Abstract
-
Background
- Carbon monoxide (CO) poisoning can lead to significant morbidity and mortality. However, relatively few studies have investigated its long-term mortality impact. This nationwide population-based cohort study examined the association between CO poisoning and long-term mortality.
-
Methods
- This retrospective study utilized data from the National Health Insurance Service database in South Korea. We compared the patients with CO poisoning to those without CO poisoning. Inverse probability treatment weights were applied to both groups to control for potential confounding factors. Subsequently, mortality was assessed using the incidence rate and Cox proportional hazard ratios.
-
Results
- This study included 23,387 patients with CO poisoning and 359,851 without it. Over a median follow-up period of 7.6 years after CO poisoning diagnosis, the mortality risk was 2.6 times higher in patients with CO poisoning compared to that in the control group. In a long-term follow-up of patients surviving beyond 30 days, mortality remained 2.18 times higher. Additionally, a higher mortality risk was observed in the relatively younger age group (18–39 years) and the group with fewer underlying diseases, as indicated by a Charlson Comorbidity Index score of 0.
-
Conclusions
- CO poisoning is associated with an elevated long-term mortality rate particularly in a relatively young and healthy population.
-
Keywords: carbon monoxide; carbon monoxide poisoning; mortality
INTRODUCTION
Despite an estimated global cumulative incidence of 137 carbon monoxide (CO) poisoning cases and 4.6 deaths per million, there has been no significant decrease in the incidence of CO poisoning [1]. In contrast, a few Northeast Asian countries are experiencing an alarming upward trend. Taiwan has witnessed a surge in CO poisoning cases, with the incidence of suicide by charcoal burning increasing nearly 25-fold [2,3]. Similarly, China experienced a rising trend in CO poisoning from 1990 to 2019 [4]. The late 2000s saw a spike in CO suicides following the high-profile death of a famous actor due to CO poisoning. Additionally, South Korea has seen a rise in CO poisoning due to its growing population and the reckless use of camping supplies such as fuel and heating appliances [3,5,6].
CO poisoning, caused by the incomplete combustion of hydrocarbons, is a significant health concern due to its high toxicity [7-13]. CO’s affinity for hemoglobin is over 200 times greater than that of oxygen, leading to the formation of carboxyhemoglobin and subsequent cellular hypoxia [14]. Moreover, CO triggers inflammation, disrupts mitochondrial respiration, and generates free radicals, contributing to cardiac and neurological injuries [7]. While research has explored the complications of CO poisoning, such as epilepsy, venous thromboembolism, and myocardial infarction, long-term mortality data from large-scale populations remains scarce. This nationwide population-based cohort study addresses this gap by examining the association between CO poisoning and long-term mortality.
MATERIALS AND METHODS
This study was conducted in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of Hanyang University Hospital (protocol codes 2023-10-025 and October 19, 2023). Given the retrospective nature of this study, the need for written informed consent was waived.
Study Design and Setting
This population-based study used data from the National Health Insurance Service (NHIS) database in South Korea. South Korea operates a government led single payer health insurance system. The NHIS, a mandatory universal public health insurance system, covers approximately 97% of the Korean population and provides medical aid to 3% of those with the lowest income. The NHIS serves approximately 50 million people.
Data categorization was based on the International Statistical Classification of Diseases, 10th Revision (ICD-10) codes. The NHIS database includes patient information, including sex, age, income, date of death, and medical history, encompassing medication prescriptions and procedures. Researchers cannot identify personal information due to the anonymized nature of data transmission.
Patients with CO poisoning between January 2005 and December 2021 were included and identified using the ICD-10 code T58 for CO poisoning. To establish a control group, we evaluated the initial control pool. This pool comprised individuals who were approximately 1:8 matched to the CO poisoning group based on age and sex and were provided by the NHIS for research purposes. To refine the definition of acute intoxication, patients with CO poisoning were defined as those diagnosed with CO poisoning in the emergency department (ED) during the study period. The ED diagnosis was based on the emergency medical care fees billed upon utilizing emergency services in South Korea.
Study Population
To ensure follow-up beyond 5 years, patients diagnosed with CO poisoning in 2004 (during the wash-out period) and from 2017 to 2021 were excluded. Patients without emergency medical management fees, those under 18 years of age, and those with missing covariates were excluded from the study.
Study Covariables
We divided the study population into four income quartiles to assess socioeconomic status. Overall comorbidity burden was determined using the Charlson Comorbidity Index (CCI), which evaluates the following comorbidities: hypertension, diabetes mellitus, dyslipidemia, chronic pulmonary disease, ischemic heart disease, myocardial infarction, congestive heart failure, stroke, dementia, solid cancer, hematologic malignancy, and chronic kidney disease/end stage renal disease. Additionally, we identified psychotic, bipolar, substance related, depressive, unspecified mood, and anxiety disorders. Disease severity was categorized as mild, moderate, or severe, corresponding to discharge, general ward admission, and intensive care unit admission, respectively.
Study Outcomes
The primary objective of this study was to compare the long-term mortality risk between patients with CO poisoning and controls. The study population was followed up until either their date of death or December 31, 2021. We assessed short-term mortality within the initial 30 days following a CO poisoning diagnosis and long-term mortality in patients surviving beyond 30 days. Additionally, we aimed to identify risk factors associated with long-term mortality in patients with CO poisoning.
Statistical Analysis
Categorical variables are presented as numbers and percentages. To compare categorical variables between the two groups, Fisher’s exact test was employed. The Shapiro-Wilk test was utilized to assess the normality of continuous variables. Normally distributed continuous variables are represented as mean and standard deviation. In contrast, non-normally distributed variables are represented by the median and interquartile range (IQR). Either the Student t-test or the Wilcoxon rank-sum test was performed, depending on the normality test results.
The propensity score was estimated using logistic regression, incorporating all covariates. The inverse probability of treatment weighting (IPTW) method was applied using the estimated propensity scores. The primary analysis results are presented for both the patient and control groups after applying IPTW. The standardized mean difference (SMD) was employed to evaluate the balance between the patient and control groups before and after IPTW for each covariate. An SMD value of less than 0.1 was considered negligible regarding the differences between the two groups.
The Cox proportional hazards model was used to calculate the hazard ratio (HR), 95% CI, and P-value. To analyze the risk of mortality based on general characteristics, the number of deaths and person-years of observation were calculated, and the incidence rate was estimated per 1,000 person-years. The Kaplan-Meier method was employed to describe survival curves and probabilities for both groups. Statistical analyses were conducted using the SAS Enterprise Guide, version 7.1 (SAS Institute Inc.). The significance level was set at P<0.05; any P-value below 0.05 was considered statistically significant.
RESULTS
Baseline Characteristics of the Study Population
Between 2005 and 2021, 59,282 patients with CO poisoning were identified, while the initial control group comprised 469,456 individuals. Following the application of exclusion criteria to both groups, 35,895 and 106,705 individuals were excluded, respectively, resulting in 23,387 patients with CO poisoning and 359,851 controls (Figure 1). Table 1 summarizes the baseline characteristics of the study population. In both groups, most individuals were aged 40–64 years, accounting for 42.8% and 42.9%, respectively. Males constituted 55.7% and 53.1% of patients in the CO poisoning and control groups, respectively. Regarding income, the lowest quartile was more prevalent in the CO poisoning group (33.7%), while the highest quartile was relatively low (18%). The CO poisoning group had a lower proportion of individuals with a CCI score of 0 and a higher proportion with scores of 1, 2, and 3 or more than that in the control group. The prevalence of underlying psychiatric disorders was higher in the CO poisoning group (23.8%) than in the control group (12.1%). Additionally, the CO poisoning group had a higher proportion of individuals in the moderate to severe categories.
Characteristics of the Population after Adjustment by IPTW
The IPTW results demonstrated that the SMD of all variables converged to nearly 0.1, indicating a well-balanced comparison between patients with CO poisoning and controls. Table 1 outlines the baseline characteristics of the two groups. No statistically significant differences were observed in any variables between the two groups. For all covariates, the SMD was less than 0.1, confirming the absence of substantial differences between the two groups.
Incidence Rate and Risk of Mortality in the CO Patient Group Versus The Control Group
The cohort of CO patients had a median follow-up duration of 7.6 years (IQR, 6.0–9.9 years), while the control group had a median follow-up duration of 8.0 years (IQR, 6.8–10.7 years). Long-term mortality was significantly higher in the CO poisoning group compared to that in the control group (18.84 vs. 7.13 per 1,000 person-years, P<0.001) (Table 2). The HR for mortality was 2.60 (95% CI, 2.55–2.66) in the CO poisoning group compared to that in the controls. Similarly, 30-day follow-up mortality was significantly higher in patients with CO poisoning (HR, 1.61; 95% CI, 1.34–1.93]). Moreover, long-term mortality in individuals surviving for 30 days or more was significantly elevated in this group (HR, 2.18; 95% CI, 2.14–2.23). The cumulative incidence probability of mortality exhibited a significant difference between patients with patients with CO poisoning and controls (log-rank P<0.001) (Figure 2).
When considering all variables, the HR for mortality was significantly higher in the CO poisoning group than that in the control group (Figure 3). In the CO poisoning group, the HR for the age group 18–39 years was particularly high at 11.38 (95% CI, 10.32–12.55), and the HR for individuals with a CCI score of 0 was significantly elevated at 4.04 (95% CI, 3.89–4.19). Additionally, the relatively lower income group (Q3, Q4) showed a higher HR compared to the higher income group (Q1, Q2). The figures for the number of risks, number of deaths, and incident rates are provided in Supplementary Table 1.
DISCUSSION
Even after adjusting for potential confounders, the mortality risk among patients with CO poisoning remained 2.6 times higher than in controls during a median follow-up duration of 7.6 years after CO poisoning diagnosis. This elevated risk persisted in both the 30-day follow-up (1.61 times higher mortality) and the long-term follow-up for patients surviving beyond 30 days (2.18 times higher mortality). A higher mortality risk was observed in the relatively younger age group (18–39 years) and the group with fewer underlying diseases, as indicated by a lower CCI.
Our study’s nationwide approach enabled us to comprehensively evaluate long-term mortality rates among patients with CO poisoning. While previous studies have analyzed national claims data, their scale was limited, with no study involving tens of thousands of patients [15]. Our comprehensive subgroup analyses identified groups with higher risk factors for mortality. We adjusted risk estimates by controlling for covariates and employed IPTW to strengthen causal influence. By identifying CO poisoning groups with higher mortality than the control group, we provide valuable insights for developing effective policies aimed at prevention and post-poisoning management.
Two key factors were considered in evaluating the association between CO poisoning and long-term mortality. Firstly, CO poisoning is a severe condition linked to significant morbidity. Studies have shown an increased risk of myocardial infarction and venous thromboembolism during the first month following [9,16]. Additionally, research indicates that CO poisoning can lead to cardiac fibrosis, stroke, and epilepsy [8,17,18]. Apart from direct solid organ damage, studies have reported an increased risk of adrenal insufficiency as an endocrine issue following CO poisoning [19]. There is a possibility of death due to these complications following CO poisoning. The second factor involves intentional exposure to CO poisoning, followed by the recurrence of suicide as the cause of death. According to one study, 35.2% of CO poisoning cases involved intentional exposures [20]. A previous suicide attempt is a strong predictor of future suicide, with approximately 30% of individuals who attempt suicide making repeated attempts, and the all-cause mortality rate was 11.6% three months after a suicide attempt [21,22]. The incidence of suicide varies across countries and is relatively high in South Korea [23].
Despite an HR of 1.61 within the initial 30 days, the HR during the follow-up period for survivors within the initial 30 days was even higher at 2.18. This emphasizes the importance of ongoing management after initial treatment for CO poisoning. Previous studies reported an HR of 8.4 for epilepsy following CO poisoning compared to that in the control group [8]. Additionally, research indicates that more than 6 years after CO poisoning, the CO poisoning group had a 1.84-fold higher risk of ischemic stroke than that in the control group [18]. Furthermore, 1 year after CO poisoning, the incidence of adrenal insufficiency was 2.1 times higher in the CO poisoning group compared to that in the control group [19].
In Figure 3, compared to the controls, HRs of CO poisoning were higher among the relatively healthy group who were young, had a low CCI, and had mild disease severity. We think that it might be because older individuals, those with high CCI, and those with high severity are more likely to die from other causes even without CO poisoning, resulting in a comparatively lower HR (Supplementary Table 1). For example, the incident rate of death per 1,000 person-years among the controls aged 18–39 was 0.62, while it was 7.36 for those with CO poisoning. However, for those aged 65 and over, the incident rate was 35.59 for the controls and 62.59 for those with CO poisoning. In other words, the proportion of patients who would not have died if not for CO poisoning is higher in the relatively healthy group. And we cautiously suggest that suicide, being the leading cause of death among teens and people in their twenties and thirties in Korea, may have influenced mortality rates in an otherwise healthy demographic [24]. Additionally, it was observed that the lower income groups (Q3, Q4) exhibited relatively higher mortality rates compared to the higher income groups (Q1, Q2). We considered two possible reasons to explain this result. Firstly, there may be issues related to medical costs and insurance. In South Korea, there is a public health insurance system that covers approximately 64.5% of total medical expenses [25]. However, previous studies have reported that having private insurance in addition to the NHIS is associated with lower costs, increased inpatient utilization, and lower mortality, particularly among high-income individuals who are more likely to have private insurance [26,27]. We think that differences in healthcare utilization may contribute to the differences in mortality. Secondly, individuals with higher socio-economic status are more likely to make greater use of preventive healthcare services, which enhances the likelihood of better post-treatment management. CO poisoning can lead to numerous complications after the initial poisoning event, such as delayed neuropsychiatric syndrome, myocardial infarction, and venous thromboembolism. Preventive management of these complications could have influenced the observed differences in mortality rates.
There are two ways of being exposed to CO poisoning: intentional and unintentional. Previous research in South Korea indicates that approximately 65% of CO poisoning cases are unintentional, while about 35% are intentional [20]. The most common sources of unintentional exposure are fires and charcoal, and there is a growing incidence of CO exposure during campus activities, especially with the recent population increase [6]. Beyond providing appropriate treatment, preventing safety incidents requires societal attention. This includes considering ventilation needs, adherence to safety regulations, and installing CO detectors. If intentional exposure is suspected, early psychiatric referral may be crucial to preventing suicide reattempts [22]. Referral to psychiatric services within seven days has been associated with a decreased risk of suicide reattempts. Additionally, given the increase in CO poisoning suicides following a well-known actor's suicide, it is necessary to exercise caution when reporting on such celebrity suicides to mitigate the potential "Werther effect," where media reporting on a celebrity's suicide can influence others to take similar actions.
A previous study reported a 5.24-fold standardized mortality ratio for all-cause mortality in patients with CO poisoning compared to that in controls [15]. We attribute the differences between our study and the previous findings to several factors. First, the previous study focused on patients admitted to the intensive care unit, which likely contributed to the higher mortality rate due to the increased disease severity of patients in that cohort. Secondly, including children aged 0–18 years in the previous study may have elevated the risk. Our study excluded pediatric cases, and our findings and those of previous studies suggest a trend of increased HR among younger age groups [15]. Additionally, our study included approximately 53 times more patients with CO poisoning than in previous studies.
This holds significant implications in public health. In several countries in Northeast Asia including South Korea, there is an increasing prevalence of CO poisoning contrary to global trends. Moreover, over 80% of CO poisoning patients are relatively young individuals, not elderly over 65 years old. CO poisoning elevates the risk of death by approximately 11 times in the younger age group of 18–39 years. Given these results, there is a critical need for heightened awareness. Young patients presenting to the emergency room with CO poisoning require not only hospital-level follow-up but also national-level strategies.
This study had several limitations. Firstly, the national claims database lacks clinical and laboratory data, such as duration of CO exposure, carboxyhemoglobin levels, and exposure intentionality. Secondly, in order to maximize the association between CO poisoning and mortality, we used IPTW and included covariates that may affect mortality. However, due to the limitations of the data, we could not determine the cause of death. Identifying the cause of death could have been more effective in preventing mortality. Further research is needed. Thirdly, only ED based patients were included. Patients with CO poisoning seeking outpatient care were excluded because the study population was defined as those with both an emergency medical care fee and a diagnosis of CO poisoning. However, considering that CO poisoning primarily occurs after suicide attempts or accidents (e.g., fires, gas leaks), we believe that the number of patients with CO poisoning visiting outpatient facilities may be relatively low. Fourth, a high HR was observed in patients with psychotic disorders, with anxiety disorders showing the highest results among them. However, we were unable to determine the specific mechanisms behind this finding.
The long-term mortality risk among patients with CO poisoning was significantly higher than that of matched controls. This difference was particularly evident in younger patients and those without underlying conditions. CO poisoning poses a significant social burden, necessitating increased social awareness, preventive measures, and long-term monitoring of post-poisoning complications. Additionally, survivors of suicide attempts should receive ongoing psychiatric care.
KEY MESSAGES
▪ Our study investigated the long-term mortality of carbon monoxide poisoning patients using National Health Insurance Service data.
▪ Carbon monoxide poisoning is associated with an elevated long-term mortality rate, particularly in a relatively young and healthy population.
▪ Although the short-term 30-day mortality rate was also high, survivors beyond 30 days had an even higher mortality rate.
▪ We provide valuable insights for developing effective policies aimed at prevention and post-poisoning management.
NOTES
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CONFLICT OF INTEREST
No potential conflict of interest relevant to this article was reported.
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FUNDING
This research was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) and funded by the Korean government (MSIT) (NRF-2021R1C1C1004929).
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ACKNOWLEDGMENTS
None.
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AUTHOR CONTRIBUTIONS
Conceptualization: BSK, HK, THL. Methodology: BSK, YC, KHY. Software: SHL, BSK, KHY, SRR. Formal analysis: SRR, SHL, BSK, JL. Investigation: SRR, SHL. Data curation: SRR, SHL. Visualization: SHL. Supervision: BSK, JO. Validation: BSK, YC, JO. Writing - original draft: SHL. Writing - review & editing: BSK, THL, HK, JO. All authors read and agreed to the published version of the manuscript.
SUPPLEMENTARY MATERIALS
Supplementary materials can be found via https://doi.org/10.4266/acc.2024.00199.
Figure 1.Flowchart of the study population. CO: carbon monoxide.
Figure 2.Cumulative incidence of mortality between the two groups during the follow-up period. CO: carbon monoxide.
Figure 3.Increased mortality in carbon monoxide poisoning versus matched controls, stratified analysis according to age group, sex, income, Charlson Comorbidity Index (CCI), psychiatric disorder, severity. Severity was categorized as mild, moderate, and severe, corresponding to discharge, general ward admission, and intensive care unit admission, respectively. Q: Quartile; d/o: disorder.
Table 1.Demographic characteristics of study population and after IPTW adjustment
|
Variable |
Before IPTW
|
After IPTW
|
|
CO poisoning (n=23,387) |
Control (n=359,851) |
SMD |
CO Poisoning (n=191,841) |
Control (n=191,397) |
SMD |
|
Age (yr) |
18–39 |
9,340 |
39.9 |
144,451 |
40.1 |
–0.004 |
73,932 |
38.5 |
76,753 |
40.1 |
–0.032 |
|
40–64 |
10,009 |
42.8 |
154,210 |
42.9 |
–0.001 |
81,837 |
42.7 |
82,030 |
42.9 |
–0.004 |
|
≥65 |
4,038 |
17.3 |
61,190 |
17.0 |
0.007 |
36,072 |
18.8 |
32,613 |
17.0 |
0.046 |
|
Sex |
Male |
13,034 |
55.7 |
191,196 |
53.1 |
0.052 |
100,744 |
52.5 |
102,009 |
53.3 |
–0.016 |
|
Female |
10,353 |
44.3 |
168,655 |
46.9 |
–0.052 |
91,097 |
47.5 |
89,388 |
46.7 |
0.016 |
|
Income |
Q1 (Highest) |
4,199 |
18.0 |
91,614 |
25.5 |
–0.183 |
48,310 |
25.2 |
47,849 |
25.0 |
0.004 |
|
Q2 |
5,314 |
22.7 |
90,511 |
25.2 |
–0.057 |
48,183 |
25.1 |
47,855 |
25.0 |
0.003 |
|
Q3 |
5,990 |
25.6 |
89,859 |
25.0 |
0.015 |
47,506 |
24.8 |
47,861 |
25.0 |
–0.006 |
|
Q4 (Lowest) |
7,884 |
33.7 |
87,867 |
24.4 |
0.206 |
47,842 |
24.9 |
47,833 |
25.0 |
–0.001 |
|
CCI |
0 |
13,455 |
57.5 |
232,007 |
64.5 |
–0.143 |
120,914 |
63.0 |
122,561 |
64.0 |
–0.021 |
|
1 |
5,483 |
23.4 |
74,997 |
20.8 |
0.063 |
40,495 |
21.1 |
40,191 |
21.0 |
0.003 |
|
2 |
2,197 |
9.4 |
28,756 |
8.0 |
0.050 |
16,043 |
8.4 |
15,464 |
8.1 |
0.010 |
|
≥3 |
2,252 |
9.6 |
24,091 |
6.7 |
0.108 |
14,389 |
7.5 |
13,182 |
6.9 |
0.024 |
|
Psychiatric disorder (yes) |
5,576 |
23.8 |
43,576 |
12.1 |
0.309 |
24,854 |
13.0 |
24,526 |
12.8 |
0.004 |
|
Psychotic d/o |
431 |
1.8 |
2,585 |
0.7 |
0.100 |
1,605 |
0.8 |
1,514 |
0.8 |
0.006 |
|
Bipolar d/o |
538 |
2.3 |
1,683 |
0.5 |
0.157 |
1,121 |
0.6 |
1,117 |
0.6 |
0.000 |
|
Substance related d/o |
697 |
3.0 |
1,165 |
0.3 |
0.210 |
956 |
0.5 |
943 |
0.5 |
0.001 |
|
Depressive d/o |
2,841 |
12.2 |
14,756 |
4.1 |
0.298 |
8,757 |
4.6 |
8,796 |
4.6 |
–0.002 |
|
Unspecified mood d/o |
134 |
0.6 |
944 |
0.3 |
0.048 |
530 |
0.3 |
541 |
0.3 |
0.000 |
|
Anxiety d/o |
4,079 |
17.4 |
33,639 |
9.4 |
0.239 |
18,866 |
9.8 |
18,838 |
9.8 |
0.000 |
|
Severity |
Mild |
18,908 |
80.9 |
321,213 |
89.3 |
–0.238 |
170,030 |
88.6 |
169,848 |
88.7 |
–0.003 |
|
Moderate |
4,182 |
17.9 |
36,938 |
10.3 |
0.221 |
20,758 |
10.8 |
20,550 |
10.7 |
0.003 |
|
Severe |
297 |
1.3 |
1,700 |
0.5 |
0.086 |
1,054 |
0.6 |
999 |
0.5 |
0.004 |
Table 2.Incidence rate and risk of mortality in CO poisoning versus controls
|
Variable |
No. at risk |
No. at death |
Person years |
IR (/1,000 PY) |
HR (95% CI) |
P-value |
|
Overall |
Control |
191,397 |
12,040 |
1,688,675 |
7.13 |
Reference |
|
|
CO poisoning |
191,841 |
28,529 |
1,514,045 |
18.84 |
2.60 (2.55–2.66) |
<0.001 |
|
30-Day follow-up |
Control |
191,397 |
118 |
4 |
29,278.37 |
Reference |
|
|
CO poisoning |
191,841 |
5,134 |
88 |
58,673.09 |
1.61 (1.34–1.93) |
<0.001 |
|
Survivor ≥30 days |
Control |
191,279 |
11,922 |
1,688,671 |
7.06 |
Reference |
|
|
CO poisoning |
186,707 |
23,395 |
1,513,958 |
15.45 |
2.18 (2.14 – 2.23) |
<0.001 |
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