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

Jens-Ulrik Stæhr Jensen; Lars Hein; Bettina Lundgren; Morten Heiberg Bestle; Thomas Mohr; Mads Holmen Andersen; Klaus Julius Thornberg; Jesper Løken; Morten Steensen; Zoë Fox; Hamid Tousi; Peter Søe-Jensen; Anne Øberg Lauritsen; Ditte Gry Strange; Nanna Reiter; Katrin Thormar; Paul Christian Fjeldborg; Kim Michael Larsen; Niels-Erik Drenck; Maria Egede Johansen; Lene Ryom Nielsen; Christian Ostergaard; Jesper Kjær; Jesper Grarup; Jens D Lundgren; Procalcitonin And Survival Study (PASS) Group

doi:10.1136/bmjopen-2011-000635

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

Jens-Ulrik Stæhr Jensen, Lars Hein, Bettina Lundgren, Morten Heiberg Bestle, Thomas Mohr, Mads Holmen Andersen, Klaus Julius Thornberg, Jesper Løken, Morten Steensen, Zoë Fox, Hamid Tousi, Peter Søe-Jensen, Anne Øberg Lauritsen, Ditte Gry Strange, Nanna Reiter, Katrin Thormar, Paul Christian Fjeldborg, Kim Michael Larsen, Niels-Erik Drenck, Maria Egede JohansenLene Ryom Nielsen, Christian Ostergaard, Jesper Kjær, Jesper Grarup, Jens D Lundgren, Procalcitonin And Survival Study (PASS) Group

Department of Immunology and Microbiology

52 Citations (Scopus)

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 guidelinebased 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 highexposure versus 3016/6949 (43.4%) in the 'standardexposure 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 m2/24 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.

Original language	English
Journal	B M J Open
Volume	2
Issue number	2
Pages (from-to)	e000635
ISSN	2044-6055
DOIs	https://doi.org/10.1136/bmjopen-2011-000635
Publication status	Published - 2012

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10.1136/bmjopen-2011-000635

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Jensen, J.-U. S., Hein, L., Lundgren, B., Bestle, M. H., Mohr, T., Andersen, M. H., Thornberg, K. J., Løken, J., Steensen, M., Fox, Z., Tousi, H., Søe-Jensen, P., Lauritsen, A. Ø., Strange, D. G., Reiter, N., Thormar, K., Fjeldborg, P. C., Larsen, K. M., Drenck, N.-E., ... Procalcitonin And Survival Study (PASS) Group (2012). Kidney failure related to broad-spectrum antibiotics in critically ill patients: secondary end point results from a 1200 patient randomised trial. B M J Open, 2(2), e000635. https://doi.org/10.1136/bmjopen-2011-000635

Jensen, J-US, Hein, L, Lundgren, B, Bestle, MH, Mohr, T, Andersen, MH, Thornberg, KJ, Løken, J, Steensen, M, Fox, Z, Tousi, H, Søe-Jensen, P, Lauritsen, AØ, Strange, DG, Reiter, N, Thormar, K, Fjeldborg, PC, Larsen, KM, Drenck, N-E, Johansen, ME, Nielsen, LR, Ostergaard, C, Kjær, J, Grarup, J, Lundgren, JD & Procalcitonin And Survival Study (PASS) Group 2012, 'Kidney failure related to broad-spectrum antibiotics in critically ill patients: secondary end point results from a 1200 patient randomised trial', B M J Open, vol. 2, no. 2, pp. e000635. https://doi.org/10.1136/bmjopen-2011-000635

@article{7ec439f3eb62400e99de56db03625aa2,

title = "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 guidelinebased 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 highexposure versus 3016/6949 (43.4%) in the 'standardexposure 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 m2/24 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.",

author = "Jensen, {Jens-Ulrik St{\ae}hr} and Lars Hein and Bettina Lundgren and Bestle, {Morten Heiberg} and Thomas Mohr and Andersen, {Mads Holmen} and Thornberg, {Klaus Julius} and Jesper L{\o}ken and Morten Steensen and Zo{\"e} Fox and Hamid Tousi and Peter S{\o}e-Jensen and Lauritsen, {Anne {\O}berg} and Strange, {Ditte Gry} and Nanna Reiter and Katrin Thormar and Fjeldborg, {Paul Christian} and Larsen, {Kim Michael} and Niels-Erik Drenck and Johansen, {Maria Egede} and Nielsen, {Lene Ryom} and Christian Ostergaard and Jesper Kj{\ae}r and Jesper Grarup and Lundgren, {Jens D} and {Procalcitonin And Survival Study (PASS) Group}",

year = "2012",

doi = "10.1136/bmjopen-2011-000635",

language = "English",

volume = "2",

pages = "e000635",

journal = "B M J Open",

issn = "2044-6055",

publisher = "BMJ Publishing Group",

number = "2",

}

TY - JOUR

T1 - Kidney failure related to broad-spectrum antibiotics in critically ill patients

T2 - secondary end point results from a 1200 patient randomised trial

AU - Jensen, Jens-Ulrik Stæhr

AU - Hein, Lars

AU - Lundgren, Bettina

AU - Bestle, Morten Heiberg

AU - Mohr, Thomas

AU - Andersen, Mads Holmen

AU - Thornberg, Klaus Julius

AU - Løken, Jesper

AU - Steensen, Morten

AU - Fox, Zoë

AU - Tousi, Hamid

AU - Søe-Jensen, Peter

AU - Lauritsen, Anne Øberg

AU - Strange, Ditte Gry

AU - Reiter, Nanna

AU - Thormar, Katrin

AU - Fjeldborg, Paul Christian

AU - Larsen, Kim Michael

AU - Drenck, Niels-Erik

AU - Johansen, Maria Egede

AU - Nielsen, Lene Ryom

AU - Ostergaard, Christian

AU - Kjær, Jesper

AU - Grarup, Jesper

AU - Lundgren, Jens D

AU - Procalcitonin And Survival Study (PASS) Group

PY - 2012

Y1 - 2012

N2 - 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 guidelinebased 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 highexposure versus 3016/6949 (43.4%) in the 'standardexposure 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 m2/24 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.

AB - 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 guidelinebased 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 highexposure versus 3016/6949 (43.4%) in the 'standardexposure 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 m2/24 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.

U2 - 10.1136/bmjopen-2011-000635

DO - 10.1136/bmjopen-2011-000635

M3 - Journal article

C2 - 22411933

SN - 2044-6055

VL - 2

SP - e000635

JO - B M J Open

JF - B M J Open

IS - 2

ER -

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

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