Heterogeneity of treatment effect: the case for individualising oxygen therapy in critically ill patients

Critical Care volume 29, Article number: 50 (2025) 

Published: 28 January 2025

Abstract

Oxygen therapy is ubiquitous in critical illness but oxygenation targets to guide therapy remain controversial despite several large randomised controlled trials (RCTs). Findings from RCTs evaluating different approaches to oxygen therapy in critical illness present a confused picture for several reasons. Differences in both oxygen target measures (e.g. oxygen saturation or partial pressure) and the numerical thresholds used to define lower and higher targets complicate comparisons between trials. The duration of and adherence to oxygenation targets is also variable with consequent substantial variation in both the dose and the dose separation. Finally, heterogeneity of treatment effects (HTE) may also be a significant factor. HTE is defined as non-random variation in the benefit or harm of a treatment, in which the variation is associated with or attributable to patient characteristics. This narrative review aims to make the case that such heterogeneity is likely in relation to oxygen therapy for critically ill patients and that this has significant implications for the design and interpretation of trials of oxygen therapy in this context. HTE for oxygen therapy amongst critically ill patients may explain the contrasting results from different clinical trials of oxygen therapy. Individualised oxygen therapy may overcome this challenge, and future studies should incorporate ways to evaluate this approach.

 

Hyperoxemia after reperfusion in cardiac arrest patients: a potential dose–response association with 30-day survival

by Akil Awad, Per Nordberg, Martin Jonsson, Robin Hofmann, Mattias Ringh, Jacob Hollenberg, Jens Olson and Eva Joelsson-Alm 

Critical Care volume 27, Article number: 86 (2023) Published: 06 March 2023

Background

Hyperoxemia may aggravate reperfusion brain injury after cardiac arrest. The aim of this study was to study the associations between different levels of hyperoxemia in the reperfusion period after cardiac arrest and 30-day survival.

Methods

Nationwide observational study using data from four compulsory Swedish registries. Adult in- and out-of-hospital cardiac arrest patients admitted to an ICU, requiring mechanical ventilation, between January 2010 and March 2021, were included. The partial oxygen pressure (PaO2) was collected in a standardized way at ICU admission (± one hour) according to the simplified acute physiology score 3 reflecting the time interval with oxygen treatment from return of spontaneous circulation to ICU admission. Subsequently, patients were divided into groups based on the registered PaO2 at ICU admission. Hyperoxemia was categorized into mild (13.4–20 kPa), moderate (20.1–30 kPa) severe (30.1–40 kPa) and extreme (> 40 kPa), and normoxemia as PaO2 8–13.3 kPa. Hypoxemia was defined as PaO2 < 8 kPa. Primary outcome was 30-day survival and relative risks (RR) were estimated by multivariable modified Poisson regression.

Results

In total, 9735 patients were included of which 4344 (44.6%) were hyperoxemic at ICU admission. Among these, 2217 were classified as mild, 1091 as moderate, 507 as severe, and 529 as extreme hyperoxemia. Normoxemia was present in 4366 (44.8%) patients and 1025 (10.5%) had hypoxemia. Compared to the normoxemia group, the adjusted RR for 30-day survival in the whole hyperoxemia group was 0.87 (95% CI 0.82–0.91). The corresponding results for the different hyperoxemia subgroups were; mild 0.91 (95% CI 0.85–0.97), moderate 0.88 (95% CI 0.82–0.95), severe 0.79 (95% CI 0.7–0.89), and extreme 0.68 (95% CI 0.58–0.79). Adjusted 30-day survival for the hypoxemia compared to normoxemia group was 0.83 (95% CI 0.74–0.92). Similar associations were seen in both out-of-hospital and in-hospital cardiac arrests.

Conclusion

In this nationwide observational study comprising both in- and out-of-hospital cardiac arrest patients, hyperoxemia at ICU admission was associated with lower 30-day survival.

High-Flow Nasal Oxygen in Coronavirus Disease 2019 Patients With Acute Hypoxemic Respiratory Failure: A Multicenter, Retrospective Cohort Study*

 

High-Flow Nasal Oxygen in Coronavirus Disease 2019 Patients With Acute Hypoxemic Respiratory Failure: A Multicenter, Retrospective Cohort Study*

 

by Xia, Jingen; Zhang, Yi; Ni, Lan; Chen, Lei; Zhou, Changzhi; Gao, Chang; Wu, Xiaojing; Duan, Jun; Xie, Jungang; Guo, Qiang; Zhao, Jianping; Hu, Yi; Cheng, Zhenshun; Zhan, Qingyuan

Critical Care Medicine: November 2020 - Volume 48 - Issue 11 - p e1079-e1086

Objectives:  

An ongoing outbreak of coronavirus disease 2019 is spreading globally. Acute hypoxemic respiratory failure is the most common complication of coronavirus disease 2019. However, the clinical effectiveness of early high-flow nasal oxygen treatment in patients with coronavirus disease 2019 with acute hypoxemic respiratory failure has not been explored. This study aimed to analyze the effectiveness of high-flow nasal oxygen treatment and to identify the variables predicting high-flow nasal oxygen treatment failure in coronavirus disease 2019 patients with acute hypoxemic respiratory failure.

Design:

A multicenter, retrospective cohort study. Setting: Three tertiary hospitals in Wuhan, China. Patients: Forty-three confirmed coronavirus disease 2019 adult patients with acute hypoxemic respiratory failure treated with high-flow nasal oxygen. Interventions: None.

Measurements and Main Results:

Mean age of the enrolled patients was 63.0 ± 9.7 years; female patients accounted for 41.9%. High-flow nasal oxygen failure (defined as upgrading respiratory support to positive pressure ventilation or death) was observed in 20 patients (46.5%), of which 13 (30.2%) required endotracheal intubation. Patients with high-flow nasal oxygen success had a higher median oxygen saturation (96.0% vs 93.0%; p < 0.001) at admission than those with high-flow nasal oxygen failure. High-flow nasal oxygen failure was more likely in patients who were older (p = 0.030) and male (p = 0.037), had a significant increase in respiratory rate and a significant decrease in the ratio of oxygen saturation/Fio2 to respiratory rate index within 3 days of high-flow nasal oxygen treatment. In a multivariate logistic regression analysis model, male and lower oxygen saturation at admission remained independent predictors of high-flow nasal oxygen failure. The hospital mortality rate of the cohort was 32.5%; however, the hospital mortality rate in patients with high-flow nasal oxygen failure was 65%.

Conclusions:

High-flow nasal oxygen may be effective for treating coronavirus disease 2019 patients with mild to moderate acute hypoxemic respiratory failure. However, high-flow nasal oxygen failure was associated with a poor prognosis. Male and lower oxygenation at admission were the two strong predictors of high-flow nasal oxygen failure.

Oxygen Thresholds and Mortality During Extracorporeal Life Support in Adult Patients

Oxygen Thresholds and Mortality During Extracorporeal Life Support in Adult Patients

Munshi, L et al
Critical Care Medicine: December 2017 - Volume 45 - Issue 12 - p 1997–2005

Objectives: Extracorporeal life support can lead to rapid reversal of hypoxemia and shock; however, it can also result in varying degrees of hyperoxia. Recent data have suggested an association between hyperoxia and mortality; however, this conclusion has not been consistent across the literature. We evaluated the association between oxygenation thresholds and mortality in three cohorts of extracorporeal life support patients. 
Design: We performed a retrospective cohort study using the Extracorporeal Life Support Organization Registry. Setting: We evaluated the relationship between oxygenation measured 24 hours after extracorporeal membrane oxygenation onset and mortality (2010–2015). Patients: The extracorporeal life support cohorts were as follows: 1) veno-venous extracorporeal membrane oxygenation for respiratory failure, 2) veno-arterial extracorporeal membrane oxygenation for cardiogenic shock, and 3) extracorporeal cardiopulmonary resuscitation. Interventions: The relationships between hypoxemia (PaO2 < 60mm Hg), normoxia (PaO2 60–100mm Hg), moderate hyperoxia (PaO2 101–300mm Hg), extreme hyperoxia (PaO2 > 300 mm Hg), and mortality were evaluated across three extracorporeal life support cohorts. 
Measurements and Main Results: Seven hundred sixty-five patients underwent veno-venous extracorporeal membrane oxygenation, 775 patients underwent veno-arterial extracorporeal membrane oxygenation, and 412 underwent extracorporeal cardiopulmonary resuscitation. During veno-venous extracorporeal membrane oxygenation, hypoxemia (odds ratio, 1.68; 95% CI, 1.09–2.57) and moderate hyperoxia (odds ratio, 1.66; 95% CI, 1.11–2.50) were associated with increased mortality compared with normoxia. There was no association between oxygenation and mortality for veno-arterial extracorporeal membrane oxygenation. Moderate hyperoxia was associated with increased mortality during extracorporeal cardiopulmonary resuscitation compared with normoxia (odds ratio, 1.77; 95% CI, 1.03–3.30). An exploratory analysis did not find more specific PaO2 thresholds associated with mortality within moderate hyperoxia. 
Conclusions: Moderate hyperoxia was associated with increased mortality in patients undergoing veno-venous extracorporeal membrane oxygenation for respiratory failure and extracorporeal cardiopulmonary resuscitation. Hypoxemia was associated with an increased mortality in veno-venous extracorporeal membrane oxygenation. No association was seen between oxygenation and mortality in veno-arterial extracorporeal membrane oxygenation which may be due to early death driven by the underlying disease.