Can Indices of Myocardial Damage Predict Carbon Monoxide Poisoning Outcomes?

Background: Carbon monoxide causes electrical, functional, and morphological changes in the heart. It is not clear, however, whether the indices of myocardial damage can predict the patient’s prognosis after carbon monoxide poisoning. This retrospective study aimed to investigate the relation between the carboxyhemoglobin level and electrocardiographic (ECG) changes and whether the ECG changes and troponin I levels are related to the patient’s prognosis after carbon monoxide poisoning. Results: Carboxyhemoglobin, troponin I, and ECG parameters were measured in 70 patients with carbon monoxide poisoning. The QT and RR intervals were measured for each ECG lead in all patients, and the corrected QT interval and corrected QT dispersion were calculated. The correlation between the maximum corrected QT interval and the carboxyhemoglobin level was signicant (P=0.0072, R 2 =0.1017), as were the relationships between QT dispersion and carboxyhemoglobin (P<0.001, R 2 =0.2358) and the corrected QT dispersion and carboxyhemoglobin (P<0.001, R 2 =0.2613). The multivariate logistic analysis showed that the signicant predictors of sequential disability were hyperbaric oxygen therapy (P=0.0182), corrected QT dispersion (P=0.0062), and troponin I level (P=0.0002). Conclusions: Patients’ prognosis following carbon monoxide poisoning can be predicted based on corrected QT dispersion and the troponin I level. Patients with myocardial damage should be monitored not only for their cardiovascular outcome but also for their neurological outcome and their prognosis.


Background
Carbon monoxide is a colorless, odorless, non-irritating gas. It is produced endogenously in small amounts as a byproduct of the catabolism of heme molecules 1 . It can also be inhaled when hydrocarboncontaining fuels are not completely burned 1,2 . Survivors of carbon monoxide poisoning may suffer neurological and psychiatric sequelae 1 . Carbon monoxide causes electrical, functional, and morphological changes in the heart 3 . The QT interval has long been known to vary signi cantly among the individual leads of a surface 12-lead electrocardiogram 3 .
A potential clinical application of this inter-lead difference was proposed in 1990 by Day et al., who suggested that the inter-lead difference in the QT interval might provide a measure of repolarization inhomogeneity, which they called "QT dispersion" 3,4 . Although it has been established that carbon monoxide induces electrocardiographic (ECG) changes and alterations of cardiac biomarkers 3, 5 , it is not clear whether the indices of myocardial damage can predict the patient's prognosis after carbon monoxide toxicity. Hence, this study aimed to investigate the relation between carboxyhemoglobin and ECG changes and whether the ECG changes and troponin I levels are related to the prognosis of patients with carbon monoxide poisoning.

Methods
The study group of this retrospective study included 70 consecutive patients with carbon monoxide poisoning (42 men, 28 women; age 52±18 years) who had been admitted to St. Mary's Hospital, Kurume, Japan for treatment between June 2013 and September 2019. Clear electrocardiograms were available for each patient. Patients' carbon monoxide poisoning had been con rmed by arterial blood analysis.
Carboxyhemoglobin measurements were performed in the ambulance and/or at admission. The highest values were adopted. Encephalopathy was de ned as the development or the recurrence of symptoms such as di culty concentrating, dementia, psychomotor retardation, Parkinsonism, and amnesia or the diagnose from magnetic resonance imaging at discharge or until 6 weeks after admission.
QT interval measures and cardiac enzymes All 12-lead electrocardiograms were obtained at a paper speed of 25mm/sec with standard lead positions. QT and RR intervals were measured on each electrocardiogram in all patients. The QT interval was measured from the beginning of the QRS complex to the end of the T wave. The QT intervals for each lead were measured and corrected for heart rate (QTc) using Bazett's formula (QT/√RR) 6 . The QTc dispersion was the difference between the leads with the shortest and longest QTc intervals 4 . QT intervals were measured upon admission to the emergency department. Additionally, blood samples were obtained and the troponin I level was determined.

Statistical analysis
Retrospective statistical analyses were performed using JMP and SAS university edition software (SAS Institute Inc., Cary, NC, USA). Results are presented as means ± SDs. Independent samples t-test was used to compare continuous variables and Chi-square test or Fisher's exact test was used for categorical variables. Spearman correlation analysis and logistic analysis were used to examine the relationships between carboxyhemoglobin levels and clinical variables. A value of P<0.05 was considered to indicate statistical signi cance.

Patients
Altogether, 70 patients were included in the study. Clinical characteristics of the patients are presented in Table 1. Two patients died after admission. In all, 12 patients were diagnosed with encephalopathy at or after discharge, whereas no patients exhibited cardiomyopathy at or after discharge.

Correlation between carboxyhemoglobin and QT intervals
The correlation between maximum QT intervals and the carboxyhemoglobin levels was not signi cant.
The comparison between the patients with and without sequential disability.
There are not difference in sex and age between the patients with and without sequential disability. The frequencies of the patients taking minor tranquilizers, major tranquilizers, antidepressants, and other drugs did not change with or without sequential disability ( Table 2). Maximum QT interval (p=0.0269), corrected maximum QT interval (p=0.0002), QT dispersion (p=0.0003) and corrected QT dispersion (p=0.0001) in the patients with sequential disability were signi cantly longer than them without it ( Table  2). There was no difference in the carboxyhemoglobin level between the patients with and without sequential disability ( Table 2).

Logistic analyses
Death, carbon monoxide encephalopathy, and cardiomyopathy at or after discharge were de ned as sequential disabilities. However, none of the patients in this study had cardiomyopathy. The reference values for the maximum QTc interval, QTc dispersion, carboxyhemoglobin level, and troponin I level were established based on the Classi cation and Regression Tree. Univariate logistic analysis showed that the signi cant predictors of sequential disability were smoking (P=0.0361), consciousness disorder on admission (P=0.0072), maximum QTc interval time (>484 ms; P=0.0009), QTc dispersion (>46 ms; P=0.0003), high concentration of carboxyhemoglobin (>44%; P=0.0044), and high troponin I level (>0.36 ng/ml; P<0.001; Table 3). The multivariate logistic analysis indicated that the signi cant predictors of sequential disability were hyperbaric oxygen therapy (P=0.0182), QTc dispersion (P=0.0062), and troponin I level (P=0.0002; Table 3).

Discussion
Carbon monoxide poisoning, a serious health problem, is associated with a high incidence of severe morbidity and mortality. It causes myocardial toxicity and life-threatening arrhythmias. Carbon monoxide reduces the oxygen-carrying capacity of blood and binds with cardiac myoglobin, causing a rapid decrease in myocardial oxygen reserves 6 . Several studies have shown that carbon monoxide intoxication causes increased QT intervals and QT dispersions [6][7][8] . This study showed that QTc dispersion and carboxyhemoglobin are signi cantly related. Furthermore, QTc dispersion and troponin I are predictors of sequential disability.

Correlation between carboxyhemoglobin and QT intervals
The QT interval is an indicator of ventricular repolarization on the electrocardiogram. A prolonged QT interval re ects impaired myocardial refractoriness. QT dispersion re ects the physiological variability of regional ventricular repolarization. Increased QT dispersion is related to the heterogeneity of regional ventricular repolarization and is accepted as a marker for arrhythmia and sudden death 9 . In this study, the QTc interval and QTc dispersion correlated with the carboxyhemoglobin level. Hanci et al. also reported that the QTc interval and QTc dispersion show good correlations with carboxyhemoglobin 10 . Increased QTc dispersion and interval in carbon monoxide toxicity might be caused by carbon monoxide on the myocardium, which causes homogeneous impulse formation in the ventricles.

The relation between the prognosis of patients with carbon monoxide toxicity and cardiac markers
The univariate logistic analysis indicated that the predictors of sequential disability in patients with carbon monoxide toxicity were smoking, consciousness disorder, maximum QTc interval, QTc dispersion, carboxyhemoglobin, and troponin I. The multivariate analysis revealed that the signi cant predictors of sequential disability were hyperbaric oxygen therapy, QTc dispersion, and troponin I. Note that the multivariate analysis did not nd that carboxyhemoglobin was related to a poor outcome. The prognosis of patients with carbon monoxide toxicity could be predicted by the duration of carbon monoxide exposure and its concentration. Conversely, carboxyhemoglobin was not necessarily related to the exposure time or the concentration of the carbon monoxide. Because patients with carbon monoxide toxicity usually receive treatment immediately after the rescue, carboxyhemoglobin was not measured at its peak concentration.
Hampson et al. found that carboxyhemoglobin measurement was a poor predictor of clinical status in patients with carbon monoxide poisoning 11 . Moreover, mortality was associated with the absolute difference in carboxyhemoglobin 11 . Satran et al., however, reported that moderate-to-severe carbon monoxide poisoning causes myocardial injury when assessed by electrocardiography or biomarkers 5 . Henry et al. reported that patients with myocardial injury (cardiac troponin I >0.7 ng/ml, the creatine kinase-MB level, and/or diagnostic ECG changes) had increased mortality 12 .
Carbon monoxide-mediated toxicity results from several factors. Carbon monoxide binds to hemoglobin with an a nity 200-250 times that of oxygen. Thus, exposure to carbon monoxide, even in low concentrations, results in competitive binding to hemoglobin, reduced oxygen delivery, and profound tissue hypoxia 13 . Carbon monoxide also binds to cytochrome-c oxidase, directly interfering with cellular respiration 14 . These mechanisms are believed to cause neurological injury and likely contribute to myocardial injury as well 12 . Although there were no patients with cardiomyopathy at/after discharge in this study, the indices of myocardial injury could lead to neurological injury or even mortality. The mechanisms described in uence this result.

Limitations
The primary limitations of this study were the small sample population, single-center design, and retrospective nature. Because our subjects included both intentional and unintentional patients, the beginning time of the carbon monoxide exposure could not be found out in many patients. Therefore the exposure time could not be calculated exactly. Despite these limitations, the study may act as a good basis for further study of the topic. The ndings must be con rmed in prospective, multicenter studies with larger populations.

Conclusion
The prognosis for patients with carbon monoxide poisoning may be predicted based on the QTc dispersion value and the troponin I level. Patients with myocardial damage should be monitored not only for their cardiovascular outcome but also for their neurological outcome and their prognosis.

Consent for publication
Not applicable

Competing interests
There are no competing interests to declare in this study.