Description of the included studies
The main characteristics of the studies included in the meta-analysis are summarized in Table 1 (general anesthesia) and Table 2 (regional anesthesia). Thirty-seven studies were first included (Fig. 1). Then, 3 RCT by Schietroma et al. were excluded from analysis taking into account the retraction of 2 of them due to the falsification of the statistics11,12 and one of them for plagiarism and similarities of data with those previously published by another group13. The validity of the 3 non-retracted studies from this group14,15,16 has also been questioned because all 6 RCT of this group reported results markedly different from the pooled results of all other published trials systematically in favor of the high FiO2 group. Consequently, as previous authors8,9,10, we followed the conclusions of the extensive re-analysis of the whole work from Schietroma’s group17 and did not include data from any study of this group in our meta-analysis.
In addition, the randomized study by Anthony et al.18 was excluded as they assessed a bundle of five measures including 80% FiO2 during the surgery and the first 2 postoperative hours as compared with a standard of care using 30% FiO2. Indeed, the specific role of high or low FiO2 could not be individualized from other measures such as perioperative warming to maintain normothermia or reduction of intravenous fluids during the surgery in this study18. Eventually, 30 randomized studies were included in this meta-analysis for a total of 18,055 patients, among which 24 compared high vs. low intraoperative FiO2 during general anesthesia (n = 15,871 patients)19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42 and 6 during regional anesthesia (n = 2184 patients)43,44,45,46,47,48. High FiO2 was 80% in all studies except in Park’s study (FiO2 60%)37; and low FiO2 was 30% in all studies except in Lin’s study (FiO2 40%)38, Pryor’s and Park’s studies (FiO2 35%)20,37, Mayank’s study (FiO2 33%)33, and Admadé’s study (room air)45.
Concerning surgeries performed under general anesthesia, studies mainly included patients undergoing abdominal surgery (exclusively for 18 and mixed with other surgeries for 3 out of the 24 studies) (Table 1). Concerning surgeries performed under loco-regional anesthesia, the 6 studies included caesarean section patients treated with epidural anesthesia (Table 2). SSI was the main judgment criterion in 22 studies19,20,21,22,24,25,26,28,29,30,32,33,34,35,39,41,43,44,45,46,47,48, and a secondary endpoint in the 8 remaining studies23,27,31,36,37,38,40,42.
SSI were diagnosed using the CDC definition21,24,26,27,28,29,31,32,33,35,36,39,41,42,46,47, ASEPSIS definition25,30,34,48, or other trial-specific definitions19,20,22,23,37,38,40,43,44,45, in respectively 16, 4 and 10 out of the 30 included studies. Confounding factors influencing the incidence of SSI were variously considered. Antibiotic prophylaxis was protocolized in all studies but sometimes incompletely followed. Maintenance of perioperative normothermia was protocolized in only 13/30 studies19,21,22,23,24,25,27,31,32,33,34,36,38. Amount of perioperative fluid administered and fluid management strategy was protocolized in 9/30 studies19,21,22,24,29,33,34,40,42.
Meta-analysis and sub-group analyses depending on anesthetic modalities
The Oxford quality-scoring system of the 30 studies included in the meta-analysis is summarized in Fig. 2.
Meta-analysis of the 30 studies showed no significant benefit of high FiO2 on the prevention of SSI (RR0.90, 95%CI 0.79 to 1.03) (Fig. 3a). There was evidence of heterogeneity (τ2 = 0.04, χ2 test for heterogeneity p = 0.02, I2 = 38%). Visual inspection of the funnel-plot showed no clear evidence of publication bias, as confirmed by Egger’s test (Z = − 0.774, p = 0.44) and the rank correlation test (Kendall’s τ = − 0.103, p = 0.44) (Fig. 3b).
Considering sub-group analyses depending on anesthetic modalities, a moderate benefit was found in patients operated under general anesthesia (RR 0.86, 95%CI 0.75–0.99) (Fig. 3a). There was evidence of heterogeneity (τ2 = 0.04, χ2 test for heterogeneity p = 0.02, I2 = 41%). Visual inspection of the funnel-plot showed no clear evidence of publication bias, as confirmed by Egger’s test (Z = − 0.822, p = 0.41) and the rank correlation test (Kendall’s τ = − 0.109, p = 0.48) (Fig. 3b). According to the GRADE methodology, the overall quality of evidence for prevention of surgical site infection was assessed as low due to biases in individual trials and inconsistency between studies (I2 = 41%).
Meta-analysis of the 6 studies that included patients operated on under regional anesthesia showed no significant benefit of high FiO2 on the prevention of SSI (RR 1.17, 95%CI 0.90–1.52—Fig. 3a), with good between-study homogeneity (τ2 = 0.00, χ2 test for heterogeneity p = 0.53, I2 = 0%). Visual inspection of the funnel-plot showed no clear evidence of publication bias, as confirmed by Egger’s test (Z = − 0.561, p = 0.58) and the rank correlation test (Kendall’s τ = − 0.067, p = 1.00) (Fig. 3b). According to GRADE methodology, the overall certainty for prevention of surgical site infection was assessed as moderate, taking into account the absence of inconsistency (I2 = 0%) but biases in individual studies and the imprecision of the 95%CI around the estimate.
Considering that it has been suggested that nitrous oxide could impair human immune functions, sensitivity analyses were conducted: (1) on the 22 studies that used the same second gas in both the high and low FiO2 groups, i.e. excluding the 2 studies that compared “low FiO2 + nitrous oxide” to “high FiO2 + nitrogen”22,23, and the “low FiO2 + nitrous oxide” group of Chen’s study27“; showing no significant effect of high intraoperative FiO2 (RR 0.89, 95%CI 0.76–1.03—Fig. 4a); and (2) on the 20 studies that did not use nitrous oxide as second gas, neither in the high nor low FiO2 groups; showing no significant effect of high intraoperative FiO2 (RR 0.87, 95%CI 0.75–1.01—Fig. 4b).
Types of surgery
Considering that the type of surgery is an important factor associated with the occurrence of SSI, a sensitivity analysis was conducted on the 18 studies having exclusively included patients operated from abdominal surgeries19,20,21,22,24,25,27,29,30,32,33,34,35,36,37,38,39,40 and on the subgroup of patients from the 3 studies having included mixed surgeries who were operated from abdominal surgeries, after having obtained additional data regarding these subgroups from the authors23,26,42. No significant benefit of high FiO2 on the prevention of SSI in abdominal surgery was found (RR0.89, 95%CI 0.76–1.04) (Fig. 5).
Types of SSI
Considering that superficial SSI, sometimes only treated by local measures of the wound, may be not associated to the same morbidity and mortality than deep SSI, a sensitivity analysis was conducted on the 15 studies for which data on superficial and deep SSI were available or retrieved from the authors. No significant benefit of high FiO2 on the prevention of deep SSI was found (RR0.97, 95%CI 0.83–1.14) (Fig. 6).