Oxygen, Is There Such a Thing as Too Much? Investigating the Impact of Hyperoxia on Outcomes

Allison M. Janda, MD

Expert researchers studying the implications of hyperoxia and hypoxia presented the evidence surrounding oxygen management in the AUA session, “Intraoperative Oxygen Administration, Mechanisms, and Outcomes – The Perioperative Sweet Spot?” on Saturday, March 19 at the IARS 2022 Annual Meeting. Drs. Josh Billings, Cynthia Ju and Shahzad Shaefi focused on the role of oxygen, implications of hyperoxia, variation of perioperative oxygen management, modulations of hypoxic injury, and the current state of research on the topic. Moderator Ines Koerner, MD, PhD, tied together all the presentations in a robust discussion exploring the challenges of comparing studies in the ICU to intraoperative studies.

Josh Billings, MD, MSc, Associate Professor, Critical Care Medicine, Cardiothoracic Anesthesiology and Resident Research Coordinator at Vanderbilt University Medical Center, kicked off the panel with a great summary of how hyperoxia impacts tissue oxygenation. He introduced the idea that tissue hypoxia may not be solely due to a decrease in oxygen tension, but also due to a decrease in perfusion, and therefore even in the context of hyperoxia and adequate blood oxygen content, tissue oxygenation may be inadequate. He then described the downside of hyperoxia, oxygen toxicity, which can increase reactive oxygen species production, oxidative damage, alter gene expression, vasoconstriction, decreased oxygen consumption and disrupt hypoxia inducible factor (HIF) signaling, which can increase organ damage.

So, what should we do in the operating room to balance this issue? The WHO’s 2016 Guidelines on the Prevention of Surgical Site Infection recommended 80% fraction of inspired oxygen (FiO2) to decrease surgical site infections, but Dr. Billings noted that the evidence supporting this statement is weak and that hyperoxia may in fact harm patients. To describe oxygen administration practices during surgery, Dr. Billings and his team studied a broad, diverse study sample across participating hospitals within the Multicenter Perioperative Outcomes Group (study underway, Open Science Framework Registration available). They found a median FiO2 near 55%, drastically different from the WHO recommendations. Factors associated with increased median FiO2 were ASA status >/=4, open heart cardiac surgery, cases for which a troponin was measured postoperatively and a case with an intraoperative desaturation. After accounting for patient factors, the median FiO2 varied significantly between hospitals, anesthesiologists and anesthesia in-room providers (residents and CRNAs). Notably, only 3.5% of the variance in intraoperative FiO2 was explained by patient factors, whereas the medical center explained 23.3% of the variation. These findings support that there is a significant amount of nonpatient centered variation and therefore equipoise exists in FiO2 administration since there is rationale to support both the administration of oxygen in excess and limiting oxygen administration, and clinical practice of both strategies. Dr. Billings closed his talk by highlighting the context of this practice variation they observed. There is considerable opportunity to improve perioperative care if specific oxygen management strategies are shown to be beneficial or harmful as more evidence is generated.

Cynthia Ju, PhD, Professor, Vice Chair for Research, Department of Anesthesiology, and Joseph C. Gabel, M.D. Endowed Chair In Anesthesiology at University of Texas at Houston, discussed the “Role of Hypoxia-Inducible Transcription Factors During Hepatic Injury,” focusing on hepatic ischemia reperfusion injury and how hypoxia can modulate hepatic ischemia reperfusion injury. Dr. Ju explained how the transcription factor, hypoxia inducible factor (HIF), is degraded in normoxic conditions, but under hypoxic conditions, HIF is activated, translocated to the nucleus, and turns on genes involved in multiple cellular functions including angiogenesis, immune responses, cancer, tissue inflammation, and hypoxia adaptation. Dr. Ju performed a study (Ju et al., 2021) which found that a micro RNA found in hepatic tissue, miR122, is upregulated in hypoxic conditions, was significantly upregulated upon hepatic ischemic reperfusion, and is induced by HIF. They also found that miR122 provides a protective role in liver reperfusion injury. This profound protective function for hepatic ischemia reperfusion injury was also amplified by the finding that miR122 downregulates PHD1, a prolyl hydroxylase that causes HIF degradation, further stabilizing HIF through a feed-forward loop. This has many clinical implications regarding application to hepatic transplant to reduce the negative impact of hepatic ischemia reperfusion injury.

In his presentation, “Friend or Foe: The Clinical Evidence for Oxygen,” Shahzad Shaefi, MD, MPH, Associate Professor of Anaesthesia at Harvard Medical School and a cardiac anesthesiologist and intensivist at Beth Israel Deaconess Medical Center, provided a tour through the clinical evidence behind oxygen therapy after cardiac arrest, in the ICU and in the OR. In patients who survived cardiac arrest, it was found that patients with hyperoxia had increased in-hospital mortality (Kilgannon, 2010). Furthermore, the study showed that every 100mmHg of hyperoxia was associated with an increased risk of mortality by 24% ( Kilgannon, 2011).

Dr. Shaefi then summarized multiple trials set in the ICU, including the Oxygen-ICU Trial, a randomized control trial that showed that ICU mortality was significantly reduced when lower FiO2s were used compared to standard treatment. However, the ICU-ROX trial, a pragmatic trial which studied usual practice vs. conservative oxygen therapy approaching FiO2 of 21%, did not find any significant difference in ventilator-free days. The LOCO2 trial studying patients with acute respiratory distress syndrome was prematurely ended since they showed that the conservative oxygen treatment group had higher 28-day mortality than the standard treatment group. The HOT-ICU trial was a large, randomized control study in the ICU that randomized patients to a target PaO2 of 90mmHg PaO2 or target PaO2 target of 60mmHg, and found no difference in 90-day mortality. A meta-analysis published in The Lancet in 2018 (Chu et al., 2018) synthesized the evidence and favored a conservative approach, but there are some ICU studies (HOT-ICU and ICU-ROX) that have conflicting evidence that have since been published and were not included in that 2018 meta-analysis. In the ORs, the PROXI Trial showed that 80% FiO2 administration did not result in a difference in risk of surgical site infection compared to 30% FiO2 administration. This trial also contained a subgroup analysis examining longitudinal survival showed 80% oxygen in the perioperative period significantly increased long-term mortality in cancer patients undergoing abdominal surgery (Meyhoff et al., 2012).

In the cardiac surgery population, the SO-COOL trial studied the association of hyperoxia and kidney injury in cardiac surgery and found no difference in acute kidney injury, length of stay or other markers of organ damage. Additionally, a recent trial published in Anesthesiology randomized 100 cardiac surgical patients to either 100% FiO2 or 35% FiO2 and found no differences in postoperative cognitive dysfunction between the groups (Shaefi et al., 2021). Dr. Shaefi concluded by saying that although there are conflicting results which could be attributable to the heterogeneous definitions of hyperoxia, patient cohorts and protocols, there is an increasing acceptance that normoxia or avoidance of extreme hyperoxia is good practice and saves costs but emphasized that more studies are needed.

The Q&A session was moderated by Ines Koerner, MD, PhD, Professor of Anesthesiology and Perioperative Medicine, School of Medicine, Professor of Neurological Surgery, School of Medicine, Vice Chair for Critical Care, Anesthesiology and Perioperative Medicine, School of Medicine and Medical Director of the Neurosciences ICU at Oregon Health & Science University. A great discussion explored the challenges of comparing studies in the ICU to intraoperative studies. Dr. Shaefi emphasized that the two settings have very different considerations and therefore should be studied separately, and more work is needed. Dr. Billings discussed additional details regarding his oxygen management MPOG study, outlining that they selected to report the median instead of mean to avoid the perturbations around induction and emergence, and that they did adjust for baseline SpO2 on arrival to the OR. Dr. Ju received a question regarding potential miR122 administration during liver transplant. She responded that it is likely more feasible to introduce the donor organ to miR122 to avoid the systemic effects of the miR122, but agreed that this would be an exciting clinical application of her data. The panel closed by emphasizing that anesthesiologists are very well-suited to study this refined question and help investigate the impact of hyperoxia on outcomes with elegant study design.