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The Role of Perioperative High Inspired Oxygen Therapy in Reducing Surgical Site Infection: A Meta-Analysis

Togioka, Brandon MD; Galvagno, Samuel DO; Sumida, Shawn MD; Murphy, Jamie MD; Ouanes, Jean-Pierre DO; Wu, Christopher MD

doi: 10.1213/ANE.0b013e31823fada8
Patient Safety: Research Reports

BACKGROUND: The clinical role of hyperoxia for preventing surgical site infection remains uncertain because randomized controlled trials on this topic have reported disparate results. Our objective in this systematic review was to determine whether perioperative hyperoxia reduces surgical site infection.

METHODS: An electronic search was conducted using the National Library of Medicine's MEDLINE, Cochrane Collaboration's CENTRAL, and EMBASE databases. Included studies consisted of randomized controlled trials in an adult population with a clearly defined comparison of high oxygen versus low oxygen or control, and with a documented assessment for perioperative infection. Pooled estimates for odds ratios (ORs) with 95% confidence intervals were obtained for our primary outcome (surgical site infection) using the Cochrane Collaboration's RevMan version 5.0.25 (Cochrane Collaboration, Oxford, UK). ORs were calculated using a random effects model.

RESULTS: The literature search ultimately yielded 7 trials, enrolling 2728 patients, that were included in the analysis. There were 1358 patients randomly assigned to hyperoxia and 1370 to control. The pooled infection rate in the hyperoxia group was 15.5% versus 17.5% in the control group. Hyperoxia resulted in an OR of 0.85 for surgical site infection (95% confidence interval: 0.52, 1.38) (P = 0.51). However, 2 subgroup analyses (general anesthesia and colorectal surgery trials) showed a benefit for high inspired oxygen therapy of decreasing surgical site infection.

CONCLUSIONS: Perioperative high inspired oxygen therapy overall was not found to be beneficial for preventing surgical site infection based on this meta-analysis. The positive results of 2 subgroup analyses (general anesthesia and colorectal surgery trials) suggest a benefit for hyperoxia in decreasing surgical site infection. Additional studies are needed to further investigate this intervention.

Published ahead of print December 9, 2011 Supplemental Digital Content is available in the text.

From the Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University, Baltimore, Maryland.

Supported by the Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University.

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Christopher Wu, MD, Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University, Carnegie 280, 600 North Wolfe St., Baltimore, MD 21287. Address e-mail to chwu@jhmi.edu.

Accepted October 24, 2011

Published ahead of print December 9, 2011

With the advent of “pay for performance” medicine, surgical site infections have become a timely topic for anesthesiologists and surgeons in part because it is an easily measurable quality outcome in the estimated 45 million inpatient surgical procedures performed in the United States annually.1 Advances have been made in understanding the link between surgical site infection and perioperative normoglycemia, normothermia, and appropriate prophylactic antibiotic use. Despite these advances, surgical site infection remains one of the most common nosocomial infections among surgical patients, accounting for 17% of all hospital-acquired infections.2 Surgical site infections are associated with increased health care cost, increased morbidity, and prolonged hospitalization.3

The risk of infection at a surgical site is related to the number of bacteria that reach the surgical wound and the body's ability to kill those bacteria within the first few hours of the wound-healing process.4 The oxidative killing of bacteria by neutrophils has been shown to be one of the major defenses used by the body to kill those bacteria that reach the surgical wound.5,6 The leukocyte killing rate can be substantially impaired when leukocytes are placed in a low oxygen environment, such as that often found in wound tissue, where the local microvascular supply is disrupted by surgical trauma, thrombosis, or edema.7 It was hypothesized that increasing tissue oxygen tension within surgical wounds might enhance neutrophil killing capacity, thus resulting in reduced rates of surgical site infection.7 Some randomized controlled trials examining the potential beneficial effect of supplemental perioperative oxygen administration showed a statistically significant reduction in surgical site infection when high inspired oxygen therapy was used.810 Previous meta-analyses of randomized controlled trials in this area11,12 found that high inspired oxygen therapy was helpful in reducing the incidence of surgical site infection; however, some randomized controlled trials1315 published subsequent to these meta-analyses indicated no benefit from perioperative high inspired oxygen therapy in decreasing surgical site infection. Based on these inconclusive results, the clinical role of hyperoxia for preventing surgical site infection remains undecided. The objective of this systematic review was to determine whether perioperative hyperoxia reduces surgical site infection.

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METHODS

The aim of this study was to identify all relevant randomized controlled trials evaluating the role of hyperoxia compared with low oxygen or controls in the prevention of surgical site infection. An electronic search was conducted on July 12, 2010 using the National Library of Medicine's MEDLINE database (Appendix 1). In addition, the Cochrane Collaboration's CENTRAL database, the EMBASE database, and the authors' own personal files were searched. Searches were limited to human adults; however, there were no language restrictions. Inclusion and exclusion criteria were determined a priori. The search process was conducted iteratively, until no duplicate citations were found in the reference lists of the included articles. Included studies consisted of randomized controlled trials in an adult population with a clearly defined comparison of high oxygen versus low oxygen or control, with a documented assessment for perioperative infection. Hyperbaric ventilation studies were excluded, because the current review sought to determine the effect of hyperoxia that could be achieved at 1 atmosphere pressure only. Case reports, review articles, editorials, comments, and abstracts without sufficient detail for analysis were excluded. This analysis was conducted in accordance with the guidelines published by the QUOROM (Quality of Reporting of Meta-analyses).16

Data extraction was completed by 2 independent reviewers (BT and SS) who were given full-text versions of each article. There were no disagreements in data extraction for the variables analyzed in this meta-analysis. Data were extracted using a standard scoring sheet that was created before the literature search was completed. The primary outcome variable was the incidence of surgical site infection. Study quality was assessed for all articles by scoring each trial for both a Cochrane Quality17 and Jadad Score.18 Both the diagnostic criteria used to define surgical site infection and the time elapse allowed between date of surgery and diagnosis of surgical site infection varied among studies.

Pooled estimates for odds ratios (ORs) with 95% confidence intervals (CIs) were obtained for the primary outcome (surgical site infection) using the Cochrane Collaboration's RevMan version 5.0.25 (Cochrane Collaboration, Oxford, UK). ORs were calculated using a random effects model. Heterogeneity was assessed by the Cochrane Q statistic and calculation of an I2 value with thresholds for low (25%–49%), moderate (50%–74%), and high (>75%) levels.19 Sensitivity analyses were performed to evaluate the effect of excluding the largest study, the opposite study, the lowest quality study, studies that included nitrous oxide, studies that mandated aggressive fluid management, studies that mandated conservative fluid management, studies that included neuraxial anesthesia, and studies that involved patients undergoing noncolorectal procedures. Publication bias was assessed by calculating a funnel plot of standard error of the log of the OR (y-axis) as a function of log of the OR (x-axis). A 2-sided P value ≤0.05 was considered significant.

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RESULTS

The initial literature search produced 658 citations (Fig. 1). After screening titles and abstracts, this list was narrowed to 9 articles. A search of references did not yield any additional studies that met criteria for inclusion. One article20 was excluded because it was noted that it did not assess perioperative infection. Another article21 was excluded because the inspired oxygen (28%) in the hyperoxia group was lower than that of the control group (30%). A third article10 was excluded because it was designed to test the avoidance of nitrous oxide with no primary intention to investigate the delivery of high inspired oxygen therapy in the perioperative period. Before submission of the review for publication, but after the initial literature search, 1 additional article that met all inclusion criteria was published.15 This trial was included for qualitative and quantitative synthesis.

Figure 1

Figure 1

Characteristics of the included trials are described in Tables 1 and 2. In the 7 trials included for analysis, the interval period allowed for diagnosis of surgical site infection varied from 2 weeks to 1 month after the surgical date. Criteria for the diagnosis of surgical site infection also varied among trials. Definitions for surgical site infection varied from wound purulence with a positive culture, to findings that supported a change in management or a particular score using the ASEPSIS scoring system.22 The hyperoxia group in each trial received 80% oxygen. The control group was given between 30% and 35% oxygen. Three of the 7 included trials were multicentered and were conducted in Europe or across multiple continents. Studies tended to focus on operations involving the abdominopelvic region. All studies included postoperative hyperoxia for at least 2 hours after surgery, with 1 study continuing oxygenation for 6 hours.8 Nitrous oxide was used in 3 studies.15,23,24

Table 1

Table 1

Table 2

Table 2

A total of 2728 patients were pooled from the 7 included trials: 1358 were randomized to hyperoxia and 1370 were randomized to control. The pooled infection rate in the hyperoxia group was 15.5% whereas the infection rate was 17.5% in the control group. As shown in Figure 2, hyperoxia resulted in an OR of 0.85 for surgical site infection (95% CI: 0.52, 1.38; P = 0.51). A sensitivity analysis was performed to find whether excluding the largest study, the opposite study, the lowest quality study, studies that included nitrous oxide, studies that mandated aggressive fluid management, or studies that mandated conservative fluid management would have a significant effect on the results of the meta-analysis (Fig. 3). In none of these subgroup analyses did the results differ from our overall finding that hyperoxia was not associated with reduced rates of surgical site infection. When studies that included neuraxial anesthesia were excluded, a significant benefit from hyperoxia was observed (OR = 0.66; 95% CI: 0.46, 0.93; P = 0.02) (Fig. 4) (see Appendix 2 for further discussion). A subgroup analysis of patients undergoing colorectal surgery also showed a significant benefit from hyperoxia (OR = 0.48; 95% CI: 0.32, 0.71; P = 0.0003) (Fig. 5).

Figure 2

Figure 2

Figure 3

Figure 3

Figure 4

Figure 4

Figure 5

Figure 5

To assess for publication bias, a funnel plot was constructed by graphing the log of the OR and the standard error of the log of the OR as the x- and y-axis, respectively. As shown in Figure 6, an inverted and symmetric funnel was observed, centered around a value of 1 on the x-axis, indicating a low potential for publication bias. Heterogeneity was assessed in our meta-analysis with an I2 value of 70% (P = 0.003) (Fig. 2).

Figure 6

Figure 6

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DISCUSSION

Our systematic review and meta-analysis did not find evidence that supplemental oxygen reduced surgical site infection when all published trials comparing hyperoxia with control were included; however, a post hoc analysis showed that based on the sample size available, the study was underpowered to detect the 2% (17.5%–15.5%) absolute risk reduction that we found. This finding is in contrast to prior meta-analyses performed on this topic.11,12 Al-Niaimi and Safdar11 found that high inspired perioperative oxygen therapy was associated with a reduced rate of surgical site infection (relative risk [RR] = 0.70; 95% CI: 0.52, 0.94). However, the degree of heterogeneity in this study was high (I2 = 77%), and not accounted for. One way of dealing with unexplained heterogeneity is to incorporate it into a random effects model, which, for any group of trials with heterogeneity, may potentially result in a larger CI (i.e., a more conservative estimate). When a random effects model was used, the result was no longer statistically significant (RR = 0.74; 95% CI: 0.39, 1.43).

A meta-analysis by Qadan et al.12 similarly found a benefit in decreasing surgical site infection when perioperative high inspired oxygen therapy was given (RR = 0.74; 95% CI: 0.60, 0.92). This meta-analysis included a trial by Myles et al.10 in which there was no primary intention to supplement oxygen. Myles et al. devised their study to evaluate whether avoidance of nitrous oxide may shorten hospital length of stay and decrease postoperative complications such as surgical site infection. Supplemental oxygen was given in this study to most of the patients enrolled; however, it was a secondary effect that led to those not receiving nitrous oxide to receive high inspired oxygen therapy. When the Myles et al.10 study was excluded, the results were no longer statistically significant (RR = 0.74; 95% CI: 0.53, 1.04).12

The pooled surgical site infection rates of 15.5% and 17.5% in the hyperoxia and control groups, respectively, are nearly double the rates published by the National Healthcare Safety Network.25 Some of the discrepancy in rates may be related to the use of varying definitions for surgical site infection. For instance, the National Healthcare Safety Network excludes stitch abscesses from their definition26 whereas all of the trials included in our meta-analysis, with the exception of the trial by Meyhoff et al.,14 have a definition that is potentially inclusive of stitch abscesses. Furthermore, the mix of surgical cases varies between our meta-analysis and the National Healthcare Safety Network because our meta-analysis included more gastrointestinal procedures, which tend to be associated with higher rates of infection.

Multiple subgroup analyses were completed and the results of each of these analyses were consistent with our overall finding that hyperoxia is not associated with reduced rates of surgical site infection. The exclusion of trials that provided nitrous oxide to patients was considered because nitrous oxide has been shown to both directly suppress cell-mediated immunity and interfere with vitamin B12 and folate metabolism, leading to impaired DNA synthesis, both of which could, at least theoretically, contribute to increased rates of surgical site infection.27 We did not find that the inclusion of trials that involved nitrous oxide significantly affected the results of our meta-analysis. An evaluation of trials based on fluid management strategies was considered because both hypovolemia and overadministration of crystalloid can affect surgical site infection.28 Hypovolemia decreases blood flow to wounds, and wound hypoperfusion has been shown to aggravate infections in animals.28 Moreover, edema can prohibit oxygen delivery. We did not find evidence that the fluid management strategy significantly affected the results of our meta-analysis.

Interestingly, a subgroup analysis of trials in which patients were not given neuraxial anesthesia showed a significant benefit for hyperoxia decreasing surgical site infection. A recently published study by Chang et al.29 noted a significant correlation between the use of general (versus neuraxial) anesthesia and an increase in surgical site infection in patients having total hip or knee replacements (OR = 2.21; 95% CI: 1.25, 3.90). Although further investigation of this topic is needed (it seems that patients who received general anesthesia may have had longer procedures predisposing them to infection), Sessler30 proposes multiple mechanisms for how regional anesthesia may decrease rates of surgical site infection: neuraxial anesthesia may attenuate the inflammatory response to surgery, may improve wound perfusion via direct peripheral vasodilatation, and may provide superior analgesia thus possibly decreasing catecholamine-associated peripheral vasoconstriction. It is hypothesized that neuraxial anesthesia alone may increase tissue perfusion and tissue oxygen tension, allowing greater numbers of more effective neutrophils to migrate to the site of a surgical wound. Including such patients in a trial comparing differing levels of inspired oxygen may make it difficult to find a statistically significant benefit from high inspired oxygen therapy.

A subgroup analysis of trials in which patients underwent only colorectal surgery also showed a significant benefit of hyperoxia in decreasing surgical site infection. This result is in contrast to the findings published by Brar et al.31 Some of the discrepancy in results can be attributed to the inclusion of an additional study (Bickel et al.15) in our analysis as well as the exclusion of the trial by Myles et al.10 As discussed earlier, the study by Myles et al.10 was not designed with the primary intention of supplementing oxygen, and thus may have clouded the interpretation of any meta-analysis designed to investigate the effect of varying oxygen levels on surgical site infection. It is unclear why the colorectal patient population would stand to benefit more from hyperoxia than the general surgical population. More likely than a unique response to hyperoxia in this surgical population is the higher likelihood of finding a statistical benefit secondary to higher rates of surgical site infection in the colorectal surgical population.32 Colorectal surgery is a “clean-contaminated” procedure in which a surgical wound is exposed to a significant bacterial load. Starting with a higher baseline rate for surgical site infection would increase the power of a study to find a benefit from high inspired oxygen therapy.

The trial by Pryor et al.24 deserves attention because the findings suggested that hyperoxia was associated with a higher rate of surgical site infection. There are several possible explanations for this result. First, a higher body mass index was found in the group receiving a high fraction of inspired oxygen. Obesity decreases wound oxygen tensions, results in lower prophylactic antibiotic tissue concentrations, and predisposes toward more difficult hygienic practices in the hospital, all of which may theoretically lead to an increased rate of surgical site infection.33 Second, patients assigned to the 80% oxygen group had longer operations, lost more blood, and required larger fluid administration; these factors tend to increase the chance of developing a surgical site infection.24 Lastly, wound infection was defined in this study by retrospective chart review, and the study was truncated after the evaluation of 160 patients because of the higher incidence of surgical site infection found in the hyperoxia group.24

There are several limitations to our work. All meta-analyses have well-recognized limitations in part because of an inability to control for differences among studies. The results of this meta-analysis cannot be extrapolated to conclude that all levels of high inspired perioperative oxygen are unlikely to be beneficial. The choice of 80% and 30% oxygen concentrations in the studies used in this meta-analysis are somewhat arbitrary, and the use of other concentrations of oxygen may produce different results. Variables that differed among studies in this meta-analysis include perioperative antibiotic use, surgical operations performed, the absence or presence of neuraxial anesthesia, the use of nitrous oxide, the definition of surgical site infection, fluid management strategy, patient populations studied, and the duration of perioperative oxygen supplementation. A change in any of these variables might theoretically influence the overall outcome. Lastly, the Surgical Care Improvement Project was implemented in 2006; thus, Surgical Care Improvement Project measures (appropriate antibiotic selection and timing, appropriate hair removal, etc.) exerted a variable influence on the trials included in this meta-analysis, which may have influenced our results.

In summary, a meta-analysis of all trials that met our inclusion criteria did not show that high inspired perioperative oxygen therapy is beneficial for preventing surgical site infections. This is in contrast to 2 previously published meta-analyses11,12 that suggest an association between a decrease in surgical site infection and the use of high inspired oxygen therapy. Interestingly, 2 subgroup analyses (trials that excluded neuraxial anesthesia and trials that involved colorectal surgery only) showed a benefit for high inspired oxygen therapy decreasing surgical site infection. The positive results of the above-mentioned subgroup analyses point to a need for additional studies to further investigate this intervention.

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DISCLOSURES

Name: Brandon Togioka, MD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Brandon Togioka approved the final manuscript.

Name: Samuel Galvagno, DO.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Samuel Galvagno approved the final manuscript.

Name: Shawn Sumida, MD.

Contribution: This author helped conduct the study, analyze the data, and write the manuscript.

Attestation: Shawn Sumida approved the final manuscript.

Name: Jamie Murphy, MD.

Contribution: This author helped conduct the study, analyze the data, and write the manuscript.

Attestation: Jamie Murphy approved the final manuscript.

Name: Jean-Pierre Ouanes, DO.

Contribution: This author helped conduct the study and write the manuscript.

Attestation: Jean-Pierre Ouanes approved the final manuscript.

Name: Christopher Wu, MD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Christopher Wu approved the final manuscript.

This manuscript was handled by: Sorin Brull, MD.

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    APPENDIX 1: SEARCH STRATEGY USED FOR LITERATURE SEARCH

    • MEDLINE search: oxygen[Title/Abstract] AND infection [Title/Abstract] Limits: Randomized Controlled Trial, Case Reports
    • Cochrane Collaboration's CENTRAL database search: oxygen in Keywords and infection in Keywords in Cochrane Database of Systematic Reviews
    • EMBASE search: ‘oxygen'/exp AND ‘infection'/exp AND ([Cochrane review]/lim OR [controlled clinical trial]/lim OR [randomized controlled trial]/lim) AND [humans]/lim AND [1-1-1945]/sd NOT [12-7-2010]/sd
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    APPENDIX 2: FURTHER DISCUSSION OF FIGURE 4

    The P value calculated in Figure 4 without correction for multiple comparisons and large heterogeneity. The P value was calculated using the Cochrane Collaboration's RevMan version 5.0.25 using the procedure described by DerSimonian and Laird for fitting the random effects model for meta-analysis. DerSimonian and Laird obtain an estimate for τ2 using the method of moments. Alternative methods may be preferable for calculating the treatment effect for Figure 4 on the smaller sample size included in this subgroup analysis. On the basis of the stated statistical method uncertainty, the results depicted may be unreliable.

    © 2012 International Anesthesia Research Society