Clinical characteristics and the risk factors analysis in patients with delayed encephalopathy after acute carbon monoxide poisoning

Abstract

Introduction

Acute carbon monoxide poisoning (ACMP) remains a leading cause of morbidity and mortality from fatal inhaled poisoning. Delayed encephalopathy after ACMP (DEACMP) has become one of the most complex and serious complications.

Methods

In this research, an observational study was performed from January 2016 to December 2019 to investigate the potential relevant risk factors of DEACMP with data collected from Level 3 medical facilities located in Northern China. Within the 4-year data collection period, the final study cohort consisted of 240 (117 males, 123 females).

Results

Uni-variable analysis identified older age, medical history of cerebrovascular accident, basic disease of diabetes, and longer duration of loss of consciousness as relevant factors for DEACMP; while multivariable logistic regression revealed that the older age (OR, 1.45; 95% CI, 1.25–1.69; P < 0.01), longer duration of loss of consciousness (OR, 1.39; 95% CI, 1.36–1.45; P < 0.01), and cerebrovascular accidents occurring (OR, 1.23; 95% CI, 1.03–1.47; P = 0.04) were independent predictors for DEACMP.

Discussion

Furthermore, additional research is needed to testify to the relevance and to elucidate the potential pathogenesis, consequently determining the clinical guideline and approving the best prevention and treatment strategy for DEACMP.

Keywords

acute carbon monoxide poisoning delayed encephalopathy risk factor the prognosis loss of consciousness

Introduction

Acute carbon monoxide poisoning (ACMP) remains one of the leading causes of morbidity and death of fatal inhaled poisoning, with an estimated incidence and mortality rate of 0.5 to 1.0 per million population in the United States and over 200 people hospitalized in the UK.^1,2 The prevalence may be higher in less economically developed countries or regions.^2,3

In general, ACMP occurs by the reason of such causes as inhalation of incomplete combustion of oil, fuel gas, briquettes, or charcoal in a closed area or exhaust gas from automobiles, resulting in dysfunction and damage to the central nervous and cardiovascular systems.⁴ There have been several studies exploring and elaborating the pathogenesis of ACMP, including ischemia hypoxia theory, cytotoxicity theory, and apoptosis theory.⁵

Of the diverse CO-related neurological and cardiovascular issues, delayed encephalopathy after ACMP (DEACMP), which is characterized by a series of neuropsychiatric symptoms after a “false recovery period” of approximately 2 days to 2 months (with an average duration of 22 days), has become one of the most complex and serious complications with 10–30% morbidity.^3,6 According to the clinical data, these neurological and psychiatric symptoms commonly include mental disorders, dementia, intellectual disability, increased muscle tone in the limbs, urinary and fecal incontinence, and coma.^7,8 Identifying the risk factors for DEACMP would, consequently, be conducive to assisting doctors in recognizing high-risk patients and adopting proactive measurement, for instance, hyperbaric oxygen (HBO) therapy to minimize the risk.^9,10

Several researchers have been exploring the risk factors of DEACMP in the literature, which approve that age, hypertension, coma duration, smoking habits, and degree of intoxication might be the main potential risk factors.^11,12 However, it remains unclear whether the results, including risk factors and clinical characteristics, are to some extent underpowered and applicable in contemporary management and prognosis, thereby warranting efforts to explore new diagnostic and predicting methods for DEACMP. Meanwhile, the guidelines or consensus on the prevention and treatment of DEACMP have not been well-established.¹³

Hospitals in China are divided into levels 1, 2, and 3. Level 3 hospitals are the most advanced hospitals, providing high-level specialized medical and health services, and carrying out higher education and research tasks to several regions at the regional level or above. Therefore, Level 3 hospitals in China are the main line medical facilities to treat patients with DEACMP. This observational study was performed to investigate the potential relevant risk factors of DEACMP with data collected from Level 3 medical facilities located in Northern China, where the source of CO exposure was mainly attributed to the indoor coal stove in cold winters. Then, by analyzing data from a real-world cohort, this study aimed to provide possible data support for the development of clinical prevention and treatment strategies for DEACMP patients.

Materials and methods

Study population

This retrospective observational cohort study included patients with ACMP. In this retrospective observational cohort study, the requirement for patient consent was waived by the ethics committee given that the research utilized existing medical records. The study was approved by the committee of the First Hospital Affiliated Zhengzhou University School (Ethical number 2019-KY-190). The study protocol adhered to the ethical guidelines of the 1975 Declaration of Helsinki.

The study population was divided into two groups based on whether there is concurrent DEACMP: (1) the DEACMP group; and (2) the Non-DEACMP group. A total of 521 ACMP patients who met the diagnostic criteria of acute carbon monoxide poisoning at First Hospital Affiliated Zhengzhou University School between January 2016 and December 2019 were enrolled in the study, and 76 patients were excluded as result of incomplete information. The diagnostic criteria of ACMP were as follows: (1) the history of CO exposure; (2) the presence of symptoms consistent with ACMP; and (3) carboxy-hemoglobin (COHb) level >10% in smokers and >5% in non-smokers.¹⁴ The DEACMP patients met the diagnostic criteria of delayed encephalopathy caused by carbon monoxide poisoning according to the handbook. Meanwhile, Magnetic Resonance Imaging was performed to diagnose DEACMP, with lesions located in special signs such as the globus pallidus, sub cortical white matter, and basal ganglia. Participants with the following situations were excluded: (1) co-existing disease with similar symptoms to delayed onset encephalopathy before ACMP, including senile dementia, Parkinson’s disease, paralysis of one and both limbs, epilepsy, schizophrenia; (2) age >90; (3) acute cerebrovascular accidents after regaining consciousness; (4) prolonged bed rest due to serious cardiovascular and cerebrovascular diseases; (5) incomplete data.¹⁵ Moreover, in this study, 34 patients with incomplete case information collection and 2 deceased patients during follow-up were excluded. Ultimately, a total of 240 ACMP participants were included in the analysis (Figure 1). Patient follow-up was conducted through outpatient clinical visits or telephone.

Figure 1.

Flowchart of selection process and data assessments of the present study.

Data collection and assessments

All data were collected by 3 trained investigators from an electronic medical recording system. These investigators were blinded to the aim of this research to minimize bias. The collected clinical characteristics included demographic data (such as gender, age, economic income, occupation, and marital status), basic vital signs (height, weight, heart rate (HR), systolic blood pressure (SBP), body temperature, and diastolic blood pressure (DBP)), history of cerebrovascular accident, past diseases (hypertension, diabetes, and coronary heart disease), clinical presentation, laboratory data, and echocardiographic results. Electronic medical records were used to gather this information.

Statistical analysis

Continuous variables and categorical variables were represented by mean ± standard deviation (SD) and number (proportion), respectively. The two-tailed Student t-test under normal distribution was used for univariate variable comparison, otherwise, the Mann-Whitney U-test was applied for nonnormal distribution. The comparison of categorical variables is conducted using the chi-square test or Fisher’s exact test. Then the variables that reached statistical significance in the univariate analysis were included in a multivariate logistic regression model designed to determine independent risk factors for DNS and calculate their odds ratios (OR) and 95% confidence intervals (CI). All statistical analysis was conducted using IBM SPSS Statistics 25. SPSS software was used to input various patient information, conduct data analysis based on the adopted statistical methods, and obtain results. The analysis results were used to create charts. P < 0.05 was considered statistically significant.

Results

Research population

As depicted in Figure 1, within the 4-year data collection period, a total of 521 cases of acute carbon monoxide poisoning were screened. Of them, 281 cases were excluded due to the above criteria, and the final study cohort consisted of 240 cases (117 males, 123 females). During follow-up, 72 patients developed DEACMP, while 168 patients were not combined with DEACMP.

Baseline characteristics

The baseline characteristics of the patients, as shown in Table 1, revealed significant differences between the DEACMP group and Non-DEACMP groups in terms of age (P < 0.05). Additionally, in terms of clinical presentation, there were no significant differences in body temperature, breath, and blood pressure among the groups (P > 0.05). According to the data analysis, older patients with ACMP exhibited a higher prevalence of DEACMP. Meanwhile, patients with cerebrovascular accidents held a higher risk of DEACMP compared to those who did not have the above-mentioned diseases (P < 0.05). Similarly, diabetes was found to be a significant factor among the various pathogenic factors. The incidence of delayed encephalopathy was higher among participants with diabetes compared to those without. However, patients with ACMP tended to have similar habits of smoking and drinking with or without delayed encephalopathy (P > 0.05). Additionally, the DEACMP groups showed longer periods of loss of consciousness in comparison to Non-DEACMP groups (P < 0.05). No significant difference in COHb levels at the initial hospital consultation was observed between the two groups in this study (P > 0.05). At the same time, the plasma levels of white blood cells (WBC), creatine kinase (CK), gamma-glutamyl transpeptidase (GGT), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were similar among the two groups (P > 0.05). As for the HBO therapy, part of the patients in the two groups accepted this therapy, and no significant difference was shown in the two groups in terms of delayed encephalopathy morbidity (P > 0.05).

Table 1.

Baseline characteristics and potential risk factors for delayed encephalopathy after carbon monoxide poisoning.

Clinical characteristics	DEACMP group (n = 72)	Non-DEACMP group (n = 168)	P-value
Male, n (%)	26 (36.11)	91 (54.17)
Female, n (%)	46 (63.89)	77 (45.83)
Age (years)	60.51 ± 11.33	42.33 ± 23.58	<0.01
Body temperature	36.54 ± 0.21	36.51 ± 0.23	0.34
Heart rate, bpm	77.29 ± 13.11	78.81 ± 11.14	0.36
Breathe	18.91 ± 3.43	19.20 ± 2.39	0.45
SBP, mmHg	105.35 ± 11.32	107.05 ± 19.92	0.50
DBP, mmHg	71.53 ± 8.36	71.81 ± 9.31	0.83
Cerebrovascular accident, n (%)	10 (13.89)	3 (1.79)	<0.01
Smoking history, n (%)	12 (16.67)	32 (19.05)	0.066
Drinking history, n (%)	5 (6.94)	19 (11.31)	0.30
History of hypertension, n (%)	22 (30.56)	25 (14.88)	0.05
History of diabetes, n (%)	13 (18.06)	10 (5.95)	<0.01
History of CAD, n (%)	7 (9.72)	6 (3.57)	0.05
Loss of consciousness	33 (45.83)	67 (39.88)	0.39
Duration of loss of consciousness (hours)	25.46 ± 5.80	9.89 ± 5.76	<0.01
COHB level at first hospital consultation (%)	25.78 ± 3.15	23.67 ± 6.73	0.41
WBC, ×10^9/L	8.69 ± 5.18	11.17 ± 15.81	0.20
CK-MB, U/L	280.03 ± 871.93	2116.86 ± 9070.25	0.09
CK, U/L	18.77 ± 12.53	56.79 ± 163.40	0.05
GGT, U/L	32.91 ± 60.05	28.76 ± 32.03	0.49
AST, U/L	44.78 ± 64.07	80.74 ± 197.61	0.13
ALT, U/L	42.08 ± 80.25	57.32 ± 130.20	0.36
BUN, mmol/L	5.80 ± 3.27	6.18 ± 5.71	0.60
HBO therapy, n (%)	59 (81.94)	140 (83.33)	0.79

Multiple-factor analysis for DEACMP morbidity

These potential risk factors were then evaluated in the multivariable logistic regression model. Table 2 showed the older age (OR, 1.45; 95% CI, 1.25–1.69; P < 0.01), longer duration of loss of consciousness (OR, 1.39; 95% CI, 1.36–1.45; P < 0.01), and cerebrovascular accidents occurring (OR, 1.23; 95% CI, 1.03–1.47; P = 0.04) were independent predictors for DEACMP.

Table 2.

Independent risk factors identified by logistic regression for delayed encephalopathy.

Variables	β	OR	95% CI	P value
Age	0.32	1.45	(1.25–1.69)	<0.01
Cerebrovascular accident	1.05	1.23	(1.03–1.47)	0.04
History of diabetes	2.45	2.18		0.85
Duration of loss of consciousness	1.56	1.39	(1.36–1.45)	<0.01

Figure 2 also visually illustrated the impact of various factors on the occurrence of delayed encephalopathy.

Figure 2.

Forest plot of independent risk factors identified by logistic regression for delayed encephalopathy.

Discussion

In this study, the characteristics and patterns of ACMP were assessed and certain key factors were discovered to associated with a significantly increased risk of morbidity in patients with DEACMP. The elderly (60.51 ± 11.33 years) and patients who had the duration of loss of consciousness (15.46 ± 5.80 h) were more commonly present with DEACMP by the multivariate logistic regression model. Most cases were encountered in ACMP patients with diabetes and cerebrovascular accidents.¹⁶ This finding is crucial for determining clinical guidelines and developing the advanced prevention and best treatment strategies for DEACMP patients.

Previous research has focused on evaluating the risk factors of the incidence of DEACMP in the general population all over the world. These studies have identified that demographic data and past medical history were two key factors affecting the outcomes of ACMP. Firstly, there was sufficient proof showing that age, male, and comorbidities were found to be independent predictors for DEACMP.^17,18 In terms of age, most investigators approved that older people tended to have delayed neurological sequelae cause of their worse body functions and healthy conditions.¹⁹ This study demonstrated that the average ages in the DEACMP group were 60.51 ± 11.33, while 42.33 ± 23.58 years in the Non-DEACMP group. The significant difference also approved the common issue that the elderly were more likely to have DEACMP. However, no obvious difference had been found between the sex and DEACMP morbidity in our research. Interestingly, the role of age and sex as predictors of DEACMP remains controversial. The study of reference 16 revealed age and sex had no relationship with the occurrence of delayed neurological sequelae.¹⁴ Region differences and medical standards discrepancies may be the root cause of this debate. Secondly, considering the the past medical history observed in DEACMP patients, it is reasonable to suspect that the presence of basic disease in patients with ACMP may be related to outcomes, such as delayed encephalopathy.²⁰ According to the follow-up study, diabetes and hypertension were the primary risk factor for patients with DEACMP, although diabetes and hypertension did not attain statistical significance in our study, patients with ACMP who exhibit comorbidity of both conditions necessitate heightened vigilance and prompt institution of active, standardized therapeutic interventions. Meanwhile, cerebrovascular accidents were found to be associated with DEACMP, since the vessel function affected blood supply to the brain and metabolism of various organs and tissues.²¹ Hence, it was reasonable that patients without coronary artery disease would have a better prognosis in terms of brain neurocognition.

The clinical characteristics, such as symptoms and signs of patients, reflect the severity of CO poisoning, and thus it is reasonable that they can be employed for the evaluation of DEACMP. Researches have indicated that a longer duration of loss of consciousness was related to the occurrence and development of delayed encephalopathy in ACMP patients, but voluntary exposure, headache, and transient loss of consciousness failed to predict carbon monoxide intoxication delayed encephalopathy.²² Of note, in this study, the period of loss of consciousness reached almost a day or even longer, indicating that the impact of coma on delayed encephalopathy required patients to experience a sufficiently long period of coma for significant differences in outcomes to occur. On the contrary, the blood parameters in the results were not observed a significant difference in DEACMP. Specifically, the significant difference in COHb level at first hospital consultation was not found between the two groups (P > 0.05). The COHb level only indicates the binding rate between CO and Hb. Therefore, it decreases over time when patients leave the CO environment and stop inhaling CO. At the same time, oxygen management is often included in ambulance transportation in Level 3 hospitals, which further reduces the level of COHb. Therefore, no significant correlation was observed between COHb levels at emergency admission and the development of DEACMP. What’s more, as mentioned above, more recent findings that patients having myocardial injury had elevated risk and prognostic factors for the development of DEACMP. This is supported by higher expression levels of the parameters that related to myocardial injury, such as S-100B, creatine kinase, troponin, and creatine kinase-MB in patients with DEACMP.^23–26 However, the application of these parameters in clinical practice warrants more clinical researches, and there is still controversy on several blood parameters. In this study, the limitation of sample size and incomplete blood testing indexes lead to this issue.

The pathogenesis of DEACMP is still poorly understood and several potential mechanisms that can account for the observed features in individuals have been proposed. The primary theory was hypoxia. As is well known, CO has an affinity for hemoglobin 300 times that of oxygen, and carbon monoxide in carboxyhemoglobin is 3600 times slower than oxygen, which lead to hypoxia after carbon monoxide poisoning, which is considered a factor associated with delayed encephalopathy.^27,28 Hence, the timely treatment for ACMP seems to be oxygenation, which simulates cerebral ischemia/reperfusion injury. Hyperbaric oxygen therapy refers to an intervention measure in which an individual breathes nearly 100% oxygen in a high-pressure chamber, where the pressure is greater than sea level pressure. Although carbon monoxide poisoning is one of the indications for HBO treatment, as well as there is evidence to suggest that HBO treatment is related to lower mortality rates, the impact of HBO treatment on delayed encephalopathy development remains controversial.²⁹ Another crucial mechanism is immune-mediated injury. CO poisoning also cause adduct formation between myelin basic protein (MBP) and malonylaldehyde, resulting in an immunological cascade.³⁰ Cerebrospinal fluid-MBP can serve as a sensitive predictor of both the development and outcomes of DNS.³¹ ACMP also lead to the formation of adducts between malondialdehyde and myelin basic protein, leading to an immune cascade reaction. However, the content of WBC, documented as a predictor of DEACMP, was not found as a prognostic value previously in this study. This will be partially attributed to the diverse follow-up intervals of their studies. In addition, metabolic dysfunction of brain, cytotoxicity of neurotransmitter production, reactive oxygen species accumulation, and cell death occurrence were elaborated to explain and analyze the occurrence and development of DEACMP.^32–35

Despite the notable findings, this study has some limitations that acknowledge.³⁶

First and foremost, this was an observational and retrospective study with inherent limitations in controlling for baseline characteristics of patients. This limitation may have influenced the results and conclusions drawn from the data. To further validate the findings and enhance statistical significance, a larger sample size and extended time span should be considered in future studies. Secondly, the existing data was not complete enough, since incomplete diagnostic tests (e.g., computerized tomography results, electroencephalogram) were important indicators for diagnosing the occurrence and development of DEACMP. Thirdly, unstandardized protocols for HBO therapy confounded the results of this study, future studies should endeavor to establish standardized protocols for hyperbaric oxygen therapy to guarantee uniformity in patient management and facilitate precise comparisons across treatment cohorts. Lastly, more standardized and longer follow-up times need to be taken into account, and this study also needs to pay extra attention to the community, as patients with only mild symptoms may seek treatment at Level 1 or 2 medical facilities, resulting in biased results.

Conclusion

In summary, the presence of older age, medical history of cerebrovascular accident, and longer duration of loss of consciousness are associated with a significantly increased risk of DEACMP morbidity in individuals. Further research is needed to confirm the relevance of these factors and to elucidate the potential underlying mechanisms. This information is crucial for determining clinical guidelines and developing the advanced prevention and best treatment strategies for DEACMP.

Footnotes

ORCID iD

Yanxia Gao

Statements and declarations

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by grants from The Key Scientific Research Projects of Institutions of Higher Learning in Henan Province (24A320025).

Conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Appendix

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