title: Milrinone for cardiac dysfunction in critically ill adult patients: a systematic review of randomised clinical trials with meta-analysis and trial sequential analysis.
abstract: BACKGROUND
  Milrinone is an inotrope widely used for treatment of cardiac failure. Because previous meta-analyses had methodological flaws, we decided to conduct a systematic review of the effect of milrinone in critically ill adult patients with cardiac dysfunction.
  
  
  METHODS
  This systematic review was performed according to The Cochrane Handbook for Systematic Reviews of Interventions. Searches were conducted until November 2015. Patients with cardiac dysfunction were included. The primary outcome was serious adverse events (SAE) including mortality at maximum follow-up. The risk of bias was evaluated and trial sequential analyses were conducted. The quality of evidence was assessed by the Grading of Recommendations Assessment, Development and Evaluation criteria.
  
  
  RESULTS
  A total of 31 randomised clinical trials fulfilled the inclusion criteria, of which 16 provided data for our analyses. All trials were at high risk of bias, and none reported the primary composite outcome SAE. Fourteen trials with 1611 randomised patients reported mortality data at maximum follow-up (RR 0.96; 95% confidence interval 0.76-1.21). Milrinone did not significantly affect other patient-centred outcomes. All analyses displayed statistical and/or clinical heterogeneity of patients, interventions, comparators, outcomes, and/or settings and all featured missing data.
  
  
  CONCLUSIONS
  The current evidence on the use of milrinone in critically ill adult patients with cardiac dysfunction suffers from considerable risks of both bias and random error and demonstrates no benefits. The use of milrinone for the treatment of critically ill patients with cardiac dysfunction can be neither recommended nor refuted. Future randomised clinical trials need to be sufficiently large and designed to have low risk of bias.
authors.affiliation: Department of Critical Care, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands. g.koster@umcg.nl.
authors.forename: Geert
authors.identifier: http://orcid.org/0000-0002-8927-3077
authors.initials: G
authors.lastname: Koster
authors.affiliation: Department of Anaesthesiology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
authors.forename: Hanneke J
authors.initials: HJ
authors.lastname: Bekema
authors.affiliation: The Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, 2100, Copenhagen, Denmark.
authors.forename: Jørn
authors.initials: J
authors.lastname: Wetterslev
authors.affiliation: The Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, 2100, Copenhagen, Denmark.
authors.forename: Christian
authors.initials: C
authors.lastname: Gluud
authors.affiliation: Department of Critical Care, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands.
authors.forename: Frederik
authors.initials: F
authors.lastname: Keus
authors.affiliation: Department of Critical Care, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands.
authors.forename: Iwan C C
authors.initials: IC
authors.lastname: van der Horst
mesh_terms: D000328:Adult; D016638:Critical Illness / Q000401:mortality; D006331:Heart Diseases / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D020105:Milrinone / Q000008:administration & dosage / Q000009:adverse effects*; D058987:Phosphodiesterase 3 Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D016032:Randomized Controlled Trials as Topic
chemical_list: D058987:Phosphodiesterase 3 Inhibitors; D020105:Milrinone
keywords: Heart failure; Milrinone; Systematic review; Trial sequential analysis