Abstract
Background:
The rationale for hyperoxygenation in controlling surgical site infection (SSI) has been described in many studies yet has not been defined clearly. Some studies in colorectal surgery have reported beneficial effects, whereas studies in gynecologic surgery have reported either no effect or a deleterious effect. This study assessed the effectiveness of hyperoxygenation on the reduction of SSI in patients undergoing emergency abdominal surgery.
Patients and Methods:
Eligible patients were assigned randomly to two groups (study group, 80% oxygen or control group, 30% oxygen). The patients in the study group received 80% oxygen and the patients in the control group received 30% oxygen intra-operatively and for two hours after surgery. Arterial blood gas analysis was done after resuscitation, at the end of the surgery, and at two hours after extubation. All patients were assessed for SSI, post-operative nausea and vomiting, and respiratory complications. Patients were followed post-operatively for 14 days. Surgical site infection was diagnosed according to U.S. Centers for Disease Control and Infection (CDC) criteria and by aerobic wound cultures.
Results:
After exclusion, 85 patients in the control group and 93 patients in the study group were analyzed. There was no difference for baseline, intra-operative, and post-operative characteristics between the two groups, except for higher oxygen saturation at closure and two hours post-operatively, in the 80% group (p = 0.01). Surgical site infection occurred in 29 patients (34.11%) in 30% fraction of inspired oxygen (FIO2) group and in 19 patients (20.43%) in 80% FIO2 group (p = 0.04). The risk of SSI was 59% lower in the 80% FIO2 group (adjusted odds ratio, 0.41; 95% confidence interval [CI], 0.19–0.88 vs. the 30% FIO2 group). There were no differences in post-operative nausea and vomiting and respiratory complications between the two treatment groups.
Conclusions:
Administration of 80% peri-operative hyperoxygenation in emergency abdominal surgery reduces SSI and is a cost-effective method.
Surgical site infection (SSI) is the most common hospital-acquired infection in surgical patients [1]. It increases hospital cost, duration of hospital stay, morbidity, and may add to mortality [2].
The etiology of SSI is multifactorial. It involves nutritional, immunologic, and hemodynamic status, appropriate prophylactic antibiotic agents, operative time and technique, core body temperature, blood transfusions, post-operative pain, and tissue oxygen tension [1,3–7]. The number of pathogens that reach the incision and the body's immunity to eliminate those pathogens within the first few hours of incision healing will determine SSI rate [2]. Oxygen-dependent bactericidal activity of neutrophils is one of the fundamental defenses of the immune system to eliminate those pathogens that reach the surgical site. Disruption of the local microvascular supply by surgical trauma, thrombosis, or edema is responsible for low oxygen concentration in the surgical site [8].
Healing of incision depends on the partial pressure of oxygen (P
The rationale for hyperoxygenation and its mechanism in controlling SSI has been described in many research studies and with conflicting results. Studies in colorectal surgery have shown a beneficial effect of hyperoxygenation with a halving of SSI frequency, whereas studies on other types of surgery have revealed no effect or even a detrimental effect [15–17].
In the present study, we assessed the effect of hyperoxygenation in patients undergoing emergency abdominal surgery on the incidence of SSI 14 days after surgery and compared the frequency of immediate post-operative adverse effects between hyperoxygenated (80%) patients and patients who received 30% oxygen.
Patients and Methods
Our study was a double-blind, randomized, placebo-controlled trial done in a tertiary care hospital in India. The study protocol was approved by the institute ethics committee (Human Studies) and the scientific advisory committee. All consecutive patients aged between 13 and 80 years of age undergoing emergency abdominal surgery over two years, belonging to American Society of Anesthesiologists (ASA) class ≤ III were included. Patients with known pulmonary comorbidity, state of immune-compromise, hemodynamic instability requiring inotropic support, and patients requiring ventilator support were excluded from the study.
Eligible patients who consented for the study were assigned randomly, by block randomization (blocks of 10), into one of the two groups using the sealed envelope technique (group A, 80% oxygen group and group B, 30% oxygen group) [18]. Both the participating patient and surgeon assessing the outcome were blinded to the group allotment.
Study protocol
All eligible patients were resuscitated with intravenous fluids, and gastric decompression was done using a nasogastric tube in intestinal obstruction or peritonitis. After resuscitation, blood investigations including blood culture, complete blood count, renal function tests, liver function tests, and arterial blood gas analysis were done.
Antibiotic agents were administered as per our institute antibiotic policy. As per the protocol, patients who underwent clean surgeries were managed with a single dose of antibiotic and those with uncomplicated clean-contaminated surgeries received 24 hours of antibiotic therapy. All patients with complicated, contaminated, and dirty wounds received 1 g of ceftriaxone and 500 mg of metronidazole for five days post-operatively. Antibiotic agents were changed depending on the intra-operative peritoneal fluid aerobic culture and antibiotic sensitivity. Data regarding demography, pre-operative hemoglobin, comorbidity, smoking, and ASA category were recorded.
As a part of rapid sequence induction, all patients received pre-oxygenation for three minutes and Injection (Inj.) fentanyl 2 mcg/kg intravenous as a premedication. As per anesthetist choice, Inj. midazolam, Inj. sodium thiopentone or Inj. ketamine was used for induction. Inj. rocuronium or Inj. succinylcholine was used as a muscle relaxant. Anesthesia was maintained with isoflurane (1 minimum alveolar concentration [MAC]) with air and oxygen mixture. For the study group, 80% oxygen with 20% air mixture was given, and for the control group, 30% oxygen with 70% air was given. At the end of the surgery, arterial blood gas (ABG) analysis was done. For patients who underwent appendectomy under local anesthesia, oxygen was given intra-operatively through non-rebreathing mask at a rate of 14 L/min in the study group and 2 L/min in the control group that approximately corresponds to 80% and 30% oxygen, respectively.
Emergency department resident surgeons performed all of the surgeries. After surgery, all incisions were primarily closed; the incision was cleaned with an antiseptic solution, and sterile dry gauze was applied over the incision. In all patients, intra-operative data regarding the type of anesthesia (general anesthesia or spinal anesthesia), mean arterial pressure, and the volume of intravenous fluids received were recorded. Core body temperature at the end of surgery measured by an esophageal probe was recorded. Arterial blood gas analysis was done pre-operatively after resuscitation, at incision closure. and at two hours post-operatively and P
After the surgical procedure, all extubated patients without inotropic support were analyzed. In the post-operative ward, they were given oxygen with a non-rebreathing mask for two hours. In the study group, patients received oxygen at a rate of 14 L/min, and in the control group, patients received oxygen at a rate of 2 L/min. Arterial blood gas was repeated two hours after extubation. All patients received adequate analgesia post-operatively (morphine 5 mg intramuscularly every eight hours and paracetamol 1 g intravenously every eight hours). Post-operative nausea and vomiting was graded using a scale of 0 to 3 (0, no nausea; 1, nausea present; 2, nausea requiring antiemetic; 3, vomiting present). If the patient had severe nausea or vomiting, ondansetron 4 mg was given intravenously.
In patients with the clinical suspicion of respiratory complications such as pneumonia, atelectasis, or acute respiratory distress syndrome (ARDS), a radiologic confirmation was obtained post-operatively. For all patients, the surgical site was inspected after 48 hours for any evidence of infection. In those with clinical evidence of infection in the form of soakage/staining of dressing on the first post-operative day, the dressing was changed. The incision was assessed periodically for seroma, any signs of infection, or breakdown until discharge of the patient. After hospital discharge, the patients were advised to follow-up in the surgical outpatient clinic on post-operative day 14 to assess the surgical site. We used the U.S. Centers for Disease Control and Prevention (CDC) definitions for the diagnosis of SSI and classified them as superficial, deep wound, or organ/space infection [19]. In the presence of infection, a swab was also taken for aerobic culture and appropriate antibiotic agents were given depending on culture and sensitivity reports.
Statistical methods
The sample size was calculated with SSI as the primary outcome. From the previous studies, our hospital's SSI rate was 46% in emergency abdominal surgeries; a 50% reduction in SSI rate was considered relevant. With 80% power and 5% level of significance, it was estimated that a minimum sample of 89 patients in each group would be required.
SPSS Statistics, version 22.0 (IBM Corp, Armonk, NY) was used for statistical analysis. Surgical site infection after emergency abdominal surgery was taken as the primary outcome, whereas PONV and respiratory complications were taken as secondary outcomes. Demographic data and baseline clinical characteristics of both the groups were expressed in mean, median, range, and standard deviation and were compared. The normality of distribution of continuous variables was assessed using the Kolmogorov-Smirnov test. Chi-square test was used to compare categorical variables. Continuous quantitative variables were compared using a two-tailed Student t-test. A repeated measure analysis of variance (ANOVA) was used to compare the P
Results
Among the 220 patients enrolled, 25 patients from the control group and 17 patients from the study group were excluded because of intra-operative cardiac instability, desaturation, and requirement of a post-operative ventilator and inotrope support. Eighty-five patients from the control group and 93 patients from the study group were analyzed. The baseline characteristics were comparable between the two groups and are shown in Table 1. Sixty-six patients in the study group and 61 patients in the control group underwent surgery under general anesthesia. Twenty-seven patients in the study group and 24 patients in the control group underwent surgery under spinal anesthesia. The most common surgical procedure was appendectomy, followed by omental patch closure (Graham patch) for duodenal ulcer perforation. The intra-operative and immediate post-operative characteristics of both groups were comparable except for higher P
Patient Characteristics of the Study and Control Groups
Independent Student t-test.
Chi-square test.
CHD = coronary heart disease; CKD = chronic kidney disease; ASA = American Society of Anesthesiologists.
Intra-Operative Measurements of Study and Control Groups
Independent Student t-test.
MAP = mean arterial pressure; SD = standard deviation.
Comparison of Pao2 and ANOVA of Pao2 during Pre-Operative, End-Operative, and Two Hours Post-Operative, between the Two Groups
Comparison between pre-operative and end-operative P
Comparison between pre-operative and post-operative P
Comparison between end-operative and post-operative P
p-value was analyzed by Student t-test.
Indicates post hoc test (Tukey HSD).
P
Surgical site infection was observed in 19 cases (20.43%) in the study group and 29 (34.11%) in the control group. The difference in the incidence of SSI in both groups was statistically significant (p = 0.04). The rate of respiratory complications, PONV were similar in both the study and control groups (Table 4). Of the 19 SSI in the study group, wound swab culture showed negative growth in three SSIs and positive growth in 16 SSIs. Of the 29 infections in the control group, wound swab showed negative culture in four patients. On subgroup analysis in patients undergoing surgery under regional anesthesia, SSI rates in both groups did not differ significantly (p = 0.13).
Comparison of Outcomes between the Two Groups
Chi-square test.
SSI = surgical site infection; PONV = post-operative nausea and vomiting.
In the study group, of 19 SSIs, 13 infections were superficial and six cases were deep incision infections. In the control group, of 29 SSIs, 24 patients had superficial infections and five had deep incision infections. The rate of SSI was more in patients who were 60 years or older in both groups. The SSI rate was 1.5 times higher if the patient was a known smoker. The rate of SSI was similar in males and females in both groups. The SSI rate was 2.9 times higher if a patient had any comorbidity such as hypertension, diabetes, coronary heart disease, or chronic kidney disease (Table 5).
Factors Affecting SSI and Their Risk Analysis by Multiple Logistic Regression
Chi-square test.
SSI = surgical site infection; CI = confidence interval.
In this study group, 12 patients (12.9%) had PONV, and in the control group, 16 patients (18.82%) had PONV. Four patients in the study group and nine patients in the control group received ondansetron 4 mg intravenously for severe PONV. Respiratory complications were similar in both the study and control groups. In the study group, eight (8.6%) patients developed respiratory complications, of whom four patients developed atelectasis, and four cases had pneumonia. Five patients had atelectasis in the control group, and two patients had pneumonia for a total of seven patients (8.2%) with respiratory complications.
Discussion
Surgical site infection is the most common hospital-acquired infection in surgical patients [1]. It results in delayed incision healing, and prolonged hospital stays, adding to hospital cost, and increased morbidity and mortality [2].
In recent years, SSI is a common preventable outcome that has been the focus of improvement of the quality of care. Factors such as antibiotic drug selection and timing of administration, prevention of peri-operative hypothermia, maintenance of euglycemia, meticulous details to surgical technique and adequate post-operative pain control have been proved to reduce the SSI rate [14–17].
In addition to its effects on SSI and PONV, hyperoxygenation is shown to influence incision healing. The formation of scars after surgical incision requires hydroxylation of proline and lysine residues, as substrate oxygen catalyzes the prolyl and lysyl hydroxylases. However, the Michaelis-Menton constant (Km) for oxygen of prolyl hydroxylase is 20 to 25 mm Hg. By increasing P
We evaluated the effect of hyperoxygenation on SSI and PONV on patients undergoing emergency open abdominal surgeries. We observed SSI in 19 cases (20.43%) in the study group and 29 cases (34.11%) in the control group. After considering the multiple factors affecting the SSI by multiple logistic regression analysis, the risk reduction associated with supplemental peri-operative hyperoxygenation observed was 59%. This was similar to the 54% risk reduction in SSI risk associated with 80% FIO2 by Belda et al. [15] on 300 elective colorectal surgeries.
These results were similar to the study results of Grief et al. [18] on 500 colorectal surgeries where the incidence of wound infection in the control group was more than two times that of the study group (11.2% vs. 5.2%). Hopf et al. [19] studied the effect of hyperoxygenation in surgical patients and determined that the rate of incision infection is inversely proportional to the oxygen tension of the subcutaneous wound (Psq
Pryor et al. [16] obtained contrasting results in their study of 165 patients using 80% oxygen in the study group and 35% oxygen in the control group. The SSI rate was higher in the study group than the control group (25% vs. 11.3%). However, this could be attributed to differences in the patients' baseline and intra-operative characteristics in both groups. Obesity (body mass index [BMI] >30 kg/m2), which is a factor for SSI, was high among patients in the 80% oxygen group (23.8% vs. 11.3%). In addition, patients in the 80% oxygen group had more prolonged operations, more blood loss, and required increased fluid replacement, which could have indirectly contributed to the increased incision infections in their study [16].
The incidence of a positive culture of pathogenic organisms from surgical sites in the study group was 17.2%, whereas it was 30.6% in the control group. This difference was also found to be statistically significant. In the study by Grief et al. [18], SSI was considered only when there was positive growth in the culture whereas Belda et al. [15] used the CDC definition for defining SSI. In our study, we studied the incidence of SSI by using both CDC criteria and a positive culture of pathogens, both showing a lesser infection rate in the 80% oxygen group.
In our study, patients were followed up post-operatively for 14 days for diagnosing SSI. Belda et al. [15] and Pryor et al. [16] in their studies also followed the patients for 14 days to study SSI occurrence. Mayzler et al. [20] and Myles et al. [21] followed the patients for 30 days for diagnosing SSI. In the study by Mayzler et al. [20] only one patient developed SSI 15 days after surgery at the post-operative visit. Grief et al. [18] estimated that 70% of SSI occurs in the first ten days of the post-operative period. In the study by Sudharsanan et al. [22], the mean day of occurrence of post-operative incision infection was 5.15. It was concluded in various studies that most of the incision infections occur within the first two weeks of surgery; therefore, patients were followed for 14 days in our study [23].
The present study included the commonly performed emergency surgical procedures and was not specific to a particular surgery type. Hence, there is heterogeneity in our study. Bickel et al. [1] included only patients undergoing an emergency appendectomy in their study. Belda et al. [15] conducted their study on patients undergoing elective colorectal surgeries. Hyperoxygenation decreased the incidence of SSI irrespective of the type of surgical procedure in our study.
Patients with malignancies have a higher susceptibility to infection and delay in incision healing because of the disease process and associated malnutrition. The number of patients who had undergone emergency surgery for malignancy was less in our study than the studies by Belda et al. [15] and Grief et al. [18]. Kadija et al. [24] observed in their study that malignancy was associated with four- to five-fold increased risk of surgical site infection. The number of patients with malignancies in both the study and control groups in our study is comparable, therefore the confounding effects of malignancy in incision infection need not be considered in our study.
In the study by Meyhoff et al. [17], all patients underwent surgery under general anesthesia with oxygen and nitrous oxide. Our study included patients who underwent emergency abdominal surgeries under both general as well as local anesthesia. Subgroup analysis done for patients who underwent surgery under regional anesthesia showed a lesser SSI rate in the study group than the control group, although it was not statistically significant.
In patients older than 60 years of age, the number of patients with SSI was more in both groups. After multiple logistic regression analysis, the risk of SSI in those older patients was 5.9 times higher compared with other younger patients. The numbers of patients having comorbidities were comparable between the two groups. The risk of getting SSI in a patient with at least one comorbidity (diabetes, hypertension, congestive heart disease, chronic kidney disease) was 2.9 times compared with patients without comorbidities.
Previous studies identified smoking as a risk factor for SSI [25]. In our study, the risk of SSI was 1.5 times higher in smokers than non-smokers, but it was not statistically significant. One reason for this is because of the time-limited effect of smoking on tissue oxygenation [18]. Most of the smokers in our study did not have access to smoking in the immediate pre-operative and post-operative period, therefore, sustained tissue oxygenation reduction was prevented.
There was no statistically significant difference in mean core body temperature between the two groups. Hypothermia stimulates thermoregulatory vasoconstriction and thereby decreases partial pressure of oxygen in the tissues. At low P
Elevated partial pressure of oxygen in the blood can cause pulmonary absorption atelectasis and oxygen radical formation in lung microvessels [18]. Usually, oxygen-induced atelectasis is a short-term effect, and it resolves spontaneously even before the patient's mobilization. However, patients of both groups had similar incidence and severity of atelectasis and poorly aerated lung fields in the first post-operative day. The incidence of atelectasis in our study was 4.3% and 5.9% in the study and control groups, respectively. Similar findings were observed in their study by Meyhoff et al. [17], in which the incidence of post-operative atelectasis was 7.9% and 7.1%, respectively, in the study and control groups.
The incidence of PONV was less in the 80% oxygen group (12.9% vs. 18.8%), although this difference was not statistically significant (p = 0.3). Meyhoff et al. [17] found a marked reduction in the rate of severe nausea or vomiting in the first 24 hours of surgery in the 80% oxygen group. In their study, patients in the study group received 80% oxygen with 20% nitrous oxide, and those in the control group received 30% oxygen with 70% nitrous oxide. Severe PONV was seen in 23% cases in the 30% oxygen group and only in 10% cases in the 80% oxygen group [17]. Because nitrous oxide is a proven risk factor for PONV, this difference in their study may be because of the effect of nitrous oxide [17,21].
Conclusions
In this prospective double-blind randomized controlled trial, we assessed the effect of peri-operative hyperoxygenation on SSI incidence in patients undergoing emergency abdominal surgery. In conclusion, 80% peri-operative hyperoxygenation during and two hours after emergency abdominal surgery is beneficial in reducing SSI. The incidence of PONV was not reduced, and there was no increased risk of respiratory complications after administration of 80% oxygen. Because SSI incidence is greater after emergency surgery, it is one of the cost-effective methods in reducing SSI.
Footnotes
Authors' Contributions
Conception and design: Sarath Chandra Sistla; Collection and assembly of data: Prasad Yerra; Data analysis and interpretation: Balamourougan Krishnaraj, Gomathi Shankar; Literature review: Prasad Yerra, Sudharsanan Sundaramurthi; Supervision: Sujatha Sistla, Pankaj Kundra; Manuscript writing: Prasad Yerra, Sudharsanan Sundaramurthi, Balamourougan Krishnaraj; Critical review: Sarath Chandra Sistla, Sujatha Sistla. Sudharsanan Sundaramurthi is the guarantor of this article. All authors approved the final version.
Funding Information
No support was received.
Author Disclosure Statement
No competing financial interests exist.
