High-flow Oxygen and Nitric Oxide inhalation versus high-flow oxygen alone to prevent intubation in hypoxaemic Respiratory failure (HONOR): a pilot randomised controlled trial protocol.

High-flow Oxygen and Nitric Oxide inhalation versus high-flow oxygen alone to prevent intubation in hypoxaemic Respiratory failure (HONOR): a pilot randomised controlled trial protocol. | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article High-flow Oxygen and Nitric Oxide inhalation versus high-flow oxygen alone to prevent intubation in hypoxaemic Respiratory failure (HONOR): a pilot randomised controlled trial protocol. Luke Churchill, Oystein Tronstad, Karen Hay, Peter Thomas, Kiran Shekar This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6574612/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 26 Nov, 2025 Read the published version in Pilot and Feasibility Studies → Version 1 posted 5 You are reading this latest preprint version Abstract Background: When conventional oxygen therapies fail, endotracheal intubation and invasive mechanical ventilation are the current standard of care in patients with acute hypoxaemic respiratory failure. However, invasive mechanical ventilation is associated with increased hospital and intensive care length of stay, healthcare costs, and morbidity and mortality. Inhaled nitric oxide has the potential to treat hypoxaemia and potentially prevent the need for invasive mechanical ventilation. Aims and objectives : The objective of this study is to examine the feasibility and effectiveness of high-flow oxygen and nitric oxide gas inhalation compared with high-flow oxygen alone in preventing invasive mechanical ventilation for patients with acute hypoxaemic respiratory failure. Methods: In this pilot, randomised controlled feasibility study, 40 patients admitted to the intensive care unit with acute hypoxaemic respiratory failure will be randomised on a 1:1 ratio to receive one of two interventions: high-flow oxygen and nitric oxide gas inhalation (intervention) or high-flow oxygen alone (control) via high-flow nasal cannula. Feasibility, demographic, outcome, and safety data will be collected at several timepoints during participants’ admission. Discussion: This protocol outlines a structured method for investigating the effects of inhaled nitric oxide gas in preventing invasive mechanical ventilation for patients with acute hypoxaemic respiratory failure. Considering the risks, costs, and poorer outcomes associated with invasive mechanical ventilation, less invasive means of respiratory support warrant further investigation. The study will assist in planning a larger, multi-centre definitive trial. Trial registration: This study is registered on the Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12622001411730. Registered 4 th September 2022, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=384881 Acute respiratory failure endotracheal intubation invasive mechanical ventilation inhaled nitric oxide high-flow oxygen oxygen therapy Figures Figure 1 Figure 2 1. INTRODUCTION Acute hypoxaemic respiratory failure is a common and life-threatening consequence of a diverse group of conditions 1 , 2 . When conventional oxygen therapies (COT) (≤ 15 L/min oxygen via nasal prongs, cannula or mask) 3 or non-invasive ventilation (NIV) fail to correct hypoxaemia, invasive mechanical ventilation (IMV) is required. The use of IMV is common throughout the world and is increasing annually 4 , 5 . Patients on IMV represent approximately 3% of acute hospitalisations and 30% of intensive care unit (ICU) admissions both internationally and in Australia 1 , 2 , 6 – 8 . However, outcomes of IMV are highly dependent on factors such as aetiology, age, co-morbidities, and severity of illness 9 . Whilst often a life-saving intervention, intubation and IMV are not without inherent risks. Risks include laryngeal injury, injury to lung parenchyma, adverse haemodynamic consequences (e.g., decreased venous return, blood pressure, and cardiac output) and predisposition to infection (e.g. ventilator-associated pneumonia (VAP)) 10 – 13 . Emergent endotracheal intubation also carries an especially high risk, with reported intubation-related cardiac arrest (occurring within 20 minutes after successful intubation) rates of up to 23% 14 . Despite evidence demonstrating a decrease in mortality rates over time, up to 30–40% of patients receiving IMV will not survive their ICU admission 15 and many survivors experience reduced quality of life, impaired physical function, and increased psychological conditions such as depression, anxiety and post-traumatic stress disorder 16 , 17 . Invasive mechanical ventilation is also associated with significant increases in hospital and ICU length of stay (LOS) 6 , 18 , with increased cost burden ranging from 25–59% extra per ICU patient per day receiving IMV 7 , 19 , 20 . Reducing the incidence, risks, and costs associated with IMV is a major priority for healthcare providers, consumers, health system administrators, taxpayers, and policymakers 6 . By averting an artificial airway and IMV, patients with acute respiratory failure (ARF) supported with less invasive means can often avoid intravenous sedation and costly complications, such as VAP, ICU-acquired weakness, and line sepsis 6 . Avoiding intubation also facilitates patient-centric aims of early rehabilitation, speech, and oral feeding which may improve patient outcomes and reduce hospital and ICU LOS. High-flow oxygen (HFO 2 ) delivered through nasal cannula and NIV are routinely used in the treatment of ARF 21 – 23 . In a randomised clinical trial in patients with ARF, HFO 2 therapy demonstrated a non-significant reduction in IMV compared with COT and NIV, however, resulted in a better 90-day survival 24 . In this study, the rates of intubation were lowest in the HFO 2 therapy group (38%), compared with COT and NIV (47% and 50% respectively). The leading cause of intubation across groups (> 70%) was worsening ARF and hypoxaemia, warranting further investigation into the most optimal strategies to mitigate this. The addition of inhaled Nitric Oxide (iNO) to nasal HFO 2 may allow hypoxaemia to be corrected and potentially avoid IMV 25 , 26 . As a potent vasodilator, iNO has the ability to provide selective pulmonary vascular dilation in well-ventilated sections of the lungs, improving ventilation-perfusion mismatch 26 , 27 . Significant improvements in oxygenation have been demonstrated in infants with ARF on nasal continuous positive airway pressure with iNO 28 . Results within the adult population remain inconsistent, with short-term improvements in the ratio of the partial pressure of arterial oxygen (PaO 2 ) to fraction of inspired oxygen (FiO 2 ) ratio (PF) often being transient or not sustained 29 – 33 . However, the primary means of delivering iNO was either via COT or mechanical ventilation and not via nasal HFO 2 . Literature demonstrating the effects of iNO combined with HFO 2 (HFO 2 + iNO) in the adult population remains sparse. One multi-centre cohort study evaluated the effectiveness of HFO 2 + iNO in patients with respiratory failure from coronavirus disease (COVID-19) 34 . In this population, HFO 2 + iNO did not reduce oxygen requirements in the majority of patients. However, a subset of patients considered responders (defined as a decrease in supplemental oxygen delivered via high-flow nasal cannula (HFNC) 12 hours after iNO initiation), had a trend toward decreasing need for IMV compared to non-responders 34 . Outside of this patient population, only case reports exist of the successful use of HFO 2 + iNO for preventing IMV. These reports demonstrated improvements in oxygenation within the hospital setting and maintaining safe oxygen levels during transport to and from hospital 35 , 36 . Therefore, to further investigate the potential benefits of HFO 2 + iNO in preventing IMV, further research is needed in its potential to reduce the need for IMV. 2. AIMS The aims of this pilot study are to examine the feasibility, intubation rates, and clinical outcomes when comparing HFO 2 + iNO gas inhalation to HFO 2 alone in patients with hypoxaemic, non-hypercapnic ARF. Based on the physiologic rationale 25 , 37 , prior investigations 28 , 35 , 36 , and our anecdotal experience, we hypothesise that HFO 2 + iNO therapy is superior to HFO 2 in preventing IMV in patients with ARF. This pilot study is a requisite initial step in exploring the proposed intervention 38 in preparation for a larger scale, multi-centre definitive trial. The feasibility and safety outcomes of the study protocol will inform future budget and protocol development whilst providing initial effect estimates to inform sample size calculation. 3. METHODS 3.1 Design This will be an open label, 1:1 parallel group, single-centre, pilot (n = 40) randomised controlled trial. The study protocol has been reported using the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) statement guidelines 39 and the associated publication from the study will be reported in accordance with the CONSORT extension for randomised pilot and feasibility trials 40 . The SPIRIT figures (Figs. 1 and 2) outline the schedule of enrolment, interventions and assessments 39 . 3.2 Setting and sample This study will be conducted in a 27-bed adult ICU at a large urban Australian tertiary referral hospital specialising in cardiothoracic surgery and medicine. As a pilot trial, it is not required to be powered to detect statistical significance. A sample of 40 eligible patients will be recruited over a period of 12–18 months. Assuming the proportion of patients who progress to IMV is 0.38 24 , a sample of 20 per group will produce an exact 95% CI width of 0.44. 3.3 Recruitment and consent Patients presenting with type I acute hypoxaemic respiratory failure (PaO 2 < 60 mm Hg with normal or subnormal PaCO 2 ) 41 will have arterial blood gas (ABG) sampling as per standard care for this patient cohort. Aligning with previous research investigating HFO 2 in ARF 24 , if the PF ratio is less than 300 mm Hg, they will be screened for suitability to participate in the study by a member of the research team. Written informed consent will be obtained from all suitable patients, their next of kin, or another substitute decision maker (SDM) as appropriate. Owing to the nature of their injury, potential participants are unlikely to have the capacity to provide written consent at the time of recruitment. Verbal consent from an SDM will be allowed if geographical or infection control visitor restrictions prevent face-to-face informed consent processes. Written consent will be sought later if a SDM is able to attend in person or are able to return a consent form provided to them via email. Should there be no SDM available initially, study procedures will be performed and consent to continue will be sought from the SDM, or the participant (should they regain capacity to consent) within a maximum of three days. Participants and/or their SDM can decline study assessments and discontinue participation at any time without explanation or penalty. Simple random allocation will be applied, with participants allocated in a 1:1 ratio to either the control or intervention arm via a computer-generated random sequence program. 3.4 Inclusion and exclusion criteria Patients will need to meet all inclusion criteria and no exclusion criteria (Table 1 ) to be eligible to participate. Table 1 Inclusion/exclusion criteria for review. Inclusion Exclusion • Age ≥ 18 years • Admitted to ICU • De novo type I respiratory failure (hypoxaemia in the absence of chronic lung condition) 24 • PF ratio 24 hours • Arterial line in-situ for blood gas sampling • Ability to provide informed consent, or consent via a SDM • Congenital or acquired methaemoglobinaemia reductase deficiency • Bleeding diathesis • Intracranial haemorrhage • Severe left ventricular failure • Underlying chronic respiratory failure or exacerbation of asthma (including chronic obstructive pulmonary disease (COPD) or other chronic respiratory disease) • Documented cardiogenic pulmonary oedema or acute coronary syndrome • Hypercapnic respiratory failure with PaCO 2 > 45 mm Hg • Deterioration of neurologic status demonstrated by Glasgow Coma Scale (GCS) ≤ 12 • Urgent need for intubation (evaluated by the medical officer in charge) • Haemodynamic instability (defined by systolic arterial blood pressure < 90 mm Hg or mean arterial blood pressure < 65 mm Hg) • Use of vasopressors • Do not intubate orders • Enrolled in any other trial of targeted oxygen therapy ICU: intensive care unit; HFO 2 : high-flow oxygen; Hg: mercury; mm: millimetres; PaCO 2 : partial pressure of arterial carbon dioxide; PF: ratio of partial pressure of arterial oxygen to fraction of inspired oxygen; SDM: substitute decision maker. 3.5 Blinding Due to the nature of the interventions, participants receiving the interventions and the clinicians providing care will be aware of the treatment allocation. During the consent process, participants will be informed of the two interventions and be made aware that both are considered standard of care at the study site. 3.6 Study interventions Participants will receive one of two interventions: HFO 2 alone or HFO 2 + iNO as detailed below. High Flow Oxygen (HFO 2 ) alone (control group) : Initial FiO 2 set at 100% with an initial flow of 60 L/min FiO 2 will be titrated down in the first hour, targeting oxygen saturation (SpO 2 ) > 92% and PaO 2 > 60 mm Hg Further reduction in FiO 2 every subsequent two hours maintaining SpO 2 > 92% and PaO 2 > 60 mm Hg Flows will be reduced in increments of 10 L/min if needed for tolerance, to a minimum of 30 L/min Heated humidification to ensure delivery of HFO 2 into the nares at a temperature set at 37°C High Flow Oxygen and Nitric Oxide (HFO 2 + iNO) (intervention group) : High flow oxygen therapy as described above, with the addition of: iNO initially set at 20 parts per million (ppm) via HFNC by medical team, administered by ICU nursing staff, and weaned as per the following: After 24 hours of study drug administration, wean iNO 1 ppm every 20 minutes or as directed by the treating ICU Consultant, provided: PaO 2 > 60 mm Hg and SpO 2 > 92% for greater than 6 hours with an FiO 2 ≤ 50% FiO 2 may be increased up to a maximum of 60% to compensate for any drop in oxygenation If nil decrement in oxygenation seen, iNO will be further weaned at a rate of 1 ppm/20 minutes to 0 ppm) or as directed by ICU Consultant If desaturation persists (SpO 2 15 minutes, iNO will be returned to the most recent level prior to weaning or escalated up to a maximum of 20 ppm to maintain patient oxygenation iNO inhalation will be maintained if the patient in the HFO 2 + iNO arm requires NIV Blood sampling : As per standard of care for patients with ARF within ICU, regular ABGs (approximately four to six per day) are collected via an arterial line to monitor several indices within the blood (such as PaO 2 , PaCO 2 , PF ratios, serum creatinine, and methaemoglobin (MetHb) levels). Further ABGs can also be requested by the medical treating team as clinically indicated. To monitor responses to therapy within the study, participants will have several ABGs completed at pre-determined timepoints (Fig. 1), most of which will occur as part of standard care within ICU. However, specific timepoints (such as six and 12 hours after study inclusion) may require additional ABGs. In these instances, approximately 4ml of blood will be collected from participants via their arterial line for analysis within ICU. No further ABGs will be collected if/when an arterial line is removed, therefore, negating the requirement of an arterial stab. Intervention timing : Timing of interventions and assessments during the study will occur via the schedules outlined in Figs. 1 and 2. EQ-5D-5L: EuroQol 5-Dimension 5-Level; hr: hour; HR: heart rate; ICU: intensive care unit; PaO 2 : partial pressure of arterial oxygen; PF: ratio of partial pressure of arterial oxygen to fraction of inspired oxygen; ROX: respiratory rate-oxygenation; RR: respiratory rate; SBP: systolic blood pressure; SpO 2 : oxygen saturation. 3.7 Outcome measurements Feasibility outcomes a) Eligibility (% of screened patients that meet criteria) b) Recruitment (% of all eligible patients recruited using approved consent methods) c) Retention (% of pts withdrawing consent) d) Protocol fidelity (% of pts in intervention group receiving HFO 2 + iNO for at least 22 hours a day (accounting for times where/if iNO is ceased (e.g. transport, investigations, mobility away from the bedspace)) Primary outcomes a) Number of patients in each arm progressed to IMV within 28 days b) MetHb levels measured via ABGs at timepoints listed in Fig. 2 c) Daily serum creatinine and urine output levels to monitor renal function and/or renal impairment Secondary Outcomes (Specific timepoints in Fig. 2) a. Change in PaO 2 relative to baseline b. Change in PF ratio relative to baseline c. Physiological data o Respiratory rate (RR) o SpO 2 o Systolic blood pressure (SBP) o Heart rate (HR) d. Illness severity as estimated by daily sequential organ failure assessment (SOFA) scores 42 e. Worst daily PF ratio f. ROX index scores g. Reason for intubation o Respiratory failure o Circulatory failure o Neurological failure o Surgery h. Participant experience survey (Appendix 1) i. ICU LOS j. Hospital LOS k. Mechanical ventilation hours l. Number of ventilator free days at day 28 m. Time to mobilisation (minimum classification 4 (standing) on the ICU mobility scale) 43 n. Best mobility (within first 24 hours and during whole length of stay) o. Daily delirium incidence (Confusion Assessment Method for the ICU (CAM-ICU) score) p. Retrospective pre-ICU EuroQol 5-Dimension 5-Level (EQ-5D-5L) questionnaire q. EQ-5D-5L (collected within 5–7 days of discharge from the ICU) r. Need for anxiolytic and sedative medication during admission s. ICU mortality 3.8 Data collection Feasibility data including eligibility and recruitment will be gained from the electronic screening log. The screening log will be used to document all patients who have been screened and identify those who consented to enrol in the study and those who were not enrolled, remarking the specific reason for exclusion. Data in relation to demography, physiology, admission severity of illness, haemodynamic data, details of haemodynamic support, and hepatic and renal functions will be collected by local data managers from electronic medical records. Safety data will be collected for each patient including (i) MetHb levels, (ii) daily serum creatinine and urine output levels to monitor renal function and/or renal impairment, and (iii) adverse and serious adverse events (see section 3.9 below for further details). 3.9 Data handling and record keeping Case Report Forms (CRF’s) will be collected initially in hard copy before being transferred to an electronic format which will be stored on a password protected Queensland Health server. Paper documents will be stored in a secured locked cabinet at the study site under the supervision of the principal investigator and study coordinator. An electronic copy of the data will be maintained via a password protected spreadsheet, and the principal investigator and study coordinator will be responsible for its management. The study team will ensure all steps are taken to maintain confidentiality and security over the study documentation. Documents will be maintained for a minimum of 15 years following the completion of the study, as per Good Clinical Practice (GCP) guidelines. 3.10 Safety considerations 3.10.1 Methaemoglobin levels across groups Nitric oxide oxidizes heme iron to the ferric state, resulting in the formation of MetHb 44 . Methaemoglobin has higher oxygen affinity and decreased oxygen-carrying capacity due to fewer hemes to bind oxygen 45 . Safe levels of MetHb within previous trials for iNO are considered 5% for four participants in the iNO group and three participants in the control group 33 . Whilst this risk remains extremely low, MetHb levels will be monitored in all participants in this study via ABGs during the timepoints listed in Fig. 2. 3.10.2 Renal impairments across groups Previous literature has demonstrated that iNO may induce renal impairment 33 . Depending on the definition, renal impairment in participants receiving iNO range from 5–13% 29, 46 , 47 . However, of these results, only one study demonstrated a statistically significant increase in renal impairment in the intervention group when comparing to a control group of COT 47 . To further examine rates of renal impairment within this study, daily serum creatinine and urine output levels will be collected and compared across both groups. Renal impairment will be classified by the Acute Kidney Injury Network (AKIN) criteria 48 (Appendix 2). 3.10.3 Adverse and serious events Any adverse event (AE) associated with the conduct of the study will be collected and reported to the study sponsor (Metro North Hospital and Health Service). Additionally, an annual safety report will be provided to the approving human research ethics committee in line with the local requirement at the study site. The defined AEs for the trial are: • Renal complications (including new haemofiltration/dialysis and/or acute kidney injury defined by the AKIN classification/staging system of acute kidney injury, Appendix 2) • MetHb levels > 5% Serious adverse events (SAEs): The definition of a SAE is one that fulfills at least one of the following: • Is fatal - results in death • Is life threatening • Requires prolongation of existing hospitalisation • Results in persistent or significant disability or incapacity 49 Given that critically ill patients are likely to meet any of the above listed criteria during their ICU admission, only SAE’s that are thought to be related to the study will be reported. SAE’s will be reported to the study sponsor within 24 hours of becoming aware of the event. For all events, a medically qualified study investigator will review the event and assign the causality relationship between the study intervention and the event (possibly, probably, or definitely related). SAEs will also be periodically reviewed by an independent Data and Safety Monitoring Committee (DSMC). The DSMC consists of suitably qualified experts, including medical specialists and a biostatistician. There are no competing interests from the DSMC, and they remain independent from the study sponsor. A DSMC charter is kept within the study site file, only accessible to study personnel. Interim analysis of key efficacy and safety data will be undertaken by the DSMC when 50% of the projected total number of participants have been evaluated for the primary endpoint. The DSMC will meet after 25%, 50% and 100% of the projected total number of participants have been recruited. After each meeting the DSMC will make one of several recommendations that may include continuing the study, proposing protocol changes, extending recruitment, or stopping the study early. If protocol changes are required, the trial registry will be updated accordingly, and study personnel will be notified and provided with the new protocol. 3.11 Statistical analysis The criterion for success of the pilot study is that the definitive trial will be feasible if fidelity to the protocol is at least 70%. We expect protocol fidelity to be ~ 85%. With a sample size of 40, the estimated fidelity of 85% can be estimated with a 95% confidence interval of width 22% (74%-96%). The lower bound of this 95% confidence interval is above the specified level to claim success. If fidelity is less than that specified, reasons will be investigated, and the protocol modified accordingly. Consistent with published recommendations for pilot studies, we will refrain from a detailed inferential statistical analysis in this pilot study 38 . The sample size is based on the pragmatics of recruitment and the necessities for examining feasibility. Inclusion of HFO 2 as control group in this pilot is deliberate and will allow realistic examination of recruitment, randomisation, and implementation of interventions. Categorical variables will be summarised as frequencies (percentage) and continuous measures will be summarised as mean (standard deviation) or median (interquartile range) as appropriate. Binary primary outcome measures for each group will be presented with estimated proportions with 95% confidence intervals to convey precision. Kaplan-Meier curves will be plotted to explore time from enrolment to intubation or death in each group. For outcome measures with continuous repeated measures, within-group change, between-group differences, and differences in rates of change over time will be explored using mixed effects linear regression modelling. 4. DISCUSSION The use of IMV is increasing annually 4 , 5 but carries several risks to patients including VAP, adverse haemodynamic responses, and potential injuries to the upper airway and lung parenchyma 10 – 13 . Furthermore, significant increases in hospital and ICU LOS, and healthcare costs have been demonstrated for patients receiving IMV compared to non-ventilated patients 6 , 7 , 18 – 20 . Whilst the addition of iNO has demonstrated positive trends for reducing the need for IMV in certain patient populations 34 – 36 , these results remain inconsistent. The use of iNO with HFO2 offers a less invasive form of respiratory support. Reducing the incidence of IMV and IMV-related complications will improve the patient experience, patient outcomes, reduce ICU and hospital LOS 6 , and result in substantial cost saving for the health service. Without IMV, patients need not go into induced coma, can retain autonomy, eat, drink, exercise, and rehabilitate which may translate into better long-term physical, cognitive, and psychological outcomes. Equally, integrating patients’ feedback and self-reported experiences across groups is important to achieve appropriate health care decisions that integrate both health care staff and patients. 5. LIMITATIONS This single-centre, pilot study will sample 40 patients. As a pilot study, it is not powered to detect statistically significant differences in primary and/or secondary outcomes between groups. The ICU undertaking the study specialises in cardiothoracic medicine and surgery. Therefore, the results of the study may not be generalisable to other patient cohorts. With several consecutive timepoints allocated for blood collections to assess oxygenation and safety measures (Fig. 2), adherence in obtaining these measures may fluctuate, dependent on patient acuity. Finally, obtaining participant experience surveys may at times prove difficult, depending on factors like delirium and the level of respiratory distress a patient experiences at this timepoint. 6. TRIAL STATUS As at the time of writing this manuscript, the study has not commenced recruitment. The study protocol (version 2, 13th December 2024) has been approved by an authorised human research ethics committee (HREC/2024/MNHA/112848). Study recruitment is planned to commence June 2025 and be completed by December 2026. Declarations 7.1 Ethics approval and consent to participate This study has been approved by an authorised human research ethics committee (HREC/2024/MNHA/112848, protocol version 2) and is compliant with local legislative requirements. The study will be conducted in accordance with the ethical principles of human research outlined by the Declaration of Helsinki, the GCP guidelines, and in line with the local regulatory statements for ethical conduct of research at the study site. 7.2 Dissemination policy The results of this study will be published in a relevant and accepting peer-reviewed journal. Participants will not be identified in the dissemination of results. It is intended that the results of this study will be disseminated via scientific conference presentations, posters and the hospital, and publications. 7.3 Consent for publication Not applicable. 7.4 Availability of data and materials Not applicable. 7.5 Competing interests The authors declare that they have no competing interests. 7.6 Funding This trial is supported by a Clinical Research Fellowship from the University of Queensland. 7.7 Authors’ contributions LC : Lead author and corresponding author, responsible for conceptualisation, methodology, writing – original draft; OT : Responsible for conceptualisation, methodology, writing – review and editing; KH : Responsible for conceptualisation, methodology, writing – review and editing; PT : Responsible for conceptualisation, methodology, writing – review and editing; KS : Senior author, responsible for conceptualisation, methodology, writing – original draft. All authors read and approved the final manuscript. The authorship threshold stipulated by the International Committee of Medical Journal Editors (ICMJE) was also met by all authors. 7.8 Acknowledgements Nil acknowledgements to declare. References Esteban A, Anzueto A, Frutos F, Alía I, Brochard L, Stewart TE et al. Characteristics and outcomes in adult patients receiving mechanical ventilation: a 28-day international study. 2002;287(3):345–55. Wunsch H, Linde-Zwirble WT, Angus DC, Hartman ME, Milbrandt EB, Kahn JMJCcm. Epidemiol Mech Vent use United States. 2010;38(10):1947–53. Zhu Y, Yin H, Zhang R, Ye X, Wei J. High-flow nasal cannula oxygen therapy versus conventional oxygen therapy in patients after planned extubation: a systematic review and meta-analysis. Crit Care. 2019;23(1):1–12. Carson SS, Cox CE, Holmes GM, Howard A, Carey TSJJ. The changing epidemiology of mechanical ventilation: a population-based study. 2006;21(3):173–82. Needham DM, Bronskill SE, Calinawan JR, Sibbald WJ, Pronovost PJ, Laupacis AJCcm. 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Rossaint R, Falke KJ, Lopez F, Slama K, Pison U, Zapol WMJNEJoM. Inhaled nitric oxide for the adult respiratory distress syndrome. 1993;328(6):399–405. Teman NR, Thomas J, Bryner BS, Haas CF, Haft JW, Park PK et al. Inhaled nitric oxide to improve oxygenation for safe critical care transport of adults with severe hypoxemia. 2015;24(2):110–7. Gebistorf F, Karam O, Wetterslev J, Afshari A. Inhaled nitric oxide for acute respiratory distress syndrome (ARDS) in children and adults. Cochrane database Syst reviews. 2016(6). Sahni R, Ameer X, Ohira-Kist K, Wung JJJP. Non-invasive inhaled nitric oxide in the treatment of hypoxemic respiratory failure in term and preterm infants. 2017;37(1):54. Dellinger RP, Zimmerman JL, Taylor RW, Straube RC, Hauser DL, Criner GJ, et al. Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: results of a randomized phase II trial. Inhaled Nitric Oxide in ARDS Study Group. Crit Care Med. 1998;26(1):15–23. Michael JR, Barton RG, Saffle JR, Mone M, Markewitz BA, Hillier K, et al. Inhaled nitric oxide versus conventional therapy: effect on oxygenation in ARDS. Am J Respir Crit Care Med. 1998;157(5):1372–80. Mehta S, Simms H, Levy M, Hill N, Schwartz W, Nelson D, et al. Inhaled nitric oxide improves oxygenation acutely but not chronically in acute respiratory distress syndrome: a randomized, controlled trial. J Appl Res. 2001;1(2):73–84. Troncy E, Collet J-P, Shapiro S, Guimond J-G, Blair L, Ducruet T, et al. Inhaled nitric oxide in acute respiratory distress syndrome: a pilot randomized controlled study. Am J Respir Crit Care Med. 1998;157(5):1483–8. Karam O, Gebistorf F, Wetterslev J, Afshari A. The effect of inhaled nitric oxide in acute respiratory distress syndrome in children and adults: a Cochrane Systematic Review with trial sequential analysis. Anaesthesia. 2017;72(1):106–17. Chandel A, Patolia S, Ahmad K, Aryal S, Brown AW, Sahjwani D, et al. Inhaled Nitric Oxide via High-Flow Nasal Cannula in Patients with Acute Respiratory Failure Related to COVID-19. Clin Med Insights: Circ Respiratory Pulmonary Med. 2021;15:11795484211047065. Costabile P, Gelmini T, Martonick M, Hillock B, McNelly C, Romer L, et al. Use of High Flow Nasal Cannula with Inhaled Nitric Oxide During Pediatric Air Transport. Am Acad Pediatrics; 2018. Ismail A, Sharara-Chami R, El-Khatib MJA. care i. Combination of high-flow nasal cannula oxygen therapy and inhaled nitric oxide in a paediatric patient with respiratory distress. 2014;42(4):521. Akmal A, Hasan MJA. Role of nitric oxide in management of acute respiratory distress syndrome. 2008;3(3):100. Leon AC, Davis LL, Kraemer HCJJ. The role and interpretation of pilot studies in clinical research. 2011;45(5):626–9. Chan A-W, Tetzlaff JM, Altman DG, Laupacis A, Gøtzsche PC, Krleža-Jerić K, et al. SPIRIT 2013 statement: defining standard protocol items for clinical trials. Ann Intern Med. 2013;158(3):200–7. Eldridge SM, Chan CL, Campbell MJ, Bond CM, Hopewell S, Thabane L et al. CONSORT 2010 statement: extension to randomised pilot and feasibility trials. BMJ. 2016;355. Slattery M, Vasques F, Srivastava S, Camporota L. Management of acute respiratory failure. Medicine. 2020;48(6):397–403. Vincent J-L, Moreno R, Takala J, Willatts S, De Mendonça A, Bruining H, et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. Springer-; 1996. Tipping CJ, Bailey MJ, Bellomo R, Berney S, Buhr H, Denehy L, et al. The ICU mobility scale has construct and predictive validity and is responsive. A multicenter observational study. Annals Am Thorac Soc. 2016;13(6):887–93. Young J, Dyar O, Xiong L, Howell S. Methaemoglobin production in normal adults inhaling low concentrations of nitric oxide. Intensive Care Med. 1994;20(8):581–4. Raut M, Maheshwari A. Inhaled nitric oxide, methemoglobinemia, and route of delivery. Saudi J Anaesth. 2017;11(3). Taylor RW, Zimmerman JL, Dellinger RP, Straube RC, Criner GJ, Davis K Jr, et al. Low-dose inhaled nitric oxide in patients with acute lung injury: a randomized controlled trial. JAMA. 2004;291(13):1603–9. Lundin S, Mang H, Smithies M, Stenqvist O, Frostell C. Inhalation of nitric oxide in acute lung injury: results of a European multicentre study. Intensive Care Med. 1999;25(9):911–9. Mehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C, Warnock DG, et al. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care. 2007;11(2):1–8. National Health Medical Research Council. Safety monitoring and reporting in clinical trials involving therapeutic goods. Australian Government Canberra; 2016. Kendrick KR, Baxi SC, Smith RM. Usefulness of the modified 0–10 Borg scale in assessing the degree of dyspnea in patients with COPD and asthma. J Emerg Nurs. 2000;26(3):216–22. Frat J-P, Thille AW, Mercat A, Girault C, Ragot S, Perbet S, et al. High-flow oxygen through nasal cannula in acute hypoxemic respiratory failure. N Engl J Med. 2015;372(23):2185–96. Davey HM, Barratt AL, Butow PN, Deeks JJ. A one-item question with a Likert or Visual Analog Scale adequately measured current anxiety. J Clin Epidemiol. 2007;60(4):356–60. Supplementary Files APPENDICES.docx SPIRITFillablechecklist15Aug2013HONOR.doc Cite Share Download PDF Status: Published Journal Publication published 26 Nov, 2025 Read the published version in Pilot and Feasibility Studies → Version 1 posted Editorial decision: Minor revision 07 Aug, 2025 Reviewers agreed at journal 13 Jul, 2025 Reviewers invited by journal 10 Jul, 2025 Editor assigned by journal 05 May, 2025 First submitted to journal 01 May, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6574612","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":483696397,"identity":"6ccbea75-d7d6-4434-96ea-f3d1286cd4d5","order_by":0,"name":"Luke Churchill","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0002-7542-1331","institution":"The Prince Charles Hospital","correspondingAuthor":true,"prefix":"","firstName":"Luke","middleName":"","lastName":"Churchill","suffix":""},{"id":483696398,"identity":"6d84ca87-9996-4824-8bc8-bd1663db4be0","order_by":1,"name":"Oystein Tronstad","email":"","orcid":"","institution":"The Prince Charles Hospital","correspondingAuthor":false,"prefix":"","firstName":"Oystein","middleName":"","lastName":"Tronstad","suffix":""},{"id":483696399,"identity":"41667cf6-8ce9-41f6-a448-005bf2b2c38a","order_by":2,"name":"Karen Hay","email":"","orcid":"","institution":"QIMR: QIMR Berghofer Medical Research Institute","correspondingAuthor":false,"prefix":"","firstName":"Karen","middleName":"","lastName":"Hay","suffix":""},{"id":483696400,"identity":"f75feefc-1863-4cbb-8b42-44e147bde92a","order_by":3,"name":"Peter Thomas","email":"","orcid":"","institution":"Royal Brisbane and Woman's Hospital Health Service District: Royal Brisbane and Women's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Peter","middleName":"","lastName":"Thomas","suffix":""},{"id":483696401,"identity":"e3761416-4d20-47fb-b041-f6518f593306","order_by":4,"name":"Kiran Shekar","email":"","orcid":"","institution":"The Prince Charles Hospital","correspondingAuthor":false,"prefix":"","firstName":"Kiran","middleName":"","lastName":"Shekar","suffix":""}],"badges":[],"createdAt":"2025-05-02 00:16:24","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6574612/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6574612/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s40814-025-01726-1","type":"published","date":"2025-11-26T15:58:27+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":87028688,"identity":"cb27e371-a211-4ed8-911a-77a324a365c9","added_by":"auto","created_at":"2025-07-18 12:34:58","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":123383,"visible":true,"origin":"","legend":"\u003cp\u003eSchedule of enrolment and interventions.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6574612/v1/6cf51791af9b561d1dde4727.jpg"},{"id":87028689,"identity":"6b1bb43f-a3be-4a6e-8bd5-f7b3e67f3c0f","added_by":"auto","created_at":"2025-07-18 12:34:58","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":152514,"visible":true,"origin":"","legend":"\u003cp\u003eSchedule of assessments and collection of outcomes.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6574612/v1/8ee12a94ddb9d345a0fe2843.jpg"},{"id":97178597,"identity":"0ac63a1b-0c02-486c-9466-8b6b4aaaa331","added_by":"auto","created_at":"2025-12-01 16:11:18","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1038604,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6574612/v1/31f36478-586e-44c1-bf3b-cfdde7826fad.pdf"},{"id":87028692,"identity":"f38f0281-e17b-475c-9943-58da7451ec60","added_by":"auto","created_at":"2025-07-18 12:34:58","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":125466,"visible":true,"origin":"","legend":"","description":"","filename":"APPENDICES.docx","url":"https://assets-eu.researchsquare.com/files/rs-6574612/v1/e8d1f6a18ed5cab010de52f6.docx"},{"id":87028695,"identity":"ea51b26f-b540-4b3b-ad23-2720c1f87eb2","added_by":"auto","created_at":"2025-07-18 12:34:58","extension":"doc","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":125952,"visible":true,"origin":"","legend":"","description":"","filename":"SPIRITFillablechecklist15Aug2013HONOR.doc","url":"https://assets-eu.researchsquare.com/files/rs-6574612/v1/380bf5d5d60b153261fc29f6.doc"}],"financialInterests":"","formattedTitle":"High-flow Oxygen and Nitric Oxide inhalation versus high-flow oxygen alone to prevent intubation in hypoxaemic Respiratory failure (HONOR): a pilot randomised controlled trial protocol.","fulltext":[{"header":"1. INTRODUCTION","content":"\u003cp\u003eAcute hypoxaemic respiratory failure is a common and life-threatening consequence of a diverse group of conditions\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. When conventional oxygen therapies (COT) (\u0026le;\u0026thinsp;15 L/min oxygen via nasal prongs, cannula or mask)\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e or non-invasive ventilation (NIV) fail to correct hypoxaemia, invasive mechanical ventilation (IMV) is required. The use of IMV is common throughout the world and is increasing annually\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. Patients on IMV represent approximately 3% of acute hospitalisations and 30% of intensive care unit (ICU) admissions both internationally and in Australia\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. However, outcomes of IMV are highly dependent on factors such as aetiology, age, co-morbidities, and severity of illness\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eWhilst often a life-saving intervention, intubation and IMV are not without inherent risks. Risks include laryngeal injury, injury to lung parenchyma, adverse haemodynamic consequences (e.g., decreased venous return, blood pressure, and cardiac output) and predisposition to infection (e.g. ventilator-associated pneumonia (VAP))\u003csup\u003e\u003cspan additionalcitationids=\"CR11 CR12\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. Emergent endotracheal intubation also carries an especially high risk, with reported intubation-related cardiac arrest (occurring within 20 minutes after successful intubation) rates of up to 23%\u003csup\u003e14\u003c/sup\u003e. Despite evidence demonstrating a decrease in mortality rates over time, up to 30\u0026ndash;40% of patients receiving IMV will not survive their ICU admission\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e and many survivors experience reduced quality of life, impaired physical function, and increased psychological conditions such as depression, anxiety and post-traumatic stress disorder\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. Invasive mechanical ventilation is also associated with significant increases in hospital and ICU length of stay (LOS)\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e, with increased cost burden ranging from 25\u0026ndash;59% extra per ICU patient per day receiving IMV\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eReducing the incidence, risks, and costs associated with IMV is a major priority for healthcare providers, consumers, health system administrators, taxpayers, and policymakers\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. By averting an artificial airway and IMV, patients with acute respiratory failure (ARF) supported with less invasive means can often avoid intravenous sedation and costly complications, such as VAP, ICU-acquired weakness, and line sepsis\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. Avoiding intubation also facilitates patient-centric aims of early rehabilitation, speech, and oral feeding which may improve patient outcomes and reduce hospital and ICU LOS.\u003c/p\u003e\u003cp\u003eHigh-flow oxygen (HFO\u003csub\u003e2\u003c/sub\u003e) delivered through nasal cannula and NIV are routinely used in the treatment of ARF\u003csup\u003e\u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. In a randomised clinical trial in patients with ARF, HFO\u003csub\u003e2\u003c/sub\u003e therapy demonstrated a non-significant reduction in IMV compared with COT and NIV, however, resulted in a better 90-day survival\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. In this study, the rates of intubation were lowest in the HFO\u003csub\u003e2\u003c/sub\u003e therapy group (38%), compared with COT and NIV (47% and 50% respectively). The leading cause of intubation across groups (\u0026gt;\u0026thinsp;70%) was worsening ARF and hypoxaemia, warranting further investigation into the most optimal strategies to mitigate this.\u003c/p\u003e\u003cp\u003eThe addition of inhaled Nitric Oxide (iNO) to nasal HFO\u003csub\u003e2\u003c/sub\u003e may allow hypoxaemia to be corrected and potentially avoid IMV\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e. As a potent vasodilator, iNO has the ability to provide selective pulmonary vascular dilation in well-ventilated sections of the lungs, improving ventilation-perfusion mismatch\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. Significant improvements in oxygenation have been demonstrated in infants with ARF on nasal continuous positive airway pressure with iNO\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. Results within the adult population remain inconsistent, with short-term improvements in the ratio of the partial pressure of arterial oxygen (PaO\u003csub\u003e2\u003c/sub\u003e) to fraction of inspired oxygen (FiO\u003csub\u003e2\u003c/sub\u003e) ratio (PF) often being transient or not sustained\u003csup\u003e\u003cspan additionalcitationids=\"CR30 CR31 CR32\" citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e. However, the primary means of delivering iNO was either via COT or mechanical ventilation and not via nasal HFO\u003csub\u003e2\u003c/sub\u003e.\u003c/p\u003e\u003cp\u003eLiterature demonstrating the effects of iNO combined with HFO\u003csub\u003e2\u003c/sub\u003e (HFO\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;+\u0026thinsp;iNO) in the adult population remains sparse. One multi-centre cohort study evaluated the effectiveness of HFO\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;+\u0026thinsp;iNO in patients with respiratory failure from coronavirus disease (COVID-19)\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e. In this population, HFO\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;+\u0026thinsp;iNO did not reduce oxygen requirements in the majority of patients. However, a subset of patients considered responders (defined as a decrease in supplemental oxygen delivered via high-flow nasal cannula (HFNC) 12 hours after iNO initiation), had a trend toward decreasing need for IMV compared to non-responders\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e. Outside of this patient population, only case reports exist of the successful use of HFO\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;+\u0026thinsp;iNO for preventing IMV. These reports demonstrated improvements in oxygenation within the hospital setting and maintaining safe oxygen levels during transport to and from hospital\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e. Therefore, to further investigate the potential benefits of HFO\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;+\u0026thinsp;iNO in preventing IMV, further research is needed in its potential to reduce the need for IMV.\u003c/p\u003e"},{"header":"2. AIMS","content":"\u003cp\u003eThe aims of this pilot study are to examine the feasibility, intubation rates, and clinical outcomes when comparing HFO\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;+\u0026thinsp;iNO gas inhalation to HFO\u003csub\u003e2\u003c/sub\u003e alone in patients with hypoxaemic, non-hypercapnic ARF. Based on the physiologic rationale\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e, prior investigations\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e, and our anecdotal experience, we hypothesise that HFO\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;+\u0026thinsp;iNO therapy is superior to HFO\u003csub\u003e2\u003c/sub\u003e in preventing IMV in patients with ARF. This pilot study is a requisite initial step in exploring the proposed intervention\u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e in preparation for a larger scale, multi-centre definitive trial. The feasibility and safety outcomes of the study protocol will inform future budget and protocol development whilst providing initial effect estimates to inform sample size calculation.\u003c/p\u003e"},{"header":"3. METHODS","content":"\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n \u003ch2\u003e3.1 Design\u003c/h2\u003e\n \u003cp\u003eThis will be an open label, 1:1 parallel group, single-centre, pilot (n\u0026thinsp;=\u0026thinsp;40) randomised controlled trial. The study protocol has been reported using the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) statement guidelines\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e and the associated publication from the study will be reported in accordance with the CONSORT extension for randomised pilot and feasibility trials\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e. The SPIRIT figures (Figs.\u0026nbsp;1 and 2) outline the schedule of enrolment, interventions and assessments\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n \u003ch2\u003e3.2 Setting and sample\u003c/h2\u003e\n \u003cp\u003eThis study will be conducted in a 27-bed adult ICU at a large urban Australian tertiary referral hospital specialising in cardiothoracic surgery and medicine. As a pilot trial, it is not required to be powered to detect statistical significance. A sample of 40 eligible patients will be recruited over a period of 12\u0026ndash;18 months. Assuming the proportion of patients who progress to IMV is 0.38\u003csup\u003e24\u003c/sup\u003e, a sample of 20 per group will produce an exact 95% CI width of 0.44.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\n \u003ch2\u003e3.3 Recruitment and consent\u003c/h2\u003e\n \u003cp\u003ePatients presenting with type I acute hypoxaemic respiratory failure (PaO\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;\u0026lt;\u0026thinsp;60 mm Hg with normal or subnormal PaCO\u003csub\u003e2\u003c/sub\u003e)\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e will have arterial blood gas (ABG) sampling as per standard care for this patient cohort. Aligning with previous research investigating HFO\u003csub\u003e2\u003c/sub\u003e in ARF\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e, if the PF ratio is less than 300 mm Hg, they will be screened for suitability to participate in the study by a member of the research team. Written informed consent will be obtained from all suitable patients, their next of kin, or another substitute decision maker (SDM) as appropriate. Owing to the nature of their injury, potential participants are unlikely to have the capacity to provide written consent at the time of recruitment. Verbal consent from an SDM will be allowed if geographical or infection control visitor restrictions prevent face-to-face informed consent processes. Written consent will be sought later if a SDM is able to attend in person or are able to return a consent form provided to them via email. Should there be no SDM available initially, study procedures will be performed and consent to continue will be sought from the SDM, or the participant (should they regain capacity to consent) within a maximum of three days. Participants and/or their SDM can decline study assessments and discontinue participation at any time without explanation or penalty.\u003c/p\u003e\n \u003cp\u003eSimple random allocation will be applied, with participants allocated in a 1:1 ratio to either the control or intervention arm via a computer-generated random sequence program.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n \u003ch2\u003e3.4 Inclusion and exclusion criteria\u003c/h2\u003e\n \u003cp\u003ePatients will need to meet all inclusion criteria and no exclusion criteria (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e) to be eligible to participate.\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003cdiv align=\"left\" class=\"colspec\"\u003e\u003cbr\u003e\u003c/div\u003e\n \u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eInclusion/exclusion criteria for review.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eInclusion\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eExclusion\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026bull; Age\u0026thinsp;\u0026ge;\u0026thinsp;18 years\u003c/p\u003e\n \u003cp\u003e\u0026bull; Admitted to ICU\u003c/p\u003e\n \u003cp\u003e\u0026bull; \u003cem\u003eDe novo\u003c/em\u003e type I respiratory failure (hypoxaemia in the absence of chronic lung condition)\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003e\u0026bull; PF ratio\u0026thinsp;\u0026lt;\u0026thinsp;300 mm Hg\u003c/p\u003e\n \u003cp\u003e\u0026bull; High flow nasal cannula determined by ICU medical team to be primary method for delivery of oxygen therapy\u003c/p\u003e\n \u003cp\u003e\u0026bull; Anticipated HFO\u003csub\u003e2\u003c/sub\u003e requirement\u0026thinsp;\u0026gt;\u0026thinsp;24 hours\u003c/p\u003e\n \u003cp\u003e\u0026bull; Arterial line in-situ for blood gas sampling\u003c/p\u003e\n \u003cp\u003e\u0026bull; Ability to provide informed consent, or consent via a SDM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026bull; Congenital or acquired methaemoglobinaemia reductase deficiency\u003c/p\u003e\n \u003cp\u003e\u0026bull; Bleeding diathesis\u003c/p\u003e\n \u003cp\u003e\u0026bull; Intracranial haemorrhage\u003c/p\u003e\n \u003cp\u003e\u0026bull; Severe left ventricular failure\u003c/p\u003e\n \u003cp\u003e\u0026bull; Underlying chronic respiratory failure or exacerbation of asthma (including chronic obstructive pulmonary disease (COPD) or other chronic respiratory disease)\u003c/p\u003e\n \u003cp\u003e\u0026bull; Documented cardiogenic pulmonary oedema or acute coronary syndrome\u003c/p\u003e\n \u003cp\u003e\u0026bull; Hypercapnic respiratory failure with PaCO\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;\u0026gt;\u0026thinsp;45 mm Hg\u003c/p\u003e\n \u003cp\u003e\u0026bull; Deterioration of neurologic status demonstrated by Glasgow Coma Scale (GCS)\u0026thinsp;\u0026le;\u0026thinsp;12\u003c/p\u003e\n \u003cp\u003e\u0026bull; Urgent need for intubation (evaluated by the medical officer in charge)\u003c/p\u003e\n \u003cp\u003e\u0026bull; Haemodynamic instability (defined by systolic arterial blood pressure\u0026thinsp;\u0026lt;\u0026thinsp;90 mm Hg or mean arterial blood pressure\u0026thinsp;\u0026lt;\u0026thinsp;65 mm Hg)\u003c/p\u003e\n \u003cp\u003e\u0026bull; Use of vasopressors\u003c/p\u003e\n \u003cp\u003e\u0026bull; Do not intubate orders\u003c/p\u003e\n \u003cp\u003e\u0026bull; Enrolled in any other trial of targeted oxygen therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003eICU: intensive care unit; HFO\u003csub\u003e2\u003c/sub\u003e: high-flow oxygen; Hg: mercury; mm: millimetres; PaCO\u003csub\u003e2\u003c/sub\u003e: partial pressure of arterial carbon dioxide; PF: ratio of partial pressure of arterial oxygen to fraction of inspired oxygen; SDM: substitute decision maker.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003e3.5 Blinding\u003c/h2\u003e\n \u003cp\u003eDue to the nature of the interventions, participants receiving the interventions and the clinicians providing care will be aware of the treatment allocation. During the consent process, participants will be informed of the two interventions and be made aware that both are considered standard of care at the study site.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n \u003ch2\u003e3.6 Study interventions\u003c/h2\u003e\n \u003cp\u003eParticipants will receive one of two interventions: HFO\u003csub\u003e2\u003c/sub\u003e alone or HFO\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;+\u0026thinsp;iNO as detailed below.\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eHigh Flow Oxygen (HFO\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003c/sub\u003e\u003cstrong\u003e) alone (control group)\u003c/strong\u003e:\u003c/p\u003e\n \u003cul\u003e\n \u003cli\u003e\n \u003cp\u003eInitial FiO\u003csub\u003e2\u003c/sub\u003e set at 100% with an initial flow of 60 L/min\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eFiO\u003csub\u003e2\u003c/sub\u003e will be titrated down in the first hour, targeting oxygen saturation (SpO\u003csub\u003e2\u003c/sub\u003e)\u0026thinsp;\u0026gt;\u0026thinsp;92% and PaO\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;\u0026gt;\u0026thinsp;60 mm Hg\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eFurther reduction in FiO\u003csub\u003e2\u003c/sub\u003e every subsequent two hours maintaining SpO\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;\u0026gt;\u0026thinsp;92% and PaO\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;\u0026gt;\u0026thinsp;60 mm Hg\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eFlows will be reduced in increments of 10 L/min if needed for tolerance, to a minimum of 30 L/min\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eHeated humidification to ensure delivery of HFO\u003csub\u003e2\u003c/sub\u003e into the nares at a temperature set at 37\u0026deg;C\u003c/p\u003e\n \u003c/li\u003e\n \u003c/ul\u003e\n \u003cp\u003e\u003cstrong\u003eHigh Flow Oxygen and Nitric Oxide (HFO\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003c/sub\u003e\u0026thinsp;\u003cstrong\u003e+\u0026thinsp;iNO) (intervention group)\u003c/strong\u003e:\u003c/p\u003e\n \u003cp\u003eHigh flow oxygen therapy as described above, with the addition of:\u003c/p\u003e\n \u003cul\u003e\n \u003cli\u003e\n \u003cp\u003eiNO initially set at 20 parts per million (ppm) via HFNC by medical team, administered by ICU nursing staff, and weaned as per the following:\u003c/p\u003e\n \u003cul\u003e\n \u003cli\u003e\n \u003cp\u003eAfter 24 hours of study drug administration, wean iNO 1 ppm every 20 minutes or as directed by the treating ICU Consultant, provided:\u003c/p\u003e\n \u003cul\u003e\n \u003cli\u003e\n \u003cp\u003ePaO\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;\u0026gt;\u0026thinsp;60 mm Hg and SpO\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;\u0026gt;\u0026thinsp;92% for greater than 6 hours with an FiO\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;\u0026le;\u0026thinsp;50%\u003c/p\u003e\n \u003cul\u003e\n \u003cli\u003e\n \u003cp\u003eFiO\u003csub\u003e2\u003c/sub\u003e may be increased up to a maximum of 60% to compensate for any drop in oxygenation\u003c/p\u003e\n \u003c/li\u003e\n \u003c/ul\u003e\n \u003cp\u003e\u003c/p\u003e\n \u003c/li\u003e\n \u003c/ul\u003e\n \u003cp\u003e\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eIf nil decrement in oxygenation seen, iNO will be further weaned at a rate of 1 ppm/20 minutes to 0 ppm) or as directed by ICU Consultant\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eIf desaturation persists (SpO\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;\u0026lt;\u0026thinsp;92%) for \u0026gt;\u0026thinsp;15 minutes, iNO will be returned to the most recent level prior to weaning or escalated up to a maximum of 20 ppm to maintain patient oxygenation\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eiNO inhalation will be maintained if the patient in the HFO\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;+\u0026thinsp;iNO arm requires NIV\u003c/p\u003e\n \u003c/li\u003e\n \u003c/ul\u003e\n \u003cp\u003e\u003c/p\u003e\n \u003c/li\u003e\n \u003c/ul\u003e\n \u003cp\u003e\u003cstrong\u003eBlood sampling\u003c/strong\u003e:\u003c/p\u003e\n \u003cp\u003eAs per standard of care for patients with ARF within ICU, regular ABGs (approximately four to six per day) are collected via an arterial line to monitor several indices within the blood (such as PaO\u003csub\u003e2\u003c/sub\u003e, PaCO\u003csub\u003e2\u003c/sub\u003e, PF ratios, serum creatinine, and methaemoglobin (MetHb) levels). Further ABGs can also be requested by the medical treating team as clinically indicated. To monitor responses to therapy within the study, participants will have several ABGs completed at pre-determined timepoints (Fig.\u0026nbsp;1), most of which will occur as part of standard care within ICU. However, specific timepoints (such as six and 12 hours after study inclusion) may require additional ABGs. In these instances, approximately 4ml of blood will be collected from participants via their arterial line for analysis within ICU. No further ABGs will be collected if/when an arterial line is removed, therefore, negating the requirement of an arterial stab.\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eIntervention timing\u003c/strong\u003e:\u003c/p\u003e\n \u003cp\u003eTiming of interventions and assessments during the study will occur via the schedules outlined in Figs. 1 and 2.\u003c/p\u003e\n \u003cp\u003eEQ-5D-5L: EuroQol 5-Dimension 5-Level; hr: hour; HR: heart rate; ICU: intensive care unit; PaO\u003csub\u003e2\u003c/sub\u003e: partial pressure of arterial oxygen; PF: ratio of partial pressure of arterial oxygen to fraction of inspired oxygen; ROX: respiratory rate-oxygenation; RR: respiratory rate; SBP: systolic blood pressure; SpO\u003csub\u003e2\u003c/sub\u003e: oxygen saturation.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n \u003ch2\u003e3.7 Outcome measurements\u003c/h2\u003e\n \u003cp\u003eFeasibility outcomes\u003c/p\u003e\n \u003cp\u003ea) Eligibility (% of screened patients that meet criteria)\u003c/p\u003e\n \u003cp\u003eb) Recruitment (% of all eligible patients recruited using approved consent methods)\u003c/p\u003e\n \u003cp\u003ec) Retention (% of pts withdrawing consent)\u003c/p\u003e\n \u003cp\u003ed) Protocol fidelity (% of pts in intervention group receiving HFO\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;+\u0026thinsp;iNO for at least 22 hours a day (accounting for times where/if iNO is ceased (e.g. transport, investigations, mobility away from the bedspace))\u003c/p\u003e\n \u003cp\u003ePrimary outcomes\u003c/p\u003e\n \u003cp\u003ea) Number of patients in each arm progressed to IMV within 28 days\u003c/p\u003e\n \u003cp\u003eb) MetHb levels measured via ABGs at timepoints listed in Fig.\u0026nbsp;2\u003c/p\u003e\n \u003cp\u003ec) Daily serum creatinine and urine output levels to monitor renal function and/or renal impairment\u003c/p\u003e\n \u003cp\u003eSecondary Outcomes (Specific timepoints in Fig.\u0026nbsp;2)\u003c/p\u003e\n \u003cp\u003ea. Change in PaO\u003csub\u003e2\u003c/sub\u003e relative to baseline\u003c/p\u003e\n \u003cp\u003eb. Change in PF ratio relative to baseline\u003c/p\u003e\n \u003cp\u003ec. Physiological data\u003c/p\u003e\n \u003cp\u003eo Respiratory rate (RR)\u003c/p\u003e\n \u003cp\u003eo SpO\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\n \u003cp\u003eo Systolic blood pressure (SBP)\u003c/p\u003e\n \u003cp\u003eo Heart rate (HR)\u003c/p\u003e\n \u003cp\u003ed. Illness severity as estimated by daily sequential organ failure assessment (SOFA) scores\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e42\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003ee. Worst daily PF ratio\u003c/p\u003e\n \u003cp\u003ef. ROX index scores\u003c/p\u003e\n \u003cp\u003eg. Reason for intubation\u003c/p\u003e\n \u003cp\u003eo Respiratory failure\u003c/p\u003e\n \u003cp\u003eo Circulatory failure\u003c/p\u003e\n \u003cp\u003eo Neurological failure\u003c/p\u003e\n \u003cp\u003eo Surgery\u003c/p\u003e\n \u003cp\u003eh. Participant experience survey (Appendix 1)\u003c/p\u003e\n \u003cp\u003ei. ICU LOS\u003c/p\u003e\n \u003cp\u003ej. Hospital LOS\u003c/p\u003e\n \u003cp\u003ek. Mechanical ventilation hours\u003c/p\u003e\n \u003cp\u003el. Number of ventilator free days at day 28\u003c/p\u003e\n \u003cp\u003em. Time to mobilisation (minimum classification 4 (standing) on the ICU mobility scale)\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003en. Best mobility (within first 24 hours and during whole length of stay)\u003c/p\u003e\n \u003cp\u003eo. Daily delirium incidence (Confusion Assessment Method for the ICU (CAM-ICU) score)\u003c/p\u003e\n \u003cp\u003ep. Retrospective pre-ICU EuroQol 5-Dimension 5-Level (EQ-5D-5L) questionnaire\u003c/p\u003e\n \u003cp\u003eq. EQ-5D-5L (collected within 5\u0026ndash;7 days of discharge from the ICU)\u003c/p\u003e\n \u003cp\u003er. Need for anxiolytic and sedative medication during admission\u003c/p\u003e\n \u003cp\u003es. ICU mortality\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003e3.8 Data collection\u003c/h2\u003e\n \u003cp\u003eFeasibility data including eligibility and recruitment will be gained from the electronic screening log. The screening log will be used to document all patients who have been screened and identify those who consented to enrol in the study and those who were not enrolled, remarking the specific reason for exclusion. Data in relation to demography, physiology, admission severity of illness, haemodynamic data, details of haemodynamic support, and hepatic and renal functions will be collected by local data managers from electronic medical records.\u003c/p\u003e\n \u003cp\u003eSafety data will be collected for each patient including (i) MetHb levels, (ii) daily serum creatinine and urine output levels to monitor renal function and/or renal impairment, and (iii) adverse and serious adverse events (see section \u003cspan class=\"InternalRef\"\u003e3.9\u003c/span\u003e below for further details).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n \u003ch2\u003e3.9 Data handling and record keeping\u003c/h2\u003e\n \u003cp\u003eCase Report Forms (CRF\u0026rsquo;s) will be collected initially in hard copy before being transferred to an electronic format which will be stored on a password protected Queensland Health server. Paper documents will be stored in a secured locked cabinet at the study site under the supervision of the principal investigator and study coordinator. An electronic copy of the data will be maintained via a password protected spreadsheet, and the principal investigator and study coordinator will be responsible for its management.\u003c/p\u003e\n \u003cp\u003eThe study team will ensure all steps are taken to maintain confidentiality and security over the study documentation. Documents will be maintained for a minimum of 15 years following the completion of the study, as per Good Clinical Practice (GCP) guidelines.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n \u003ch2\u003e3.10 Safety considerations\u003c/h2\u003e\n \u003cdiv id=\"Sec14\" class=\"Section3\"\u003e\n \u003ch2\u003e3.10.1 Methaemoglobin levels across groups\u003c/h2\u003e\n \u003cp\u003eNitric oxide oxidizes heme iron to the ferric state, resulting in the formation of MetHb\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e44\u003c/span\u003e\u003c/sup\u003e. Methaemoglobin has higher oxygen affinity and decreased oxygen-carrying capacity due to fewer hemes to bind oxygen\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e. Safe levels of MetHb within previous trials for iNO are considered\u0026thinsp;\u0026lt;\u0026thinsp;5%\u003csup\u003e27\u003c/sup\u003e. Pooled data (1275 participants with ARDS receiving iNO) demonstrated MetHb levels\u0026thinsp;\u0026gt;\u0026thinsp;5% for four participants in the iNO group and three participants in the control group\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e. Whilst this risk remains extremely low, MetHb levels will be monitored in all participants in this study via ABGs during the timepoints listed in Fig.\u0026nbsp;2.\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv id=\"Sec15\" class=\"Section3\"\u003e\n \u003ch2\u003e3.10.2 Renal impairments across groups\u003c/h2\u003e\n \u003cp\u003ePrevious literature has demonstrated that iNO may induce renal impairment\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e. Depending on the definition, renal impairment in participants receiving iNO range from 5\u0026ndash;13%\u003csup\u003e29, \u003cspan class=\"CitationRef\"\u003e46\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e47\u003c/span\u003e\u003c/sup\u003e. However, of these results, only one study demonstrated a statistically significant increase in renal impairment in the intervention group when comparing to a control group of COT\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e47\u003c/span\u003e\u003c/sup\u003e. To further examine rates of renal impairment within this study, daily serum creatinine and urine output levels will be collected and compared across both groups. Renal impairment will be classified by the Acute Kidney Injury Network (AKIN) criteria\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e48\u003c/span\u003e\u003c/sup\u003e (Appendix 2).\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv id=\"Sec16\" class=\"Section3\"\u003e\n \u003ch2\u003e3.10.3 Adverse and serious events\u003c/h2\u003e\n \u003cp\u003eAny adverse event (AE) associated with the conduct of the study will be collected and reported to the study sponsor (Metro North Hospital and Health Service). Additionally, an annual safety report will be provided to the approving human research ethics committee in line with the local requirement at the study site.\u003c/p\u003e\n \u003cp\u003eThe defined AEs for the trial are:\u003c/p\u003e\n \u003cp\u003e\u0026bull; Renal complications (including new haemofiltration/dialysis and/or acute kidney injury defined by the AKIN classification/staging system of acute kidney injury, Appendix 2)\u003c/p\u003e\n \u003cp\u003e\u0026bull; MetHb levels\u0026thinsp;\u0026gt;\u0026thinsp;5%\u003c/p\u003e\n \u003cp\u003eSerious adverse events (SAEs):\u003c/p\u003e\n \u003cp\u003eThe definition of a SAE is one that fulfills at least one of the following:\u003c/p\u003e\n \u003cp\u003e\u0026bull; Is fatal - results in death\u003c/p\u003e\n \u003cp\u003e\u0026bull; Is life threatening\u003c/p\u003e\n \u003cp\u003e\u0026bull; Requires prolongation of existing hospitalisation\u003c/p\u003e\n \u003cp\u003e\u0026bull; Results in persistent or significant disability or incapacity\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e49\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003eGiven that critically ill patients are likely to meet any of the above listed criteria during their ICU admission, only SAE\u0026rsquo;s that are thought to be related to the study will be reported. SAE\u0026rsquo;s will be reported to the study sponsor within 24 hours of becoming aware of the event. For all events, a medically qualified study investigator will review the event and assign the causality relationship between the study intervention and the event (possibly, probably, or definitely related). SAEs will also be periodically reviewed by an independent Data and Safety Monitoring Committee (DSMC). The DSMC consists of suitably qualified experts, including medical specialists and a biostatistician. There are no competing interests from the DSMC, and they remain independent from the study sponsor. A DSMC charter is kept within the study site file, only accessible to study personnel. Interim analysis of key efficacy and safety data will be undertaken by the DSMC when 50% of the projected total number of participants have been evaluated for the primary endpoint. The DSMC will meet after 25%, 50% and 100% of the projected total number of participants have been recruited. After each meeting the DSMC will make one of several recommendations that may include continuing the study, proposing protocol changes, extending recruitment, or stopping the study early. If protocol changes are required, the trial registry will be updated accordingly, and study personnel will be notified and provided with the new protocol.\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\n \u003ch2\u003e3.11 Statistical analysis\u003c/h2\u003e\n \u003cp\u003eThe criterion for success of the pilot study is that the definitive trial will be feasible if fidelity to the protocol is at least 70%. We expect protocol fidelity to be ~\u0026thinsp;85%. With a sample size of 40, the estimated fidelity of 85% can be estimated with a 95% confidence interval of width 22% (74%-96%). The lower bound of this 95% confidence interval is above the specified level to claim success. If fidelity is less than that specified, reasons will be investigated, and the protocol modified accordingly.\u003c/p\u003e\n \u003cp\u003eConsistent with published recommendations for pilot studies, we will refrain from a detailed inferential statistical analysis in this pilot study\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e. The sample size is based on the pragmatics of recruitment and the necessities for examining feasibility. Inclusion of HFO\u003csub\u003e2\u003c/sub\u003e as control group in this pilot is deliberate and will allow realistic examination of recruitment, randomisation, and implementation of interventions.\u003c/p\u003e\n \u003cp\u003eCategorical variables will be summarised as frequencies (percentage) and continuous measures will be summarised as mean (standard deviation) or median (interquartile range) as appropriate. Binary primary outcome measures for each group will be presented with estimated proportions with 95% confidence intervals to convey precision. Kaplan-Meier curves will be plotted to explore time from enrolment to intubation or death in each group. For outcome measures with continuous repeated measures, within-group change, between-group differences, and differences in rates of change over time will be explored using mixed effects linear regression modelling.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"4. DISCUSSION","content":"\u003cp\u003eThe use of IMV is increasing annually\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e but carries several risks to patients including VAP, adverse haemodynamic responses, and potential injuries to the upper airway and lung parenchyma\u003csup\u003e\u003cspan additionalcitationids=\"CR11 CR12\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. Furthermore, significant increases in hospital and ICU LOS, and healthcare costs have been demonstrated for patients receiving IMV compared to non-ventilated patients\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. Whilst the addition of iNO has demonstrated positive trends for reducing the need for IMV in certain patient populations\u003csup\u003e\u003cspan additionalcitationids=\"CR35\" citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e, these results remain inconsistent.\u003c/p\u003e\u003cp\u003eThe use of iNO with HFO2 offers a less invasive form of respiratory support. Reducing the incidence of IMV and IMV-related complications will improve the patient experience, patient outcomes, reduce ICU and hospital LOS\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e, and result in substantial cost saving for the health service. Without IMV, patients need not go into induced coma, can retain autonomy, eat, drink, exercise, and rehabilitate which may translate into better long-term physical, cognitive, and psychological outcomes. Equally, integrating patients\u0026rsquo; feedback and self-reported experiences across groups is important to achieve appropriate health care decisions that integrate both health care staff and patients.\u003c/p\u003e"},{"header":"5. LIMITATIONS","content":"\u003cp\u003eThis single-centre, pilot study will sample 40 patients. As a pilot study, it is not powered to detect statistically significant differences in primary and/or secondary outcomes between groups. The ICU undertaking the study specialises in cardiothoracic medicine and surgery. Therefore, the results of the study may not be generalisable to other patient cohorts. With several consecutive timepoints allocated for blood collections to assess oxygenation and safety measures (Fig.\u0026nbsp;2), adherence in obtaining these measures may fluctuate, dependent on patient acuity. Finally, obtaining participant experience surveys may at times prove difficult, depending on factors like delirium and the level of respiratory distress a patient experiences at this timepoint.\u003c/p\u003e"},{"header":"6. TRIAL STATUS","content":"\u003cp\u003eAs at the time of writing this manuscript, the study has not commenced recruitment. The study protocol (version 2, 13th December 2024) has been approved by an authorised human research ethics committee (HREC/2024/MNHA/112848). Study recruitment is planned to commence June 2025 and be completed by December 2026.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cem\u003e7.1 Ethics approval and consent to participate\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThis study has been approved by an authorised human research ethics committee (HREC/2024/MNHA/112848, protocol version 2) and is compliant with local legislative requirements. The study will be conducted in accordance with the ethical principles of human research outlined by the Declaration of Helsinki, the GCP guidelines, and in line with the local regulatory statements for ethical conduct of research at the study site.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e7.2 Dissemination policy\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe results of this study will be published in a relevant and accepting peer-reviewed journal. Participants will not be identified in the dissemination of results. It is intended that the results of this study will be disseminated via scientific conference presentations, posters and the hospital, and publications.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e7.3 Consent for publication\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e7.4 Availability of data and materials\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e7.5 Competing interests\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e7.6 Funding\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThis trial is supported by a Clinical Research Fellowship from the University of Queensland.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e7.7 Authors’ contributions\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLC\u003c/strong\u003e: Lead author and corresponding author, responsible for conceptualisation, methodology, writing – original draft; \u003cstrong\u003eOT\u003c/strong\u003e: Responsible for conceptualisation, methodology, writing – review and editing; \u003cstrong\u003eKH\u003c/strong\u003e: Responsible for conceptualisation, methodology, writing – review and editing; \u003cstrong\u003ePT\u003c/strong\u003e: Responsible for conceptualisation, methodology, writing – review and editing; \u003cstrong\u003eKS\u003c/strong\u003e: Senior author, responsible for conceptualisation, methodology, writing – original draft. All authors read and approved the final manuscript. The authorship threshold stipulated by the International Committee of Medical Journal Editors (ICMJE) was also met by all authors.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e7.8 Acknowledgements\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eNil acknowledgements to declare.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eEsteban A, Anzueto A, Frutos F, Al\u0026iacute;a I, Brochard L, Stewart TE et al. Characteristics and outcomes in adult patients receiving mechanical ventilation: a 28-day international study. 2002;287(3):345\u0026ndash;55.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWunsch H, Linde-Zwirble WT, Angus DC, Hartman ME, Milbrandt EB, Kahn JMJCcm. Epidemiol Mech Vent use United States. 2010;38(10):1947\u0026ndash;53.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZhu Y, Yin H, Zhang R, Ye X, Wei J. 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Ann Intern Med. 2013;158(3):200\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eEldridge SM, Chan CL, Campbell MJ, Bond CM, Hopewell S, Thabane L et al. CONSORT 2010 statement: extension to randomised pilot and feasibility trials. BMJ. 2016;355.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSlattery M, Vasques F, Srivastava S, Camporota L. Management of acute respiratory failure. Medicine. 2020;48(6):397\u0026ndash;403.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVincent J-L, Moreno R, Takala J, Willatts S, De Mendon\u0026ccedil;a A, Bruining H, et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. Springer-; 1996.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTipping CJ, Bailey MJ, Bellomo R, Berney S, Buhr H, Denehy L, et al. The ICU mobility scale has construct and predictive validity and is responsive. A multicenter observational study. Annals Am Thorac Soc. 2016;13(6):887\u0026ndash;93.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYoung J, Dyar O, Xiong L, Howell S. Methaemoglobin production in normal adults inhaling low concentrations of nitric oxide. Intensive Care Med. 1994;20(8):581\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRaut M, Maheshwari A. Inhaled nitric oxide, methemoglobinemia, and route of delivery. Saudi J Anaesth. 2017;11(3).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTaylor RW, Zimmerman JL, Dellinger RP, Straube RC, Criner GJ, Davis K Jr, et al. Low-dose inhaled nitric oxide in patients with acute lung injury: a randomized controlled trial. JAMA. 2004;291(13):1603\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLundin S, Mang H, Smithies M, Stenqvist O, Frostell C. Inhalation of nitric oxide in acute lung injury: results of a European multicentre study. Intensive Care Med. 1999;25(9):911\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C, Warnock DG, et al. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care. 2007;11(2):1\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNational Health Medical Research Council. Safety monitoring and reporting in clinical trials involving therapeutic goods. Australian Government Canberra; 2016.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKendrick KR, Baxi SC, Smith RM. Usefulness of the modified 0\u0026ndash;10 Borg scale in assessing the degree of dyspnea in patients with COPD and asthma. J Emerg Nurs. 2000;26(3):216\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFrat J-P, Thille AW, Mercat A, Girault C, Ragot S, Perbet S, et al. High-flow oxygen through nasal cannula in acute hypoxemic respiratory failure. N Engl J Med. 2015;372(23):2185\u0026ndash;96.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDavey HM, Barratt AL, Butow PN, Deeks JJ. A one-item question with a Likert or Visual Analog Scale adequately measured current anxiety. J Clin Epidemiol. 2007;60(4):356\u0026ndash;60.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"pilot-and-feasibility-studies","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pafs","sideBox":"Learn more about [Pilot and Feasibility Studies](http://pilotfeasibilitystudies.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/PAFS/default.aspx","title":"Pilot and Feasibility Studies","twitterHandle":"@MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Acute respiratory failure, endotracheal intubation, invasive mechanical ventilation, inhaled nitric oxide, high-flow oxygen, oxygen therapy","lastPublishedDoi":"10.21203/rs.3.rs-6574612/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6574612/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e\u0026nbsp; When conventional oxygen therapies fail, endotracheal intubation and invasive mechanical ventilation are the current standard of care in patients with acute hypoxaemic respiratory failure. However, invasive mechanical ventilation is associated with increased hospital and intensive care length of stay, healthcare costs, and morbidity and mortality. Inhaled nitric oxide has the potential to treat hypoxaemia and potentially prevent the need for invasive mechanical ventilation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAims and objectives\u003c/strong\u003e: The objective of this study is to examine the feasibility and effectiveness of high-flow oxygen and nitric oxide gas inhalation compared with high-flow oxygen alone in preventing invasive mechanical ventilation for patients with acute hypoxaemic respiratory failure.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e In this pilot, randomised controlled feasibility study, 40 patients admitted to the intensive care unit with acute hypoxaemic respiratory failure will be randomised on a 1:1 ratio to receive one of two interventions: high-flow oxygen and nitric oxide gas inhalation (intervention) or high-flow oxygen alone (control) via high-flow nasal cannula. Feasibility, demographic, outcome, and safety data will be collected at several timepoints during participants’ admission.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDiscussion:\u003c/strong\u003e This protocol outlines a structured method for investigating the effects of inhaled nitric oxide gas in preventing invasive mechanical ventilation for patients with acute hypoxaemic respiratory failure. Considering the risks, costs, and poorer outcomes associated with invasive mechanical ventilation, less invasive means of respiratory support warrant further investigation. The study will assist in planning a larger, multi-centre definitive trial.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration:\u003c/strong\u003e This study is registered on the Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12622001411730. Registered 4\u003csup\u003eth\u003c/sup\u003e September 2022, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=384881\u003c/p\u003e","manuscriptTitle":"High-flow Oxygen and Nitric Oxide inhalation versus high-flow oxygen alone to prevent intubation in hypoxaemic Respiratory failure (HONOR): a pilot randomised controlled trial protocol.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-18 12:34:53","doi":"10.21203/rs.3.rs-6574612/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Minor revision","date":"2025-08-07T14:12:03+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2025-07-13T05:16:56+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-07-10T20:33:23+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-05-05T12:17:41+00:00","index":"","fulltext":""},{"type":"submitted","content":"Pilot and Feasibility Studies","date":"2025-05-01T20:15:45+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"pilot-and-feasibility-studies","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pafs","sideBox":"Learn more about [Pilot and Feasibility Studies](http://pilotfeasibilitystudies.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/PAFS/default.aspx","title":"Pilot and Feasibility Studies","twitterHandle":"@MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"0c0eb21b-3537-4964-a189-847180b67d2f","owner":[],"postedDate":"July 18th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-12-01T16:04:19+00:00","versionOfRecord":{"articleIdentity":"rs-6574612","link":"https://doi.org/10.1186/s40814-025-01726-1","journal":{"identity":"pilot-and-feasibility-studies","isVorOnly":false,"title":"Pilot and Feasibility Studies"},"publishedOn":"2025-11-26 15:58:27","publishedOnDateReadable":"November 26th, 2025"},"versionCreatedAt":"2025-07-18 12:34:53","video":"","vorDoi":"10.1186/s40814-025-01726-1","vorDoiUrl":"https://doi.org/10.1186/s40814-025-01726-1","workflowStages":[]},"version":"v1","identity":"rs-6574612","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6574612","identity":"rs-6574612","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}