Glucagon

Nine cases of symptomatic bradycardia are presented in which treatment with intravenous glucagon was administered when atropine failed to improve the patient's condition significantly. Although the cause often was not obvious at presentation, all nine subjects took oral medications that could have contributed to the development of symptomatic bradycardia. Eight of nine patients demonstrated clinical improvement 5 to 10 min after glucagon administration, which was consistent with its peak clinical action. Beta-blockers, calcium channel blockers, and digoxin were ultimately thought to have contributed to the majority of these presentations. This report suggests that glucagon may have a role in the treatment of symptomatic bradycardia, particularly in the presence of beta-adrenergic blockade and perhaps calcium channel blockade. Furthermore, the results in these cases suggest that future clinical trials should not be limited to drug-induced symptomatic bradycardia.

(CHEST 1998; 114:323-326)

Key words: beta-adrenergic blockers; bradycardia; glucagon

The cardiostimulatory properties of glucagon most commonly are utilized for reversing the cardiovascular depression associated with acute beta-blocker ingestion. Recently, Love and Howell[1] reported three cases of symptomatic bradycardia in adults not related to acute beta-blocker ingestion in which glucagon obviated the need for further therapy. Since that time, nine additional cases of symptomatic bradycardia have been encountered that expand upon that initial experience of Love and Howell.[1] This report summarizes that experience.

CASE REPORTS

Presented are nine cases of symptomatic bradycardia collected as a convenience sample from July 1996 to March 1997. All those receiving glucagon therapy for symptomatic bradycardia during this period are included in this report. As best as can be determined, only one patient meeting our criteria (noted further on) did not receive glucagon. This patient was receiving thrombolytic therapy for an acute myocardial infarction. Glucagon was withheld due to concern over predicting its effects in an unstable patient receiving multiple cardioactive medications simultaneously (eg, thrombolytics, nitrates, dobutamine). All patients presented with bradycardia (heart rate of less than 60 beats/min), systolic blood pressure less than 100 mm Hg, and symptoms consistent with decreased end-organ perfusion. All received a minimum of 1.0 mg of atropine intravenously and were considered by the treating physicians to require further therapy because of an inadequate response. Subsequently, each patient was given glucagon intravenously (Eli Lilly; Indianapolis). If other therapeutic modalities were utilized, they are noted.

PATIENT 1

A 69-year-old woman presented with weakness, fatigue, and dizziness. On examination, she appeared lethargic and confused. Her medications included metoprolol tartrate. Her heart rate and BP improved within 5 min of receiving 3 mg of glucagon and mental status improved to baseline within 1 h. Glucagon infusion at 3 mg/h was continued for another 14 h. Calcium chloride was added after improvement in vital signs.

PATIENT 2

A 65-year-old woman presented after a syncopal episode with nausea and shortness of breath. Her medications included verapamil and atenolol. Her symptoms and vital signs improved dramatically within 10 min of receiving 3 mg intravenous glucagon. An infusion at 3 mg/h was continued for 11 h. No other therapeutic intervention was required.

PATIENT 3

A 73-year-old woman presented with altered mental status. Her medications included atenolol. An initial 1-mg bolus of glucagon improved her BP and pulse rate. She had two further episodes of hypotension and bradycardia, which responded to subsequent 1-mg boluses of glucagon. Her hemodynamics remained stable on a 3 mg/h glucagon infusion. Upon arrival at the ICU, the glucagon administration was discontinued and dopamine therapy was initiated. The patient again became bradycardic and hypotensive and remained confused until the following day when her symptoms and vital signs spontaneously improved.

PATIENT 4

A 51-year-old man presented with fatigue and weakness and appeared confused 2 weeks after therapy with verapamil and methyldopa for hypertension was started. Mental status and cardiovascular status improved with 3 mg of glucagon. Calcium therapy was added after clinical improvement. Glucagon infusion, 3 mg/h, was discontinued after 6 1/2 h.

PATIENT 5

An 82-year-old man complained of weakness, nausea, and shortness of breath upon his arrival. Long-term medications included digoxin and enalapril maleate. No change in cardiovascular symptoms or vital signs was noted with administration of 3 mg of glucagon. Both improved with digoxin-specific Fab fragments.

PATIENT 6

A 68-year-old woman had chief complaints of weakness and nausea. She appeared lethargic. Her family was concerned that she may have taken extra verapamil. The patient's mental status, chief complaints, and cardiovascular status improved 5 min after 3.0 mg of glucagon was administered; a maintenance infusion was initiated, and no other therapy was required.

PATIENT 7

A 46-year-old woman presented with lethargy and shallow respirations. The paramedics reported that she may have taken someone else's propranolol hydrochloride. Cardiovascular status improved with administration of 7.0 mg of glucagon. Maintenance glucagon infusion at 5 mg/h was continued for 6 h.

PATIENT 8

A 77-year-old man who complained of feeling poorly for several days had a syncopal episode. In the emergency department, he was poorly responsive with hypotension and bradycardia despite administration of high-dose dopamine and norepinephrine. Glucagon, 3.0 mg, was given, and improvement in vital signs at 5 and 10 min was noted.

PATIENT 9

A 65-year-old man developed nausea, vomiting, and abdominal pain within 12 h of presentation. Metoprolol therapy was reportedly initiated 5 days prior for hypertension. The heart rate was 44 beats/min and BP was 94/55 mm Hg. After atropine and with dopamine at 40 [micro]g/kg/min, the heart rate was 74 beats/min and BP was 67/41 mm Hg. Within 10 min of intravenous glucagon (10 mg) administration, his BP dramatically improved, and the patient's condition appeared to stabilize on a maintenance infusion of 6 mg/h. He converted to a sinus rhythm within 1 h and was at his baseline without complaint when the glucagon infusion was discontinued 12 h later.

COMMENT

Further details for each patient are provided in Table 1. The associated cardiac rhythm was determined to be junctional in five, sinus in three, and uncertain in one. The heart rates and BP after atropine administration and again 5 to 10 min after the glucagon bolus are reported in Table 1. The pulse increased in all but one instance; in six patients, the increase was greater than 11 beats/min. The systolic pressure also increased by 19 to 81 mm Hg in all but one patient. Two of eight patients whose vital signs improved were intubated (cases 8 and 9), making symptom evaluation difficult. Of the remaining six patients, five demonstrated associated improvement in presenting complaints by patient and physician assessment.

(*) Abbreviations: AE=adverse drug effect; AG=after glucagon; BG=before glucagon; J=junctional rhythm; MI=myocardial infarction; OD=overdose; P=systoLic BP determined by pulse palpation rather than ausculation; S=sinus rhythm.

All nine patients were receiving long-term therapy with either a beta-blocker (six patients), a calcium channel blocker (five patients), or digoxin (one patient). In six, medication levels were done and are reported in Table 2. Discharge diagnoses were "adverse drug effect" in six, acute overdose in one, acute myocardial infarction in one, and uncertain cause in one.

Table 2--Long-term Drug Therapy That Potentially Contributed to Cases of Symptomatic Bradycardia

DISCUSSION

Glucagon acts on the cellular membrane at a site distinct from the beta-adrenergic receptor. Glucagon increases intracellular cyclic adenosine monophosphate levels and alters the flux of calcium ions. Its cardiovascular effects include directly increasing automaticity at the sinoatrial and atrioventricular nodes, as well as increasing myocardial contractility and peripheral vasodilation. Studies on healthy canines have shown that glucagon is capable of "changing the escape pacemaker to a higher focus in the conducting system and converting an escape mechanism originating below the AV nodal, regions to a rhythm originating at or above the AV node."[2]

Glucagon generally is considered the drug of choice for cardiovascular depression resulting from beta-blocker overdose. Glucagon also is effective for hypotension resulting from calcium channel blocker ingestion. In the presence of beta-blocker intoxication, glucagon avoids the use of high-dose catecholamines that are required to competitively overcome beta-receptor blockade and the complications that can result from other unopposed cardiovascular effects (eg, alpha activity). Aggregate clinical data[3] and canine studies[4,5] suggest that glucagon improves bradycardia, myocardial contractility, hypotension, and end-organ hypoperfusion resulting from beta-blocker intoxication. The peripheral vasodilatory properties of glucagon may be responsible for that minority of patients who remain hypotensive with therapy. This appears to be more likely in the presence of a second vasodilating medication.[6]

Symptomatic bradycardia is a relatively common emergency department presentation particularly among elderly patients. Beta-blockers and calcium channel blockers are frequently implicated as the cause, while their presence complicates treatment alternatives. As demonstrated by these nine cases, a history of therapeutic beta-blocker use as well as the cause of symptomatic bradycardia often are not readily apparent at presentation. Consequently, glucagon may be a safer and more effective treatment alternative to catecholamines in symptomatic bradycardia patients.

To date, no controlled studies have examined the effect of glucagon on symptomatic bradycardia. We previously reported three geriatric patients in whom the need for a temporary pacemaker was avoided by administering glucagon.[1] In this follow-up report, 8 of 9 additional patients experienced improvement in key cardiovascular parameters within 5 to 10 min of glucagon administration. It appears that the positive inotropic action of glucagon is often as important to clinical improvement as is its positive chronotropic activity.[1]

Four of these cases were thought to be the result of an adverse drug effect, and one each resulted from acute overdose of beta-blockers, acute anterior myocardial infarction, and unknown cause (case 9). The one treatment failure was a case of digoxin toxicity. It is unclear whether this represents a circumstance in which glucagon therapy is ineffective. Previous clinical work suggests that glucagon may be an inconsistent inotrope in the presence of chronic ventricular dysfunction.[7] Glucagon is an endogenous polypeptide hormone with no serious side effects. Its only common adverse effects are nausea and vomiting, which are usually self-limited and easily controlled by antiemetics if needed.[1,8] Although glucagon increases serum glucose and decreases serum potassium, these effects do not appear to be clinically significant in this setting.[7] Peak clinical effects occur 5 to 10 min after intravenous administration and are gone by 30 min. An initial bolus of 50 [micro]g/kg is generally recommended,[1] though higher doses may provide additional effects.[9] A maintenance infusion of 1 to 10 mg/h generally is considered necessary due to a short half-life.[3,9,10] According to the experience from this study, increasing the maintenance infusion during the first hour or using multiple glucagon boluses may be necessary to maintain serum levels until a steady state is reached. Hospital supplies of glucagon tend to be limited; this problem can and often does pose difficulties in emergency circumstances.[9] The radiology department may be an additional source of glucagon, where it is used to relax gastrointestinal smooth muscle during imaging procedures. When a clinician administers glucagon, he or she should know that the diluent provided for clinical reconstitution contains 2 mg/mL of phenol. Consequently, when glucagon is reconstituted as recommended, large doses place the patient at risk for phenol toxicity.[11] For this reason, glucagon was reconstituted in 0.9% NaCl or 5% dextrose in water in this series.

Theoretically, the profile of cardiovascular actions would appear to make glucagon useful in the treatment of symptomatic bradycardia. The nine cases reported here and the three previously reported[1] demonstrate that glucagon therapy may "buy time" for more definitive therapy, such as pacemaker placement, or obviate the need for further therapy altogether. The most obvious advantage to glucagon therapy is in the presence of beta-blocker therapy, which may contribute to the patient's illness. Both this and a broader spectrum of causes for symptomatic bradycardia deserve closer scrutiny by controlled studies.

REFERENCES

[1] Love JN, Howell JM. Glucagon therapy in the treatment of symptomatic bradycardia. Ann Emerg Med 1997; 29: 181-83

[2] Lipski JI, Kaminsky D, Donoso E, et al. Electrophysiological effects of glucagon on the normal canine heart. Am J Physiol 1972; 222:1107-12

[3] Weinstein RS. Recognition and management of poisoning with beta adrenergic blocking agents. Ann Emerg Med 1984; 13:1123-31

[4] Love JN, Leasure JA, Mundt DJ, et al. A comparison of amrinone and glucagon therapy for cardiovascular depression associated with. propranolol toxicity in a canine model. J Toxicol Clin Toxicol 1992; 30:399-412

[5] Lucchesi BR. Cardiac actions of glucagon. Circ Res 1968; 22:777-87

[6] Love JN, Leasure JA, Mundt DJ. A comparison of combined amrinone and glucagon therapy to glucagon alone for cardiovascular depression associated with propranolol toxicity. Am J Emerg Med 1993; 11:360-63

[7] Armstrong PW, Gold HK, Daggett WM, et al. Hemodynamic evaluation of glucagon in symptomatic heart disease. Circulation 1971; 44:67-73

[8] Lvoff R, Wilcken DEL. Glucagon in heart failure and in cardiogenic shock: experience in 50 patients. Circulation 1972; 45:534-42

[9] Love JN, Tandy TK. Beta adrenoreceptor antagonist toxicity: a survey of glucagon availability [letter]. Ann Emerg Med 1993; 22:267-68

[10] Frishman W, Jacob H, Eisenberg E, et al. Clinical pharmacology of the new beta-adrenergic blocking drugs: part 8. Self-poisoning with beta-adrenoceptor blocking agents: recognition and management. Am Heart J 1979; 98:798-811

[11] Mofenson HC, Caraccio TR, Laudano J. Glucagon for propranolol overdose [letter]. JAMA 1986; 255:2025

(*) From the Department of Emergency Medicine, Georgetown University Hospital (Drs. Love, Sachdeva, Curtis, and Howell), Washington, DC, and Johns Hopkins School of Medicine (Dr. Bessman), Baltimore, Md.

Manuscript received June 18, 1997; revision accepted December 2, 1997.

Reprint requests: Jeffrey N. Love, MD, Department of Emergency Medicine, Georgetown University Hospital, 3800 Reservoir Rd, NW, Washington, DC 20007

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