Setting intraoperative fraction of inspired oxygen

Introduction

Each year, millions of patients undergo surgery under general anaesthesia (1). Oxygen, the most ubiquitous drug used in the operative setting, is often not titrated to any particular effect, but to the anaesthesiologist’s preference and usual practice. The choice of a high inspired fraction of inspired oxygen (FiO₂) is commonplace in the operating room (2) and, in general, differs significantly from the intensive care setting. Safety criteria along with a debatable effect on a decrease in surgical site infection (SSI) are the potential reasons to justify a high FiO₂ usage. Based on the latter, several organizations such as the World Health Organization (WHO) (3) or Centers for Disease Control (CDC) (4) have issued recommendations to keep high FiO₂ during surgery and the immediate postoperative period. In this article, we will review the evidence behind these beneficial effects and several potential side effects of a high FiO₂ intraoperative strategy.

Safety criteria to advocate for a high FiO₂ usage during anaesthesia

At induction of anaesthesia, using high FiO₂ increases alveolar oxygen concentration which prolongs time-to-hypoxemia onset after apnea. The goal of preoxygenation is to achieve an expired oxygen concentration above 0.9, which is usually achieved after 3 to 5 min. In a healthy adult, this will provide an apnea time around 8 to 10 min. In the setting of an unanticipated difficult airway this could provide of invaluable help. Several populations known to present with rapid desaturation after apnea, such as children, obese patients and pregnant women, may specially benefit from this intervention (5,6). National guidelines often recommend setting a high FiO₂ before induction of anaesthesia and during bag-mask ventilation. Continuous positive airway pressure (CPAP), non-invasive ventilation (NIV) and high-flow nasal cannula (HFNC) are interesting options to improve the efficacy of preoxygenation and have been tested in different scenarios (7-9).

Intraoperative and postoperative

SSI is one of the commonest complications after surgery with incidences varying depending on the type of surgery. A recent global report found SSIs to occur in 9% of all gastrointestinal surgeries in high-income countries whereas the incidence doubled when only surgery considering to be dirty was analysed. When low-income countries were studied, SSIs were up to 40% (10). SSIs have been associated with severe complications thereafter, such as anastomotic leak and sepsis and septic shock. SSIs prolong hospital length of stay as well as increase health-care costs (11-14).

Peripheral tissue hypoxia at the surgical wound might impair the innate immune system to cope with bacteria migrating and replicating inside the tissues. Oxygen is an essential element for neutrophils since this cell mediates its primary effect through an oxidative mechanism (15,16). Hence, increasing oxygen pressure at the tissue level (PtO₂) could potentially provide useful to reduce SSIs. Oxygen transport depends on both cardiac output and arterial oxygen content; which is a function of the haemoglobin level and its saturation and, also, of the dissolved content of oxygen (17). Once accomplishing a stable cardiac output and an appropriate haemoglobin level with saturation above 97%, the increase in PtO₂ will come from the increase in arterial pressure of oxygen (PaO₂). Hence, a plausible approach to increase PtO₂ is to achieve supraphysiologic PaO₂ by means of increasing FiO₂ (18). This strategy has been a matter of debate for years with several randomized controlled trials (RCT) aiming to answer this question. Greif et al., was the first to show on a 500-patient sample undergoing open abdominal surgery that FiO₂ 0.8 as compared to FiO₂ 0.3 in the intraoperative and early postoperative period reduced SSIs by more than 50% (19). Later, several authors using similar designs found comparable results (20,21). However, additional RCTs did not replicate these findings, including the largest RCT performed in this field to date, which included almost 1,400 patients (22-26). A meta-analysis carried out by the WHO that included 15 trials found a significant effect for a high FiO₂ in decreasing SSIs which led this organisation to recommend the usage of FiO₂ 0.8 during surgery and the first few hours in the postoperative period (3). Importantly, some of the previous articles suggesting a beneficial effect of a high FiO₂ strategy, that were included in this meta-analysis, have been retracted in the last few years (27). Since then, additional meta-analysis not including these articles have found conflicting results of setting a FiO₂ 0.8 as compared to a FiO₂ 0.3–0.35 (28,29). For these reasons, the WHO recently updated their recommendations; while keeping the advice to maintain FiO₂ at 0.8, the strength of the recommendation was weakened from strong to conditional (30).

Beyond the usual differences in designs and outcomes between trials that often makes a straightforward comparison difficult, we would like to highlight that a non-homogeneous ventilatory strategy in the previous studies might have affected the efficacy of FiO₂. Kurz et al., noticed important differences in PaO₂ in the group allocated to high FiO₂ that these authors consider related to different PEEP strategies (24). Of note, only the first trial conducted by Greif et al. measured PtO₂; hence we cannot be confident to state that the high FiO₂ group in these studies had shown a better oxygen delivery (19). It is also noteworthy that hypoxemia (even small deviations from 100 mmHg) was very uncommon in these studies making impossible to draw conclusions whether avoiding hypoxemia could be more important that increasing PaO₂ in already normoxemic patients. Observational data has also shown that most of the patients (more than 97%) under general anaesthesia shows blood oxygen saturation (SpO₂) ≥96% (2). In another line of thought, it is also remarkable that the vast majority of patients enrolled in these studies underwent abdominal surgery via an open approach. There is nowadays extensive research showing that laparoscopic or minimal invasive surgery reduces SSIs (31-34) and the ongoing growth of these approaches might make the small, if ever present, effect of a high FiO₂ undetectable.

Importantly, oxygen as any other drug has the potential to cause adverse effects. However, most trials that did not show a beneficial effect of a high FiO₂ strategy did not report more complications (22-26) as neither meta-analysis did (35).

Potential risks associated with a high FiO₂ strategy

Respiratory

During anaesthesia the loss of diaphragmatic tone leads to a decrease in functional residual capacity (FRC) that moves the lung volume closer to residual volume. This could lead to end-expiratory lung volume (EELV), which is the equivalent to FRC under mechanical ventilation, to become smaller than the closing capacity. Also, compressive atelectasis can ensue which cause airway to collapse. All of this may produce dependent lung portions to become closed or partially closed. In this situation, gas inside the alveoli pass to the circulation but cannot be replaced with ventilation leading to dependent lung collapse. Oxygen through its greater diffusion capacity as compared to nitrogen might favour this situation to happen; which, in its turn, could lead to hypoxemia and respiratory failure after extubation (36). However, physiological data has shown that when FiO₂ is set at 0.8 or below, resorption atelectasis do not increase significantly (37). Also, use of positive end-expiratory pressure (PEEP) during mechanical ventilation might minimize this effect. In line with these data, most trials targeting a high FiO₂ did not report an increase in respiratory complications after the use of a high FiO₂ during surgery.

Moreover, a high alveolar oxygen concentration could, through an increase in oxidative stress at the lung, be associated with hyperoxic acute lung injury. In the past, there has been extensive research performed in animals showing that breathing high oxygen concentrations for a prolonged period leads to lung injury. This research, in general, conducted in healthy animals showed that breathing FiO₂ ≥0.8 for several days cause pulmonary damage in a wide variety of species. Also, as the concentration decreases, the time needed to cause harm increases markedly (38). From the observations mentioned, it seems that hyperoxic acute lung injury occurs after inhalation of high FiO₂ that occurs for days or even weeks; which is a condition not met in anaesthesia in the operating room. Notwithstanding, there is some evidence to suggest that already injured lungs or those ventilated in a nonprotective way can be more susceptible to high FiO₂ exposure; even at concentrations around 0.6 (39). Although, it is unlikely that a short term exposure to a high FiO₂ will be detrimental for the lung, we should be aware that oxygen is a potential toxic element when used at high doses and could potentially work as a “second-hit” in situations where lungs are at risk of presenting further damage such as in septic shock or acute respiratory distress syndrome (ARDS).

Neurologic

Oxygen is known to be capable of causing acute neurologic toxicity when used at hyperbaric conditions such as those experienced during scuba diving. Thresholds for acute neurologic injury has been set around 1.3–1.6 bar (40) which is a condition never met in a normobaric situation. Hence, oxygen neurologic toxicity is not a concern in the intraoperative setting.

Vascular

There is concern that hyperoxia could contribute to myocardial vasoconstriction through a competing mechanism with nitric oxide or to an increase in reactive oxygen species (41). In 2015, a multicentre trial where 441 patients with ST-elevation myocardial infarction was published. In this study patients with an SpO₂ >94% were randomized to receive 8 L/min of oxygen or no supplemental oxygen on arrival of paramedics and up to transfer to the cardiac care unit. The patients that received supplemental oxygen had an increased rate of recurrent myocardial infarction as well as the frequency of cardiac arrhythmias and showed a larger infarct size at 6 months on magnetic resonance imaging (42). Evidence coming from the stroke literature is conflicting with both observational studies and small trials showing no difference with supplementation, detrimental effects or even short-lived beneficial outcomes (43). However, an RCT performed in the intensive care unit compared the effect of two FiO₂ strategies on the outcome of ventilated patients. The liberal approach consisted of allowing SpO₂ ≥97% and PaO₂ to increase up to 150 mmHg while the conservative approach targeted SpO₂ in the 94–98% range with PaO₂ between 70 and 100 mmHg. In this study, the conservative approach showed an absolute 8.6% mortality reduction (from an overall 20.2% mortality in the liberal group) with fewer episodes of shock, liver failure and bloodstream infections (44). However, literature coming from cardiac surgery does not support the notion that high intraoperative FiO₂ is associated with an increase rate of complications. (45,46). A large RCT that randomized surgical patients to high FiO₂vs. FiO₂ 0.3 will probably present results soon regarding the effect of this strategy not only on SSIs but on vascular complications and, also, renal failure (47).

Conclusions

After several decades and many studies trying to assess whether a high FiO₂ strategy would result protective in terms of SSIs reduction, the available data is not conclusive. In the past century, investigators showed that increasing tissue oxygen availability at the time of surgery would reduce local complications. However, increasing FiO₂ does not necessarily translate immediately into a PtO₂ rise since oxygen delivery is affected upon several factors such as the haemoglobin level and the cardiac output. Also, ventilatory management affects the oxygen gradient between the alveoli and the circulation. Kurz et al. demonstrated that in their high-FiO₂ group, PaO₂ would differ markedly between subjects depending on the level of PEEP used, an observation also evident from our clinical practice. Since, the study by Greif et al. was the only one to measure PtO₂, we cannot be certain that the intervention in the studies was effective to increase oxygen availability at the tissues to a level to be effective in reducing SSIs. This observation underscores the importance of ventilatory management in assessing the interaction with FiO₂ to maximize PaO₂ and PtO₂. In this line, a large RCT studying the effect of a high FiO₂ approach, using a standardized open lung strategy to all patients, will soon show results (47). Also, most of these studies were performed more than a decade ago and a majority of patients enrolled were operated with an open approach. Given the growth of the laparoscopic techniques and the reduction in SSIs demonstrated with them, the positive effects observed by a high intraoperative FiO₂ might dilute even more.

On the other hand, adverse effects of a high FiO₂ strategy in the intraoperative setting seem not to be relevant. Even though, literature coming from the intensive care suggest hyperoxemia is associated with complications and increased mortality in wide populations of critical care patients, the studies performed in the operating room have not shown this relationship. Importantly, research done in cardiac surgery did not show an increase in myocardial damage or renal failure in subjects allocated to a high-FiO₂ strategy. Although the differences in the outcomes between the studies could possibly be explained by dissimilar populations between the surgical setting and the critical care environment as well as a very different exposition time to high FiO₂ between one setting and the other; we should all be aware that oxygen as any other drug has the potential to cause side effects when used in a large concentration for a long period of time.

At this time point, we feel the literature is conclusive in acknowledging the importance of keeping an adequate oxygen delivery to tissues in order avoid complications, and particularly SSIs. To maintain an adequate oxygenation level with the use of a careful ventilatory strategy, to keep the cardiac output stable, to avoid severe anaemia, to prevent patients from developing hypothermia, or to keep blood glucose levels below 200 mg/dL are all essential factors in any anaesthetist’s good intraoperative management. Regarding FiO₂ supplementation, studies, however, have not been conclusive to recommend a high-FiO₂ strategy to all patients undergoing major surgery but have shown that this approach seems safe when restricted to the operating theatre and the first hours after surgery. In settings with limited resources and where SSIs incidence is very high, or in situations where keeping oxygen delivery might be difficult such as in the case of acute anaemia or patients who refuse transfusion, a high-FiO₂ strategy could prove useful to reduce SSIs; however, evidence of benefit in this subgroup is lacking.

In conclusion, the research published so far does not support the use to high-FiO₂ during surgery to all subjects undergoing major surgery. New evidence coming from a large RCT will soon shed light on this field.

Acknowledgments

None.

Footnote

Conflicts of Interest: C Ferrando received support in form of a grant from Air-Liquidé for research purposes. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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