Objective
The purpose of this study was to investigate whether supplemental oxygen during and for 2 hours after cesarean delivery reduces the incidence of postcesarean infectious morbidity.
Study Design
We conducted a randomized, controlled trial from 2008-2010. Women who underwent cesarean delivery were randomly assigned to receive either 2 L of oxygen by nasal cannula during cesarean delivery only (standard care) or 10 L of oxygen by nonrebreather mask (intervention group) during and for 2 hours after cesarean delivery. Women who underwent scheduled or intrapartum cesarean delivery were eligible and were observed for 1 month after the procedure. The primary composite outcome was maternal infectious morbidity, which included endometritis and wound infection.
Results
Five hundred eighty-five women were included in the final analysis. Infectious morbidity occurred in 8.8% of patients in the standard care group and in 12.2% of patients in the supplemental oxygen group. There was no significant difference in the rate of infectious morbidity between the standard care and intervention groups (relative risk, 1.4; 95% confidence interval, 0.9–2.3).
Conclusion
Supplemental oxygen does not reduce the rate of postcesarean delivery infectious morbidity, including endometritis and wound infection.
In 2007, 1.4 million live births (32%) in the United States were by cesarean delivery. Because of this, postoperative infectious complications remain a common and important source of maternal morbidity, occurring in 5-25% of patients who undergo cesarean delivery. Infection typically requires treatment with intravenous antibiotics and prolongs hospitalization by an average of 3 days, which significantly increases the cost of delivery. Although antibiotic prophylaxis can reduce the incidence of infectious morbidity, additional interventions could have significant public health benefits.
The concept that perioperative oxygen therapy could reduce the risk of postoperative infection is biologically plausible. The first few hours after tissue is contaminated by bacteria likely constitutes a critical period during which wound infections are established. Oxidative killing, the mechanism for the bactericidal activity of neutrophils, depends on the production of bactericidal superoxide radicals from molecular oxygen. The rate of this reaction, which is catalyzed by the reduced nicotinamide adenine dinucleotide phosphate–linked oxygenase, depends on the partial pressure of oxygen in the tissue. All wounds disrupt the local vascular supply, which causes wounds to be hypoxic when compared with normal tissue. Leukocyte bacterial killing capacity is impaired at the low oxygen tensions that often are found in wounds, and perioperative arterial and wound oxygen tension can be increased by a higher fraction of inspired oxygen (FiO 2 ).
Oxygen for the prevention of postsurgical infectious morbidity has been studied in patients who have undergone general and gynecologic surgery procedures with general anesthesia, and study results have been conflicting. Two trials suggested a significant reduction in the frequency of surgical wound infections when 80%, compared with 30%, oxygen was administered during and after surgery. Conversely, 2 additional trials did not detect a difference in rates of postoperative infection in patients who received supplemental oxygen. One study was stopped prematurely because wound infections were more common in patients who received supplemental oxygen, and a trial that included women who had undergone cesarean delivery was stopped for futility.
The aim of our study was to assess the effect of a high perioperative oxygen concentration on postcesarean delivery infectious morbidity in women undergoing cesarean delivery. Our primary outcome measure was surgical site infection, which included both wound infection and endometritis. We hypothesized that 10 L of oxygen by face mask during and for 2 hours after cesarean delivery would reduce the frequency of surgical site infections.
Methods
We conducted a randomized controlled trial of supplemental oxygen for the prevention of postcesarean delivery infectious morbidity at Washington University in St. Louis, MO. Institutional review board approval was obtained before patient enrollment, and written informed consent was obtained from all participants. Patients who underwent scheduled or intrapartum cesarean delivery with regional anesthesia were eligible for participation. Women were recruited for study participation from the antepartum service and labor and delivery. Exclusion criteria included emergency surgery in which the participant was unable to provide informed consent, human immunodeficiency virus infection, chronic corticosteroid therapy or other immunosuppressive therapy, general anesthesia, and a diagnosis of extrauterine infection (ie, pyelonephritis or pneumonia) before cesarean delivery. Acute chorioamnionitis was not an exclusion criterion.
After written consent was obtained, patients were randomly assigned in a 1:1 scheme to receive either supplemental oxygen or standard care. Randomization was achieved with opaque envelopes that contained the assigned study group; the envelopes were opened after the patients had agreed to participate in the study but before surgery. Women in the supplemental oxygen group received oxygen at a flow rate of 10 L/min (corresponding to an FiO 2 of approximately 80%) by nonrebreather mask (CareFusion, Yorba Linda, CA) during and for 2 hours after cesarean delivery. Compliance with supplemental oxygen by face mask was assessed by the anesthesiologist intraoperatively and by the postpartum nurse at 30, 60, 90, and 120 minutes after surgery. Women who were assigned to the standard care group received oxygen at a flow rate of 2 L/min (corresponding to a FiO 2 of 25-30%) by nasal cannula (Salter Labs, Arvin, CA) during the cesarean delivery only. Oxygen saturation was assessed both intraoperatively and postoperatively for both groups; women with oxygen saturations <95% were supplied supplemental oxygen, as needed, to maintain appropriate oxygenation. Women in both groups received standard preoperative skin preparation and prophylactic antibiotics. During the study period, cefazolin was used as primary preoperative prophylaxis, and clindamycin was used for patients with penicillin allergy. Subcutaneous depth was measured by the primary operative team with a sterile ruler; demographic, intrapartum, and operative information was abstracted from the medical records. The operative decision to place subcutaneous sutures was left to the surgical team.
The primary outcome for this study was a composite outcome that consisted of endometritis and wound infection. Strict diagnostic criteria were used for infectious outcomes. A patient was diagnosed with endometritis if she had an oral temperature of >38°C after the first 24 hours following the procedure and either (1) fundal or lower abdominal tenderness greater than expected or (2) foul-smelling or purulent lochia. Endometritis was diagnosed only if other causes for the patient’s signs and symptoms were not identified. Patients had to be treated with intravenous antibiotics for a diagnosis of endometritis to meet our study definition. The diagnosis of wound infection required wound opening >1 cm or other surgical intervention (such as laparotomy or debridement of tissue) plus at least 1 of the following: (1) purulent drainage from the wound, (2) erythema or induration of the surrounding tissues, (3) maternal oral temperature >38°C, or (4) radiographic evidence of infection. Secondary outcomes were defined before the study was initiated and included the need for wound opening >1 cm because of wound hematoma or seroma, hospital readmission, and need for intravenous antibiotics after the first 24 hours after the procedure. We also collected data on immediate neonatal outcomes that included Apgar scores, special care nursery or neonatal intensive care unit (NICU) admission, umbilical artery pH, O 2 , and CO 2 , and antibiotic administration after birth. Physicians were provided with educational materials regarding the diagnosis of endometritis and wound infection before study initiation and intermittently throughout the study period. All outcomes were assessed by the primary care team, and the diagnoses were abstracted from the chart by study personnel (research nurse or investigator). The medical record was reviewed at the time of the 2-4 week postoperative visit, and all women who did not return for a postoperative visit within 4 weeks or who had planned follow-up visits at an outside clinic were contacted by the research nurse by telephone to inquire about postoperative complications. The data collection form was used as a prompt during the telephone interviews to ensure standardization.
The primary comparison for our study was supplemental oxygen vs standard care with respect to the primary outcome of infectious morbidity. Data were analyzed with the intent-to-treat principle, and a separate analysis was completed that analyzed only those patients who were treated according to protocol. Before study initiation, it was decided that patients who unexpectedly required general anesthesia or delivered vaginally after randomization would be excluded from the intent-to-treat analysis because the baseline risk for infectious morbidity is very different in this patient population and because developing 1 of these 2 very late exclusion criteria could not be related to the intervention. We performed a sensitivity analysis that included these patients to determine whether study results remained stable. Analysis included unpaired t tests for normally distributed continuous variables, Mann-Whitney U test for nonnormally distributed continuous variables, and chi-squared or Fisher’s exact tests for categoric data. Stratified analyses with the Mantel-Haenszel test and logistic regression were performed to assess for confounding and interaction. Risk ratios with 95% confidence intervals were calculated for outcomes by treatment arms. A probability value of < .05 was considered significant. No interim analyses were planned or conducted. The study protocol included a continuous (daily) process of monitoring and reporting of maternal and neonatal adverse events by the research team (research nurse and investigators). Adverse events were reported to the Human Research Protection Office and the institutional review board as they occurred. Because of this adverse event monitoring process and because oxygen was not deemed a high-risk agent for adverse effects, the institutional review board did not require a data and safety monitoring board for this study.
For the initial sample size calculation, we estimated the rate of infectious morbidity, which consisted of endometritis and wound infection, to be 15%. To detect a 50% reduction in surgical site infection with 80% power and an alpha error of 0.05, 278 women per arm were required. After 50% of the subjects had been enrolled, the calculated sample size of 556 women was increased by approximately 10% to account for the observed loss to follow-up rate, which resulted in a final sample size of 606 women.
Results
Between February 2008 and March 2010, 606 participants were enrolled and randomly assigned to the 2 study groups. Twenty-one patients developed exclusion criteria after study enrollment, including 13 patients who required general anesthesia, 6 patients who had a vaginal delivery before their cesarean delivery, 1 patient who had evidence of extrauterine infection, and 1 patient who was excluded because of previous enrollment in a conflicting study. Of these 21 patients, 7 women were in the standard care group, and 14 women were in the supplemental oxygen group. Five hundred eighty-five women were included in the final analysis ( Figure ). Overall, 535 patients (91.5%) received their allotted study treatment, and 6 women in each group (2.1% of the total study population) were lost to follow-up evaluation in the postpartum period. Those patients who were lost to follow-up evaluation remained in the analysis and were considered to not have experienced infectious morbidity. There were 63 of 297 women (21.2%) in the standard care group and 70 of 288 women (24.3%) in the supplemental oxygen group who underwent telephone interview as their primary follow-up session ( P = .50). Participants who had a protocol deviation that changed the amount of oxygen that they received remained in their assigned study group for the intent-to-treat analysis. Additional oxygen to maintain maternal saturation of 95% was required in 18 women (5.9%) in the standard care group; none of the women in the supplemental oxygen group required additional oxygen therapy. Women who received 10 L of oxygen by face mask were encouraged to continue supplemental oxygen therapy for 2 hours after delivery; at 30 minutes after delivery, 214 of 288 women (74.3%) were compliant. At 1 hour, compliance was 189 of 288 women (65.6%); at 90 minutes, 172 of 288 women (59.7%) were still wearing their nonrebreather mask, and by 2 hours after delivery, only 97 of 288 women (33.7%) were compliant with supplemental oxygen.
