Updated meta-analysis on intraoperative inspired fraction of oxygen and the risk of surgical site infection in adults undergoing general and regional anesthesia

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 statistics^11,12 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 group^14,15,16 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 authors^8,9,10, 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.

Flow diagram of study selection.

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 studies^{19,20,21,22,24,25,26,28,29,30,32,33,34,35,39,41,43,44,45,46,47,48}, and a secondary endpoint in the 8 remaining studies^{23,27,31,36,37,38,40,42}.

SSI were diagnosed using the CDC definition^{21,24,26,27,28,29,31,32,33,35,36,39,41,42,46,47}, ASEPSIS definition^25,30,34,48, or other trial-specific definitions^{19,20,22,23,37,38,40,43,44,45}, 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 studies^{19,21,22,23,24,25,27,31,32,33,34,36,38}. Amount of perioperative fluid administered and fluid management strategy was protocolized in 9/30 studies^{19,21,22,24,29,33,34,40,42}.

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.

Risk of bias summary for the 30 studies included in the meta-analysis. Green circles represent low risk of bias, yellow circles represent unclear of moderate risk of bias, and red circles represent high risk of bias.

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).

Forest plot analysis of high vs. low intraoperative FiO₂ on the incidence of SSI (a), within the subgroups of patients operated under general anesthesia and loco-regional anesthesia; and corresponding funnel plots (b). The X-axis of forest plots represents relative risk, and each row on the Y-axis represents an individual study. The blue squares and horizontal lines represent point estimates and corresponding 95% confidence intervals of the individual studies. The black diamonds represent the overall analysis.

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.

Sensitivity analyses

Second gases

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).

Sensitivity analysis of high versus low intraoperative FiO₂ on the incidence of SSI in patients operated under general anesthesia restricted to the 22 studies that used the same second gas in both the high and low FiO₂ group (a); and to the 20 studies that did not use nitrous oxide as second gas, neither in the high nor low FiO₂ groups (b).

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 surgeries^{19,20,21,22,24,25,27,29,30,32,33,34,35,36,37,38,39,40} 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 authors^23,26,42. 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).

Sensitivity analysis of high vs. low intraoperative FiO₂ on the incidence of SSI in patients operated from abdominal surgery, included in the 18 studies having exclusively included patients operated from abdominal surgeries and in the 3 studies having included mixed surgeries.

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).

Sensitivity analysis of high versus low intraoperative FiO₂ on the incidence of deep SSI in patients included in the 15 studies for which data regarding superficial and deep SSI were available or retrieved from the authors.