Optimal Use of Bicarbonate Therapy
Hennepin County Medical Center
Int J Med Toxicol 1999; 2(2):3
See also NEW CASE - SUMMARY - 1999; 2(2): 2
What is the correct dose of bicarbonate?
Given the general agreement that hypertonic sodium bicarbonate (HSB, 1 molar, 1 meq/ml) is the mainstay of treatment for tricyclic antidepressant (TCA) cardiotoxicity (and for other drugs that prolong QRS duration), it is unsettling that guidelines for dosing HSB have not been established. There are in fact no controlled studies in humans demonstrating that bicarbonate is effective, let alone what dose is optimal. Anecdotal case reports and retrospective case series support a beneficial effect of HSB, but virtually all recommendations regarding dose, method of delivery (bolus v. infusion), the endpoints for therapy, and the use of alternative therapies (hypertonic NaCl, sodium-free buffers, hyperventilation), are extrapolated from animal studies.
Many controlled animal studies support a role for HSB in reducing TCA-induced QRS duration, ameliorating hypotension, and treating ventricular dysrhythmias, but few address the issue of dose. Common doses used in these studies, and found effective, are 2-6 meq/kg administered as a bolus or rapid infusion (1-5). In one rat study, 6 meq/kg was more effective than 3 meq/kg (2). Adverse effects have not been reported, but these studies were not designed to detect them. Common practice in patients has been to start with somewhat lower doses (50-100 meq HSB), largely in deference to our familiarity and comfort with this dose from other clinical settings. Anecdotal data support the efficacy of this dose range, but it is far from clear that it is optimal. Much higher doses, up to 500 ml of 1 molar sodium lactate (which is rapidly metabolized to bicarbonate) have been used successfully to treat patients with quinidine or other Class I antiarrhythmic drug toxicity, although as infusions rather than bolus doses (6,7). While adverse effects have not been reported, experience with these very high doses is limited.
Since pH and sodium both count, why do most people make a drip by adding bicarbonate to D5W. Why not add bicarbonate to 0.9% NaCl and make a high sodium high bicarbonate drip?
The current patient received a bicarbonate infusion in addition to HSB boluses. Some studies suggest that HSB works in part by increasing the serum sodium concentration. If this is so, then diluting HSB (which is 7 N) in a liter of i.v. fluid (whether D5W or 0.9% NaCl) would render it less hypertonic and possibly less effective. Interestingly, the relative roles of the sodium and bicarbonate moieties of HSB in reversing cardiotoxicity seem to vary with different TCAs or Class I antiarrhythmic agents and perhaps with the study design as well (sodium more important for desipramine, flecainide, mexiletine, pH more important for amitriptyline, imipramine) (8-11). While the reason for this is not clear, it suggests that administering HSB as boluses of the 1M solution is preferred, as it confers the benefits of both increasing blood pH and increasing blood sodium concentration. For the same reasons, substituting 1M NaCl or hyperventilation for HSB may provide less benefit in some circumstances.
What is the endpoint of therapy (pH, blood pressure, ECG)? Is having a QRS of 120 msec better than having a QRS of 140 msec?
Monitoring of blood pH has been suggested as an endpoint for therapy. Because acidosis aggravates TCA cardiotoxicity (2), returning blood pH at least to normal seems reasonable. However, the benefit of HSB is observed in animals even in the absence of acidosis. Because an excessively high blood pH even in the absence of TCA toxicity can cause ventricular dysrhythmias or (in the case of hyperventilation) seizures, common but empirical recommendations are to administer HSB as needed up to a blood pH of 7.5 or 7.55 (12). A case report of an adverse outcome in the face of very high HSB dose and profound alkalemia (pH 7.83) underscores this concern (13). In the current case, the patient received the equivalent of about 12 ampules (533 meq) of sodium bicarbonate over a "short" period of time, in addition to other i.v. fluids. While the blood pH rose only to 7.61, fluid overload with pulmonary edema resulted, illustrating a second mechanism by which excessive HSB may be harmful.
QRS prolongation is a marker of patients at risk of adverse events such as hypotension or dysrhythmia, rather than an adverse event itself. Most clinicians agree that hypotension which is not readily responsive to fluids, or ventricular dysrhythmias should be treated with HSB. The value of prophylactic HSB (treating QRS prolongation in the absence of other cardiovascular complications) is not established. Survival of rats given a continuous amitriptyline infusion was improved by HSB and duration of sinus rhythm was modestly prolonged, but this regimen was not compared to waiting for complications to occur before giving HSB (5). Because the effects of HSB are prompt, one could argue for reserving its use for hypotension or dysrhythmias and thereby minimizing the risk of excessive HSB administration. A recommended but untested middle ground is to reserve HSB for patients with a QRS duration of 0.14 sec or any prolonged QRS duration that is rapidly increasing (14). This approach acknowledges that there is no cutoff for risk of complications, but that a QRS of 0.16 sec carries a substantial risk of ventricular dysrhythmia (15).
As in the current case, seizures may aggravate or precipitate TCA cardiotoxicity (16,17), perhaps via the resulting acidosis. Immediate hyperventilation and/or HSB to correct the acidosis is reasonable. There is no evidence, however, that HSB affects seizure risk per se.
When should hypertonic saline or hyperventilation alone be considered?
By the reasoning above, HSB is preferred to these measures unless contraindicated. Hyperventilation may be considered in a patient with hypernatremia or severe volume overload, and hypertonic saline might be considered in a severely alkalotic (but not hypernatremic) patient, a rare circumstance. Whether the greater theoretical safety of these alternatives, in these selected circumstances, balances their possibly lesser efficacy is unclear. Other risks with these therapies, such as impaired venous return with hyperventilation, should also be considered.
Hyperventilation as a preventive measure has been shown in dogs to reduce the development of QRS prolongation and ventricular arrhythmias (8). Hyperventilation is therefore used by some as a prophylactic measure on the grounds that it is safer than HSB. Although this approach is appealing, whether hyperventilation is in fact safer than HSB is untested. Animal studies of hyperventilation have involved concurrent anesthesia so that the possibility of hyperventilation aggravating seizures could not be adequately assessed.
What is appropriate HSB therapy for the current patient?
HSB was optional at the time of intubation since the patient had neither hypotension nor ventricular dysrhythmia, and the QRS duration was only modestly prolonged at 0.12 sec. The acidosis at the time was respiratory and should have corrected with intubation and ventilation.
Administering a bolus of 50-100 meq HSB after the seizure, which provoked hypotension, was reasonable. Additional bolus HSB was also reasonable in view of the persistent hypotension, but with monitoring of the serum sodium concentration and pH to avoid the excessive alkalemia that followed. The optimal fluid challenge for this patients is a matter of opinion, but experience suggests that TCA-induced hypotension which does not improve with 1 L of 0.9% saline is unlikely to improve with additional fluid alone (18). The use of a pressor/inotrope was therefore both appropriate and successful. This is in keeping with animal studies that show prolonged survival with various pressor/inotropic agents in animals with TCA-induced hypotension, and an additive effect with HSB (5,19-21).
- McCabe JL, Cobaugh DJ, Menegazzi JJ, Fata J. Experimental tricyclic antidepressant toxicity: a randomized, controlled comparison of hypertonic saline solution, sodium bicarbonate, and hyperventilation. Ann Emerg Med. 1998; 32:329-333.
- Pentel PR, Benowitz NL. Efficacy and mechanism of action of sodium bicarbonate in the treatment of desipramine toxicity in rats. J Pharmacol Exp Ther. 1984; 230:12-19.
- Hedges JR, Baker B, Tasset JJ, Otten EJ, Dalsey WC, Severud SA. Bicarbonate therapy for the cardiovascular toxicity of amitriptyline in an animal model. J Emerg Med. 1985; 3:253.
- Brown TCK, Barker GA, Dunlop ME, Loughnan PM. The use of sodium bicarbonate in the treatment of tricyclic antidepressant-induced arrhythmias. Anaesth Intensive Care. 1973; 1:203.
- Knudsen K, Abrahamsson J. Epinephrine and sodium bicarbonate independently and additively increase survival in experimental amitriptyline poisoning. Crit Care Med. 1997; 25:669-674.
- Wasserman F, Brodsky L, Dick MM, Kathe JH, Rodensky PL. Successful treatment of quinidine and procainamide intoxication: Report of three cases. N Engl J Med. 1958; 259:797-802.
- Chouty F, Funck-Bretano C, Leenhardt A. Intravenous sodium lactate as a treatment of Class I antiarrhythmic agents overdose. Circulation. 1989; 80:II420.
- Nattel S, Mittleman M. Treatment of ventricular tachyarrhythmias resulting from amitriptyline toxicity in dogs. J Pharmacol Exp Ther. 1984; 231:430-435.
- Stone CK, Kraemer CM, Carroll R, Low R. Does a sodium-free buffer affect QRS width in experimental amitriptyline overdose. Ann Emerg Med. 1995; 26:58-60.
- Bou-Abboud E, Nattel S. Relative role of alkalosis and sodium ions in reversal of class I antiarrhythmic drug-induced sodium channel blockade by sodium bicarbonate. Circulation. 1996; 94:1954-1961.
- Ranger S, Sheldon R, Fermini B, Nattel S. Modulation of flecainide's cardiac sodium channel blocking actions by extracellular sodium: A possible cellular mechanism for the action of sodium salts in flecainide cardiotoxicity. J Pharmacol Exp Ther. 1993; 264:1160-1167.
- Shannon M, Liebelt EL. Toxicology reviews: targeted managment strategies for cardiovascular toxicity from tricyclic antidepressant overdose: the pivotal role for alkalinization and sodium loading. Pediatr Emerg Care. 1998; 14:293-298.
- Wrenn K, Smith B, Slovis C. Profound alkalemia during treatment of tricyclic antidepressant overdose: A potential hazard of combined hyperventilation and intravenous bicarbonate. Am J Emerg Med. 1992; 10:553-555.
- Pentel, P.R., Keyler, D.E. and Haddad, L.M. Tricyclic antidepressants and selective serotonin reuptake inhibitors. In: Clinical Management of Poisoning and Drug Overdose, edited by Haddad, L.M., Shannon, M.W. and Winchester, J.F. Philadelphia: W.B. Saunders Company, 1998, p. 437-451.
- 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; 3Z3:474.
- Ellison DW, Pentel PR. Clinical features and consequences of seizures due to cyclic antidepressant overdose. Am J Emerg Med. 1989; 7:5-10.
- Taboulet P, Michard F, Muszynski J, Galloit-Guiley M, Bismuth C. Cardiovascular repercussions of seizures during cyclic antidepressant poisoning. Clin Toxicol. 1995; 33:205-211.
- Langou RA, Van Dyke C, Tahan SR, Cohen LS. Cardiovascular manifestations of tricyclic antidepressant overdose. Am Heart J. 1980; 100:458-463.
- Follmer CH, Lum BK. Protective action of diazepam and of sympathomimetic amines against amitriptyline induced toxicity. J Pharmacol Exp Ther. 1982; 222:424.
- Sangster B, de Groot G, Borst C, de Wildt D. Dopamine and isoproterenol in imipramine intoxication in the dog. Clin Toxicol. 1985; 23:407.
- Knudsen K, Abrahamsson J. Effects of epinephrine and norepinephrine on hemodynamic parameters and arrhythmias during a continuous infusion of amitriptyline in rats. Clin Toxicol. 1993; 31:461-471.
Int J Med Toxicol 1999; 2(2):3
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