Impact of Permissive Hypoxia and Hyperoxia Avoidance on Clinical Outcomes in Septic Patients Receiving Mechanical Ventilation: A Retrospective Single-Center Study

Abstract

Different ventilatory strategies may affect survival in septic patients requiring mechanical ventilation. In this retrospective before-and-after study, we examined the effects of permissive hypoxia and hyperoxia avoidance on mortality in mechanically ventilated adult (≥18 years) septic patients at a Japanese university hospital. In April 2017, our hospital’s mechanical ventilation policy changed from a conventional oxygenation target (SpO₂: ≥96%.) to more conservative targets with permissive hypoxia (SpO₂: 88-92% or PaO₂: 60 mmHg) and hyperoxia avoidance (reduced oxygenation for PaO₂ >110 mmHg). Patients were divided into a pre-change group (April 2015 to March 2017; n=83) or post-change group (April 2017 to March 2019; n=130). Using a multiple logistic regression model, we examined the association of the post-change group with intensive care unit (ICU) mortality. The post-change group did not have a significantly lower adjusted ICU mortality (odds ratio: 0.67, 95% confidence interval: 0.33-1.43; P=0.31) than the pre-change group. However, there were significant differences in mechanical ventilation duration (pre-change: 11.0 days, post-change: 7.0 days; P=0.01) and ICU stay (pre-change: 11.0 days, post-change: 9.0 days; P=0.02). Although the new ventilation policy did not affect ICU mortality, the reductions in mechanical ventilation duration and ICU stay may improve patient turnover and ventilator access.

Introduction

Patients with sepsis often require mechanical ventilation for respiratory dysfunction, and the use of different ventilatory strategies can affect survival rates¹. As mortality rates have been reported to exceed 30% in mechanically ventilated septic patients^{2, 3}, the improvement of mechanical ventilation protocols may have important implications for survivability.

A randomized controlled trial is currently examining the effects of permissive hypoxia in mechanically ventilated patients with respiratory dysfunction⁴, and a recent review indicated that permissive hypoxia may provide a better risk-benefit profile than the restoration of normoxia⁵. The dissociation curve of arterial oxygen tension (PaO₂) and oxyhemoglobin saturation (SpO₂) has been shown to be relatively flat when the latter exceeds 90%⁶, which supports the rationale of using permissive hypoxia. On the other hand, hyperoxia may have detrimental effects on survival among patients in critical condition^7,8. Therefore, a combined oxygenation strategy involving permissive hypoxemia and hyperoxia avoidance may improve the prognosis of mechanically ventilated patients with sepsis. However, there is a lack of evidence on the clinical effects of this strategy in a real-world setting.

Until March 31, 2017, our hospital’s ventilation policy was to attain an SpO₂ target of ≥ 96%. On April 1, 2017, this policy changed to an SpO₂ target of 88–92% or a PaO₂ target of 60 mmHg; in cases where PaO₂ exceeds 110 mmHg, the fraction of inspiratory oxygen (FiO₂) or peak inspiratory pressure (PIP) settings are reduced. In this study, we hypothesized that this policy shift to permissive hypoxia and hyperoxia avoidance would improve clinical outcomes in adult septic patients requiring mechanical ventilation. To test this hypothesis, we conducted a retrospective study to compare mortality in patients before and after this policy change.

Methods

Results

Discussion

In this retrospective before-and-after study, we examined the differences in ICU mortality and other outcomes between septic patients who had undergone mechanical ventilation with conventional oxygenation targets and those who had undergone mechanical ventilation with permissive hypoxia and hyperoxia avoidance. Although the latter approach did not significantly improve patient survival, it was associated with reductions in mechanical ventilation duration and ICU stay. Accordingly, permissive hypoxia and hyperoxia avoidance may help to increase patient turnover and access to ventilators. This optimization of resource utilization in the ICU is crucial for situations where ventilators and ICU beds are in low supply.

Current trials are underway to investigate the potential benefits of conservative ventilatory strategies. The Targeted OXygen therapY in Critical illness (TOXYC) study is a multicenter randomized controlled trial being conducted in the UK to compare the effects of SpO₂ targets of 88–92% and ≥ 96% on outcomes in mechanically ventilated patients with respiratory failure¹¹. Similarly, the Handling Oxygenation Targets in the Intensive Care Unit (HOT-ICU) trial in Denmark is comparing the effects of PaO₂ targets of 8 kPa (60 mmHg) and 12 kPa (90 mmHg) on 90-day mortality in adults with hypoxemic respiratory failure¹². In a previous before-and-after study of 105 adults who required mechanical ventilation for more than 48 hours at an Australian tertiary care hospital, it was found that an SpO₂ target of 90–92% was associated with significant risk reductions for new non-respiratory organ failure and 28-day mortality when compared with conventional oxygen therapy¹³. In contrast, an Australian multicenter randomized controlled trial found no significant differences in ICU mortality or 90-day mortality between SpO₂ targets of 88–92% and ≥ 96%. Although some studies did not detect any significant differences in outcomes between permissive hypoxia and conventional oxygenation strategies^14,15, one study reported an association between permissive hypoxia and reduced mortality¹⁶. Another study found no significant associations between conservative oxygen therapy and reductions in mortality or hospital stay in septic patients¹⁷, which corroborates our findings. A retrospective cohort study conducted in the Netherlands reported that neither FiO₂ nor positive end-expiratory pressure settings were reduced in 78% of mechanically ventilated ICU patients with PaO₂ exceeding 120 mmHg for FiO₂ targets of 0.21–0.4¹⁸. We posit that permissive hypoxia and hyperoxia avoidance may contribute to the reduction of mechanical ventilation duration and ICU stay due to the continuous and aggressive management in response to each patient’s oxygenation levels.

The use of high-concentration oxygen therapy is associated with pulmonary cellular damage and decreased mucus clearance, which can depress the immune system and elevate the risk of pneumonia¹⁹. In particular, severe lung injury occurs more easily for PaO₂ of 450 mmHg or more and FiO₂ of 0.6 or more¹⁹. Other studies have also reported that hyperoxia after nontraumatic cardiac arrest or stroke is associated with increased mortality^{20, 21}. An analysis of immunocompromised patients found that high-concentration oxygen therapy was significantly associated with increased complications, but not with mortality²². It should be noted that our hospital’s policy does not dictate strict oxygenation control in which targets must be met at all times. Instead, it requires that physicians adjust the oxygen fractions and/or ventilatory mode settings after recognizing the occurrence of unsupportable hypoxia and hyperoxia. We found no signs of adverse events resulting from this policy.

As our ICU uses APRV for all patients with respiratory failure, this study is characterized by its focus on APRV-treated cases. Extracorporeal membrane oxygenation was not used in our patients during the study period. Previous studies have shown that APRV allows the continuous and rapid improvement of oxygenation in ARDS patients^22–24. The use of APRV in our respiratory failure patients (including ARDS patients) may have contributed to improvements in oxygenation, and warrants further investigation. In addition, neuromuscular blocking drugs were only used in 3 emergent intubation cases (pre-change: 1, post-change: 2). Prone positioning was performed for all patients in both groups by nursing staff. However, prone positioning for more than 12 hours can place a heavy workload on medical staff, and was not utilized in cases where patient safety could not be ensured. In this way, there were no prominent inter-group differences in the use of therapies that could potentially affect respiratory failure rates.

Our findings should be considered in the context of several limitations. First, this was a retrospective single-center study with a relatively small sample size, and our results may lack generalizability. Second, the before-and-after design of this study may have introduced biases such as observer bias or history bias. To reduce these potential biases and improve the validity of our findings, we employed multivariate logistic regression analyses and propensity score matching to account for variations in baseline characteristics. However, multicenter prospective studies are needed to confirm or refute our findings. Third, there may be confounding factors that were not included in analysis. For example, the analysis did not account for differences in underlying disease. Severe diseases such as chronic heart failure, obstructive and/or restrictive pulmonary disease, and chronic kidney failure would affect patient prognosis. In addition, the management of critically ill patients (e.g., early mobilization) may have improved over time, and it is possible that this and other unidentified confounding factors had influenced the mechanical ventilation duration and ICU stay during the relatively long study period. Fourth, we did not use any other ventilatory mode apart from APRV. Therefore, our results may have generalizability issues for other ventilatory modes. Finally, we could not explain why reductions in mechanical ventilation duration and ICU stay did not lead to corresponding reductions in hospital stay. In Japan, acute care hospitals also fulfill the roles that would be assumed by subacute care hospitals in other countries. Therefore, these longer hospitalization durations may have been less affected by the shorter ICU stay.

Conclusions

The policy of permissive hypoxia and hyperoxia avoidance for septic patients requiring mechanical ventilation did not significantly improve prognosis. However, the shift in oxygenation targets was associated with reductions in mechanical ventilation duration and ICU stay. This would increase access to ventilators and other resources in the ICU. Nevertheless, further studies using larger study populations and multiple institutions are needed to verify our findings.

Declarations

Data availability

The data set used in this study is available from the corresponding author on reasonable request.

Acknowledgements

We thank the patients and their families for their participation in the study.

Author contributions

KN, Takeshi Umegaki, YN, and TK were responsible for the study concept and design. KN, Takeshi Umegaki, SO, TS, NA, Takeo Uba, TS, and MK treated the patients, participated in the collection, and collected data. KN, Takeshi Umegaki, and MK performed the statistical analysis. KN and Takeshi Umegaki wrote the manuscript. All authors undertook critical editing of the manuscript. All authors read and approved the final manuscript.

Additional Information

Competing interests

The authors declare no competing interests.

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