Background

Material in this chapter has been reproduced with permission from Elfeky et al.1 and Elfeky et al.2 These are Open Access articles distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: https://creativecommons.org/licenses/by/4.0/. The text below includes minor additions and formatting changes to the original text.

More than 5 million surgical procedures take place in the UK each year and patients routinely receive supplemental oxygen as part of these procedures.3 Perioperative supplemental oxygen may potentially reduce complications. However, the best practice for intraoperative oxygen administration and the effect of different amounts of oxygen on postoperative clinical outcomes remains unknown.

In recent years, surgery has become progressively safer globally, thanks to technological advances and interventions such as the global Safe Surgery programme by the World Health Organization (WHO).4 While challenges over resources remain in low- and middle-income countries, the intraoperative period is generally safer in developed countries, especially for elective surgery.5 The Fourth National Audit Project of anaesthetic practice in the UK in 2015 showed that incidence of serious airway complications during a general anaesthetic to be 46 events per million general anaesthetics.6 Similarly, a 2020 retrospective analysis of patients data from Italy has shown that the mortality rate for patients undergoing surgery at a tertiary centre over a period of 12 years to be just under 2%.7 A US study from 2008 showed that the mortality rate in the first 48 postoperative hours to be 0.57%.8 However, surgical patients remain at risk of developing complications in the immediate and later postoperative period, which can lead to mortality and serious morbidity. Estimates of attributable mortality vary from 1% to 4%, although some studies suggest that more than one in five deaths occur in a small group of high-risk patients.3,9,10 Analysis of routine data from all NHS hospitals in England, including patients aged ≥ 18 years undergoing non-obstetric surgery between 1 January 2010 and 31 December 2015 revealed that one in four surgical patients had a chronic disease with an associated 10-fold increase in risk of postoperative death.11

Surgical site infection (SSI) is a common healthcare-associated infection and complicates up to 10–20% of operations and substantially contributes to the global burden of mortality and morbidity with considerable strain on healthcare resources.12 Current epidemiological data indicate that the overall prevalence of healthcare-associated infections in England is 6.4% [95% confidence interval (CI) 4.7 to 8.7%], with SSIs being the third most common category (15.7%).13

Surgical site infections represent a significant challenge for the health service: they lead to delayed recovery, prolonged hospital stay with exposure to further complications and healthcare-associated infections, delayed and compromised wound healing. Delays to discharge in turn lead to lower bed availability and thus to delays to the overall waiting list. Furthermore, the requirement with multiple courses of antibiotics and the exposure to nosocomial infection can increase the risk of antimicrobial resistance. Antimicrobial resistance is a growing threat to health and to the safe practice of surgery worldwide.14 In 2020, the Centers for Disease Control and Prevention (CDC) in the United States estimated that more than 2.8 million multidrug-resistant bacterial infections occur annually, leading to 35,000 deaths.15 Bacterial infections unsuccessfully treated are projected to be associated with the deaths of 10 million people per year by 2050, at a cost of US$100 trillion to the global economy through loss of productivity.16 As antibiotic prophylaxis is one of the pillars of safe surgery, the emergence of multiple strains of antibiotic-resistant bacteria will threaten the ability to perform even basic surgery in the future.17 We should therefore investigate strategies to reduce the incidence of SSIs and other infective postoperative complications.

Some of the most common postoperative complications affect the respiratory tract, with incidences ranging from 9% to 40%, depending on the definition used.18,19 A number of factors promote pulmonary complications among patients undergoing major surgery. Anaesthesia can lead to reduced functional residual capacity, hypoxaemia, and impaired central respiratory drive, while surgical manipulation can restrict ventilation, damage respiratory muscles and cause atelectasis. When combined with pre-existing respiratory disease and postoperative pain, the risk of pneumonia, respiratory failure and death is increased.19

Perioperative oxygen and post-surgical complications

One strategy that has been suggested to reduce the incidence of SSI is the use of perioperative oxygen. The aim of oxygen administration in the perioperative setting is the prevention or treatment of hypoxaemia and to reduce the risk of both operative and postoperative complications. Hypoxaemia is lack of oxygen in the blood, usually defined in terms of partial pressure of arterial oxygen (PaO₂), arterial oxygen saturation of haemoglobin (SaO₂) or peripheral oxygen saturation (SpO₂). Perioperative hypoxaemia is common20–23 and the risk is higher in patients who are older, those who receive opiates or who undergo prolonged anaesthesia. Postoperative hypoxaemia has been linked to increased risk of cardiopulmonary complications,24,25 delirium,26 prolonged hospital stay20,23 and mortality.27 The consequences of hypoxaemia during surgery and the presumed safety of hyperoxaemia have made the administration of supplemental oxygen a foundational component of anaesthesia. In addition to 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. These advantages include a reduction in ischaemic tissue injury by increasing perioperative arterial and tissue oxygen tension and improved healing of anastomotic sites.28 However, liberal use of supplemental oxygen leading to hyperoxaemia may have harmful effects mediated by increased generation of reactive oxygen species (ROS), which modify cellular lipids, DNA and proteins, hyperoxic vasoconstriction and decreased ventilation.29–31 These effects are associated with reduced cardiac, pulmonary and renal blood flow, atelectasis, respiratory complications and higher mortality.32–34 The findings from a 2022 large multicentre cohort study also suggested that increased supraphysiological oxygen administration during surgery was associated with a higher incidence of kidney, myocardial and lung injury.35

Oxygen is a ubiquitous therapy in modern anaesthesia because it is cheap and potentially simple to implement. Although supplemental oxygen is routinely administered to almost all patients during surgery, the best practice for intraoperative oxygen administration remains unknown. The WHO guidelines recommend that adults undergoing general anaesthesia with tracheal intubation for surgical procedures should receive high-concentration oxygen (80%) intraoperatively and postoperatively for 2–6 hours.36 However, this recommendation has generated substantial controversy and there is ongoing debate surrounding the overall safety of using high concentrations of oxygen.37–39

Concerns were based on evidence from clinical settings other than perioperative care and were countered by the available direct evidence. Other concerns could be addressed by clarifying the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology40 and providing explanations of the WHO guideline development process.41,42 Moreover, there were issues that required further investigation of the available evidence, including concerns regarding exclusion of recently published data, about trials using nitrous oxide (N₂O) in the control group, and safety issues.37,43–46 WHO responded to the commentaries,41 and agreed with the need to evaluate emerging evidence on effectiveness and safety. Finally, one trial included in the WHO initial review has since been retracted because of non-reproducible statistics.47 Further retracted trials authored by Schietroma et al. were identified,48,49 and other (not retracted) trials were sufficiently compromised and required further investigation.50–52

The WHO’s recommendations in 2016 would also appear to contradict consensus opinion in other clinical contexts. A large meta-analysis of over 16,000 patients, published in the Lancet in 2018, concluded that liberal use of oxygen in acutely unwell patients to maintain saturations above 96% was associated with increased in-hospital [risk ratio (RR) 1.21, 95% CI 1.03 to 1.43, high quality] and 30-day mortality (RR 1.14, 95% CI 1.01 to 1.29, high quality).53 While this study explicitly excluded patients undergoing elective surgery, observation of a harm signal across such a large and broad group of acutely unwell patients should be cause for concern for those advocating high-dose oxygen therapy in patients undergoing surgery. An additional concern that has more recently emerged from the literature is the potential adverse effect of high-dose perioperative oxygen therapy on longer-term outcomes. Such outcomes have also been studied across three follow-up analyses from the Danish PROXI trial,34,54,55 a randomised controlled trial (RCT) of 1386 patients undergoing acute or elective laparotomy and given either 30% or 80% oxygen during and after surgery.56 A 2-year post hoc analysis of the PROXI data revealed that the incidence of acute myocardial infarction was over twice as frequent in those patients given 80% oxygen in comparison to 30% [hazard ratio (HR) 2.86, 95% CI 1.10 to 7.44].54 When controlling for broader incidence of cardiac complications, researchers found statistically significant increase in any heart disease or death in patients treated with higher fractions of oxygen (HR 1.24, 95% CI 1.06 to 1.45). An additional 2-year follow-up study demonstrated an increase in long-term mortality in cancer patients who received 80% oxygen (HR 1.45, 95% CI 1.10 to 1.90),34 with evidence of harm continuing at 4 years in relation to cancer-free survival time (HR 1.19, 95% CI 1.01 to 1.42).57 It is worth noting that these post hoc analyses were not included in the WHO 2016 guidelines for SSI prevention. The PROXI (Effect of high perioperative oxygen fraction on SSI and pulmonary complications after abdominal surgery) trial56 was originally powered to detect a reduction in SSI only, and therefore these post hoc analyses should still be treated with some caution; once an experimental group has been associated with one adverse outcome, it is not surprising that there might also be other adverse associations too. Despite this concern, the PROXI findings present an important new avenue for oxygen research and a starting point for hypotheses to be generated.

In 2018, the WHO updated its guidelines on SSI and, having excluded the Schietroma studies, the evidence level of high FiO₂ in perioperative settings was downgraded to conditional.58 The WHO recommendation is not supported by clinical guidelines issued by other organisations.59 The World Federation of Societies of Anaesthesiologists recommends 30–40% FiO₂ for intubated patients.46 Lead authors from the ENIGMA trial and the Cleveland Clinic study state that current evidence does not support the use of supplemental oxygen to prevent SSI. The dissonance between oxygen guidelines and evidence from clinical outcomes is reflected in prescribing practices among UK anaesthetists. A 2018 multicentre retrospective observational study conducted across 29 UK hospitals demonstrated that intraoperative oxygen administration by anaesthetists varied widely from 25% to 100% FiO₂, with no obvious down-titration of oxygen in response to sustained supranormal blood oxygen levels.60 An intraoperative FiO₂ of 50% currently represents standard intraoperative practice in the UK, with surgical patients often experiencing moderate levels of hyperoxaemia. This is similar to the pattern of intraoperative oxygen administration among anaesthetists in Australia and New Zealand, where most anaesthetists routinely administer an intermediate level of oxygen.61 However, this differs from both WHO’s recommendation of using an FiO₂ of 80% intraoperatively and the value that previous interventional oxygen therapy trials have used to represent standard care (typically FiO₂ = 30%).

In addition to intraoperative oxygen administration, there are other strategies to optimise oxygenation in the immediate postoperative period, such as continuous positive airway pressure (CPAP) and high-flow nasal oxygen (HFNO). These methods have been shown to reduce postoperative pulmonary complications (PPCs) and unplanned reintubation rate in certain cohorts of high-risk patients but the certainty in evidence was low.62,63 They are also more labour-and resource-intensive and require additional equipment, which makes their ubiquitous application more challenging.

This uncertainty has led to a lack of standardised approach in perioperative oxygen therapy and marked variability in the care of patients undergoing surgery,37 which may mean that patients may be exposed to unintended harm.37 Reducing harm and risk of complications in patients undergoing surgery is one of the top research priorities in James Lind Alliance research prioritisation with patients and clinical research community.64

Existing literature

The clinical effectiveness of perioperative oxygen therapy in improving patient outcomes is a highly complex area. Effects may vary in different patient groups such as age groups (e.g. adult vs. children vs. neonates), different underlying condition (e.g. cancer vs. non-cancer), different types of anaesthesia (e.g. general anaesthesia, regional anaesthesia or sedation) or different types of surgery (e.g. cardiothoracic surgery, trauma, elective or emergency abdominal surgery).

Many systematic reviews have explored the use of different oxygen strategies in the perioperative setting.63,65–76 It is possible to summarise the existing literature in two broad areas: oxygen strategy and delivery device.

Oxygenation strategy: what is the clinical effectiveness of higher versus lower fraction of inspired oxygen or targets of arterial oxygenation?

Maintaining high FiO₂ levels has been proposed as an inexpensive, easy and effective strategy to reduce the incidence of SSIs.77 The rationale for its use is that increased tissue oxygenation within surgical wounds might enhance oxidative killing of microbes by neutrophils reducing the risk of wound infection.78,79

There are substantial disagreements in published reviews on whether hyperoxaemia reduces the incidence of SSI and, if effective, which patient population may benefit. Some systematic reviews concluded that hyperoxaemia significantly reduces risk of SSI in all patients,67,71 while others found no evidence of benefit overall except in certain subgroups.68,69,72 A 2015 Cochrane review comparing the impact of FiO₂ ≥ 60% with a control of FiO₂ ≤ 40% concluded that a high FiO₂ did not reduce risk of SSI.70 However, there was some very low-certainty evidence that particular subgroups may benefit when preoperative antibiotics were given with a high FiO₂. Other potential, albeit uncertain, benefits of hyperoxaemia include improved anastomotic integrity in intestinal surgery52 and reduced postoperative nausea and vomiting.71,74

There are concerns about the harmful effects of hyperoxaemia through oxidative stress, generation of ROS80 and direct toxic effects on cardiovascular81 and respiratory system.82,83 A large registry of more than 73,000 patients reported that median FiO₂ was associated in a dose-dependent manner with increased risk of respiratory complications and 30-day mortality.33 Increased ROS levels have been linked to tumorigenic processes.84 In a large RCT of FiO₂ 80% compared with FiO₂ 30% in abdominal surgery, patients with cancer had a 45% increase in long-term mortality in the high FiO₂ group.56

More recent systematic reviews, examining the safety of hyperoxaemia, concluded that the incidence of atelectasis, myocardial infarction and intensive care unit (ICU) admission did not differ significantly in patients treated with FiO₂ 80% compared with FiO₂ 30–35% across all surgery73 and in cardiac surgery.85

Delivery device: what is the clinical effectiveness of non-invasive respiratory support such as continuous positive airway pressure or high-flow nasal oxygen compared to conventional oxygen therapy?

Non-invasive respiratory support strategies, such as non-invasive ventilation (NIV) and HFNO, have been proposed to improve oxygenation in hypoxaemic patients and to reduce the risk of post-surgical complications.86 NIV (including postoperative CPAP) uses a high-pressure source to deliver a higher inspiratory pressure (peak inspiratory pressure) in addition to constant background pressure (peak end-expiratory pressure). HFNO delivers heated and humidified high-flow oxygen of up to around 60 l/minute via nasal cannulae designed to create positive airway pressures.87 Physiologically, NIV and HFNO are associated with improved lung compliance and lung recruitment,88 but may cause harm through both volutrauma, barotrauma and patient intolerance.89,90

Published systematic reviews have examined the use of postoperative CPAP in variety of settings.65,91,92 A Cochrane review examined the prophylactic use of CPAP compared with conventional oxygen therapy (COT) for preventing postoperative mortality and adverse events following major abdominal surgery.63 They reported very low‐certainty evidence that postoperative CPAP may reduce atelectasis, pneumonia and reintubation, but its effects on mortality, hypoxia or admission to ICU for invasive ventilation are uncertain. A separate Cochrane review examined the use of CPAP in the treatment of respiratory failure following upper abdominal surgery.65 The study reported low-certainty evidence that CPAP may reduce the rate of tracheal intubation and the length of ICU stay. No difference was found in mortality or hospital length of stay. There was insufficient evidence to examine harm. In a 2020 guideline review, the European Society of Anaesthesiology and the European Society of Intensive Care Medicine recommended that CPAP should be used for preventing and treating postoperative hypoxaemia after abdominal surgery instead of COT.86 The benefits of perioperative CPAP for other patient groups remains uncertain, guideline recommendations are weak and based on low to very low-certainty evidence.

We identified five systematic reviews published between 2017 and 2020 that explored the use of HFNO in the immediate postoperative period, albeit only in the adult population.62,66,93–96 A review in patients with postoperative respiratory failure or at high risk of developing postoperative respiratory failure reported HFNO reduced rates of reintubation and mortality compared with standard oxygen therapy, although subgroups analyses showed benefits were limited to the cardiothoracic population.66 A review of prophylactic use of postoperative HFNO that included mostly cardiothoracic surgery populations, reported reduced reintubation rates although subgroup analysis showed the effect was limited to high-risk groups.62