Introduction Amitriptyline is a tricyclic antidepressant. In general, toxicity effects develop within 30 min of overdose and peak from 2 h to 6 h. Anticholinergic effects predominate in cases of low dose ingestion. In cases of high dose ingestion, marked depression of the central nervous system is coupled with cardiotoxicity, seizures and hypotension.
Patients and methods Amitriptyline-intoxicated patients admitted to the emergency department (ED) of Dicle University Hospital were evaluated between January 2005 and April 2007. Social and demographic status, clinical and laboratory findings, treatments and outcomes were recorded. Age, sex, marital status, time of hospital admission, consciousness levels, ECG findings, requirement for respiratory support, follow-up periods and antidepressant overdose risk assessment (ADORA) criteria were analysed using SPSS software.
Results A total of 110 cases of overdose by amitriptyline was evaluated. Suicide attempts by amitriptyline overdose in adult single women were the commonest finding. The commonest symptoms seen during initial examinations were sinus tachycardia (66.3%), altered mental state (78.1%) and hypotension (7.3%). Mechanical ventilatory support was required in 9.1% of cases. Most patients (n=76, 69.1%) were treated in the ED (p=0.001). 60 (54.5%) patients were discharged from the ED within 24 h after admission (p<0.0001).
Conclusion Most of the patients were young single women. Altered mental state and tachycardia were the commonest symptoms. The initial symptoms of amytriptyline overdose patients may be life threatening, but effective supportive treatments were helpful. There was high correlation between ADORA criteria and the dose ingested.
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Imipramine, amitriptyline, their /V-demethyl derivatives and other similar compounds were the first successful antidepressants and, since the early 1960s, have been widely used for the treatment of major depression.1 These agents block the reuptake of synaptic transmitters such as norepinephrine, dopamine and serotonin in the central nervous system (CNS). Tricyclics are well absorbed from the gastrointestinal tract. Tricyclics exhibit high protein binding in the plasma.2 3 Elimination is mainly by hepatic metabolism. The half-lives of tricyclics and their metabolites range from 25 to 30 h but may be longer in the overdose setting.3
Clinical toxicity effects generally develop within 30 min of overdose and peak in 2–6 h. In cases of low overdose, anticholinergic effects predominate.4 Any dose greater than 5 mg/kg per day has the potential to produce tricyclic antidepressant (TCA) toxicity. Life-threatening symptoms usually occur with ingestions of more than 10 mg/kg in adults.2 In cases of high overdose, marked CNS depression is coupled with cardiotoxicity, seizures and hypotension. Ventricular tachyarrhythmia, atrioventricular and intraventricular conduction delays, terminal bradycardia and decreased cardiac output may occur. Increasing duration of the QRS complex correlates with an increased risk of cardiac arrhythmias and seizures. In the evaluation of clinical findings for poisoning by antidepressant medications, the antidepressant overdose risk assessment (ADORA) criteria are used. These criteria are: prolongation of the QRS interval; arrhythmias; altered mental status; seizure; respiratory depression and hypotension.4
In this study we evaluated Dicle University emergency department (ED) patients with amitriptyline overdose by their social demographic, clinical and laboratory findings and outcomes. We aimed to utilise the ADORA criteria for clinical findings of patients' pure amitriptyline overdoses.
Materials and methods
In this study, all patients over 15 years of age who were admitted to Dicle University Hospital ED for amitriptyline overdose ingestion from January 2005 to March 2007 were enrolled. Age, gender, martial status, admitted time, ingested dose, initial symptoms, physical examination, ECG and arterial blood gas findings, the need for endotracheal intubation and/or mechanical ventilatory support, follow-up period, ADORA criteria, performed treatment attempts (gastric emptying, activated charcoal, etc), hospitalisation and discharging features were recorded and analysed statistically.
Table 1 lists the ADORA criteria. Patients with one or more of the criteria were classified as high risk (HR). Patients not displaying any of these criteria within 6 h from ED application of ADORA were classified as low risk (LR).4
We evaluated our pure amitriptyline overdose patients with ADORA criteria for the first 6 h from ED admission and did not repeat this evaluation. The toxic dose for amitriptyline is over 10 mg/kg. Most of our cases were young women and, because of our region's anthropological features, we accepted 50 kg as the overdose quantity. We could not detect blood amitriptyline levels due to the limitations of our laboratory, so we compared ADORA criteria with pure amitriptyline overdose patients.
Statistical analyses were performed using the Student's t test for comparing mean of groups and the χ2 test for non-parametric data. Statistical significance was set at the 5% level.
During to our study 129 amitriptyline overdose patients were admitted to our emergency service. We excluded 19 patients because of the co-ingestion of different drugs. The social demographic features of our 110 amitriptyline overdose patients are shown in table 2. For our retrospective study the number of women (n=99, 90%) was scientifically more than men (n=11, 10%; p<0.0001). The average age for the women was (22.7±8.3 years) and for the men (24.0±6.9 years; p>0.05). Cases were admitted to our hospital 2.18±1.44 h after ingestion.
Single cases (n=78, 71%) were statistically more than married patients (n=32, 29%; p<0.0001). Most of the overdose events happened at home (n=107, 97.3%); the remainder (n=3, 2.7%) occurred elsewhere. Most of the ingestions (n=109, 99.1%) were suicide attempts.
We classified overdose patients into two groups based on their ADORA score: the HR group (n=96, 87.3%) and the LR group (n=14, 12.7%). The initial symptoms for our overdose patients by order of their frequency were altered mental status (n=86, 78.1%) and tachycardia (n=73, 66.3%; p<0.0001).
Hypoxia was seen (n=25, 22.7%) in 110 patients in the arterial blood gases. We intubated 10 (9.1%) of them and initiated mechanical ventilatory support.
Most of our patients (n=76, 69.1%) were treated in our ED and the rest of them (n=34, 30.9%) were followed in the intensive care unit (ICU). We discharged 60 (54.5%) patients from our ED 24 h after admission (p<0.0001). Gastric lavage alone was performed in one (0.9%) patient, active charcoal alone was administered to eight (7.3%) patients and 76 (69%) of the total number of cases received both treatments. We applied combined therapy to high ingested dose patients whose ADORA criteria were positive (10 cases needed ventilatory support).
Amitriptyline overdoses were seen every month, and the distribution of cases shows a particular regulation month by month. Nevertheless, amitriptyline overdose patients were still decreasing (see supplementary figure 1, available online only).
For our 14 (12.7%) of 110 patients' initial examination, we could not find any clinical features of overdose. In contrast, 96 (87.3%) patients had major overdose symptoms that were related to ADORA criteria. The most common initial features of toxicity were altered mental status (n=86, 78.1%) and arrhythmias (n=73, 66.3%; p<0.001) (table 1).
There were no statistical differences between the groups with regard to gender, mechanical ventilatory support and hospitalisation period (p>0.05). We found a significant difference in marital status and treatment unit between the two groups (p<0.05). Fifty-five patients ingested over 500 mg amitriptyline, 53 of them were in the HR group. The relationship between the ingestion of over 500 mg and high ADORA criteria was statistically significant in this study (p=0.004). The mean average amount of amitriptyline ingested by the HR group was higher than the LR group (HR 520.31±278.6, LR 301.79±128.4; p<0.001; table 3). None of the patients died.
TCA is the most common agent for antidepressant overdoses.5 6 TCA feature many characteristic signs and symptoms when present at toxic levels, but asymptomatic patients may deteriorate rapidly; history and physical examination alone are insufficient to predict severe poisoning.7 In the USA, TCA account for the third largest number of deaths, and amitriptyline is the most common single causative agent.8
Amitriptyline is one of the most commonly prescribed and sold antidepressant agents; also it is the agent most commonly involved in suicide or possible suicide caused by antidepressants in many countries.9 Deaths related to amitriptyline are often ascribed to suicidal tendencies, and the high rate of mortality is due to CNS and cardiovascular toxicities.10
Young female patients constitute a large part of intoxications according to case reports in the literature.6 11 Harrigan et al7 reported a case series with three patients who were all women and were aged 18, 24 and 31 years. Two of them presented within 2 h of intoxication and the other within 6 h. In a study of Unverir et al12 TCA were the most frequently ingested antidepressants (58.4%). Opipramol and amitriptyline accounted for the majority of TCA (31.2%, n=111 and 23.3%, n=83, respectively). In their study, 78% of cases were women and the mean age was 28±10 years for all patients. The mean time of admission to the ED after ingestion was 3.39±4.9 h (0.1–48). In our study, most of the cases were women (90%), the mean age for female patients was 22.5±7.9 years and 23.2±8.1 years for male patients. There was no significant difference between female and male patients' ages. Generally, patients presented to our ED within 2.18±1.44 h after ingestion. Single patients (71%) constituted a large part of the intoxicated cases as a result of our religion's social structure, we think. Young women are forced into arranged marriages by their families and domestic violence still happens to women in our religion. For married patients economic problems are the main reason for taking an overdose.
In a study by Unverir et al12 a total of 97.5% of patients' ingested drugs for suicide and the rest of them ingested for sleeping, relaxing, accidentally etc. Substantially all of our overdose patients were suicide attempts.
The abnormal findings in amitriptyline overdosage include anticholinergic symptoms (pupil dilatation, tachycardia, urinary retention, etc.), cardiac complications (a prolonged QTc interval or QRS duration, sinus tachycardia), respiratory depression/insufficiency, hypotension, impaired consciousness (from lethargy to coma), convulsions and rarely adult respiratory distress syndrome.13 In a study by Koppel et al,14 the most frequent symptoms in both groups were impaired consciousness, anticholinergic symptoms, seizures, arrhythmia and hypotension. Respiratory insufficiency necessitated respiratory therapy in 63 of the patients.14 Zhu et al15 reported 20 adult cases of amitriptyline poisoning. The main symptoms were coma in different degrees, pupil dilatation, tachycardia and urinary retention. Hypertension, hypothermia and convulsive attacks appeared in some of the patients. ECG was abnormal in half of the patients.
TCA overdosage can cause life-threatening cardiac effects,16 but sinus tachycardia is the most commonly seen symptom in patients.2 Seizures determine the seriousness of intoxication, although a number of studies found a seizure rate of between 4% and 24%.6 17 The most commonly seen symptoms were altered mental status (78.2%) and tachycardia (66.4%) in our initial examination. Hypotension and seizures were the other symptoms. ECG was administered to all patients, 66.3% of them were abnormal. The seizure rate was low (n=1, 0.9%). Most of our amitriptyline patients were in the HR group (87.3%).
Intubation depends on the patient's symptoms, Glasgow Coma scale and laboratory findings. Intubation is mostly reported in TCA intoxications (23–68%).18 Unverir et al12 reported a total 9.6% intubation rate, but 23 of their 24 amitriptyline overdosage cases required intubation (95.8%). In our study, 22.7% of cases had hypoxic arterial blood gas results and 9.1% of cases were intubated for mechanical ventilatory support. All of the intubated patients were in the HR group, had altered mental status and had ingested for suicide.
TCA intoxicated patients require ICU more than other depressant overdosages.5 Similarly, the follow-up period is longer than other depressant overdosage. A study reported 14 h for this period.6 Unverir et al12 reported a mean observation time in the ED for 356 patients admitted to hospital because of antidepressant poisoning of 6.0±6.8 h (range 0.5–72). The percentage of patients who were observed for less than 8 h was 62.1% (n=221). Patients who were poisoned by TCA were observed in the ED significantly longer than those poisoned by selective serotonin re-uptake inhibitor agents (8.54 and 6.51 h). We observed 69.1% of cases in the ED and 30.9% required ICU observation. In total, 54.5% of patients were discharged from the ED within 24 h after admission. Although amitriptyline overdose patients' initial symptoms seems to be life threatening, effective supportive treatments (eg, respiratory) dramatically decreased mortality.
In amitriptyline poisoning, therapy includes primary detoxification by gastric lavage and repeated administration of activated charcoal.13 In a TCA intoxication study, Philips et al5 applied gastric lavage to 70% of patients and gave activated charcoal to 96% of their patients. Bosch et al19 have also stated that gastric lavage was performed in 71% of patients with antidepressant poisoning, 93% were given activated charcoal and 21% were administered sodium bicarbonate. Unverir et al12 reported that gastric lavage alone was performed and activated charcoal alone was administered in 3.9% (n=14) and 17.1% (n=61) of patients, respectively; combined gastric lavage and activated charcoal was performed in 63.8% (n=227) of patients. In the present study, gastric lavage alone was performed in one (0.9%) patient, active charcoal alone was administered to eight (7.3%) patients and 76 (69%) of the total number of cases received both treatments. High ingested dose patients who had ADORA criteria were treated aggressively (eg, mechanical ventilatory support was applied to 10 patients). Similarly, the combined therapy rate is high for our report because, despite prehospital lavage and charcoal administration, lower intestinal motility suggested poor elimination of TCA, so we repeated the combined therapy.
Previous studies have reported June and July to be the months in which the most instances of intoxication are seen.11 20 Variously, Unverir et al12 suggested that the ingestion of antidepressants was most frequent in July and October (11% and 10.7%, respectively). June was the month with the most hospitalisations in the present study. We reported that amitriptyline overdoses could be seen in every month; however, amitriptyline overdose patients were still decreasing.
Previously, it was determined that 70.9% of the remaining 306 patients (n=217) had major poisoning clinical findings related to the ADORA criteria. The most commonly seen symptoms were arrhythmias (41.3%) and altered mental status (35.7%).12 Foulke et al4 suggested cardiac arrhythmias or conduction defects as an ADORA criterion (systolic blood pressure (<90 mm Hg), supraventricular or ventricular arrhythmias, seizures and respiratory failure). We evaluated sinus tachycardia as a supraventricular arrhythmia in the same way that Unverir et al12 suggested sinus tachycardia as a cardiac arrhythmia. They confirmed a range as 41.8% for sinus tachycardia. Caravati et al21 detected major toxicity in 65 (61%) patients of 106 TCA intoxicated patients. We confirmed major clinical findings for intoxication, which were germane to ADORA criteria in 87.3% of cases. The most frequently reported symptoms were altered mental status and arrhythmias.
In the evaluation of clinical findings for poisoning by antidepressant medications, the ADORA criteria are used. Patients with one or more of the criteria were classified as high risk. Risk evaluation of the patients should obviously include careful assessment of the respiratory status.4 We also used the ADORA criteria to evaluate overdosage patients' clinical findings. Our 55 patients ingested more than 500 mg amitriptyline, 53 of them were in the HR group. The relationship between ingestion greater than 500 mg and high ADORA criteria was statistically significant for our study (p=0.004). A high correlation between ADORA criteria and the ingested dose showed the relationship between ADORA criteria and the dose-dependent clinical toxicity risk.
In conclusion, most of our patients were young single women. Clinical findings were evaluated by the ADORA criteria. Altered mental status and tachycardia were the most commonly seen symptoms. Although amitriptyline overdose patients' initial symptoms seems to be life threatening, effective supportive treatments (eg, respiratory) dramatically decreased mortality.
We cannot detected blood levels but a high correlation between ADORA criteria and the ingested dose showed the relationship between ADORA criteria and the dose-dependent clinical toxicity risk.
Competing interests None.
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