Table 1.
Study characteristics. AE: adverse event, APP: awake prone-positioning, CPAP: continuous positive airway pressure, FiO2: inspiratory fraction of oxygen, HFNC: high-flow nasal cannula, ICU: intensive care unit, IQR: inter-quartile range, NIV: non-invasive ventilation, PaCO2: carbon dioxide partial pressure, PaO2: oxygen partial pressure, PEEP: positive end-exspiratory pressure, RR: relative risk, SD: standard deviation, WHO: world health organization.
| Authors | Population | Intervention | Comparator | Outcomes | Results per Endpoint |
|---|---|---|---|---|---|
| High-flow nasal cannula vs. non-invasive ventilation | |||||
| Perkins et al. [25] Standard care in both arms: Dexamethasone and Tocilizumab added as standard care in June 2020 and January 2021, respectively Recruitment: from April 2020 to May 2021 with ca. 90% of patients recruited between September 2020 and March 2021 |
n = 797 (allocated) age (years): mean 57.6 (SD 13.0) in HFNC, 56.7 (SD 12.5) in CPAP sex: 65.2% male vs. 68.4% male comorbidities: none in 34% vs. 39%, hypertension, morbid obesity, type 2 diabetes requiring medication, chronic lung disease clinical status at enrolment: inpatients not intubated with hypoxemic respiratory failure PaO2/FiO2 ratio 139 vs. 132, resp. rate 25 vs. 26 |
n = 417 HFNC Local policies, and clinical discretion informed decisions regarding choice of device, set-up, titration, and discontinuation of treatment, mean flow 51 L/min adherence to intended treatment protocol: 92.1% |
n = 380 NIV Local policies, and clinical discretion informed decisions regarding choice of device, set-up, titration, and discontinuation of treatment, mean PEEP 9.5 (SD 8.4) adherence to intended treatment protocol: 91.6% |
Endotracheal intubation or death within 30 days In-hospital mortality 30-day mortality Endotracheal intubation within 30 days Mean length of stay in hospital (SD) Serious adverse event (as no. of patients with at least one) Adverse events (as no. of patients with at least one) Adverse events (as total no. of events per patients) |
HFNC 184/414 vs. NIV 137/377: RR 1.22 (1.03 to 1.45) 88/404 vs. 72/364: RR 1.10 (0.83 to 1.45) 78/415 vs. 63/378: RR 1.13 (0.83 to 1.52) 170/414 vs. 126/377: RR 1.23 (1.02 to 1.48) 18.3 (20.0) vs. 16.4 (17.5) 0/417 vs. 7/380: RR 0.06 (0.00 to 1.06) 86/417 vs. 130/380: RR 0.60 (0.48 to 0.76) 157/417 vs. 200/380 |
| Grieco et al. [26] Standard care in both arms: Dexamethasone 100%, Remdesivir 81%. Sedation allowed but discouraged (continuous infusion 18%HFNC group vs. 37% in the helmet group). Awake proning allowed, 60% in HFNC vs. 0% in NIV underwent proning. Other aspects according to the clinical practice in each institution. Recruitment: from October 2020 to December 2020 |
n = 109 (allocated) age (years): 63 (IQR 55–69) (intervention) 66 (IQR 57–72) (control) sex: male 84% vs. 77% comorbidities: hypertension, diabetes mell., smoking, immunocompromised state, history of cancer clinical status at enrolment: inpatients not intubated with hypoxemic respiratory failure with PaO2/FiO2 ratio equal or below 200: PaO2/FiO2 ratio 102 vs. 105, PaCO2 34 vs. 34 mmHg, resp. rate 28 vs. 28 |
n = 55 HFNC for at least 48 h with 60 L/min and FiO2 titrated to SpO2 goal 92%. Stepwise weaning allowed when FiO2 was equal to or lower than 40% and respiratory rate lower than 25/min adherence to intended treatment protocol: received by 87% for 48 h or until intubation, one participant crossed over, other participants were weaned early according to the trial protocol |
n = 55 Helmet NIV for at least 48 h with initial PS 10–12 mbar and PEEP of 10–12 mbar and FiO2 titrated to SpO2 goal 92%. Stepwise weaning allowed when FiO2 was equal to or lower than 40% and respiratory rate lower than 25/min adherence to intended treatment protocol: received by 91% for 48 h or until intubation, 4% received it at least 16 h per day, 4% interrupted treatment, 2% did not receive the allocated treatment |
Days free of respiratory support within 28 days Endotracheal intubation within 28 days 28-day mortality 60-day mortality In-hospital mortality Adverse events (predefined selection of AEs relevant in respiratory and intensive care medicine, as total no. of events per patients) |
Mean (SD) in HFNC vs. NIV: 15 (11) vs. 13 (11) with MD 2 days (95% CI, −2 to 6) 28/55 vs. 16/54: RR 1.72 (1.06 to 2.79) 10/55 vs. 8/54: RR 1.23 (0.52 to 2.87) 12/55 vs. 13/54: RR 0.91 (0.46 to 1.80) 14/55 vs. 13/54: RR 1.06 (0.55 to 2.04) 70/55 vs. 37/54 |
| Nair et al. [27] Standard care in both arms: clinical management and drug therapy as per institutional protocols without further specification except: awake proning was encouraged, but only in almost all HFNC participants regularly performed. Recruitment: from August 2020 to December 2020 |
n = 109 (allocated) age (years): HFNC 57 (IQR 48–65) vs. NIV 57.5 (IQR 47–64) sex: male 80% vs. 64.8% comorbidities: Diabetes mell., hypertension, coronary heart disease, chronic kidney disease clinical status at enrolment: hospitalised, not intubated with hypoxemic respiratory failure despite O2 insufflation: PaO2/FiO2 ratio 105 vs. 111, PaCO2 34 vs. 32 mmHg, resp. rate 30 vs. 31 |
n = 55 HFNC through large-bore binasal prongs with a high-flow heated humidifier device, initial gas flow 50 L/min and FIO2 of 1.0, flow and FIO2 were subsequently adjusted between 30–60 L/min and 0.5–1.0, to maintain SpO2 of 94% or more. adherence to intended treatment protocol: Not quantified, but “Increased subject compliance and ease with which awake proning could be facilitated in HFNC group could have influenced the outcome in favor of the latter.” |
n = 54 NIV with either mask/helmet device connected to an ICU ventilator, PS of 10–20 cm H2O (aim of obtaining an expired tidal volume of 7–10 mL per kg of predicted body weight), PEEP 5–10 cm H2O, FIO2 0.5–1.0 titrated to target SpO2 > 94%. adherence to intended treatment protocol: Not quantified, but “Although NIV was initiated with PS 10–20 cm H2O, most of the subjects required PS) 5 cm H2O, [...]. Subjects on NIV usually felt claustrophobic and frequently complained of dry mouth, leading to repeated detachments of the oxygenation interface. Moreover, most of the subjects on NIV were not compliant.” The incompliance with NIV could have been even higher than expected due to aggressive initial ventilator settings. |
Intubation or death Intubation within 7 days In-hospital mortality Ventilator-free days at 28 d |
HR 0.51 (95% CI 0.28–0.94, p = 0.03) 15/55 vs. 25/54: RR 0.59 (0.35 to 0.99) 16/55 vs. 25/54: RR 0.63 (0.38 to 1.04); HR 0.54 (0.29 to 1.01) median 28.0 (IQR 27–28) vs. 27.5 (27–28) These data are implausible to us, given that 27% vs. 46% of patients were intubated within 7 days and the respective Kaplan-Meier estimator in the publication. This might be due to an unreported particular definition of this complex endpoint prone to misinterpretation. |
| awake prone positioning | |||||
| Ehrmann et al. [28] Recruitment: 4 April 2020–26 January 2021 |
n = 1121 | n = 564 | n = 557 | intubation or death | RR 0.86 (95% CI 0.75 to 0.98) |
| age (years) 61.5 ± 13.3 (intervention) 60.7 ± 13.3 (control) |
(awake) prone positioning for as long as possible | unrestricted (self) positioning except prone | 28-day mortality | RR 0.87 (0.71 to 1.07) | |
| comorbidities diabetes mellitus, chronic heart disease, obesity |
intubation within 28 days | RR 0.83 (0.71 to 0.96) | |||
| clinical status inpatient treatment, need for HFNC or NIV, no mechanical ventilation (i.e., WHO clinical progression scale 6) |
hospitalization: length of hospital stay (censored at 28 days) | difference of means −0.2 days (−1.35 to 0.96) | |||
| skin lesions | RR 0.5 (0.16 to 1.56) | ||||
| weaning from HFNC (time to event in days) | difference of means -0.9 days (0.35 to 1.45) | ||||
| Rosén et al. [29] Recruitment: 7 October 2020–7 February 2021 |
n = 75 | n = 36 | n = 39 | intubation within 30 days | RR 1.00 (0.53 to 1.90) |
| age (years) 65 (IQR 53–74; intervention) 65 (IQR 55–70; control) |
(awake) prone positioning ≥16 h/day | unrestricted (self) positioning except prone | 30-day mortality | RR 2.17 (0.58 to 8.03) | |
| comorbidities diabetes mellitus, arterial hypertension, obesity |
hospitalization: length of hospital stay (censored after 30 days) | difference of means −2.0 days (−7.16 to 3.16) | |||
| clinical status inpatient treatment, need for HFNC or NIV, no mechanical ventilation (i.e., WHO clinical progression scale 6) |
skin lesions | RR 0.24 (0.06 to 1.04) | |||
| days free of HFNC | difference of means 2.0 days (0.13 to 3.87) | ||||