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Comparison of Noninvasive Mechanical Ventilation With High-F… : Critical Care Medicine

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KEY POINTS

Question: This trial was conducted to compare the effectiveness of high-flow nasal cannula (HFNC), helmet, and face-mask noninvasive ventilation (NIV) for hypoxic respiratory failure in COVID-19.

Findings: The results of this study are indeterminate to show a difference in endotracheal intubation rate with the HFNC, face-mask continuous positive airway pressure (CPAP), and helmet CPAP (44%, 45%, and 46%, respectively).

Meaning: This trial found no difference in the effectiveness between the three modalities of NIV for hypoxemic respiratory failure in COVID-19.

Acute hypoxemic respiratory failure is the leading cause of hospital admission for patients with COVID-19. These patients often receive invasive mechanical ventilation (IMV) (1). Noninvasive respiratory support can optimize respiration by reducing the shunt and dead space and by improving hypoxic pulmonary vasoconstriction and right ventricular function (2). This can forego intubation, IMV and its complications (3–7), and off-load ICUs. However, the role of noninvasive ventilation (NIV) in hypoxemic respiratory failure and acute respiratory distress syndrome (ARDS) remains controversial in moderate and severe forms (8–11). Studies comparing NIV or high-flow nasal cannula (HFNC) with standard oxygen therapy have shown conflicting results (9,12–18).

The helmet interface decreases air leaks and is better tolerated (10,18–32). However, there is no concrete evidence of superiority, and the helmet interface is not widely available; hence, a face-mask interface is used (33–36).

None of the randomized controlled trials (RCTs) have compared the three arms: HFNC, face-mask continuous positive airway pressure (CPAP), and helmet CPAP in COVID-19 ARDS, which this trial aimed to do. The primary objective was to compare the rate of endotracheal intubation within 28 days of acute hypoxemic respiratory failure with that of COVID-19. The secondary objectives included 28- and 90-day mortality.

METHODS

This randomized controlled, open-label trial with parallel arms, HFNC, NIV with face-mask CPAP, and helmet CPAP, was planned to be conducted at tertiary level hospitals in Oman. Ethical approval was obtained from the Medical Research Ethics Committee (MREC) of the University Hospital (MREC No. 2202) and the Ministry of Health (No. MoH/CSR/20/23759), Oman. Registration was done at ClinicalTrials.gov (NCT04715243). Written informed consent was obtained. Patient privacy was respected following the MREC guidelines and the Declaration of Helsinki 1975.

Adult patients with confirmed COVID-19 by polymerase chain reaction and admitted for less than 48 hours since their presentation, requiring oxygen therapy, HFNC or NIV for less than 4 hours, and a Pao2/Fio2 ratio of less than 300 on oxygen were eligible for the study. Exclusion criteria were the following: admission for more than 48 hours, hemodynamic instability, Glasgow Coma Scale score of less than 8, active intracranial pathology, inability to cooperate or protect the airway, not for resuscitation/intubation, known pregnancy or type 2 respiratory failure, tracheostomized, or on home oxygen therapy.

The treatments were initiated immediately after randomization in each arm following the protocol (Supplement Fig. 1, links.lww.com/CCM/H363). With HFNC, the flow started at 30 L/min and titrated to a maximum of 60 L/min. The Fio2 started at 60% and titrated to maintain oxygen saturation (Spo2) of more than 92%. The helmet CPAP was started either at a flow rate of 40 L/min and expiratory positive end-expiratory pressure valve at 8–10 cm H2O if HFNC mode on the ventilator or CPAP of 8–10 cm H2O on a single-limb NIV (e.g., Respironics V60; Philips, Amsterdam, The Netherlands) as per availability. Subsequently, the CPAP was titrated to a maximum of 15 cm H2O. The Fio2 was titrated to maintain Spo2 at more than 92%. If the patient developed hypercapnia, the flow was increased up to 60 L/min in high-flow mode, followed by pressure support mode if there was no favorable result with higher flow. Dual-limb tubing with pressure support was used if ICU ventilators were used. In the face-mask CPAP group, CPAP was started at 5 cm H2O and was titrated up to a maximum of 15 cm H2O. The Fio2 was adjusted to aim for Spo2 greater than 92%. The target tidal volume was 4–6 cc/kg of ideal body weight.

Breaks from treatment were permitted for comfort and oral intake. The vital signs and the patient’s respiratory status were monitored. Arterial blood gas (ABG) and respiratory rate oxygenation (ROX) index were assessed 2 hourly.

The study protocol allowed crossover to face-mask CPAP if the patient did not tolerate HFNC/helmet CPAP (Supplement Fig. 2, links.lww.com/CCM/H363). The criteria for crossover were claustrophobia despite sedation and significant nasal irritation. If they did not tolerate the primary technique (HFNC or helmet CPAP), they were allowed to crossover to face-mask CPAP, considered the control in our study. Crossover was also planned from face-mask CPAP to HFNC and then helmet CPAP if required, but crossover did not happen in this arm as it was well tolerated (Supplement Fig. 2, links.lww.com/CCM/H363).

Weaning from CPAP (both face-mask and helmet) was considered when the patient could tolerate CPAP of 10 cm H2O and Fio2 at 40%. Subsequently, CPAP was reduced by 2 cm H2O every 4–6 hours until a minimum of 5 cm H2O was achieved. Furthermore, oxygenation was provided with a venturi mask and a simple face-mask. Weaning from HFNC was started when Fio2 was reduced to 40% by reducing flow gradually to 10–20 L/min. Thereafter, oxygenation was achieved with a simple face-mask if the patient’s respiratory rate was less than 25/min and Spo2 was greater than 94% without signs of distress.

The technique was considered failed when the patients failed to achieve any of the following: Spo2 greater than or equal to 92% or respiratory rate less than or equal to 30/min, or Pao2/Fio2 greater than 100 for all treatment arms, and in addition, ROX index less than 2.85 at 2 hours and less than 3.85 at 12 hours for the HFNC arm, and thence intubation was performed. An objective assessment was performed every 2 hours.

The primary outcome was the proportion of patients requiring endotracheal intubation within 28 days following randomization. The secondary outcome was the proportion of patients who died within 28 and 90 days following randomization.

The data were collected at the emergency departments and high-dependency units at the participating centers from February 4, 2021, to August 9, 2021. The following information was collected for each patient: age, sex, body mass index (BMI), vaccination status, Acute Physiology and Chronic Health Evaluation II score, comorbidities, smoking history, and indication for NIV. In addition, ABG, renal function, liver function, serum ferritin, C-reactive protein, lactate dehydrogenase, d-dimer levels, and chest radiograph findings; the settings of NIV or HFNC; vitals; and other treatments such as steroids (e.g., dexamethasone), anti-interleukin (IL) (e.g., tocilizumab), antibiotics, convalescent plasma, vasopressors, and renal replacement therapy were recorded.

This is a three-parallel-arms trial to evaluate the efficacy of helmet CPAP and HFNC treatments compared with face-mask CPAP as the control arm. The trial’s primary outcome (need for intubation) followed a Bernoulli distribution. The null hypothesis assumed no significant difference in the cumulative incidence of intubation among the three treatment arms. In contrast, the alternative hypothesis assumed helmet CPAP and HFNC were superior to face-mask CPAP. The treatment effects were 0.2, and the cumulative incidence of intubation in the face-mask CPAP arm was 0.5 (15,20). A sample size of 360 participants (120 per group) was required to achieve a marginal power of 0.90 with a two-sided significance level of 0.025 for multiple comparisons (Bonferroni correction) and an effect size of 0.2.

Randomization was done with sequence generation using a permuted block of nine patients. Each concealed envelope of nine was randomly assigned at a ratio of 1:1:1 for the three treatment sites. The allocation was concealed with sealed and secure envelopes, which were selected in a sequence. Our research assistant supervised the enrollment of participants, random allocation sequences, and intervention assignment processes. Stratification of randomization was done for the University Hospital and the Ministry of Health site, which involved the Field and Royal Hospitals. The envelopes were opened when the patients were randomized at each site. Blinding could not be done because of the nature of the intervention.

Baseline characteristics were reported using the mean (sd) for continuous variables and numbers (proportions) for categorical variables. One-way analysis of variance was used to compare continuous variables, and Pearson chi-square or Fisher exact test was used for categorical variables. Intention-to-treat analysis was used to analyze the primary efficacy endpoints. Fisher exact test and chi-square test were used for between-group differences in the proportion of patients requiring intubation or died, as appropriate. A generalized linear regression model was used to evaluate the effects of interventions on both primary and secondary outcomes. The effect size was reported using the relative risk (RR) with 95% CI. Age and severe Pao2/Fio2 ratio were identified as predictors of intubation and mortality, and both adjusted and unadjusted RR (95% CI) were estimated. Age was categorized as greater than or equal to 55 years, the mean age of intubated patients. The Kruskal-Wallis rank test was used to compare the median time to develop the outcome (intubation and death) across the randomized groups. Using Kaplan-Meier curve plots, the log-rank test was used to compare the time from enrollment to endotracheal intubation or 28- and 90-day mortality for the three groups.

Due to significant crossover, an unplanned post hoc analysis was performed to investigate the crossover effect among the groups. First, propensity scores for the crossover were created using a logistic regression model with the following covariates: age, BMI, gender, and the Pao2/Fio2 ratio at admission. Then, the probabilities for the crossover were estimated from the propensity scores using inverse probability weighting (IPW) method. Finally, the impact of the treatment group (after crossover) was assessed using logistic regression model using weights from the IPW (Supplement Tables 2s and 3s, links.lww.com/CCM/H363).

All p values reported for primary and secondary endpoints were based on two-sided tests of 0.05. SAS Studio (SAS Institute, Cary, NC) and Stata MP 17.0 (StataCorp LLC, College Station, TX) software were used to analyze the data. The IPW was conducted using R program Version 4.1.3 (R Core Team, Vienna, Austria).

RESULTS

During the study period, 421 participants with COVID-19 hypoxic respiratory failure were assessed for eligibility, of which 159 were randomized. After exclusions, 47 patients were randomized to HFNC, 52 to face-mask CPAP, and 52 to helmet CPAP groups (Fig. 1). Interim analysis was conducted when recruitment of cases was nearly halted due to a decline in the severity of COVID-19 cases, with very few patients requiring respiratory support after August 9, 2021. Almost 50% of the cases (151/320) were enrolled during this period. An explanatory analysis was performed to determine whether continuing the study to the preplanned sample size of 362 would have yielded a significant outcome difference. The study’s conditional power for intubation was 0.002, and the predictive power for success was 0.033. The conditional and predictive powers for mortality were 0.043 and 0.135, respectively. These results supported the interim analysis, indicating that continuation of the trial would not have yielded any significant difference in the outcome.

F1
Figure 1.:

Participants’ enrollment, randomization, and inclusion in the primary and secondary analysis. CPAP = continuous positive airway pressure, HFNC = high-flow nasal cannula, ICP = intracranial pressure, NIV = noninvasive ventilation, O2 = oxygen.

The enrolled patients had a mean BMI (±sd) of 31 (±6), 32 (±7), and 32 (±6) for the HFNC, face-mask CPAP, and helmet CPAP groups, respectively (Table 1). At the time of enrollment, 77.8% (n = 112) had severe ARDS (Pao2/Fio2 < 100 mm Hg) and 99% had bilateral pulmonary infiltrates. The Pao2/Fio2 (±sd) ratios were almost similar for the three groups. Treatment received was similar across the groups for steroids (149, 99%), antibiotics (149, 99%), IL-receptor inhibitors/anti-IL (117, 77%), and anticoagulation (150, 99%). During NIV, the prone position was administered to more than half of the patients (79, 52%). Sedation with dexmedetomidine was used in six (13%), seven (13%), and 12 (23%) patients in the HFNC, face-mask CPAP, and helmet CPAP groups, respectively. Anti-IL treatment was used for 36 (76%), 42 (81%), and 39 (80%) patients in the HFNC, face-mask CPAP, and helmet CPAP groups, respectively (Supplement Table 1s, links.lww.com/CCM/H363).


TABLE 1. -
Baseline Patient Characteristics































Characteristics at Baseline High-Flow Nasal Cannula (n = 47) Face-Mask CPAP (n = 52) Helmet CPAP (n = 52)
Age, yr, mean ± sd 53 ± 13 52 ± 11 51 ± 14
Male sex, n (%) 36 (77) 40 (75) 37 (67)
Body mass index, mean ± sd 31 ± 6 32 ± 7 32 ± 6
Acute Physiology and Chronic Health Evaluation II, mean ± sd 8.0 ± 4.3 8.5 ± 3.6 8.5 ± 4.0
Sequential Organ Failure Assessment score, mean ± sd 3.0 ± 1.4 2.6 ± 1.1 2.7 ± 1.2
Chest radiograph bilateral infiltrates, n (%) 47 (100) 51 (98) 52 (100)
Systolic BP, mean ± sd 131 ± 14 136 ± 20 136 ± 19
Mean BP, mean ± sd 95 ± 10 97 ± 14 98 ± 15
Heart rate, mean ± sd 90 ± 16 94 ± 20 91 ± 19
Respiratory rate, mean ± sd 38 ± 7 38 ± 7 37 ± 10
Arterial blood gas


 pH, mean ± sd 7.43 ± 0.05 7.43 ± 0.04 7.43 ± 0.04
 Pco
2, mean ± sd 		36 ± 4 36 ± 4 36 ± 5
 Po
2, mean ± sd 		62 ± 19 60 ± 18 68 ± 22
 Pao
2/Fio
2, mean ± sd 		83 ± 31 82 ± 36 84 ± 34
 Pao
2/Fio
2: 200–300, n (%)		 0 (0) 1 (2) 0 (0)
 Pao
2/Fio
2: 100–200, n (%)		 9 (19) 10 (19) 12 (24)
 Pao
2/Fio
2: < 100, n (%)		 34 (80) 40 (78) 38 (76)
 Oxygen saturation , mean ± sd 87 ± 12 87 ± 14 87 ± 13
 Serum WBC, mean ± sd 8.3 ± 4.2 8.2 ± 3.6 9.2 ± 4.3
 Serum creatinine, mean ± sd 99 ± 101 85 ± 31 71 ± 22
 C-reactive protein, mean ± sd 146 ± 86 146 ± 93 143 ± 84
 Serum lactate dehydrogenase, mean ± sd 549 ± 232 644 ± 311 606 ± 235
 Serum ferritin, mean ± sd 1,192 ± 913 1,571 ± 1,137 1,326 ± 977
 
d-dimer, mean ± sd 		2.5 ± 6.3 3.3 ± 8.0 4.45 ± 11.0
 Serum lactate, mean ± sd 1.5 ± 0.6 1.5 ± 0.8 1.54 ± 0.6
Comorbidities, n (%)


 Hypertension 13 (28) 16 (31) 17 (33)
 Diabetes 12 (26) 15 (29) 17 (33)

BP = blood pressure, CPAP = continuous positive airway pressure.

The HFNC group’s initial oxygen flow was set at 46 ± 10 L/min, with a mean Fio2 of 0.82 ± 0.17. The ROX index values at 2, 6, and 12 hours were 4.29 ± 1.40, 4.38 ± 1.51, and 4.69 ± 1.89, respectively. On average, the HFNC was used for 7.8 ± 6.3 days, with a daily usage of 20.7 ± 3.6 hours. The face-mask CPAP group had an initial mean CPAP setting of 9 ± 2 cm H2O, a mean tidal volume delivered of 378 ± 62 cm H2O, and a mean Fio2 of 0.81 ± 0.18. On average, face-mask CPAP was used for 5.5 ± 5.7 days, with a daily usage of 19.4 ± 4.8 hours. In the helmet CPAP group, the mean CPAP setting was 11 ± 2 cm H2O, and the mean Fio2 was 0.83 ± 0.15. On average, the helmet CPAP was used for 5.2 ± 4.9 days, with a daily usage of 19.7 ± 5.1 hours.

Crossover to other interventions happened for 28 patients (59%) in the HFNC group and 20 patients (38%) in the helmet CPAP group to the face-mask CPAP. The main reasons for crossover were patient comfort, claustrophobia with helmet CPAP, and nasal irritation for HFNC. There was excellent tolerance to face-mask CPAP; hence, there was no crossover from face-mask CPAP to other modalities.

Primary Outcome

The cumulative incidence of intubation was 45% with HFNC, 46% with face-mask CPAP, and 46% with helmet CPAP arm (p = 0.99). Using face-mask CPAP as the reference group, we did not observe a reduction in the risk of intubation with HFNC (RR, 0.97; 95% CI, 0.63–1.49) or helmet CPAP (RR, 1.0; 95% CI, 0.66–1.51) (Table 2). The median time to intubation was 7 days with HFNC, 5.5 days with face-mask CPAP, and 4.5 days with the helmet CPAP arm (p = 0.11). Most of the patients (83%) were intubated due to respiratory failure. The survival analysis (Fig. 2) for the cumulative incidence of intubation within 28 days yielded no significant difference between the three groups (p = 0.14).


TABLE 2. -
Primary and Secondary Outcomes













Outcome, Intubation Within 28 d Study Group
p 		Relative Risk (95% CI)
HFNC (n = 47) Face-Mask CPAP (n = 52) Helmet CPAP (n = 52) HFNC vs Face-Mask CPAP Helmet CPAP vs Face-Mask CPAP
Cumulative incidence, n (%) 21 (45) 24 (46) 24 (46) 0.99 — —
Interval between enrollment and intubation, d, median (interquartile range) 7 (4–13) 5.5 (1–9) 4.5 (1.5–7) 0.19 — —
Unadjusted analysis intubation — — — — 0.97 (0.63–1.49) 1.00 (0.66–1.51)
Adjusted analysis intubationa — — — — 0.97 (0.63–1.49) 1.02 (0.68–1.52)
Reason for intubation, n (%)

— —
 Respiratory failure 18/22 (86) 22/24 (92) 18/24 (75) 0.30 — —
 Circulator failure 3/21 (14) 0 5/24 (21) 0.05 — —
 Neurologic 0 2/24 (8) 0 0.33 — —

CPAP = continuous positive airway pressure, HFNC = high-flow nasal cannula.

aAnalysis adjusted for age and severe Pao2/Fio2 ratio.

F2
Figure 2.:

Kaplan-Meier plot of the cumulative hazard of intubation from enrollment to day 28. HFNC = high-flow nasal cannula, NIV = noninvasive ventilation.

Secondary Outcomes

The 28- and 90-day cumulative mortality was 23% and 43% with the HFNC group, 32% and 38% with the face-mask CPAP group, and 38% and 40% with the helmet CPAP group (p = 0.24 and 0.89), respectively (Table 3). The overall cumulative mortality (90 d) was 40.4%. The median time between enrollment and death was 17.5 days with HFNC, 22 days with face-mask CPAP, and 19 days with helmet CPAP (p = 0.84). Using a generalized linear regression model, compared with face-mask CPAP, the unadjusted RR for death for the HFNC group was 1.11 (95% CI, 0.69–1.78) and for the helmet CPAP group was 1.05 (95% CI, 0.65–1.69). Survival analysis (Fig. 3) for the 90-day cumulative mortality yielded no significant difference between the three groups (p = 0.92).


TABLE 3. -
Secondary Outcome Analysis













Secondary Outcome, Mortality Study Group
p 		Relative Risk (95% CI)
HFNC (n = 47) Face-Mask CPAP (n = 52) Helmet CPAP (n = 52) HFNC vs Face-Mask CPAP Helmet CPAP vs Face-Mask CPAP
28 d, no. of patients, n (%) 11/47 (23) 16/52 (32) 20/52 (38) 0.24 — —
90 d, no. of patients, n (%) 20/47 (43) 20/52 (38) 21/52 (40) 0.89 — —
Interval between enrollment and death, d, median (interquartile range) 17.5 (10–27.5) 22 (13–26.5) 19 (8–25) 0.84 — —
Unadjusted analysis—mortality — — — — 1.11 (0.69–1.78) 1.05 (0.65–1.69)
Adjusted analysis—mortalitya

1.16 (0.73–1.83) 1.17 (0.74–1.83)
Adjusted analysis crossed-over groups—mortalityb — — — — 0.73 (0.41–1.31) 0.98 (0.65–1.48)

— — — — (HFNC and face-mask CPAP combined) vs helmet CPAPc
Adjusted analysis—mortalitya — — — — 1.09 (0.74–1.60)

CPAP = continuous positive airway pressure, HFNC = high-flow nasal cannula.

aAnalysis adjusted for age ≥ 55 and severe Pao2/Fio2 ratio.

bAnalysis considering patients who crossed over within 24 hr in the new group and comparing them to face-mask CPAP adjusted for age ≥ 55 and severe Pao2/Fio2 ratio.

cRelative risk for 90-d mortality controlling for age ≥ 55 and severe Pao2/Fio2 ratio (HFNC and face-mask CPAP combined and compared with helmet CPAP).

F3
Figure 3.:

Kaplan-Meier plot shows the cumulative death hazard from enrollment to day 90. HFNC = high-flow nasal cannula, NIV = noninvasive ventilation.

Post Hoc Analysis

Within the first 24 hours of randomization, 16 patients (34%) in the HFNC group and eight (15%) in the helmet CPAP group crossed over to face-mask CPAP. The IPW analysis was performed to account for the crossover. In this post hoc analysis, when compared with face-mask CPAP, HFNC and helmet CPAP reduced the risk of intubation with odds ratios of 0.1 (p = 0.00001) and 0.5 (p = 0.01), respectively (Supplement, links.lww.com/CCM/H363). Additionally, other post hoc analysis was performed for mortality. In this analysis, a modified-treatment-received analysis was performed, combining the patients who crossed over to face-mask CPAP (76 patients) as a control group and comparing them to HFNC (31 remaining patients) and helmet CPAP (44 remaining patients). Using a generalized linear regression model, in comparison to face-mask CPAP as the reference group adjusting for age greater than or equal to 55 and severe Pao2/Fio2, RR for death was 0.73 (95% CI, 0.41–1.31) and 0.98 (95% CI, 0.65–1.48) for the HFNC and helmet CPAP groups, respectively. Another explanatory analysis was performed by combining the HFNC and face-mask CPAP as one group and comparing them to the helmet CPAP group. Compared with the combined group, the RR for death within 90 days for the helmet CPAP group was 1.09 (95% CI, 0.74–1.60).

Adverse events were infrequent. Subcutaneous emphysema was observed in five patients (one with face-mask CPAP and four with helmet CPAP). All five patients required intubation later and eventually died due to multiple organ failure. Eye irritation and pressure ulcers at the nasal bridge were observed in one patient each.

DISCUSSION

In this multicenter randomized, open-label trial comparing three interventions, helmet CPAP, face-mask CPAP, and HFNC, for hypoxemic respiratory failure in COVID-19 patients, no difference was found in the rate of endotracheal intubation with the intention-to-treat analysis. In addition, there was no significant difference in 28- and 90-day mortality among the three groups. The time elapsed from randomization to endotracheal intubation was similar among the three groups. Most patients were intubated because of worsening respiratory parameters.

The recommendation of NIV as the first-line therapy for acute respiratory failure is still evolving (37). Furthermore, the type of noninvasive interface is more controversial based on the risk of aerosolization, the effectiveness of positive pressure development, rebreathing of carbon dioxide, improvement of ventilator-free days, and mortality benefits. To further the findings of previous trials (20,38), this study was designed to find benefits in the rate of endotracheal intubation and mortality with the three interfaces of noninvasive respiratory supports for COVID-19-associated respiratory failure. Previous studies have compared two of these three arms, but this trial compared all three arms together at a multicenter level.

The primary outcome of this study (rate of intubation) was similar to that reported by Duan et al (38). They compared HFNC with NIV as first-line therapy for critically ill patients with COVID-19 and found no difference in intubation rate or mortality and duration of therapy. Another recent study by Arabi et al (39) found no significant difference in mortality with helmet CPAP compared with usual respiratory care for acute hypoxemic respiratory failure due to COVID-19 pneumonia. In contrast, Grieco et al (21) studied the use of helmet CPAP followed by HFNC versus only HFNC for COVID-19 respiratory failure and found a significant difference in the rate of endotracheal intubation but no difference in respiratory support-free days within 28 days. They used pressure-support ventilation in the helmet group. In the present study, CPAP was used. Additionally, the patient had moderate-to-severe ARDS.

We found no significant difference in mortality rates among the three arms in this study. In contrast, in previous trials, helmet CPAP improved the survival and rate of endotracheal intubation compared with face-mask CPAP or HFNC (17,21). In the first trial by Patel et al (17) comparing helmet CPAP to face-mask CPAP, all patients received face-mask CPAP for the first few hours before randomization. In this study, patients were randomized directly to one of three interventions. Recently, the RECOVERY-RS trial by Perkins et al (40) compared CPAP and HFNC with conventional oxygen therapy. In this trial, the composite primary outcome of endotracheal intubation or mortality within 30 days was 36% in the CPAP group compared with 44% in the conventional oxygen therapy group, which was statistically significant. On the other hand, the outcome in the HFNC group (44%) compared with the conventional oxygen therapy group (45%) was not significantly different.

Strength of This Study

This trial compared the interfaces of NIV: helmet and face-mask CPAP and HFNC. Compared with previous studies (17,21,40), the patients in this study were sicker with Pao2/Fio2 less than 200. Although prematurely terminated, strict protocol and standard guidelines were followed. This study provides essential insights into managing critically ill COVID-19 patients with moderate-to-severe ARDS with different interfaces of noninvasive respiratory support, which can be helpful in the future pandemics.

Limitations

The first limitation of this study is the small sample size due to the paucity of severe COVID-19 cases halfway through the study. Due to this, it is difficult to say if the primary outcome is a factual finding. Although post hoc analysis is done, the results should still be taken cautiously. Another limitation of this study is the high rates of crossover. To account for the crossover selection bias, an IPW analysis showed that HFNC and helmet CPAP decrease the risk of intubation. This may be a true impact due to the superiority of both strategies or a limitation of the IPW analysis to deal with the crossover. Hence, this should be interpreted cautiously. In addition, the IPW assumes that all factors affecting the probability of crossover are included in propensity score estimation, which is generally a difficult assumption to fulfill. Therefore, we suggest confirmation of this finding with yet another study. Another limitation is using a ventilator for helmet CPAP, which can give rise to hypercapnia, although none of our patients developed it.

Interpretation

This study found no difference in intubation and mortality rate with HFNC, face-mask CPAP, and helmet CPAP when used for moderate-to-severe ARDS in COVID-19 cases. Providing positive pressure through any of these NIV techniques was found beneficial. As the trial was terminated prematurely, the results should be concluded with caution.

SUMMARY

This exploratory RCT tested HFNC, face-mask CPAP, and helmet CPAP for acute hypoxemic respiratory failure due to COVID-19. These noninvasive respiratory devices were similar in intubation rate (44–46%) and mortality rate (23–38%). The positive pressure ventilation achieved with these techniques imparts a beneficial effect, and none of the three interfaces was superior. Compared with face-mask CPAP, the RR of intubation was approximately 1 for HFNC and helmet CPAP. No significant complications were associated with any of the procedures. Although the trial is prematurely terminated, these techniques can be crucial in avoiding IMV and its complications in acute hypoxemic respiratory failure due to COVID-19. This finding can be helpful in future pandemics or crises that encounter a severe paucity of invasive mechanical ventilators.

ACKNOWLEDGMENTS

We thank Dr. Abdullah Balkhair (Department of Medicine, Sultan Qaboos University Hospital, Muscat, Oman), Dr. Khalid Al Rasadi (Department of Biochemistry, Sultan Qaboos University Hospital, Muscat, Oman), Dr. Maher Al Bahrani (Department of Anesthesia, Royal Hospital, Muscat, Oman), and Dr. Mohammed Busafi (Department of Emergency Medicine, Royal Hospital, Muscat, Oman).

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