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Hong Kong Journal of Emergency Medicine The use of glucagon and other antidotes in a case of beta-blocker and calcium channel blocker overdose β HT Fung , CH Lai , OF Wong , KK Lam , CW Kam We report a case of metoprolol and nifedipine overdose complicated by hypotension which responded to intravenous boluses of calcium chloride and glucagon. The blood pressure was subsequently stabilised by continuous glucagon infusion with the aid of an insulin-dextrose drip. The discussion is focused on the role of antidotes and catecholamine inotropes in the management of beta-blocker and calcium channel blocker poisoning. (Hong Kong j.emerg.med. 2007;14:113-118) β Keywords: Adrenergic beta-antagonists, antidotes, calcium channel blockers, glucagon, overdose β Case A 45-year-old female with hypertension, diabetes mellitus, hyperlipidaemia and renal impairment was brought to the emergency department (ED) in September 2006 for drowsiness after drug overdose. The history obtained from the patient and her sister suggested ingestion of 60 tablets of metoprolol, slow-release nifedipine and prazosin 10 hours ago. She had a Glasgow Coma Scale (GCS) of 14/15, blood pressure (BP) 79/54 mmHg, pulse rate 55/min, respiratory rate 18/min, SpO2 98% on room air and blood glucose 8.6 mmol/L. The ECG showed sinus bradycardia and first-degree heart block with PR interval Correspondence to: Fung Hin Tat, MRCP, FRCSEd, FHKAM(Emergency Medicine) Tuen Mun Hospital, Accident & Emergency Department, Tsing Chung Koon Road, Tuen Mun, N.T., Hong Kong Email: [email protected] Lai Cing Hon, MBBS, MRCSEd, FHKAM(Emergency Medicine) Wong Oi Fung, MBChB, MRCSEd Lam Ka Keung, MBBS, MRCSEd, FHKAM(Emergency Medicine) Kam Chak Wah, MRCP, FRCSEd, FHKAM(Emergency Medicine) of 226 msec. Two hundred millilitres of normal saline were administered as intravenous bolus but the BP 30 minutes later was 75/57 mmHg. After receiving intravenous glucagon 3 mg over 5 minutes, her BP increased to 88/63 mmHg. With a second dose of glucagon at 6 mg and 10 ml of 10% calcium chloride administered 17 minutes later, the BP rose to 107/78 mmHg and she vomited twice. Calcium chloride 1 g was repeated and glucagon infusion at 9 mg/h was commenced. Actrapid HM 6 IU/h based on an estimated body weight of 60 kg and dextrose 6 g/h were subsequently added in view of a BP of 92/63 mmHg at the end of the first hour of glucagon infusion. The blood pressure at one hour after placing on insulin-dextrose alone was 95/57 mmHg and then glucagon infusion at 9 mg/h was reintroduced after the arrival of the pharmacy stock. One hour post-glucagon resumption the BP was 114/79 mmHg. In the rest of the ED stay, the BP readings were all above 100/60 mmHg, ranging from 110/70 to 120/80 mmHg most of the time, except for one occasion of 97/61 mmHg half-an-hour after an inadvertent interruption of the glucagon infusion. Hong Kong j. emerg. med. Vol. 14(2) Apr 2007 114 Her GCS improved to 15/15 eight hours after the ED attendance. The pulse rate was stable between 60 and 70/min. The PR interval, 226 ms on arrival, reached a peak of 238 ms (Figure 1) 7 hours later but was normalised to 184 ms 25 hours post-attendance. There was no hypoglycaemic episode and the blood glucose during insulin therapy varied between 7 and 17 mmol/L. One hour after the two doses of calcium chloride, the serum albumin adjusted calcium was 3.11 mmol/L, falling spontaneously to 2.62 mmol/L after 18 hours. The renal function was deranged with urea 13.2 mmol/L and creatinine 173 umol/L on presentation. The creatinine was corrected 18 hours later to 118 umol/L, identical to that four months previously. The glucagon and insulin dextrose infusions were gradually tapered down in response to the haemodynamic improvement. The duration of glucagon infusion was 20 hours and the cumulative dose inclusive of the first two boluses was 109 mg. The hyperinsulinaemic euglycaemia therapy was tapered off after 23 hours. Other drug treatments undertaken were 1 L of normal saline over 23 hours and 4 doses of 50 g activated charcoal. The treatments offered were summarised in Table 1. After regaining full consciousness, she admitted that she had taken 30 tablets of hypnotics and other medications with an estimated amount of 4,200 mg of metoprolol, 1,120 mg of slow-release nifedipine, 84 mg of prazosin, Figure 1. ECG showing sinus bradycardia and first-degree heart block. Table 1. Summary of the treatment given to the patient Treatment Total dose Duration Glucagon 109 mg (including 9 mg of loading dose) 20 hours Calcium 26 mmol (in 2 doses) Dextrose-insulin drip Maximum rate of Actrapid HM 6 IU/h and dextrose 6 g/h 23 hours Normal saline 1L 23 hours Activated charcoal 50 g for 4 doses Fung et al./Beta-blocker and calcium channel blocker overdose 2,240 mg of gliclazide and 280 mg of fluvastatin. She developed dizziness about one hour later but she managed to go home for sleep. Awareness of the surroundings was present only after ED arrival. She was discharged on the next day from the ED following psychiatric consultation. 115 calcium administration hypercalcaemia in poisoning settings, there is a paucity of experience so far. Our case's serum calcium level was 3.11 mmol/L after 26 mmol of intravenous calcium but there were no obvious symptoms and signs of hypercalcaemia. The hypercalcaemia of 4.8 mmol/L in a verapamil-poisoned patient treated with 30 g of calcium gluconate dropped to normal after four days with no sequela.6 Discussion In overdose of beta-blockers, metoprolol is second to propranolol in the occurrence of cardiovascular morbidity which is aggravated by cardiovascular coingestants, primarily calcium channel blockers, cyclic antidepressants and neuroleptics. 1 The different receptor selectivity in the heart and vasculature of different calcium channel blockers may be lost in the overdose situation. Hypotension, dysrhythmia and sinus node depression develop equally commonly in poisoning of verapamil, diltiazem and nifedipine but verapamil accounts for more frequent and more severe atrioventricular node conduction block.2 Overdose of prazosin, a post-synaptic alpha-1-adrenergic receptor antagonist, causes hypotension and tachycardia.3,4 The bradycardia in our case could be ascribed to metoprolol with or without nifedipine whereas the first-degree atrioventricular block was more likely due to metoprolol. Onset of symptoms and signs may help differentiate metoprolol from slow-release nifedipine poisoning as the former usually has an earlier onset. However the early dizziness in this patient may be explained by both the hypnotic effect and the metoprolol-induced hypoperfusion. Moreover the haemodynamic status was unknown in the many hours before the ED presentation. Both calcium channel blockers and beta-blockers hinder calcium entry through the L-type calcium channels in myocytes and vascular smooth muscle cells. Calcium administration improves BP and cardiac conduction in calcium channel blocker intoxication.2 It was reported to restore palpable pulses in a case of atenolol-induced electromechanical dissociation. 5 A dose response relationship probably exists but the optimal dose has not been determined yet. 2,6 Concerning possible detrimental effects of post- The binding of glucagon on myocardial glucagon receptor, as demonstrated by 125I-glucagon studies, bypasses the beta-adrenergic receptor and increases the intracellular calcium available for actin-myosin coupling through Gs protein mediated adenylate cyclase activation, phosphodiesterase inhibition and arachidonic acid release.7-10 The optimal chronotropic action of glucagon relies on normal serum calcium level according to rat studies. 11 The post-calcium therapy hypercalcaemia in human case reports was inconsequential, but attenuation on glucagon's action, if any, remains to be determined. In animal models of propranolol overdose, glucagon consistently augments the heart rate but the benefits on BP, cardiac output and survival rate are less clear. Glucagon appears to increase the heart rate and cardiac output and circumvent the atrioventricular block in animals overdosed with calcium channel blocker. However it does not significantly affect the mean arterial pressure and mortality rate. The implication of many of these animal studies was limited by insufficient glucagon dosage, unblinded design and small number of animals. 12 Studies on the role of glucagon in human poisoning are lacking. Glucagon was noticed reversing hypotension within two minutes in a nifedipine poisoned patient failing calcium chloride treatment.13 Glucagon requirement of 108 mg over 33 hours and 120 mg over 24 hours had been observed in two cases poisoned by nifedipine and propranolol respectively. 14,15 In a case of mixed amlodipine and atenolol overdose, the patient recovered fully after receiving 264 mg of glucagon in 52 hours. 16 The favourable outcome in these cases could not be completely attributed to glucagon because of the co-administration of other inotropes. Our patient was given calcium chloride in the first hour of Hong Kong j. emerg. med. Vol. 14(2) Apr 2007 116 in calcium channel blocker and beta-blocker intoxication. Insulin administration promotes cellular glucose uptake and restores calcium influx. Though not always effective, hyperinsulinaemia and euglycaemia treatment is successful in many case reports of calcium channel blocker overdose and one case of combined calcium channel blocker and betablocker overdose. In the 16 aforementioned cases, the maximum infusion rate of insulin and glucose was 1 IU/kg/h and 75 g/h respectively.16,19 The insulin dose for our case was initiated at only 0.1 IU/kg/h because at that juncture the BP was marginally low at 92/63 mmHg whilst on 9 mg/h of glucagon and it was clinically judged to be the appropriate dose to start with. While under insulin dextrose alone, the drop of BP to 97/61 mmHg during the 30 minutes period of interruption of glucagon infusion suggests that the insulin-dextrose dose was suboptimal for our patient. ED attendance. In the following period, she was maintained on infusions of glucagon and insulin-dextrose. The absence of inotropes and the transient BP drop during interruption of glucagon infusion suggested glucagon was the principal agent in stabilising the haemodynamic status throughout her ED stay beyond the first hour of presentation. Owing to the limited experience of the outcome of the post-calcium hypercalcaemia as well as the expected efficacy and safety profile of glucagon, glucagon is a reasonable choice over calcium as continuous infusion in our case. Glucagon's clinical action is peaked in 5 to 10 minutes and disappears by 30 minutes.17 It is recommended to be given in 3 to 5 mg as initial dose, followed by higher doses up to 10 mg in case of poor response. The subsequent infusion rate should begin at the 'response dose' per hour.18 The first two doses in our case were 17 minutes apart and the therapeutic effect of them might have overlapped. Therefore we decided the 'response dose' to be the sum of the initial two doses. The only adverse effect of glucagon detected in our case was transient vomiting. Catecholamine support in beta-blocker overdose produces mixed successful and failed results. By means of competing for the beta-receptors, the dose of betaagonist may need to be excessively high and pure betaagonists like isoproterenol in considerable amount may Switching of fatty acid utilisation to carbohydrate in the myocardium and insulin secretion inhibition occur Table 2. A general guide for the specific treatment of poisoning of beta-blockers and calcium channel blockers (The sequence and choice may need individualised adjustment. Closed monitoring and supportive care are always important.)2,16,18-23 Beta-blocker Calcium channel blocker Asymptomatic 1. Decontamination 1. Decontamination Mild toxicity (mild hypotension or mild bradycardia) 1. Decontamination 2. Fluid bolus 3. Atropine for bradycardia 1. Decontamination 2. Fluid bolus 3. Atropine for bradycardia Moderate toxicity (Failure of the above treatment or severe hypotension or severe bradycardia or hypoperfusion) 1. 2. 3. 4. 5. 6. Decontamination Fluid bolus Glucagon Calcium for hypotension Atropine for bradycardia Insulin-dextrose (delayed onset) 1. 2. 3. 4. 5. 6. 7. Decontamination Fluid bolus Calcium mainly for hypotension Glucagon Atropine for bradycardia Catecholamine Insulin-dextrose (delayed onset) Severe toxicity (Failure of the above treatment or cardiogenic shock) 1. The above 2. Catecholamine (high dose needed) 3. Electromechanical support 1. The above 2. Electromechanical support Fung et al./Beta-blocker and calcium channel blocker overdose cause undue peripheral vasodilatation. The potential deleterious effects on the microcirculation and unopposed alpha-receptor stimulated hypertension of mixed alpha and beta-adrenergic medications such as epinephrine, dopamine and norepinephrine should also be recognised.20,21 A review suggested that glucagon, effective in 86% of cases in increasing the heart rate and BP, should be the agent of choice in managing haemodynamically compromised patients poisoned by beta-blockers. The other agents in descending order of effectiveness are epinephrine, pacemaker, isoproterenol, dopamine and atropine.22 Given the close similarities of antidotal and supportive treatments in poisoning of beta-blockers and calciumchannel blockers, a suggested guide on their uses is formulated in Table 2.2,16,18-23 As evidence is limited in some aspects and clinical parameters are not always identical among individuals, clinicians should exercise modifications if needed. Conclusion Despite the long-standing utilisation of calcium and glucagon, as well as increasing recognition of insulindextrose as antidotes for beta-blocker and calcium channel blocker intoxication, there is a paucity of human trials evaluating their efficacies often because of ethical concerns in poisoning settings. Our case and the up-to-date evidence favour glucagon as an effective and safe agent. The role of glucagon relative to the conventional catecholamine vasopressors as maintenance therapy in drug overdose deserves consideration. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. References 1. 2. Love JN, Howell JM, Litovitz TL, Klein-Schwartz W. Acute beta blocker overdose: factors associated with the development of cardiovascular morbidity. J Toxicol Clin Toxicol 2000;38(3):275-81. Ramoska EA, Spiller HA, Winter M, Borys D. A oneyear evaluation of calcium channel blocker overdoses: toxicity and treatment. Ann Emerg Med 1993;22(2): 17. 18. 117 196-200. McClean WJ. Letter: Prazosin overdose. Med J Aust 1976;1(16):592. Lenz K, Druml W, Kleinberger G, Laggner A, Schneeweiss B. Acute intoxication with prazosin: case report. Hum Toxicol 1985;4(1):53-6. P e r t o l d i F, D ' O r l a n d o L , M e r c a n t e W P. Electromechanical dissociation 48 hours after atenolol overdose: usefulness of calcium chloride. Ann Emerg Med 1998;31(6):777-81. Buckley N, Dawson AH, Howarth D, Whyte IM. Slowrelease verapamil poisoning. Use of polyethylene glycol whole-bowel lavage and high-dose calcium. Med J Aust 1993;158(3):202-4. Levey GS, Fletcher MA, Klein I, Ruiz E, Schenk A. Characterization of 125 I-glucagon binding in a solubilized preparation of cat myocardial adenylate cyclase. Further evidence for a dissociable receptor site. J Biol Chem 1974;249(9):2665-73. Yagami T. Differential coupling of glucagon and betaadrenergic receptors with the small and large forms of the stimulatory G protein. Mol Pharmacol 1995;48(5): 849-54. Mery PF, Brechler V, Pavoine C, Pecker F, Fischmeister R. Glucagon stimulates the cardiac Ca 2+ current by activation of adenylyl cyclase and inhibition of phosphodiesterase. Nature 1990;345(6271):158-61. Sauvadet A, Rohn T, Pecker F, Pavoine C. Arachidonic acid drives mini-glucagon action in cardiac cells. J Biol Chem 1997;272(19):12437-45. Chernow B, Zaloga GP, Malcolm D, Willey SC, Clapper M, Holaday JW. Glucagon's chronotropic action is calcium dependent. J Pharmacol Exp Ther 1987;241(3):833-7. Benoit B. Glucagon in β-blocker and calcium channel blocker overdoses: a systematic review. J Toxicol Clin Toxicol 2003;41(5):595-602. Walter FG, Frye G, Mullen JT, Ekins BR, Khasigian PA. Amelioration of nifedipine poisoning associated with glucagon therapy. Ann Emerg Med 1993;22(7): 1234-7. Papadopoulos J, O'Neil MG. Utilization of a glucagon infusion in the management of a massive nifedipine overdose. J Emerg Med 2000;18(4):453-5. Agura ED, Wexler LF, Witzuburg RA. Massive propanolol overdose. Successful treatment with highdose isoproterenol and glucagon. Am J Med 1986;80 (4):755-7. Yuan TH, Kerns WP 2nd, Tomaszewski CA, Ford MD, Kline JA. Insulin-glucose as adjunctive therapy for severe calcium channel antagonist poisoning. J Toxicol Clin Toxicol 1999;37(4):463-74. Love JN, Sachdeva DK, Bessman ES, Curtis LA, Howell JM. A potential role for glucagon in the treatment of drug-induced symptomatic bradycardia. Chest 1998; 114(1):323-6. Brubacher J. β-adrenergic antagonists. In: Wonsiewicz MJ, Edmonson KG, Boyle PJ, editors. Goldfrank's toxicologic emergencies, 8th ed. New York: McGraw- 118 Hill; 2006. pp. 924-41. 19. Megarbane B, Karyo S, Baud FJ. The role of insulin and glucose (hyperinsulinaemia/euglycaemia) therapy in acute calcium channel antagonist and beta-blocker poisoning. Toxicol Rev 2004;23(4):215-22. 20. Taboulet P, Cariou A, Berdeaux A, Bismuth C. Pathophysiology and management of self-poisoning with beta-blockers. J Toxicol Clin Toxicol 1993;31(4): 531-51. Hong Kong j. emerg. med. Vol. 14(2) Apr 2007 21. Gandy W. Severe epinephrine-propranolol interaction. Ann Emerg Med 1989;18(1):98-9. 22. Weinstein RS. Recognition and management of poisoning with beta-adrenergic blocking agents. Ann Emerg Med 1984;13(12):1123-31. 23. DeRoos F. Calcium channel blockers. In: Wonsiewicz MJ, Edmonson KG, Boyle PJ, editors. Goldfrank's toxicologic emergencies, 8th ed. New York: McGrawHill; 2006. pp. 911-23.