Effect of hyperbaric oxygen on symptoms of dementia in patients with delayed encephalopathy after acute carbon monoxide poisoning

Abstract

Objective

Delayed encephalopathy after acute carbon monoxide poisoning (DEACMP) is the most severe complication of carbon monoxide poisoning, which seriously endangers patients’ quality of life. This study aims to investigate the efficacy of hyperbaric oxygen (HBO₂) on improving dementia symptoms in patients with DEACMP.

Methods

A retrospective analysis was performed on DEACMP patients, who visited Xiangya Hospital, Central South University from June 2014 to June 2020. Among them, patients who received conventional drug treatment combined with HBO₂ treatment were included in an HBO₂ group, while those who only received conventional drug treatment were included in a control group. HBO₂ was administered once daily. Patients in the HBO₂ group received 6 courses of treatment, with each course consisting of 10 sessions. The Hasegawa Dementia Scale (HDS) was used to diagnose dementia, and the Clinical Dementia Rating (CDR) was used to grade the severity of dementia for DEACMP. The Alzheimer’s Disease Assessment Scale-Cognitive Section (ADAS-Cog), the Functional Activities Questionnaire (FAQ), the Neuropsychiatric Inventory (NPI), and the Clinician’s Interview-Based Impression of Change-Plus Caregiver Input (CIBIC-Plus) were performed to assess cognitive function, ability to perform activities of daily living (ADL), behavioral and psychological symptoms, and overall function. The study further analyzed the results of objective examinations related to patients’ dementia symptoms, including magnetic resonance imaging detection of white matter lesions and abnormal electroencephalogram (EEG). The changes of the above indicators before and after treatment, as well as the differences between the 2 groups after treatment were compared.

Results

There was no significant difference in the HDS score and CDR grading between the 2 groups before treatment (both P>0.05). After treatment, the score of ADAS-Cog, FAQ, NPI, and CIBIC Plus grading of the 2 groups were significantly improved, and the improvement of the above indicators in the HBO₂ group was greater than that in the control group (all P<0.05). The effective rate of the HBO₂ group in treating DEACMP was significantly higher than that of the control group (89.47% vs 65.87%, P<0.05). The objective examination results (white matter lesions and abnormal EEG) showed that the recovery of patients in the HBO₂ group was better than that in the control group.

Conclusion

Hyperbaric oxygen can significantly relieve the symptoms of dementia in patients with DEACMP.

Carbon monoxide (CO) is an odorless, tasteless, and colorless gas resulting from the incomplete combustion of hydrocarbons^[1]. CO enters the lung and binds to hemoglobin to form high-affinity carboxyhemoglobin (COHb), which blocks oxygen transport. When the blood concentration of COHb exceeds 15%, it will cause clinical symptoms in patients; when it rises to 70%, it will lead to unconsciousness and even death^[2].

More seriously, survivors may develop a delayed neurologic syndrome called delayed encephalopathy after acute carbon monoxide poisoning (DEACMP) after an interval of several days to several weeks post-exposure to CO^[3]. Up to 95% of DEACMP patients experience a cognitive impairment that is difficult to manage and can severely affect patients’ life quality^[4].

The recognized mechanism of DEACMP is still unclear, and growing evidence indicates that DEACMP is related to abnormal neuroinflammation, oxidative stress, apoptosis, and immune-mediated injury^[5].

Hyperbaric oxygen (HBO₂) refers to the inhalation of pure oxygen that is isobaric with the environment when the body is in a hyperbaric condition. HBO₂ is considered the best treatment for acute CO poisoning and has good results in treating DEACMP^[6-7]. However, there has been limited clinical research on the effects of HBO₂ on symptoms of dementia in patients with DEACMP. This study aims to explore the influence of HBO₂ on symptoms of dementia in patients with DEACMP by neuropsychological evaluations.

1. Patients and methods

1.1. Ethics

The Ethics Committee of the Xiangya Hospital, Central South University approved the study protocol (No. 201312706). All of the recruited patients provided written informed consent.

1.2. Patients

A retrospective analysis was performed on DEACMP patients who visited Xiangya Hospital, Central South University from June 2014 to June 2020. The inclusion criteria were as follows: 1) The following diagnostic criteria for DEACMP^[8] were met. a) A clear history of acute CO poisoning; b) normal or nearly normal performance in the lucid interval; c) brain white matter in brain magnetic resonance imaging (MRI) showing bilateral demyelinating lesions. 2) Hasegawa Dementia Scale (HDS) score ≤30.5. 3) Patients and immediate family members agreed to authorize patient-related information to this study under the premise of privacy protection. The following exclusion criteria were applied: 1) Failure to complete HBO₂ therapy or related tests in the study protocol; 2) Previous personal or family history of a mental disorder; 3) Substance abuse; 4) Long-term use of a sedative, antidepressant, or intelligence-promoting medication; 5) A pre-existing disease affecting memory and cognitive ability or other pre-existing severe diseases, such as cardiovascular diseases, liver diseases, kidney diseases, diseases of the hematopoietic system, or other organ dysfunction.

1.3. Methods

1.3.1. Treatment

Conventional drug therapy included decreasing intracranial pressure, preventing or treating brain edema, improving brain circulation, promoting brain cell metabolism, relieving tremors, and maintaining water, electrolyte, and acid-base balance.

HBO₂ therapy was administered in an air compression chamber (YCQ34230/0.3/0.7-0.1-50 VIII w, Yantai Hoto Oxygen Industrial Equipment Co., Ltd., Shandong, China) at a pressure of 0.22 MPa. Pressurization time was 15 minutes, pressure stabilization time was 90 minutes (mask inhalation of 80 minutes with 100% oxygen), and decompression time was 15 minutes. HBO₂ was administered once daily, with each treatment session lasting 120 minutes. Each patient received 6 courses of HBO₂, with each treatment course consisting of 10 sessions. Each course of HBO₂ was separated by an interval of 5 days.

1.3.2. Neuropsychological evaluation

Before treatment, all patients were assessed for dementia severity using the Clinical Dementia Rating (CDR).

Neuropsychological tests were performed to assess cognitive function, ability to perform activities of daily living (ADL), behavioral and psychological symptoms, and overall function.

Cognitive function was assessed using the Alzheimer’s Disease Assessment Scale-Cognitive Section (ADAS-Cog)^[9]. The lower the score, the better the cognitive function. The ability to perform ADL was assessed using the Functional Activities Questionnaire (FAQ)^[10]. The total score is 30. A score >9 indicates an impaired ability to perform ADL. Behavioral and psychological symptoms were assessed using the Neuropsychiatric Inventory (NPI)^[11]. The sum of the scores on the 12 items is the final score on the NPI (0-144 points). The scale is completed by family members who have regular contact with the patient (at least once a week), are familiar with the patient’s condition, and can evaluate it according to the instructions. The overall function was assessed using the Clinician’s Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus)^[12], which was designed to detect overall patient status changes. The CIBIC-Plus is divided into 4 areas and has 7 grades (1, significantly improved; 2, improved; 3, slightly improved; 4, no change; 5, slightly worse; 6, worse; 7, severely worse). The effective rate=(Grade 1+Grade 2+Grade 3)/all cases×100%.

1.3.3. Neuropsychological testers

Two graduate students were appointed as testers responsible for implementing the neuropsychological tests. Both testers were trained and required to be kind and gentle in a tone to persuade the patient to cooperate with the test procedure and to keep the information provided as simple as possible. The testing environment was quiet, well-ventilated, comfortable, and well-lit. Generally, the tests were performed with only the tester and the patient in the room, avoiding distraction by others at the bedside. Tests were performed strictly with the manual of each set of scales, using the unified guidance language. According to the manual, testers implemented the time limits and provided a certain range of assistance if necessary. The testers also carefully used language that the patients could easily understand. The testers were required to avoid giving more hints than allowed in the guidelines and regulations.

1.3.4. Assessment of white matter lesions

This study used the modified Scheltens’ scale to assess the size and quantity of cerebral white matter lesions of the paraventricular and deep white matter on MRI^[13]. In the study, the score of paraventricular lesions was 0-6 points, and lesions in the posterior, anterior horn, and body of the lateral ventricle were assessed. The score of each site was 0-2 points, and then the sum was calculated. The evaluation criteria for each site were as follows: No lesion, 0 point; lesion less than 5 mm, 1 point; lesion 6 to 10 mm, 2 points. The score of deep white matter high signal was 0-24 points, and lesions in frontal, parietal, temporal, and occipital lobes were assessed. The score of each region was 0-6 points. The evaluation criteria were as follows: No lesions, 0 point; lesion size ≤3 mm and number ≤5, 1 point; lesion size ≤ 3 mm and number ≥6, 2 points; lesion size 4-10 mm and number ≤5, 3 points; lesion size 4-10 mm and number ≥6, 4 points; lesion size ≥11 mm and number ≥1, 5 points; lesion fused, 6 points. In order to ensure accuracy, all ratings were evaluated by 2 trained researchers.

1.3.5. Assessment of abnormal electroencephalogram

The diagnosis of electroencephalogram (EEG) was made by 2 senior doctors in the EEG room of our hospital. The diagnosis results were divided into normal, mild abnormal, moderate abnormal, and severe abnormal. The diagnostic criteria are as described earlier^[14].

1.3.6. Timing of assessments

All patients received neuropsychological tests, MRI, and EEG on the first day of treatment and the next day after the end of 6 courses of treatment.

1.3.7. Safety analysis

Blood, urine, and stool routines, liver and kidney function tests, electrocardiography, and other routine examinations were performed on all patients. During treatment, all patients were observed for adverse drug reactions, including nausea, vomiting, diarrhea, muscle spasm, insomnia, dizziness, fatigue, and impaired reaction times. Patients received HBO₂ therapy were monitored closely for signs of oxygen poisoning, decompression sickness, and barotrauma.

1.4. Statistical analysis

All statistical analyses were performed using SPSS software (Version 22; SPSS, Inc., Chicago, IL). Normally distributed data were expressed as mean±standard deviation (SD). The patient data were compared using the chi-squared test. The ADAS-Cog, FAQ, NPI, and the modified Scheltens’ scale scores were compared between the groups using the independent samples t test (the data satisfy the homogeneity of variance). The CDR, CIBIC-Plus, and EEG abnormal results were rated according to grade; the Wilcoxon method was used to test the rank sum of the graded data in the 2 samples. P<0.05 was considered statistically significant.

2. Results

2.1. Participants characteristics

This study recruited 78 patients hospitalized with DEACMP for the first time in our hospital. Among them, 39 patients (HBO₂ group) received HBO₂ therapy combined with conventional drug therapy, other 39 patients (control group) received only conventional drug therapy. Finally, 5 patients were excluded (1 in the HBO₂ group and 4 in the control group), leaving data for 73 patients available in the HBO₂ group (n=38) and the control group (n=35). None of the patients had received HBO₂ before. There was no significant difference in age, gender, illness duration, HDS score, or CDR score between the 2 groups (all P>0.05, Table 1).

Table 1.

Demographic characteristics of study participants

Groups	Gender/No.		Age/ years	HDS*/No.			CDR score/No.
	Male	Female		Dementia	Suspicious	Subnormal	0	0.5	1	2	3
Control	21	14	49.14±15.069	1	11	23	0	0	9	14	12
HBO2	18	20	47.32±14.241	2	9	27	0	0	5	18	15
χ 2/t/Z	1.168		0.533		0.731		0.959
P	0.280		0.596		0.694		0.337

*Dementia: 0-10.5 points; Suspicious: 11.0-21.5 points; Subnormal: 22.0-30.5 points. HDS: Hasegawa Dementia Scale; CDR: Clinical Dementia Rating; HBO₂: Hyperbaric oxygen.

2.2. ADAS-Cog score

Before treatment, the 2 groups had no significant difference in cognitive function (P=0.246, Table 2). After the completion of treatment, cognitive function improved in both groups (P=0.033 for the Control Group and P<0.001 for the HBO₂ group). And the ADAS-Cog score decreased more significantly in the HBO₂ group than that in the control group (P=0.013, Table 2), representing a more noticeable improvement in cognitive function.

Table 2.

Comparison of ADAS-Cog score between the 2 groups ( $\overline{\mathit{x}}$ ±s)

Groups	n	Before treatment	After treatment	t	P
Control	35	51.40±12.202	45.89±14.206	2.229	0.033
HBO2	38	54.79±12.523	37.13±15.212	6.274	<0.001
t		-1.170	2.536
P		0.246	0.013

ADAS-Cog: Alzheimer’s Disease Assessment Scale-Cognitive Section; HBO₂: Hyperbaric oxygen.

2.3. FAQ score

Before treatment, ADL damage was similar in both groups (P=0.193, Table 3). After the completion of treatment, the FAQ scores in both groups was significantly decreased (P<0.001 in both groups), and the FAQ score decreased more significantly in the HBO₂ group than that in the control group (P=0.042, Table 3).

Table 3.

Comparison of FAQ score between the 2 groups ( $\overline{\mathit{x}}$ ±s)

Groups	n	Before treatment	After treatment	t	P
Control	35	21.74±6.814	15.91±5.982	4.678	<0.001
HBO2	38	19.97±5.952	13.03±5.952	6.213	<0.001
t		1.315	2.066
P		0.193	0.042

FAQ: Functional Activities Questionnaire; HBO₂: Hyperbaric oxygen.

2.4. NPI score

Consistent with the above results, after treatment, the NPI scores of the 2 groups were both reduced (P=0.004 and P<0.001 in the control group and the HBO₂ group, respectively), and the NPI score was decreased more significantly in the HBO₂ group than that in the control group (P=0.029, Table 4).

Table 4.

Comparison of NPI score between the 2 groups ( $\overline{\mathit{x}}$ ±s)

Groups	n	Before treatment	After treatment	t	P
Control	35	92.69±24.857	75.43±20.820	3.090	0.004
HBO2	38	90.61±20.885	64.79±19.835	5.423	<0.001
t		0.388	2.236
P		0.699	0.029

NPI: Neuropsychiatric Inventory; HBO₂: Hyperbaric oxygen.

2.5. CIBIC-Plus grading and effective rate

We further analyzed the differences in efficacy between the 2 groups. After treatment, the CIBIC-Plus scores were significantly lower in the HBO₂ group than in the control group (Z=-2.303, P=0.021; Table 5). The efficacy rate was 68.57% in the control group and 89.47% in the HBO₂ group, and the difference between the 2 groups was statistically significant (χ²=4.876, P=0.027; Table 5).

Table 5.

Comparison of CIBIC-Plus grading and effective rate between the 2 groups

Groups	n	CIBIC-Plus grading/No.							Efficacy rate/%
		1	2	3	4	5	6	7
Control	35	4	9	11	6	4	1	0	68.57
HBO2	38	9	13	12	3	1	0	0	89.47
Z/χ 2		-2.303							4.876
P		0.021							0.027

CIBIC-Plus: Clinician’s Interview-Based Impression of Change-Plus Caregiver Input; HBO₂: Hyperbaric oxygen.

2.6. White matter lesions

MRI results showed that the scores of the modified Scheltens’ scale in the 2 groups were significantly reduced after treatment (P<0.001 in both groups), and the score was decreased more significantly in the HBO₂ group than that in the control group (P=0.011, Table 6).

Table 6.

Comparison of the modified Scheltens’ scale scores between the 2 groups ( $\overline{\mathit{x}}$ ±s)

Groups	n	Before treatment	After treatment	t	P
Control	35	19.40±4.692	14.46±5.543	4.662	<0.001
HBO2	38	20.50±4.942	10.89±6.017	8.055	<0.001
t		-0.973	2.624
P		0.334	0.011

HBO₂: Hyperbaric oxygen.

2.7. EEG classification

Similar to the results of the MRI examination, EEG abnormalities were reduced in the 2 groups after treatment, and the abnormal rates of EEG in the control group and the HBO₂ group decreased from 80% (28/35) and 81.58% (31/38) to 54.29% (19/35) and 31.58% (12/38), respectively. The results showed that HBO₂ was more effective in alleviating EEG abnormalities, especially those with moderate and severe abnormalities (P=0.037, Table 7).

Table 7.

Comparison of EEG classification between the 2 groups

Groups	n	Before treatment/No.				After treatment/No.
		Normal	Mild	Moderate	Severe	Normal	Mild	Moderate	Severe
Control	35	7	15	8	5	16	10	6	3
HBO2	38	7	16	10	5	26	8	3	1
Z		-0.255				-2.090
P		0.799				0.037

EEG: Electroencephalogram; HBO₂: Hyperbaric oxygen.

2.8. Safety profiles

Regarding subjective symptoms, 1 patient in the control group developed nausea and vomiting, and another reported mild insomnia. One patient in the HBO₂ group reported slight dizziness, and another complained of slight insomnia. All adverse reactions were mild and resolved spontaneously. There was no significant difference in the incidence of adverse events between the 2 groups (P>0.05). For objective examination, no noticeable abnormalities were found in the blood, urine, stool routines, liver and kidney function tests, or electrocardiography. Our observation showed no cases of oxygen poisoning, decompression sickness, or air pressure injury in the HBO₂ group.

3. Discussion

Dementia is an acquired syndrome of cognitive impairment involving memory, learning, orientation, understanding, judgment, calculation, language, visual space, and other functions. Dementia is enough to interfere with ADL, social relationships, and job performance. At a particular stage of the disease, it is often accompanied by mental, behavioral, and personality abnormalities. Characterizing a chronic and progressive nature^[15], dementia is the primary clinical manifestation of DEACMP^[16].

Clinical experience has confirmed that neuropsychological evaluation is essential in patients with dementia^[17]. Neuropsychological tests are being used increasingly in these patients, and its role in diagnosing and treating dementia has been valued. This clinical study used the HDS to diagnose dementia and the CDR tools to grade the severity of dementia for DEACMP. The ADAS-Cog, FAQ, NPI, and CIBIC-Plus were then used to evaluate the effect of HBO₂ on the symptoms of dementia in the study groups.

The results of the experiment showed that HBO₂ could significantly reduce the scores of ADAS-Cog, FAQ, NPI, and CIBIC-Plus in the DEACMP patients, playing a stable role in relieving patients’ cognitive dysfunction, including language, memory, practice, behavior, and improving patients’ daily living ability and overall functional status. The results indicated that HBO₂ is an effective means to improve cognitive function in patients with DEACMP. Our result is similar to the previous study. Xiang et al^[18] found that HBO₂ could improve the Mini-Mental State Examination (MMSE) scale score, reduce the National Institutes of Health Stroke Scale (NIHSS) scores of DEACMP patients, and improve the cognitive function of patients. More interestingly, a previous study^[19] has found that the cognitive function of DEACMP patients after finishing HBO₂ treatment can further improve over the next year. Moreover, in addition to treating dementia caused by DEACMP, HBO₂ significantly relieves various causes of dementia, such as vascular dementia^[20], Alzheimer’s disease^[21], traumatic brain injury^[22], and even post-COVID cognitive impairment^[23].

Increasing oxygen supply and tissue oxygen partial pressure is the most basic mechanism of HBO₂ in treating dementia^[24]. Raised oxygen partial pressure can promote a series of chain reactions, such as reducing intracellular edema and intracranial pressure, promoting cellular aerobic metabolism, and improving mitochondrial function^[25]. Subsequently, HBO₂ improves the function and state of the central nervous system by reducing oxidative stress and neuroinflammation, inhibiting nerve cell apoptosis, promoting angiogenesis, and the secretion of neurotrophic factors^{[22, 26-27]}.

Along with gray matter, white matter organizes human behavior and enables the extraordinary repertoire of human cognitive capacities. White matter demyelination is the responsible pathological change in diseases with dementia symptoms, including Alzheimer’s disease, vascular dementia, and DEACMP^[28-29]. White matter lesions on MRI often appear earlier than cognitive function changes and can be used to predict the trend of dementia symptoms in patients over a while^[30]. Consistent with the changes in dementia symptoms, this study found that HBO₂ can significantly reduce the range of white matter lesions and the pathological changes of dementia.

EEG is another vital examination for diagnosing and assessing clinical changes in dementia. Increased activity of slow wave (theta and delta frequencies) in EEG and decreased activity in the alpha frequency band are typical findings in dementia^[31]. This experiment found that with the relief of dementia symptoms in DEACMP patients, their abnormal EEG also recovered to varying degrees. This also confirmed that HBO₂ not only changes the clinical symptoms of DEACMP but also promotes the recovery of abnormal brain electrical activity to normal.

The results of this study show that HBO₂ can significantly reduce ADAS-Cog, FAQ, NPI, CIBIC-Plus, the modified Scheltens’ scale scores, and abnormal EEG classification in patients with DEACMP, as well as improve their cognitive function, enhance ADL performance, and attenuate mental and behavioral changes, thereby relieving the symptoms of dementia, reducing pathological changes and abnormal brain electrical activity, enhancing the therapeutic efficacy in patients with DEACMP, and being more conducive to recovery.

Contributions: HUANG Fangling Experimental operation, data analysis, and paper writing; HUANG Yanqing and WANG Su’e Data collecting and analysis; HUANG Xu Data collecting; PENG Zhengrong Research design, paper revision and supervision. All authors have approved the final version of the manuscript.

Funding Statement

This work was supported by the Natural Science Foundation of Hunan Province (2021JJ31089) and the Scientific Research Project of Health Commission of Hunan Province (202203104548), China.

Conflict of Interest

The authors declare that they have no conflicts of interest to disclose.

Note

http://xbyxb.csu.edu.cn/xbwk/fileup/PDF/2023111669.pdf