Intermediate Normal Versus High Normal Oxygen Levels in the Emergency Department for Severe Traumatic Brain Injury (INACHOS)

Intermediate Normal Versus High Normal Oxygen Levels in the Emergency Department for Severe Traumatic Brain Injury

Impact of Intermediate Normal Compared to High Normal Oxygen Levels on Outcomes of Patients Presenting in the Emergency Department With Severe Traumatic Brain Injury (INACHOS): a Pilot Randomized Controlled Trial

Despite almost universal usage of supplemental oxygen therapy in patients presenting in the emergency department with traumatic brain injury (TBI), optimal oxygen levels are unclear. The investigators propose a pilot multi-center randomized controlled trial to test the hypothesis that maintaining intermediate normal as opposed to high normal oxygen levels in patients presenting in the emergency department with TBI is feasible, and to obtain preliminary data on the efficacy of the two approaches to oxygen therapy. The aim is that the investigators produce pilot data, which could inform the design of potential subsequent larger clinical trials.

Despite the worldwide burden of traumatic brain injury (TBI), medical research on the field as opposed to other health problems is underrepresented. Consequently, there are few data to support commonly used interventions for the management of TBI, especially in the setting of the emergency department. For example, despite almost universal usage of supplemental oxygen therapy, the effects of different oxygenation levels under normobaric conditions on outcomes of patients presenting in the emergency department with TBI are unknown. On the one hand, liberal oxygenation may provide a margin of safety against hypoxemia and may be needed to meet the high oxygen demands of an acutely altered brain physiology. On the other hand, there are increasing concerns that excessive oxygen supplementation may have harmful effects, such as central nervous system toxicity, cerebral vasoconstriction, impaired immunity leading to predisposition to infections (including pneumonia) and acute lung injury/acute respiratory distress syndrome. Such effects could be avoided by intermediate normal oxygen levels. Taken together, the relative merits and risks of the abovementioned two approaches to oxygen therapy (namely, intermediate normal versus high normal oxygen levels) of patients with TBI in terms of important clinical outcomes (namely, development of nosocomial pneumonia, acute respiratory distress syndrome, disability and mortality) remain undefined. This suggests the need for randomized controlled trials. However, randomized controlled trials focusing on patient-centered outcomes should be preceded by pilot randomized controlled trials, which demonstrate a separation in treatment and protocol compliance (feasibility) associated with the studied interventions. Therefore, the investigators propose a pilot multi-center randomized controlled trial to test the hypothesis that maintaining intermediate normal as opposed to high normal oxygen levels in patients presenting in the emergency department with TBI is feasible, and to obtain preliminary data on the efficacy of the two approaches to oxygen therapy.

Traumatic Brain Injury, Acute Respiratory Failure, Acute Respiratory Distress Syndrome, Acute Brain Injury

emergency care, acute respiratory failure, trauma, oxygen, disability, acute care, critical care, mortality, brain injury, mechanical ventilation

Enrolled patients will be randomly allocated using opaque sealed envelopes to either "intermediate normal oxygen" or "high normal oxygen" group. The asymptomatic maximal procedure, with an allocation ratio of 1:1 and a maximum tolerated imbalance of 2 will be used to randomize subjects.

To avoid selection bias, the allocation sequence will be blinded from researchers involved in patient enrolment. Although study subjects will be unaware of the assigned group, blinding of treating clinicians is not considered feasible.

For the "intermediate normal oxygen" group, an oxygen saturation by pulse oximetry (SpO2) of 95-97% will be recommended in the light of the Improving Oxygen Therapy in Acute-illness (IOTA) meta-analysis. The acceptable lower limit of PaO2 will be set to 80 mmHg according to a recent consensus of experts endorsed by the European Society of Intensive Care Medicine. The lower-limit and higher-limit monitor alarm for SpO2 will be set at 94% and 98%, respectively. In case that the emergency department of a study site uses ventilators, which allow for only two options of FiO2 titration (namely, "air mix" and "FiO2 of 1.0"), then the "intermediate normal oxygen" group should receive "air mix".

For the "high normal oxygen" group, an oxygen saturation by pulse oximetry (SpO2) of 99-100% will be recommended. The lower-limit monitor alarm for SpO2 will be set at 98%. No upper alarm limit for SpO2 will be set. In case that the emergency department of a study site uses ventilators, which allow for only two options of FiO2 titration (namely, "air mix" and "FiO2 of 1.0"), then the "high normal oxygen" group should receive "FiO2 of 1.0".

Oxygen to achieve assigned SpO2 (or FiO2) targets will be administered to study subjects. The treating clinician can alter oxygenation targets at any time if deemed necessary. The oxygenation goal will be based on SpO2 rather than arterial oxygen saturation (SaO2) or arterial pressure oxygen (PaO2) from arterial blood gases. However, PaO2 can be used instead in situations where the treating clinician considers that peripheral perfusion is poor or SpO2 readings are unreliable. Assigned SpO2 targets will apply to the study subjects for a total duration of 6 hours from intubation or until death or until transfer to the operating theater (whatever comes first).

SpO2 will be recorded each hour for a total duration of 6 hours from intubation. Subsequently, mean area-under-curve (AUC) will be calculated for each group. This will demonstrate the feasibility of the study.

FiO2 will be recorded each hour for a total duration of 6 hours from intubation. Subsequently, mean area-under-curve (AUC) will be calculated for each group. This will demonstrate the feasibility of the study.

PaO2 will be recorded at least once during 6 hours from intubation. Subsequently, PaO2 values (mmHg) will be calculated for each group. This will demonstrate the feasibility of the study.

A combined outcome of disability and mortality at 6 months using the Extended Glasgow Outcome Score will be assessed

Inclusion Criteria: Adult patient ≥18 years Glasgow Coma Scale ≤ 8 Non-penetrating traumatic brain injury Intubated patient Exclusion Criteria: Age <18 years Lack of intention to admit to the intensive care unit Moribund patient expected to die within 24 hours Expected need for mechanical ventilation < 24 hours Time interval from intubation to group allocation more than 60 minutes Penetrating traumatic brain injury Pregnancy Lack of equipoise of the treating clinician Lack of informed consent

Asehnoune K, Seguin P, Allary J, Feuillet F, Lasocki S, Cook F, Floch H, Chabanne R, Geeraerts T, Roger C, Perrigault PF, Hanouz JL, Lukaszewicz AC, Biais M, Boucheix P, Dahyot-Fizelier C, Capdevila X, Mahe PJ, Le Maguet P, Paugam-Burtz C, Gergaud S, Plaud B, Constantin JM, Malledant Y, Flet L, Sebille V, Roquilly A; Corti-TC Study Group. Hydrocortisone and fludrocortisone for prevention of hospital-acquired pneumonia in patients with severe traumatic brain injury (Corti-TC): a double-blind, multicentre phase 3, randomised placebo-controlled trial. Lancet Respir Med. 2014 Sep;2(9):706-16. doi: 10.1016/S2213-2600(14)70144-4. Epub 2014 Jul 24. Erratum In: Lancet Respir Med. 2014 Sep;2(9):e15.

Asehnoune K, Balogh Z, Citerio G, Cap A, Billiar T, Stocchetti N, Cohen MJ, Pelosi P, Curry N, Gaarder C, Gruen R, Holcomb J, Hunt BJ, Juffermans NP, Maegele M, Midwinter M, Moore FA, O'Dwyer M, Pittet JF, Schochl H, Schreiber M, Spinella PC, Stanworth S, Winfield R, Brohi K. The research agenda for trauma critical care. Intensive Care Med. 2017 Sep;43(9):1340-1351. doi: 10.1007/s00134-017-4895-9. Epub 2017 Jul 29.

Dewan MC, Rattani A, Gupta S, Baticulon RE, Hung YC, Punchak M, Agrawal A, Adeleye AO, Shrime MG, Rubiano AM, Rosenfeld JV, Park KB. Estimating the global incidence of traumatic brain injury. J Neurosurg. 2018 Apr 27;130(4):1080-1097. doi: 10.3171/2017.10.JNS17352.

Andrews PJ, Sinclair HL, Rodriguez A, Harris BA, Battison CG, Rhodes JK, Murray GD; Eurotherm3235 Trial Collaborators. Hypothermia for Intracranial Hypertension after Traumatic Brain Injury. N Engl J Med. 2015 Dec 17;373(25):2403-12. doi: 10.1056/NEJMoa1507581. Epub 2015 Oct 7.

The Lancet Neurology. A rally for traumatic brain injury research. Lancet Neurol. 2013 Dec;12(12):1127. doi: 10.1016/S1474-4422(13)70266-7. No abstract available.

Xu F, Liu P, Pascual JM, Xiao G, Lu H. Effect of hypoxia and hyperoxia on cerebral blood flow, blood oxygenation, and oxidative metabolism. J Cereb Blood Flow Metab. 2012 Oct;32(10):1909-18. doi: 10.1038/jcbfm.2012.93. Epub 2012 Jun 27.

Vilalta A, Sahuquillo J, Merino MA, Poca MA, Garnacho A, Martinez-Valverde T, Dronavalli M. Normobaric hyperoxia in traumatic brain injury: does brain metabolic state influence the response to hyperoxic challenge? J Neurotrauma. 2011 Jul;28(7):1139-48. doi: 10.1089/neu.2010.1720. Epub 2011 Jun 30.

Tolias CM, Reinert M, Seiler R, Gilman C, Scharf A, Bullock MR. Normobaric hyperoxia--induced improvement in cerebral metabolism and reduction in intracranial pressure in patients with severe head injury: a prospective historical cohort-matched study. J Neurosurg. 2004 Sep;101(3):435-44. doi: 10.3171/jns.2004.101.3.0435.

Hafner S, Beloncle F, Koch A, Radermacher P, Asfar P. Hyperoxia in intensive care, emergency, and peri-operative medicine: Dr. Jekyll or Mr. Hyde? A 2015 update. Ann Intensive Care. 2015 Dec;5(1):42. doi: 10.1186/s13613-015-0084-6. Epub 2015 Nov 19.

Vincent JL, Taccone FS, He X. Harmful Effects of Hyperoxia in Postcardiac Arrest, Sepsis, Traumatic Brain Injury, or Stroke: The Importance of Individualized Oxygen Therapy in Critically Ill Patients. Can Respir J. 2017;2017:2834956. doi: 10.1155/2017/2834956. Epub 2017 Jan 26.

Raj R, Bendel S, Reinikainen M, Kivisaari R, Siironen J, Lang M, Skrifvars M. Hyperoxemia and long-term outcome after traumatic brain injury. Crit Care. 2013 Aug 19;17(4):R177. doi: 10.1186/cc12856.

Brenner M, Stein D, Hu P, Kufera J, Wooford M, Scalea T. Association between early hyperoxia and worse outcomes after traumatic brain injury. Arch Surg. 2012 Nov;147(11):1042-6. doi: 10.1001/archsurg.2012.1560.

Chu DK, Kim LH, Young PJ, Zamiri N, Almenawer SA, Jaeschke R, Szczeklik W, Schunemann HJ, Neary JD, Alhazzani W. Mortality and morbidity in acutely ill adults treated with liberal versus conservative oxygen therapy (IOTA): a systematic review and meta-analysis. Lancet. 2018 Apr 28;391(10131):1693-1705. doi: 10.1016/S0140-6736(18)30479-3. Epub 2018 Apr 26.

Panwar R, Hardie M, Bellomo R, Barrot L, Eastwood GM, Young PJ, Capellier G, Harrigan PW, Bailey M; CLOSE Study Investigators; ANZICS Clinical Trials Group. Conservative versus Liberal Oxygenation Targets for Mechanically Ventilated Patients. A Pilot Multicenter Randomized Controlled Trial. Am J Respir Crit Care Med. 2016 Jan 1;193(1):43-51. doi: 10.1164/rccm.201505-1019OC.

Robba C, Poole D, McNett M, Asehnoune K, Bosel J, Bruder N, Chieregato A, Cinotti R, Duranteau J, Einav S, Ercole A, Ferguson N, Guerin C, Siempos II, Kurtz P, Juffermans NP, Mancebo J, Mascia L, McCredie V, Nin N, Oddo M, Pelosi P, Rabinstein AA, Neto AS, Seder DB, Skrifvars MB, Suarez JI, Taccone FS, van der Jagt M, Citerio G, Stevens RD. Mechanical ventilation in patients with acute brain injury: recommendations of the European Society of Intensive Care Medicine consensus. Intensive Care Med. 2020 Dec;46(12):2397-2410. doi: 10.1007/s00134-020-06283-0. Epub 2020 Nov 11.

Busl KM. Nosocomial Infections in the Neurointensive Care Unit. Neurosurg Clin N Am. 2018 Apr;29(2):299-314. doi: 10.1016/j.nec.2017.11.008.

Girardis M, Busani S, Damiani E, Donati A, Rinaldi L, Marudi A, Morelli A, Antonelli M, Singer M. Effect of Conservative vs Conventional Oxygen Therapy on Mortality Among Patients in an Intensive Care Unit: The Oxygen-ICU Randomized Clinical Trial. JAMA. 2016 Oct 18;316(15):1583-1589. doi: 10.1001/jama.2016.11993.

Siemieniuk RAC, Chu DK, Kim LH, Guell-Rous MR, Alhazzani W, Soccal PM, Karanicolas PJ, Farhoumand PD, Siemieniuk JLK, Satia I, Irusen EM, Refaat MM, Mikita JS, Smith M, Cohen DN, Vandvik PO, Agoritsas T, Lytvyn L, Guyatt GH. Oxygen therapy for acutely ill medical patients: a clinical practice guideline. BMJ. 2018 Oct 24;363:k4169. doi: 10.1136/bmj.k4169. No abstract available.

Mackle DM, Bailey MJ, Beasley RW, Bellomo R, Bennett VL, Deane AM, Eastwood GM, Finfer S, Freebairn RC, Litton E, Linke NJ, McArthur CJ, McGuinness SP, Panwar R, Young PJ; Australian and New Zealand Intensive Care Society Clinical Trials Group. Protocol summary and statistical analysis plan for the intensive care unit randomised trial comparing two approaches to oxygen therapy (ICU-ROX). Crit Care Resusc. 2018 Mar;20(1):22-32.