The main factor of interest in this study was the relationship between oxygen supplementation fraction received during anesthesia induction and the development of desaturation or post-operative respiratory distress in non-critically ill patients. Routine pure oxygen supplementation for non-critical or generally healthy patients during induction is still a debated topic (Ball et al. 2017). There is currently no clinical evidence demonstrating the advantages of routine pure oxygen during induction of anesthesia, while intraoperative oxygen overexposure defined as hyperoxemia (SpO2 > 98%) and substantial oxygen exposure (FIO2 > 0.5) can potentially be harmful and increase postoperative complications (Suzuki et al. 2018). Although the time duration to reach desaturation (SpO2 < 90%) was significantly prolonged in patients receiving higher fractions of inspired oxygen (FIO2 > 0.8) (Edmark et al. 2003), an apneic time for more than 200 seconds with the supplement of FIO2 0.6 during induction should be sufficient for establishing a secure airway in generally healthy patients. Therefore, this trial tested the alternative hypothesis that FIO2 0.6 was non-inferior to the current common practice of routine pure oxygen supplementation in the prevention of desaturation during anesthesia induction.
This study was prematurely terminated after recruitment of 302 patients due to the safety concerns raised by the DSMB members, as all patients who developed primary endpoint received FIO2 0.6, and time-to-event analysis and the lowest mean SpO2 confirmed the increased hypoxemic events during the induction period of anesthesia in the FIO2 0.6 study group. Therefore, the null hypothesis of non-inferiority could not be rejected. The incidence of hypoxemia during induction phase by giving 60% inspired oxygen was 3.9% in our study, which is considerably higher than the previous report (Ehrenfeld et al. 2010). It was found that supplementation of 60% FIO2 during induction phase may provide an estimated number needed-to-harm (NNH) of 31 in developing desaturation that requires urgent medical intervention. The lowest SpO2 in the FIO2 0.6 group ranged from 78–92%, and these patients were switched to receive pure oxygen for rescue therapy. None of these patients developed any clinically significant consequences. Since there were no differences in patient characteristics and proportion of difficult intubation between the two groups, lower inspiratory oxygen fraction (i.e. FIO2 0.6) during preoxygenation and assisted ventilation before endotracheal intubation increased risk of desaturation in patients with ASA PS I-III. Our results indicated that four out of the five patients who developed the primary endpoint had BMI’s greater than 30 kg/m2. Obese patients have increased oxygen demand and CO2 production, and as a result they are prone to rapid desaturation during apnea or hyponea due to reduced functional residual capacity and expiratory reserve volume, while the total lung compliance is decreased exponentially (Pelosi et al. 1998; Peppard et al. 2009).
Since the patients who developed primary endpoint were switched to 100% oxygen therapy during induction, these patients were included in the FIO2 group for the subsequent analysis of the secondary endpoints (as-treated analysis). The main short-term outcomes after ETGA is concerned with the occurrence of acute respiratory distress or desaturation following removal of endotracheal tube. A total of 11 cases of desaturation after extubation in the OR or at PACU were found during the study. In the FIO2 0.6 group, two case developed a SpO2 ≤ 92% in the OR, but none developed desaturation at PACU. However, there were 9 cases of desaturation in the FIO2 1.0 group, including one patient who developed the primary endpoint was switched to pure oxygen treatment. Although the incidence of desaturation was not statistically different (1.4% vs 5.8% for FIO2 0.6 vs FIO2 1.0; P = 0.064) between the two study groups, this unanticipated result highlights that the odds of developing desaturation after removal of endotracheal tube in ETGA patients is 78% lower in patients receiving FIO2 0.6 than those with pure oxygen exposure (odd ratio 0.22, 95% CI 0.22–1.05) during induction of anesthesia. Since the effect size of pure oxygen is considered high (i.e. 4.4 times higher than FIO2 0.6) in the development of post-extubation hypoxemia, the clinical impact of oxygen fractions used for anesthesia induction should not be overlooked. Previous studies suggested that surgical- and anesthesia-related risk factors for postoperative acute respiratory distress include long surgical duration > 2 h, emergency operation, high-risk surgery and perioperative fluid overload (Morris et al. 1998; Chapman et al 2005; Gupta et al. 2011; Attaallah et al. 2019). As high-risk and emergency surgeries were excluded, perioperative fluid overload and prolonged operation times are the two main potential confounding factors for postoperative respiratory distress in this trial. Our database showed that there were no differences in average operation time or total fluid administered during operation between the two groups (Table 1).
Pulmonary atelectasis occurs in 85–90% of healthy anesthetized adults and is one of the leading causes of postoperative hypoxemic events (Karcz and Papadakos 2013). Besides procedure- and anesthetic-related factors, the composition of inspired gas is another important factor that influences the formation of pulmonary atelectasis during general anesthesia (Sun et al. 2015; Quintero-Cifuentes et al. 2018). Edmark et al. found that the mean areas of lung atelectasis immediately after apnea was higher in patients received 100% oxygen compared to those oxygenated with FIO2 0.6 (10 cm2 vs 0.3 cm2, P < 0.001) (Edmark et al. 2003). Another clinical observational study compared the effects of gas composition on the formation of atelectasis and gas exchange during the induction of general anesthesia (Rothen et al. 1995). Compared with FIO2 0.3, the degree of atelectasis (1.6 ± 1.6 cm2 vs 4.7 ± 4.5 cm2) and intrapulmonary shunt (3.2 ± 2.7% to 9.8 ± 5.7%) were significantly increased in the FIO2 1.0 group (Rothen et al. 1995). Therefore, some early studies have suggested that a lower concentration of oxygen mixed with nitrogen may ameliorate the early formation of atelectasis and pulmonary shunt during anesthesia induction (Rothen et al. 1996; Edmark et al. 2011). Our study provides further evidence that high FIO2 administration during induction may increase the formation of absorption atelectasis and pulmonary shunt, which in turn, may impact the gas exchange and tissue oxygenation at the emergence and recovery phases of anesthesia.
The results of this study indicate that, in generally healthy patients (ASA PS I-III), low fraction oxygen supplementation (FIO2 0.6) during induction of ETGA appears to affect tissue oxygen tension at two ways: it increases incidence of desaturation during induction, but seems to have protective effects against respiratory distress after endotracheal tube removal. Since increased BMI could be a confounding factor for the development of desaturation during induction, it would be reasonable to repeat follow-up studies in non-obese patients who receive ETGA. Our study examining lower risk population showed that the overall incidence of hypoxemia after removal of endotracheal tube in the FIO2 1.0 group was 6.0%, which is comparable with the incidences reported in general population (9.3–21%) (Ehrenfeld et al. 2010; Sun et al. 2015; Quintero-Cifuentes et al. 2018). Given that more than 200 million major surgical procedures are performed worldwide each year (Weiser et al. 2008), a NNH of 23 to 26 by administrating FIO2 1.0 during induction could be clinically significant to result in post-anesthesia hypoxemic events.
It should be noted that there are several limitations in this study. First, the fact that the trial was early terminated may have reduced the statistical power needed to determine the difference between the two treatment groups. Secondly, this was an open-label trial in which our anesthetic team was not blinded to the treatment groups. However, it is not practical to conceal the inspired oxygen fractions during anesthesia. Furthermore, blinding the anesthetist-in-charge to oxygen concentrations may be unethical, as tissue desaturation usually progresses very rapidly after the patient has been paralyzed. Nevertheless, the research team members who recorded the secondary endpoints in the ward were blinded to the treatment. Thirdly, obese patients have been recognized as an independent risk factor for early desaturation during apnea (Bouroche and Bourgain 2015; Goudra et al. 2014), but they were included in this study and might confound the primary endpoint. Our initial study design aimed to investigate the effect of inspired oxygen fractions on the perioperative outcomes in relatively healthy patients (ASA PS I-III), as they are more likely to achieve beneficial outcomes from lower oxygen fractions than critically ill patients (Nimmagadda et al. 2017). Although we excluded patients with BMI > 35 kg/m2 (class II obesity), our study specified that class I obese (BMI 30-34.9 kg/m2 patients may also benefit from high inspired oxygen fractions during induction. Fourthly, this was a pragmatic clinical trial testing the outcomes of two different oxygen fractions used for anesthesia induction in a broad routine clinical practice. Therefore, endotracheal intubation and extubation timing was primarily decided by the anesthetist-in-charge based on the patient’s clinical responses and anesthetic depth, which resulted in a number of different time points in regards to development of desaturation. Fifthly, this study failed to specify the optimal oxygen concentration for anesthesia induction, and can only provide the estimated range of 60% to100%. Future studies may wish to look into more specific oxygen concentrations for optimal anesthesia induction. Sixthly, we did not routinely measure the recovery of neuromuscular function before extubation of endotracheal tube. The residual curarisation effect of neuromuscular blocking agents on spontaneous ventilation could affect the occurrence of respiratory distress after extubation. Seventhly, our study did not show any differences in SSI occurrence, as some studies have suggested that higher fraction oxygen supplementation can reduce risk of SSI’s (Belda et al. 2005; Chu et al. 2018). Since high risk procedures and patients with major comorbidities were excluded from this study, the incidence of postoperative SSI was relatively low in our study, thereby limiting our ability to detect difference between the two groups. Lastly, growing evidence suggests that critically ill patients might also benefit from low optimal oxygen therapy (Chu et al. 2018; Damiani et al. 2018). However, our results are not applicable to patients with ASA ≥ IV, advanced systemic diseases, active lung diseases, difficult airway and those who receive emergency and major operations.
As compared with FIO2 1.0, this clinical study shows that FIO2 0.6 supplementation in with ASA PS I-III surgical patients receiving ETGA significantly increases the risk of hypoxemia during induction. Obese patients (BMI > 30 kg/m2) are associated with higher risk of developing desaturation when FIO2 0.6 is administered during the preoxygenation and induction phases of anesthesia. However, administration of 100% FIO2 during anesthesia induction may increase incidence of hypoxemic events after endotracheal tube removal and the return of spontaneous ventilation in the OR and at PACU. Although our study was underpowered to conclude the statistical difference, the brief period of substantially high oxygen exposure at the beginning of anesthesia could be a potential contributing factor to postoperative acute respiratory distress in patients receiving general anesthesia.