Kidney failure related to broad-spectrum antibiotics in critically ill patients: secondary end point results from a 1200 patient randomised trial.

OBJECTIVES: To explore whether a strategy of more intensive antibiotic therapy leads to emergence or prolongation of renal failure in intensive care patients. DESIGN: Secondary analysis from a randomised antibiotic strategy trial (the Procalcitonin And Survival Study). The randomised arms were conserved from the primary trial for the main analysis. SETTING: Nine mixed surgical/medical intensive care units across Denmark. PARTICIPANTS: 1200 adult intensive care patients, 18+ years, expected to stay +24 h. EXCLUSION CRITERIA: bilirubin >40 mg/dl, triglycerides >1000 mg/dl, increased risk from blood sampling, pregnant/breast feeding and psychiatric patients. INTERVENTIONS: Patients were randomised to guideline-based therapy ('standard-exposure' arm) or to guideline-based therapy supplemented with antibiotic escalation whenever procalcitonin increased on daily measurements ('high-exposure' arm). MAIN OUTCOME MEASURES: Primary end point: estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m(2). Secondary end points: (1) delta eGFR after starting/stopping a drug and (2) RIFLE criterion Risk 'R', Injury 'I' and Failure 'F'. Analysis was by intention to treat. RESULTS: 28-day mortality was 31.8% and comparable (Jensen et al, Crit Care Med 2011). A total of 3672/7634 (48.1%) study days during follow-up in the high-exposure versus 3016/6949 (43.4%) in the 'standard-exposure arm were spent with eGFR <60 ml/min/1.73 m(2), p<0.001. In a multiple effects model, 3 piperacillin/tazobactam was identified as causing the lowest rate of renal recovery of all antibiotics used: 1.0 ml/min/1.73 m(2)/24 h while exposed to this drug (95% CI 0.7 to 1.3 ml/min/1.73 m(2)/24 h) vs meropenem: 2.9 ml/min/1.73 m(2)/24 h (2.5 to 3.3 ml/min/1.73 m(2)/24 h)); after discontinuing piperacillin/tazobactam, the renal recovery rate increased: 2.7 ml/min/1.73 m(2)/24 h (2.3 to 3.1 ml/min/1.73 m(2) /24 h)). eGFR <60 ml/min/1.73 m(2) in the two groups at entry and at last day of follow-up was 57% versus 55% and 41% versus 39%, respectively. CONCLUSIONS: Piperacillin/tazobactam was identified as a cause of delayed renal recovery in critically ill patients. This nephrotoxicity was not observed when using other beta-lactam antibiotics. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00271752.

Procalcitonin-guided interventions against infections to increase early appropriate antibiotics and improve survival in the intensive care unit: a randomized trial.

OBJECTIVE: For patients in intensive care units, sepsis is a common and potentially deadly complication and prompt initiation of appropriate antimicrobial therapy improves prognosis. The objective of this trial was to determine whether a strategy of antimicrobial spectrum escalation, guided by daily measurements of the biomarker procalcitonin, could reduce the time to appropriate therapy, thus improving survival. DESIGN: Randomized controlled open-label trial. SETTING: Nine multidisciplinary intensive care units across Denmark. PATIENTS: A total of 1,200 critically ill patients were included after meeting the following eligibility requirements: expected intensive care unit stay of ≥ 24 hrs, nonpregnant, judged to not be harmed by blood sampling, bilirubin <40 mg/dL, and triglycerides <1000 mg/dL (not suspensive). INTERVENTIONS: : Patients were randomized either to the "standard-of-care-only arm," receiving treatment according to the current international guidelines and blinded to procalcitonin levels, or to the "procalcitonin arm," in which current guidelines were supplemented with a drug-escalation algorithm and intensified diagnostics based on daily procalcitonin measurements. MEASUREMENTS AND MAIN RESULTS: The primary end point was death from any cause at day 28; this occurred for 31.5% (190 of 604) patients in the procalcitonin arm and for 32.0% (191 of 596) patients in the standard-of-care-only arm (absolute risk reduction, 0.6%; 95% confidence interval [CI] -4.7% to 5.9%). Length of stay in the intensive care unit was increased by one day (p = .004) in the procalcitonin arm, the rate of mechanical ventilation per day in the intensive care unit increased 4.9% (95% CI, 3.0-6.7%), and the relative risk of days with estimated glomerular filtration rate <60 mL/min/1.73 m was 1.21 (95% CI, 1.15-1.27). CONCLUSIONS: Procalcitonin-guided antimicrobial escalation in the intensive care unit did not improve survival and did lead to organ-related harm and prolonged admission to the intensive care unit. The procalcitonin strategy like the one used in this trial cannot be recommended.

The Procalcitonin And Survival Study (PASS) - a randomised multi-center investigator-initiated trial to investigate whether daily measurements biomarker Procalcitonin and pro-active diagnostic and therapeutic responses to abnormal Procalcitonin levels, can improve survival in intensive care unit patients. Calculated sample size (target population): 1000 patients.

BACKGROUND: Sepsis and complications to sepsis are major causes of mortality in critically ill patients. Rapid treatment of sepsis is of crucial importance for survival of patients. The infectious status of the critically ill patient is often difficult to assess because symptoms cannot be expressed and signs may present atypically. The established biological markers of inflammation (leucocytes, C-reactive protein) may often be influenced by other parameters than infection, and may be unacceptably slowly released after progression of an infection. At the same time, lack of a relevant antimicrobial therapy in an early course of infection may be fatal for the patient. Specific and rapid markers of bacterial infection have been sought for use in these patients. METHODS: Multi-centre randomized controlled interventional trial. Powered for superiority and non-inferiority on all measured end points. Complies with, "Good Clinical Practice" (ICH-GCP Guideline (CPMP/ICH/135/95, Directive 2001/20/EC)). Inclusion: 1) Age > or = 18 years of age, 2) Admitted to the participating intensive care units, 3) Signed written informed consent.Exclusion: 1) Known hyper-bilirubinaemia. or hypertriglyceridaemia, 2) Likely that safety is compromised by blood sampling, 3) Pregnant or breast feeding. Computerized Randomisation: Two arms (1:1), n = 500 per arm: Arm 1: standard of care. Arm 2: standard of care and Procalcitonin guided diagnostics and treatment of infection. Primary Trial Objective: To address whether daily Procalcitonin measurements and immediate diagnostic and therapeutic response on day-to-day changes in procalcitonin can reduce the mortality of critically ill patients. DISCUSSION: For the first time ever, a mortality-endpoint, large scale randomized controlled trial with a biomarker-guided strategy compared to the best standard of care, is conducted in an Intensive care setting. Results will, with a high statistical power answer the question: Can the survival of critically ill patients be improved by actively using biomarker procalcitonin in the treatment of infections? 700 critically ill patients are currently included of 1000 planned (June 2008). Two interim analyses have been passed without any safety or futility issues, and the third interim analysis is soon to take place. Trial registration number at clinicaltrials.gov: Id. nr.: NCT00271752).