Am. J. Trop. Med. Hyg., 108(5), 2023, pp. 1035–1041 doi:10.4269/ajtmh.22-0793 Copyright © 2023 The author(s) Oxygen Consumption with High-Flow Nasal Oxygen versus Mechanical Ventilation— An International Multicenter Observational Study in COVID–19 Patients (PROXY–COVID) Michela Botta,1* Oriol Caritg,2 David M.P. van Meenen,1 Andre s Pacheco,2 Anissa M. Tsonas,1 Willemijn E. Mooij,1 Alessia Burgener, Tosca Manrique Hehl, Gentle S. Shrestha, Janneke Horn,1,4 Pieter R. Tuinman,5 Frederique Paulus,1,6 1 1 3 Oriol Roca,7,8,9 and Marcus J. Schultz1,10,11 1 Department of Intensive Care, Amsterdam University Medical Centers, location AMC, Amsterdam, The Netherlands; 2Department of Intensive Care, Vall d’Hebron University Hospital, Barcelona, Spain; 3Department of Critical Care Medicine, Tribhuvan University Teaching Hospital, Kathmandu, Nepal; 4Amsterdam Neurosciences, Amsterdam UMC Research Institute, Amsterdam, The Netherlands; 5Department of Intensive Care, Amsterdam University Medical Centers, location VUMC, Amsterdam, The Netherlands; 6Urban Vitality, Centre of Expertise, Faculty of Health, Amsterdam University of Applied Sciences, Amsterdam, The Netherlands; 7Department of Intensive Care, Parc Taulı de Sabadell University Hospital, Barcelona, Spain; 8Departament de Medicina, Universitat Auto  noma de Barcelona, Bellaterra, Spain; 9Ciber Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain; 10Mahidol–Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand; 11Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom Abstract. The COVID–19 pandemic led to local oxygen shortages worldwide. To gain a better understanding of oxy- gen consumption with different respiratory supportive therapies, we conducted an international multicenter observational study to determine the precise amount of oxygen consumption with high-flow nasal oxygen (HFNO) and with mechanical ventilation. A retrospective observational study was conducted in three intensive care units (ICUs) in the Netherlands and Spain. Patients were classified as HFNO patients or ventilated patients, according to the mode of oxygen supplementa- tion with which a patient started. The primary endpoint was actual oxygen consumption; secondary endpoints were hourly and total oxygen consumption during the first two full calendar days. Of 275 patients, 147 started with HFNO and 128 with mechanical ventilation. Actual oxygen use was 4.9-fold higher in patients who started with HFNO than in patients who started with ventilation (median 14.2 [8.4–18.4] versus 2.9 [1.8–4.1] L/minute; mean difference 5 11.3 [95% CI 11.0–11.6] L/minute; P , 0.01). Hourly and total oxygen consumption were 4.8-fold (P , 0.01) and 4.8-fold (P , 0.01) higher. Actual oxygen consumption, hourly oxygen consumption, and total oxygen consumption are substantially higher in patients that start with HFNO compared with patients that start with mechanical ventilation. This information may help hospitals and ICUs predicting oxygen needs during high-demand periods and could guide decisions regarding the source of distribution of medical oxygen. INTRODUCTION study, “Oxygen Consumption with High-Flow Nasal Oxygen versus Mechanical Ventilation—An International Multicenter The coronavirus disease 2019 (COVID–19) pandemic taught Observational Study in COVID–19 patients” (PROXY–COVID). us that oxygen scarcity is a serious but, above all, realistic sce- PROXY-COVID was a substudy of a larger observational nario in healthcare systems worldwide.1–3 Indeed, in several study in ICU patients with acute hypoxemic respiratory fail- parts of the world, there have been shorter or longer periods ure due to COVID–19. Our aim was to compare the amount of oxygen shortages, both in high-income and in low- and of supplemental oxygen used with HFNO versus mechanical middle-income countries.4–7 Shortages may have been exac- ventilation during the first two full calendar days of oxygen erbated by the increased use of high-flow oxygen supplemen- support in the ICU. tation, often called “high-flow nasal oxygen” (HFNO).8–10 Although it is obvious that HFNO consumes more oxygen than supplementation with lower flow oxygen support such MATERIALS AND METHODS as noninvasive and invasive ventilation, it remains unclear precisely how great the difference in oxygen consumption is. Study design. PROXY-COVID is a substudy of a large ret- A difference in oxygen consumption at a patient level may rospective observational study, “Practice of Adjunctive Treat- be less important, but at a department or hospital level, it is ments in Critically Ill COVID–19 Patients” (PRoAcT-COVID). vital to understand this difference for various reasons. For PRoAcT-COVID is a study that focused on care processes, instance, it could help intensive care unit (ICU) staff predict including respiratory support, in critically ill COVID–19 patients department oxygen needs during high-demand periods. Fur- in the first year of the outbreak in Europe. PROXY-COVID was thermore, it could help hospitals in decisions regarding the performed in the Academic Medical Center and the Free Uni- source of medical oxygen (e.g., liquid oxygen or pressure versity Medical Center, two academic hospitals in Amsterdam, swing adsorption plant, oxygen concentrators or oxygen The Netherlands, and in the Vall d’Hebron University Hospital, cylinders) as well as the infrastructure (e.g., oxygen concen- an academic hospital in Barcelona, Spain, from October 2020 trators, oxygen cylinders, or piped oxygen).11–13 to December 2020. The Institutional Review Boards of the par- To improve our understanding of oxygen consumption ticipating hospitals approved the study protocol of PRoAcT- with HFNO versus mechanical ventilation, we conducted a COVID and this substudy and waived the need for individual patient informed consent because of the observational nature of the investigation (11 December 2020; W20_526 # 20.583). PRoAcT-COVID and the substudy PROXY-COVID are regis- * Address correspondence to Michela Botta, Department of Intensive Care, location AMC, Amsterdam University Medical tered at clinicaltrials.gov (study identifier NCT04719182). Centers, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. Inclusion and exclusion criteria. Patients were eligible E-mail: m.botta@amsterdamumc.nl for participation in this substudy if they were 1) aged . 18 years 1035 1036 BOTTA AND OTHERS and 2) admitted to the ICU of one of the participating hospitals calendar days of ICU admission. Secondary outcomes were for 3) acute hypoxemic respiratory failure due to reverse tran- oxygen consumption per hour (hourly oxygen consumption) scriptase polymerase chain reaction– confirmed COVID–19. and total oxygen consumption (total oxygen consumption) in Patients were excluded if a patient did neither receive HFNO or the same time frame. mechanical ventilation during the first two full calendar days of Power calculation. No formal sample size calculation ICU admission. We also excluded patients who received extra- was performed. The number of available patients served as corporeal life support, including extracorporeal membrane oxy- the sample size. genation or extracorporeal CO2 removal within that timeframe. Statistical analysis plan. Continuous data are reported Data collected. Demographics, comorbidities, home med- as medians with interquartile ranges and categorical data as ication, and outcomes were collected at baseline. The Sim- numbers with percentages. plified Acute Physiology Score II was calculated using data The number of patients in the HFNO patients group and in collected in the first 24 hours after arrival in the ICU. Outcomes the ventilated patients group are reported in the Consoli- collected in this study were the last day of ventilation, last day dated Standards of Reporting Trials diagram. The groups in the ICU, last day in the hospital, and life status up to day 90. were compared using a Wilcoxon–Mann–Whitney test for For every 2 hours in the first two full calendar days, we col- continuous data and a Fisher exact test for categorical data. lected the following data to determine oxygen consumption: Missing values, when not present in more than 5% of the oxygen supplementation mode in use (i.e., HFNO, noninvasive observations, were treated as follows: the mean between ventilation, or invasive ventilation). With HFNO, we collected the the two proximal observations was calculated for every fraction of inspired oxygen (FiO2) and the airflow. With noninva- missing variable (i.e., VT, RR, FiO2, airflow) to be able to cal- sive ventilation and invasive ventilation, we collected FiO2 and culate the supplemental oxygen as in Eqs. (1) and (2). the level of positive end-expiratory pressure, as well as the Actual oxygen consumption, hourly oxygen consumption, inspiratory tidal volume (VT) and the respiratory rate (RR). In and total oxygen consumption at patient level were compared addition, we collected the saturation of arterial oxygen by between the two groups using the Wilcoxon–Mann– Whitney pulse oximetry (SpO2), and partial pressure of arterial oxygen, test and presented in distribution graphs. Actual oxygen con- for every arterial blood gas analysis performed in the first two sumption was plotted over time in a line graph showing mean full days. and standard deviation, in combination with FiO2 and with air Patient classification. We created two groups of patients. flow during HFNO, and minute ventilation during ventilation. Patients who started with HFNO were placed in the HFNO Actual oxygen consumption was compared between the patient group; patients who started with mechanical ventila- two groups and over time with repeated measures analysis of tion, whether noninvasive or invasive, were placed in the variance. Data were log transformed when skewed, and if sig- ventilated patient group. In both groups, patients could have nificant, a pairwise comparison between the two groups for received the alternative means of oxygen supplementation every time points was performed with Bonferroni correction. (i.e., a patient that started with HFNO could continue with In a preplanned subgroup analysis, patients that alter- mechanical ventilation, and vice versa). In all patients, nonin- nately received HFNO and ventilation in the first two full days vasive ventilation and invasive ventilation were applied using were excluded so that only patients who exclusively received HFNO or ventilation could be compared. high-end ICU ventilators. All analyses were conducted in R Studio v. 4.0.3 (R Founda- Calculations. First, we calculated the amount of supple- tion, Vienna, Austria), and the significance level was set at 0.05. mental oxygen per minute at each timepoint. During HFNO, we used the following equation: RESULTS Supplemental oxygen ðL=minuteÞ5 [Eq. 1] air flow ðL=minuteÞ  ðFiO2 2 0:21Þ Between October 1, 2020, and December 31, 2020, of a total of 313 screened patients, 289 were eligible for participa- For patients under invasive ventilation or noninvasive ven- tion (Figure 1). Of these patients, 13 were excluded because tilation, we used the following equation: they had received extracorporeal membrane oxygenation, Supplemental oxygen ðL=minuteÞ5 [Eq. 2] and one was excluded for incomplete ventilation data. Of the VT ðLÞ  RR  ðFiO2 2 0:21Þ remaining patients, 147 started with HFNO, and 128 started with mechanical ventilation. Patients were mostly male with a Supplemental oxygen per minute was then calculated medical history of hypertension and diabetes mellitus (Table 1). using Eqs. (1) and (2) at every timepoint (i.e., every 2 hours). Patients who started with HFNO were younger, less sick, and The amount of supplemental oxygen used between each died less often than patients who started with ventilation. timepoint was calculated based on the assumption that the Mode of oxygen supplementation. Of the HFNO patients, supplemental oxygen per minute did not change over the 54% continued with this mode of oxygen supplementa- subsequent 2 hours. The total amount of supplemental oxy- tion for the complete first two full days; the other patients gen used over the first full calendar day (Day 1) and the sec- switched to ventilation (37%) or low-flow oxygen (9%) within ond full calendar day (Day 2) was calculated by adding the this timeframe. Of the ventilated patients, the vast majority supplemental oxygen used between each timepoint. The continued with this mode: 10% switched to HFNO or another supplemental oxygen per minute for every patient thus cor- mode of oxygen supplementation (Figure 2 and Supplemental responds to the mean of all observations within the first two Figure 1). full days for each patient. Oxygen consumption. Actual oxygen consumption was Outcomes. The primary outcome was oxygen consumption 4.9-fold higher in HFNO patients compared with ventilated per minute (actual oxygen consumption) during the first two full patients (median 14.2 [8.4–18.4] versus 2.9 [1.8–4.1] L/minute; OXYGEN CONSUMPTION WITH HFNO VERSUS MECHANICAL VENTILATION 1037 FIGURE 1. Consolidated Standards of Reporting Trials flow diagram. ECMO 5 extracorporeal membrane oxygenation; HFNO 5 high flow nasal oxygen. mean difference 5 11.3 [95% CI: 11.0–11.6] L/minute; P , mean difference 5 13.8 [95% CI: 13.5–14.2] L/minute; P , 0.01) (Figures 3 and 4). Hourly oxygen consumption and total 0.01), and hourly oxygen consumption and total oxygen con- oxygen consumption were 4.8-fold and 4.8-fold higher in sumption were 5.3–fold and 5.3–fold higher (Figure 3 and Sup- HFNO patients compared with ventilated patients. plemental Figure 2). Subgroup analysis. The findings of the preplanned sub- group analysis, including 206 patients (Supplemental Table 1), DISCUSSION did not change the results. Actual oxygen consumption was 5.3-fold higher in HFNO patients compared with ventilated The findings of this international study in critically ill patients (median 15.5 [11.7–20.8] versus 2.9 [1.8–4.0] L/minute; patients with acute hypoxemic respiratory failure due to TABLE 1 Baseline patient characteristics Characteristic HFNO patients (N 5 147) Ventilated patients (N 5 128) P Age, years 61 (53–70) 65 (58–72) 0.02 Male gender, n (%) 101 (70.1) 93 (72.7) 0.69 Body mass index, kg/m2 28.7 (26.0–31.7) 28.7 (25.0–32.5) 0.63 SAPS II,* n/N (129/147), 33 (27–39) (102/128) 51 (41–63) , 0.01 Comorbidities, n (%) Arterial hypertension 56 (38.1) 57 (44.5) 0.33 Cardiovascular disease 26 (17.7) 29 (22.7) 0.36 Diabetes mellitus 45 (30.6) 34 (26.6) 0.51 Chronic kidney disease 19 (12.9) 13 (10.2) 0.57 Pulmonary disease 17 (11.6) 20 (15.6) 0.38 Malignancy 13 (8.8) 11 (8.6) 1.00 Home medication, n (%) Systemic corticosteroids 12 (8.2) 7 (5.5) 0.48 ACE inhibitors 25 (17.1) 27 (21.1) 0.44 Angiotensin II receptor blockers 22 (15.1) 15 (11.7) 0.48 Beta blockers 26 (17.8) 27 (21.1) 0.54 Insulin 18 (12.3) 19 (14.8) 0.60 Oral antidiabetics 35 (24.0) 23 (18.0) 0.24 Statins 47 (32.2) 39 (30.5) 0.80 Calcium channel blockers 25 (17.1) 24 (18.8) 0.75 Anticoagulation 16 (11.0) 17 (13.3) 0.58 ICU mortality, n (%) 25 (17.0) 52 (40.9) , 0.01 ACE 5 angiotensin converting enzyme; HFNO 5 high flow nasal oxygen; ICU 5 intensive care unit; SAPS 5 Simplified Acute Physiology Score. Data are median (plus interquartile range) or n (%). * SAPS II was not available for all patients. 1038 BOTTA AND OTHERS FIGURE 2. Mode of oxygen supplementation over time. HFNO 5 high flow nasal oxygen. COVID–19 can be summarized as follows: 1) actual oxygen supplementation created local oxygen shortages in both consumption with HFNO greatly exceeds actual oxygen resource-limited settings and high-income countries.15 For consumption in patients receiving ventilation; consequently this reason, HFNO use was restricted in India during the sec- 2) hourly and total oxygen consumption is much higher in ond surge of the COVID–19 pandemic.16 Although informa- patients receiving HFNO, a difference that persisted even tion on the exact reasons for oxygen shortages at a local when excluding patients that switched from HFNO to mechan- level remain scarce, there are obvious reasons for it. For ical ventilation within the first two full days of ICU care. instance, there have been reports of shortages due to pro- Our study has several strengths. First, it was an international blems with the delivery of oxygen to healthcare facilities, study, including patients admitted to the ICUs of three aca- related to high costs or unpaid bills. Also, there have been demic hospitals in two European countries. This increases the reports on lack of oxygen cylinders, for example, because external validity of our findings. Second, we captured oxygen healthcare providers themselves started stockpiling and hoard- supplementation data every 2 hours, providing us the opportu- ing them.7 Another example is related to the poorly organized nity to calculate various measures of oxygen consumption in a electricity arrangements, wherein electricity outages cannot be fairly precise way. Indeed, to our best knowledge, this is the dealt with at a local level. This is especially problematic if oxy- first study that estimated actual, hourly, and daily data on oxy- gen supplementation depends on local production, at the hos- gen consumption in a cohort of critically ill COVID–19 patients pital in a local plant or near the patient with bedside oxygen receiving either HFNO or ventilation. In addition, data were col- concentrators, which all need electricity. lected by trained data collectors, and the amount of missing One previous study reported data regarding oxygen con- data was low; in addition, we strictly followed the predefined sumption under experimental condition for noninvasive and analysis plan. Finally, only high-end ICU ventilators were used, invasive ventilation.17 The actual oxygen consumption in that for noninvasive and invasive ventilation, meaning we had no study is comparable to our results; however, oxygen con- differences in bias flow, oxygen delivery, and leak compensa- sumption during HFNO was not measured, and to our best tion between these two forms of mechanical ventilation. knowledge there are no comparable studies in patients receiv- Although oxygen has been listed in 2017 in the WHO ing HFNO. Differences between that study and our study in Essential Medicines Lists for both adults and children to treat the amounts of oxygen consumed can be explained by the hypoxemia,14 it was already a scarce resource in limited- simplified formula to calculate the oxygen consumption we resource settings before the ongoing pandemic. In the past used, but maybe also the more precise description of oxygen 2 years, the incessant surges of patients in need of oxygen consumption, including changes over hours in our study. OXYGEN CONSUMPTION WITH HFNO VERSUS MECHANICAL VENTILATION 1039 FIGURE 3. Actual oxygen consumption, fraction of inspired oxygen (FiO2) and airflow/minute volume over time. Panels on the left show the primary analysis, panels on the right show the preplanned subgroup analysis. P values refer to the repeated measures analysis of variance. HFNO 5 high flow nasal oxygen. The findings of this study provide valuable input to the dis- exclusively HFNO, and 200 days of oxygen support for an cussion on how to guarantee local oxygen supplementation. ICU with 10 COVID–19 patients exclusively receiving noninva- Hospitals can decide to install a liquid oxygen storage tank or a sive or invasive ventilation.11 A pressure swing adsorption plant pressure swing adsorption plant. According to our results, could be more attractive, although it should be noted that out- the oxygen consumption per day is 850 L/hour * 24 hours put is affected by altitude.18 A plant that produces 1,000 L per 20,000 L during HFNO and 176 L/hour * 24 hours 4,200 L minute is sufficient for oxygen support in 70 patients or more during noninvasive or invasive ventilation. Therefore, a full liquid receiving HFNO, and more than 330 patients receiving noninva- oxygen tank of, for example, 10 K liters, which equals 8,500 K sive or invasive ventilation in case of uninterrupted production. liters of gaseous oxygen, will be sufficient for 40 days of oxy- Departments may need to take care of local oxygen storages, gen support for an ICU with 10 COVID–19 patients receiving or production. A full steel oxygen cylinder of, for example, 50 L, FIGURE 4. Cumulative frequency distribution of actual oxygen use, hourly oxygen use, and total oxygen use. P values refer to the Wilcoxon– Mann–Whitney test. HFNO 5 high flow nasal oxygen. 1040 BOTTA AND OTHERS which equals up to almost 8,000 L of gaseous oxygen, will be failure due to COVID–19. This information may help hospital sufficient for 9 hours of oxygen support for a COVID–19 systems in planning the oxygen supplies, especially during patient receiving exclusively HFNO, and 44 hours of oxygen high demand periods. support for a COVID–19 patient receiving exclusively noninva- sive or invasive ventilation. Here, an oxygen concentrator could Received December 21, 2022. Accepted for publication January 27, be more attractive to use, but a bedside oxygen concentrator 2023. can produce only up to 15 L/minute. Of note, oxygen concen- Published online March 27, 2023. trators do not have batteries, meaning that electricity outages Note: Supplemental materials appear at www.ajtmh.org. must be prevented, or covered by a local generator or other Acknowledgments: The American Society of Tropical Medicine and source. If not, enough filled oxygen cylinders should be present Hygiene has waived the Open Access fee for this article due to the as a backup oxygen source. ongoing COVID-19 pandemic. Oxygen-sparing strategies include automated oxygen titra- Financial support: Amsterdam University Medical Centers, location tion techniques,19,20 better bedside use of guidelines with strict Academic Medical Center; Netherlands Organization for Health cutoffs for SpO2 targets,21,22 and the use of prone positioning, Research and Development [ZorgOnderzoek Nederland/Medische in awake patients, that is, patients receiving HFNO23–26 or non- Wetenschappen (ZonMw)]. invasively ventilated ventilation,27 and invasively ventilated Disclosures: M. S. is partly employed by Hamilton Medical AG, out- patients.28 The amount of oxygen spared with all these mea- side of the submitted work. O. R. reports a research grant from Ham- sures has yet to be studied and could be rather small, but any ilton Medical AG and Fisher&Paykel Healthcare Ltd, speaker fees reduction in consumption, no matter how small, can help pre- from Hamilton Medical AG, Fisher&Paykel Healthcare Ltd, Aerogen vent a local “oxygen infarction” when applied on a larger scale. Ltd and Ambu, and nonfinancial research support from Timpel, all outside the submitted work. In an unfortunate situation of severe oxygen deficiency, it can of course be decided to stop applying HFNO as an intervention Authors’ addresses: Michela Botta, David van Meenen, Anissa Tso- to avoid or postpone mechanical ventilation, so that only intu- nas, Willemijn Mooij, Alessia Burgener, and Tosca Manrique Hehl, Department of Intensive Care, Amsterdam University Medical Cen- bation would follow oxygen supplementation via low-flow sys- ters, location AMC, Amsterdam, The Netherlands, E-mails: m.botta@ tems in the treatment algorithm; if this is not necessary, the amsterdamumc.nl, d.m.vanmeenen@amsterdamumc.nl, a.m.tsonas@ assessment of the infrastructural requirements regarding oxy- amsterdamumc.nl, w.e.mooij@amsterdamumc.nl, 20022982@studenti. gen supply during HFNO remains of vital importance. Finally, it uniupo.it, and t.c.manriquehehl@amsterdamumc.nl. Oriol Caritg could be useful to identify patients who will fail HFNO, so that and Andre s Pacheco, Department of Intensive Care, Vall d’Hebron University Hospital, Barcelona, Spain, E-mails: ocaritg@gmail.com these patients can be switched to invasive ventilation at an ear- and a.pacheco@vhebron.net. Gentle Shrestha, Department of lier time point to spare oxygen.29,30 Critical Care Medicine, Tribhuvan University Teaching Hospital, This study has limitations. First, we did not collect data of Kathmandu, Nepal, E-mail: gentlesunder@hotmail.com. Janneke Horn, patients receiving lower flow oxygen support other than nonin- Department of Intensive Care, Amsterdam University Medical Centers, vasive or invasive ventilation, which could also substantially location AMC, Amsterdam, The Netherlands, and Amsterdam contribute to oxygen use in the ICU. Second, we may have Neurosciences, Amsterdam UMC Research Institute, Amsterdam, The Netherlands, E-mail: j.horn@amsterdamumc.nl. Pieter-Roel underestimated oxygen consumption in ventilated patients in Tuinman, Department of Intensive Care, Amsterdam University our study. Indeed, the simplified formula we used does not con- Medical Centers, location VUMC, Amsterdam, The Netherlands, sider bias flow, which may be high in older ventilators, and lea- E-mail: p.tuinman@amsterdamumc.nl. Frederique Paulus, Department kages. Third, the study population only included patients with of Intensive Care, Amsterdam University Medical Centers, location acute hypoxemic respiratory failure due to COVID–19, meaning AMC, Amsterdam, The Netherlands, and Urban Vitality, Centre of Expertise, Faculty of Health, Amsterdam University of Applied that most patients had single-organ (i.e., respiratory) failure. Sciences, Amsterdam, The Netherlands, E-mail: f.paulus@ Patients with respiratory failure due to other causes may amsterdamumc.nl. Oriol Roca, Department of Intensive Care, Parc respond less well to HFNO and may even need support with Taulı de Sabadell University Hospital, Barcelona, Spain, Departament other levels of FiO2. Also, we restricted data collection to the first de Medicina, Universitat Auto  noma de Barcelona, Bellaterra, Spain, two full days of HFNO or ventilation, which usually lasts longer and Ciber Enfermedades Respiratorias, Instituto de Salud Carlos III, than our time frame. Fourth, our study was performed at a low Madrid, Spain, E-mail: oroca@tauli.cat. Marcus Schultz, Department of Intensive Care, Amsterdam University Medical Centers, location altitude, and findings are not easily generalizable to hospitals at AMC, Amsterdam, The Netherlands, Mahidol–Oxford Tropical Med- high altitude. Of note, we included only academic hospitals in icine Research Unit, Mahidol University, Bangkok, Thailand, and high-income countries, where care for patients—particularly Nuffield Department of Medicine, University of Oxford, Oxford, oxygen titrations—could be different from that in nonacademic United Kingdom, E-mail: marcus.j.schultz@gmail.com. hospitals in low-income countries (e.g., due to the lower number This is an open-access article distributed under the terms of the of healthcare providers at each bed). Fifth, we did not capture Creative Commons Attribution (CC-BY) License, which permits data about prone positioning, which prevents us from drawing unrestricted use, distribution, and reproduction in any medium, pro- vided the original author and source are credited. conclusions about the effect of proning on oxygen consump- tion. Last, the retrospective nature of our study did not allow us to see how well HFNO was provided and how FiO2 was titrated. 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