ROX Index for the Timing of Intubation in Nasal High Flow (ROX-1)

ROX Index Compared to Standard of Care for the Timing of Intubation in Patients Supported by Nasal High Flow: a Randomized Controlled Trial

Late or delayed intubation in patients with acute hypoxemic respiratory failure (AHRF) treated with nasal high flow (NHF) is associated with increased patient mortality. The ROX index has been designed and validated to predict outcome of NFH therapy by identifying those patients with a high risk of NHF failure and those with a high probability of success. Whether or not the ROX index may improve patient outcome remains to be shown. To do so, a strategy using the ROX index must lead to earlier intubation than commonly-used criteria.

The objective of the ROX-1 trial is to assess whether the use of an algorithm incorporating the ROX index to standard of care for the time to intubation in patients with AHRF supported with NHF isassociated with an increase in the proportion of patients who are intubated within the first 12 hours among those patients who fail on NHF.

Study Overview

• Status: Recruiting
• Conditions: Acute Hypoxemic Respiratory Failure
• Intervention / Treatment: Diagnostic test: ROX index algorithm

Detailed Description

This is a pilot study to assess whether the use of an algorithm incorporating the ROX index to traditional criteria for intubation in patients with AHRF supported with NHF is:(i) feasible; (ii) associated with a decreased time to intubation.

The ROX-1 trial is an international, multicenter, parallel, open-label randomized controlled two-arm trial that will be performed in patients with AHRF, supported by nasal high flow, who are admitted to the intensive care unit (ICU). Ethics approval will be sought from each participating institution before starting enrolmentand consent will be obtained for each patient. The coordinating center will be Hospital Universitari Vall d'Hebron in Barcelona, Spain.

All consecutive patients older than 18 years with acute hypoxemic respiratory failure who need to be supported with nasal high flow (NHF) will be enrolled if they meet all the following criteria:

1. Respiratory rate > 25 breaths/min
2. A pulse oximetry (SpO2)<92% while receiving standard oxygen administered through a facemask at 10L/min or more.
3. Pulmonary infiltrate on chest X-ray.

Patients already treated with NHF for acute respiratory failure prior to ICU admission will be enrolled if duration of NHF prior to randomization does not exceed one hour.

Non-inclusion criteria are: Patients younger than 18 years old, Patients with indication for immediate intubation, patients with do not intubate order, patients electively intubated for diagnostic or therapeutic procedure (fibrobronchoscopy, surgery), patient with post-extubation AHRF, awake ECMO, pregnancy and refusal to participate or participation in another interventional study with the same primary outcome. Reasons for non-inclusion in screend patients will be registered.

Patients admitted to the ICU with acute hypoxemic respiratory failure will be screened, included after having received study information, and signed informed consent. They will be randomized after stratification according to PaO2/FiO2, through an online 4 automatic centralized and computerized system to one of the study groups (1:1 ratio): traditional intubation criteria or traditional intubation criteria + ROX criteria. Due to the nature of the intervention, blinding will not be feasible.

Randomization will be stratified to PaO2/FiO2 in order to analyse separately those patients with a PaO2/FiO2 ratio ≤ 200 and > 200. Intubation criteria for each study arm HFNC failure will be defined as the subsequent need for invasive MV. After randomization, clinicians will set NHF to the maximum tolerated flow (up to 60L/min) and FIO2 will be titrated targeting a SpO2 between 94-98% (88-92% in case of underlying chronic lung disease). In both groups, the presence of intubation criteria will be assessed every two hours during the first 12 hours after randomization and after any clinical deterioration. Between 12 and 24 hours of NHF therapy, the presence of intubation criteria will be assessed every 4 hours. Beyond the first 24 hours after randomization, the presence of intubation criteria will be assessed once a day and after any clinical deterioration.

In the intervention arm, patients will be intubated according to both the traditional intubation criteria and the ROX index, which ever are met first. Moreover, during the first two hours of NHF supportive therapy after randomization, the ROX index will be measured every 30 minutes. If the patient has a ROX index <2.85, the NHF support will be increased to the maximum tolerated flow (up to 60L/min) and FIO2 of 1 and subsequently titrated with the target SpO2. Then, the ROX index will be recalculated in 30 minutes. If the patient is already treated with to 60L/min and FIO2 of 1 and no further increase could be done, the ROX index will be recalculated after 30 minutes of full NHF support. Then: 1) if the ΔROX is <0 the patient will be intubated; 2) if the ΔROX is 0-0.5, the ΔROX will be assessed in 30 minutes; and 3) if the ΔROX is >0.5 the patient will not be intubated, NHF will be managed as protocolized and respiratory condition will be reassessed every two hours or at any new clinical deterioration.

Between the 2 and 6 hours after randomization, the ROX index will be measured every 60 minutes. If the ROX index is <3.47, the NHF support will be also increased to the maximum tolerated flow (up to 60L/min) and FIO2 of 1 and subsequently titrated with the target SpO2. If the patient is already treated with to 60L/min and FIO2 of 1 and no further increase could be done and the ROX index will be recalculated after 30 minutes of full NHF support. As described before, the ROX index will be recalculated in 30 minutes: 1) if the ΔROX is <0 the patient will be intubated; 2) if the ΔROX is 0-0.5, the ΔROX will be reassessed in 20 minutes; and 3) if the ΔROX is >0.5 the patient will not be intubated, NHF will be managed as protocolized and respiratory condition will be reassessed hourly or at any new clinical deterioration.

Finally, between the 6 and 12 hours after randomization, the ROX index will be measured every 60 minutes. If the ROX index is <3.85, the NHF support will be increased to the maximum tolerated flow (up to 60L/min) and FIO2 of 1 and subsequently titrated with the target SpO2. If the patient is already treated with to 60L/min) and FIO2 of 1 and no further increase could be done and the ROX index will be recalculated after 30 minutes of full NHF support. Then, the ROX index will be calculated in 30 minutes and decision of intubation will be taken according to the previously described ΔROX. In the ROX group, if there is any clinical deterioration beyond the first 12 hours of treatment , the algorithm should be restarted from the beginning, considering time 0 as the time when new clinical deterioration started. End of follow-up. Enrolled patients will be followed for one month or until ICU discharge or death, whichever occurs first.

• Study Type: Interventional
• Enrollment (Estimated): 630
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Oriol Roca, MD PhD; Phone Number: +34932746209; Email: oroca@tauli.cat

Study Locations

• China
  • Chongqing, China
    • Not yet recruiting
    • First Affiliated Hospital of Chongqing Medical University
    • Contact: Jun Duan; Phone Number: MD; Email: 1062914316@qq.com
    • Principal Investigator: Jun Duan, MD
  • Shanghai, China
    • Not yet recruiting
    • Zhongshan Hospital, Fudan University
    • Contact: Ming Zhong, MD; Email: zhong.ming@zs-hospital.sh.cn
    • Principal Investigator: Ming Zhong, MD
    • Sub-Investigator: Huan Wang, MD
  • Shanghai, China
    • Recruiting
    • The Second Military Medical University Hospital
    • Sub-Investigator: Jun Wang, MD
    • Contact: Wei Zhang, MD PhD; Email: zhangweismmu@126.com
    • Principal Investigator: Wei Zhang, MD PhD
• Spain
  • Barcelona, Spain, 08035
    • Recruiting
    • Hospital Universitari Vall d'Hebron
    • Contact: Andrés Pacheco Reyes, MD; Email: andres_pacheco19@hotmail.com
    • Contact: Email: andresfrancisco.pacheco@vallhebron.cat
    • Principal Investigator: Andrés Pacheco Reyes, MD
    • Sub-Investigator: Francisco Ramos, MD
    • Sub-Investigator: Mauro Acuña, MD
  • Barcelona, Spain
    • Recruiting
    • Hospital del Mar
    • Principal Investigator: Joan R Masclans, MD PhD
    • Sub-Investigator: Irene Dot, MD
    • Contact: Irene Dot, MD; Email: idot@psmar.cat
  • Ciudad Real, Spain
    • Recruiting
    • Hospital de Ciudad Real
    • Contact: Ramón Ortiz; Email: ramonortiz1980@hotmail.com
    • Principal Investigator: Ramón Ortiz, MD
  • Guadalajara, Spain
    • Recruiting
    • Hospital Civil Fray Antonio Alcalde
    • Contact: Miguel Ibarra, MD; Email: drmiguelibarra@hotmail.com
    • Principal Investigator: Miguel Ibarra, MD
  • Palma De Mallorca, Spain
    • Recruiting
    • Hospital Son Llatzer
    • Principal Investigator: Gemma Rialp, MD PhD
    • Contact: Gemma Rialp, MD PhD; Email: grialp@gmail.com
  • Sabadell, Spain
    • Recruiting
    • Hospital Parc Tauli
    • Sub-Investigator: Marina García, MD
    • Principal Investigator: Oriol Roca, MD PhD
    • Contact: Oriol Roca, MD PhD; Email: oroca@tauli.cat
    • Sub-Investigator: Mireia Cerdà, MD
  • Sant Joan Despí, Spain, 08970
    • Recruiting
    • Hospital Moisès Broggi
    • Sub-Investigator: Edgar Cortés, MD
    • Contact: Melinda Popoviciu, MD; Email: melindarita.popoviciukoborzan@sanitatintegral.org
    • Principal Investigator: Melinda Popoviciu, MD
  • Toledo, Spain
    • Recruiting
    • Hospital Virgen de la Salud
    • Principal Investigator: Gonzalo Hernández, MD PhD
    • Contact: Gonzalo Hernández, MD PhD; Email: ghernandezm@telefonica.net
• United States
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Recruiting
      • Rush University Chicago Hospital
      • Contact: Jie Li, MD PhD; Email: jie_li@rush.edu
      • Principal Investigator: Jie Li, MD PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 120 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• All consecutive patients older than 18 years with acute hypoxemic respiratory failure who need to be supported with nasal high flow (NHF) will be considered for inclusion.

  • Criteria for initiation of NHF if they had a respiratory rate > 25 breaths/min and/or pulse oximetry (SpO2) < 92% while receiving standard oxygen administered through a facemask at 10 L/mn or more.
  • Patients already treated with NHF for acute respiratory failure prior to ICU admission will be enrolled if duration of NHF prior to randomization does not exceed one hour.

Exclusion Criteria:

• Patients younger than 18 years old.
• Patients with indication for immediate intubation.
• Patients treated with NHF for more than 1h prior to randomization.
• Patients with do-not-intubate order.
• Patients electively intubated for diagnostic or therapeutic procedures. (fibrobronchoscopy, surgery).
• Patients with no pulmonary infiltrates on chest X-ray
• Patient with post-extubation AHRF.
• Awake ECMO.
• Pregnancy.
• Refusal to participate or participation in another interventional study with the same primary outcome.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Standard of care; Patients will be intubated according to both the standard of care
Experimental: Standard of care + ROX algorithm; In the intervention arm, patients will be intubated according to both the standard of care and the ROX index, whichever are met first. If the patient has a ROX index below different thresholds after different time-point within the first 12 hours since randomization, the NHF support will be increased to the maximum tolerated flow (up to 60L/min) and FIO2 of 1 and subsequently titrated with the target SpO2. Then, the ROX index will be recalculated in 30 minutes. If the patient is already treated with to 60L/min) and FIO2 of 1 and no further increase could be done, the ROX index will be recalculated after 30 minutes of full NHF support. Then: 1) if the ΔROX is <0 the patient will be intubated; 2) if the ΔROX is 0-0.5, the ΔROX will be reassessed in 30 minutes; and 3) if the ΔROX is >0.5 the patient will not be intubated, NHF will be managed as protocolized and respiratory condition will be reassessed every two hours or at any new clinical deterioration.	Diagnostic test: ROX index algorithm; The thresholds of the ROX index for intubation are the following: After 2 hours of HFNC: ROX <2.85.; After 4 and 6 hours of HFNC: ROX <3.47; After 8, 10 and 12 hours of HFNC: ROX <3.85 If the ROX index is between the abovementioned thresholds and 4.88, the NHF support will be also increased to the maximum tolerated flow (up to 60L/min) and FIO2 of 1 and subsequently titrated with the target SpO2. If the patient is already treated with to 60L/min) and FIO2 of 1 and no further increase could be done and the ROX index will be recalculated after 30 minutes of full NHF support. The ROX index will be recalculated in 30 minutes: 1) if the ΔROX is <0 the patient will be intubated; 2) if the ΔROX is 0-0.5, the ΔROX will be reassessed in 20 minutes; and 3) if the ΔROX is >0.5 the patient will not be intubated, NHF will be managed as protocolized and respiratory condition will be reassessed every two hours or at any new clinical deterioration.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Early intubation	Proportion of patients who will be intubated in the first 12 hours after inclusion between the two groups	12 hours since HFNC onset

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intubation rate	Rate of total intubations (early plus late)	Through ICU length of stay, an average of 30 days
28-day mortality	Mortality within the first 28 days since randomization	28 days
ICU mortality	Mortality in the ICU	Through ICU length of stay, an average of 30 days
Hospital mortality	Mortality in the hospital	Through hospital length of stay, an average of 45 days
Ventilator-free days within the first 28 days	Days free of mechanical ventilation in the first 28 days in those patients who needed to be intubated	28 days since the intubation
Use of rescue treatments	Need for rescue therapies for refractory hypoxemia	Through ICU length of stay, an average of 30 days
Need for tracheotomy	Need for tracheotomy	Through ICU length of stay, an average of 30 days
ICU length of stay	Days admitted in the ICU	Through ICU length of stay, an average of 30 days
Hospital length of stay	Days admitted in the hospital	Through hospital length of stay, an average of 45 days
Rate of complications during tracheal intubation	Proportion of complications that appear during endotracheal intubation in those patients who fail	Through ICU length of stay, an average of 30 days
90-day mortality	Mortality within the first 90 days since randomization	90 days
Days free of respiratory support within the first 28 days	Days free of respiratory support (including HFNC, CPAP, NIV or invasive mechanical ventilation) in the first 28 days	28 days since randomization

Collaborators and Investigators

• Sponsor: Hospital Universitari Vall d'Hebron Research Institute
• Investigators: Principal Investigator: Oriol Roca, MD PhD, Universitat Autònoma de Barcelona (UAB)

Publications and helpful links

General Publications

• Brochard L, Mancebo J, Wysocki M, Lofaso F, Conti G, Rauss A, Simonneau G, Benito S, Gasparetto A, Lemaire F, et al. Noninvasive ventilation for acute exacerbations of chronic obstructive pulmonary disease. N Engl J Med. 1995 Sep 28;333(13):817-22. doi: 10.1056/NEJM199509283331301.
• Roca O, Caralt B, Messika J, Samper M, Sztrymf B, Hernandez G, Garcia-de-Acilu M, Frat JP, Masclans JR, Ricard JD. An Index Combining Respiratory Rate and Oxygenation to Predict Outcome of Nasal High-Flow Therapy. Am J Respir Crit Care Med. 2019 Jun 1;199(11):1368-1376. doi: 10.1164/rccm.201803-0589OC.
• Roca O, Messika J, Caralt B, Garcia-de-Acilu M, Sztrymf B, Ricard JD, Masclans JR. Predicting success of high-flow nasal cannula in pneumonia patients with hypoxemic respiratory failure: The utility of the ROX index. J Crit Care. 2016 Oct;35:200-5. doi: 10.1016/j.jcrc.2016.05.022. Epub 2016 May 31.

Study record dates

Study Major Dates

• Study Start (Actual): December 9, 2020
• Primary Completion (Estimated): December 31, 2024
• Study Completion (Estimated): June 30, 2025

Study Registration Dates

• First Submitted: December 24, 2020
• First Submitted That Met QC Criteria: January 11, 2021
• First Posted (Actual): January 13, 2021

Study Record Updates

• Last Update Posted (Actual): August 15, 2024
• Last Update Submitted That Met QC Criteria: August 12, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Keywords: High flow nasal cannula; High flow oxygen therapy; Nasal high flow
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Respiration Disorders; Respiratory Insufficiency
• Other Study ID Numbers: PR(AG)454/2020

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No