High-flow Oxygen and Nitric Oxide inhalation versus high-flow oxygen alone on the incidence of intubation in hypoxaemic Respiratory failure (HONOR): a pilot randomised controlled trial.

INTERVENTION: High‐flow oxygen (HFO2) combined with Nitric Oxide (NO) gas as per the following protocol: • Initial fraction of inspired oxygen (FiO2) set at 100% with an initial flow of 60L/min • NO set at 20 parts per million (ppm) via high‐flow nasal cannula (HFNC) as per local clinical work unit guideline. NO will be initiated by ICU nursing staff following medical approval. *Ratio of oxygen to nitric oxide is not calculable due to differences in units of measurement. • HFO2+NO support for a minimum of 24 hours, initiated as soon as possible following consent to trial. However, if emergency treatment is required rapidly, and the involvement in the research carries no more risk to participants than not participating, a consent waiver may be initiated, until a time point where the patient or their substitute decision maker can give informed consent. • HFO2+NO will be delivered with humidification (approximately 98% humidity delivered at 37°C to the nares) • Flows down‐titrated in increments of 10L/min if needed for tolerance, to a minimum of 30L/min corresponding with FiO2 listed in the table below: Flow rate FiO2 50‐60L/min 0.6 – 1.0 40L/min 0.4‐0.6 30L/min 0.21‐0.4 • After 24 hours, wean NO 1ppm every 20 minutes as per local clinical work unit guideline or as directed by the ICU Consultant • Audits of electronic notes (capturing continuous measures) within ICU will occur to assess adherence to the intervention. CONDITION: Respiratory ‐ Other respiratory disorders / diseases Respiratory Failure; ; Respiratory Failure PRIMARY OUTCOME: Feasibility (eligibility, recruitment, retention, protocol fidelity, missing data) as a composite primary measure.; ; Feasibility data will be specifically collected via paper case report forms capturing the following data:; ; a. Eligibility (% of screened patients that meet criteria); b. Recruitment (% of all eligible patients recruited using approved consent methods); c. Retention (% of patients withdrawing consent); d. Protocol fidelity (% of patients in intervention group receiving HFO2 + NO for at least 18 hours a day); e. Missing data (% of primary and secondary outcome data unable to be collected); [Assessed at the completion of the trial.] Number of patients in each arm progressed to invasive mechanical ventilation as assessed bu review of medical records.[Within 28 days of enrolment to study.] Serious Adverse Events (SAEs).; ; The definition of a serious adverse event (SAE) is one that fulfils at least one of the following criteria:; ; • Is fatal‐ results in death ; • Is life threatening; • Requires inpatient hospitalisation or prolongation of existing hospitalisation; • Results in persistent or significant disability/incapacity; [Assessed daily for the duration of the patient's hospital admission (including ICU and inpatient stay on ward or rehabilitation up to 28 days) via electronic medical records.] INCLUSION CRITERIA: • Age greater than or equal to 18 years, meeting the following criteria o De novo type I respiratory failure (hypoxaemia in the absence of chronic lung condition) (41) o PF ratio <300mmHg o High flow nasal cannula determined by ICU medical team to be primary method for delivery of oxygen therapy o Anticipated high‐flow oxygen (HFO2) requirement >24 hours o Arterial line in‐situ for blood gas sampling • Ability to provide informed consent, or consent via a substitute decision maker o Where emergency treatment is required rapidly, and the involvement in the research carries no more risk to participants than not participating, a consent waiver may be initiated, until a time point where the patient or their substitute decision maker can give informed consent SECONDARY OUTCOME: Any change in partial pressure of arterial oxygen (PaO2) assessed by arterial blood gas.[Baseline, between four to si Xhours, 12 hours, 24 hours and 48 hours post‐commencement of intervention.] Best mobility on the ICU mobility score, as assessed by review of electronic medical records.[Within first 24 hours of ICU admission and during whole hospital length of stay.] Delirium incidence as assessed by the Confusion Assessment method for the ICU (CAM‐ICU score) and recorded in the electronic medical records.[Daily for the duration of ICU admission.] Dyspnoea scores as assessed by a modified BORG scale.[Baseline and one hour post intervention.] Heart rate assessed by review of electronic medical records.[Baseline, between four to si Xhours, 12 hours, 24 hours and 48 hours post‐commencement of intervention.] Hospital length of stay as assessed by review of medical records.[On day of discharge from hospital.] Illness severity as estimated by sequential organ failure assessment (SOFA) score.[Daily for the duration of ICU admission.] Intensive care unit (ICU) length of stay (LOS) as assessed by review of electronic medical records.[At completion of ICU admission.] Mechanical ventilation hours as assessed by review of electronic medical records.[Within 28 days of ICU admission.] Methaemaglobin levels (primary outcome).[Measured via arterial blood gas at inclusion, and then one hour, between four to si Xhours, 12 hours, 24 hours and 48 hours after randomisation.] Mortality.[During ICU stay.] Mortality.[Within 90 days of randomisation.] Need for anxiolytic and sedative medication as a composite measure, assessed by review of the electronic medical records.[During hospital admission.] Number of ventilator free days as assessed by review of electronic medical records.[Within 28 days of ICU admission.] Oxygen saturations assessed by review of electronic medical records. [Baseline, between four to si Xhours, 12 hours, 24 hours and 48 hours post‐commencement of intervention.] Reason for intubation as assessed by review of electronic medical records.[Within 28 days post‐commencement of intervention.] Respiratory rate as assessed by review of electronic medical records.[Baseline, between four to si Xhours, 12 hours, 24 hours and 48 hours post‐commencement of intervention.] Respiratory rate‐oxygenation (ROX) inde Xscores as assessed by review of electronic medical records.[Baseline, between four to si Xhours, 12 hours, 24 hours and 48 hours post‐commencement of intervention.] Serum creatinine levels (primary outcome).[Daily, assessed by routine blood test in ICU.] Systolic blood pressure assessed by review of electronic medical records[Baseline, between four to si Xhours, 12 hours, 24 hours and 48 hours post‐commencement of intervention.] Time to mobilisation (Classification 4 (standing) on the ICU mobility score).[Within 28 days of ICU admission.] Urine output levels (primary outcome).[Daily, assessed by review of electronic medical records.] Worst partial pressure of arterial oxygen to fraction of inspired oxygen (PF) ratio as assessed by review of electronic medical records.[Daily for the duration of ICU admission.]