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

Abstract

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.

Article summary

Article focus

• To determine whether an increased exposure to broad-spectrum antibiotics causes renal failure in intensive care patients.

• To find out whether some of the antibiotics used in the interventional arm were more prone to cause renal failure.

Key messages

• More days with renal failure were observed in patients in the highly antibiotic exposed arm.

• Administration of piperacillin/tazobactam caused the lowest rate of renal recovery of all analysed drugs and when this drug was discontinued, renal function recovered at a fast rate.

• Use of piperacillin/tazobactam in intensive care patients can cause a slow renal recovery and this toxic effect seems at least partially reversible.

Strengths and limitations of this study

• The study is a randomised controlled trial with a high sample size and high rate of follow-up and it is the first to systematically investigate the renal toxicity of several of the analysed antibiotics. Existing end points for acute renal failure could not capture renal failure that emerged from baseline and forth, so other end points had to be designed. The study was not designed to detect persistent renal failure and more severe degrees of renal failure.