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Anaesthesia, Postoperative Care

Hyperoxia and Surgical Site Infections: is oxygen beneficial?

Using high inspired concentrations of oxygen in the perioperative period may reduce the risk of surgical site infections for patients undergoing colo-rectal surgery. It does not appear to confer benefit for other patient groups.

We live side by side with an element that both feeds us and damages us simultaneously: oxygen. Reactive oxygen species cause lipid peroxidation of cell membranes and disrupt DNA. They interfere with gene expression and cause altered cell growth and necrosis. This happens all the time, and we have developed anti-oxidant scavenging systems for clearing up the debris. So oxygen is toxic. Conversely, oxygen kills bacteria – facilitating the activity of neutrophils, thus enhancing immune function, it is anti-inflammatory,1 it is a vasoconstrictor (may reverse vasoplegia) and it redistributes blood flow to the kidneys and splanchnic circulation.2-4 Oxygen is potentially therapeutic in sepsis.5

Surgical site infections (SSI) result in significant morbidity, delayed hospital discharge and increased healthcare costs. There is a known association between SSI and hypoperfusion, contaminated wounds, perioperative hyperglycaemia and hypothermia6 and obesity. It has long been proposed that the use of perioperative hyperoxia to high risk patients may result in a reduction in the risk of SSIs. The converse argument is that hyperoxia is toxic to the lungs7;8 and results in increased atelectasis and, potentially, an increase in postoperative pulmonary complications.9

The scientific rationale for preoperative hyperoxia is that oxidative killing by neutrophils, the primary defence against surgical pathogens, depends critically on tissue oxygenation.10 Hopf and colleagues11 performed a non interventional, prospective study of subcutaneous wound oxygen tension(PsqO2) and its relationship to the development of woundinfection in surgical patients. One hundred and thirty general surgical patients were enrolled and PsqO2 was measured perioperatively. There was an inverse relationship between wound oxygen tension and the risk of developing surgical site infections (SSI). They hypothesized that manipulating FiO2 may increase PsqO2 and reduce SSIs.

Grief et al12 randomly assigned 500 patients undergoing colorectal resection to receive 30 percent or 80 percent inspired oxygen during the operation and for two hours afterward. This was a very well constructed study. Anaesthetic treatment was standardized, and all patients received prophylactic antibiotic therapy, standardized fluid regimens and kept euthermic perioperatively. Wounds were evaluated daily until the patient was discharged and then at a clinic visit two weeks after surgery. The arterial and subcutaneous partial pressure of oxygen was significantly higher in the patients given 80 percent oxygen than in those given 30 percent oxygen. The duration of hospitalization was similar in the two groups. Among the 250 patients who received 80 percent oxygen, 13 (5.2 percent; 95 percent confidence interval, 2.4 to 8.0 percent) had surgical-wound infections, as compared with 28 of the 250 patients given 30 percent oxygen (11.2 percent; 95 percent confidence interval, 7.3 to 15.1 percent; P=0.01). The absolute difference between groups was 6.0 percent (95 percent confidence interval, 1.2 to 10.8 percent) NNT 15.

These data were confirmed by a smaller study from Spain. Belda et al13 undertook a double-blind, randomizedcontrolled trial of 300 patients aged 18 to 80 years who underwentelective colorectal surgery. Patients were randomly assigned to either30% or 80% fraction of inspired oxygen (FIO2), intraoperatively,and for 6 hours after surgery. Anaesthetic treatment and antibioticadministration were standardized.A total of 143 patients received 30% perioperativeoxygen and 148 received 80% perioperative oxygen. Surgical siteinfection occurred in 35 patients (24.4%) administered 30% FIO2and in 22 patients (14.9%) administered 80% FIO2 (P=.04). Therisk of SSI was 39% lower in the 80% FIO2 group (relative risk[RR], 0.61; 95% confidence interval [CI], 0.38-0.98) vs the30% FIO2 group. After adjustment for important covariates, theRR of infection in patients administered supplemental oxygenwas 0.46 (95% CI, 0.22-0.95; P = .04). Similar results were reported by Bickel and colleagues, in a 210 patients with acute appendicitis (5.6% versus 13.6%, p = 0.4, ARR 7 NNT – 13).14

Pryor et al claimed opposite results.15 This study included 165 patients that were undergoing general surgery, and were randomized to 30% or 80% oxygen. The overall incidence of SSI was18.1%. In an intention-to-treat analysis, the incidence of infectionwas significantly higher in the group receiving FIO2 of 0.80than in the group with FIO2 of 0.35 (25.0% vs 11.3%; P = .02).FIO2 remained a significant predictor of SSI (P = .03) in multivariateregression analysis. Patients who developed SSI had a significantlylonger length of hospitalization after surgery (mean [SD], 13.3[9.9] vs 6.0 [4.2] days; P<.001).

This study was criticized for a number of reasons. It is unclear whether or not the group assignment was truly blind. Tissue oxygenation was not blind. Wound infection was identified by retrospective chart review, a highly unreliable technique. There was no standardization of fluid therapy, temperature or antibiotic prophylaxis. Patients receiving80% oxygen were more likely to be obese, had longer operations,and lost more blood. All these factors may be associated withincreased risk of SSI. Significantly more patients in the high FiO2 group went back to the PACU intubated post op. Finally, the incidence of wound infections, at 25%, was high in the hyperoxic group compared with the study by Grief, 12 but similar to the control group in the study by Belda.13

Maragakis et al16 undertook a case-control retrospective review of SSIs in patients undergoing spinal surgery. Two hundred and eight charts were reviewed. The authors claimed that the use of an FiO2 of <50% significantly increased the risk of SSI (OR, 12; 94% CI, 4.5-33; P < 0.001). This study has the same flaws as that by Prior and colleagues,(50) albeit with opposite results.

Myles et al 17 enrolled a 2,050 patients into a study that randomized them to either FiO2 of 80% or 30%, plus 70% nitrous oxide. Patients that were given a high FiO2 had significantly lower rates of major complications (odds ratio, 0.71; 95% confidence interval, 0.56-0.89; P = 0.003) and severe nausea and vomiting (odds ratio, 0.40; 95% confidence interval, 0.31-0.51; P < 0.001). Among patients admitted to the intensive care unit postoperatively, those in the nitrous oxide-free group were more likely to be discharged from the unit on any given day than those in the nitrous oxide group (hazard ratio, 1.35; 95% confidence interval, 1.05-1.73; P = 0.02). It is unclear whether these data represent a beneficial effect of oxygen or a detrimental effect of nitrous oxide.

The Proxi trial 18 included 685 patients in 14 Danish hospitals. Patients were randomized to 80% versus 30% oxygen. Temperature, fluid therapy and type of surgery were not controlled. Similar to the Pryor trial, the incidence of SSIs were in excess of 20% (20.1%) in the control group, not significantly different from the study group (19.1%). There was no difference in pulmonary complications between the groups. Clearly the extraordinarily high number of SSIs in both groups made a statistically significant difference in outcomes unlikely. A large number of patients had undergone emergency surgery and had contaminated wounds. Hence, a direct comparison with previous studies cannot be made.

However, comparisons have been made and here have been several meta-analyses (MA) of hyperoxia and surgical site infections. These differ in outcomes depending on whether or not one includes the Myles17 data. Where Myles’s study is included, the MA supports hyperoxia.19 Where it is excluded – MAs routinely exclude papers for reasons that are not always obvious – hyperoxia is shown not to be beneficial.20 My own conclusion is that there is tremendous heterogenicity between these studies: well controlled studies of colonic surgery where anaesthesia and perioperative care was standardised resulted in better outcomes. Poorly controlled studies (Pryor / Meyhoff), without standardisation resulted in very high levels of SSI in both groups. The excess adverse outcomes in the Pryor study suggests that there were substantial differences between the groups in terms of type and length of surgery, severity of illness etc. and that this study was fatally flawed.

My conclusion: if you are providing anaesthesia for bowel surgery, and will not be using nitrous oxide, 80% oxygen is unlikely to be harmful, and is potentially beneficial. Whether or not to extend this hyperoxia into the postoperative period is very controversial.

References

1.    Nathan C: Oxygen and the inflammatory cell. Nature 2003; 17: 675-6

2.    Bitterman H, Brod V, Weiss G, Kushnir D, Bitterman N: Effects of oxygen on regional hemodynamics in hemorrhagic shock. Am J Physiol 1996; 40: H203-H211

3.    Cason BA, Wisneski J, Neese RA, Stanley WC, Hickey RF, Shnier CB, Gertz EW: Effects of high arterial oxygen tension on function, blood flow distribution, and metabolism in ischemic myocardium. Circulation 1992; 85: 828-38

4.    Plewes JL, Farhi LE: Peripheral circulatory responses to acute hyperoxia. Undersea Biomed Res 1983; 10: 123-9

5.    Bitterman H: Bench-to-bedside review: Oxygen as a drug. Critical Care 2009; 13: 205

6.    Kurz A, Sessler DI, Lenhardt R: Perioperative Normothermia to Reduce the Incidence of Surgical-Wound Infection and Shorten Hospitalization. New England Journal of Medicine 1996; 334: 1209-16

7.    Fisher AB: Oxygen therapy, side effects and toxicity. Am Rev Respir Dis 1980; 122: 61-9

8.    Bitterman N, Bitterman H: Oxygen toxicity. Handbook on Hyperbaric Medicine 2006; 731-66

9.    Hedenstierna G, Edmark L, Aherdan KK: Time to reconsider the pre-oxygenation during induction of anaesthesia. Minerva Anestesiol. 2000; 66: 293-6

10.    Overdyk FJ: Bridging the Gap to Reduce Surgical Site Infections. Anesthesia & Analgesia 2010; 111: 836-7

11.    Hopf HW, Hunt TK, West JM, Blomquist P, Goodson WH, III, Jensen JA, Jonsson K, Paty PB, Rabkin JM, Upton RA, von Smitten K, Whitney JD: Wound Tissue Oxygen Tension Predicts the Risk of Wound Infection in Surgical Patients. Archives of Surgery 1997; 132: 997-1004

12.    Greif R, Akca O, Horn EP, Kurz A, Sessler DI, The Outcomes Research Group: Supplemental Perioperative Oxygen to Reduce the Incidence of Surgical-Wound Infection. The New England Journal of Medicine 2000; 342: 161-7

13.    Belda FJ, Aguilera L, Garcia de la Asuncion J, Alberti J, Vicente R, Ferrandiz L, Rodriguez R, Company R, Sessler DI, Aguilar G, Botello SG, Orti R, for the Spanish Reduccion de la Tasa de Infeccion Quirurgica Group: Supplemental Perioperative Oxygen and the Risk of Surgical Wound Infection: A Randomized Controlled Trial. JAMA: The Journal of the American Medical Association 2005; 294: 2035-42

14.    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. Archives of Surgery 2011; 146: 464-70

15.    Pryor KO, Fahey TJ, III, Lien CA, Goldstein PA: Surgical Site Infection and the Routine Use of Perioperative Hyperoxia in a General Surgical Population: A Randomized Controlled Trial. JAMA: The Journal of the American Medical Association 2004; 291: 79-87

16.    Maragakis LL, Cosgrove SE, Martinez EA, Tucker MG, Cohen DB, Perl TM: Intraoperative Fraction of Inspired Oxygen Is a Modifiable Risk Factor for Surgical Site Infection after Spinal Surgery. Anesthesiology 2009; 110:

17.    Myles PS, Leslie K, Chan MTV, Forbes A, Paech MJ, Peyton P, Silbert BS, Pascoe E, the ENIGMA Trial Group: Avoidance of Nitrous Oxide for Patients Undergoing Major Surgery: A Randomized Controlled Trial. Anesthesiology 2007; 107:

18.    Meyhoff CS, Wetterslev J+, Jorgensen LN, Henneberg SW, H+©gdall C, Lundvall L, Svendsen PE, Mollerup H, Lunn TH, Simonsen I, Martinsen KR, Pulawska T, Bundgaard L, Bugge L, Hansen EG, Riber C, Gocht-Jensen P, Walker LR, Bendtsen A, Johansson G, Skovgaard N, Helt+© K, Poukinski A, Korshin A, Walli A, Bulut M, Carlsson PS, Rodt SA, Lundbech LB, Rask H, Buch N, Perdawid SK, Reza J, Jensen KV, Carlsen CG, Jensen FS, Rasmussen LS: Effect of High Perioperative Oxygen Fraction on Surgical Site Infection and Pulmonary Complications After Abdominal Surgery. JAMA: The Journal of the American Medical Association 2009; 302: 1543-50

19.    Qadan M, Akca O, Mahid SS, Hornung CA, Polk HC, Jr.: Perioperative Supplemental Oxygen Therapy and Surgical Site Infection: A Meta-analysis of Randomized Controlled Trials. Archives of Surgery 2009; 144: 359-66

20.    Al-Niaimi A, Safdar N: Supplemental perioperative oxygen for reducing surgical site infection: a meta-analysis. Journal of Evaluation in Clinical Practice 2009; 15: 360-5

This review copyright Patrick Neligan 2012. All rights reserved. Do not reproduce without permission.

About Pat Neligan

Pat Neligan lives and works in Galway, Ireland

Discussion

5 thoughts on “Hyperoxia and Surgical Site Infections: is oxygen beneficial?

  1. The ISO2 study, published in Anesthesiology Sept 2012 [PMID: 22790961], was a controlled, randomized, multicenter trial, t comparing the effects of hyperoxygenation (fraction of inspired oxygen, 80%) with those of 30% oxygen on the frequency of surgical site infections in routine abdominal, gynecologic, and breast surgery on 434 patients. The frequency of 30-day surgical site infections was 7.2% (15/208) in the 30% group and 6.6% (15/226) in the 80% group (relative risk, 0.92; 95% CI [0.46–1.84], P = 0.81). Frequency of adverse events (nausea and vomiting, sternal pain, cough, hypotension) was similar in the two groups. Adding these data to those of eight previously published randomized trials, a meta analysis revealed the overall relative risk was 0.97; 95% CI (0.68–1.40), I2 (inconsistency degree) = 73%, (P = 0.88).
    A study in Anesthesiology in August 2012 [PMID 22569132] demonstrated that high inspired oxygen tension was not associated with increased oxygen requirement postoperatively. So, hyperoxaemia is probably neither beneficial nor harmful.

    Posted by Pat Neligan | September 24, 2012, 9:36 pm
  2. This has thrown a spanner in the works about my usual practice of using high Fi02: a reanalysis of the PROXI trial showed a higher mortality in patients having cancer surgery who were randomised to 80% oxygen.
    http://www.anesthesia-analgesia.org/content/early/2012/07/13/ANE.0b013e3182652a51.abstract.
    On a related note, reanalysis of the Hong Kong patients from the ENIGMA trial showed that nitrous oxide administration was associated with less chronic pain- http://www.ncbi.nlm.nih.gov/pubmed/21889262

    Posted by James Jarman | October 12, 2012, 12:12 am
  3. This is the paper that James is referring to (abstract posted below): http://www.anesthesia-analgesia.org/content/early/2012/07/13/ANE.0b013e3182652a51.abstract
    It is the long term follow up of the PROXI trial, mentioned in my original post. The cancer patient outcomes at 2.3 years are astonishing – a hazard ratio of 1.45. Of 1836 patients, the administration of 80% oxygen was associated with a 5% absolute risk increase of death at 2.3 years. Number needed to harm – 20. Does the high FiO2 increase the risk of metastases? This was completely unexpected. For the time being, I believe that hyperoxia is a dead duck.

    Abstract:
    BACKGROUND: A high perioperative inspiratory oxygen fraction (80%) has been recommended to prevent postoperative wound infections. However, the most recent and one of the largest trials, the PROXI trial, found no reduction in surgical site infection, and 30-day mortality was higher [this is misleading as there was no statistically significant mortality difference] in patients given 80% oxygen. In this follow-up study of the PROXI trial we assessed the association between long-term mortality and perioperative oxygen fraction in patients undergoing abdominal surgery.

    METHODS: From October 8, 2006, to October 6, 2008, 1386 patients underwent elective or emergency laparotomy and were randomized to receive either 80% or 30% oxygen during and for 2 hours after surgery. The follow-up date was February 24, 2010. Survival was analyzed using Kaplan-Meier statistics and the Cox proportional hazards model.

    RESULTS: Vital status was obtained in 1382 of 1386 patients after a median follow-up of 2.3 years (range 1.3 to 3.4 years). One hundred fifty-nine of 685 patients (23.2%) died in the 80% oxygen group compared to 128 of 701 patients (18.3%) assigned to 30% oxygen (HR, 1.30 [95% confidence interval, 1.03 to 1.64], P = 0.03). In patients undergoing cancer surgery, the HR was 1.45; 95% confidence interval, 1.10 to 1.90; P = 0.009; and after noncancer surgery, the HR was 1.06; 95% confidence interval, 0.69 to 1.65; P = 0.79.

    CONCLUSIONS: Administration of 80% oxygen in the perioperative period was associated with significantly increased long-term mortality and this appeared to be statistically significant in patients undergoing cancer surgery but not in noncancer patients.

    BACKGROUND: A high perioperative inspiratory oxygen fraction (80%) has been recommended to prevent postoperative wound infections. However, the most recent and one of the largest trials, the PROXI trial, found no reduction in surgical site infection, and 30-day mortality was higher in patients given 80% oxygen. In this follow-up study of the PROXI trial we assessed the association between long-term mortality and perioperative oxygen fraction in patients undergoing abdominal surgery.

    METHODS: From October 8, 2006, to October 6, 2008, 1386 patients underwent elective or emergency laparotomy and were randomized to receive either 80% or 30% oxygen during and for 2 hours after surgery. The follow-up date was February 24, 2010. Survival was analyzed using Kaplan-Meier statistics and the Cox proportional hazards model.

    RESULTS: Vital status was obtained in 1382 of 1386 patients after a median follow-up of 2.3 years (range 1.3 to 3.4 years). One hundred fifty-nine of 685 patients (23.2%) died in the 80% oxygen group compared to 128 of 701 patients (18.3%) assigned to 30% oxygen (HR, 1.30 [95% confidence interval, 1.03 to 1.64], P = 0.03). In patients undergoing cancer surgery, the HR was 1.45; 95% confidence interval, 1.10 to 1.90; P = 0.009; and after noncancer surgery, the HR was 1.06; 95% confidence interval, 0.69 to 1.65; P = 0.79.

    CONCLUSIONS: Administration of 80% oxygen in the perioperative period was associated with significantly increased long-term mortality and this appeared to be statistically significant in patients undergoing cancer surgery but not in noncancer patients.

    BACKGROUND: A high perioperative inspiratory oxygen fraction (80%) has been recommended to prevent postoperative wound infections. However, the most recent and one of the largest trials, the PROXI trial, found no reduction in surgical site infection, and 30-day mortality was higher in patients given 80% oxygen. In this follow-up study of the PROXI trial we assessed the association between long-term mortality and perioperative oxygen fraction in patients undergoing abdominal surgery.

    METHODS: From October 8, 2006, to October 6, 2008, 1386 patients underwent elective or emergency laparotomy and were randomized to receive either 80% or 30% oxygen during and for 2 hours after surgery. The follow-up date was February 24, 2010. Survival was analyzed using Kaplan-Meier statistics and the Cox proportional hazards model.

    RESULTS: Vital status was obtained in 1382 of 1386 patients after a median follow-up of 2.3 years (range 1.3 to 3.4 years). One hundred fifty-nine of 685 patients (23.2%) died in the 80% oxygen group compared to 128 of 701 patients (18.3%) assigned to 30% oxygen (HR, 1.30 [95% confidence interval, 1.03 to 1.64], P = 0.03). In patients undergoing cancer surgery, the HR was 1.45; 95% confidence interval, 1.10 to 1.90; P = 0.009; and after noncancer surgery, the HR was 1.06; 95% confidence interval, 0.69 to 1.65; P = 0.79.

    CONCLUSIONS: Administration of 80% oxygen in the perioperative period was associated with significantly increased long-term mortality and this appeared to be statistically significant in patients undergoing cancer surgery but not in noncancer patients.

    Posted by Pat Neligan | October 24, 2012, 2:59 pm

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