key: cord-0683077-ch7o3qa6
authors: Huang, Yan; Xiao, Feng-Ming; Tang, Wen-Jie; Qiao, Jing; Wei, Hai-Feng; Xie, Yuan-Yun; Wei, You-Zhen
title: Hydrogen inhalation promotes recovery of a patient in persistent vegetative state from intracerebral hemorrhage: A case report and literature review
date: 2022-02-06
journal: World J Clin Cases
DOI: 10.12998/wjcc.v10.i4.1311
sha: 378a6ad9b63e49b8c4e3abbb469ab02de78e3710
doc_id: 683077
cord_uid: ch7o3qa6

BACKGROUND: Persistent vegetative state (PVS) is a devastating and long-lasting clinical condition with high morbidity and mortality; currently, there are no available effective interventions. CASE SUMMARY: We report the case of an 11-year-old boy with PVS caused by severe intracerebral bleeding in the left hemisphere following anticoagulation treatment. The patient’s PVS severity showed no notable improvement after 2-mo neuroprotective treatment and rehabilitation, including nerve growth factor and baclofen, hyperbaric oxygen, and comprehensive bedside rehabilitation therapies. Daily inhalation treatment (4-6 h) of high-concentration hydrogen (H(2)) gas (66.6% H(2) + 33.3% O(2)) was provided. Surprisingly, the patient’s orientation, consciousness, ability to speak, facial expressions, and locomotor function were significantly restored, along with improvements in essential general health status, after H(2) gas inhalation treatment, which was consistent with stabilized neuropathology in the left hemisphere and increased Hounsfield unit values of computed tomography in the right hemisphere. The patient finally recovered to a near normal conscious state with a Coma Recovery Scale-Revised Score of 22 from his previous score of 3. CONCLUSION: Phase 1 clinical trials are needed to explore the safety and efficacy of H(2) gas inhalation in patients with PVS.

Urgent development of novel therapies for intracerebral hemorrhage (ICH) is required due to the high mortality of ICH and the lack of effective therapies[1]. Molecular hydrogen (H 2 ) is known to protect neurons against reactive oxygen species (ROS) induced by cerebral ischemia/reperfusion (I/R) injury[2,3]. Previous experimental studies have shown that H 2 gas can also alleviate inflammation and apoptosis [4] , in addition to reducing neuronal damage in several rat models of diseases by suppressing the expression of S100 calcium-binding protein B, phosphorylation of c-Jun N-terminal kinase, and reactive astrogliosis [5] [6] [7] . H 2 gas inhalation selectively reduces hydroxyl radical and peroxynitrite levels in vitro and exerts an antioxidant effect, reflected by decreased brain concentrations of 4-hydroxynonenal (a specific marker for lipid peroxidation), and 8-hydroxyguanosine (a nucleic acid oxidation marker) in a rat middle cerebral artery occlusion model [2] . Clinical studies have also indicated the effectiveness of H 2 gas in the treatment of hepatic, renal, cardiac, and pulmonary diseases, including chronic obstructive pulmonary disease and coronavirus disease 2019 [8] [9] [10] . H 2 gas inhalation or H 2 -rich saline treatment has beneficial effects on early brain injury after subarachnoid hemorrhage [11, 12] , delayed brain injury in subarachnoid hemorrhage, and unilateral common carotid artery occlusion with the endovascular perforation method [13] . Here, we report the case of an 11-year-old boy treated by high-concentration H 2 gas inhalation that helped with the recovery from persistent vegetative state (PVS) caused by ICH, which is the first clinical report of high-dose H 2 gas therapy in a child in a PVS after ICH. February 6, 2022

Volume 10 Issue 4

An 11-year-old boy treated with anticoagulation after aortic valve replacement surgery presented to the pediatric intensive care unit in our hospital following fever and abdominal pain for 2 d, and coma for 2 h on May 27, 2020.

An emergency brain surgical intervention was carried out immediately to relieve the intracranial pressure and, subsequently, reduce brain injury. Assisted by neuronavigation, both left ventricle and hematoma drains were established under general anesthesia. In addition, critical life support consisting of tracheostomy, intracranial pressure probe implantation, and mechanical ventilation was also established. Approximately 6 wk (41 d) after surgery, the patient was still in a completely bedridden vegetative state (VS) with a Coma Recovery Scale-Revised (CRS-R) score [14] of 3 (auditory function: 0, visual function: 0, motor function: 1, verbal function: 0, communication: 0, and arousal: 2). Although his life support relied on nasal tubefeeding, the patient had normal heartbeat and breathing rates.

As the patient's VS status did not show signs of improvement for more than 4 wk after brain surgery, he was transferred to the rehabilitation department of the same hospital and was diagnosed with PVS, and neuroprotective treatments and rehabilitation training were initiated. The neuroprotective treatments included nasal administration of nerve growth factor, baclofen, and hyperbaric oxygen. The functional rehabilitation therapies included comprehensive bedside rehabilitation therapies, such as anticonvulsive treatment, range-of-motion maintenance, and swallowing and feeding training. Unfortunately, despite these therapeutic interventions for 4 more weeks, his PVS symptoms and severity showed no improvement. Therefore, it was necessary to explore a new and safe therapeutic intervention with potential effects on the patient who had been in a VS for over 2 mo.

At the age of 3 years, the patient underwent repair of an atrial septal defect and ventricular septal defect due to complex congenital heart disease. In October 2018, the patient underwent aortic valve replacement surgery. He received warfarin anticoagulant therapy for nearly 2 years after aortic valve replacement.

The patient had no personal or family history.

The patient could occasionally open his eyes and yawn, but he had no response to pain stimulation, and could not distinguish between his family members and strangers. Moreover, he was unable to listen and follow instructions or speak. Furthermore, his body posture was abnormal, with bent elbows and ulnar deviation, wrist flexion, fists with high tonic metacarpophalangeal joints, and stiff, straightened lower limbs with inverted feet. His muscle tone was significantly high in the lower limbs with a modified Ashworth spasm scale score of 2. Additionally, the patient had no voluntary movement control and could not hold his head steady, sit down, stand alone, or walk. The patient, however, had normal reflexes, including biceps reflex +, triceps reflex +, cough reflex +, knee reflex +++, Achilles tendon reflex +++, and Babinski sign and ankle clonus +.

Blood analysis revealed mild leukocytosis of 8.35 × 10 9 /L, with predominant neutrophils (67%), and normal hematocrit and platelet count. Prothrombin and partial thromboplastin times were normal, and D-dimer was slightly increased at 1.08 mg/L. Blood biochemistry analyses and urine analysis were normal. Electrocardiogram showed a sinus rhythm, frequent atrial premature beats, abnormal left atrium, large left ventricle, and complete left bundle branch block.

A computed tomography (CT) scan of the patient showed irregularly shaped and lowdensity CT images of the left frontal, parietal, and basal ganglia regions, which covered most of the left hemisphere ( Figures 1A, 1C , and 1E). Similar low-density CT February 6, 2022

Volume 10 Issue 4 Figure 1 Effects of hydrogen therapy. A, C, and E: Severe and large-scale hemorrhage before treatment was observed in the left hemisphere, including significantly reduced computed tomography (CT) image density that covered the left prefrontal and parietal regions and the majority of the occipital gyrus; the left lateral ventricle was significantly enlarged compared to the right ventricle, and the midline brain structures also deviated from the normal position due to the hematoma and brain edema; B, D, and F: After treatment, the left hemisphere was significantly damaged by hemorrhage with a markedly enlarged left lateral ventricle and severe cerebral atrophy. However, significantly alleviated cerebral softening was observed in the right hemisphere, revealed by an increased CT number (Hounsfield units) in multiple brain regions (yellow circles), compared to those of similar brain regions (yellow circles) before treatment. The neuropathology stabilized in the left hemisphere and was alleviated in the right hemisphere after hydrogen gas inhalation treatment.

images were also observed in the posterior horn of the bilateral ventricles and the third and fourth ventricles near the sickle and sulci regions of the left brain. The left lateral ventricle was compressed and narrowed by the hematoma and cerebral edema compared to that of the right ventricle, and midline brain structures were also slightly shifted to the right.

PVS, coagulation dysfunction, ICH, brain hernia, and postsurgical syndrome after aortic valve replacement.

TREATMENT H 2 has been used in the treatment of patients in critical situations such as traumatic brain injury and cerebral ischemia, and no side effects have been reported to date [15] . After a thorough discussion and explanation of the patient's status with his family and with their permission, high-concentration H 2 (66.6% H 2 and 33.3% O 2 ) inhalation treatment was administered. The treatment was given twice daily, for 2-3 h each time, for 5 mo. The initial H 2 gas inhalation treatment started 2 mo after the patient developed PVS. February 6, 2022 Volume 10 Issue 4

To our surprise, the patient gradually began to show signs of improvement, such as spontaneous eye opening and occasional flexion/extension of his left lower limb shortly after treatment. A CT scan after treatment showed that the hematoma in the left hemisphere was replaced by an irregular cavity filled and surrounded by degenerated brain parenchyma indicated by shadows of low density on CT images after H 2 gas inhalation treatment, but the area with shadows of low density on CT images was reduced compared to that before treatment. The left lateral ventricle was markedly enlarged due to drainage of the left lateral ventricle and hematoma, as well as significant neuronal degeneration in the patient's left brain (Figures 1B, 1D, and 1F ). These shadows of low density on CT images in the left hemisphere may have been caused by cerebral edema and ICH, and reduction of the shadows of low density on CT images indicated that the brain hemorrhage and edema were stabilized by H 2 gas inhalation treatment compared to that before treatment. Furthermore, the median CT number, i.e., the X-ray attenuation coefficient, was 26 Hounsfield units (HU), 27 HU, 26 HU, 30 HU, and 34 HU in the precentral gyrus ( Figure 1B) , corpus callosum-forceps minor, internal capsule, corpus callosum-forceps-major ( Figure 1C) , and putamen in the patient's right hemisphere ( Figure 1F ), respectively, after H 2 gas inhalation treatment. These values were increased as compared to 23 HU, 24 HU, 25 HU, 24 HU, and 33 HU in the precentral gyrus ( Figure 1A) , corpus callosum-forceps minor, internal capsule, corpus callosum-forceps-major ( Figure 1C ), and putamen in the patient's right hemisphere ( Figure 1E ), respectively, before treatment. The increased CT numbers in the right hemisphere after treatment were possibly due to decreased cerebral edema and were critical to the recovery of brain function in the patient. Due to the significantly improved condition of the patient, the nasogastric tube was withdrawn, and he was switched from tube feeding to an oral liquid diet 1 mo after treatment.

In the 2 mo after the first administration of treatment, the patient's orientation and consciousness, visual pursuit, and localization to noxious stimulation also gradually recovered (Figure 2) . The patient could follow simple instructions, open his mouth when his lips were touched with a spoon, chew soft food, and voluntarily bend and straighten his left lower limb. Moreover, the patient was making steady improvement with longer treatments of H 2 gas inhalation. Ninety days after the initiation of treatment, his motor function was significantly improved, and he was able to make reproducible movements following instructions and autonomously lift his left limbs. His ability to produce facial expressions was vastly improved compared to that before H 2 gas inhalation. He could briefly communicate with others and speak words and phrases. Five months after initiation of treatment with H 2 gas inhalation, the patient had recovered to a near normal state of consciousness with a CRS-R score of 22 (auditory function: 4, visual function: 5, motor function: 5, verbal function: 3, communication: 2, and arousal: 3) along with improved speech ability. Furthermore, the patient had functional recovery (Table 1 ) and fine motor function improvements (Table 2 ) 6-7 mo after the initiation of treatment. The patient could understand simple instructions, identify items, and read numbers. He could make requests with a hand gesture, steadily hold his head straight, independently turn his body over to the right side, lift his hands up and reach his head, touch his eyes and nose with his hands, and make voluntary movements with his lower left limb.

In brief, these clinical observations suggested a possible beneficial role of high concentration H 2 gas inhalation in consciousness recovery, muscle tone, and locomotor function in this patient with ICH-induced PVS.

The brain of the PVS patient presented in this case report suffered mechanical damage due to abnormally high cerebral pressure, inflammation, oxidative stress, and other unknown injuries [16] [17] [18] [19] . The patient failed to respond to neuroprotective treatment along with other methods of rehabilitation but steadily recovered after administration of high-concentration H 2 gas inhalation treatment. CT scans revealed that the patient's left hemisphere was severely damaged with an enlarged left lateral ventricle and significantly atrophied cerebral parenchyma. However, the CT numbers in the right hemisphere were notably increased after treatment. Other treatment effects included consciousness recovery, significantly alleviated motor and cognitive functional deficits, improved speech and facial expressions, and improvements in general health. February 6, 2022

Volume 10 Issue 4 The patient failed to respond to brain surgery and brain protection and rehabilitation for nearly 2 mo. One month after hydrogen gas inhalation treatment, the Coma Recovery Scale-Revised (CRS-R) score of the patient increased from 3 to 6. After 2 more months of treatment, the patient's consciousness was significantly restored and showed greater subsequent improvements with significantly improved motor function, the ability to speak and express requests, and general health. By the end of the 5-mo treatment period with hydrogen gas inhalation, the patient had nearly recovered and stabilized to a normal consciousness state with a CRS-R score of 22. CRS-R: Coma Recovery Scale-Revised.

The possible underlying mechanisms of H 2 gas inhalation in this PVS patient may be closely related to its antioxidative and anti-inflammatory effects. ICH is devastating and life-threatening, and is associated with severe disability and a high mortality rate, accounting for 10% to 15% of deaths caused by stroke [20] . The initial mechanisms of injury after ICH include mechanical destruction by accidental and abnormally increased intracerebral pressure, hematoma expansion, and/or February 6, 2022

Volume 10 Issue 4 herniation caused by the hematoma itself [21] . Subsequent inflammation, oxidative stress, and impairment in blood flow around the hematoma contribute to edema formation, delayed cell death, and neurological deficits [17] . For example, excessive generation of ROS causes peroxidation of lipid-rich structures of the blood-brain barrier (BBB), resulting in life-threatening BBB disruption and vasogenic cerebral edema [22] . Increased oxidative stress-induced injury occurs in almost all types of brain cells (including neurons, astrocytes, and microglia) and is also closely related to ICHinduced inflammation [19, 23] . Therefore, attenuation of early brain injury by targeting oxidative stress and inflammation is a feasible intervention strategy in ICH. Previous studies have also revealed that antioxidative and anti-inflammatory agents can reduce brain atrophy and recover striatal function and memory after ICH[16, 24, 25] .

Since Ohsawa et al [2] reported that H 2 gas has antioxidant and anti-apoptotic properties that protect the brain against I/R injury and stroke by selectively neutralizing hydroxyl radicals, H 2 gas has reached the biomedical research forefront as a therapeutic medical gas. Accumulated clinical and experimental biomedical evidence in a variety of models of different diseases has suggested that molecular H 2 , administered either through gas inhalation or aqueous solution consumption, can act as a scavenger to selectively alleviate ROS and exert potent cellular protective effects. Rat models of middle cerebral artery occlusion, rats with subarachnoid hemorrhage, and a mouse model of ICH have been used to explore the neuroprotective effects of H 2 gas [18, 19] . These studies demonstrated that H 2 treatment could decrease oxidative stress, reduce cerebral infarction and hemorrhagic transformation, improve neurological functions, attenuate BBB disruption, and improve neurobehavioral function by ameliorating oxidative injury to lipids, proteins, and DNA. Therefore, oxidative stress relief may have been one of the underlying mechanisms of H 2 gas inhalation in this PVS patient regarding his recovery and other functional impro-vements.

Another mechanism underlying brain injury is its secondary inflammatory responses induced by ICH. Inflammation occurs immediately after ICH and includes astrocyte/microglia/macrophage activation and cytokine release [e.g., interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α)]. These factors are involved in the breakdown of the extracellular matrix, cellular integrity, and the BBB, in edema development, and in cell death processes [26] [27] [28] [29] [30] . Moreover, brain inflammatory responses develop into a chronic stage and result in further brain function damage, such as cognitive deficits [31] . Previous studies have shown that the anti-inflammatory properties of treatments may be effective in protecting the brain from secondary injuries caused by ICH; for example, melatonin can alleviate inflammatory responses and reduce DNA damage and mitochondrial injury after ICH [32] .

H 2 can protect tissues and cells from a variety of diseases. For instance, H 2 gas inhalation can protect lung function by ameliorating airway inflammation in a murine allergic airway inflammation model [33] . Molecular H 2 can also protect the heart from cardiotoxicity and hepatotoxicity induced by doxorubicin by inhibiting inflammation and apoptosis [34] . H 2 also reduces inflammatory responses after exercise by decreasing inflammatory cytokines (TNF-α, IL-1β, and IL-6) [35] . Moreover, the antiinflammatory effects of H 2 have been proven by its regulation of microglia in the nervous system after ischemic stroke [36] . Studies have also suggested that H 2 inhibits the degree of inflammation via inactivation of the NF-κB pathway and the NLRP3 inflammasome [24, 37] . Therefore, anti-inflammation by H 2 gas inhalation might have also played a role in promoting this patient's recovery from PVS.

It is worth noting that not all PVS patients were responsive to molecular H 2 treatment in our clinical research. We tried high-concentration H 2 inhalation in patients with acute necrotizing encephalopathy, but there was no significant therapeutic effect regarding the recovery of consciousness in some patients after several weeks of high-concentration H 2 inhalation. Considering that the pathophysiological mechanisms of neural injury and recovery of consciousness in brain diseases are complicated, the effectiveness of H 2 gas treatment might be dependent on the severity of brain damage and the multiple underlying mechanisms of molecular H 2 . Therefore, it may or may not be effective for all inflammation and oxidation-based diseases [38] .

In summary, a patient with PVS caused by ICH did not respond to routine neuronal rehabilitation treatment but recovered consciousness and locomotor function and restored his speech and emotional expression abilities following the administration of high-concentration H 2 inhalation treatment for 5 mo. Although the exact underlying mechanisms remain unclear, molecular H 2 may protect the brain from ICH due to its antioxidative stress and anti-neuroinflammatory properties. February 6, 2022

Volume 10 Issue 4

Phase 1 clinical trials are needed to determine the safety and efficacy of H 2 gas inhalation in PVS.

Intracerebral hemorrhage: an update on diagnosis and treatment

mediated brain injury after intracerebral hemorrhage in mice

Incidence and 10-year survival of intracerebral hemorrhage in a population-based registry

Intracerebral injection of autologous whole blood in rats: time course of inflammation and cell death

Molecular pathophysiology of cerebral hemorrhage: secondary brain injury

Hydrogen-Rich Saline Attenuated Subarachnoid Hemorrhage-Induced Early Brain Injury in Rats by Suppressing Inflammatory Response: Possible Involvement of NF-κB Pathway and NLRP3 Inflammasome

Early brain injury, an evolving frontier in subarachnoid hemorrhage research

NLRP3 deficiency ameliorates neurovascular damage in experimental ischemic stroke

Inflammation in intracerebral hemorrhage: from mechanisms to clinical translation

Role and mechanisms of cytokines in the secondary brain injury after intracerebral hemorrhage

Inflammatory responses after intracerebral hemorrhage: From cellular function to therapeutic targets

Neuroinflammation after Intracerebral Hemorrhage and Potential Therapeutic Targets

Potential therapeutic targets for intracerebral hemorrhage-associated inflammation: An update

Chronic inflammation, cognitive impairment, and distal brain region alteration following intracerebral hemorrhage

Melatonin Alleviates Intracerebral Hemorrhage-Induced Secondary Brain Injury in Rats via Suppressing Apoptosis, Inflammation, Oxidative Stress, DNA Damage, and Mitochondria Injury

Inhalation of hydrogen gas attenuates airway inflammation and oxidative stress in allergic asthmatic mice

Hydrogen-Rich Saline Attenuates Cardiac and Hepatic Injury in Doxorubicin Rat Model by Inhibiting Inflammation and Apoptosis

Molecular hydrogen reduces acute exercise-induced inflammatory and oxidative stress status

Effects of hydrogen on polarization of macrophages and microglia in a stroke model

Molecular hydrogen decelerates rheumatoid arthritis progression through inhibition of oxidative stress

Hydrogen does not Exert Neuroprotective Effects or Improve Functional Outcomes in Rats After Intracerebral Hemorrhage