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

Yoann El Maleh, Charlotte Fasquel, Christophe Quesnel, Marc Garnier

► To cite this version:

Yoann El Maleh, Charlotte Fasquel, Christophe Quesnel, Marc Garnier. Updated meta-analysis on intraoperative inspired fraction of oxygen and the risk of surgical site infection in adults undergoing general and regional anesthesia. Scientific Reports, 2023, 13 (1), pp.2465. 10.1038/s41598-023-27588-2. hal-03983784

HAL Id: hal-03983784

https://hal.science/hal-03983784

Submitted on 11 Feb 2023

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
# Updated meta-analysis on intraoperative inspired fraction of oxygen and the risk of surgical site infection in adults undergoing general and regional anesthesia

https://doi.org/10.1038/s41598-023-27588-2

Publisher version available at: https://www.nature.com/articles/s41598-023-27588-2

**Authors:**

Yoann El Maleh, Charlotte Fasquel, Christophe Quesnel, Mar Garnier

**Publication:**

Scientific Reports

**Publisher:**

Springer Nature

**Date:**

Feb 11, 2023

Copyright © 2023, The Author(s)

**Creative Commons**

This is an open access article distributed under the terms of the [Creative Commons CC BY](https://creativecommons.org/licenses/by/4.0/) license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

You are not required to obtain permission to reuse this article.
<figure><img src="image_2.png" /></figure>

Check for updates

OPEN

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

Yoann El Maleh<fnref n="1" />, Charlotte Fasquel², Christophe Quesnel<fnref n="1" /> & Marc Garnier<fnref n="1" />✉

This updated meta-analysis aims at exploring whether the use of systematic high vs low intraoperative oxygen fraction (FiO₂) may decrease the incidence of postoperative surgical site infection during general (GA) or regional anesthesia (RA). PubMed, Cochrane CENTRAL, ClinicalTrials.gov databases were searched from January 1st, 1999 and July, 1st 2022, for randomized and quasi-randomized controlled trials that included patients in a high and low FiO₂ groups and reported the incidence of SSI. The meta-analysis was conducted with a DerSimonian and Laird random-effects model. Thirty studies (24 for GA and 6 for RA) totaling 18,055 patients (15,871 for GA and 2184 for RA) were included. We have low-to-moderate-quality evidence that high FiO₂ (mainly 80%) was not associated with a reduction of SSI incidence compared to low FiO₂ (mainly 30%) in all patients (RR 0.90, 95%CI 0.79–1.03). Moderate inconsistency existed between studies (I² = 38%). Subgroup analyses showed a moderate protective effect in patients undergoing GA (RR 0.86, 95%CI 0.75–0.99) (low level of evidence), while high FiO₂ was not associated with a reduction of SSI in patients undergoing RA (RR 1.17, 95%CI 0.90–1.52) (moderate level of evidence). Sensitivity analyses restricted to patients ventilated without nitrous oxide (n = 20 studies), to patients operated from abdominal surgeries (n = 21 studies), and to patients suffering from deep SSI (n = 13 studies), all showed the absence of any significant effect of high FiO₂. As a conclusion there is no compelling evidence that high FiO₂ can improve postoperative patient's outcome on its own when good SSI prevention practices are properly applied. Recent well-designed and adequately powered randomized controlled trials add further weight to these results.

Surgical site infections (SSI) are the most common healthcare-associated infections and a source of morbidity and over-mortality. In 2016, a systematic review and meta-analysis assessing the effects of systematic high FiO₂ (80%) compared with standard FiO₂ (30%) concluded that high FiO₂ were associated with a reduction of SSI in patients undergoing surgery under general anesthesia<fnref n="1" />. Consequently, the WHO recommended that “adult patients undergoing general anesthesia should receive an 80% FiO₂ intra-operatively to reduce the risk of SSI”². These recommendations have sparked large debate on the benefits and harms of hyperoxemia. On the theoretical point-of-view, several pro (prevention of hypoxemia, SSI and postoperative nausea and vomiting) and con (respiratory adverse events, increased production of harmful “reactive oxygen species”) arguments have been raised by believers and detractors of high FiO₂. Accordingly, and despite these recommendations, anesthetists still used a wide range of intraoperative FiO₂ in daily practice³,⁴ and frequently changed FiO₂ settings during surgery unrelated to patients’ PaO₂ or SpO₂⁵.

Then, an updated meta-analysis still reported in 2018 a beneficial effect of high FiO₂, however with an increasingly low level of evidence⁶. Consequently, the WHO downgraded the strength of its recommendations but still recommended an 80% intraoperative FiO₂ during general anesthesia⁷. In 2019, de Jonge et al. updated

<footnote n="1">¹Sorbonne University, GRC29, Assistance Publique-Hôpitaux de Paris (APHP), DMU DREAM, Anesthesiology and Critical Care Medicine Department, Tenon University Hospital, 4 rue de la Chine, 75020 Paris, France. ²Centre Hospitalier Régional Universitaire de Brest, Service d'Anesthésie-Réanimation et Médecine Périopératoire, 29200 Brest, France. ✉email: marc.garnier@aphp.fr</footnote>
the meta-analysis in turn and reported a significantly lower incidence of SSI in intubated patients ventilated intra-operatively with high compared to low $FiO_2$ (RR 0.80 [0.64–0.99])⁸. In the same issue of the *British Journal of Anesthesia*, Mattishent et al. reported the results of a meta-analysis focused on the safety of high $FiO_2$, demonstrating the absence of significant side-effects, in particular regarding respiratory and cardiovascular events⁹. Several reasons can be suggested to explain persistent mistrust. First, de Jonge's meta-analysis still included Myles' ENIGMA study whereas it compared 80%$FiO_2$/20%$N_2$ to 30%$FiO_2$/70%$N_2$O and was originally designed to assess benefits and harms of nitrous oxide. Second, substantial heterogeneity remained, leading de Jonge and co-authors to conclude that “the evidence from the updated analysis has become weaker”. Third, this meta-analysis may have become obsolete very quickly, as new randomized studies were published in the following months. One year later, Hovaguimian et al. concluded in an updated meta-analysis of their former work of 2013, based on 8 studies, that the exclusion of the retracted studies by the group of Schietroma led to a “confidence interval [around the relative risk] wider, that now crossed the line of equality”¹⁰. However, despite this non-significant updated result, the authors concluded that “consistently with the WHO meta-analysis, high inspired oxygen could have a protective effect against surgical site infection”. It can be said that all this did not bring the debate to be closed.

The aim of this study was to update the meta-analysis on the potential beneficial effects of the administration of high intraoperative $FiO_2$ on the occurrence of SSI.

## Results

**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 group¹⁴⁻¹⁶ 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 $FiO_2$ group. Consequently, as previous authors⁸⁻¹⁰, 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% $FiO_2$ during the surgery and the first 2 postoperative hours as compared with a standard of care using 30% $FiO_2$. Indeed, the specific role of high or low $FiO_2$ 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 $FiO_2$ during general anesthesia (n = 15,871 patients)¹⁹⁻⁴² and 6 during regional anesthesia (n = 2184 patients)⁴³⁻⁴⁸. High $FiO_2$ was 80% in all studies except in Park's study ($FiO_2$ 60%)³⁷; and low $FiO_2$ was 30% in all studies except in Lin's study ($FiO_2$ 40%)³⁸, Pryor's and Park's studies ($FiO_2$ 35%)²⁰,³⁷, Mayank's study ($FiO_2$ 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 studies¹⁹⁻²²,²⁴⁻²⁶,²⁸⁻³⁰,³²⁻³⁵,³⁹,⁴¹,⁴³⁻⁴⁸, and a secondary endpoint in the 8 remaining studies²³,²⁷,³¹,³⁶⁻³⁸,⁴⁰,⁴².

SSI were diagnosed using the CDC definition²¹,²⁴,²⁶⁻²⁹,³¹⁻³³,³⁵,³⁶,³⁹,⁴¹,⁴²,⁴⁶,⁴⁷, ASEPSIS definition²⁵,³⁰,³⁴,⁴⁸, or other trial-specific definitions¹⁹,²⁰,²²,²³,³⁷,³⁸,⁴⁰,⁴³⁻⁴⁵, 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 studies¹⁹,²¹⁻²⁵,²⁷,³¹⁻³⁴,³⁶,³⁸. Amount of perioperative fluid administered and fluid management strategy was protocolized in 9/30 studies¹⁹,²¹,²²,²⁴,²⁹,³³,³⁳,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 $FiO_2$ on the prevention of SSI (RR 0.90, 95%CI 0.79 to 1.03) (Fig. 3a). There was evidence of heterogeneity ($\tau^2$ = 0.04, $\chi^2$ test for heterogeneity $p$ = 0.02, $I^2$ = 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 $\tau$ = -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 ($\tau^2$ = 0.04, $\chi^2$ test for heterogeneity $p$ = 0.02, $I^2$ = 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 $\tau$ = -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 ($I^2$ = 41%).

Meta-analysis of the 6 studies that included patients operated on under regional anesthesia showed no significant benefit of high $FiO_2$ on the prevention of SSI (RR 1.17, 95%CI 0.90–1.52—Fig. 3a), with good between-study homogeneity ($\tau^2$ = 0.00, $\chi^2$ test for heterogeneity $p$ = 0.53, $I^2$ = 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 $\tau$ = -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 ($I^2$ = 0%) but biases in individual studies and the imprecision of the 95%CI around the estimate.
<table><thead><tr><th>Study</th><th>Country</th><th>Design, n</th><th>Type of surgery</th><th>O<sub>2</sub> duration in PACU</th><th>SSI definition, follow up</th><th>SSI, n (%)</th><th>Second gas</th><th>Antibiotic prophylaxis</th><th>Temp</th><th>Fluids</th></tr></thead><tbody><tr><td>Greif et al.<sup>19</sup></td><td>Austria, Germany, USA</td><td>RCT Multicenter n = 500</td><td>Colorectal</td><td>2 h</td><td>Wound infection (pus), Day 15</td><td>FiO<sub>2</sub> 80%: 13/250 (5.2%)<br/>FiO<sub>2</sub> 30%: 28/250 (11.2%)<br/>p = 0.01</td><td>N<sub>2</sub></td><td>NP</td><td>Yes</td><td>15 ml/kg/h</td></tr><tr><td>Pryor et al.<sup>20</sup></td><td>USA</td><td>RCT Monocenter n = 160</td><td>Major abdominal laparotomy or laparoscopy</td><td>2 h</td><td>Clinical and paraclinical requiring medical support, Day 14</td><td>FiO<sub>2</sub> 80%: 20/80 (25%)<br/>FiO<sub>2</sub> 35%: 9/80 (11.3%)<br/>p = 0.02</td><td>N<sub>2</sub>O</td><td>Yes</td><td>NP</td><td>NP</td></tr><tr><td>Belda et al.<sup>21</sup></td><td>Spain</td><td>RCT Multicenter n = 291</td><td>Colorectal laparotomy</td><td>6 h</td><td>CDC, Day 14</td><td>FiO<sub>2</sub> 80%: 22/148 (14.9%)<br/>FiO<sub>2</sub> 30%: 35/143 (24.4%)<br/>p = 0.04</td><td>Air</td><td>Yes</td><td>Yes</td><td>15 ml/kg/h</td></tr><tr><td>Mayzler et al.<sup>22</sup></td><td>Israel</td><td>RCT Monocenter n = 38</td><td>Colorectal Carcinologic</td><td>2 h</td><td>Wound infection, Day 30</td><td>FiO<sub>2</sub> 80%: 2/19 (12.5%)<br/>FiO<sub>2</sub> 30%: 3/19 (17.6%)<br/>p = 0.53</td><td>N<sub>2</sub>, N<sub>2</sub>O</td><td>Yes</td><td>Yes</td><td>15 ml/kg/h</td></tr><tr><td>Myles et al.<sup>23</sup></td><td>Australia</td><td>RCT Multicenter n = 2012</td><td>Major surgery &gt; 2 h</td><td>–</td><td>Wound infection (pus or positive culture), Day 30</td><td>FiO<sub>2</sub> 80%: 77/997 (7.7%)<br/>FiO<sub>2</sub> 30%: 106/1015 (10.4%)<br/>p = 0.034</td><td>N<sub>2</sub>, N<sub>2</sub>O</td><td>Yes</td><td>NP</td><td>NP</td></tr><tr><td>Meyhoff et al.<sup>24</sup></td><td>Denmark</td><td>RCT Multicenter n = 1386</td><td>Abdominal laparotomy</td><td>2 h</td><td>CDC, Day 14</td><td>FiO<sub>2</sub> 80%: 131/685 (19.1%)<br/>FiO<sub>2</sub> 30%: 141/701 (20.1%)<br/>p = 0.64</td><td>Air</td><td>Yes (70% of cases)</td><td>Yes</td><td>Restrictive</td></tr><tr><td>Bickel et al.<sup>25</sup></td><td>Israel</td><td>RCT Monocenter n = 210</td><td>Appendectomy Mac Burney</td><td>2 h</td><td>ASEPSIS, Day 14</td><td>FiO<sub>2</sub> 80%: 6/107 (5.6%)<br/>FiO<sub>2</sub> 30%: 14/103 (13.6%)<br/>p = 0.04</td><td>N<sub>2</sub> Air</td><td>Yes</td><td>Yes</td><td>NP</td></tr><tr><td>Thibon et al.<sup>26</sup></td><td>France</td><td>RCT Multicenter n = 434</td><td>Abdominal laparoscopy/ tomy + breast cancer surgery</td><td>–</td><td>CDC, Day 30</td><td>FiO<sub>2</sub> 80%: 15/226 (6.6%)<br/>FiO<sub>2</sub> 30%: 15/208 (7.2%)<br/>p = 0.81</td><td>Air</td><td>Yes (51.5% of cases)</td><td>NP</td><td>NP</td></tr><tr><td>Chen et al.<sup>27</sup></td><td>Hong Kong</td><td>RCT Monocenter n = 91</td><td>Colorectal</td><td>24 h</td><td>CDC, Day 30</td><td>FiO<sub>2</sub> 80% + N<sub>2</sub>: 5/30 (16.7%)<br/>FiO<sub>2</sub> 30% + N<sub>2</sub>: 4/30 (13.3%)<br/>FiO<sub>2</sub> 30% + N<sub>2</sub>O: 15/31 (48.4%)<br/>p = 0.21</td><td>N<sub>2</sub>, N<sub>2</sub>O</td><td>Yes</td><td>Yes</td><td>NP</td></tr><tr><td>Stall et al.<sup>28</sup></td><td>USA</td><td>RCT Monocenter n = 235</td><td>Orthopedic trauma surgery</td><td>2 h</td><td>CDC, Day 84</td><td>FiO<sub>2</sub> 80%: 14/119 (12%)<br/>FiO<sub>2</sub> 30%: 19/116 (16%)<br/>p = 0.31</td><td>NA</td><td>Yes</td><td>NP</td><td>NP</td></tr><tr><td>Kurz et al.<sup>29</sup></td><td>USA, Ireland, Austria</td><td>RCT Multicenter n = 555</td><td>Colectomy laparotomy &gt; 2 h</td><td>1 h</td><td>CDC, Day 30</td><td>FiO<sub>2</sub> 80%: 45/285 (15.8%)<br/>FiO<sub>2</sub> 30%: 42/270 (15.6%)<br/>p = 1.00</td><td>N<sub>2</sub></td><td>Yes</td><td>NP</td><td>6–10 ml/kg/h</td></tr><tr><td>Wasnik et al.<sup>30</sup></td><td>India</td><td>RCT Monocenter n = 64</td><td>Appendectomy Mac Burney</td><td>2 h</td><td>ASEPSIS, Day 14</td><td>FiO<sub>2</sub> 80%: 0/32<br/>FiO<sub>2</sub> 30%: 0/32</td><td>NA</td><td>Yes</td><td>NP</td><td>NP</td></tr><tr><td>Chiang et al.<sup>31</sup></td><td>New Zealand</td><td>RCT Monocenter n = 37</td><td>Vascular surgery (infra-inguinal bypass)</td><td>2 h</td><td>CDC, Day 30</td><td>FiO<sub>2</sub> 80%: 6/19 (incl. 0 major SSI)<br/>FiO<sub>2</sub> 30%: 7/18 (incl. 3 major SSI)<br/>p &gt; 0.05</td><td>NA</td><td>Yes</td><td>Yes</td><td>NP</td></tr><tr><td>Kurz et al.<sup>32</sup></td><td>USA</td><td>Quasi-randomized Monocenter n = 5749</td><td>Major abdominal &gt; 2 h laparotomy or laparoscopy</td><td>–</td><td>CDC, Day 30</td><td>FiO<sub>2</sub> 80%: 118/2896 (4.1%)<br/>FiO<sub>2</sub> 30%: 112/2853 (3.9%)<br/>p = 0.77</td><td>NA</td><td>Yes</td><td>Yes</td><td>NP</td></tr></tbody></table>

Continued
<table><caption>**Table 1.** Summary of the main characteristics and results of the studies including patients under general anesthesia. O₂ oxygen, SSI surgical site infection, n number, Temp. temperature (i.e. protocol for maintenance of intraoperative normothermia), N₂ nitrogen, N₂O nitrous oxide, AA ambient air, CDC Centers for Disease Control and Prevention, ASEPSIS Additional treatment, Serous discharge, Erythema, Purulent discharge, Separation of deep tissues, Isolation of bacteria, and prolonged Stay in hospital > 14 days, RCT randomized controlled trial.</caption><thead><tr><th>Study</th><th>Country</th><th>Design, n</th><th>Type of surgery</th><th>O<sub>2</sub> duration in PACU</th><th>SSI definition, follow up</th><th>SSI, n (%)</th><th>Second gas</th><th>Antibiotic prophylaxis</th><th>Temp</th><th>Fluids</th></tr></thead><tbody><tr><td>Mayank et al.<sup>33</sup></td><td>India</td><td>RCT Monocenter n = 94</td><td>Colorectal</td><td>6 h</td><td>CDC, Day 30</td><td>FiO<sub>2</sub> 80%: 26/47 (55.3%)<br/>FiO<sub>2</sub> 30%: 19/47 (40.4%)<br/>p = 0.21</td><td>N<sub>2</sub>O</td><td>Yes</td><td>Yes</td><td>15 ml/kg/h</td></tr><tr><td>Alvandipour et al.<sup>34</sup></td><td>Iran</td><td>RCT Monocenter n = 80</td><td>Colorectal</td><td>1 h</td><td>ASEPSIS, 1 month following discharge</td><td>FiO<sub>2</sub> 80%: 2/40 (5%)<br/>FiO<sub>2</sub> 30%: 6/40 (15%)<br/>p < 0.05</td><td>N<sub>2</sub>O</td><td>Yes</td><td>Yes</td><td>6–10 ml/kg/h</td></tr><tr><td>Ferrando et al.<sup>35</sup></td><td>Spain</td><td>RCT Multicenter n = 717</td><td>Abdominal > 2 h</td><td>3 h</td><td>CDC, Day 7 (main outcome) and day 30</td><td>FiO<sub>2</sub> 80%: 31/362 (8.9%)<br/>FiO<sub>2</sub> 30%: 34/355 (9.4%)<br/>p = 0.90<br/>FiO<sub>2</sub> 80%: 52/362 (16.5%)<br/>FiO<sub>2</sub> 30%: 62/355 (19.9%)<br/>p = 0.89</td><td>Air</td><td>Yes (85% of cases)</td><td>NP</td><td>NP</td></tr><tr><td>Li et al.<sup>36</sup></td><td>China</td><td>RCT Monocenter N = 251</td><td>Abdominal > 2 h</td><td>2 h</td><td>CDC, Day 7</td><td>FiO<sub>2</sub> 80%: 12/126 (9.5%)<br/>FiO<sub>2</sub> 30%: 18/125 (14.4%)<br/>RR: 1.51, p = 0.23</td><td>Air</td><td>Yes</td><td>Yes</td><td>8 ml/kg/h</td></tr><tr><td>Lin et al.<sup>38</sup></td><td>China</td><td>RCT Monocenter N = 630</td><td>Abdominal carcinologic 2–5 h</td><td>–</td><td>Wound infection Delay ?</td><td>FiO<sub>2</sub> 80%: 40/316 (12.7%)<br/>FiO<sub>2</sub> 40%: 30/314 (9.6%)<br/>p = 0.74</td><td>Air</td><td>Yes</td><td>Yes</td><td>NP</td></tr><tr><td>Park et al.<sup>37</sup></td><td>Korea</td><td>RCT Monocenter N = 172</td><td>Abdominal surgery</td><td>15 min</td><td>Wound infection requiring re-intervention, During hospitalization</td><td>FiO<sub>2</sub> 60%: 8/87 (9%)<br/>FiO<sub>2</sub> 35%: 4/85 (5%)<br/>p = 0.25</td><td>Air</td><td>Yes</td><td>NP</td><td>NP</td></tr><tr><td>Yerra et al.<sup>39</sup></td><td>India</td><td>RCT Monocenter N = 178</td><td>Emergency abdominal surgery</td><td>2 h</td><td>CDC + microbiological culture</td><td>FiO<sub>2</sub> 80%: 29/85 (34.1%)<br/>FiO<sub>2</sub> 30%: 19/93 (20.4%)</td><td>Air</td><td>Yes</td><td>NP</td><td>NP</td></tr><tr><td>Reiterer et al.<sup>40</sup></td><td>Austria</td><td>RCT Monocenter N = 258</td><td>Major abdominal surgery > 2 h</td><td>2 h</td><td>CDC</td><td>FiO<sub>2</sub> 80%: 20/128 (15.6%)<br/>FiO<sub>2</sub> 30%: 23/130 (17.7%)<br/>p > 0.05</td><td>NA</td><td>NA</td><td>Yes</td><td>2–3 ml/kg baseline + bolus guided by oeso. doppler</td></tr><tr><td>Major Extremity Trauma Research Consortium<sup>41</sup></td><td>USA</td><td>RCT Multicenter N = 1136</td><td>Orthopedic trauma surgery</td><td>2 h</td><td>CDC, Day 182</td><td>FiO<sub>2</sub> 80%: 40/575 (7.0%)<br/>FiO<sub>2</sub> 30%: 60/561 (10.7%)<br/>RR: 0.65 [0.45–0.96]—<br/>p = 0.03</td><td>NA</td><td>Yes</td><td>NP</td><td>NP</td></tr><tr><td>Holse et al.<sup>42</sup></td><td>Denmark</td><td>RCT Multicenter N = 576</td><td>General surgery > 1 h</td><td>2 h</td><td>CDC, Day 30</td><td>FiO<sub>2</sub> 80%: 32/297 (10.8%)<br/>FiO<sub>2</sub> 30%: 32/296 (10.8%)</td><td>NA</td><td>NA</td><td>NA</td><td>2–5 ml/kg/h</td></tr></tbody></table>

**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”<sup>22,23</sup>, and the “low FiO₂ + nitrous oxide” group of Chen’s study<sup>27</sup>; 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
<table><caption>**Table 2.** Summary of the main characteristics and results of the studies including patients under regional anesthesia. O₂ oxygen, SSI surgical site infection, n number, Temp. temperature (i.e. protocol for maintenance of intraoperative normothermia), N₂ nitrogen, N₂O nitrous oxide, AA ambient air, CDC Centers for Disease Control and Prevention, ASEPSIS Additional treatment, Serous discharge, Erythema, Purulent discharge, Separation of deep tissues, Isolation of bacteria, and prolonged Stay in hospital > 14 days, RCT randomized controlled trial.</caption><thead><tr><th>Study</th><th>Country</th><th>Design, n</th><th>Type of surgery</th><th>O<sub>2</sub> duration in PACU</th><th>SSI definition, follow up</th><th>SSI, n (%)</th><th>Second gas</th><th>Antibiotic prophylaxis</th><th>Temp</th><th>Fluids</th></tr></thead><tbody><tr><td>Gardella et al.<sup>43</sup></td><td>USA</td><td>RCT Monocenter n = 143</td><td>Caesarean section under regional anesthesia</td><td>2 h</td><td>Endometritis or wound infection requiring ATB, Day 14</td><td>Mask 15 L/min: FiO<sub>2</sub> 80%: 17/69 (25%) FiO<sub>2</sub> 30%: 10/74 (14%) p = 0.13</td><td>Air</td><td>Yes (at cord clamp)</td><td>NP</td><td>NP</td></tr><tr><td>Scifres et al.<sup>44</sup></td><td>USA</td><td>RCT Monocenter n = 585</td><td>Caesarean section under regional anesthesia</td><td>2 h</td><td>Endometritis or wound infection, Day 30</td><td>10 L/min (FiO<sub>2</sub> 80%): 35/288 (12.2%) 2 L/min (FiO<sub>2</sub> 30%): 26/297 (8.8%) p = 0.18</td><td>Air</td><td>Yes</td><td>NP</td><td>NP</td></tr><tr><td>Admadé et al.<sup>45</sup></td><td>Panama</td><td>RCT Monocenter n = 343</td><td>Caesarean section under regional anesthesia</td><td>2 h</td><td>Wound infection clinical signs, Day 30</td><td>FiO<sub>2</sub> 80%: 9/164 (5.5%) AA: 13/179 (7.3%) p = 0.33</td><td>Air</td><td>Yes</td><td>NP</td><td>NP</td></tr><tr><td>Duggal et al.<sup>46</sup></td><td>USA</td><td>RCT Monocenter n = 831</td><td>Caesarean section under regional anesthesia</td><td>1 h</td><td>CDC (SSI) + Endometritis, Day 45</td><td>10 L/min (FiO<sub>2</sub> 80%): 34/416 (8.2%) 10 L/min (FiO<sub>2</sub> 30%): 34/415 (8.2%) p = 0.89</td><td>Air</td><td>Yes</td><td>NP</td><td>NP</td></tr><tr><td>Williams et al.<sup>47</sup></td><td>USA</td><td>RCT Monocenter n = 160</td><td>Caesarean section under regional anesthesia</td><td>2 h</td><td>CDC (SSI) + endometritis, Day 42</td><td>FiO<sub>2</sub> 80%: 12/83 (14.5%) FiO<sub>2</sub> 30%: 10/77 (13.0%) p = 0.79</td><td>Air</td><td>Yes (at cord clamp)</td><td>NP</td><td>NP</td></tr><tr><td>Fariba et al.<sup>48</sup></td><td>Iran</td><td>RCT Monocenter n = 122</td><td>Caesarean section under regional anesthesia</td><td>6 h</td><td>ASEPSIS, Day 14</td><td>FiO<sub>2</sub> 80%: 0/61 FiO<sub>2</sub> 30%: 1/61 p > 0.05</td><td>Air</td><td>Yes</td><td>NP</td><td>8 ml/kg</td></tr></tbody></table>

abdominal surgeries¹⁹⁻²², ²⁴, ²⁵, ²⁷, ²⁹, ³⁰, ³²⁻⁴⁰ 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).

Discussion

This updated meta-analysis performed on 30 RCT published between 2000 and July 2022 showed no significant benefit of a high FiO₂ on the prevention of SSI when considering all types of surgery and anesthetic modalities. This result is even more robust in patients having caesarean section under epidural or spinal anesthesia, leading to recommend that routine administration of supplemental oxygen to these patients should be avoided, considering the absence of any impact on neither maternal nor fetal prognosis⁴⁹. Focusing on patients operated under general anesthesia, a moderate reduction of the incidence of SSI in the high intraoperative FiO₂ group was observed (RR 0.86, 95%CI 0.75–0.99), however somewhat smaller than that reported by de Jonge et al. on studies from 1990 to 2018 (RR 0.80 [0.64–0.99])⁸. The inclusion of the large ENIGMA study in the analysis, whose sample represented more than one third of the total population included in de Jonge's meta-analysis, may be a source of discussion. Indeed, ENIGMA study, like Mayzler's study²², used nitrous oxide as second gas in the low FiO₂ group and nitrogen in the high FiO₂ group, while it has been suggested that nitrous oxide could impair human immune functions and favor SSI⁵⁰⁻⁵². However, current evidence does not support any relevant clinical effect of nitrous oxide on SSI occurrence⁵³. Consequently, despite an experimental plan not designed originally to assess the role of high vs. low FiO₂ but rather benefits and harms of nitrous oxide, we chose, as previously done by de Jonge et al. to include Myles' and Mayzler's studies in the meta-analysis. One of the advantages of our meta-analysis other the latter is the inclusion of ten new randomized studies published since then³³⁻⁴², representing 4019 additional patients. In addition, we believe de Jonge et al. missed the studies by Chiang et al. (for patients under general
<figure><img src="image_3.png" /><figcaption>**Figure 1.** Flow diagram of study selection.</figcaption></figure>

anesthesia)³¹ and Admadé et al. (for patients under general anesthesia)⁴⁵, yet published within their inclusion period in 2017 and 2013 respectively. Finally, we believe that Kurz's controlled cluster trial should have been included as this design comprised protections against biases very close to studies randomized at patient's level, and provided data based on by far the largest sample of patients. To summarize, our analysis was performed on 30 controlled trials totaling 18,055 patients, compared to 17 studies and 7817 patients in de Jonge's meta-analysis.

For all that, does this result allow us to conclude definitively that a high intraoperative FiO₂ is useful to prevent SSI in intubated patients? We believe that not at all. First, our meta-analysis, as did the previous ones, presents substantial heterogeneity making difficult to take the results at face value. Indeed, some studies included very small samples of less than 100 patients²²,²⁷,³⁰,³¹,³³,³⁴ while others included more than 500 patients²³,²⁴,²⁹,³²,³⁵,³⁸,⁴¹,⁴²,⁴⁴,⁴⁶. The incidence of SSI was also very different among studies, from a few percent in some studies²⁶,³⁰,³²,⁴² to 20% or more in others²¹,²⁴,³¹,³³,³⁹. Differences in the incidence of SSI among studies may also be explained by the heterogeneous control of the confounding risk factors of SSI, such as correct administration of antibiotic prophylaxis, perioperative maintenance of normothermia, amount of fluids infused during the perioperative period, etc. In addition, definitions and times of assessment of SSI may have differed between studies, by using CDC or ASEPSIS definitions or other “home-made” diagnostic criteria; or considering only deep of both superficial and deep SSI. Finally, the surgical site (abdominal vs. extra-abdominal), the surgical approach (laparotomy or laparoscopy), and the indication of surgery (acute vs. planned surgery, carcinologic vs. non-carcinologic surgery) were heterogeneous among studies, while these parameters are known to impact SSI incidence.
<figure><img src="image_4.png" /></figure>

a stopped early before reaching the calculated sample size, b small sample size <100 patients per group, c modified intention-to-treat analysis, d different second gas in the high and low FiO₂ groups, e SSI assessment method not described, f quasi-randomized study with FiO₂ alternated every 2 weeks at the level of the operating-room, g data collected from anesthetic and surgical usual registries (i.e. no specific data collection for the trial) whose accuracy may be questioned, h questionable external validity, including very high or very low incidence of SSI, and/or significant restrictions in the inclusion criteria, i SSI occurrence retrieved retrospectively from medical file.

<caption>**Figure 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.</caption>

Second, beyond the heterogeneity itself, the level of evidence of our meta-analysis, like others on the field, is only low to moderate depending on the considered sub-groups. For patients under general anesthesia, the numerous biases of individual studies (Fig. 1) and the imprecision of the 95%CI around the estimate despite more than 20 studies included in the meta-analysis, led to downgrade the level of evidence. As an example, adding only 5 SSI in the “high FiO₂ group”, out of a total of more than 680 SSI, makes the confidence interval
a

<table><thead><tr><th>Study or Subgroup</th><th>High FiO<sub>2</sub> Events</th><th>Total</th><th>Low FiO<sub>2</sub> Events</th><th>Total</th><th>Weight</th><th>Risk Ratio</th><th>Risk Ratio M-H, Random, 95% CI</th><th>Year</th></tr></thead><tbody><tr><td colspan="9"><strong>1.1.1 General anesthesia</strong></td></tr><tr><td>Greif, 2000</td><td>13</td><td>250</td><td>28</td><td>250</td><td>3.0%</td><td>0.46 [0.25, 0.88]</td><td>2000</td><td></td></tr><tr><td>Pryor, 2004</td><td>20</td><td>80</td><td>9</td><td>80</td><td>2.5%</td><td>2.22 [1.08, 4.58]</td><td>2004</td><td></td></tr><tr><td>Beida, 2005</td><td>22</td><td>148</td><td>35</td><td>143</td><td>4.3%</td><td>0.61 [0.38, 0.98]</td><td>2005</td><td></td></tr><tr><td>Mayzler, 2005</td><td>2</td><td>19</td><td>3</td><td>19</td><td>0.6%</td><td>0.67 [0.13, 3.55]</td><td>2005</td><td></td></tr><tr><td>Myles, 2007</td><td>77</td><td>997</td><td>106</td><td>1015</td><td>7.2%</td><td>0.74 [0.56, 0.98]</td><td>2007</td><td></td></tr><tr><td>Meyhoff, 2009</td><td>131</td><td>685</td><td>141</td><td>701</td><td>8.4%</td><td>0.95 [0.77, 1.18]</td><td>2009</td><td></td></tr><tr><td>Bickel, 2011</td><td>6</td><td>107</td><td>14</td><td>103</td><td>1.7%</td><td>0.41 [0.16, 1.03]</td><td>2011</td><td></td></tr><tr><td>Thibon 2012</td><td>15</td><td>226</td><td>15</td><td>208</td><td>2.6%</td><td>0.92 [0.46, 1.84]</td><td>2012</td><td></td></tr><tr><td>Chen, 2013</td><td>5</td><td>30</td><td>19</td><td>61</td><td>1.8%</td><td>0.54 [0.22, 1.29]</td><td>2013</td><td></td></tr><tr><td>Stall 2013</td><td>14</td><td>119</td><td>19</td><td>116</td><td>3.0%</td><td>0.72 [0.38, 1.36]</td><td>2013</td><td></td></tr><tr><td>Kurz 2015</td><td>45</td><td>285</td><td>42</td><td>270</td><td>5.5%</td><td>1.02 [0.69, 1.49]</td><td>2015</td><td></td></tr><tr><td>Wasnik 2015</td><td>0</td><td>32</td><td>0</td><td>32</td><td></td><td>Not estimable</td><td>2015</td><td></td></tr><tr><td>Chiang, 2017</td><td>6</td><td>19</td><td>7</td><td>18</td><td>1.8%</td><td>0.81 [0.34, 1.96]</td><td>2017</td><td></td></tr><tr><td>Kurz, 2018</td><td>118</td><td>2896</td><td>112</td><td>2853</td><td>7.7%</td><td>1.04 [0.81, 1.34]</td><td>2018</td><td></td></tr><tr><td>Ahvandipour, 2019</td><td>2</td><td>40</td><td>6</td><td>40</td><td>0.7%</td><td>0.33 [0.07, 1.55]</td><td>2019</td><td></td></tr><tr><td>Mayank, 2019</td><td>26</td><td>47</td><td>19</td><td>47</td><td>4.9%</td><td>1.37 [0.89, 2.11]</td><td>2019</td><td></td></tr><tr><td>Ferrando, 2020</td><td>31</td><td>362</td><td>34</td><td>355</td><td>4.5%</td><td>0.89 [0.56, 1.42]</td><td>2020</td><td></td></tr><tr><td>Li, 2020</td><td>12</td><td>126</td><td>18</td><td>125</td><td>2.7%</td><td>0.66 [0.33, 1.31]</td><td>2020</td><td></td></tr><tr><td>Lin, 2021</td><td>40</td><td>316</td><td>30</td><td>314</td><td>4.7%</td><td>1.32 [0.85, 2.07]</td><td>2021</td><td></td></tr><tr><td>Reiterer, 2021</td><td>20</td><td>128</td><td>23</td><td>130</td><td>3.7%</td><td>0.88 [0.51, 1.53]</td><td>2021</td><td></td></tr><tr><td>Park, 2021</td><td>8</td><td>87</td><td>4</td><td>85</td><td>1.1%</td><td>1.95 [0.61, 6.25]</td><td>2021</td><td></td></tr><tr><td>Yerra 2021</td><td>19</td><td>93</td><td>29</td><td>85</td><td>4.2%</td><td>0.60 [0.36, 0.99]</td><td>2021</td><td></td></tr><tr><td>Holse, 2022</td><td>11</td><td>297</td><td>11</td><td>296</td><td>2.0%</td><td>1.00 [0.44, 2.26]</td><td>2022</td><td></td></tr><tr><td>METRC, 2022</td><td>40</td><td>575</td><td>60</td><td>561</td><td>5.6%</td><td>0.65 [0.44, 0.95]</td><td>2022</td><td></td></tr><tr><td><strong>Subtotal (95% CI)</strong></td><td><strong>7964</strong></td><td></td><td><strong>7907</strong></td><td><strong>84.1%</strong></td><td></td><td><strong>0.86 [0.75, 0.99]</strong></td><td></td><td></td></tr><tr><td><strong>Total events</strong></td><td><strong>683</strong></td><td></td><td><strong>784</strong></td><td></td><td></td><td></td><td></td><td></td></tr></tbody></table>

Heterogeneity: $Tau^2 = 0.04; Chi^2 = 37.07, df = 22 (P = 0.02); I^2 = 41\%$
Test for overall effect: $Z = 2.12 (P = 0.03)$

1.1.2 Loco-regional anesthesia

<table><tbody><tr><td>Gardella, 2008</td><td>17</td><td>69</td><td>10</td><td>74</td><td>2.5%</td><td>1.82 [0.90, 3.70]</td><td>2008</td><td></td></tr><tr><td>Sifres 2011</td><td>35</td><td>288</td><td>26</td><td>297</td><td>4.3%</td><td>1.39 [0.86, 2.25]</td><td>2011</td><td></td></tr><tr><td>Admadé, 2013</td><td>12</td><td>83</td><td>10</td><td>77</td><td>2.2%</td><td>1.11 [0.51, 2.43]</td><td>2013</td><td></td></tr><tr><td>Duggal, 2013</td><td>9</td><td>164</td><td>13</td><td>179</td><td>2.0%</td><td>0.76 [0.33, 1.72]</td><td>2013</td><td></td></tr><tr><td>Williams 2013</td><td>34</td><td>416</td><td>34</td><td>415</td><td>4.6%</td><td>1.00 [0.63, 1.57]</td><td>2013</td><td></td></tr><tr><td>Fariba, 2016</td><td>0</td><td>61</td><td>1</td><td>61</td><td>0.2%</td><td>0.33 [0.01, 8.03]</td><td>2016</td><td></td></tr><tr><td><strong>Subtotal (95% CI)</strong></td><td><strong>1081</strong></td><td></td><td><strong>1103</strong></td><td><strong>15.9%</strong></td><td></td><td><strong>1.17 [0.90, 1.52]</strong></td><td></td><td></td></tr></tbody></table>

Total events 107 94
Heterogeneity: $Tau^2 = 0.00; Chi^2 = 4.16, df = 5 (P = 0.53); I^2 = 0\%$
Test for overall effect: $Z = 1.17 (P = 0.24)$

Total (95% CI) 9045 9010 100.00 0.90 [0.79, 1.03]

Total events 790 876
Heterogeneity: $Tau^2 = 0.04; Chi^2 = 45.15, df = 28 (P = 0.02); I^2 = 38\%$
Test for overall effect: $Z = 1.58 (P = 0.11)$

b

<figure><img src="image_5.png" /><figcaption>**Figure 3.** 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.</figcaption></figure>

crossing the identity line, leading to conclude to the absence of significant effect. This highlights the fragility of the conclusions that could be drawn from this unrestricted analysis.

In this context, sensitivity analyses restricted to more homogenous populations may be more informative. Along these lines, no significant effect of a high intraoperative FiO₂ was found for patients operated from abdominal surgeries under general anesthesia; no more than for patients anesthetized without nitrous oxide; or even for the prevention of deep SSI rather than all types of SSI. We believe that this absence of protective effect in these subgroups of interest strongly reduces the potential interest of systematic high intraoperative FiO₂. This becomes even more relevant when considering the results of another recent meta-analysis focusing on the effect of high vs. low intraoperative FiO₂ on respiratory outcomes, which did not report any beneficial effect on clinical outcomes such as hospital length-of-stay or mortality, and on the contrary a higher incidence of postoperative radiographic atelectasis associated with reduced postoperative PaO₂ values⁵⁴.

Finally, our results and others also demonstrate that meta-analyses are not magic tools able to overcome limits or biases presented by individual studies. In this context, considering the results of well-designed, multicenter, adequately powered randomized controlled trials, using the latest ventilatory and SSI prevention standards should be a more relevant approach than swearing by meta-analyses. In that case, the most recent randomized studies reported no difference on the incidence of SSI with high or low FiO₂ in patients undergoing general anesthesia. The PROXI study, the largest multicenter randomized controlled trial specifically designed to assess the role of high vs. low intraoperative FiO₂ on SSI³⁹, did not report any reduction of the incidence of SSI with the administration of 80% FiO₂ during colorectal surgery. Similarly, the recent multicenter randomized iPROVE-O₂ trial that included 740 patients undergoing major abdominal surgery, ventilated intraoperatively with an evidence-based protective strategy, reported a similar SSI rate between the 30% and 80% FiO₂ groups³⁵. Indeed, 80% FiO₂ did not reduce postoperative SSI (8.9% vs 9.4%, RR 0.94 95%CI (0.59–1.50)—p = 0.90), as none of the secondary outcomes including hospital length-of-stay or short-term mortality. We believe that these results from individual high-quality RCT add further weight and reinforce the conclusion that there is no compelling evidence that high FiO₂ can improve postoperative patient's outcome on its own when good SSI prevention practices are properly applied. Consequently, we believe that abrogation of the WHO recommendation on the systematic use of high intraoperative FiO₂ must be seriously discussed.

Methods

This meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The PRISMA checklist is available as a Supplementary file.
<figure><img src="image_6.png" /></figure>

Heterogeneity: Tau² = 0.04; Chi² = 34.14, df = 20 (P = 0.03); I² = 41%

Test for overall effect: Z = 1.57 (P = 0.12)

<figure><img src="image_7.png" /></figure>

Heterogeneity: Tau² = 0.04; Chi² = 28.96, df = 18 (P = 0.05); I² = 38%

Test for overall effect: Z = 1.78 (P = 0.08)

**Figure 4.** 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).

**Registration.** A standard protocol was developed and registered prior to literature search on the PROS-PERO database on June 1st 2021 (registration number CRD42021258279). The protocol is available as a Supplementary file.

**Search strategy.** A search was conducted for studies published between January 1st, 1999 and July, 1st 2022 in MEDLINE (PubMed), CENTRAL (Cochrane), EMBASE (Elsevier) and ClinicalTrials.gov databases. The last search was conducted on July, 5th 2022. The research question was formulated according to the PICO format: in adult patients undergoing general or loco-regional anesthesia (P), does a systematic high intra-operative FiO₂ (> 50%) (I) lead to reduced incidence of surgical site infection (O) compared to low FiO₂ (≤ 50%) (C)? Then, the following search equation was designed: (("Perioperative" [All Fields] OR "intraoperative" [All Fields]) AND ("FiO₂" [All Fields] OR "inspired oxygen fraction" [All Fields] OR "oxygen concentration" [All Fields]) OR ("anaesthesia" [All Fields] OR "anesthesia" [MeSH Terms] OR "anesthesia" [All Fields] OR "anaesthetics" [All Fields] OR "anesthetics" [All Fields] OR "general anesthesia" [All Fields] OR "general anaesthesia" [All Fields]))
<figure><img src="image_8.png" /><figcaption>**Figure 5.** Sensitivity analysis of high vs. low intraoperative $FiO_2$ 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.</figcaption></figure>

<figure><img src="image_9.png" /><figcaption>**Figure 6.** Sensitivity analysis of high versus low intraoperative $FiO_2$ 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.</figcaption></figure>

AND ("surgical wound infection" [MeSH Terms] OR ("surgical" [All Fields] AND "wound" [All Fields] AND "infection" [All Fields]) OR "surgical wound infection" [All Fields] OR ("surgical" [All Fields] AND "site" [All Fields] AND "infection" [All Fields]) OR "surgical site infection" [All Fields]) OR ("outcomes" [All Fields] OR "adverse effects" [All Fields] OR "adverse events" [All Fields] OR "death" [All Fields]) AND ("pulmonary complications" [All Fields] OR "atelectasis" [All Fields]). Only randomized studies (including quasi-randomized studies and cluster-randomized studies in which the intervention was not randomized at the patient level but by day, week or specific operating theatre) were included in this meta-analysis. In addition, the references of the selected articles were also screened to complete the search. Finally, the PubMed "similar article" and "citing article" functions were used to expand the search.

**Study selection.** Two authors (Y.E. and M.G.) independently screened the titles and abstracts retrieved from the systematic search for potential eligibility. In case of discrepancy, the eligibility was discussed with a
third author (C.F). To be considered for analysis, publications had to be written in English or in French. When the title and abstract indicated potential eligibility, the full-text article was analysed. The PRISMA flow diagram of study selection is presented in Fig. 1.

**Data extraction and analysis.** For each study, a first reviewer extracted the following data: first author, year of publication, study location, type of study, population studied, type of surgery, primary and secondary outcomes selected, and main results. Potential confounding factors that may influence the selected outcomes (for example the perioperative use of antibiotics, the composition of the inspired gas mixture, the use of a protocol to avoid perioperative hypothermia, etc.) were reported. A second reviewer checked independently the extracted data. In case of discrepancy, the data were discussed with a third reviewer and a consensus decision was made. Study sample size and the relevance of the research were considered at the level of each study. Then, the methodological quality of studies was rated with the Oxford quality scoring system considering the SSI outcome¹⁹.

**Meta-analysis.** A quantitative review of the extracted data was made for the judgment criterion (i.e. incidence of SSI). This primary outcome was expressed using the pooled relative risk with its 95% confidence interval (RR 95%CI). A DerSimonian and Laird random-effects model of meta-analysis was used to account for potential clinical and statistical heterogeneity. The $\chi^2$ test for heterogeneity was computed and the amount of heterogeneity was quantified by the $I^2$ statistic. The extent of heterogeneity was evaluated using the between-study variance ($\tau^2$). Sensitivity analyses including only (1) studies using the same second gas in both the high and low $FiO_2$ groups, and (2) studies using nitrogen or room air as second gas in both the high and low $FiO_2$ groups (i.e. not including studies that used nitrous oxide as second gas) were planned. Then, sensitivity analyses regarding the type of surgery (abdominal vs. non abdominal), and the type of SSI (deep vs. superficial) were also performed. According to the CDC definition, SSI were considered as “deep SSI” if they were classified as “deep” or “organ/space”.

Eventually, publication bias was evaluated by a visual inspection of funnel plots and assessed with Egger's regression test and the rank correlation test for funnel plot asymmetry. Statistical analyses were performed using Review Manager (RevMan) 5.4.1 (Cochrane Collaboration, The Nordic Cochrane Centre, Copenhagen, Denmark) and Jamovi 2.0 (The Jamovi Project).

**Quality of evidence.** The certainty of the overall evidence for the potential association between the use of high vs. low $FiO_2$ and SSI incidence was evaluated using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology, and reported as “very low”, “low”, “moderate” or “high” taking into account study limitations, inconsistency of evidence, indirectness of evidence and reporting bias³⁵.

**Data availability**

All data generated or analyzed during this study are included in this published article and its supplementary information files.

Received: 15 November 2021; Accepted: 4 January 2023

Published online: 11 February 2023

**References**

1. WHO. Web appendix 13a: summary of the systematic review on perioperative oxygenation. Global guidelines for the prevention of surgical site infection (2016).

2. WHO. Global guidelines for the prevention of surgical site infection—2016 (2016).

3. LAS Vegas investigators. Epidemiology, practice of ventilation and outcome for patients at increased risk of postoperative pulmonary complications: LAS VEGAS - an observational study in 29 countries. *Eur. J. Anaesthesiol.* **34**, 492–507. https://doi.org/10.1097/EJA.0000000000000646 (2017).

4. Morkane, C. M. et al. Intraoperative oxygenation in adult patients undergoing surgery (iOPS): A retrospective observational study across 29 UK hospitals. *Perioper. Med. Lond. Engl.* **7**, 17. https://doi.org/10.1186/s13741-018-0098-3 (2018).

5. Karalapillai, D. et al. Frequency of hyperoxaemia during and after major surgery. *Anaesth. Intensive Care* **48**, 213–220. https://doi.org/10.1177/0310057X20905320 (2020).

6. Cohen, B. et al. Effect of intraoperative hyperoxia on the incidence of surgical site infections: A meta-analysis. *Br. J. Anaesth.* **120**, 1176–1186. https://doi.org/10.1016/j.bja.2018.02.027 (2018).

7. WHO. Global Guidelines for the Prevention of Surgical Site Infection—2018 (2018).

8. de Jonge, S. et al. Effectiveness of 80% vs 30–35% fraction of inspired oxygen in patients undergoing surgery: An updated systematic review and meta-analysis. *Br. J. Anaesth.* **122**, 325–334. https://doi.org/10.1016/j.bja.2018.11.024 (2019).

9. Mattishent, K. et al. Safety of 80% vs 30–35% fraction of inspired oxygen in patients undergoing surgery: A systematic review and meta-analysis. *Br. J. Anaesth.* **122**, 311–324. https://doi.org/10.1016/j.bja.2018.11.026 (2019).

10. Hovaguimian, F., Elia, N. & Tramër, M. R. Supplemental oxygen and the risk of surgical site infection: Evidence of compromised data requires correction of previously published meta-analysis. *Anesthesiology* **131**, 932–933. https://doi.org/10.1097/ALN.0000000000002897 (2019).

11. Schietroma, M. et al. High-concentration supplemental perioperative oxygen and surgical site infection following elective colorectal surgery for rectal cancer: A prospective, randomized, double-blind, controlled, single-site trial. *Am. J. Surg.* **208**, 719–726. https://doi.org/10.1016/j.amjsurg.2014.04.002 (2014).

12. Schietroma, M. et al. RETRACTED: How does high-concentration supplemental perioperative oxygen influence surgical outcomes after thyroid surgery? A prospective, randomized, double-blind, controlled, monocentric trial. *J. Am. Coll. Surg.* **220**, 921–933. https://doi.org/10.1016/j.jamcollsurg.2015.01.046 (2015).

13. Schietroma, M. et al. Colorectal Infraperitoneal anastomosis: The effects of perioperative supplemental oxygen administration on the anastomotic dehiscence. *J. Gastrointest. Surg. Off. J. Soc. Surg. Aliment. Tract.* **16**, 427–434. https://doi.org/10.1007/s11605-011-1717-1 (2012).
14. Schietroma, M. et al. Prevention of anastomotic leakage after total gastrectomy with perioperative supplemental oxygen administration: A prospective randomized, double-blind, controlled, single-center trial. *Ann. Surg. Oncol.* **20**, 1584–1590. https://doi.org/10.1245/s10434-012-2714-7 (2013).

15. Schietroma, M. et al. supplemental peri-operative oxygen and incision site infection after surgery for perforated peptic ulcer: A randomized, Double-Blind Monocentric Trial. *Surg. Infect.* **17**, 106–113. https://doi.org/10.1089/sur.2013.132 (2016).

16. Schietroma, M. et al. Effect of high perioperative oxygen fraction on surgical site infection following surgery for acute sigmoid diverticulitis. A prospective, randomized, double blind, controlled, Monocentric Trial. *Chir. Buchar. Rom.* **111**, 242–250 (2016).

17. Myles, P. S., Carlisle, J. B. & Scarr, B. Evidence for compromised data integrity in studies of liberal peri-operative inspired oxygen. *Anaesthesia* **74**, 573–584. https://doi.org/10.1111/anae.14584 (2019).

18. Anthony, T. et al. Evaluating an evidence-based bundle for preventing surgical site infection: A randomized trial. *Arch. Surg. Chic Ill* **2011**(146), 263–269. https://doi.org/10.1001/archsurg.2010.249 (1960).

19. Greif, R., Akça, O., Horn, E.-P., Kurz, A. & Sessler, D. I. Supplemental perioperative oxygen to reduce the incidence of surgical-wound infection. *N Engl J. Med.* **342**, 161–167. https://doi.org/10.1056/NEJM200001203420303 (2000).

20. Pryor, K. O., Fahey, T. J., Lien, C. A. & Goldstein, P. A. Surgical site infection and the routine use of perioperative hyperoxia in a general surgical population: a randomized controlled trial. *JAMA* **291**, 79–87. https://doi.org/10.1001/jama.291.1.79 (2004).

21. Belda, F. J. et al. Supplemental perioperative oxygen and the risk of surgical wound infection: a randomized controlled trial. *JAMA* **294**, 2035–2042. https://doi.org/10.1001/jama.294.16.2035 (2005).

22. Mayzler, O. et al. Does supplemental perioperative oxygen administration reduce the incidence of wound infection in elective colorectal surgery? *Minerva Anestesiol.* **71**, 21–25 (2005).

23. Myles, P. S. et al. Avoidance of nitrous oxide for patients undergoing major surgery: a randomized controlled trial. *Anesthesiology* **107**, 221–231. https://doi.org/10.1097/01.anes.0000270723.30772.da (2007).

24. Meyhoff, C. S. et al. Effect of high perioperative oxygen fraction on surgical site infection and pulmonary complications after abdominal surgery: The PROXI randomized clinical trial. *JAMA* **302**, 1543–1550. https://doi.org/10.1001/jama.2009.1452 (2009).

25. Bickel, A., Gurevits, M., Vamos, R., Ivry, S. & Eitan, A. Perioperative hyperoxygenation and wound site infection following surgery for acute appendicitis: a randomized, prospective, controlled trial. *Arch. Surg. Chic Ill* **2011**(146), 464–470. https://doi.org/10.1001/archsurg.2011.65 (1960).

26. Thibon, P. et al. Effect of perioperative oxygen supplementation on 30-day surgical site infection rate in abdominal, gynecologic, and breast surgery: The ISO2 randomized controlled trial. *Anesthesiology* **117**, 504–511. https://doi.org/10.1097/ALN.0b013e3182 632341 (2012).

27. Chen, Y. et al. Leukocyte DNA damage and wound infection after nitrous oxide administration: A randomized controlled trial. *Anesthesiology* **118**, 1322–1331. https://doi.org/10.1097/ALN.0b013e31829107b8 (2013).

28. Stall, A. et al. Perioperative supplemental oxygen to reduce surgical site infection after open fixation of high-risk fractures: A randomized controlled pilot trial. *J. Trauma Acute Care Surg.* **75**, 657–663. https://doi.org/10.1097/TA.0b013e3182a1fe83 (2013).

29. Kurz, A. et al. Effects of supplemental oxygen and dexamethasone on surgical site infection: a factorial randomized trial§. *Br. J. Anaesth.* **115**, 434–443. https://doi.org/10.1093/bja/aev062 (2015).

30. Wasnik, N., Agrawal, V., Yede, J., Gupta, A. & Soitkar, S. Role of supplemental oxygen in reducing surgical site infection in acute appendicitis: Our experience of sixty four cases. *Int. J. Biomed. Adv. Res.* **15**, 6 (2015).

31. Chiang, N., Rodda, O. A., Sleigh, J. & Vasudevan, T. Perioperative warming, oxygen, and llomedin on oxygenation and healing in infrainguinal bypass surgery. *J. Surg. Res.* **220**, 197–205. https://doi.org/10.1016/j.jss.2017.06.043 (2017).

32. Kurz, A. et al. Supplemental oxygen and surgical-site infections: an alternating intervention controlled trial. *Br. J. Anaesth.* **120**, 117–126. https://doi.org/10.1016/j.bja.2017.11.003 (2018).

33. Mayank, M., Mohsina, S., Sureshkumar, S., Kundra, P. & Kate, V. Effect of perioperative high oxygen concentration on postoperative SSI in elective colorectal surgery-a randomized controlled trial. *J. Gastrointest. Surg. Off. J. Soc. Surg. Aliment. Tract.* **23**, 145–152. https://doi.org/10.1007/s11605-018-3996-2 (2019).

34. Alvandipour, M., Mokhtari-Esbue, F., Baradari, A. G., Firouzian, A. & Rezaie, M. Effect of hyperoxygenation during surgery on surgical site infection in colorectal surgery. *Ann. Coloproctology* **35**, 9–14. https://doi.org/10.3393/ac.2018.01.16 (2019).

35. Ferrando, C. et al. Effects of oxygen on post-surgical infections during an individualised perioperative open-lung ventilatory strategy: a randomised controlled trial. *Br. J. Anaesth.* **124**, 110–120. https://doi.org/10.1016/j.bja.2019.10.009 (2020).

36. Li, X.-F. et al. Comparison of low and high inspiratory oxygen fraction added to lung-protective ventilation on postoperative pulmonary complications after abdominal surgery: A randomized controlled trial. *J. Clin. Anesth.* **67**, 110009. https://doi.org/10. 1016/j.jclinane.2020.110009 (2020).

37. Park, M. et al. Perioperative high inspired oxygen fraction induces atelectasis in patients undergoing abdominal surgery: A randomized controlled trial. *J. Clin. Anesth.* **72**, 110285. https://doi.org/10.1016/j.jclinane.2021.110285 (2021).

38. Lin, X. et al. Intraoperative oxygen concentration and postoperative delirium after laparoscopic gastric and colorectal malignancies surgery: a randomized, double-blind, Controlled Trial. *Clin. Interv. Aging* **16**, 1085–1093. https://doi.org/10.2147/CIA.S3111 90 (2021).

39. Yerra, P. et al. Effect of peri-operative hyperoxygenation on surgical site infection in patients undergoing emergency abdominal surgery: a randomized controlled trial. *Surg. Infect.* **22**, 1052–1058. https://doi.org/10.1089/sur.2021.005 (2021).

40. Reiterer, C. et al. Perioperative supplemental oxygen and NT-proBNP concentrations after major abdominal surgery—A prospective randomized clinical trial. *J. Clin. Anesth.* **73**, 110379. https://doi.org/10.1016/j.jclinane.2021.110379 (2021).

41. Major Extremity Trauma Research Consortium (METRC). Effect of Supplemental Perioperative Oxygen on SSI Among Adults with Lower-Extremity Fractures at Increased Risk for Infection: A Randomized Clinical Trial. *J Bone Joint Surg Am* **2022**. https://doi.org/10.2106/JBJS.21.01317.

42. Holse, C. et al. Hyperoxia and antioxidants for myocardial injury in noncardiac surgery: A 2 × 2 factorial, blinded, randomized clinical trial. *Anesthesiology* **136**, 408–419. https://doi.org/10.1097/ALN.0000000000004117 (2022).

43. Gardella, C. et al. High-concentration supplemental perioperative oxygen to reduce the incidence of postcesarean surgical site infection: a randomized controlled trial. *Obstet. Gynecol.* **112**, 545–552. https://doi.org/10.1097/AOG.0b013e318182340c (2008).

44. Scifres, C. M., Leighton, B. L., Fogertey, P. J., Macones, G. A. & Stamilio, D. M. Supplemental oxygen for the prevention of post cesarean infectious morbidity: a randomized controlled trial. *Am. J. Obstet. Gynecol.* **205**(267), e1-9. https://doi.org/10.1016/j.ajog. 2011.06.038 (2011).

45. Admadé, B. & Reyes, O. Supplemental perioperative oxygen (80% FIO₂) for the prevention of surgical site infection after emergency cesarean section. *ISRN Infect. Dis.* **2013**, 1–4. https://doi.org/10.5402/2013/526163 (2013).

46. Duggal, N., Poddatorri, V., Noroozkhani, S., Siddik-Ahmad, R. I. & Caughey, A. B. Perioperative oxygen supplementation and surgical site infection after cesarean delivery: a randomized trial. *Obstet. Gynecol.* **122**, 79–84. https://doi.org/10.1097/AOG.0b013 e318297ec6c (2013).

47. Williams, N. L., Glover, M. M., Crisp, C., Acton, A. L. & Mckenna, D. S. Randomized controlled trial of the effect of 30% versus 80% fraction of inspired oxygen on cesarean delivery surgical site infection. *Am. J. Perinatol.* **30**, 781–786. https://doi.org/10. 1055/s-0032-1333405 (2013).

48. Fariba, F., Loghman, G., Daem, R., Dina, S. & Jamal, S. Effect of supplemental oxygen on the incidence and severity of Wound Infection after cesarean surgery. *J. Chem. Pharm. Sci.* **9**, 3320–3325 (2016).
49. Chatmongkolchart, S. & Prathep, S. Supplemental oxygen for caesarean section during regional anaesthesia. *Cochrane Database Syst. Rev.* **3**, CD006161. https://doi.org/10.1002/14651858.CD006161.pub3 (2016).

50. Skacel, P. O. et al. Studies on the haemopoietic toxicity of nitrous oxide in man. *Br. J. Haematol.* **53**, 189–200. https://doi.org/10.1111/j.1365-2141.1983.tb02011.x (1983).

51. Fröhlich, D. et al. Nitrous oxide impairs the neutrophil oxidative response. *Anesthesiology* **88**, 1281–1290. https://doi.org/10.1097/0000542-199805000-00020 (1998).

52. Schneemilch, C. E., Hachenberg, T., Ansorge, S., Ittenson, A. & Bank, U. Effects of different anaesthetic agents on immune cell function in vitro. *Eur. J. Anaesthesiol.* **22**, 616–623. https://doi.org/10.1017/s0265021505001031 (2005).

53. Sun, R. et al. Nitrous oxide-based techniques versus nitrous oxide-free techniques for general anaesthesia. *Cochrane Database Syst. Rev.* **2015**, CD008984. https://doi.org/10.1002/14651858.CD008984.pub2 (2015).

54. Lim, C.-H. et al. Effects of high versus low inspiratory oxygen fraction on postoperative clinical outcomes in patients undergoing surgery under general anesthesia: A systematic review and meta-analysis of randomized controlled trials. *J. Clin. Anesth.* **75**, 110461. https://doi.org/10.1016/j.jclinane.2021.110461 (2021).

55. Guyatt, G. H. et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. *BMJ* **336**, 924–926. https://doi.org/10.1136/bmj.39489.470347.AD (2008).

## Acknowledgements

We would like to thank Pr Olivier Huet from the Anesthesiology and Critical Care Medicine Department of Brest University Hospital for his assistance with the study.

## Author contributions

Y.E.M.: conceptualization, investigation, writing—original draft. C.F.: conceptualization, investigation, writing—review and editing. C.Q.: conceptualization, supervision, writing—review and editing. M.G.: conceptualization, investigation, supervision, methodology, formal analysis, writing—original draft, writing—review and editing.

## Competing interests

The authors declare no competing interests.

## Additional information

**Supplementary Information** The online version contains supplementary material available at https://doi.org/10.1038/s41598-023-27588-2.

**Correspondence** and requests for materials should be addressed to M.G.

**Reprints and permissions information** is available at www.nature.com/reprints.

**Publisher's note** Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

<figure><img src="image_10.png" /></figure>

**Open Access** This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

© The Author(s) 2023