Supplemental Postoperative Oxygen Does Not Reduce
Surgical Site Infection and Major Healing-related
Complications From Bariatric Surgery in Morbidly
Obese Patients:
A Randomized, Blinded Trial
Anupama Wadhwa MD*, Barbara Kabon MD†, Edith Fleischmann
MD‡, Andrea Kurz MD§, Daniel I. Sessler MD& for the Supplemental
Postoperative Oxygen Trial (SPOT) Investigators
* Associate Professor, Department of Anesthesiology & Peri-Operative Medicine
† Attending
Physician, Department of Anesthesiology and General Intensive Care,
Medical University of Vienna
‡ Professor,
Department of Anesthesiology and General Intensive Care, Medical
University of Vienna
§ Professor
and Vice-chair, Department of OUTCOMES RESEARCH, Cleveland Clinic,
Cleveland, Ohio, USA
&
Michael Cudahy Professor and Chair, Department of OUTCOMES RESEARCH, Cleveland
Clinic, Cleveland, Ohio, USA
Received from the Department of Anesthesiology & Perioperative Medicine, University
of Louisville, Louisville, KY; Department of Anesthesiology, Medical University of
Vienna, Vienna, Austria; and the Department of OUTCOMES RESEARCH, Cleveland Clinic,
Cleveland, OH.
Financial Support: This study was funded from internal sources only. Viasys
Healthcare, Inc. (Yorba Linda, CA) donated the Hi-Ox Disclaimer: None of the authors
has a personal financial interest in this research.
Running title: Supplemental Postoperative Oxygen.
Summary Statement: Extending supplemental oxygen until first postoperative morning
does not provide an additional protective effect over intra-operative supplemental
oxygen against complications in patients having laparoscopic and open gastric bypass.
Address Correspondence to:
Anupama Wadhwa, MBBS
Department of Anesthesiology & Peri-Operative Medicine
University of Louisville
530 S. Jackson Street
Louisville, KY 40202
Phone: (502) 852-1005
Fax: (502) 852-6056
Email: anwadh01@louisville.edu
On the world wide web: www.OR.org.
2
Abstract
Background: Morbidly obese patients are at a high risk for perioperative
complications, including surgical site infections. Baseline arterial oxygenation is low in
the morbidly obese, leading to low tissue oxygenation — which in turn is a primary
determinant of infection risk. We therefore tested the hypothesis that extending
intraoperative supplemental oxygen 12-18 hours into the postoperative period reduces
the risk of surgical site infection and healing-related complications.
Methods: Morbidly obese patients having open or laparoscopic bariatric surgery
were given 80% inspired oxygen intra-operatively. Postoperatively, patients were
randomly assigned to either 2 L/min of oxygen via nasal cannula or ≈80% supplemental
inspired oxygen after extubation until the first postoperative morning. The risks of
surgical site infection and of major healing-related complications were evaluated 60
days after surgery.
Results: In a pre-planned interim analysis based on the initial 400 patients, the
overall observed incidence of the collapsed composite of major complications was
13.3%; the observed incidence of components of the composite outcome ranged from
0% (peritonitis) to 8.5% (surgical wound infection). The estimated relative risk of any
one or more major complication occurring within the first 60 days after surgery,
adjusting for study site, was 0.94 [95% CI: 0.52, 1.68] (P = 0.80, Cochran-MantelHaenszel). The Executive Committee thus stopped the trial for futility.
3
Conclusion: Supplemental postoperative oxygen does not reduce the risk of
surgical site infection rate and healing-related postoperative complications in patients
having gastric bypass surgery.
4
Introduction
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 mmHg
oxygen.8,9 Oxidative killing requires molecular oxygen that is enzymatically transformed
to the bactericidal radical superoxide.10 Subcutaneous tissue oxygen values near 60
mmHg are typical in euthermic, euvolemic, healthy volunteers breathing room air.11
Perioperative subcutaneous oxygen partial pressures <40 mmHg are associated with
high infection risk whereas partial pressures >90 mmHg 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
5
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 mmHg when PaO2 reaches 300 mmHg in
non-obese patients compared with 50 mmHg in the morbidly obese with similar PaO2.22
Administration of 50% inspired oxygen, a concentration that produces a PaO2 of
approximately 300 mmHg for most patients, results in critically low (approximately 40
mmHg) perioperative subcutaneous tissue oxygenation27 in 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 aren’t just at risk of inadequate tissue
oxygenation during surgery. Obstructive sleep apnea, which is rampant in this
population, is directly proportional to the BMI29,30,31 — and 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 opioidaggravated peri-operative obstructive sleep apnea.
Morbidly obese patients may thus specifically benefit from extending the duration
of supplemental oxygen to include the first postoperative night, when the likelihood of
6
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 ≈80% supplemental inspired oxygen for 12-18 hours after gastric
bypass surgery than in those given 2 L/min 30% oxygen via nasal cannula.
7
Methods
Patients were recruited at three different hospitals: Cleveland Clinic, Cleveland,
Ohio, USA; University of Vienna, Vienna, Austria (AKH); and the Norton Hospital,
Louisville, Kentucky, USA. Approval was obtained from the Institutional Review Boards
of each of the three 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 having 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.
Protocol
Patients were premedicated with 2 to 3 mg midazolam in the pre-operative
holding area or just before anesthetic induction. Anesthesia was induced with
intravenous propofol or etomidate, and maintained with a volatile anesthetic that was
adjusted to keep mean arterial blood pressure near 90% of pre-induction value. An
inspired oxygen fraction of 1.0 was used at induction of anesthesia until tracheal
intubation and during extubation. Subsequently, patients were mechanically ventilated
with a tidal volume of 6-8 mL/kg of ideal body weight at a rate sufficient to maintain endtidal PCO2 near 40 mmHg; a PEEP of 5-10 cm H2O was applied.
Patients were given approximately 10 mL·kg-1·h-1 of crystalloid throughout
surgery, normalized to ideal body weight. Fluids were standardized at a rate of
3.5 mL·kg-1·h-1 for the first 24 postoperative hours and at a rate of 2 mL·kg-1·h-1 for the
8
subsequent 24 hours, again normalized to ideal body weight. Intraoperative core
temperature was maintained near 36°C using forced-air warming and heated
intravenous fluids.33,34 Patients were given 100% inspired oxygen before extubation.
Postoperative analgesia was provided by patient-controlled (PCA) 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 two groups were:
1. Routine oxygen administration. Extubated patients were given 2 L/min oxygen
via a nasal cannula until the first postoperative morning. This provides 24-30%
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 non-rebreathing 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 ≈80%, even at a minute ventilation of
12 L/min, which few patients exceed.36,37 When patients used a continuous
9
positive expiratory pressure (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 to 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 below 90%).
The designated oxygen management was maintained until the first postoperative
morning, which was typically 12-16 hours after extubation. Patients wore oxygen masks
or nasal prongs while in bed, but were allowed to remove them briefly as necessary
(e.g., bathroom visit). To maximize compliance with randomized oxygen management,
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.
Measurements
Demographic characteristics of patients were tabulated. We also recorded preoperative laboratory values (including plasma glucose concentration), smoking history,
and American Society of Anesthesiologists (ASA) Physical Status rating.
10
Fluids administered, estimated blood loss, urine output, 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 (CDC) SENIC score, where one point each was assigned for ≥ 3
diagnoses, surgical duration ≥ 2 h, 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 (NNISS),
in which risk was predicted based on type of surgery, ASA Physical Status rating, and
the duration of surgery.39
We recorded the times oxygen was removed either by 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 healingrelated 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 CDC criteria for surgical wounds originally proposed in 1987.38
11
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 two-week clinic visit if a problem was identified
during the phone interviews. 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.
12
Statistical Analysis
Composite outcomes, in which multiple endpoints are combined, are sensitive
measures of peri-operative status and have been used in several major outcome
studies.44,45 The use of a composite outcome was intuitive for this study because the
intervention was expected to affect many areas of patient outcome, and a single
outcome, such as surgical site infection, was unlikely to so well capture the anticipated
treatment benefit. 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. 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.
Primary analysis: We compared the randomized groups on the incidence of any
major complication using the Cochran-Mantel-Haenszel (CMH)46 statistic adjusting for
hospital (University of Vienna, Cleveland Clinic Foundation, and Norton Hospital). We
employed the Breslow-Day test 47 to assess whether the treatment effect differed across
the three hospitals.
Secondary analysis: Both the main trial data and our pilot data suggested that
the effect of oxygen (80% versus 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.
13
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 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 (≈80%) inspired
oxygen for the first 12-16 hours after surgery. We observed a 40% reduction in the
incidence of major complications.48
Our study was planned to recruit 1,276 total 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 one tailed
test in the direction favoring supplemental oxygen. Interim group sequential analyses
were planned at 25%, 50% and 75% recruitment with a gamma spending function
(gamma = -1 for efficacy and -5 for futility). Stopping boundaries were pre-specified for
futility and efficacy.
The final analysis was conducted at 400 patients; the group sequential
boundaries for efficacy and futility were P ≤ 0.0213 and P ≥ 0.2757, respectively.
Confidence intervals 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
statistic of 1.96 in the 95% confidence interval formula.
SAS version 9.3 (SAS Institute, Cary, NC, USA) 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.
14
Results
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 were being
collected and evaluated. Results from all 402 randomized patients were included in this
final analysis.
Patients were recruited at three different hospitals: Cleveland Clinic, Cleveland,
Ohio, USA; University of Vienna, Vienna, Austria (AKH); and the Norton Hospital,
Louisville, Kentucky, USA. There were two withdrawals before surgery; no further data
was collected in these two 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).
The majority of 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. Eighty-four percent of patients in both groups were given
prophylactic antibiotics within one hour before incision. Nine percent in the
supplemental oxygen group were given antibiotics more than one hour before the start
of incision, while 7% received antibiotics after incision. Two percent in the 30% group
were given antibiotics more than one hour before the start of surgery, and 14% received
antibiotics after incision. Eighty-one and eighty-four percent of patients were given a
15
cephalosporin in the supplemental and 30% groups respectively; 13% in both groups
were given vancomycin, and the rest received clindamycin.
The two groups were balanced on baseline and demographic variables
(standardized difference < 0.30, Table 2). Preoperative and intra-operative glucose
concentrations were comparable in the two groups (Tables 2 and 3). Both groups were
given similar amounts of intra-operative 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). There was one death in the supplemental group, two 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 / 400); it was almost identical in the two groups and much
lower than the 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, there was no interaction between hospital and randomized group
on the primary outcome (P = 0.36, Breslow-Day test). The Austrian center had an
16
overall complication rate of 7% (7/98; RR: 0.75 [0.14, 4.09], P = 0.70); the rate at the
Cleveland Clinic was 15% (37/253; RR: 1.17 ]0.58, 2.36], P = 0.61); and the rate in
Louisville was 18% (9/49; RR: 0.44 [0.10, 1.96[, P = 0.21, Table 4).
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 sub-analysis of the data per surgical duration.
17
Discussion
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 mmHg).27,49 Supplemental inspired oxygen (80%)
significantly increases subcutaneous oxygenation in the upper arm in morbidly obese
patients: 58 vs. 43 mmHg. Tissue oxygenation progressively increases with
supplemental oxygen to a maximum difference of about 40 mmHg after 13
postoperative hours (94 vs. 52 mmHg) Supplemental oxygen also improves tissue
oxygenation adjacent to abdominal wounds: 75 mmHg vs. 52 mmHg, 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 (≈80%) or nasal
cannula (≈30%) oxygen for 12-16 postoperative hours.
18
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 non-significant trend towards 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 towards 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
boundry was crossed at the final analysis of 400 patients (P = 0.80 > the futility
boundary of 0.2757). The Executive Committee nonetheless 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 2-6 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
19
was restricted to the postoperative period and all patients received supplemental
oxygen in the intra-operative period. Nonetheless, our results seem inconsistent with
the general theory that supplemental oxygen reduces wound infection risk. Why it 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 showing a benefit from 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 75-86%
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, the rate of wound infections 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
20
greater fat thickness than non-infected 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 percent
confidence interval, 2.95–7.81).56 Fleischmann49 and Kabon27 and their colleagues
demonstrated that obese patients need a greater FiO2 to reach the same arterial
oxygen partial pressure than non-obese patients. And finally, obese patients have 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
non-obese 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 65-95% inspired oxygen depending on their minute
ventilation and ability to tolerate a sealed mask post-operatively. Nonetheless, in a
previously published sub-study, 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 ≈30% or ≈80% inspired oxygen administered from extubation
21
through the first postoperative morning. Supplemental postoperative oxygen does not
appear to be beneficial in this population.
22
*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 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.
23
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Figure 1
32
Table 1: Primary Outcome: Major Complications Related to Infection or Healing
Incidences
Complication
Requirements for acceptance
80% / 30% Oxygen
(N total = 202 / 198)
Surgical wound infection
CDC criteria
16 / 18
Anastomotic leak
Requiring surgery
5/3
Intra-abdominal abscess
Ultrasound or CT scan
2/3
Peritonitis without leak
Surgery, excepting anastomotic leak
0/0
Positive blood culture and at least two of the
following:
Sepsis
Hypothermia/hyperthermia, tachycardia, tachypnea,
leucopenia/leukocytosis +/- DIC or multi-organ
dysfunction
1/3
Wound dehiscence
Requiring secondary suture of fascia for treatment
1/0
Intestinal Obstruction
Requiring surgery
4* / 1
Bleeding
Requiring transfusion and surgery
3/3
Death
All-cause mortality
1/2
*
One patient had intestinal obstruction twice.
Table 2: Demographic and Baseline characteristics
Variable
Age – yr
Sex (male) – no. (%)
Race – no. (%)
Caucasian
African American
Others
Body mass index – kg/m2
Smoking, Yes – no. (%)
ASA – no. (%)
I
II
III
IV
CPAP, Yes – no. (%)
Type of surgery – no. (%)
Laparoscopic
Open
Hospital – no. (%)
AKH
CCF
Norton
White blood cell count – 103/µL
Hematocrit – %
Hemoglobin – mg/dL
Glucose – mg/dL
80% Oxygen
(N = 202)
30% Oxygen
(N = 198)
45 ± 12
49 (24)
43 ± 12
36 (18)
20 (10)
180 (89)
2 (1)
46 [42, 52]
32 (16) a
27 (14)
167 (84)
4 (2)
46 [42, 54] a
25 (13) a
9 (4)
75 (37)
110 (55)
8 (4)
64 (33) a
13 (7)1
67 (34)
111 (56)
6 (3)
54 (28) a
185 (92)
17 (8)
178 (90)
20 (10)
STD †
0.11
0.15
0.15
-0.03
0.09
0.12
0.10
0.06
0.04
49 (24)
127 (63)
26 (13)
8±2b
42 [40, 44] b
14 [13, 15] b
100 [88, 119] c
49 (25)
126 (64)
23 (12)
8±2b
41 [39, 43] b
14 [13, 14] b
96 [85, 117] c
0.05
0.17
0.23
0.14
Statistics denoted by number of patients (%) or means ± SDs.
a
< 3% , b 6.5% – 9.5%, and c 16% – 18% missing values.
† Standardized
Difference is the difference (80% Oxygen group – 30% Oxygen group) in means or proportions
divided by the pooled standard deviation.
Table 3: Summary of intraoperative and postoperative variables
80% Oxygen
(N = 202)
30% Oxygen
(N = 198)
STD †
2.7 [2.1, 3.2] a
2.6 [2.0, 3.3] a
0.12
Crystalloids – L
2.4 ± 1.1 a
2.3 ± 1.1 a
0.17
Colloid – L
0 [0, 500] a
0 [0, 500] a
-0.03
Estimated blood loss – cc
100 [50, 150] a
100 [50, 150] a
0.04
Urine output – cc
250 [150, 360] a
265 [150, 411] a
-0.09
Fentanyl – mcg
350 [250, 450] a
350 [250, 450] a
0.07
5 (3) a
6 (3) a
-0.03
Ventilated (Recovery) – no. (%)
3 (1)
2 (1)
0.04
CPAP (Recovery) – no. (%)
6 (3)
3 (2)
0.10
1.2 [0.7, 2.0] c
1.3 [0.9, 2.2] c
-0.18
Glucose (POD 1) – mg/dL
127 [111, 162] b
117 [102, 141] b
0.28
Glucose (POD 2) – mg/dL
124 [105, 144] c
117 [104, 135] c
0.19
Variable
Intraoperative
Duration of surgery – hour
VC Maneuver Ventilated – no. (%)
Recovery & Postoperative
Total fluids (POD 1) – L
a
< 6%, b 18% - 20%, and c 44% - 56% missing values.
†
Standardized Difference is the difference (80% Oxygen group – 30% Oxygen group) in
means or proportions divided by the pooled standard deviation
35
Table 4: Primary analysis – Relative Risk of Major Complications (N= 400)
Major Complications Counts
Hospital
RR (95% CI) §
P¶
80% Oxygen
30% Oxygen
Total
(80% vs. 30%)
AKH
3/49 (6%)
4/49 (8%)
7/98 (7%)
0.75 (0.14, 4.09)
0.70
CCF
20/127 (16%)
17/126 (13%)
37/253 (15%)
1.17 (0.58, 2.36)
0.61
3/26 (12%)
6/23 (26%)
9/49 (18%)
0.44 (0.10, 1.96)
0.21
26/202 (13%)
27/198 (14%)
53/400 (13%)
0.94 (0.52, 1.68) †
0.80
Louisville
Overall (CMH) †
†Summary
relative risk for all hospitals adjusted by Cochran-Mantel-Haenszel (CMH). Breslow-Day test
for homogeneity of relative risks across hospital, P = 0.36.
§
Estimated using the group-sequential Z-statistic criterion of 2.303.
¶
The group sequential boundaries for efficacy and futility were P ≤ 0.0213 and P ≥ 0.2757.
36
Table 5: Secondary analysis – Relative risk of having any major complication in
80% versus 30% oxygen stratified by BMI quartiles (N=399)*
Major Complications
RR (95% CI) §
BMI quartile
80% Oxygen
30% Oxygen
Total
(80% vs. 30%)
P¶
1st: 35-42 kg/m2
8/45 (18%)
4/49 (8%)
12/ 94 (13%)
2.2 (0.58, 8.2)
0.18
2nd: 42-46 kg/m2
4/52 ( 8%)
5/43 (12%)
9/ 95 ( 9%)
0.66 (0.15, 2.9)
0.52
3rd: 46-53 kg/m2
8/59 (14%)
7/52 (13%)
15/111 (14%)
1.0 (0.33, 3.1)
0.99
4th: > 53 kg/m2
6/46 (13%)
11/53 (21%)
17/ 99 (17%)
0.63 (0.22, 1.8)
0.32
Overall (CMH) †
26 /202 (13%)
27/197 (14%)
53 /399 (13%)
0.96 (0.53, 1.7) †
0.87
*
One patient had a missing BMI value.
†Summary
relative risk across surgery types adjusted by Cochran-Mantel-Haenszel method (CMH).
Breslow-Day test for homogeneity of relative risks among BMI quartiles, P = 0.34.
§
Estimated using the group-sequential Z-statistic criterion of 2.303.
¶
The group sequential boundaries for efficacy and futility were P ≤ 0.0213 and P ≥ 0.2757.
37
Table 6: Secondary analysis – Relative risk of having any major complication in
80% versus 30% oxygen stratified by surgery type (N=400)
Major Complications
RR (95% CI) §
Surgery Type
Laparoscopic
Open
Overall (CMH) †
†Summary
P¶
(80% vs. 30%)
80% Oxygen
30% Oxygen
Total
22/185 (12%)
20/178 (11%)
42/363 (12%)
1.06 (0.54, 2.07)
0.85
4/17 (14%)
7/20 (19%)
11/37 (30%)
0.67 (0.20, 2.29)
0.46
26/202 (13%)
27/198 (14%)
53/400 (13%)
0.97 (0.54, 1.74) †
0.89
relative risk across surgery types adjusted by Cochran-Mantel-Haenszel method (CMH).
Breslow-Day test for homogeneity of relative risks between laparoscopic surgery and open surgery,
P = 0.44.
§
Estimated using the group-sequential Z-statistic criterion of 2.303.
¶
The group sequential boundaries for efficacy and futility were P ≤ 0.0213 and P ≥ 0.2757.
38
Table 7: Secondary analysis – Relative risk of having any major complication
within open surgery cases (N=133).
Major Complications
RR (95% CI) §
Study Phase
80% Oxygen
30% Oxygen
Total
(80% vs. 30%)
P¶
Main trial
4/17 (14%)
7/20 (19%)
11/37 (30%)
0.67 (0.20, 2.29)
0.46
Pilot trial
8/47 (17%)
17/49 (35%)
25/96 (26%)
0.49 (0.21, 1.20)
0.06
Overall (CMH) †
12/64 (19%)
24/69 (35%)
36/133 (27%)
0.54 (0.27, 1.10)
0.04
* Of 306 available patients from main trial, 37 patients had open surgery; 96 patients had open surgery
from the pilot trial. Therefore, total of 133 patients were used for this analysis.
†
Summary relative risk for study phase adjusted by: Cochran-Mantel-Haenszel (CMH) method
Breslow-Day test for homogeneity of relative risks between the phases, P = 0.66 (no phase difference
found)
§
Estimated using the group-sequential Z-statistic criterion of 2.303.
¶
The group sequential boundaries for efficacy and futility were P ≤ 0.0213 and P ≥ 0.2757.
39
Figure 1
40