Gas Therapies for Neuro-Protection

Cardiac arrest (CA) remains a major cause of mortality and neurologic impairment, underscoring the urgent need for innovative neuroprotective strategies. Gas therapies, including inhaled nitric oxide (NO), molecular hydrogen (H ₂), xenon (Xe), and argon (Ar), have emerged as promising neuroprotective agents. These gases exert protective effects, preserving neurologic function and improving outcomes after CA through antioxidant, anti-inflammatory, and anti-apoptotic mechanisms. Despite promising preclinical and early clinical data, large-scale trials are essential to validate their efficacy, optimize protocols, refine dosing, and ensure clinical translation. Advancing gas therapies into standard post-CA care could revolutionize neuroprotection, offering a paradigm shift in resuscitation medicine.

Key points

•
Gas therapies, such as inhaled xenon (Xe), argon (Ar), molecular hydrogen (H2), and nitric oxide (NO) have shown promising neuroprotective effects in cardiac arrest (CA) models.
•
Combining gas therapies with other post-CA care interventions like temperature management may enhance neuroprotection and functional recovery through a synergistic effect.
•
Clinical trials on gas therapies after CA are still in early stages, with limited but promising findings, highlighting the need for larger, well-designed randomized studies.

Abbreviations

Ar	Argon
CA	cardiac arrest
cGMP	cyclic guanosine monophosphate
CPR	cardiopulmonary resuscitation
GC	guanylate cyclase
GSNOR	S-nitroso glutathione reductase
H ₂	Hydrogen
IHCA	in-hospital cardiac arrest
iNO	inhaled nitric oxide
IRI	ischemia-reperfusion injury
K-ATP	ATP-sensitive potassium
MTH	mild therapeutic hypothermia
NMDA	N-methyl- d -aspartic acid
NO	Nitric oxide
-OH	hydroxyl
OHCA	out-of-hospital cardiac arrest
PCABI	post-cardiac arrest brain injury
RCT	randomized controlled trial
ROSC	return of spontaneous circulation
TREK-1	TWIK-related potassium channel-1
TTM	targeted temperature management
VF	ventricular fibrillation
Xe	Xenon

Introduction

Cardiac arrest (CA) remains a leading cause of death worldwide and is frequently associated with significant neurologic impairment. Despite advancements in resuscitation protocols and increased public awareness, survival rates with favorable neurologic outcome remain low, i.e. approximately 8% to 10%, posing a major public health challenge. ^,^, Neurologic recovery in resuscitated CA patients depends on the extent of brain injury, with clinical outcomes ranging from mild disability to brain death. ^,

The pathophysiology of post-CA brain injury (PCABI) involves a biphasic process: an initial ischemic-hypoxic insult during no-flow and low-flow states, followed by a reperfusion-induced secondary injury, ultimately leading to neuronal damage. ^, Notably, after hospital admission, withdrawal of life-sustaining treatment due to poor neurologic prognosis accounts for the majority of delayed deaths, i.e. approximately two-thirds after out-of-hospital CA (OHCA) and 25% after in-hospital CA (IHCA). ^,^,^,

Given the limited efficacy of targeted temperature management (TTM) in recent studies, ^,^,^,^,^,^, innovative therapies are urgently needed to improve neurologic outcome after initial return of spontaneous circulation (ROSC). Among emerging strategies, gas therapies have gained recognition as promising interventions for mitigating ischemia-reperfusion injury (IRI). Preclinical and clinical studies have suggested that various medical gases exert neuroprotective effects through antioxidant and anti-inflammatory mechanisms, modulation of excitotoxic pathways, and mitochondrial preservation. ^,^,^, These therapies offer a novel and targeted approach to address the complex events involved in the pathophysiology of PCABI.

In recent years, administration of inhaled gases, such as nitric oxide (NO), molecular hydrogen (H ₂), and, in particular, noble gases like xenon (Xe) and argon (Ar), has emerged as a promising therapeutic approach in resuscitation. In experimental settings, these gases have consistently demonstrated neuroprotective effects in both in vitro and in vivo models across various animal species and treatment protocols ( Table 1 ). Moreover, some of these gases, i.e. Xe, NO, and H ₂, have shown feasibility and efficacy in clinical settings, primarily when used in combination with TTM at 33°C. ^,^,^,^,

Table 1

Gas therapies (Xenon, Argon, Molecular Hydrogen and Nitric Oxide) treatment protocols in animal models of cardiac arrest

Gas Therapy	Main Mechanisms of Action	Ref	Gas Mixture (%)	Onset of Treatment (Time)	Duration of Treatment (Time)
Xenon (Xe)	NMDA receptor inhibition Modulation of TREK-1 and K-ATP channels	Derwall et al, 2008	70%	1 h post-ROSC	1 h 5 h
		Derwall et al, 2008	70%	10 min post-ROSC	1 h
		Fries et al, 2008	70%	Immediately post-ROSC	1 h 5 h
		Fries et al, 2009	70%	10 min post-ROSC	1 h
		Fries et al, 2012	70%	1 h post-ROSC	1 h
Argon (Ar)	Upregulation of ERK1/2 and PI3K-AKT pathways	Brücken et al, 2014	70% 40%	1 h post-ROSC	1 h
		Brücken et al, 2013	70%	1 h post-ROSC	1 h
		Brücken et al, 2015	70%	1 h post-ROSC	1 h
		Brücken et al, 2015	70%	3 h post-ROSC	1 h
		Brücken et al, 2017	70% + MTH	1 h post-ROSC	1 h
		Zuercher et al, 2016	50%	15 min post-ROSC	24 h
		Ristagno et al, 2014	70%	5 min post-ROSC	4 h
		Fumagalli et al, 2020	70% 50%	Immediately Post-ROSC	4 h
		Motta et al, 2024	68% (2% H ₂)	Immediately post-ROSC	4 h
		Gavriely et al, 2024	65%	During CPR	1 h
Molecular Hydrogen (H ₂)	Antioxidant and anti-inflammation properties	Hayashida et al, 2012	2% 2% + MTH	During CPR	Up to 2 h post-ROSC
		Hayashida et al, 2014	1.3% 1.3% + MTH	5 min post-ROSC	2 h
		Chen et al, 2018	2% 2% + MTH	Immediately post-ROSC	2 h
		Wang et al, 2022	2%	Immediately post-ROSC	3 h
		Huang et al, 2018	Water electrolysis-derived H ₂ gas (60%)	1 h pre-CA & 1 h post-ROSC	1 h
		Huang et al, 2018	Water electrolysis-derived H ₂ gas (60%)	1 h post-ROSC	2 h
		Huang et al, 2019	Water electrolysis-derived H ₂ gas (67%)	1 h pre-CA & 1 h post-ROSC	1 h
		Huang et al, 2019	Water electrolysis-derived H ₂ gas (67%)	1 h post-ROSC	2 h
		Cole et al, 2019	2.4%	2 h pre-CA	24 h
Nitric Oxide (NO)	Activation of GC pathway followed by cGMP production	Minamishima et al, 2011	40 ppm	1 h post-ROSC	23 h
		Brücken et al, 2015	20 ppm 40 ppm	During CPR	Up to 30 min post-ROSC
		Brücken et al, 2018	20 ppm + MTH	1 h post-ROSC	5 h
		Derwall et al, 2015	20 ppm	During CPR	Up to 5 h post-ROSC

Treatment effect is classified by a colored square as: “Supportive” (green “S”) if the gas therapy led to an improved neurologic condition in all the evaluated outcomes compared to the control group; “Neutral” (yellow “N”) if gas therapy a led to benefits in some of the analysed outcomes and no benefits in the remaining ones, compared to the control group; “Opposing” (red “O”) if the gas therapy did not demonstrate any benefit in any of the analyzed outcomes or produced detrimental effects, compared to the control group.

Abbreviations: cGMP, cyclic guanosine monophosphate; CPR, cardiopulmonary resuscitation; ERK 1/2, extracellular signal-regulated-kinase 1/2; GC, guanylate cyclase; K-ATP, adenosine triphosphate-sensitive potassium channel; MTH, mild therapeutic hypothermia; NMDA, N-methyl- d -aspartic acid; ppm, parts per million; ROSC, return of spontaneous circulation; TREK-1, TWIK-related potassium channel-1.

Inhaled gases offer several advantages over conventional medications administered via intravenous or oral routes. Their mode of delivery allows direct passage from the lungs into the arterial circulation, ensuring rapid systemic distribution. Additionally, their intrinsic gaseous properties enable excellent diffusivity and permeability across cell membranes, facilitating targeted action on key organelles, such as mitochondria and the nucleus.

This narrative review article provides a comprehensive update on available gas therapies for neuroprotection in the context of CA and cardiopulmonary resuscitation (CPR). It summarizes the mechanisms of action for these interventions, reviews key preclinical and clinical findings, and highlights needs for future research and clinical translation. More specifically, gas therapies discussed are those based on Xe, Ar, H ₂, and NO. Current evidence on gas therapies in models of CA and CPR across all the species is detailed in Table 1 , while available clinical trials, either concluded or ongoing, are reported in Table 2 .

Table 2

Summary of the past and current clinical trials, with accurate description of the treatment protocol used, on inhaled gases as therapies for cardiac arrest

Gas Therapy	Study Title, Identifier, Location	Study Design	Gas Mixture (%)	Duration of Treatment (Time)	Onset of Treatment (Time)	Number of Patients	Status
Xenon	Safety and feasibility of inhaled Xe + MTH in OHCA patients NCT00879892 Finland	Open label, controlled, two-arm randomised single center, clinical drug trial	40% Xe + MTH	24 h	At ICU admission	Enrolled 36	Completed
Xenon	Xe-HYPOTHECA NCT00879892 Finland and USA	Single-blind, phase II, RCT	40% Xe + MTH	24 h	At ICU admission	Enrolled 110	Completed
Xenon	XePOHCAS NCT03176186 USA	Prospective, single-blind, phase III, RCT	50% Xe + MTH	24 h	At ICU admission	Planned 1436	Terminated
Argon	CardioPulmonary Resuscitation with Argon CPAr NCT05482945 Italy	Prospective, controlled, single-blind, phase I/II, RCT	70% Ar	4 h	Within 4 h post-ROSC	Planned 120	Recruiting
Molecular Hydrogen	HYBRID study UMIN000012381 Japan	Open label, single arm, prospective, intervention phase I trial	2% H ₂ with O ₂	18 h	At ICU admission	Enrolled 5	Completed
Molecular Hydrogen	HYBRID II study UMIN000019820 Japan	Prospective, multicentre, double-blind, placebo-controlled, phase II RCT	2% H ₂ with O ₂	18 h	At ICU admission	Enrolled 73	Completed
Nitric Oxide	Improving outcomes in cardiac arrest with inhaled nitric oxide NCT04134078 USA	Prospective, pilot study, single center, phase I trial	40 ppm	24 h	As soon as possible post-ROSC	Enrolled 20	Terminated
Nitric Oxide	iNOOHCA NCT03079102 USA	Prospective, double-blind, controlled, phase II RCT	20 ppm	12 h	As soon as possible post-ROSC (within 4 h)	Enrolled 57	Terminated

Abbreviation: MTH, mild therapeutic hypothermia (33°C).

Xenon

Xe is the most extensively studied noble gas in biomedicine. Discovered in the late 19th century, it shares the common physical properties of noble gases, being colorless, tasteless, and odorless. Xe constitutes only 0.087 ppm of atmospheric air and is obtained through fractional distillation of liquefied air, a highly expensive process (∼$30– 60 per L) due to its low atmospheric concentration. ^, Efficient delivery of Xe in clinical settings requires a closed-circuit ventilation system.

The first reports on Xe-related biologic and behavioral effects date back to 1946, when in mice, exposure to Xe at pressures between 0.40 and 0.78 atm exhibited anesthetic potency. Since then, Xe has garnered significant interest in anesthesia due to its favorable pharmacologic properties, i.e. being environmentally friendly, highly stable, and unlikely to undergo biotransformation.

Xe’s neuroprotective properties have been extensively investigated over the past decades, with numerous preclinical studies identifying its antagonistic action on N-methyl- d -aspartic acid (NMDA) receptors as a key mechanism. Indeed, excessive activation of NMDA-type glutamate receptors is linked to neuronal excitotoxicity and ischemia-induced cell death following brain injury. Additionally, Xe exerts neuroprotective effects through interactions with TWIK-related potassium channel-1 (TREK-1) and ATP-sensitive potassium channels (K-ATP).