A 5 Years Assessment of Patients with Acute Digoxin Poisoning: A Toxicoepidemiology Study in Iran.

Background: Digoxin poisoning leads to the development of cardiac and noncardiac complications. Digoxin immune fab is a safe and effective antidote, but clinical trials have not been performed in this regard, and most of the evidence is based on prospective studies. Understanding the toxicoepidemiology pattern of digoxin poisoning could provide valuable context for better managing its acute poisoning.
Objectives: This study aimed to assess the toxicoepidemiology pattern of acute digoxin poisoning through a 5-year assessment in Iran. Methodology: In this observational study, the records of 97 patients who were referred with acute digoxin poisoning between 2010 and 2015 were evaluated. Demographic characteristics, past medical history, drug history, chief complaints, vital signs, paraclinical findings, digoxin immune fab administration, and clinical outcomes recorded.
Results: The mean age of patients was 34.02 ± 17.87 years old. About 24.7% of patients had underlying diseases, and among them, heart failure was the most prevalent disease (29.2%) 42.3% of patients needed intensive care unit (ICU) admission. The mean duration of ICU stay was 4.00 ± 2.29 days. Digoxin immune fab was administered for 4.1% of patients, and an average of 6.2 ± 2.2 vials were used for them. All patients survived, and no mortality was reported. Conclusions: Digoxin immune fab administration did not alter the mortality rate. Hence, it can be concluded digoxin immune fab is not appropriate in acute poisoning, but it may be considered in chronic poisoning. Furthermore, acute digoxin poisoning is more common in Iran, and it responds appropriately to conventional treatment. Copyright:

INTRODUCTION

Digoxin is the oldest existing treatment for heart failure. Its administration has declined compared to other agents because the newer agents have established benefits in mortality reduction. However, digoxin remains an adjunctive agent for patients with refractory symptoms.[12]

One of the main limitations to digoxin administration is related to its narrow therapeutic window as it leads to the development of cardiac and noncardiac poisoning (e.g., gastrointestinal and central nervous system toxicities).[3] The clinical manifestations of digoxin poisoning are usually nonspecific. Lethargy, confusion, anorexia, vomiting, nausea, diarrhea, and abdominal discomfort occurred in digoxin poisoning. Blurred vision and color disturbances are among rare presentations.[4] Most deaths are due to cardiac arrhythmias. There are no evidence-based guidelines for managing mild-to-moderate digoxin poisoning; hence wide variations in treatment strategies are present.[5] Severe poisoning requires hospitalization, and evidence recommended digoxin immune fab in specific situations. Although digoxin immune fab is safe and effective, clinical trials have not been performed in this regard, and most of the evidence is based on prospective studies.[6] Understanding the current toxicoepidemiology pattern of digoxin poisoning could provide valuable context for better managing its acute poisoning. This study aimed to assess the toxicoepidemiology pattern of acute digoxin poisoning through a 5-year assessment in Iran.

METHODOLOGY

This study was a retrospective observational study done in Loghman Hakim Hospital, Tehran, Iran. This center is the primary referral center for toxicity in Iran. The records of patients with acute digoxin poisoning who were hospitalized between March 2010 and March 2015 were included. The ethics committee of Shahid Beheshti University of Medical Sciences approved the protocol of the current study.

The inclusion criteria were as follows: (1) patients with acute or acute on chronic digoxin poisoning who were referred to the emergency department; (2) patients were 18 years old or older. The patients with concurrent toxicity with other pharmaceutical agents were excluded. Furthermore, all efforts were employed to complete the medical records of patients. The incomplete medical records were excluded from the study. A patient case report form was designed to extract the necessary data from each record. This form contains several sections including demographic characteristics, past medical history, drug history, chief complaints, vital signs at admission, and para-clinical findings (laboratory results, imaging findings, electrocardiography, etc.). The poisoning characteristics such as amount of ingested digoxin, the timeline of poisoning, and plasma level of digoxin were recorded. The treatment strategies and clinical outcomes of all patients were also assessed in all patients. The hospitalization duration and mortality rate were considered as indicators for clinical outcomes.

Finally, the extracted data were imported into SPSS software version 23.0 (IBM, USA). The descriptive statistics presented and Kolmogorov–Smirnov test was used to determine the normal distribution. The Chi-square or Fisher's exact test was employed to find the probable association between qualitative variables. For all the tests, the significance level was considered 5% and results were reported as mean ± standard division or percent.

RESULTS

In 5 years, 97 patients with the above-mentioned criteria were included in this study. The demographic characteristics of patients revealed that 23 (23.7%) were male. The mean age of patients was 34.02 ± 17.87 years old. 24 (24.7%) of the patients had at least one underlying disease, and among them, heart failure was the most prevalent disease (29.2%). About half of patients (46.4%) were taking other medications concurrently. Cardiovascular medications and benzodiazepines were the most used medications among the patients. 17 (17.5%) of patients had a history of digoxin consumption, and the rest of them ingested the digoxin for the first time. 93 (95.9%) of patients were aware of the ingested amount. These patients ingested 39.00 ± 35.52 tablets of digoxin. The mean time from ingestion and admission was 7.95 ± 11.12 h (minimum: 25 min; maximum: 96 h). The baseline characteristics of included patients are shown in Table 1. The laboratory result and digoxin plasma level were also recorded. The laboratory results of patients and vital signs are summarized in Table 2.

Table 1

The baseline characteristics of included patients stratified according to electrocardiogram findings

Parameter	Total (n=97), n (%)	Normal (n=31), n (%)	ECG-changes (n=66), n (%)	P
Sex
Female	74 (76.3)	22 (70.96)	52 (78.78)	0.398
Male	23 (23.7)	9 (29.03)	14 (21.21)
Age (years)	34.02±17.87 (13-89)	28.58±12.07	36.57±19.58	0.016
Underling disease
Yes	24 (24.7)	3 (9.67)	21 (31.81)	0.018
No	73 (75.3)	28 (90.32)	45 (73.77)
Co-ingestion
Yes	45 (46.4)	16 (51.61)	29 (43.93)	0.480
No	52 (53.6)	15 (48.38)	37 (56.06)
Chronic use of digoxin
Yes	17 (17.5)	5 (16.12)	12 (18.18)	0.804
No	80 (82.5)	26 (83.87)	54 (81.81)
ICU admission
Yes	41 (42.3)	8 (25.80)	33 (50)	0.024
No	56 (57.7)	23 (74.19)	33 (50)
Digoxin dose (mg)	9.75±8.75 (0.375-37.5)	7.40±6.70	10.92±9.62	0.0403
Ingestion to admission (h)	7.95±1 (0.25-96)	6.36±5.16	11.20±7.65	0.151

ECG: Electrocardiogram, ICU: Intensive care unit

Table 2

The results of laboratory findings in patients with digoxin poisoning

Parameter	Result (mean±SD)
Temperature	36.93±0.21
Systolic blood pressure	116.23±19.60
Diastolic blood pressure	72.23±14.86
Respiratory rate	15.80±2.66
Pulse rate	78.65±17.60
GCS	14.72±1.31
PH	7.38±0.06
Hco3	23.50±4.95
Pco2	39.67±7.19
Po2	44.31±22.09
Base excess	−0.83±4.33
K	4.49±0.60
Na	139.85±2.85
Creatinine	1.02±0.30
Blood urea nitrogen	30.77±25.63
Calcium	9.06±0.63
Magnesium	2.19±0.40
Digoxin plasma level at admission (ng/mL)	5.22±2.72
Digoxin plasma level at second day (ng/mL)	4.19±1.94
Digoxin plasma level at discharge day (ng/mL)	2.32±1.09

GCS: Glasgow Coma Scale, SD: Standard deviation

The electrocardiography (ECG) findings showed that 85.56% of patients had sinus rhythm, and 12.37% had atrial fibrillation. The most common ECG changes were T changes, Salvador Dali sagging, and ST-segment changes. About 91.75% of patients also had a normal axis in ECG. The ECG presentations of studied patients are summarized in Table 3.

Table 3

The electrocardiogram presentations of studied patients

ECG parameter	Value
Rate	68.12±16.44
Rhythm
Sinus	85.56
Arterial fibrillation	12.37
Premature atrial contractions	1.03
Escape rhythm	1.03
Axis
Normal	91.75
Right axis deviation	7.21
Extreme right axis deviation	1.03
Shape
T changes	32.8
Salvador dali sagging	23.00
ST changes	19.70
AV node block	14.80
Left bundle branch block	4.90
Right bundle branch block	3.30
QT prolongation	1.60

ECG: Electrocardiogram, AV: Atrioventricular

The clinical outcomes for the treatment indicated that 42.3% of patients needed intensive care unit (ICU) admission. The mean duration of ICU stay was 4.00 ± 2.29 days. Digoxin immune fab was administered for 4.1% of patients, and an average of 6.2 ± 2.2 vials were used for them. All patients survived, and no mortality was detected in this study. However, 27.83% of patients were discharged with their permission.

DISCUSSION

This observational study aimed to assess the pattern of acute digoxin poisoning. The main finding of the current study was the zero mortality rate. The mean age of patients in this study was 34 years old. However, other studies showed that the mean age for digoxin poisoning was 65 years old. The elderly population is more prone to be toxicity with digoxin. This phenomenon is due to decreasing kidney function and decreasing the volume of distribution.[7] Bahravand et al. found a linear association between age and plasma level of digoxin.[8]

Most of the patients in the current study were female; similar results were seen in Limon et al. study. They found that women are more prone to be toxic with digoxin.[9] The plasma level of digoxin revealed that most patients had a level of >2 ng/mL. This finding confirms the value of digoxin level for diagnosis and treatment follow-up. Similar results were also reported by Salehi Omran et al.[10] However, Cristodorescu et al. found that digoxin poisoning could be seen in digoxin levels <2 ng/mL.[11] In the current study, most patients with digoxin levels <2 ng/mL were young. However, most of the patients in the above-mentioned study were old. Hence, the plasma level of digoxin is not a reliable diagnostic indicator in the elderly population.

Most of the patients in the current study did not have heart failure in their past medical history. However, other studies showed that heart failure was more prevalent in their patients. These differences may probably be due to the underlying cause of poisoning. Most patients in the current study consumed digoxin for intentional suicide.

The number of patients with atrial fibrillation in this study was less than patients in Limon et al. study.[9] This difference may be due to other underlying causes such as electrolytes misbalance, alkalosis, hyperthyroidism, etc. Valizadeh et al. reported that erythromycin and clarithromycin might lead to increasing the plasma level of digoxin.[12] This elevated level may lead to atrial fibrillation. In the current study, most patients did not have any past drug history or other underlying causes. Hence, atrial fibrillation was not dominant.

Another finding of the current study showed that digoxin immune fab is not necessary for acute poisoning. The digoxin immune fab is not readily available in the pharmaceutical market of Iran, and most of the patients did not receive digoxin immune fab. Only four patients received digoxin immune fab. The mortality rate was not different between these two groups, and all patients survived. Hence, it seems that digoxin immune fab is not indicated in acute digoxin poisoning and it should be reserved for the patient with chronic digoxin poisoning. Current results also confirm the findings of Hauptman et al.,[13] who studied patients with digoxin poisoning. They found one-fifth of patients received digoxin immune fab, most within 2 days of admission and there was no difference for mortality rate or length of hospitalization compared with patients not receiving digoxin immune fab.

CONCLUSION

The findings of the current study showed that the digoxin immune fab administration did not alter the mortality rate. Hence, it can be concluded digoxin immune fab is not appropriate in acute poisoning situation; however, it is maybe an appropriate agent in the chronic poisoning situation.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.