Evaluation of serum sodium changes in tricyclic antidepressants toxicity and its correlation with electrocardiography, serum pH, and toxicity severity.

BACKGROUND: Tricyclic antidepressants (TCAs) is a group of drugs used for the depression treatment. One of the effects of these drugs is Na (sodium) channel blocking ability causing cardiac complications such as ventricular tachycardia and Torsades de pointes Arrhythmia. Sodium bicarbonate is used for treatment of these complications which may have some effect on serum sodium levels. Considering no specific research on Na changes on these patients, the serum Na changes and its correlation with ECG changes, serum pH, and TCA toxicity severity were evaluated.
MATERIALS AND METHODS: A prospective descriptive-analytic cross-sectional study was done on TCA-poisoning patients who were admitted in Noor hospital in Esfahan in last 2 years. Serum sodium levels, ECG changes, and TCA severity toxicity of 92 patients were evaluated five times during first 24 h of admission.
RESULTS: A total of 92 patients were studied. The most common symptoms were conscious level changes (81.52%) and mydriasis (64.1%). Based on toxicity severity by these symptoms the patients were classified into three groups: 12% of the patients had mild toxicity, 50% moderate, and 38% severe toxicity. There were no significant differences in mean serum Na during the time. There was not found any correlation between serum Na level, and serum pH, ECG, and toxicity severity.
CONCLUSIONS: Using sodium bicarbonate in TCA-poisoning cases does not change the serum Na levels significantly.

INTRODUCTION

Cyclic antidepressants (CAs) include a group of drugs which are used in treatment of depression as well as neurological pains, migraines, urinary incontinence, attention deficit, and hyperactivity disorder. CAs include tricyclic and quadricyclic antidepressants.[1]

TCAs act through inhibition of presynaptic norepinephrine and serotonin reuptake, thus functionally increase these neurotransmitters concentration in central nervous system receptors. Therefore, their therapeutic effect is on autonomic, central nervous, and cardiovascular systems. All the cyclic antidepressant drugs are competitive antagonists for acetyl- choline muscarinic receptors.[1]

TCAs have a variety of physiologic effects, including:

Anti-cholinergic, anti histaminic and anti muscarinic effects

Alpha adrenergic receptor inhibition

Amine uptake inhibition

Sodium channel blockage

Potassium channel antagonist

Gamma amino butyric acid (GABA) receptor antagonist[2]

One of contributing factors in TCA overdose mortality is TCA-associated cardiac toxicity.[2]

Cardiac toxicity effects of CAs such as delayed dysrhythmic disorder and hypotension result from changes in vascular tonicity which results from autonomic system function.[1]

Delayed conduction includes prolonged QRS complex and right axis shift in last 40 ms of complex axis (QRS>130 ms). Prolongation of PR, QRS, QTc intervals can occur in therapeutic as well as toxic doses in TCA intoxication. In patients with prolonged QRS time or with hypotension, lethal ventricular tachycardia can occur. Patients with acute intoxication and wide QRS complex usually have changes in their level of consciousness. Hypoxia, acidosis, hyperthermia, convulsion, and beta adrenergic agonists can make patients susceptible to ventricular tachycardia.[23] QTc prolongation results from slow depolarization which leads to torsades de pointes. Because this condition usually occurs after bradycardia it is not of acute intoxication findings.[1]

Sodium channel block is resolved after alkalization of serum and increasing serum sodium levels.[2] Therefore, sodium bicarbonate is used for treatment of two conditions discussed above.[45-8] Sodium bicarbonate with its effective alkalization effect is the base of treatment in lethal cardiac toxicity in TCA intoxication.

Although using sodium bicarbonate leads to alkalization and acidosis correction, its effect in serum sodium level with frequent administration and the level of changes with daily sodium bicarbonate administration is not yet clear. One the other hand, hypernatremia can cause convulsion and changes in level of consciousness which is difficult to distinguish from TCA intoxication symptoms. Until this date, there is no specific study on serum sodium changes in patients with TCA intoxication, so the evaluation of serum sodium changes in patients with TCA intoxication and its correlation with ECG changes and serum pH and toxicity severity (in three distinct groups) was performed.

MATERIALS AND METHODS

This was a prospective descriptive–analytic cross-sectional study performed on 92 patients admitted in Noor and Ali Asghar hospital with TCA intoxication between August 2009 and 2011.

Inclusion criteria were TCA intoxication in patients which was established with history (from patient, or other people bringing him/her or referral physician or drug with patient), sign and symptoms, positive urine sample for TCA if suspected. Exclusion criteria were concurrent use of other drugs having cardiovascular effects, including beta blockers, calcium channel blockers, digitals and carbamazepine or past history of cardiovascular disease, as well as symptom-free patients observed 6 h in ER and remained asymptomatic.

Evaluations of serum sodium level, blood PH, and ECG were performed on admission time and every 6 h for 24 h. During the study, patients were divided into three groups; first group included those with anticholinergic symptoms (mild toxicity), second group included those with CNS symptoms (including convulsion and coma, moderate toxicity) as well as anticholinergic symptoms, and third group included those with cardiac symptoms plus anticholinergic and CNS (severe toxicity).

Patients were treated according to the center protocol and obtained data was recorded in checklists.

Serum results were compared with results of ECG changes (QRS complex with, QTc interval time and R wave size in aVR), blood PH changes, and intoxication severity (according to the 3 groups).

Eventually obtained data was processed through statistical software, SPSS 17.0. ANOVA and Pearson correlation tests were used for statistical analysis.

RESULTS

A total of 92 patients were evaluated including 28 males (30.4%) and 64 females (69.4%) with a mean age of 27.5 and in a range of 16–65 during 2 years (2009-2011).

Patients’ sodium level on admission and every 6 h was tested; mean sodium level on admission was 137.50 and after 6, 12, 18, 24 h was 136.83, 137.13, 137.76, and 137.86, respectively [Table 1].

Table 1

Mean serum sodium level over the time in TCA-poisoning patients

Although there was no significant change in sodium level changes during time [Table 1], Pearson correlation coefficient showed there was a reverse relation between number of pills taken and serum sodium levels, especially on admission and the correlation decreases with time (r= –0.47 and P-value < 0.001).

Blood PH evaluation showed there was a significant increasing pattern of PH and the most increase was in first 6 h. Mean blood PH on admission was 7.29 which after 6 h reached 7.34 and gradually increased in next hours. [Table 2]

Table 2

Mean blood PH changes in TCA-poisoning patients

Potassium levels showed a decrease after 12 h comparing to admission time and then increased reaching initial number. [Table 3]

Table 3

Mean blood potassium changes in TCA-poisoning patients

Results regarding the mean width of QRS complex, QTc interval time and mean R wave size in aVR on admission has been presented in Table 4.

Table 4

Mean ECG changes in TCA-poisoning patients

During the study, patients symptoms was evaluated, which was consistent of three groups: CNS, anti–cholinergic, and cardiovascular symptoms [Table 5].

Table 5

Clinical symptoms in TCA-poisoning patients

In cardiovascular symptom evaluation, 58 patients had no symptoms (63.04%), while wide QRS complex was observed in 34 patients (36.95%) [Table 5].

There were no significant changes in serum sodium levels over the time. Serum sodium level 6 h after admission had a direct weak relation with blood PH at the same time (r=0.17 and P-value < 0.05). Serum sodium level 6 h after admission had reverse weak relation with QRS complex width (r= -0.25 and P-value < 0.05) [Table 6].

Table 6

Relation of different factors with serum sodium level in TCA-poisoning patients

Based on toxicity severity by these symptoms, patients were classified into three groups: 12% of the patients had mild toxicity, 50% moderate and, and 38% severe toxicity.

DISCUSSION

Antidepressant intoxication is common because these drugs are often available to depressed patients who have a high suicide risk.

Considering that the most important cardiotoxic effect of the CAs is sodium channel blockade and the cardiac sodium channel is responsible for cardiac cell depolarization, its inhibition leads to slowed depolarization of individual cardiac cells. This, in turn, leads to slowing depolarization wave across the myocardium. The ECG manifestation of slowed depolarization is prolongation of the QRS complex, the hallmark of CA overdose. Sodium channel blockade in vitro can be partly reversed by increasing the pH or sodium concentration, providing that hypertonic sodium bicarbonate (NaHCO3) has an important role in restoring cardiac arrhythmias.

Given the proven effectiveness of hypertonic sodium bicarbonate and sodium concentration in CAs intoxication, this hypothesis aroused in mind that sodium concentration changes may have correlation with severity of CAs poisoning.

As far as we have searched there is no specific article evaluating serum sodium changes in patients with TCA intoxication.

In our study, 92 patients (28 males, 64 females; mean age 27.5) which got our criteria included in this study entered. In this study, many factors including serum sodium and potassium, blood PH and ECG changes were evaluated which were recorded on admission and every 6 h for 24 h (five times).

Considering sodium concentration, there was no specific study except one published in 2009, in which from 52 children who were studied, hyponatremia was reported in 26.9% of them.[9] In our study, hyponatremia was detected in 25% cases on admission and this not occurred at other times of measurement, however in performed statistical evaluations there was no significant change in mean serum sodium concentration.

There was not found any correlation between serum Na level, and serum pH, ECG, and toxicity severity.

CONCLUSION

Serum sodium concentration changes at different times after admission in patients with TCA intoxication according to statistical evaluations are not generally considerable. It has no correlation with blood PH, ECG changes, and severity of poisoning. However, compared with normal values, 25% of patients had hyponatremia on admission time, which was much more obvious in high doses of drug. If the number of TCA tablets ingested by the patients was considered, serum sodium concentration changes play a significant role and have a correlation with blood PH, ECG changes, and severity of poisoning.