Clinical outcomes of adverse cardiovascular events in patients with acute dapsone poisoning

Study design and data collection

This was a retrospective observational study that included consecutive patients diagnosed with acute dapsone poisoning at a regional emergency center between January 2006 and June 2014. Serum high sensitivity troponin I levels (hs-TnI; Siemens Healthcare Diagnostics, Newark, DE, USA; normal range <0.046 ng/mL) were measured in all included patients. Dapsone ingestion was confirmed by patients or guardians, and dapsone toxicity was confirmed by the treating emergency physician and verified by serum methemoglobin levels. The study exclusion criteria were age <18 years, end-stage renal disease, and the absence of serum TnI measurement during the first 48 hours after arrival at the emergency department.

The following data were obtained from the medical records of the included patients: age, gender, amount ingested, underlying disease, initial symptoms and signs, initial Glasgow Coma Scale (GCS) score, initial systolic blood pressure, and treatment, including methylene blue, gastric irrigation, activated charcoal, and multidose activated charcoal. Electrocardiograms, when available, were reviewed by an experienced cardiologist (HSO) and ventricular dysrhythmias and signs of ischemic change were noted. Serum methemoglobin, hs-TnI, and beta-type natriuretic peptide levels at the time of initial presentation were also recorded. Data collection was conducted by two emergency physicians who were blinded to the study objectives and hypothesis. Both underwent training before data collection to reduce bias by disagreement.

ACVE was defined by at least one of the following: 1) myocardial injury as evidenced by hs-TnI elevation within 48 hours of presentation or electrocardiography (ECG) signs of ischemia including ST elevation, ST depression, or T wave inversion; 2) shock, as defined by hypotension requiring vasopressor support; 3) ventricular dysrhythmia, including ventricular tachycardia, ventricular fibrillation, or torsades des pointes; and 4) cardiac arrest [11-16]. We included only ACVEs that were apparent during the first 48 hours because we wanted to identify early predictors of mortality and minimize the possibility that an ACVE was secondary to malfunction of other organs or systems or multiple organ failure in the terminal stage.

General characteristics of each case of acute dapsone poisoning, including mortality and the incidence of ACVE, were assessed, and we compared characteristics of survivors and non-survivors to examine the relationship between ACVEs and mortality. This study was approved by the institutional review board of Wonju College of Medicine, Yonsei University.

Statistical analyses

Statistical analyses were performed using IBM SPSS Statistics ver. 20 (IBM, Armark, NY, USA). Categorical variables were presented as frequencies and percentages, and continuous variables as medians and interquartile ranges after assessment for normality using the Shapiro-Wilk test. The chi-square test or Fisher’s exact test was used to compare categorical variables and the Mann-Whitney U-test was used to compare continuous variables. Predictors of mortality were identified by multiple logistic regression analysis. P-values of <0.05 were considered statistically significant.

Characteristics of patients with acute dapsone poisoning

Among 74 consecutive patients who had acute dapsone poisoning during the study period, 61 patients (16 men [26.2%], age 18 to 91 years, median 67 years) were included in this retrospective study and 13 were excluded (five who were <18 years old, one with end stage renal disease, and seven who did not have serum hs-TnI measurements within 48 hours of arrival).

The amount of dapsone ingested varied from 300 mg (3×100 mg tablets) to 3 g (30×100 mg tablets). The pills were ingested intentionally in all cases. Hypertension was the most common cardiovascular risk factor. Common signs and symptoms at initial presentation were cyanosis (40 patients, 65.6%), dyspnea (30 patients, 49.2%), and headache (8 patients, 13.1%). Other symptoms included nausea, vomiting, general weakness, dizziness, and seizures (Table 1).

Table 1.

General and laboratory characteristics of patients with acute dapsone poisoning

ACVE in the form of myocardial injury occurred in 19 patients (31.1%); among them, 12 (19.7%) had elevated hs-TnI and 10 (16.4%) had ECG changes (4 with ST depression and 6 with T wave inversion); shock was reported in one patient in this group (1.6%). No cases of ventricular dysrhythmia or cardiac arrest were noted. Median initial hs-TnI and beta-type natriuretic peptide levels were 0.015 ng/mL and 56.83 pg/mL, respectively. Regarding treatment, 59 patients (96.7%) received methylene blue and nine (14.8%) received multidose activated charcoal. Fourteen of the 61 patients (23.0%) ultimately died from pneumonia or multiple organ failure (Table 1).

Comparison of survivors and non-survivors

There were 14 non-survivors and 47 survivors (77.0%). As a group, the non-survivors were older than the survivors (median age 80 vs. 64 years, P=0.005) and had significantly lower GCS scores at arrival. The rate of ACVE was significantly higher among the nonsurvivors (64.3% vs. 21.3%, P=0.006). Finally, there was a significant difference in median total dose of methylene blue between non-survivors and survivors (2,425 vs. 800 mg, P=0.004) (Table 2).

Table 2.

Comparison of survivors and non-survivors

Multiple logistic regression analysis showed that among age, initial GCS score, and presence of ACVE, only ACVE (odds ratio, 5.690; 95% confidence interval, 1.428 to 22.675; P=0.014) was significantly associated with mortality (Table 3).

Table 3.

Early predictors of mortality