Efficacy of Hypertonic Saline for Tricyclic Antidepressant Overdose
By: Sahaphume Srisuma, MD and James Dazhe Cao, MD
(Rocky Mountain Poison and Drug Center)
Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital) and Stephen Alerhand, MD (@SAlerhand)
Cardiac sodium channel blockade is one of the most concerning effects of tricyclic antidepressant (TCA) overdose. This toxicity initially presents on the electrocardiogram (ECG) as widening of QRS complex and/or rightward shift of the terminal 40 milliseconds of QRS complex resulting in prominent R in aVR. Terminally, TCA sodium channel blockade progresses to ventricular dysrhythmias and cardiovascular collapse.
Sodium bicarbonate (NaHCO3), so called “hypertonic sodium bicarbonate,” is a “standard treatment” for cardiac sodium channel blockade from TCA toxicity. Although the exact mechanism by which sodium bicarbonate ameliorates toxic effects of TCA’s has not been fully elucidated, the two postulated mechanisms have been described:
1) sodium loading is aimed to overwhelm the sodium channel blockade effect
2) bicarbonate is aimed to increase pH which in turn may increase protein binding of free TCA and increase percentage of non-ionized TCA which has less binding affinity to cardiac sodium channels.
When using NaHCO3, sodium and pH should be monitored to prevent side effects from hypernatremia and alkalemia, respectively. In refractory cases with pH higher than 7.60 following NaHCO3 administration, the administration of hypertonic saline may be a useful clinical adjunct in the management of TCA cardiac sodium channel blockade.
Canine Purkinje Fiber Model
In 1984, Drs. Sasyniuk and Jhamandas compared effect of sodium hypernatremia, sodium bicarbonate, and pH in canine Purkinje fibers with amitriptyline toxicity. They found that action potential amplitude and conduction velocity were increased in all three groups compared to control; magnitude of improvement is highest in sodium bicarbonate group. 
Nattel and Mittleman studied a canine model with amitriptyline toxicity. Using 2 mEq/kg of NaHCO3 and hypertonic saline, they found that NaHCO3 significantly reduced frequency of ventricular dysrhythmias but only found variable responses in the hypertonic saline group. They also demonstrated that alkalinization by hyperventilation significantly prevented dysrhythmias from amitriptyline toxicity. The authors concluded that NaHCO3 was beneficial largely because of alkalinization. 
Drs. Pentel and Benowitz studied a rodent model with desipramine toxicity. They found that NaHCO3 and hypertonic saline were equally effective in decreasing QRS duration and raising mean arterial pressure, whereas hyperventilation was not. 
McCabe et al. compared effects of hypertonic saline (15 mEq/kg), sodium bicarbonate (3 mEq/kg), and hyperventilation in swine model with severe nortriptyline toxicity. They found that the QRS complex 10 minutes after treatment was narrowest in hypertonic saline group, follow by sodium bicarbonate, hyperventilation, and control group, respectively. They also noted that the systolic blood pressure at 10 minutes after treatment was highest in hypertonic saline group. 
The three aforementioned animal studies are fraught with heterogeneity – each using different animal species, TCAs, and dosing of hypertonic saline. Of the studies with a positive response to hypertonic saline, doses of 3-15 mEq/kg were used – much higher than typical molar equivalents of sodium administered with NaHCO3 in humans (starting 1-2 mEq/kg).
Human Case Reports
The evidence for hypertonic saline for TCA toxicity in humans resides in case reports. One of the better documented cases was reported by Drs. McKinney and Rasmussen in 2003. They report severe nortriptyline toxicity in a young lady who had QRS widening with frequent ventricular ectopy, coma, and hypotension. Despite having received large volume expansion, dopamine infusion, and 200 ml of 8.4% NaHCO3 bolus (200 mEq NaHCO3), she had refractory QRS widening, ventricular ectopy and hypotension. Due to severe cardiac toxicity despite alkalemia (pH 7.49-7.54), a hypertonic saline bolus was given (7.5% NaCl 200 ml or 257 mEq NaCl). Within 3 minutes of hypertonic saline bolus, ventricular ectopic beat was resolved, QRS narrowed, and her blood pressure improved. 
Discussion and Application
Evidence for hypertonic saline use in cardiac toxicity from TCAs is derived from in vitro cellular model, animal studies, and human case reports. NaHCO3 therapy has more supporting data and human experience in TCA toxicity and should be the “standard treatment.” In the authors’ opinion, hypertonic saline can be a helpful adjunct in TCA toxicity, especially when patients are near the upper limits of alkalemia.
To generate the sodium gradient equal to the recommended NaHCO3 1-2 mEq/kg initial bolus (1-2 mL/kg of 8.4% NaHCO3), we recommend using bolus dose of 2-4 mL/kg of 3% NaCl (514 mEq/L) or NaCl 1-2 mEq/kg. Even though there is no study comparing the efficacy between bolus and infusion of hypertonic saline for cardiac toxicity from TCA, we believe that bolus dosing of NaHCO3 and hypertonic saline is likely to provide more benefit. Bolus dosing may generate a greater sodium gradient necessary to overwhelm the cardiac sodium blockade effect. We recommend bolus NaHCO3 or hypertonic saline and observe for response on EKG. If QRS complex is not narrowing or mildly improving, consider a repeat bolus.
Caution should be taken when administering hypertonic saline with concern for osmotic demyelination syndrome (central pontine myelinolysis). However, with a dose of 1-2 mEq/kg of NaCl, the overall risk of hyperosmolar injury is low, and the safety profile should be similar to the administration of NaHCO3 boluses.
The evidence for hypertonic saline in TCA cardiac toxicity is based on case report level human data and heterogeneous animal studies. Mechanistically, hypertonic saline should generate a sufficient sodium gradient to help overcome TCA-induced sodium channel blockade. In the setting of severe toxicity refractory to NaHCO3 with alkalemia, hypertonic saline may be considered in the treatment algorithm.
References / Further Reading
 Sasyniuk BI, Jhamandas V. Mechanism of reversal of toxic effects of amitriptyline on cardiac Purkinje fibers by sodium bicarbonate. The Journal of pharmacology and experimental therapeutics. 1984;231:387-94.
 Nattel S, Mittleman M. Treatment of ventricular tachyarrhythmias resulting from amitriptyline toxicity in dogs. The Journal of pharmacology and experimental therapeutics. 1984;231:430-5.
 Pentel P, Benowitz N. Efficacy and mechanism of action of sodium bicarbonate in the treatment of desipramine toxicity in rats. The Journal of pharmacology and experimental therapeutics. 1984;230:12-9.
 McCabe JL, Cobaugh DJ, Menegazzi JJ, Fata J. Experimental tricyclic antidepressant toxicity: a randomized, controlled comparison of hypertonic saline solution, sodium bicarbonate, and hyperventilation. Annals of emergency medicine. 1998;32:329-33.
 McKinney PE, Rasmussen R. Reversal of severe tricyclic antidepressant-induced cardiotoxicity with intravenous hypertonic saline solution. Annals of emergency medicine. 2003;42:20-4.