Correcting Hypocapnia in Aneurysmal Subarachnoid Hemorrhage.

Official title

Safety and Efficacy of Normobaric Facemask Oxygen for Hypocapnia in Aneurysmal Subarachnoid Hemorrhage(FOCAL): A Prospective, Multicenter, Proof-of-concept Pilot Study

Overview

Based on the clinical observation that over half of the patients in the management of aneurysmal subarachnoid hemorrhage(aSAH) present with spontaneous hyperventilation, which is significantly associated with delayed cerebral ischemia and poor neurological outcomes, this prospective pilot study is designed to investigate the safety and efficacy of normobaric facemask oxygen for hypocapnia in aSAH.

Detailed description

Spontaneous hyperventilation (SH) is highly prevalent following aneurysmal subarachnoid hemorrhage (aSAH) and is significantly associated with poor neurological outcomes.The core pathophysiological mechanism involves hypocapnia induced by hyperventilation, which triggers cerebral vasoconstriction and consequently leads to a decrease in cerebral blood flow (CBF).Although this response may transiently reduce intracranial pressure, persistent cerebral vasoconstriction markedly increases the risk of delayed cerebral ischemia (DCI) and secondary brain injury. Therefore, maintaining the arterial partial pressure of carbon dioxide (PaCO2) within the physiological range of mmHg is recommended to minimize the detrimental effects of hypocapnia.

Currently, there is a lack of standardized management strategies for hypocapnia resulting from SH after aSAH. Based on physiological principles, low-flow (\<5 L/min) oxygen delivery via a facemask may effectively correct hypocapnia by promoting the rebreathing of carbon dioxide within the dead space of the facemask.10 A randomized controlled trial investigating psychogenic hyperventilation syndrome provides preliminary evidence for this approach, demonstrating that low-flow (3 L/min) facemask oxygen therapy can relieve symptoms more rapidly and improve patient comfort compared to traditional breathing training.11

However, high-level evidence regarding the safety, efficacy, and impact on neurological outcomes of using low-flow facemask oxygen therapy (functioning as a rebreathing mask) as a targeted intervention for correcting hypocapnia in aSAH patients remains scarce. Consequently, this proof-of-concept prospective study aims to systematically evaluate the operational safety and clinical effectiveness of rebreathing facemask oxygen therapy for correcting hypocapnia in patients with aSAH.

Interventions

• Behavioral Normobaric Facemask Oxygen
  Oxygen is to be delivered via a rebreathing facemask (ensuring no one-way valve is present), with a fractional inspired oxygen (FiO2) of 25-41% and an oxygen flow rate of ≤ 5 L/min. The goals are to maintain patient SpO2 \> 95%, PaCO2 between 35-42 mmHg, and, where feasible (particularly in centers with the capability for monitoring), an intracranial pressure (ICP) of \< 15 mmHg.
• Behavioral control group
  Using nasal cannula for oxygen inhalation or not using oxygen inhalation at all. Monitor and record the patient's SpO2, systolic blood pressure, diastolic blood pressure, PaCO2, and also monitor the intracranial pressure (ICP) at a center with monitoring capabilities.

Primary outcome measures

• modified Rankin Scale (mRS) >3 [Time frame: 90-day follow-up visit]
• Incidence of delayed cerebral injury (DCI) [Time frame: 30 days after onset]

Secondary outcome measures (11)

• Montreal Cognitive Assessment (MoCA) [Time frame: 90-day follow-up visit]
• Cerebral Vasospasm [Time frame: Participants will be followed for the duration of the hospital stay, an expected average of 2 weeks]
• Glasgow Coma Score(GCS) [Time frame: Enrollment, 30 days after onset, and 90-day follow-up visit]
• The modified Rankin Scale (mRS) [Time frame: 30 days after onset]
• modified Rankin Scale (mRS) [Time frame: 30 days after onset]
• Barthel Index (BI) score [Time frame: 90-day follow-up visit]
• All-cause mortality [Time frame: 90-day follow-up visit]
• Complication of severe dependent survival [Time frame: 90-day follow-up visit]
• Treated aneurysm rebleeding [Time frame: 90-day follow-up visit]
• Probable or definite bleed from another aneurysm [Time frame: 90-day follow-up visit]
• Incidence of adverse events [Time frame: 90-day follow-up visit]

Eligibility criteria

Inclusion criteria

• Age > 18 years.
• Confirmed diagnosis of aneurysmal subarachnoid hemorrhage (aSAH), with the presence of an aneurysm verified by computed tomography (CT), CT angiography (CTA), or digital subtraction angiography (DSA).
• Hunt-Hess grade II-IV.
• Presence of hypocapnia on arterial blood gas analysis, defined as PaCO2 < 35 mmH;
• PaO2 > 90 mmHg.

Exclusion criteria

• Presence of brain herniation or refractory intracranial hypertension, defined as a baseline intracranial pressure (ICP) > 25 mmHg that responds poorly to conventional ICP-lowering therapy;
• Primary respiratory diseases (e.g., chronic obstructive pulmonary disease, severe asthma) known to cause chronically elevated baseline PaCO2;
• Severe acid-base disturbances other than respiratory alkalosis.
• Severe cardiac insufficiency, severe hepatic or renal dysfunction, malignant tumors, or other severe comorbidities that significantly impact prognosis;
• Before the onset of the disease, the mRS score was greater than 2, and there were other factors causing disability.
• Life expectancy < 3 months;
• Any other condition deemed by the investigator to pose a high risk warranting exclusion.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

China · 1 center

• School of Medicine Chinese University of Hong Kong-SHENZHEN — Shenzhen

Publications

• Yang L, Yuan D, Luo Z, Li Y, Zhu X. The low-flow mask oxygen could be a more effective, comfortable, and easy-to-follow treatment for psychogenic hyperventilation syndrome: A double-blind, randomized controlled trial. Int Emerg Nurs. 2025 Aug;81:101636. doi: 10.1016/j.ienj.2025.101636. Epub 2025 Jun 17. PMID 40532319
• Darkwah Oppong M, Wrede KH, Muller D, Santos AN, Rauschenbach L, Dinger TF, Ahmadipour Y, Pierscianek D, Chihi M, Li Y, Deuschl C, Sure U, Jabbarli R. PaCO2-management in the neuro-critical care of patients with subarachnoid hemorrhage. Sci Rep. 2021 Sep 28;11(1):19191. doi: 10.1038/s41598-021-98462-2. PMID 34584136
• Cai G, Zhang X, Ou Q, Zhou Y, Huang L, Chen S, Zeng H, Jiang W, Wen M. Optimal Targets of the First 24-h Partial Pressure of Carbon Dioxide in Patients with Cerebral Injury: Data from the MIMIC-III and IV Database. Neurocrit Care. 2022 Apr;36(2):412-420. doi: 10.1007/s12028-021-01312-2. Epub 2021 Jul 30. PMID 34331211
• Su R, Li HL, Wang YM, Zhang L, Zhou JX. Association of dynamic changes in arterial partial pressure of carbon dioxide with neurological outcomes in aneurysmal subarachnoid hemorrhage. Heliyon. 2024 Oct 10;10(20):e39197. doi: 10.1016/j.heliyon.2024.e39197. eCollection 2024 Oct 30. PMID 39640813
• Carrera E, Schmidt JM, Fernandez L, Kurtz P, Merkow M, Stuart M, Lee K, Claassen J, Sander Connolly E, Mayer SA, Badjatia N. Spontaneous hyperventilation and brain tissue hypoxia in patients with severe brain injury. J Neurol Neurosurg Psychiatry. 2010 Jul;81(7):793-7. doi: 10.1136/jnnp.2009.174425. Epub 2009 Dec 3. PMID 19965840
• Coles JP, Fryer TD, Coleman MR, Smielewski P, Gupta AK, Minhas PS, Aigbirhio F, Chatfield DA, Williams GB, Boniface S, Carpenter TA, Clark JC, Pickard JD, Menon DK. Hyperventilation following head injury: effect on ischemic burden and cerebral oxidative metabolism. Crit Care Med. 2007 Feb;35(2):568-78. doi: 10.1097/01.CCM.0000254066.37187.88. PMID 17205016
• Coles JP, Minhas PS, Fryer TD, Smielewski P, Aigbirihio F, Donovan T, Downey SP, Williams G, Chatfield D, Matthews JC, Gupta AK, Carpenter TA, Clark JC, Pickard JD, Menon DK. Effect of hyperventilation on cerebral blood flow in traumatic head injury: clinical relevance and monitoring correlates. Crit Care Med. 2002 Sep;30(9):1950-9. doi: 10.1097/00003246-200209000-00002. PMID 12352026
• Robba C, Battaglini D, Abbas A, Sarrio E, Cinotti R, Asehnoune K, Taccone FS, Rocco PR, Schultz MJ, Citerio G, Stevens RD, Badenes R; ENIO collaborators. Clinical practice and effect of carbon dioxide on outcomes in mechanically ventilated acute brain-injured patients: a secondary analysis of the ENIO study. Intensive Care Med. 2024 Feb;50(2):234-246. doi: 10.1007/s00134-023-07305-3. Epub 2024 Jan PMID 38294526

Identifiers

NCT: NCT07343232 · CUHKShenzhen

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗