SCCM Resource Library-Prone Positioning in Awake Patients With COVID-19-Associated Respiratory Failure: The PROCARF Trial

Video Transcription

care physician with focus on septic shock, acute respiratory failure, mechanical ventilation, nutrition, and point of care ultrasound.  I'm going to present you the results of the PROCARB study, prone positioning in awake patients with COVID-19 associated respiratory failure.  Before this study, early in the pandemic, the published studies regarding awake prone  positioning, or APP, consisted of some hypotheses generating small series only, reporting transient  improvement in oxygenation generally, but those studies were not able to measure the effect on patient-centered outcomes like intubation or death.  When we designed this study, there were around 14-15 reports of the use of APP, but were all retrospective of small sample size, and they didn't add useful or solid information  regarding the benefits of APP, and the surviving sepsis campaign enlisted APP as one of the main research priorities.  So we developed this protocol for APP in two hospitals of western Mexico. We had a capacity of almost 100 beds for care of patients with COVID-19, exclusively  for COVID-19 at the same time, in the two hospitals of this study. We early in the pandemic, we standardized the management of the respiratory failure  for these patients, including the criteria and the timing for intubation. And before the authorization by the Institutional Review Board, we trained all the healthcare  staff regarding the measurements to be taken on this protocol, the procedure of helping patients to undergo a wake-prone positioning, and we stressed the need for a strict adherence  to this protocol. We only included patients with confirmed COVID through PCR test, adult patients, all those  patients who needed the initiation of high-flow nasal cannula, those were patients who already  failed to conventional oxygen through non-rebreathing mask, and we had some exclusion criteria. The main exclusion criteria was the need for immediate intubation.  This study was, the process of randomization was stratified by SENDER, this was a superiority randomized control trial.  Of course, the blinding was not possible for this kind of intervention, and one of the key components of the success in this study was the real-time communication between study  investigators and on-site clinicians. We were always, almost immediately aware of each patient in whom high-flow nasal cannula was indicated.  We had a daily communication with on-site clinicians, several times a day, to emphasize the protocol adherence.  The management with high-flow nasal cannula was standardized, this was the device we had  in our hospitals, it's the Vapotherm, maximal flow is 40, and F502 was titrated to a capillary saturation above 92%.  And another key component of the success for this study is that, unlike other studies, our protocol was healthcare staff-driven instead of self-driven.  You know, in some studies, patients were only instructed to perform APP, but here the healthcare  staff was actively encouraging to do APP in those patients of the intervention group, and discouraging APP in the patients of the control group.  We took all kinds of measures to improve compliance to APP, smartphones, some TV screens, pillows, and physical help of the healthcare staff.  The primary outcome was intubation at 28 days, you can see here the criteria. We excluded patients with do-not-resuscitate or intubate orders, however, we unexpectedly  found that many patients refused intubation several days after enrollment. So we have to add a secondary outcome named treatment success, which means alive and never  been intubated, because this variable was a better reflection of the disease progression and efficacy of APP.  We joined to this meta-trial group, this meta-trial collaboration is already published, and consisted  of a pooled analysis of the primary outcomes, which were similar between our studies in six countries, and as I said before, we had the largest sample size, and this was the  only individual study in which a significant benefit was found. We didn't plan interim analysis, but we had to stop early due to a detection of superiority  of APP at the meta-trial level.  Interestingly, we had a high compliance rate, and all patients in the intervention group underwent APP for at least one hour, and only 16 patients in the control group were excluded  from the per-protocol analysis, because they were prone for more than one hour. Intubation characteristics were similar between groups, 216 patients were included in intervention  group, and 214 patients in the control group with similar characteristics. So regarding the outcomes, the intubation rate, this primary outcome, was 30% in the  intervention group, and 43% in the control group. Mortality was similar between groups, but we, interestingly, we found a significant difference in time to intubation.  Those patients in the intervention group were intubated 0.6 days later compared to patients on control group, it's a small difference, but significant, and moreover, we also found  a significant decrease in hospital length of stay in patients of APP, two days shorter in patients of APP, 11 versus 13 days.  We run a subgroup analysis on the presence of silent hypoxemia when patients arrived to the triage area of the hospitals, they were defined according to the lack of symptoms  of respiratory distress, despite a lower oxygen capillary saturation, less than 90%, without supplementary oxygen.  So this silent hypoxemia was present in a third of the populations, 117 patients had silent hypoxemia.  The baseline characteristics were very similar between silent and the snake hypoxemia, except  for a slightly lower respiratory rate, 25 versus 26, and a slightly lower lung ultrasound score, 18 versus 19.  Regarding outcomes, we found something similar, a decrease in intubation rate, and we found here a decrease in mortality in patients with silent hypoxemia.  There was no difference in hospital length of stay between these subgroups. The time on APP was more than nine hours, for a median of six days.  The physiological variables improved, but were more evident and sustained, as you can see in this figure, in the patients who eventually succeed.  Remember those patients who were discharged alive and have never intubated. As you can see, especially with respiratory rate, it was more evident a decrease in respiratory  rate and in a sustained fashion, unlike patients who eventually were intubated or dead. And interestingly, regarding lung ultrasound score, those patients who were intubated had  no change in this score, unlike patients with treatment success, who had a significant decrease in this score, 2.4 points was this decrease of those patients with success.  We did some raw curve analysis and found some variables associated to success, and those four variables were the variables with the highest area under the curve associated  to success. The best was the average time on APP within the first three days, as you can see with  a cut-off of eight hours or more, this had an area under the curve of 0.96, with a very good sensitivity and specificity for success.  We had a variable identified with a good discrimination for success, respiratory rate at enrollment, with a cut-off of less of 25.  The variable, this delta ROCS, the change, the improvement in the ROCS index of 1.2 was associated with success, this after the end of the first session of APP.  And this delta, this improvement in lung ultrasound score, a change, an improvement in two points  of lung ultrasound score, it also had a good sensitivity and specificity for prediction of success.  As you can see, more than equal or more than eight hours on APP as average within the first  three days was associated with a 94% of success compared to 15% in those patients who were prone for less than eight hours.  We did a multivariate adjustment for calculation of success probability, and we found a good  linear correlation between time on APP and this probability of success with a good correlation coefficient and significant.  And interestingly, again, patients with silent hypoxemia had a longer time on APP, more than 12 hours, compared with the patients with dyspneic hypoxemia, more than seven hours.  And this could explain in part the improved outcomes associated to this clinical presentation of silent hypoxemia.  And just as a sensitivity analysis, we run a Cox proportional hazards regression and found a significantly higher hazard ratios for success, 13.2 for success, and a hazard  ratio of 5.7 for survival in those patients who had eight hours or more on APP within the first three days.  So this study has as many strengths, this is, as I said before, the largest individual randomized control trial, and we had a high adherence to the protocol, our population  was very homogeneous, including treatment with high-flow nasal cannula, and we can report  some predictors for success, including lung ultrasound, and report some outcomes in patients with silent hypoxemia. These outcomes in this subgroup of patients is barely reported.  It also had limitations, early termination of the trial, according to the meta-trial level, this interim analysis at the meta-trial level.  We didn't protocolize the use of non-invasive ventilation, and in fact, in our study it was used mainly as a rescue therapy, almost all patients were intubated, who were indicated  non-invasive ventilation, and well, these results are not generalizable to patients with other devices other than high-flow nasal cannula.  Lack of blinding is also a limitation, and these interesting results of predictors came only from post-hoc analysis, this should be proven in other largest trials.  So in conclusion, APP reduced intubation rate and hospital length of stay. We provide some important predictor variables for success, and we stress that the success  of this study, of this therapy in our country, is very related to a protocol that should be healthcare-staff driven, instead of the same patient, and you should aim for a minimum  of 8 hours a day, of time of promposition. Thank you.

Video Summary

The speaker presents the results of the PROCARB study on prone positioning in awake patients with COVID-19 associated respiratory failure. Before this study, there were limited studies on awake prone positioning and its effect on patient outcomes. The study was conducted in two hospitals in Mexico, with standardized management for respiratory failure in COVID-19 patients. Patients with confirmed COVID-19 were included if they required high-flow nasal cannula. The primary outcome was intubation at 28 days, and a significant benefit was found in the intervention group with a lower intubation rate and shorter hospital stay compared to the control group. A subgroup analysis showed a decrease in intubation rate and mortality in patients with silent hypoxemia. The study identified several predictor variables for success, including time on prone positioning and improvement in lung ultrasound score. The study emphasizes the importance of a protocol-driven approach and aims for a minimum of 8 hours of prone positioning daily.

Asset Subtitle

Pulmonary, Infection, 2022

Asset Caption

INTRODUCTION/HYPOTHESIS: Awake prone positioning (APP) has been increasingly used in patients with acute respiratory failure due to COVID-19; however, most data supporting this therapy are observational/retrospective. The aim of this trial was to compare the outcomes in COVID-19 patients managed with APP versus standard care (SC). METHODS: Randomized controlled superiority trial, which included patients with COVID-19 and requirement of oxygen through high-flow nasal cannula (HFNC). Patients were randomized to remain in APP as long as possible or SC while HFNC therapy was needed. The primary outcome was intubation rate; treatment failure, defined as intubation or death without intubation, and mortality were secondary, with a follow-up to 28 days. Baseline characteristics, physiological response to APP, factors associated to failure, and adverse events were also analyzed. RESULTS: We enrolled 216 patients to APP and 214 to SC. Baseline characteristics were similar. Intubation rate was 30% in APP and 43% in SC patients (RR 0.70; 95%CI 0.54-0.90, p=0.006); mortality was 33% and 37%, respectively (RR 0.89; 95%CI 0.69-1.15, p=0.37). At multivariate analysis, the factors associated to an increased risk of failure were respiratory rate at enrollment (p= < 0.001), SpO2/FiO2 at enrollment (p= < 0.001), absence of silent hypoxemia (p=0.01), lung ultrasound score at enrollment (p= < 0.001) and D-dimer at hospital admission (p= < 0.001). Mean daily duration of APP was 9.4 h (5.6-12.9), with a median of 6 days (3.7-9.0). At ROC curve analysis, the best predictors of treatment failure were a daily duration of APP < 7.7h (AUROC 0.96, p= < 0.001), respiratory rate at enrollment ≥25 bpm (AUROC 0.93, p= < 0.001), D-dimer >1.4 mg/dL (AUROC 0.82, p= < 0.001), and a decrease in respiratory rate < 3 bpm after the first session of APP (AUROC 0.79, p= < 0.001). The most common adverse events were back pain in 16 (7.4%) patients and intravascular lines dislodgement in 14 (6.5%). CONCLUSIONS: We found APP is associated with a reduced risk of intubation, with no difference in mortality. As a safe and effective procedure, we suggest APP should be encouraged to all COVID-19 patients requiring oxygen support with HFNC, aiming for the longest daily duration as possible, with closer monitoring of patients with predictive factors of failure.

Meta Tag

Content Type Presentation

Knowledge Area Pulmonary

Knowledge Area Infection

Knowledge Level Intermediate

Knowledge Level Advanced

Membership Level Select

Tag Respiratory Failure

Tag COVID-19

Tag Infectious Diseases

Year 2022

Keywords

PROCARB study

prone positioning

awake patients

COVID-19 associated respiratory failure

intubation rate

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