PPAG News


Posted by: Matthew Helms on Nov 14, 2018

 

Kim Friend, PharmD , Ji Lee, PharmD, BCPPS, Bryan Hayes, PharmD, DABAT, FAACT, FASHP
Massachusetts General Hospital


 

Sodium bicarbonate (NaHCO3) is used for multiple indications including tricyclic antidepressant (TCA) and salicylate poisoning.  NaHCO3 possesses alkalinizing properties and may be used to replace electrolytes. It dissociates into sodium and bicarbonate, which can buffer excess hydrogen ions resulting in raised blood pH.[1]

In March of 2017, the Food and Drug Administration (FDA) declared a national shortage of injectable NaHCO3 due to manufacturing delays and an increase in demand.[2] During this critical shortage, hospitals have resorted to removing NaHCO3 from crash carts and rationing supplies to focus use in the most critical scenarios.  Currently, the most obvious substitute, sodium acetate, is also in short supply.

TCAs are pharmacologically complex and work on multiple receptors, including sodium membrane channels. Blockade of these channels slow depolarization of the myocardium resulting in delayed conduction and reduced automaticity of the atria and ventricles.[4] Toxic effects after TCA overdose appear within 1-2 hours of ingestion. Patients presenting to the emergency department after a TCA overdose often exhibit altered mental status, seizures, and hypotension with QRS prolongation on EKG.  A QRS interval >100 milliseconds (msec) was predictive of seizures and >160 msec with ventricular dysrhythmias, in one study.[5] 

Salt loading using NaHCO3 or hypertonic saline (HTS) overwhelms the sodium channel to reverse the effects of TCAs and generates a gradient. NaHCO3 has the possible added benefit of increasing pH, which may escalate TCA plasma protein binding resulting in reduced pharmacologically active unbound drug and reduced insult to myocardial contractility.[6]

In the absence of NaHCO3, HTS may be a reasonable treatment alternative but remains controversial due to lack of evidence.  Thus far, animal studies show evidence of corrected QRS widening and hypotension with HTS. Pentel and Benowitz demonstrated that 6 mEq/kg of HTS was non-inferior to NaHCO3 in reversing QRS prolongation secondary to desipramine toxicity in rats.[7]  More recently, a randomized, controlled comparison of HTS with NaHCO3 for TCA toxicity by McCabe and colleagues, evaluated the effects of these agents at treating nortriptyline toxicity in swine.[7]  Twenty-four animal subjects were divided equally into 4 treatment arms: control (10 mL/kg D5W), sodium bicarbonate (3 mEq/kg of 8.4% NaHCO3), hypertonic saline (10 mL/kg of 7.5% HTS), and hyperventilation (to maintain a target pH 7.5-7.6 + 10 mL/kg D5W).  Treatment groups were evaluated for efficacy against TCA toxicity and mortality defined as survival at 60 minutes. The results of this experiment indicated that HTS was more effective at reversing cardiotoxicity caused by TCA overdose than NaHCO3. QRS duration was recorded as mean±standard deviation at baseline, during toxicity, and post treatment among each arm. Swine treated with HTS demonstrated a decrease in QRS by 78±14 ms while those treated with NaHCO3 exhibited a decrease in QRS duration by 51±28 ms.[7] The improvement in QRS duration between the HTS and NaHCO3 treatment arms proved statistically significant (p<0.05). [8] Furthermore, the HTS arm exhibited higher survival rate (83%) at 60 minutes compared with NaHCO3 (33%).

Though limited, human case reports have demonstrated success with HTS in TCA overdose patients refractory to NaHCO3.  Most notably, a 29-year old woman admitted to the ICU after 8g ingestion of nortriptyline was intubated, treated with gastric lavage, hyperventilation, vasopressor therapy with dopamine and norepinephrine with only transient improvement.[9]  Subsequently, with a pH approaching 7.5, she was given additional sodium with 7.5% HTS via rapid infusion.  Within three minutes, EKG monitoring showed narrowing of the QRS and resolution of hypotension. Currently, no published reports exist in the pediatric population.

While data remains scant, HTS may be a reasonable treatment option for TCA overdose in the absence of NaHCO3, sodium acetate, and in refractory cases. Drs. S. Srisruma and J. Cao of the Rocky Mountain Poison and Drug Center in Denver, Colorado suggest HTS may be helpful as adjunct therapy in TCA toxicity in alkalotic patients.[3]  

The sodium content in 100 mL of 3% HTS is equivalent to that in 50 mL of 8.4% NaHCO3.  HTS has been shown to be safe and effective when administered via a peripheral line, although central access is preferred.[12]  HTS should be used with caution due to risk of hyperchloremic acidosis, hypernatremia, and osmotic demyelination if administered too rapidly.  The risks of therapy should be weighed against the potential benefits.  Further studies are warranted and NaHCO3 remains the agent of choice, if accessible.

Resources:

  1. National Center for Biotechnology Information. PubChem Compound Database; CID=516892. <https://pubchem.ncbi.nlm.nih.gov/compound/sodium_bicarbonate#section=Top> Accessed 22 May 2017.
  2. “FDA Drug Shortages.” Accessdata.fda.gov. N.p., n.d. Wb. 22 May 2017
  3. http://www.emdocs.net/efficacy-of-hypertonic-saline-for-tricyclic-antidepressant-overdose/
  4. Feighner JP. Mechanism of action of antidepressant medications. J Clin Psychiatry. 1999;60 Suppl 4:4-11.
  5. Boehnert MT, Lovejoy FH. Value of the QRS duration versus the serum drug level in predicting seizures and ventricular arrhythmias after an acute overdose of tricyclic antidepressants. N Engl J Med. 1985;313(8):474-9.
  6. Kerr GW, Mcguffie AC, Wilkie S. Tricyclic antidepressant overdose: a review. Emerg Med J. 2001;18(4):236-41.
  7. Pentel P, Benowitz N: Efficacy and mechanism of toxicity of desipramine toxicity in rats. J Pharmacol Exp Ther. 1984;230:12-19.
  8. McCabe JL, Cobaugh, Menegazzi JJ, et al. Experimental tricyclic antidepressant toxicity: a randomised, controlled comparison of hypertonic saline solution, sodium bicarbonate and hyperventilation. Ann Emerg Med. 1998;32:329-33.
  9. McKinney PE, Rasmussen R. Reversal of severe tricyclic antidepressant-induced cardiotoxicity with intravenous hypertonic saline solution. Annals of Emergency Medicine. 2003;42:20-4.
  10. Høegholm A, Clementsen P. Hypertonic sodium chloride in severe antidepressant overdosage. J Toxicol Clin Toxicol. 1991;29(2):297-8.
  11. Paksu MS, Zengin H, Ilkaya F, et al. Can empirical hypertonic saline or sodium bicarbonate treatment prevent the development of cardiotoxicity during serious amitriptyline poisoning? Experimental research. Cardiovasc J Afr. 2015;26(3):134-9.
  12. Brenkert TE, Estrada CM, McMorrow SP, et al. Intravenous hypertonic saline use in the pediatric emergency department. Pediatric Emer Care 2013;29:71-73.