title: Glycemic control, mortality, and hypoglycemia in critically ill patients: a systematic review and network meta-analysis of randomized controlled trials.
abstract: OBJECTIVE
  It is unclear whether tight glycemic control is warranted in all critically ill adults. We employed network meta-analysis to examine the risk of mortality and hypoglycemia associated with different glycemic control targets in critically ill adults.
  
  
  METHODS
  Electronic databases were searched up to 2016 for randomized controlled trials comparing various insulin regimens in critically ill adults with hyperglycemia. Two reviewers independently extracted information and evaluated quality with the Cochrane risk-of-bias tool. Four glycemic control groups were compared: tight (blood glucose: 4.4 < 6.1 mmol/l), moderate (6.1 < 7.8 mmol/l), mild (7.8 < 10.0 mmol/l), and very mild (10.0 to < 12.2 mmol/l). Network meta-analysis was performed by a frequentist approach with multivariate random effects meta-analysis.
  
  
  RESULTS
  Thirty-six randomized trials (17,996 patients) were identified. Compared with very mild control, tight control did not reduce the risk of short-term mortality [relative risk (RR) 0.94 (95 % CI 0.83-1.07, p = 0.36)], and neither did mild control [RR 0.88 (0.73-1.06), p = 0.18] or moderate control [RR 1.1 (0.66-1.84), p = 0.72]. However, severe hypoglycemia (<2.2 mmol/l) was more frequent with tight control than very mild control [RR 5.49 (3.22-9.38), p < 0.001] or mild control [RR 4.47 (2.5-8.03), p < 0.001]. Stratified analyses (cause of death, ICU type, time period, or diabetes) did not find significant between-group differences. Ranking analysis revealed the following hierarchy for avoiding death (highest to lowest rank): mild control, tight control, and very mild control.
  
  
  CONCLUSIONS
  Network meta-analysis showed no mortality benefit of tight glycemic control in critically ill patients, but fivefold more hypoglycemia versus mild or very mild control.
authors.affiliation: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo, 113-8655, Japan. bqx07367@yahoo.co.jp.
authors.forename: Tomohide
authors.initials: T
authors.lastname: Yamada
authors.affiliation: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo, 113-8655, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Shojima
authors.affiliation: Department of Data Science, The Institute of Statistical Mathematics, Tokyo, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Noma
authors.affiliation: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo, 113-8655, Japan.
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Yamauchi
authors.affiliation: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo, 113-8655, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001786:Blood Glucose / Q000032:analysis; D016638:Critical Illness / Q000401:mortality*; D005260:Female; D017052:Hospital Mortality; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy* / Q000401:mortality*; D007003:Hypoglycemia / Q000188:drug therapy* / Q000401:mortality*; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007328:Insulin / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D016032:Randomized Controlled Trials as Topic
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin
keywords: Glycemic control; Hypoglycemia; Meta-analysis; Mortality