COVID-19 Awake Proning – All Hype?

Background: Facilities around the world have seen surges of COVID-19 pneumonia  patients who have required protracted hospitalizations leading to overwhelmed hospital systems. Awake proning is a practice that was adopted early in the pandemic as a means to avoid, or at least delay, endotracheal intubation to lessen the burden of ICU care.  Proning helps improve lung recruitment, reduce ventilation/perfusion mismatch, and reduces alveolar strain in intubated patients.  Numerous small trials and anecdotes of awake proning have shown improvements in oxygenation and respiratory rate.However, whether these surrogate physiological endpoint improvements translate to better clinical outcomes (i.e. intubation and mortality) is still largely unknown.

Paper: Pavlov I et al. Awake Prone Positioning in Non-Intubated Patients With Acute Hypoxemic Respiratory Failure Due to COVID-19: A Systematic Review and Meta-Analysis. Research Square 2020. [Link is HERE]

Clinical Question: Does awake proning of non-intubated patients with acute hypoxemic respiratory failure due to COVID-19 result in reduced intubation and mortality compared to standard care?

What They Did:

• Systematic review and meta-analysis of observational trials comparing in-hospital intubation and mortality rates in patients treated with awake proning vs standard care

Outcomes:

• In-hospital intubation rate
• In-hospital mortality
• Proportion of physiological “responders” to awake proning
  • Responders defined as:
    • Increase of PaO2/FiO2 ratio ≥20%
    • If PaO2/FiO2 not reported, an increase of SpO2/FiO2 ratio ≥20% was considered a response

Inclusion:

• Original research reports of COVID-19 patients
• Patients treated with awake proning and/or HFNC or NIV or conventional oxygen therapy

Exclusion:

• Languages other than English or Chinese
• Study protocols, review articles, abstracts, editorials
• Research on newborns or animals
• Reports of fewer than 3 cases

Results:

• 46 published and 4 unpublished trials included
  • 2994 patients
• Intubation Rate (25 studies with 870pts):
  • Awake Prone: 27% (95% CI 19 to 37%)
  • Standard Care: 30% (95% CI 20 to 42%)
  • P = 0.71 (not statistically significant)
  • Subgroup analysis according to duration of awake proning (<4hr/d vs ≥4hr/d), the device (HFNC vs CPAP vs NIV), and severity of ARDS (PaO2/FiO2 <150mmHg vs PaO2/FiO2 ≥150mmHg) did not demonstrate any significant differences
• Mortality (20 studies with 767pts):
  • Awake Prone: 11% (95% CI 6 to 20%)
  • Standard Care: 22% (95% CI 13 to 36%)
  • P = 0.10 (not statistically significant
  • Subgroup analysis did not demonstrate any significant differences in mortality across predetermined subgroups
• Awake proning was associated with significant improvement of oxygenation parameters in the 19 studies (n = 381) that reported this outcome
  • 13 studies (n = 271) all showed improved SpO2 or PaO2 with awake proning
  • 9 of 10 studies (n = 192 of 198) all showed improved PaO2/FiO2 with awake proning
  • 7 studies all showed improved PaO2/FiO2 ≥20% with awake proning
  • 3 studies (n = 72) showed improvement in PaO2/FiO2 which was sustained after patients returning to supine position
  • 1 study (n = 46) showed improvement in PaO2/FiO2 was sustained in only 50% of patients after returning to supine position
  • 1 study (n = 26) showed improvement in PaO2/FiO2 was lost after returning to supine position

Strengths:

• Search included multiple databases for published studies (including non-peer reviewed publications) as well as reference lists of the individual studies to identify all studies
• If outcomes of intubation rate and mortality were not reported or not clear, corresponding authors were contacted for clarifications
• Evaluated potential sources of heterogeneity including baseline disease severity (PaO2/FiO2) at initiation of therapy, duration of awake proning, timing of awake proning initiation and type of respiratory support (conventional oxygen therapy, HFNC, NIV) across groups and studies
• Large sample size with 921 patients treated with awake proning

Limitations:

• No formal assessment of bias of included studies
• Only included observational studies, that were small and had high heterogeneity (i.e. Futile to attempt to pool the data)
• Observational data makes it impossible to determine why certain patients were prone and others were not
• Selection bias both for proning and not proning
• Unclear from institution to institution, or study to study, how long patients were prone and staff’s comfortability with proning
• Intubation criteria were not uniformly defined across studies and a subjective decision based on physician’s judgment
• Type of O2 support (conventional oxygen therapy, HFNC, CPAP/NIV) was not balanced between groups
• Subgroup analyses were limited by the fact that many patients most likely had various devices used through the course of their disease
• Without individual patient data cannot account for uncontrolled differences between patients treated with awake proning vs usual care
• Overall mortality rate was rather low which suggests selection and publication bias

Discussion:

• This systematic review and meta-analysis demonstrated that awake proning improved oxygenation but did not change the frequency of intubation or mortality in patients with acute hypoxemic respiratory failure secondary to COVID-19…BUT…
  • A 3% difference in intubation is meaningful in a large well-done study as is a 11% mortality difference. So although not statistically significant in this review, I think many would agree, both of these are clinically meaningful outcomes
  • This systematic review is hypothesis generating for a large RCT, but there is a clear trend towards benefit that can’t be ignored
• Three pre-specified subgroup analyses on the probability of intubation and mortality:
  • PaO2/FiO2 <150mmHg vs ≥150mmH
  • Respiratory support devices HFNC vs CPAP/NIV
  • Awake proning duration
• As papers were heterogenous, established objective definitions:
  • Awake proning = All patients proned
  • Some awake proning = ≥10% of patients were proned
  • No awake proning = <10% of patients were proned
• At worst awake proning could result in delayed intubations and self-induced lung injury (controversial) however there were no obvious signals of harm

Author Conclusion: “In this prospective meta-analysis of observational studies of patients with acute hypoxemic respiratory failure due to COVID-19, APP did not result in lower intubation or mortality rates, despite reported improvements in oxygenation parameters.  Data from randomized controlled trials are needed. Routine implementation of APP outside of a clinical trial is not supported by current evidence.”

Clinical Take Home Point: This systematic review and meta-analysis is a summation of methodologically flawed studies (which are the best evidence available at this time), however the conclusions drawn from them should also be taken with a grain of salt.  All the included trials were small, observational, had wide confidence intervals and high heterogeneity between studies making the interpretation of this review an absence of evidence, rather than absence of benefit. 

References:

1. Pavlov I et al. Awake Prone Positioning in Non-Intubated Patients With Acute Hypoxemic Respiratory Failure Due to COVID-19: A Systematic Review and Meta-Analysis. Research Square 2020. [Link is HERE]

Post Peer Reviewed By: Anand Swaminathan, MD (Twitter: @EMSwami)