-treat (ITT) population. Discussion The CLASSIC trial results will provide important evidence to guide clinicians' choice regarding the IV fluid therapy in adults with septic shock.Peer reviewe

Hydroxyethyl starch 130/0.42 versus Ringer's acetate in severe sepsis.

To access publisher's full text version of this article. Please click on the hyperlink in Additional Links field.Hydroxyethyl starch (HES) [corrected] is widely used for fluid resuscitation in intensive care units (ICUs), but its safety and efficacy have not been established in patients with severe sepsis. In this multicenter, parallel-group, blinded trial, we randomly assigned patients with severe sepsis to fluid resuscitation in the ICU with either 6% HES 130/0.42 (Tetraspan) or Ringer's acetate at a dose of up to 33 ml per kilogram of ideal body weight per day. The primary outcome measure was either death or end-stage kidney failure (dependence on dialysis) at 90 days after randomization. Of the 804 patients who underwent randomization, 798 were included in the modified intention-to-treat population. The two intervention groups had similar baseline characteristics. At 90 days after randomization, 201 of 398 patients (51%) assigned to HES 130/0.42 had died, as compared with 172 of 400 patients (43%) assigned to Ringer's acetate (relative risk, 1.17; 95% confidence interval [CI], 1.01 to 1.36; P=0.03); 1 patient in each group had end-stage kidney failure. In the 90-day period, 87 patients (22%) assigned to HES 130/0.42 were treated with renal-replacement therapy versus 65 patients (16%) assigned to Ringer's acetate (relative risk, 1.35; 95% CI, 1.01 to 1.80; P=0.04), and 38 patients (10%) and 25 patients (6%), respectively, had severe bleeding (relative risk, 1.52; 95% CI, 0.94 to 2.48; P=0.09). The results were supported by multivariate analyses, with adjustment for known risk factors for death or acute kidney injury at baseline. Patients with severe sepsis assigned to fluid resuscitation with HES 130/0.42 had an increased risk of death at day 90 and were more likely to require renal-replacement therapy, as compared with those receiving Ringer's acetate. (Funded by the Danish Research Council and others; 6S ClinicalTrials.gov number, NCT00962156.)Danish Research Council 271-08-0691 09-066938 Rigshospitalet Research Council Scandinavian Society of Anesthesiology and Intensive Care Medicine ACTA Foundation Fresenius Kab

Comparing the effect of hydroxyethyl starch 130/0.4 with balanced crystalloid solution on mortality and kidney failure in patients with severe sepsis (6S-Scandinavian Starch for Severe Sepsis/Septic Shock trial): Study protocol, design and rationale for a double-blinded, randomised clinical trial

Peer reviewe

Pulmonary mucormycosis in the aftermath of critical COVID-19 in an immunocompromised patient:Mind the diagnostic gap

Mucormycosis has recently been recognized as a severe complication of COVID-19 with high fatality rates. We report a fatal case of COVID-19 associated mucormycosis (CAM) in a non-diabetic immunocompromised patient, who was first misdiagnosed and treated for COVID-19 associated aspergillosis (CAPA). The risk factors and initial clinical presentation of CAPA and CAM are similar, but CAM has a more aggressive course and CAPA and CAM are treated differently. Dedicated diagnostic workup is essential to ensure early treatment of CAM with surgical debridement and targeted antifungal therapy

Piperacillin/tazobactam vs carbapenems for patients with bacterial infection:Protocol for a systematic review

INTRODUCTION: Early empirical broad-spectrum antimicrobial therapy is recommended for patients with severe infections, including sepsis. β-lactam/β-lactamase inhibitor combinations or carbapenems are often used to ensure coverage of likely pathogens. Piperacillin/tazobactam is proposed as a carbapenem-sparing agent to reduce the incidence of multidrug-resistant bacteria and superinfections. In the recently published MERINO trial, increased mortality from piperacillin/tazobactam was suggested in patients with bacteraemia with resistant Escherichia coli or Klebsiella species. Whether these findings also apply to empirical piperacillin/tazobactam in patients with other severe infections, including sepsis, is unknown. We aim to assess the benefits and harms of empirical and definitive piperacillin/tazobactam vs carbapenems for patients with severe bacterial infections.METHODS AND ANALYSIS: This protocol has been prepared according to the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols statement, the Cochrane Handbook and the Grading of Recommendations, Assessment, Development, and Evaluation approach. We will include randomised clinical trials assessing piperacillin/tazobactam vs carbapenems in patients with severe bacterial infections of any origin. The primary outcome will be all-cause short-term mortality ≤ 90 days. Secondary outcomes will include all-cause long-term mortality > 90 days, adverse events, quality of life, use of life support, secondary infections, antibiotic resistance, and length of stay. We will conduct meta-analyses, including pre-planned subgroup and sensitivity analyses for all assessed outcomes. The risk of random errors in the meta-analyses will be assessed by trial sequential analysis