Introduction

Carbon monoxide (CO) is an odorless and colorless gas emitted due to the incomplete combustion of organic compounds [1]. Carbon monoxide poisoning (COP) remains a very important issue in public health worldwide because it causes numerous accidental and intentional injuries and subsequent economic and social losses [1,2,3,4]. In the USA, around 50,000 exposures and 1000–2000 accidental deaths due to COP occur annually [2]. The primary toxicity of COP is due to its high affinity to hemoglobin, which is about 200–250 times than that of oxygen. This causes hypoxic injuries in all internal organs of the victims [1]. In addition to hypoxia, other mechanisms, including oxidative stress and inflammatory responses, are also responsible for subsequent organ damage and even death [1, 3, 5,6,7].

The heart and the brain are the organs most commonly damaged by COP because they have the highest oxygen demands [1, 8, 9, 12,13,14]. A study enrolling 230 patients with moderate to severe COP reported that 37% of patients had myocardial infarction following COP [12]. The risk for mortality in COP patients with myocardial infarction afterwards was higher than in the COP patients without myocardial infarction [15]. COP may also contribute to other cardiac dysfunction including arrhythmia and left ventricular systolic dysfunction [16]. Another study performing angiograms in COP patients with myocardial infarction reported that all the patients had normal coronary arteries, which suggested that COP-related myocardial infarction was caused not via coronary artery occlusion, but via hypoxia, oxidative stress, inflammatory response, and myocardial stunning [11]. Hyperbaric oxygen therapy (HBOT) is suggested as the preferred choice for treating severe COP because it reduces subsequent complications, especially neurological sequelae [1,2,3, 8,9,10]; however, it remains unclear whether HBOT reduces the risk for myocardial infarction, and therefore we conducted this study to clarify this issue. Our hypothesis was that HBOT may reduce the risk for myocardial infarction following COP.

Methods

Data Sources

The Nationwide Poisoning Database (NPD) is a sub-dataset of the National Health Insurance Research Database (NHIRD), which contains all poisoning cases, including instances of COP, diagnosed in Taiwan between 1999 and 2013. NHIRD, which is a large, computerized database derived by the National Health Insurance Administration (the former Bureau of National Health Insurance) and maintained by the National Health Research Institutes, provides subsets of data to scientists in Taiwan for research purposes [17].

Identification of Patients and Definitions of Variables

Patients diagnosed with the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes of 986, E868, E952, or E982 during either admission or ambulance care between 1999 and 2012 were identified as having suffered from COP (Fig. 1). These COP patients were then divided into two cohorts “with HBOT” and “without HBOT.” The general criteria for the choice of HBOT in COP patients are carboxyhemoglobin level > 25%, pregnancy, cardiovascular dysfunction, and severe poisoning (e.g., unconsciousness, severe acidosis, or neurological signs) [18, 19]. The “with HBOT” cohort was defined as the patients who were labeled with 47054C, 9395, 59003B, 59004B, 59003A, or 59004A as their management codes during the index admission or emergency department care. In contrast, the “without HBOT” cohort was defined as the patients who were not labeled with any of the abovementioned management codes. Variables of demographic data and underlying comorbidities included for analysis were as follows: age, sex, hypertension (ICD-9-CM codes: 401–405), diabetes (ICD-9-CM code: 250), hyperlipidemia (ICD-9-CM code: 272), coronary artery disease (ICD-9-CM codes: 410–414), malignancy (ICD-9-CM codes: 140–208), congestive heart failure (ICD-9-CM code: 428), chronic obstructive pulmonary disease (ICD-9-CM code: 496), liver disease (ICD-9-CM codes: 570–576), renal disease (ICD-9-CM codes: 580–593), connective tissue disease (ICD-9-CM code: 710), HIV infection (ICD-9-CM codes: 042, 07953, V08), and alcoholism (ICD-9-CM codes: 291, 303, 305.0, 357.5, 425.5, 535.3, 571.0–571.3, V113). Age was divided into subgroups of < 20, 20–34, 34–50, 51–64, and ≥ 65 years [20]. Monthly income was divided into subgroups of < 19,999, 20,000–39,999, and ≥ 40,000 New Taiwan Dollars [21]. Concomitant conditions with COP during the index admission or emergency department care were defined as suicide (management codes: 94.0, 94.1 or ICD-9-CM codes: E950–E959), drug poisoning (ICD-9-CM codes: 960–989, exclusion of 986), acute respiratory failure (ICD-9-CM codes: 518.81, 518.84 or management codes: 960, 9601, 9602, 9603, 9604, 9605, 9390, 9391, 311), myocardial infarction (ICD-9-CM code: 410), acute hepatitis (ICD-9-CM code: 573.3), and acute renal failure (ICD-9-CM codes: 584 or management code: 339.5).

Fig. 1
figure 1

Flow chart of this study. COP carbon monoxide poisoning, HBOT hyperbaric oxygen therapy

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Comparison of the Risk for Myocardial Infarction Between Patients With and Without HBOT

We compared the risk for myocardial infarction between the two cohorts by following up until 2013 (Fig. 1). Stratified analyses by age subgroups, sex, underlying comorbidities, monthly income, concomitant conditions of suicide, drug poisoning, and acute respiratory failure, and follow-up periods were also performed. Investigation of the independent predictors for the risk of myocardial infarction in patients with and without HBOT was also performed.

Ethics Statement

This study was approved by the Institutional Review Board at Chi-Mei Medical Center and conducted according to the Declaration of Helsinki. Informed consents were waived because data in the NPD are de-identified, and the welfare of the participants is not affected.

Statistical Analysis

For comparisons of demographic data, underlying comorbidities, monthly income, and concomitant conditions between the two cohorts and the two sexes, we used the two-sample t test and the Chi-square test for continuous variables and categorical variables, respectively. Cox proportional hazard regression analyses were used for comparing the risks of myocardial infarction and for investigating independent predictors. The Kaplan–Meier method and log-rank test were also used to compare the cumulative incidence rates for myocardial infarction during follow-up periods. We used SAS 9.4 for Windows (SAS Institute, Cary, NC, USA) for all statistical analyses and set the significance level at 0.05 (two-tailed).

Results

In total, 25,737 COP patients were identified, including 7278 patients with HBOT (28.28%) and 18,459 patients without HBOT (71.72%) (Table 1). The mean age ± standard deviation was 36.0 ± 16.5 years, and patients with HBOT were younger than the patients without HBOT (34.9 ± 14.7 vs. 36.4 ± 17.1 years, p < 0.001). Both cohorts had a nearly equal sex ratio. Patients with HBOT had lower prevalence rates of underlying comorbidities of hypertension, diabetes, hyperlipidemia, coronary artery disease, malignancy, congestive heart failure, chronic obstructive pulmonary disease, liver disease, renal disease, and alcoholism than patients without HBOT. The monthly income was not different between the two cohorts. In the comparison of concomitant conditions, there were higher percentages of suicide, acute respiratory failure, and acute renal failure in patients with HBOT than in patients without HBOT. The prevalence of myocardial infarction during the index admission or emergency department care was lower in patients with HBOT than in patients without HBOT (0.36% vs. 0.67%, p = 0.003).

Table 1 Comparison of age, sex, underlying comorbidities, monthly income, and concomitant conditions between COP patients with and without HBOT between 1999 and 2012
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Overall, patients with HBOT were at a lower risk for myocardial infarction than patients without HBOT after adjusting for age, sex, hypertension, diabetes, hyperlipidemia, coronary artery disease, congestive heart failure, chronic obstructive pulmonary disease, liver disease, renal disease, connective tissue disease, HIV infection, alcoholism, monthly income, suicide, drug poisoning, and respiratory failure [adjusted hazard ratio (AHR): 0.69]. However, this difference did not reach statistical significance [95% confidence interval (CI) 0.45–1.07] (Table 2). The Kaplan–Meier method and log-rank test showed a lower risk for myocardial infarction in patients with HBOT than in patients without HBOT during the follow-up (Fig. 2). The stratified analysis revealed that male patients with HBOT had a significantly lower risk for myocardial infarction than male patients without HBOT (AHR: 0.45; 95% CI 0.24–0.83), but females patients with HBOT had a similar risk to female patients without HBOT (AHR: 1.04; 95% CI 0.55–1.96). Patients with HBOT had a significantly lower risk for myocardial infarction in the first 2 weeks following COP than patients without HBOT following COP (AHR: 0.22; 95% CI 0.05–0.96). In patients with the underlying comorbidity of coronary artery disease, HBOT was associated with a lower risk for myocardial infarction (AHR: 0.51), but the difference did not reach statistical significance (95% CI 0.25–1.05). In the analyses stratified by age subgroups, underlying comorbidities, monthly income, and concomitant conditions of suicide, drug poisoning, acute respiratory failure, and follow-up periods at > 2 weeks, no differences between the two cohorts reached statistical significance.

Table 2 Comparison of the risk of myocardial infarction between COP patients with and without HBOT by Cox proportional hazard regression analysis
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Fig. 2
figure 2

Risk of myocardial infarction between COP patients with and without HBOT by Kaplan–Meier method and log-rank test. COP carbon monoxide poisoning, HBOT hyperbaric oxygen therapy

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In patients with HBOT, independent predictors for the risk of myocardial infarction were hypertension (AHR: 4.68; 95% CI 1.64–13.39) and chronic obstructive pulmonary disease (AHR: 5.74; 95% CI 1.60–20.57) (Table 3). In patients without HBOT, independent predictors for the risk of myocardial infarction were older age, male sex, hypertension, diabetes, coronary artery disease, and congestive heart failure.

Table 3 Independent predictors of myocardial infarction in COP patients with and without HBOT by Cox proportional hazard regression analysis
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Comparisons of age, underlying comorbidities, monthly income, and concomitant conditions among male and female COP patients with and without HBOT were shown in the Table 4. The Kaplan–Meier method and log-rank test showed a lower risk of myocardial infarction in male patients with HBOT than in male patients without HBOT during the follow-up. However, the difference between patients with and without HBOT was not significant in the female population (Fig. 3).

Table 4 Comparison of age, underlying comorbidities, monthly income, and concomitant conditions among male and female COP patients with and without HBOT between 1999 and 2012
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Fig. 3
figure 3

Risk for myocardial infarction between male and female COP patients with and without HBOT by Kaplan–Meier method and log-rank test. COP carbon monoxide poisoning, HBOT hyperbaric oxygen therapy

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Discussion

Overall, this study demonstrated that HBOT showed a trend toward reducing the risk for myocardial infarction in COP patients. Stratified analyses showed that HBOT reduced the risk for myocardial infarction in male patients for a follow-up period of < 2 weeks. After 2 weeks following COP, there was no significant difference in the risk of myocardial infarction between patients with and without HBOT. In patients with HBOT, independent predictors of myocardial infarction were hypertension and chronic obstructive pulmonary disease. In patients without HBOT, independent predictors of myocardial infarction were older age, male sex, hypertension, diabetes, coronary artery disease, and congestive heart failure.

Acceleration of the elimination of carboxyhemoglobin and COP-related direct disruption of cellular oxidative processes by HBOT are probably the mechanisms involved in reducing myocardial infarction. To our knowledge, there is no human study addressing this issue in the literature. A meta-analysis of randomized controlled trials showed that oxygen inhalation did not benefit patients with acute myocardial infarction when performed with normal oxygen saturation; however, this study did not include HBOT for the analyses [22]. Some animal studies have shown that HBOT can limit infarct size in rabbit hearts and that the earlier the initiation of treatment, the better the outcome [23, 24], which are compatible with our finding that HBOT reduced acute myocardial infarction within 2 weeks following COP. The standard treatment for COP is the administration of 100% oxygen at atmospheric pressure (normobaric oxygen), which can shorten the half-life of carboxyhemoglobin approximately fivefold faster than room air [1]. HBOT can further hasten the elimination of carboxyhemoglobin [1], and therefore it is theoretically used to treat COP, especially in patients with a high risk for subsequent complications. The most common and concerning complications after COP are the neurological sequelae [1, 3, 25]. Whether HBOT is better than normobaric oxygen in reducing the neurological sequelae is still being debated [1, 3, 25]. One of the best known studies supporting HBOT in reducing the neurological sequelae is the double-blind, randomized trial by Weaver et al. in 2002, which showed that HBOT reduced neurological sequelae at 6 weeks and 12 months [25]. However, several studies have challenged the positive effect of HBOT. For example, a 2011 review by Cochrane reported that existing and randomized trials did not establish whether HBOT reduces the incidence of neurological sequelae in COP patients [1]. Although their findings did not support the use of HBOT for COP, the authors of the review suggested that an additional study, such as a multicenter randomized controlled trial, is needed to clarify this issue [1].

Our stratified analyses showed that HBOT reduced the risk of myocardial infarction in male patients, but not in female patients. A study reported that male COP patients have more comorbidities and are at a higher risk for subsequent mortality than female COP patients [4]. Therefore, HBOT may have more benefits for the male population. The lower risk of developing myocardial infarction in females as compared to males is a well-known fact, and the difference was also observed in patients with COP [14]. The protecting effect of estrogen is generally recognized as a major factor contributing to the sex difference [26]. We speculate that the protecting effect of estrogen was a main reason why the beneficial effect of HBOT against myocardial infraction following COP was smaller in women. To our knowledge, however, there is no study comparing the differences in the impact of HBOT on myocardial infarction between the two sexes. The independent predictors for patients with and without HBOT were different, which suggested that HBOT has modification effects on the impacts of certain risk factors for myocardial infarction. Specifically, in patients without HBOT, the independent predictors of myocardial infarction were similar to the conventional risk factors for myocardial ischemia, including older age, male sex, hypertension, diabetes, coronary artery disease, and congestive heart failure, but in patients with HBOT only hypertension and chronic obstructive pulmonary disease appeared to be independent predictors. HBOT may have a greater impact on reducing myocardial infarction following COP in the patients with older age, male sex, diabetes, coronary artery disease, and congestive heart failure.

The generally applied criteria for the choice of HBOT in the COP patients do not take comorbidities, except cardiovascular dysfunction, into account, and many differences in comorbidities between groups that got HBOT versus not were observed in our study. This might affect the incidence of myocardial infarction. Nonetheless, after adjusting for these comorbidities, we still observed a decreased risk in the patients who received HBOT.

This study has the strength of being the first, large, and nationwide study on the effect HBOT on subsequent myocardial infarction following COP. However, it has some limitations. First, we might underestimate the number of patients with myocardial infarction by using the ICD-9-CM code to identify patients. However, the misclassification should be non-differential because the diagnosis of myocardial infarction was unlikely to be affected by the administration of HBOT. Second, we did not include certain socioeconomic variables, such as smoking, obesity, family history, diet, physical activity, and stress, which are risk factors for myocardial infarction and possible confounding factors in this study. However, we have included several underlying comorbidities that may be surrogates for these unavailable variables in our database, and therefore the impact may be minimal. Third, the modification effect on the impacts of older age, male sex, diabetes, coronary artery disease, and congestive heart failure in this study is novel. Validation of the finding and clarification of the mechanisms are also needed in the future. Lastly, although this was a nationwide population-based study, the results may not be generalizable to other nations because of the differences in race, culture, and medical resources.

Conclusions

This nationwide population-based cohort study demonstrated that HBOT shows a trend toward reducing subsequent risk for myocardial infarction following COP. The effect of HBOT in reducing the risk for myocardial infarction was significant in males and in the acute follow-up period of < 2 weeks. These results provide us with an important reference for the treatment of COP patients in the future. However, further studies are warranted to delineate the underlying mechanisms of this process and to validate our findings.