Surgical site infections and healing-related complications are among the most common serious complications of anesthesia and surgery.1–4 The morbidity and related cost associated with surgical infections and the resulting major complications are considerable; estimates of prolonged hospitalization vary from 5 to 20 days per infection.5–7
Oxidative killing is the most important immune defense against surgical pathogens, with killing intensity increasing throughout the range of 0 to ≥150 mm Hg oxygen.8,9 Oxidative killing requires molecular oxygen that is enzymatically transformed into the bactericidal radical superoxide.10 Subcutaneous tissue oxygen values near 60 mm Hg are typical in euthermic, euvolemic, healthy volunteers breathing room air.11 Perioperative subcutaneous oxygen partial pressures <40 mm Hg are associated with high infection risk, whereas partial pressures >90 mm Hg are rarely associated with infection.12,13 Adequate tissue oxygenation is also necessary for collagen deposition (scar formation), which is an essential step in wound healing and tissue repair.14
The partial pressure of oxygen in subcutaneous tissues (PsqO2) varies widely, even in patients whose arterial hemoglobin is fully saturated. Factors known to influence tissue oxygen tension include core15 and local temperature,16 smoking,17 anemia,18 perioperative fluid management,19 neuraxial anesthesia,20 and uncontrolled surgical pain.21 As might be expected, increasing the fraction of inspired oxygen augments tissue oxygen tension.22 Supplemental perioperative oxygen was found to reduce the risk for anastomotic leak23 and wound infection in some randomized studies,22,24 but not in others.25,26
Morbidly obese patients are at high risk of wound infection and healing-related complications. Low tissue oxygenation presumably contributes to infection risk in these patients. For example, PsqO2 approaches 120 mm Hg when PaO2 reaches 300 mm Hg in nonobese patients compared with 50 mm Hg in the morbidly obese with similar PaO2.22 Administration of 50% inspired oxygen, a concentration that produces a PaO2 of approximately 300 mm Hg for most patients, results in critically low (approximately 40 mm Hg) perioperative subcutaneous tissue oxygenation27 in the morbidly obese, a value associated with a high risk of infection.28 Obese patients are thus on the “steep part of the curve” relating PsqO2 to neutrophil production of high-energy oxidative species.8
Morbidly obese surgical patients are not just at risk of inadequate tissue oxygenation during surgery. Obstructive sleep apnea, which is rampant in this population, is directly proportional to the body mass index (BMI).29–31 The associated arterial desaturation is especially severe after surgery because the syndrome is markedly worsened by opioid analgesics. Obstructive sleep apnea reduces arterial oxygenation during sleep30,32 and presumably also reduces tissue oxygenation intermittently. Supplemental oxygen may thus be especially helpful in the morbidly obese since baseline tissue oxygenation is low and, in many cases, will be further reduced by opioid-aggravated perioperative obstructive sleep apnea.
Morbidly obese patients may thus especially benefit from extending the duration of supplemental oxygen to include the first postoperative night, when the likelihood of hypoxia-related complications may be the highest due to residual effects of general anesthesia and opioid analgesia. We therefore tested the hypothesis that the risk of major complications related to infection or inadequate healing is lower in morbidly obese patients who are given approximately 80% supplemental inspired oxygen for 12 to 16 hours after gastric bypass surgery than in those given approximately 30% oxygen (2 L/min via nasal cannula).
Patients were recruited at 3 different hospitals: Cleveland Clinic, Cleveland, Ohio; University of Vienna, Vienna, Austria (AKH); and the Norton Hospital, Louisville, Kentucky. Approval was obtained from the IRBs of each of the 3 participating hospitals, and written informed consent was obtained from each patient. Patients having Roux-en-Y gastric bypass, either open or laparoscopic, with anticipated primary wound closure were included. We excluded patients with a history of fever or infection within 24 hours of surgery, a history of susceptibility to malignant hyperthermia, or with current heart and lung disease.
Patients were premedicated with 2 to 3 mg midazolam in the preoperative holding area or just before anesthetic induction. Anesthesia was induced with IV propofol and maintained with a volatile anesthetic that was adjusted to keep mean arterial blood pressure near 90% of the preinduction value. An inspired oxygen fraction of 1.0 was used at induction of anesthesia until tracheal intubation and during extubation. All patients were standardized to receive 80% inspired oxygen during the intraoperative period. Patients’ lungs were mechanically ventilated with a tidal volume of 6 to 8 mL/kg of ideal body weight at a rate sufficient to maintain end-tidal PCO2 near 40 mm Hg; a positive end-expiratory pressure of 5 to 10 cm H2O was applied.
Patients were given approximately 10 mL/kg/h of crystalloid throughout surgery, normalized to ideal body weight. Fluids were standardized at a rate of 3.5 mL/kg/h for the first 24 postoperative hours and at a rate of 2 mL/kg/h for the subsequent 24 hours, again normalized to ideal body weight. Intraoperative core temperature was maintained near 36°C using forced-air warming and heated IV fluids.33,34 Patients were given 100% inspired oxygen before tracheal extubation. Intraoperative analgesia was provided with IV fentanyl titrated at the discretion of individual anesthesiologists. Each morbidly obese patient may have had different requirements of opioids, so the protocol was not strict. Postoperative analgesia was provided by patient-controlled morphine or hydromorphone.
Patients were assigned 1:1 to routine or supplemental postoperative oxygen. Randomization was based on reproducible computer-generated codes that were maintained in sequentially numbered opaque envelopes until the end of surgery. Randomization was stratified by study site. The 2 groups are listed below:
1. Routine oxygen administration: Extubated patients were given 2 L/min oxygen via a nasal cannula until the first postoperative morning. This provides 24% to 30% inspired oxygen in most patients.35 When patients used a continuous positive expiratory pressure (CPAP) machine at home and could not maintain oxygen saturation ≥90% with the nasal cannula alone, they were switched to their CPAP machines at an inspired oxygen concentration (FIO2) to 30%. FIO2 was maintained at 30% in patients who remained intubated. Additional oxygen was given as necessary to maintain oxygen saturation ≥90%.
2. Supplemental oxygen administration: After extubation, patients were given 10 L/min of oxygen via a nonrebreathing Hi-Ox mask (Viasys Healthcare, Inc., Yorba Linda, CA), a valved manifold system. An oxygen flow of 5 L/min produces a supplemental inspired concentration of approximately 80%, even at a minute ventilation of 12 L/min, which few patients exceed.36,37 When patients used a CPAP machine at home and could not maintain oxygen saturation ≥90% with the Hi-Ox mask, they were switched to their CPAP machines at an inspired oxygen concentration of 80%. In patients who experienced claustrophobia or severe discomfort from the Hi-Ox mask, a venturi style dual-dial mask was substituted at an oxygen flow rate of 15 L/min. This mask delivers nebulized oxygen, which makes it more comfortable for patients and delivers approximately 60% inspired oxygen. FIO2 was maintained at 0.8 in patients who remained intubated.
The oxygen flowmeters were concealed from blinded surgeons and nursing staff. The nurses were instructed not to change the oxygen settings until the first postoperative morning, unless clinically indicated (oxygen saturation <90%).
The designated oxygen management was maintained until the first postoperative morning. Patients wore oxygen masks or nasal prongs while in bed but were allowed to remove them briefly as necessary (e.g., to visit the bathroom). To encourage compliance with the randomized oxygen assignment, an investigator visited patients when they first arrived on the surgical ward from the recovery room, the evening of surgery, and the first postoperative morning.
Demographic characteristics of patients were tabulated. We also recorded preoperative laboratory values (including plasma glucose concentration), smoking history, and American Society of Anesthesiologists Physical Status rating.
Fluids administered, estimated blood loss, urine output, and amount of opioids used were recorded daily throughout hospitalization. If blood gas analyses were obtained for clinical reasons, the results were recorded.
We also recorded the amount of morphine sulfate or hydromorphone given from the end of surgery until the first and second postoperative mornings. Patients were asked to rate their pain on a 100-mm-long visual analog scale at 30-minute intervals for the first hour of recovery and on the first and second postoperative mornings. Blood glucose was measured on first and second postoperative mornings.
Baseline risk of infection was evaluated using the Centers for Disease Control and Prevention Study on Efficacy of Nosocomial Infection Control (SENIC) score, where 1 point each was assigned for ≥3 diagnoses, surgical duration ≥2 hours, abdominal site of surgery, and the presence of a contaminated or dirty-infected wound.38 The score was slightly modified from its original form by our use of admission, rather than discharge, diagnoses. Infection risk was further quantified using the National Nosocomial Infection Surveillance System, in which risk was predicted based on the type of surgery, American Society of Anesthesiologists Physical Status rating, and the duration of surgery.39
We recorded the times oxygen was removed by either the patient or the nurse. A blinded investigator, who did not have any contact with the patient on the day of surgery or first postoperative day, began evaluations for surgical site infection and healing-related complications on the second postoperative day. As in our previous studies,24,40,41 surgical wounds were considered infected when they met the 1992 revision42 of the Centers for Disease Control criteria for surgical wounds originally proposed in 1985.38 Infections were classified as superficial incisional, deep incisional, and peritoneal infections, according to the criteria.
Wound healing and infections were also numerically scored using the ASEPSIS system.43 This is an established and validated system for quantifying surgical wound infections and evaluating wound healing. The score was derived from the weighted sum of points assigned for the following factors: (1) duration of antibiotic administration, (2) drainage of pus under local anesthesia, (3) debridement of the wound under general anesthesia, (4) serous discharge, (5) erythema, (6) purulent exudate, (7) separation of deep tissues, (8) isolation of bacteria from discharge, and (9) hospitalization exceeding 14 days.
Patients were discharged from the hospital based on the decisions made by the attending surgeons, who were blinded to randomization. After discharge, an investigator blinded to postoperative oxygen management evaluated patients every fifth day via a phone call until the 30th postoperative day, and then on the 45th and 60th postoperative days. When patients reported an infection or complication, an investigator would begin daily phone calls and medical records were obtained as necessary from local providers.
Patients were examined during their 2-week clinic visit, if they reported symptoms suggestive of infection during the phone interviews. If patients were not available during phone calls, the investigator called them every other day until they responded. We included complications up to 60 days after surgery instead of the standard 30 days because in a preliminary study, major complications potentially related to infection or healing occurred in 5% of the patients between 30 and 60 postoperative days.
Composite outcomes, in which multiple end points are combined, are sensitive measures of perioperative status and have been used in several major outcome studies.44,45 Our a priori list of qualifying major complications and the requirements for diagnosis are shown in Table 1. Our primary outcome was the occurrence of any major complication in a patient within 60 days of surgery.
We compared the randomized groups on the incidence of any major complication using the Cochran–Mantel–Haenszel46 statistic adjusting for hospital (University of Vienna, Cleveland Clinic Foundation, and Norton Hospital). We used the Breslow–Day test47 to assess whether the treatment effect differed across the 3 hospitals. The primary analysis was an “intention-to treat” analysis; in addition, a “per protocol” analysis was implemented for the information purpose. Furthermore, we compared the randomized groups on the number of major complications using a Poisson regression adjusting for hospitals.
Both the main trial data and our pilot data suggested that the effect of oxygen (80% vs 30%) may vary by type of surgery (we suspected an effect mainly for open cases); we therefore assessed the oxygen treatment effect within surgery type (laparoscopic and open). We first assessed the interaction between oxygen and surgery type using for the main trial data using the Breslow–Day test, and then assessed the oxygen effect separately for open and laparoscopic surgeries. Finally, we assessed the treatment effect combining the open cases from the main trial (9% open) and pilot trial (98% open) using the Cochran–Mantel–Haenszel method.
Sample Size Consideration
Our sample size estimate was based on the preliminary data collected at the University of Louisville Hospital in 96 patients undergoing open Roux-en-Y gastric bypass randomized to either 30% or supplemental (approximately 80%) inspired oxygen for the first 12 to 16 hours after surgery. We observed a 40% reduction in the incidence of major complications.48
Our study was planned to recruit 1276 patients (638 per group) to have 90% power at the 5% significance level to detect a 25% reduction or more in incidence of major complications in the supplemental versus 30% oxygen group using a 1-tailed test in the direction favoring supplemental oxygen. Interim group sequential analyses were planned at 25%, 50%, and 75% recruitment with a γ spending function (γ = −1 for efficacy and −5 for futility). Stopping boundaries were prespecified for futility and efficacy.
The final analysis was conducted in 400 patients; the group sequential boundaries for efficacy and futility were P ≤ 0.0213 and P ≥ 0.2757, respectively. Confidence intervals (CIs) were adjusted for the interim analysis by using the group sequential critical value (Z = 2.303 at n = 400) for significance instead of the traditional Z statistics of 1.96 in the 95% CI formula.
SAS version 9.3 (SAS Institute, Cary, NC) was used for the statistical analyses. East 5 statistical software (Cytel Inc., Cambridge, MA) was used to design the trial and conduct the interim monitoring.
We conducted our first planned interim analysis after enrollment of the first 307 patients (24% of total planned enrollment) was complete. The Executive Committee closed the trial based on concerns of futility of the intervention and recruitment difficulties; consequently, the projected sample size was not reached. Ninety-five additional patients were randomized while outcomes data on the 307 patients were being collected and evaluated. Results from all 402 randomized patients were included in this final analysis. There were 2 withdrawals before surgery; no further data were collected in these 2 patients, and thus 400 patients were included in the final analysis; 198 were assigned to nasal cannula oxygen and 202 to supplemental oxygen (Fig. 1).
Many patients had laparoscopic Roux-en-Y gastric bypass (91%); the remainder had open Roux-en-Y gastric bypass (9%). The type of surgery and approach varied among the sites. Twenty-three percent of patients in the supplemental oxygen group received antibiotics more than 1 hour before the start of incision; 72% received antibiotics within 1 hour before incision, while 5% received antibiotics after incision; 8% of patients who received antibiotics in the 30% group were given antibiotics >1 hour before the start of surgery, 78% received antibiotics within 1 hour before incision, and 14% received antibiotics after incision; 31% in the supplemental and 34% in the 30% group were given cephalosporin; 7% in the supplemental group and 6% in the 30% group were given vancomycin; and 1 patient in the supplemental group received ciprofloxacin.
The 2 groups had similar baseline and demographic variables (standardized difference <0.30, Table 2). Preoperative and intraoperative glucose concentrations were comparable in the 2 groups (Tables 2 and 3). Both groups were given similar amounts of intraoperative crystalloids and opioids. The median duration of surgery was 2.7 hours in the 80% oxygen group and 2.6 hours in the 30% oxygen group (Table 3). Nasal cannula oxygen was well tolerated. Among the patients randomized to supplemental oxygen (n = 202), only 32 patients (16%) did not tolerate the tightly fitting Hi-Ox mask and were instead given supplemental oxygen with an open humidified mask at a flow rate of 15 L/min.
Among the observed complications, surgical wound infection was the most common, occurring in 8.5% of patients. The incidence of surgical wound infection was similar in patients randomized to either supplemental oxygen (8%, 16 of 202) or 30% oxygen (9%, 18 of 198). The observed median ASEPSIS score was 1 (interquartile range: 0–4) within each group. There was 1 death in the supplemental group and 2 deaths in the 30% oxygen group (Table 1).
The overall observed incidence of the collapsed composite major complication (Table 1) was 13% (i.e., 53 of 400); it was almost identical in the 2 groups and much lower than anticipated in the 30% group. The estimated relative risk (supplemental versus nasal cannula oxygen adjusted for study site) was 0.94 (95% CI: 0.52–1.68; P = 0.80). Furthermore, per protocol analysis, where 32 patients who did not tolerate the Hi-Ox mask were eliminated from the comparison, provided a consistent result (RR: 1.01 [0.55–1.84], P = 0.98).
There was no interaction between hospital and randomized group on the primary outcome (P = 0.36, Breslow–Day test). The Austrian center had an overall complication rate of 7% (7 of 98; RR: 0.75 [0.14–4.09], P = 0.70); the rate at the Cleveland Clinic was 15% (37 of 253; RR: 1.17 [0.58–2.36], P = 0.61); and the rate in Louisville was 18% (9 of 49; RR: 0.44 [0.10–1.96], P = 0.21, Table 4).
No difference was found in the number of major complications between the supplemental group (176 [87%], 22 [11%], 1 [0.5%], and 3 [1.5%] patients had 0 to 3 major complications, respectively) and the 30% oxygenation group (171 [86%], 23 [12%], 2 [1%], and 2 [1%], respectively), P = 0.92. The estimated ratio of number of complications was 0.97 (95% CI: 0.55–1.72) for the supplemental group versus the 30% oxygenation group, as per the Poisson regression analysis adjusting for hospitals.
No interaction was found between BMI quartile and the effect of randomized group on incidence of major complications (P = 0.34, Breslow–Day test, Table 5) nor did the effect of supplemental oxygen on major complications depend on type of surgery (P = 0.44, Breslow–Day test). Furthermore, there was no supplemental oxygen effect within laparoscopic surgery (RR: 1.06 [0.54–2.07]) or open Roux-en-Y gastric bypass surgery (RR: 0.67 [0.20–2.29], Table 6).
Within open Roux-en-Y gastric bypass surgery, the relative risks between the supplemental group and the 30% group were not different between the main trial and the pilot trial (P = 0.66, Breslow–Day test, Table 7). Since the number of complications was so low, we did not perform subanalysis of the data per surgical duration.
All surgical wounds become contaminated. What determines whether inevitable contamination progresses to clinical infection is largely the adequacy of host defense. The primary host defense against surgical pathogens is oxidative killing by bacteria, a process that depends on the partial pressure of oxygen over the entire range of physiologic values. Superoxide radical production is necessary for host defense and correlates directly with the inspired oxygen concentration.
Obese patients having laparoscopic surgery require more inspired oxygen to produce similar arterial oxygen partial pressures than lean individuals. They also have significantly lower subcutaneous oxygen tensions (36–41 vs 57 mm Hg).27,49 Supplemental inspired oxygen (80%) significantly increases subcutaneous oxygenation in the upper arm in morbidly obese patients: 58 vs 43 mm Hg. Tissue oxygenation progressively increases with supplemental oxygen to a maximal difference of about 40 mm Hg after 13 postoperative hours (94 vs 52 mm Hg). Supplemental oxygen also improves tissue oxygenation adjacent to abdominal wounds: 75 vs 52 mm Hg, P = 0.005.37
We were thus unsurprised that supplemental postoperative oxygen almost halved the risk of infection-related complications in our preliminary study of morbidly obese patients having open Roux-en-Y gastric bypass (n = 96).48 There was, nonetheless, no statistically significant difference in the risk of surgical site infections or associated complications in the 400 patients we randomized to supplemental (approximately 80%) or nasal cannula (approximately 30%) oxygen for 12 to 16 postoperative hours. Major complications were chosen to be serious and plausibly related to infection or wound healing, both of which were likely to be improved by supplemental oxygen. Use of a composite outcome was intuitive for this study because we expected supplemental oxygen to reduce the risk of various complications; a single outcome, such as surgical site infection, was unlikely to capture the anticipated treatment benefit so well.
The most obvious difference between the preliminary study and full trial was that a laparoscopic approach was used in 91% of the patients in the full trial, whereas all the preliminary cases were open. Although there was a nonsignificant trend toward a benefit from supplemental oxygen in open procedures in the full trial (n = 37, relative risk 0.67 [95% CI: 0.2–2.3]), there was no overall benefit when open and laparoscopic cases were combined. Since the current surgical trend is toward laparoscopic procedures even in the most morbidly obese patients, it is the results in all patients (mostly laparoscopic) that are most relevant to current practice.
The overall rate of surgical site infections and complications (13%) was lower in both groups than the 25% we expected based on previous studies25,50,51 and our preliminary data.48 However, as more Roux-en-Y gastric bypasses are done laparoscopically and surgical technique improves, the incidence of complications has decreased even in the largest patients.52,53 Neither the futility nor efficacy boundaries were crossed after recruitment of the initial quarter of the patients. However, the futility boundary was crossed at the final analysis of 400 patients (P = 0.80 > the futility boundary of 0.2757). The Executive Committee thus stopped the trial since the probability of identifying a significant difference was low even if the trial continued to completion.
When we started the trial, available evidence suggested that supplemental oxygen, continued to –6 hours postoperatively, almost halved infection risk.22 However, the extent to which supplemental oxygen might be protective for wound infection is now unclear after recent publications of the PROXI and ISO2 trials.25,54 Our current results do not directly address optimal intraoperative oxygen management since randomization was restricted to the postoperative period and all patients received supplemental oxygen in the intraoperative period. Nonetheless, our results seem inconsistent with the general theory that supplemental oxygen reduces wound infection risk.
Why supplemental oxygen does not further reduce surgical site infections and complications in the morbidly obese population remains unclear, especially given the overwhelming evidence that tissue oxygenation is a key determinant of oxidative killing and that oxidative killing is the primary defense against bacterial contamination.8,9 But it is possible that oxygen is no longer effective after the “decisive period” for infection has passed, which is determined to be within a few hours after contamination, which is the incision.
Aside from the timing and duration of supplemental oxygen administration, the major difference between previous trials of supplemental oxygen and our current results is that our patients were morbidly obese. The obese patient population was selected in this study for providing supplemental oxygen since perioperative tissue oxygenation is normally low in this population,22 and high inspired concentrations are required to return tissue partial pressures to the normal range.27 Tissue oxygenation is also impaired by frequent hypoxemic episodes during sleep by the presence of obstructive sleep apnea, which has a prevalence approaching 75% to 86% in this obese population.30–32
Consistent with their many risk factors, wound infections and infection-related complications are common in the obese. In 189 patients having colorectal procedures, for example, wound infection risk significantly correlated with the thickness of subcutaneous fat: 8% of those with <2 cm of subcutaneous fat developed a wound infection compared with 27% with >4.5-cm fat. Infected wounds had 1.2 ± 0.4 cm greater fat thickness than noninfected wounds.55 Another study of 608 patients having digestive tract surgery reported that, after multivariable analysis, obese patients (BMI >30 kg/m2) had an adjusted odds ratio for surgical site infection of 4.8 (95% CI, 2.95–7.81).56
Fleischmann et al.49 and Kabon et al.27 demonstrated that obese patients need a greater FIO2 to reach the same arterial oxygen partial pressure than nonobese patients. And finally, obese patients had lower tissue oxygen partial pressures in both the upper arm and near the incision, even when oxygen administration was adjusted to provide comparable arterial oxygen partial pressures. Nonetheless, supplemental postoperative oxygen did not reduce the risk of infection or a composite of major complications plausibly related to infection or wound healing. Supplemental postoperative oxygen thus seems unlikely to prove beneficial in nonobese subjects also, although the theory would be well worth testing in surgical populations at special risk of infection such as colorectal surgery.
We were unable to precisely control inspired oxygen concentration in patients assigned to supplemental oxygen. Patients randomized to supplemental postoperative oxygen thus received between 65% and 95% inspired oxygen, depending on their minute ventilation and ability to tolerate a sealed mask postoperatively. Nonetheless, in a previously published substudy, we showed that supplemental oxygen substantially increases subcutaneous oxygenation in the arm and adjacent to the surgical incision, suggesting that our administration methods were effective.49
In summary, the composite risk of wound infection and major complications related to infection or wound healing was similar in gastric bypass patients who were randomly assigned to approximately 30% or approximately 80% inspired oxygen administered from tracheal extubation through the first postoperative morning. Supplemental postoperative oxygen does not appear to be beneficial in this population.
APPENDIX. SUPPLEMENTAL POSTOPERATIVE OXYGEN TRIAL (SPOT) INVESTIGATORS
SPOT investigators from the University of Louisville included Anupama Wadhwa, MD, Mukadder Orhan Sungur, MD, Ryu Komatsu, MD, Ozan Akça, MD, Jorge Rodriguez, MD, and Raghavendra Govinda, MD. Investigators from the Cleveland Clinic included Daniel I. Sessler, MD, Andrea Kurz, MD, Ramatia Mahboobi, MD, Ankit Maheshwari, MD, Angela Bonilla, MD, Xuegin Ding, MD, Bledar Kovachi, MD, Jing You, MS, Edward J. Mascha, PhD, Luke Reynolds, BS, James Beckman, BS, Karen Steckner, MD, FRCPC, and Sara Kazerounian. Investigators from Vienna include Edith Fleischmann, MD, Barbara Kabon, MD, Erol Erdik, MD, Gerhard Prager, MD, Eva Obwegeser, MD, and Ratzenboeck Ina, MD.
Name: Anupama Wadhwa, MD.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Attestation: Anupama Wadhwa has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
Name: Barbara Kabon, MD.
Contribution: This author helped conduct the study and write the manuscript.
Attestation: Barbara Kabon reviewed the analysis of the data and approved the final manuscript.
Name: Edith Fleischmann, MD.
Contribution: This author helped conduct the study and write the manuscript.
Attestation: Edith Fleischmann has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Andrea Kurz, MD.
Contribution: This author helped design the study, conduct the study, and write the manuscript.
Attestation: Andrea Kurz reviewed the analysis of the data and approved the final manuscript.
Name: Daniel I. Sessler, MD.
Contribution: This author helped design the study, conduct the study, analyze the data, write the manuscript, and mentored the study.
Attestation: Daniel I. Sessler has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
This manuscript was handled by: Sorin J. Brull, MD, FCARCSI (Hon).
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