Disclaimer: The aim of these rapid reviews is to retrieve, appraise, summarize and update the available evidence on COVID-related health technology. The reviews have not been externally peer- reviewed; they should not replace individual clinical judgement and the sources cited should be checked. The views expressed represent the views of the authors and not necessarily those of their host institutions. The views are not a substitute for professional medical advice.

Copyright Claims: This review is an intellectual property of the authors and of the Institute of Clinical Epidemiology, National Institutes of Health-UP Manila and Asia-Pacific Center for Evidence Based Healthcare Inc.

INTRODUCTION

Reports of pneumonia of unknown etiology in Wuhan City, Hubei province, China heralded the coronavirus disease 2019 (COVID-19) pandemic.1 The Chinese Center for Disease Control and Prevention reported that 4.7% of suspected and confirmed COVID-19 cases were classified as critical, having respiratory failure, septic shock, and/ or multiple organ dysfunction.2 Fifty-three percent of deaths among COVID-19 patients in Wuhan were due to respiratory failure.3

Using an air-oxygen blender, active heated humidifier, single heated circuit, and a nasal cannula, high-flow nasal cannula (HFNC) therapy provides higher flow

rates and more predictable fraction of inspired oxygen as compared to conventional oxygen devices.4 An RCT among non-COVID-19 patients with acute hypoxic respiratory failure showed a reduction in 90-day mortality compared to COT.5 Moreover, a number of systematic reviews and meta-analyses revealed that HFNC resulted in decreased need for escalation to mechanical ventilation, and improved patient dyspnea scores and comfort levels but had no significant effect on mortality and ICU length of stay, as compared to COT in acute respiratory failure.6-9

We sought to rapidly review and summarize current evidence on the effectiveness and safety of noninvasive respiratory support (i.e. HFNC, noninvasive ventilation [NIV], and COT) in treating COVID-19 patients with acute hypoxemic respiratory failure.

METHODS

A literature search for guidelines and primary studies on high-flow nasal cannula oxygenation in COVID-19 patients was conducted on electronic databases (PubMed, CENTRAL, ClinicalTrials.gov, ISRCTN Registry, and medRxiv), UpToDate (include society links), and Google Scholar on April 21, 2020.

Articles on effectiveness and safety were selected based on the following inclusion criteria:

•Population:  COVID-19 patients with acute hypoxemic respiratory failure

Table 1. Characteristics of studies included

•Intervention:  High-flow nasal cannula oxygen therapy

•Comparison:  Noninvasive ventilation (e.g. bilevel positive airway pressure [BiPAP], continuous positive airway pressure), conventional oxygen therapy

•Outcomes:  failure of respiratory support (escalation to mechanical ventilation), mortality, length of hospital stay, length of ICU stay, transmission rate, and noso- comial pneumonia rate

•Study designs:  Any study design including systematic reviews, randomized controlled trials, observational studies, and case reports/series

Search terms included the following and their variations: COVID-19, coronavirus, high flow nasal cannula, high flow nasal oxygen. No language restrictions were applied. Articles retrieved in languages other than English were processed using Google Translate.

A cursory review of the Twitter feed of the Phil- ippine Society for Microbiology and Infectious Diseases (@psmidorg) and the Philippine College of Chest Physicians (@philchestorg) was done on April 24, 2020 to identify additional references.

RESULTS

Included Studies

We found 6 observational studies of COVID-19 patients from China which reported the use of noninvasive

Study	Design	Location	Population (n)	Age
Wang Y	Case series	Wuhan city,	COVID-19 patients,	64 years
		China	severe and critically ill	(IQR 52-72)
		(single center)	(n = 344)

		Any comorbidity	Initial respiratory			Outcome/s
	Sex		support (n)			of interest
		(most common)
			HFNC	NIV	COT	reported
	F: 48% NR		35	34	—	Mortality
		(Hypertension: 41%)				Ventilatory
						support
						(noninvasive /
						invasive)

respiratory support, treatment failure, and mortality.10-15 We also found one before-and-after study on COVID-19 patients given HFNC.16  Characteristics of these studies are summarized in Table 1.

Caution is needed in interpreting the results, and causality cannot be concluded. These studies provide at most low-quality evidence owing to their retrospective nature, small sample sizes, and significant confounding. RCTs are urgently needed in this area.

Effectiveness

Failure of Respiratory Support

Two observational studies reported intubation rates among COVID-19 patients on HFNC and NIV but provided conflicting results12. -13 There was no available comparison for COT with treatment failure as the outcome.

One case series reported higher intubation rates in those given HFNC (23/35 [66%]) compared with those on NIV (0/34 [0%]).13 No additional characteristics on patients who received HFNC or NIV were provided.  Meanwhile, in another retrospective study, two (12%) of the 17 patients who received HFNC were intubated while 5 (29%) required NIV as rescue treatment.12  Only one of the 9 (11%) patients initially given NIV progressed to invasive mechanical ventilation.  Compared with patients where HFNC therapy succeeded, the treatment failures had significantly lower baseline respiratory rate (mean 23 vs. 26 breaths/min,p = 0.02) and PaO2/FiO2 ratio (median 159 vs. 223 mmHg, p = 0.02), and PaO2/FiO2 ratio at 1-2 hours from initiation (median 142 vs. 209 mmHg, p = 0.03).  These may suggest that patients in the HFNC failure group were more ill at baseline.

Although failure of initial respiratory support was higher among patients on HFNC compared with those on NIV in both studies, we cannot conclude about the superiority of HFNC or NIV because of methodological limitations (i.e. retrospective study, no control group, no control for confounders) and potentially unequal groups at baseline.

Mortality

Limited evidence for mortality come from the 5 observational studies.10-13,15 Characteristics of patients who received HFNC, NIV, or COT were not explicitly described, and so we were unable to determine if both groups were comparable. Rates of death were consistently lower in patients given HFNC therapy compared with those on NIV or COT across all 5 studies (Table 2).

Table 2. Mortality rates at Day 28 (unless otherwise specified)

Study	HFNC	NIV	COT
Liao	0/31 (0%)	1/22 (4.5%)	2/79 (2.5%)
Luo (during study period)	74/106 (70%)	48/56 (86%)	—
Wang Y	28/35 (80%)	27/34 (79%)	—
Yang	16/33 (48%)	23/29 (79%)	—
Zhou (in-hospital)	33/41 (81%)	24/26 (92%)	—

Additionally, a single-center case series in Anhui province, China followed the use of HFNC oxygen in four severe and four critical patients with COVID-19 (mean age: 61.38 ± 18.97 years).16 Six of the eight patients on HFNC developed acute respiratory distress syndrome (ARDS). All patients received low-dose corticosteroids, and four were treated with tocilizumab in addition to antiviral and antibacterial agents. The patients had a mean baseline O2 saturation of 87.75% (SD: 2.86) and were put on HFNC with an initial 100% oxygen concentration and a mean flow rate of 50.0 L/min (SD: 7.56). Within 24 hours of initiation of HFNC therapy, O2 saturations improved (mean 96.62%, SD: 1.60). Respiratory support was deescalated to COT after a mean of 7.38 (± 2.07) days, and all patients were eventually discharged.

Safety

We found no studies reporting on the risk of transmission of the SARS-CoV-2 infection to health care workers or other patients from, nor development of nosocomial pneumonia in COVID-19 patients on HFNC oxygen.

A study from Singapore compared the coughing distance of healthy volunteers (n = 5) with and without a HFNC.17 Droplet dispersion distance was higher with the application of a well-fitted HFNC system (mean 2.91 m, SD: 1.09) compared to baseline (2.48 m, SD: 1.03). The mean difference was 0.42 m (SD: 0.34). The authors caution that four of five volunteers’ droplets with and without HFNC use went beyond the 2-meter physical distancing recommended by the WHO.

Ongoing Studies

There are at least two ongoing trials (one RCT in the United Kingdom, one prospective cohort in China) comparing HFNC oxygenation with NIV or COT in COVID-19 patients. Outcomes to be reported include intubation rate, mortality rate, length of stay in a critical care unit, and length of hospital stay. Both trials are expected to be completed by the second quarter of 2021 (Appendix A).

Recommendations from Guidelines

Society guidelines from several countries18-21 and the World Health Organization (WHO)22 recommend the use of high-flow nasal cannula (HFNC) oxygen therapy in COVID-19 patients presenting with acute hypoxemic respiratory failure. HFNC is recommended particularly when patients fail to respond to COT. The Irish Thoracic Society recommends initiating HFNC therapy with a flow rate 30 L/min and FiO2 > 70% to target peripheral O2 saturations above 90%.18 Italian societies recommend a higher flow rate of 70 L/min.20 The Surviving Sepsis Campaign’s weak recommendation favoring HFNC in acute hypoxemic respiratory failure was based on indirect evidence of effectiveness in non-COVID-19 patients.19

Meanwhile, the National Health Service (NHS) in the United Kingdom, the Philippine Society for Microbiology and Infectious Diseases (PSMID), and the Philippine College of Chest Physicians (PCCP) do not recommend high-flow nasal oxygenation in COVID-19 patients citing risks of pathogen dispersal and transmission, and paucity of evidence for efficacy.23-25 PSMID recommends early invasive mechanical ventilation, or the use of non-rebreather masks instead when patients do not consent to intubation.24

The Australian and New Zealand Intensive Care Society (ANZICS), on the other hand, discourages routine use of NIV in COVID-19 patients due to higher rates of failure, delayed intubation, and increased risk of aerosolization.21 Bilevel positive airway pressure (BiPAP) therapy is reserved as an option for hypercapnic respiratory failure.18,23

Due to risks of aerosolization, patients receiving HFNC oxygen or NIV are preferably admitted in negative pressure rooms. Wearing surgical mask over the HFNC was also mentioned to decrease the risk of particle dispersal.18,23

CONCLUSIONS

Very low-quality evidence suggests reduced mortality (5 retrospective studies) but higher failure rates of initial respiratory support (2 retrospective studies) in COVID-19 patients given HFNC oxygenation compared with NIV and COT. Further studies, RCTs in particular, are urgently needed in this area.

Guidelines recommend added infection control precautions, i.e. wearing a surgical mask over the cannula, and admitting the patient in a negative pressure room, whenever using HFNC or NIV due to increased risk of aerosolization.

Declaration of Conflicts of Interest

Dr. Villanueva, Dr. Cruz, and Dr. Palileo-Villanueva have nothing to disclose.

REFERENCES

1.World Health Organization. Pneumonia of unknown cause – China [Internet]. 2020 [cited 2020 Apr]. Available from: https://www.who. int/csr/don/05-january-2020-pneumonia-of-unkown-cause-china/en/

2.Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: Summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. JAMA. 2020; 323(13):1239–42.

3.Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020; 46(5):846-8.

4.Nishimura M. High-flow nasal cannula oxygen therapy in adults: physiological benefits, indication, clinical benefits, and adverse effects. Respir Care. 2016;61(4):529-41.

5.Frat JP, Thille AW, Mercat A, Girault C, Ragot S, Perbet S, et al. FLORALI Study Group. High-flow oxygen through nasal cannula in acute hypoxemic respiratory failure. N Engl J Med. 2015; 372(23):2185-96.

6.Huang CC, Lan HM, Li CJ, Lee TH, Chen WL, Lei WY, et al. Use High-flow nasal cannula for acute respiratory failure patients in the emergency department: a meta-analysis study. Emerg Med Int. 2019; 2019:2130935.

7.Ni YN, Luo J, Yu H, Liu D, Liang BM, Liang ZA. The effect of high-flow nasal cannula in reducing the mortality and the rate of endotracheal intubation when used before mechanical ventilation compared with conventional oxygen therapy and noninvasive positive pressure ventilation: a systematic review and meta-analysis. Am J Emerg Med. 2018; 36(2):226-33.

8.Ou X, Hua Y, Liu J, Gong C, Zhao W. Effect of high-flow nasal cannula oxygen therapy in adults with acute hypoxemic respiratory failure: a meta-analysis of randomized controlled trials. CMAJ. 2017; 189(7):E260-7.

9.Rochwerg B, Granton D, Wang DX, Helviz Y, Einav S, Frat JP, et al. High flow nasal cannula compared with conventional oxygen therapy for acute hypoxemic respiratory failure: a systematic review and meta-analysis. Intensive Care Med. 2019; 45(5):563-72.

10.Liao X, Chen H, Wang B, Jin X, Li Z, Zhang Z, et al. Critical care for severe COVID-19: a population-based study from a province with low case-fatality rate in China [Internet]. 2020 [cited 2020 Apr]. Available  from:  https://www.medrxiv.org/content/10.1101/2020.03. 22.20041277v4.full.pdf [preprint]

11.Luo X,Xia H,Yang W et al.Characteristics of patients with COVID-19 during epidemic ongoing outbreak in Wuhan, China [Internet]. 2020 [cited 2020 Apr].  Available  from:  https://www.medrxiv.org/content/ 10.1101/2020.03.19.20033175v1.full.pdf [preprint]

12.Wang K, Zhao W, Li J, Shu W, Duan J. The experience of high-flow nasal cannula in hospitalized patients with 2019 novel coronavirus- infected pneumonia in two hospitals of Chongqing, China. Ann Intensive Care. 2020; 10(1):37.

13.Wang Y, Lu X, Li Y, Chen H, Chen T, Su N, et al. Clinical course and outcomes of 344 intensive care patients with COVID-19. Am J Respir Crit Care Med. 2020; 201(11):1430-4.

14.Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020; 8(5):475-81.

15.Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054–62.

16.Geng S, Mei Q, Zhu C, Yang T, Yang Y, Fang X, et al. High flow nasal cannula is a good treatment option for COVID-19. Heart Lung. 2020; S0147-9563(20)30113-8. doi: 10.1016/j.hrtlng.2020.03.018

17.Loh, NW, Tan, Y, Taculod, J, et al. The impact of high-flow nasal cannula (HFNC) on coughing distance: implications on its use during the novel coronavirus disease outbreak. Can J Anaesth. 2020; 67(7):893-4. doi: 10.1007/s12630-020-01634-3

18.Irish Thoracic Society & Irish Respiratory Society. Respiratory

management of patients with COVID-19 algorithm version 1 [Internet]. 2020 [cited 2020 Apr]. Available from: https:// irishthoracicsociety.com/wp-content/uploads/2020/03/COVID- Respiratory-Management-Guideline09.04.20.pdf.

19.European Society of Intensive Care Medicine & Society of Critical Care Medicine. Surviving sepsis campaign: guidelines on the management of critically ill adults with oronavirus disease 2019 (COVID-19) [Internet]. 2020 [cited 2020 Apr]. Available from: https://www.esicm. org/wp-content/uploads/2020/03/SSC-COVID19-GUIDELINES. pdf.

20.Associazione Italiana Pneumologi Ospedelieri - Italian Thoracic Society. Managing respiratory care of patients with COVID-19 [Internet]. 2020 [cited 2020 Apr]. Available from: https://ers.app. box.com/s/j09ysr2kdhmkcu1ulm8y8dxnosm6yi0h.

21.Australian and New Zealand Intensive Care Society. COVID-19 Guidelines, Version 1 [Internet]. 2020 [cited 2020 Apr]. Available from:  https://www.anzics.com.au/wp-content/uploads/2020/03/ ANZICS-COVID-19-Guidelines-Version-1.pdf.

22.World Health Organization. Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected: Interim guidance, Version 1.2. 2020 March 13 [Internet]. 2020 [cited 2020 Apr]. Available from: https://www.who.int/publications-detail/ clinical-management-of-severe-acute-respiratory-infection-when- novel-coronavirus-(ncov)-infection-is-suspected

23.National Health Service. Guidance for the role and use of non-invasive ventilator support in adult patients with COVID-19 (confirmed or suspected) Version 3 [Internet]. 2020 [cited 2020 Apr] .Available from: https://www.england.nhs.uk/coronavirus/wp-content/uploads/ sites/52/2020/03/specialty-guide-NIV-respiratory-support-and- coronavirus-v3.pdf.

24.Philippine Society for Microbiology and Infectious Diseases. Interim uidelines on the clinical management of adult patients with suspected or confirmed COVID-19 infection, Version 2.1 [Internet]. 2020 [cited 2020 Apr]. Available from: https://www.psmid.org/cpg-for-covid-19- ver-2-1-as-of-march-31-2020/

25.Philippine College of Chest Physicians. Algorithm on the respiratory management of critically ill with suspected and/or confirmed COVID-19 [Internet]. 2020 [cited 2020 Apr]. Available from: https://twitter.com/philchestorg/status/1243682818133131264/ photo/1

In adult patients with known or suspected COVID-19, does the use of continuous positive airway pressure (CPAP) or high-flow nasal oxygen (HFNO), compared with standard care reduce mortality or need for tracheal intubation?

ISRCTN16912075

Adaptive pragmatic open- label multicenter RCT

Known or suspected SARS-CoV-2 infection with respiratory failure

United Kingdom

Arm 1: Continuous positive airway pressure (CPAP), administered according to local protocol/ guidelines. Administration will be left to clinical discretion.

Arm 2: High flow nasal oxygen (HFNO) will be administered according to local protocol/ guidelines. Administration will be left to clinical discretion.

Arm 3: Standard care. Standard oxygen therapy according to local protocol/guidelines.

Composite outcome comprising	Recruiting
tracheal intubation or mortality
within 30 days	Trial end date:
Secondary:	May 5, 2021

1.Intubation rate

2.Time to intubation

3.Time to death (mortality), obtained from hospital record or other source

4.Mortality in critical care (level 2/3)

5.Mortality during hospital stay

6.Mortality at 30 days, obtained from hospital record or other source

7.Length of stay in critical care (level 2/3)

8.Length of stay in hospital