2025 Volume 50 Issue 3 Pages 117-123
Prolongation of QRS duration (prolonged QRS) is associated with severe outcomes in non-tricyclic antidepressant poisoning. However, factors other than xenobiotics affecting QRS duration have not yet been investigated. Hence, this study aimed to identify factors contributing to prolonged QRS. This study was a single-center retrospective case control study. Patients who had overdosed on drugs or orally ingested xenobiotics that they would not normally ingest orally were included in the study. Patients were divided into two groups: prolonged QRS and normal QRS. Subsequently, these groups were compared. We performed a logistic regression analysis with the factors extracted by comparison as explanatory variables and prolonged QRS as the objective variable. In total, 108 patients were analyzed; 19 belonged to the prolonged QRS group. In the prolonged QRS group, factors such as male sex, low level of potassium, and xenobiotic ingestion resulted in prolonged QRS. In a logistic regression analysis, significant differences were observed in terms of male sex (odds ratio [OR], 27.00; 95% confidence interval [CI], 5.93-123.00; p<0.001), xenobiotics ingested that resulted in prolonged QRS (OR, 8.55; 95% CI, 1.84-39.70; p<0.001), and potassium levels (OR, 0.15; 95% CI, 0.03-0.88; p=0.035). Ingestion of sodium channel blockers, male sex, and low level of potassium may contribute to prolonged QRS.
Prolongation of QRS duration (prolonged QRS) with sodium channel blockers, particularly in tricyclic antidepressant poisoning, is a predictor of severe disease (Matthew and Erica, 2017). Tricyclic antidepressant poisoning causes rapid deterioration; therefore, cardiovascular toxicity, including prolonged QRS and hypotension, in patients with acute poisoning should be treated as tricyclic antidepressant poisoning until tricyclic antidepressant poisoning is ruled out (Matthew and Erica, 2017).
In contrast, analysis of data from the Toxicology Investigators Consortium Core Registry showed that the number of cases of tricyclic antidepressant poisoning had decreased over time (Tang et al., 2024), and the frequency of encountering tricyclic antidepressant poisoning is decreasing.
QRS duration can also be prolonged by sodium channel blocker overdoses other than tricyclic antidepressant poisoning (Bruccoleri and Burns, 2016). Recently, a large retrospective observational study (Simon et al., 2024) on prolonged QRS in sodium channel blocker poisoning reported that prolonged QRS was associated with severe outcomes of poisoning with six drugs: diphenhydramine, amitriptyline, bupropion, quetiapine, nortriptyline, and cocaine. However, this study did not include patient background or blood test results other than acidosis in the analysis, and factors other than xenobiotics that affect the QRS duration were not investigated.
We conducted a retrospective study to test the hypothesis that factors other than drugs influence the QRS duration in patients with acute poisoning. This study aimed to investigate the factors contributing to prolonged QRS in patients with acute poisoning by comparing patients with and without prolonged QRS.
This study was a single-center retrospective case control study in Japan. Patients who were treated in the emergency department of the emergency and critical care center of Iizuka Hospital between January 1, 2022, and December 31, 2023, and who were suspected of acute poisoning by doctors in the emergency department were included in the study. Acute poisoning was defined as patients who had overdosed on drugs or orally ingested xenobiotics that they would not normally ingest, which referred to natural toxins such as mushrooms, and chemicals such as detergents, pesticides, and herbicides. Patients aged <15 years and those with isolated acute alcohol intoxication were excluded from the study.
Patient information was retrospectively collected from electronic medical records for the following variables: age, sex, symptoms (central nervous system depression, agitation, vomiting, and seizures), preexisting medical conditions (renal disease, liver disease, cardiac disease, depression, bipolar disorder, schizophrenia, borderline personality disorder, adjustment disorder, alcohol use disorder, and dementia), and whether any drugs were prescribed that caused prolonged QRS, xenobiotics and their intake estimated from the drug containers and hearsay from the individual and other relevant persons, whether xenobiotics were ingested that result in prolonged QRS, whether ethanol was consumed simultaneously, height and weight, cardiac arrest at presentation, vital signs at presentation (systolic blood pressure, mean arterial pressure, heart rate), 12-lead electrocardiogram (sinus rhythm or not, QRS duration), blood gas findings (pH, HCO3-, sodium, potassium, chloride, ionized calcium), xenobiotics and their serum concentrations detected using liquid chromatography–tandem mass spectrometry (LC-MS/MS), treatment (activated charcoal administration, gastric lavage, hemodialysis, tracheal intubation, sodium bicarbonate administration), intensive care unit (ICU) admission or not, and in-hospital mortality.
Xenobiotics resulting in prolonged QRS were defined as follows: tricyclic antidepressants (Cathleen, 2017), mirtazapine (Christine, 2017), escitalopram (Christine, 2017), venlafaxine (Christine, 2017), quinidine (Lavonas et al., 2023), procainamide (Cathleen, 2017), flecainide (Cathleen, 2017), acebutolol (Jeffrey, 2017), carvedilol (Jeffrey, 2017), propranolol (Jeffrey, 2017), chlorpromazine (Cathleen, 2017), haloperidol (Cathleen, 2017), pimozide (Cathleen, 2017), quetiapine (David, 2017), lamotrigine (Cathleen, 2017), lacosamide (Lavonas et al., 2023), topiramate (Lavonas et al., 2023), zonisamide (Lavonas et al., 2023), carbamazepine (Lavonas et al., 2023), hydroxychloroquine (Lavonas et al., 2023), quinine (Lavonas et al., 2023), cocaine (Lavonas et al., 2023), diphenhydramine (Lavonas et al., 2023), and amantadine (Cathleen, 2017). We used the 12-lead electrocardiogram that was performed when the patient was first examined in the emergency department for our study, and did not include the electrocardiogram taken after the patient was admitted to the ward. A prolonged QRS was defined as ≥100 msec. Blood gas analysis did not distinguish between the arterial and venous blood. At our hospital, the doctor who treated the patient can order serum drug poisoning screening at their discretion. Serum drug poisoning screening was performed using the LC/MS/MS Rapid Toxicology Screening System Ver. 2 (Shimadzu Corporation, Kyoto, Japan).
The patients were divided into two groups: prolonged QRS and normal QRS. Continuous variables were analyzed using the Mann-Whitney U test and categorical variables were analyzed using the Fisher's exact probability test. Subsequently, to identify independent factors associated with prolonged QRS, we were planning a multivariate analysis, including age and sex, factors exhibiting significance (p<0.05) in the comparison of the two groups. As a result, we performed a logistic regression analysis with prolonged QRS as the objective variable and age and sex, potassium levels, xenobiotics ingested that result in prolonged QRS as explanatory variables and calculated the odds ratio (OR), 95% confidence interval (95% CI), and p-value. We used the median and interquartile range (IQR) and proportions to describe continuous and categorical variables, respectively. All statistical analyses were performed with EZR version 1.61 (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R version 4.2.2 (The R Foundation for Statistical Computing, Vienna, Austria). More precisely, it is a modified version of R commander designed to add statistical functions frequently used in biostatistics (Kanda, 2013).
During the study period, 11,441 patients were treated in the emergency department of Iizuka Hospital, of whom 108 were eligible and whose data were analyzed (Fig. 1).
Study flowchart.
Table 1 shows the comparison between the prolonged QRS (n=19) and normal QRS groups (n=89). There were significantly more men in the prolonged QRS group than in the normal QRS group (73.7% vs. 16.9%, p<0.001). No significant differences in patient symptoms were observed. Significantly more patients with liver disease were in the prolonged QRS group than in the normal QRS group (21.1% vs. 5.6%, p=0.049). Prescribed drugs that caused prolonged QRS were significantly more common in the prolonged QRS group than in the normal QRS group (47.4% vs. 19.1%, p=0.016), and ingested xenobiotics that resulted in prolonged QRS were also significantly more common in the prolonged QRS group than in the normal QRS group (52.6% vs. 20.2%, p=0.007). Although no significant differences were observed between the two groups in terms of vital signs, the median potassium level was significantly lower in the prolonged QRS group than in the normal QRS group as per blood gas findings (3.3 [IQR, 3.1-3.6] vs. 3.7 [IQR, 3.3-3.9], p=0.019). No significant differences were observed between the two groups in terms of treatment, ICU admission, or in-hospital mortality. Table 2 shows the class of xenobiotics suspected to be the cause of acute poisoning. Most of the patients who participated in this study were taking co-ingestants, and this table shows the total number of them. Among the 89 patients in the nQRS group, 15 (16.9%) were not submitted to serum drug screening, while among the 19 patients in the pQRS group, 1 (5.3%) was not submitted to serum drug poisoning screening.
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| nQRS (N=210) | pQRS (N=122) | |
|---|---|---|
| Analgesics (%) | 29 (13.8) | 5 (4.1) |
| Sedatives (%) | 73 (34.8) | 43 (35.2) |
| Antidepressants (%) | 6 (2.9) | 19 (15.6) |
| Antipsychotics (%) | 12 (5.7) | 23 (18.9) |
| Antiepileptics (%) | 2 (1.0) | 6 (4.9) |
| Sympathomimetics (%) | 24 (11.4) | 2 (1.6) |
| Circulatory drugs (%) | 3 (1.4) | 2 (1.6) |
| Antihistamines (%) | 7 (3.3) | 9 (7.4) |
| Respiratory drugs (%) | 10 (4.8) | 1 (0.8) |
| Other drugs (%) | 35 (16.7) | 11 (9.0) |
| Others (%) | 9 (4.3) | 1 (0.8) |
Table 3 shows the results of the logistic regression analysis with prolonged QRS as the objective variable and age, sex, ingested xenobiotics that resulted in prolonged QRS, and potassium levels as explanatory variables. Significant differences were observed in terms of male sex (OR, 27.00; 95% CI, 5.93-123.00; p<0.001), ingested xenobiotics that resulted in prolonged QRS (OR, 8.55; 95% CI, 1.84-39.70; p<0.001), and potassium levels (OR, 0.15; 95% CI, 0.03-0.88; p=0.035).
| OR | 95%CI | P value | |
|---|---|---|---|
| Age | 1.01 | 0.97~1.05 | 0.57 |
| Male | 27.00 | 5.93~123.00 | <0.001 |
| Ingestion of xenobiotics that cause pQRS | 8.55 | 1.84~39.70 | <0.001 |
| Potassium | 0.15 | 0.03~0.88 | 0.035 |
“Ingestion of xenobiotics that cause pQRS” indicates that an overdose of xenobiotics causing prolonged QRS was presumed from the current medical history. OR: odds ratio, 95%CI; 95% confidence interval.
Table 4 shows a list of patients presumed to have ingested xenobiotics that caused prolonged QRS. This group comprised 28 individuals, and in two cases, the xenobiotics remained undetected in the serum.
| No. | QRS, msec | Age | Sex | K, mmol/L | Xenobiotics | Estimated amount, mg | Serum concentration by LC-MS/MS, µg/mL | Death |
|---|---|---|---|---|---|---|---|---|
| 1 | 160 | 48 | Male | 3 | Mirtazapine | 90 | 0.11 | |
| 2 | 148 | 48 | Male | 3.4 | Mirtazapine | 135 | 0.05 | |
| 3 | 144 | 82 | Female | 3.6 | Mirtazapine | 630 | 0.1 | |
| 4 | 112 | 48 | Female | 3.1 | Quetiapine | 375 | 0.012 | ● |
| 5 | 108 | 76 | Female | 3.5 | Escitalopram | 60 | 0.16 | |
| 6 | 104 | 24 | Male | 3.3 | Diphenhydramine | 300 | ND | |
| 7 | 104 | 50 | Male | 3 | Chlorpromazine | 150 | 0.01 | |
| 8 | 102 | 50 | Male | 3.3 | Quetiapine | 250 | ND | |
| 9 | 100 | 35 | Male | 4 | Amoxapine | 1425 | 20.07 | |
| 10 | 100 | 50 | Male | 3.3 | Quetiapine | 125 | 1.27 | |
| 11 | 92 | 26 | Female | 3.2 | Lacosamide | 900 | NL | |
| 12 | 90 | 21 | Female | 3.3 | Diphenhydramine | 1200 | 1.54 | |
| 13 | 90 | 30 | Female | 3.7 | Escitalopram | 20 | 0.15 | |
| 14 | 88 | 50 | Female | 3.8 | Lamotrigine | 5400 | 29.28 | |
| 15 | 86 | 24 | Female | 4 | Chlorpromazine | 362.5 | 0.73 | |
| 16 | 86 | 55 | Female | 4.1 | Quetiapine | 1200 | NS | |
| 17 | 86 | 56 | Male | 3.2 | Chlorpromazine | Unknown | 0.005 | |
| 18 | 84 | 25 | Female | 3.6 | Chlorpromazine | 500 | 0.32 | |
| 19 | 82 | 21 | Female | 4.5 | Lamotrigine | Unknown | 4.49 | |
| 20 | 82 | 36 | Female | 3.9 | Chlorpromazine | 250 | 0.03 | |
| 21 | 82 | 84 | Female | 3.8 | Chlorpromazine | 1000 | 0.97 | |
| 22 | 80 | 53 | Female | 4 | Quetiapine | 2025 | 0.17 | |
| 23 | 78 | 39 | Female | 3.2 | Diphenhydramine | 600 | 0.61 | |
| 24 | 76 | 19 | Female | 3.4 | Diphenhydramine | 1050 | 0.64 | |
| 25 | 76 | 61 | Female | 3.7 | Chlorpromazine | 175 | 0.007 | |
| 26 | 76 | 84 | Female | 4 | Diphenhydramine | 600 | 0.13 | |
| 27 | 74 | 45 | Male | 3.9 | Chlorpromazine | 275 | 0.018 | |
| Venlafaxine | Unknown | NL | ||||||
| 28 | 72 | 82 | Female | 4.1 | Mirtazapine | 495 | 1.98 |
This table lists patients presumed to have overdosed xenobiotics prolonged QRS. K; Potassium, Xenobiotics; Xenobiotics prolonged QRS, ND; Not detected, NL; Not Listed, NS; Not submitted, LC-MS/MS; Liquid Chromatograph-tandem Mass Spectrometer.
In this study, none of the patients in the prolonged QRS group was administered sodium bicarbonate. One patient in the prolonged QRS group died 4 days after admission; however, the underlying cause of death was not investigated through an autopsy or other means. The patient was transported to our emergency and critical care center for seizures and was presumed to have overdosed on 375 mg of quetiapine. The patient was admitted to the hospital without any invasive procedures such as tracheal intubation, and the serum concentration of quetiapine at that time was 0.012 µg/mL, a concentration below the therapeutic range.
In the logistic regression analysis of this study, xenobiotic ingestion resulting in prolonged QRS, male sex, and low levels of potassium were associated with prolonged QRS in patients with acute poisoning, particularly drug overdose.
Sex is a contributing factor to the variation in the QRS duration. In a study of sex and race in QRS duration, Santhanakrishnan et al. (2016) reported that QRS duration is longer in men than in women and in Asians than in Caucasians.
Regarding the relationship between potassium levels and 12-lead electrocardiography, hyperkalemia causes intraventricular conduction disturbances, resulting in prolonged QRS, but hypokalemia can also prolong QRS duration (El-Sherif and Turitto, 2011). A retrospective observational study (Kildegaard et al., 2024) conducted on 79,599 patients to investigate the association between hypokalemia and electrocardiographic abnormalities reported a significantly prolonged QRS duration in the hypokalemic group compared with that in the group with normal potassium levels.
Uncertainty remains regarding the history of current illness in patients with acute poisoning. In a prospective study (Pohjola-Sintonen et al., 2000), information based on interviews with patients and their companions or circumstantial evidence (e.g., drug containers found) was compared with the results from drug analyses of various body fluids, and in 18% of cases, the discrepancies were considered clinically important. In our study, 28 patients presumed to have ingested xenobiotics that caused prolonged QRS were detected, but in at least two of them, the presumed xenobiotics were not detected in the serum.
Acute poisoning of sodium channel blockers leads to QRS prolongation, hypotension, convulsions, ventricular arrhythmia, and cardiovascular collapse (Lavonas et al., 2023). Such symptoms are mainly caused by blocking cardiac sodium channels. The severe symptoms of poisoning by sodium channel blockers, especially tricyclic antidepressants, are treated with sodium bicarbonate. Indications include conduction delays (QRS complex >100 msec) and hypotension (Matthew and Erica, 2017). On the other hand, it has been pointed out that the response to treatment with sodium bicarbonate in cases of poisoning by sodium channel blockers other than tricyclic antidepressants is variable (Chan and Buckley, 2024) and the indication for sodium bicarbonate in this situation is not clear (Bruccoleri and Burns, 2016). In a recently published retrospective observational study by Simon et al. (2024) of 800 poisoned patients with prolonged QRS, prolonged QRS duration of ≥120 msec was associated with serious outcomes such as seizures and ventricular arrhythmias in six single-xenobiotic overdoses. However, Simon et al. did not investigate factors other than xenobiotics, such as electrolytes, that could affect QRS duration, and it remains unclear whether treatment, such as sodium bicarbonate administration, played a role in prognosis. In our study, none of the patients in the prolonged QRS group also was administered sodium bicarbonate and in-hospital mortality did not differ significantly between the prolonged QRS and normal QRS groups. The administration of sodium bicarbonate may result in a further reduction of potassium levels in patients with prolonged QRS due to acute poisoning, potentially exacerbating their condition.
This study had some limitations. First, the small number of patients did not allow adequate logistic regression analysis. Although height (Kofler et al., 2017) and heart rate (Mason et al., 2016) have been suggested to influence the QRS duration, we could not analyze them as explanatory variables. Moreover, although some significant factors were detected in the univariate analysis, not all of them could be included in the multivariate analysis due to the limited number of participants in this investigation; however, the following factors had originally been anticipated for inclusion in the multivariate analysis: age, gender, xenobiotics ingested that resulted in prolonged QRS, and potassium levels. The reason we had planned to include potassium levels in the multivariate analysis was because we had assumed that elevated potassium levels would be a confounding factor for prolonged QRS. Second, we used QRS duration as a surrogate marker instead of true endpoints such as death. The reason for this is that the possibility of serious outcomes such as death is low in cases of acute poisoning (Gummin et al., 2022). Simon et al. reported that prolonged QRS was an independent prognostic factor in the six most common single xenobiotic exposures associated with prolonged QRS (Simon et al., 2024), but the value of prolonged QRS in the poisoning with other sodium channel blockers is still unclear. Third, this was a retrospective observational study, and there may have been unadjusted confounding factors. Additionally, because this was a single-center study, the results may not be generalizable. Fourth, although our hospital can measure the serum concentrations of 200 or more drugs by LC-MS/MS, it does not cover all xenobiotics, and some xenobiotics are estimated from clinical information, such as statements by the patient or their companions or drug containers brought by emergency medical services, which may not be reliable. Finally, electrocardiographic follow-up data for patients with prolonged QRS were lacking. In tricyclic antidepressant poisoning, the time until the prolonged QRS disappears varies greatly, ranging from a few hours to several days (Matthew and Erica, 2017), and a similar course may be followed in poisoning by xenobiotics other than tricyclic antidepressants. However, in practice, the follow-up time of electrocardiograms varies widely, the timing of follow-up may not have been appropriate, and some patients were not followed up with 12-lead electrocardiograms; therefore, we did not include the follow-up of patients with 12-lead electrocardiograms in this study. This aspect should be explored in future prospective studies.
ConclusionIngestion of sodium channel blockers, male sex, and low level of potassium may contribute to prolonged QRS.
The abstract of this paper was presented at the 46th Annual Meeting of the Japanese Society of Clinical Toxicology, held on July 24, 2024, and July 25, 2024.
Conflict of interestThe authors declare that there is no conflict of interest.
