Awake Prone Position in COVID-19-Related Acute Respiratory Failure: A Meta-analysis of Randomized Controlled Trials

doi:10.21203/rs.3.rs-2079845/v1

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Awake Prone Position in COVID-19-Related Acute Respiratory Failure: A Meta-analysis of Randomized Controlled Trials

https://doi.org/10.21203/rs.3.rs-2079845/v1

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Journal Publication

published 26 Apr, 2023

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Background

We aimed to investigate the effects of awake prone positioning (APP) in acute hypoxemic, non-intubated patients due to COVID-19 infections.

Methods

A collection of databases including PubMed, EMBASE, Web of Science and Cochrane Central Register were searched up to June 1, 2022. All randomized trials investigating the effects of the APP were included in the present meta-analysis. The primary outcome was intubation rate, and the secondary outcome included the length of intensive care unit (ICU) and hospital stay, and mortality. Prescribed sub-group analysis was also conducted.

Results

A total of 10 randomized trials enrolling 2324 patients were finally included in the present study. The results indicated APP was associated with a significant reduction of intubation rate (OR 0.77, 95% CI 0.63 to 0.93, P = 0.007). However, no differences could be observed in length of ICU stay or hospitalization, or mortality. Sub-group analysis suggested that patients in the ICU settings (OR 0.74, 95% CI 0.60 to 0.91, P = 0.004), patients whose median APP time was more than 4 hours (OR 0.77, 95% CI 0.63 to 0.93, P = 0.008), and patients with an average baseline SpO₂ to FiO₂ ratio less than 200 mmHg (OR 0.75, 95% CI 0.61 to 0.92) were more likely to benefit from APP with significant reduced intubation rate.

Conclusion

Based on the current evidence, non-intubated patients with hypoxemic respiratory failure due to COVID-19 infection conducted with APP was associated with significantly induced intubation rate. However, no differences in ICU or hospital length of stay, or mortality could be observed between APP and usual care.

COVID-19

hypoxemic respiratory failure

intubation

awaken prone position

Prone position is widely used in severe acute respiratory distress syndrome (ARDS) patients since its effects on improving oxygenation and mortality have been proved(1, 2). Awake prone position, which means prone position for non-intubated patients, has been attempted for patients with acute respiratory failure many years ago(3) and its potential effects in avoiding intubation was shown in a recent study(4).

During the COVID-19 pandemic APP has been broadly performed worldwide and incorporated into clinical guidelines and expert consensus statements(5, 6). Multiple previous observational studies reported improved oxygenation with APP in COVID-19-related acute respiratory failure patients, but none of them demonstrated a benefit in avoiding intubation or reducing mortality definitely(7). Since last year, some randomized controlled studies tried to discussed whether APP could reduce intubation and mortality, but the controversy still exists. In August, 2021, an international randomized controlled meta-trial which included more than 1100 patients showed that APP significantly reduced intubation rate for patients with COVID-19-related respiratory failure requiring support with high-flow nasal cannula(8). A recently published meta-analysis included ten RCTs (1985 patients) and 19 observational studies (2669 patients) also supported APP in reducing intubation need(9). However, Alhazzani and colleagues’ study(10) overturned this conclusion since their study didn’t find benefits of prone position in reducing intubation and improving outcomes.

Considering the controversy about APP in clinical effects, we did this meta analysis to evaluate the effects of APP in intubation rate and mortality. We believe these findings can help clinicians in their daily practice and maximise the benefits for patients with COVID-19 during the ongoing pandemic.

This study was prepared according to the Preferred Reporting Items for Systemic Reviews and Meta-Analyses (PRISMA) statement (Additional File 1) and our protocol was registered in the International Prospective Register of Systematic Reviews (CRD42022337846).

Information Sources

Two reviewers searched databases including PubMed, EMBASE, Cochrane Central Register and Web of Science from Jan 1, 2020, to June 10, 2022. We included studies only in English with no limitations in locations. When potentially relevant reviews or meta-analyses were found, a retrograde search was conducted to assess for further studies.

Search Strategy

Following key words were introduced in the search, including “prone position”, “awake or non-intubated”, “COVID-19” and “SARS-CoV-2”. The completed search strategy was provided in the Additional File 2.

Eligibility Criteria

Trials that met the following criteria were included in this meta-analysis: (1) study population with acute hypoxemic respiratory failure due to suspected or confirmed COVID-19 infection, who were not intubated; (2) the intervention would be APP, with no restrictions on durations; (3) the control group of usual care, with no restrictions on positionings; (4) reported the outcomes of interest, and (5) study design would be randomized controlled trials. The exclusion criteria included: (1) in vitro or animal experiments; (2) pediatric or pregnant subjects; (3) non-randomized study design; (4) lack any of results on outcomes of interest.

Study Selection

Titles and abstracts were initially reviewed separately by two reviewers. When potentially relevant studies were found, the complete manuscripts were obtained for further review. All the studies were reviewed, assessed and selected by two separate reviewers, with any disputes solved by consensus or discussion with a third reviewer.

Data Items

The following information was extracted from the studies: (1) subject characteristics, including the demographic information of age and gender, the baseline oxygenations (evaluated by SpO₂ to FiO₂ or PaO₂ to FiO₂), the settings of the trials (ICU or ward); (2) details in interventions, including the daily and overall duration of prone position, (3) outcomes of interest. The primary outcomes were the intubation rate; and the second outcomes were clinical parameters, including the improvement of oxygenations if available, the length of ICU stay and hospitalization, mortality.

Risk of Bias Assessment

Internal validity and risk of bias of the enrolled studies were evaluated by two independent reviewers using Cochrane Collaboration’s Handbook protocols(11). The risk of bias of the studies was assessed as “Yes”, “No” or “Unclear” following scrutinization of the methods and procedures taken in the articles.

Summary Measures

Continuous variables were presented as means with standard deviations (SD), and converted if medians with interquartile ranges (IQR) or 95% confidence intervals (CI) were used; and were compared by mean difference (MD) or standard mean difference (SMD) according to the uniformity of the units of the parameters. Categorical variables described as frequencies or proportions and estimated by odds ratios (OR) with 95% CIs.

Statistical Analysis

The data obtained from the enrolled studies were calculated using Review Manager 5.4 (The Nordic Cochrane Centre, Cochrane Collaboration, Copenhagen). Mantel-Haenszel statistics were used for dichotomous variable measurements, and an inverse variance model was applied for continuous variable comparisons. A random-effects model was used to better accommodate for heterogeneity. Cochrane I-square statistics was applied to evaluate the heterogeneity between studies, and I-square > 50% was defined as high heterogeneity. As for sensitivity analysis, each study was sequentially removed with remaining dataset re-analyzed to calculate the statistical significance or favoring directions to evaluate the robustness of the results.

Univariate meta-regression involving the factors of study design and performance was used to find the potential sources contributing to heterogeneity between studies. The prescribed potential factors included the sample size, the overall intubation rate, APP duration, settings (ICU)

Prescribed sub-group analysis dividing the studies by average baseline oxygenations evaluated by PaO₂ to FiO₂ ratio or SpO₂ to FiO₂ ratio; and the different settings of the studies including ICU settings and non-ICU settings.

Study Selection and Characteristics

We identified a total of 326 articles with our search strategy. We screened 235 titles and abstracts after 32 duplicates were removed. A final of 10 randomized controlled trials enrolling 2324 patients were included in this meta-analysis(8, 10, 12–19) (Fig. 1). The detailed risks of bias assessment of the enrolled trials were described in Additional File 3.

Among the 10 included studies, 5 studies were set in the ICU(8, 10, 13, 14, 17), and 5 studies were in the general wards(12, 15, 16, 18, 19); the final overall intubation rate ranged from zero to 66.7%(17); the reported baseline SpO2 to FiO2 ratio varied from less than 150 mmHg(8, 10) to more than 300 mmHg(12, 16, 19); and the APP procedures were variable, with the average daily duration of APP varied between less than 1 hour to approximately 9 hours. The characteristics of the enrolled trials was presented in Table 1.

Synthesis of Results

Primary outcomes

All the ten studies reported patients requiring intubation as an outcome and the results revealed a significant decrease in APP group compared with the control group, with an OR of 0.77 ((95% CI 0.63 to 0.93, P = 0.007) (Fig. 2A).

Secondary outcomes

We compared the clinical outcomes between APP group and control group and found that APP decreased neither ICU length of stay (P = 0.40), nor length of hospital stay (P = 0.14) (Additional File 4). There was no significant difference between APP group and control group in all-cause mortality (P = 0.42) (Fig. 2B).

Sub-group analysis

A prescribed sub-group analysis was deployed for further interpretation, and we found that patients with average baseline SpO₂/FiO₂< 200mmHg (OR 0.75, 95% CI 0.61 to 0.92, P = 0.006) and patients who received an averaged accumulated APP more than 4 hours (OR 0.77, 95% CI 0.63 to 0.93, P = 0.008) were likely to benefit from APP with reduced intubation rate. In the subgroup patients admitted to ICU, APP decreased intubation rate significantly (OR 0.74, 95% CI 0.60 to 0.91, P = 0.004) (Fig. 3).

Risk of Bias and Sensitivity Analysis

Both fixed and random models were used to test the results and we found no change in statistical significance. Each individual study was removed with remaining studies analyzed, and we found that the statistical significance was obliviated when the study by Ehrmann et al(8) were removed from the analysis, which suggested that the result might not be robust (Additional File 5). Visual inspection of the funnel plots revealed asymmetry on the distribution of the results, which suggested possible publish bias of the studies (Additional File 6).

Meta-regression

Although no significant heterogeneity could not be observed by I-square statistics (I-square = 0), a meta-regression analysis was conducted. However, we did not find factors that potentially associated with heterogeneity between studies, including the sample size, the number of sites, the overall intubation rate, the average hour of APP, and whether the patients were in the ICU setting or general wards (Additional File 7).

In the present meta-analysis, we included ten trails enrolling 2324 patients with COVID-19-related acute hypoxemic respiratory failure and found that APP significantly decreased intubation rate. Our findings were consistent with a recently published meta-analysis(9), which included ten RCTs that included a total of 1985 patients, and 19 observational studies that included a total of 2669 patients. However, a latest RCT implemented in 21 hospitals with 400 patients overthrown this conclusion(10). Our study validated the effect of APP in reducing the intubation rate for COVID-19-related respiratory failure patients.

The findings of subgroup analysis showed specific group of COVID-19-related respiratory failure patients who can benefit from APP. Those who received APP treatment for more than 4 hours or those whose baseline SaO₂/FiO₂< 200 mmHg were more likely avoiding intubation. Patients in ICU were also tend to benefit from APP. However, in this meta-analysis, we used an average APP time, so the patients in the individual group may not be precisely APP for the appointed time, a patient-level meta-analysis may solve this issue.

For moderate to severe ARDS patients using invasive mechanical ventilation, prone position was a very important treatment which can significantly improve patients’ outcome(2). Subsequent studies found that prone position was a time-dependent therapy which meant only when the duration of prone position was more than 12 hours, its effects began to reveal(20). For COVID-19-related respiratory failure patients, there was also a threshold duration time of APP and our results showed that when patients received APP more than 4 hours within one day, its benefits in avoiding intubation revealed. Considering the comforts, risks and compliance of APP for COVID-19 patients, maybe a threshold of 12 hours for prone position treatment isn’t applicable for APP. More relevant data are needed to establish an appropriate duration goal for APP.

We also compared with the patients in the ICU settings and those in non-ICU settings and found that the patients in the ICU settings were significantly associated with a decreased intubation rate, which we thought, could be explained by the following reasons. First, the patients enrolled in the ICU maybe more severe, and they were more likely to progress to intubation than non-ICU patients. Second, the patients in ICU were related to intensive monitoring, higher nursing to patient ratios, and their adherence to APP was higher.

The main mechanisms of prone position in improvement of ARDS patients’ condition include increasing end-expiratory lung volume, decreasing alveolar shunt, decreasing tidal hyperinflation of the ventral regions and promoting the recruitment of the dorsal regions of the lung, which leads to better ventilation-perfusion matching(21). For COVID-19 related respiratory failure patients who received APP, all these mechanisms exist(22). Moreover, awake patients with spontaneous breathing during prone positioning could lead to improved gas exchange, decreased inspiratory effort and lung stress, and attenuated systemic inflammatory response(23). A recent study also demonstrated that for patients with COVID-19-induced acute hypoxemic respiratory failure (AHRF) and treated by high flow nasal cannula oxygen therapy (HFNC) and APP, APP was associated with improvements of the aeration of the dorsal lung zones(24). These might explain the effects of awake prone position in avoiding intubation. However, there were many bias factors such as the duration of awake prone position, the compliance of this treatment and the severity of included patients in recent researches about APP. What’s more, some researchers found that after three days of APP treatment lung aeration only improved in COVID-19 patients who eventually avoided intubation/death(25), which meant there were individual differences in patients’ response to APP. Further studies on mortality are warranted.

This study had several limitations. As for the nature of enrolled studies, the APP performance could not be blinded to the subjects or investigators, which would potentially bring bias to the results; two of the included studies reported no intubation or mortality, with did not contribute to the pooled results; we used the average value of the included studies for the sub-group analysis, and a patient-level meta-analysis may be warranted.

Based on the current evidence, non-intubated patients with acute hypoxemic respiratory failure due to COVID-19 infection conducted with APP was associated with significantly induced intubation rate. However, no differences in ICU or hospital length of stay, or mortality could be observed between APP and usual care. Sub-group analysis suggested patients admitted to ICU and with a lower SpO2 to FiO2 ratio was more likely to benefit from APP.

APP: Awake prone position, ICU: Intensive care unit, OR: Odds ratio, CI: Confidence interval, SpO2: Transcutaneous oxygen saturation, FiO2: inspired oxygen, ARDS: Acute respiratory distress syndrome, RCT: Randomized controlled trial, PRISMA : Preferred Reporting Items for Systemic Reviews and Meta-Analyses, PaO2: Partial pressure of arterial oxygen, SD: Standard deviations, IQR: Interquartile ranges, MD: Mean difference, SMD: Standard mean difference, AHRF: Acute hypoxemic respiratory failure, HFNC: High flow nasal cannula oxygen therapy.

Ethical approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

This work was partially supported by Jiangsu Province’s Key Discipline/Laboratory of Medicine (ZDXKA2016025), Jiangsu Provincial Key Research and Development Program (SBE2018750279), National Natural Science Foundation of China (80001817) and Nanjing Medical Science and Technology Development Project (YKK20234).

Authors’ contributions

W-C carried out the analysis and interpretation of data and participated in drafting, editing and submitting the manuscript. The articles were reviewed by two reviewers (W-C and ZH-H) independently in accordance with the inclusion criteria. Disagreements were resolved by consensus and discussion including a third reviewer (Q-S). The quality of the articles was assessed by W-C and F-P independently, with disagreements resolved by consulting a third reviewer (Q-S). Y-Y was responsible for the conception, design and coordination of the study and for revising the manuscript for important intellectual content. All authors read and approved the final manuscript.

Acknowledgements

Not applicable.

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Guerin C, Reignier J, Richard JC, et al. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med. 2013;368(23):2159–68.
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Table 1 Characteristics of the enrolled studies. APP awake prone position, NR not reported, SpO₂ transcutaneous oxygen saturation, FiO₂ inspired oxygen fraction. SpO₂ to FiO₂ ratio was estimated by following formula S/F = 64 + 0.84×(P/F) if P/F were reported in the study.

Study	Settings	Patient Number	Estimated baseline S/F, mmHg	Overall intubation rate, %	Daily APP duration, hour
Alhazzani 2022	ICU	400	133.9±52.5	37.3	4.8 (1.8 to 8.0)
Ehrmann 2021	ICU	1121	148.2±43.5	36.4	5.0 (1.6 to 8.8)
Fralick 2022	Non-ICU	250	303.9±18.4	4.4	6 (1.5 to 12.8)
Gad 2021	ICU	30	163.45±109.9	20.0	each session last for 1 to 2 h according to pat to tolerability with 3-hs apart during waking hours.
Jayakumar 2021	ICU	60	226.1±164.8	13.3	a minimum of 6-h in a day
Johnson 2021	Non-ICU	30	NR	6.7	1.6 (0.2 to 3.1)
Kharat 2021	Non-ICU	27	329.3±56.0	0.0	4.9 ± 3.6
Rampon 2022	Non-ICU	293	396 (306-387)	2.0	NR
Rosen 2021	ICU	75	160±87.5	66.7	9.0 ± 4.6 (control group, 3h）
Taylor 2021	Non-ICU	40	NR	0.0	10 to 120 min per day

No competing interests reported.

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published 26 Apr, 2023

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Editorial decision: Major revision
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You are reading this latest preprint version

Awake Prone Position in COVID-19-Related Acute Respiratory Failure: A Meta-analysis of Randomized Controlled Trials

Status:

Journal Publication

Version 1

Abstract

Background

Methods

Results

Conclusion

Figures

Background

Methods

Information Sources

Search Strategy

Eligibility Criteria

Study Selection

Data Items

Risk of Bias Assessment

Summary Measures

Statistical Analysis

Results

Study Selection and Characteristics

Synthesis of Results

Primary outcomes

Secondary outcomes

Sub-group analysis

Risk of Bias and Sensitivity Analysis

Meta-regression

Discussion

Conclusion

Abbreviations

Declarations

Ethical approval and consent to participate

Consent for publication

Availability of data and materials

Competing interests

Funding

Authors’ contributions

Acknowledgements

References

Tables

Additional Declarations

Supplementary Files

Status:

Journal Publication

Version 1