Excessive amounts of supplemental oxygen, a foundational component of anaesthesia, can have harmful effects in some cases, a recent cohort study in the US has found.
Apart from an improved safety margin in the event of airway compromise, a high fraction of inspired oxygen (FIO2) has been thought to offer several other advantages to patients during surgery, including a reduction in ischaemic tissue injury by increasing perioperative arterial and tissue oxygen tension, lower risk of surgical site infection, and improved healing of anastomotic sites.
However, it’s estimated that >80% of patients undergoing general anaesthesia are exposed to oxygen administration exceeding that required to maintain normal blood oxygen levels. Supraphysiological oxygenation has been suggested as contributing to pulmonary, myocardial, and renal injury, but clinical evidence is limited, and a best practice strategy for selection of intraoperative FIO2 remains unknown.
This multicentre cohort study, led by scientists from Vanderbilt University and pubished in The BMJ, tested the hypothesis that administration of oxygen exceeding what is needed to maintain haemoglobin saturation during surgery is associated with increased kidney injury, myocardial injury, and lung injury.
The researchers concluded that increased intraoperative oxygen exposure was associated with adverse renal, cardiac and pulmonary outcomes in a large, diverse cohort of surgical patients. They said a large clinical trial to detect small but clinically significant effects on organ injury and patient-centred outcomes is needed to guide oxygen administration during surgery.
In an accompanying editorial, professors Michele Samaja and Davide Chiumello wrote that oxygen can be a double-edged sword, that it could, in some circumstances, lead to highly reactive compounds that cause damage and functional impairment to vital tissues like the brain, disrupting the redox balance, weakening the antioxidant barrier, and increasing the vulnerability of tissues to oxidative injury during periods of both hypoxaemia and hyperoxaemia.
Study details
Oxygen during surgery and postoperative organ injury: US cohort study
David McIlroy, Matthew Shotwell, Marcos Lopez, Michelle Vaughn, Joanna Solsen, Cassandra Hennessy, Jonathan Wanderer, Matthew Semler, Todd Rice, Sachin Kheterpal, Frederic Billings, on behalf of the Multicenter Perioperative Outcomes Group
Published in The BMJ on 30 November 2022
Abstract
Objective
To examine whether supraphysiological oxygen administration during surgery is associated with lower or higher postoperative kidney, heart, and lung injury.
Design
Observational cohort study.
Setting
42 medical centres across the United States participating in the Multicenter Perioperative Outcomes Group data registry.
Participants
Adult patients undergoing surgical procedures ≥120 minutes’ duration with general anaesthesia and endotracheal intubation who were admitted to hospital after surgery between January 2016 and November 2018.
Intervention
Supraphysiological oxygen administration, defined as the area under the curve of the fraction of inspired oxygen above air (21%) during minutes when the haemoglobin oxygen saturation was greater than 92%.
Main outcomes
Primary endpoints were acute kidney injury defined using Kidney Disease Improving Global Outcomes criteria, myocardial injury defined as serum troponin >0.04 ng/mL within 72 hours of surgery, and lung injury defined using international classification of diseases hospital discharge diagnosis codes.
Results
The cohort comprised 350 647 patients with median age 59 years (interquartile range 46-69 years), 180 546 women (51.5%), and median duration of surgery 205 minutes (interquartile range 158-279 minutes). Acute kidney injury was diagnosed in 19 207 of 297 554 patients (6.5%), myocardial injury in 8972 of 320 527 (2.8%), and lung injury in 13 789 of 312 161 (4.4%). The median fraction of inspired oxygen was 54.0% (interquartile range 47.5%-60.0%), and the area under the curve of supraphysiological inspired oxygen was 7951% min (5870-11 107% min), equivalent to an 80% fraction of inspired oxygen throughout a 135-minute procedure, for example. After accounting for baseline covariates and other potential confounding variables, increased oxygen exposure was associated with a higher risk of acute kidney injury, myocardial injury, and lung injury. Patients at the 75th centile for the area under the curve of the fraction of inspired oxygen had 26% greater odds of acute kidney injury (95% confidence interval 22% to 30%), 12% greater odds of myocardial injury (7% to 17%), and 14% greater odds of lung injury (12% to 16%) compared with patients at the 25th centile. Sensitivity analyses evaluating alternative definitions of the exposure, restricting the cohort, and conducting an instrumental variable analysis confirmed these observations.
Conclusions
Increased supraphysiological oxygen administration during surgery was associated with a higher incidence of kidney, myocardial, and lung injury. Residual confounding of these associations cannot be excluded.
Editorial response
Oxygen administration during general anaesthesia for surgery
Michele Samaja, Davide Chiumello
Published in The BMJ on 30 November 2022
Oxygen can be a double-edged sword
Oxygen is routinely administered to almost all patients undergoing general anaesthesia, to ensure adequate oxygenation from intubation until awakening, the period when complications due to hypoxaemia are most likely to occur.
Currently, the optimal target for oxygen administration is not yet clear and varies from normal arterial oxygen saturation to hyperoxaemia (usually defined as >97-98% arterial oxygen saturation). The hyperoxaemia strategy has been widely used since a seminal study highlighted the benefits of liberal (80%) compared with restrictive (30%-35%) inspired oxygen to reduce the risk of postoperative infection.
Accordingly, the 2016 World Health Organization guidelines recommend that patients receive a liberal fraction of inspired oxygen during general anaesthesia and in the immediate postoperative period.
Basic research, however, shows that oxygen can be a double-edged sword. It is a fundamental substrate for the oxidative phosphorylation that feeds biological energy to every aerobic cell. But in certain circumstances, oxygen may give rise to highly reactive compounds that cause damage and functional impairment to vital tissues such as the brain, disrupting the redox balance, weakening the antioxidant barrier, and increasing the vulnerability of tissues to oxidative injury during periods of both hypoxaemia and hyperoxaemia.
In a clinical context, one large cross-sectional study performed during general anaesthesia in Japan reported that 83% of the participants had a “preventable hyperoxaemia”, defined as >98% arterial oxygen saturation. Subsequent studies showed no substantial benefit associated with 80% inspired oxygen (compared with 30%) in reducing the risk of infection, and others showed that supraphysiological oxygen administration may be associated with worse outcomes than restrictive strategies.
Accordingly, the current British Thoracic Society guidelines recommend keeping arterial oxygen saturation in the 94-98% range to avoid harm from both hypoxaemia and hyperoxaemia.
In a linked paper, McIlroy and colleagues add to this evidence the results of a retrospective multicentre cohort study evaluating the association between high fractional oxygen administration during general anaesthesia and postoperative organ injury (primary endpoint), and 30-day mortality (secondary endpoint). All participants had surgical procedures that lasted longer than 120 minutes and >92% arterial saturation throughout the procedure. To quantify the participants’ exposure to supraphysiological oxygen, McIlroy and colleagues used an algorithm to calculate the area under the curve plotting administered oxygen >21% against the time spent with oxygen saturation >92%.
Their study included 350 647 adults from 42 centres in the United States and documented postoperative organ injury in 6.5% (kidneys), 2.8% (myocardium), and 4.4% (lungs) of participants. The median area under the curve quantifying supraphysiological inspired oxygen was equivalent, for example, to a patient receiving 80% inspired oxygen throughout a 135-minute procedure, or 60% oxygen throughout a 204-minute procedure.
Supraphysiological oxygen administration was associated with a higher risk of organ injury: Patients at the 75th centile of area under the curve had 26% greater odds of acute kidney injury (95% confidence interval 22% to 30%), 12% greater odds of myocardial injury (7% to 17%), and 14% greater odds of lung injury (12% to 16%) than those at the 25th centile. In addition, it was also associated with 30-day mortality (odds ratio 1.06, 0.98 to 1.15).
Unlike previous studies, this new investigation leaves little room for uncertainty: supraphysiological oxygen administration and saturation are associated with a higher risk of organ damage, although the absolute risk remains low.
Future research on this topic could deal with some of the study’s acknowledged limitations. Firstly, not all participants were screened for kidney and heart injury after their surgery (postoperative serum creatinine and troponin levels were measured in 58% and 10%, respectively). Secondly, it is unclear how the findings would change if the threshold definition for supraphysiological oxygen were increased. Thirdly, the authors were unable to consider confounders such as diet, lifestyle, and drug use, which can influence the strength of the antioxidant barrier and hence susceptibility to organ injury.
Future researchers could also consider the oxygen-carrying capacity of blood (haematocrit, haemoglobin concentration) and include an outcome measuring cognitive impairment because experimental evidence suggests that brain tissue is particularly vulnerable to redox imbalance.
Finally, observational analyses such as this cannot be used to infer a causal link between supraphysiological oxygen and organ injury. Experimental studies may be more suitable to help establish cause and effect.
Despite such limitations, McIlroy and colleagues’ study suggests it is time to reconsider the liberal use of oxygen during general anaesthesia. The study also highlights the role of basic research in paving the road to clinical research, following the paradigm “from bench to bedside – and back”. Research collaborations between biochemists and anaesthesiologists should be encouraged, especially to identify cause-effect relationships between supraphysiological oxygen administration and organ injury.
The BMJ Editorial Response – Oxygen can be a double-edged sword (Open access)
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