title: The effects of high perioperative inspiratory oxygen fraction for adult surgical patients.
abstract: BACKGROUND
  Available evidence on the effects of a high fraction of inspired oxygen (FIO2) of 60% to 90% compared with a routine fraction of inspired oxygen of 30% to 40%, during anaesthesia and surgery, on mortality and surgical site infection has been inconclusive. Previous trials and meta-analyses have led to different conclusions on whether a high fraction of supplemental inspired oxygen during anaesthesia may decrease or increase mortality and surgical site infections in surgical patients.
  
  
  OBJECTIVE
  To assess the benefits and harms of an FIO2 equal to or greater than 60% compared with a control FIO2 at or below 40% in the perioperative setting in terms of mortality, surgical site infection, respiratory insufficiency, serious adverse events and length of stay during the index admission for adult surgical patients.We looked at various outcomes, conducted subgroup and sensitivity analyses, examined the role of bias and applied trial sequential analysis (TSA) to examine the level of evidence supporting or refuting a high FIO2 during surgery, anaesthesia and recovery.
  
  
  METHODS
  We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, BIOSIS, International Web of Science, the Latin American and Caribbean Health Science Information Database (LILACS), advanced Google and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) up to February 2014. We checked the references of included trials and reviews for unidentified relevant trials and reran the searches in March 2015. We will consider two studies of interest when we update the review.
  
  
  METHODS
  We included randomized clinical trials that compared a high fraction of inspired oxygen with a routine fraction of inspired oxygen during anaesthesia, surgery and recovery in individuals 18 years of age or older.
  
  
  METHODS
  Two review authors extracted data independently. We conducted random-effects and fixed-effect meta-analyses, and for dichotomous outcomes, we calculated risk ratios (RRs). We used published data and data obtained by contacting trial authors.To minimize the risk of systematic error, we assessed the risk of bias of the included trials. To reduce the risk of random errors caused by sparse data and repetitive updating of cumulative meta-analyses, we applied trial sequential analyses. We used Grades of Recommendation, Assessment, Development and Evaluation (GRADE) to assess the quality of the evidence.
  
  
  RESULTS
  We included 28 randomized clinical trials (9330 participants); in the 21 trials reporting relevant outcomes for this review, 7597 participants were randomly assigned to a high fraction of inspired oxygen versus a routine fraction of inspired oxygen.In trials with an overall low risk of bias, a high fraction of inspired oxygen compared with a routine fraction of inspired oxygen was not associated with all-cause mortality (random-effects model: RR 1.12, 95% confidence interval (CI) 0.93 to 1.36; GRADE: low quality) within the longest follow-up and within 30 days of follow-up (Peto odds ratio (OR) 0.99, 95% CI 0.61 to 1.60; GRADE: low quality). In a trial sequential analysis, the required information size was not reached and the analysis could not refute a 20% increase in mortality. Similarly, when all trials were included, a high fraction of inspired oxygen was not associated with all-cause mortality to the longest follow-up (RR 1.07, 95% CI 0.87 to 1.33) or within 30 days of follow-up (Peto OR 0.83, 95% CI 0.54 to 1.29), both of very low quality according to GRADE. Neither was a high fraction of inspired oxygen associated with the risk of surgical site infection in trials with low risk of bias (RR 0.86, 95% CI 0.63 to 1.17; GRADE: low quality) or in all trials (RR 0.87, 95% CI 0.71 to 1.07; GRADE: low quality). A high fraction of inspired oxygen was not associated with respiratory insufficiency (RR 1.25, 95% CI 0.79 to 1.99), serious adverse events (RR 0.96, 95% CI 0.65 to 1.43) or length of stay (mean difference -0.06 days, 95% CI -0.44 to 0.32 days).In subgroup analyses of nine trials using preoperative antibiotics, a high fraction of inspired oxygen was associated with a decrease in surgical site infections (RR 0.76, 95% CI 0.60 to 0.97; GRADE: very low quality); a similar effect was noted in the five trials adequately blinded for the outcome assessment (RR 0.79, 95% CI 0.66 to 0.96; GRADE: very low quality). We did not observe an effect of a high fraction of inspired oxygen on surgical site infections in any other subgroup analyses.
  
  
  CONCLUSIONS
  As the risk of adverse events, including mortality, may be increased by a fraction of inspired oxygen of 60% or higher, and as robust evidence is lacking for a beneficial effect of a fraction of inspired oxygen of 60% or higher on surgical site infection, our overall results suggest that evidence is insufficient to support the routine use of a high fraction of inspired oxygen during anaesthesia and surgery. Given the risk of attrition and outcome reporting bias, as well as other weaknesses in the available evidence, further randomized clinical trials with low risk of bias in all bias domains, including a large sample size and long-term follow-up, are warranted.
authors.affiliation: Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, Copenhagen, Denmark, DK-2100.
authors.forename: Jørn
authors.initials: J
authors.lastname: Wetterslev
authors.forename: Christian S
authors.initials: CS
authors.lastname: Meyhoff
authors.forename: Lars N
authors.initials: LN
authors.lastname: Jørgensen
authors.forename: Christian
authors.initials: C
authors.lastname: Gluud
authors.forename: Jane
authors.initials: J
authors.lastname: Lindschou
authors.forename: Lars S
authors.initials: LS
authors.lastname: Rasmussen
mesh_terms: D000328:Adult; D000368:Aged; D000758:Anesthesia; D002423:Cause of Death; D006801:Humans; D007902:Length of Stay; D008875:Middle Aged; D010100:Oxygen / Q000008:administration & dosage* / Q000009:adverse effects*; D010102:Oxygen Inhalation Therapy / Q000009:adverse effects* / Q000379:methods / Q000401:mortality; D016032:Randomized Controlled Trials as Topic; D012131:Respiratory Insufficiency / Q000209:etiology*; D015983:Selection Bias; D013514:Surgical Procedures, Operative / Q000401:mortality*; D013530:Surgical Wound Infection / Q000209:etiology*
chemical_list: D010100:Oxygen