Hydrogen inhalation promotes recovery of a patient in persistent vegetative state from intracerebral hemorrhage:A case report and literature review

INTRODUCTION

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) 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 Hgas 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[5-7].Hgas inhalation selectively reduces hydroxyl radical and peroxynitrite levelsand 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 Hgas in the treatment of hepatic,renal,cardiac,and pulmonary diseases,including chronic obstructive pulmonary disease and coronavirus disease 2019[8-10].Hgas inhalation or H-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 Hgas inhalation that helped with the recovery from persistent vegetative state (PVS) caused by ICH,which is the first clinical report of high-dose Hgas therapy in a child in a PVS after ICH.

CASE PRESENTATION

Chief complaints

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.

History of present illness

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.

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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.

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

History of past illness

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.

Personal and 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+.

Physical examination

The patient had no personal or family history.

Laboratory examinations

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Imaging examinations

Since Ohsawa[2] reported that Hgas has antioxidant and anti-apoptotic properties that protect the brain against I/R injury and stroke by selectively neutralizing hydroxyl radicals,Hgas 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,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 Hgas[18,19].These studies demonstrated that Htreatment 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 Hgas inhalation in this PVS patient regarding his recovery and other functional impro-vements.

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[16-19].The patient failed to respond to neuroprotective treatment along with other methods of rehabilitation but steadily recovered after administration of high-concentration Hgas 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.The possible underlying mechanisms of Hgas inhalation in this PVS patient may be closely related to its antioxidative and anti-inflammatory effects.

FINAL DIAGNOSIS

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

TREATMENT

Hhas 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(66.6% Hand 33.3% O) inhalation treatment was administered.The treatment was given twice daily,for 2-3 h each time,for 5 mo.The initial Hgas inhalation treatment started 2 mo after the patient developed PVS.

OUTCOME AND FOLLOW-UP

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 Hgas 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 Hgas inhalation treatment compared to that before treatment.Furthermore,the median CT number,,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 Hgas 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 Hgas 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 Hgas inhalation.He could briefly communicate with others and speak words and phrases.Five months after initiation of treatment with Hgas 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.

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DISCUSSION

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Blood analysis revealed mild leukocytosis of 8.35 × 10/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.

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 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].

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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 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.

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 [,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[26-30].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].

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

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It is worth noting that not all PVS patients were responsive to molecular Htreatment in our clinical research.We tried high-concentration Hinhalation 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 Hinhalation.Considering that the pathophysiological mechanisms of neural injury and recovery of consciousness in brain diseases are complicated,the effectiveness of Hgas treatment might be dependent on the severity of brain damage and the multiple underlying mechanisms of molecular H.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 Hinhalation treatment for 5 mo.Although the exact underlying mechanisms remain unclear,molecular Hmay protect the brain from ICH due to its antioxidative stress and anti-neuroinflammatory properties.

CONCLUSION

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