A Glucagon Drug- Induced Symptomatic Bradycardia*

tuberculosis from sputum specimens. J Clin Microbiol 1995; A Potential Role for Glucagon
in the Treatment of Drug-
33:2582-86 Induced Symptomatic
Bradycardia*
12 Welch K, Brown G, Jonas V, et al. Performance of the
Jeffrey N. Love, MD; Deepak K. Sachdeva, MD;
Gen-Probe amplified Mycobacterium tuberculosis direct
test in a laboratory that infrequently isolates Mycobacte¬ Edward S. Bessman, MD; Liesl A. Curtis, MD; and

rium tuberculosis. Diagn Microbiol Infect Dis 1995; 22: John M. Howell, MD

297-99 Nine cases of symptomatic bradycardia are pre¬
sented in which treatment with intravenous gluca¬
13 Vlaspolder F, Singer P, Roggeveen C. Diagnostic value of an gon was administered when atropine failed to im¬
amplification method (Gen-Probe) compared with that of prove the patient's condition significantly. Although
culture for the diagnosis of tuberculosis. J Clin Microbiol the cause often was not obvious at presentation, all
nine subjects took oral medications that could have
1995; 33:2699-2703 contributed to the development of symptomatic bra¬
dycardia. Eight of nine patients demonstrated clini¬
14 Zolnir-Dovc M, Poljak M, Seme K, et al. Evaluation of two cal improvement 5 to 10 min after glucagon admin¬
commercial amplification assays for detection of Mycobacte¬ istration, which was consistent with its peak clinical
rium tuberculosis complex in respiratory specimens. Infection action. Beta-blockers, calcium channel blockers, and
digoxin were ultimately thought to have contributed
1995; 23:216-21 to the majority of these presentations. This report
suggests that glucagon may have a role in the treat¬
15 Miller N, Hernandez S, Cleary T. Evaluation of Gen-Probe ment of symptomatic bradycardia, particularly in the
amplified Mycobacterium tuberculosis direct test and PCR presence of beta-adrenergic blockade and perhaps
for direct detection of Mycobacterium tuberculosis in clinical calcium channel blockade. Furthermore, the results
in these cases suggest that future clinical trials
specimens. J Clin Microbiol 1994; 32:393-97 should not be limited to drug-induced symptomatic
bradycardia. (CHEST 1998; 114:323-326)
16 Bodmer T, Gurtner A, Schopfer K, et al. Screening of
respiratory tract specimens for the presence of Mycobacte¬ Key words: beta-adrenergic blockers; bradycardia; glucagon
rium tuberculosis by using the Gen-Probe amplified Myco¬
rW^ he cardiostimulatory properties of glucagon most com-
bacterium tuberculosis direct test. J Clin Microbiol 1994; ¦*¦ monly are utilized for reversing the cardiovascular
depression associated with acute beta-blocker ingestion.
32:1483-87 Recently, Love and Howell1 reported three cases of
symptomatic bradycardia in adults not related to acute
17 Ehlers S, Permann M, Zaki W, et al. Evaluation of a beta-blocker ingestion in which glucagon obviated the
need for further therapy. Since that time, nine additional
commercial rRNA target amplification assay for detection cases of symptomatic bradycardia have been encountered
of Mycobacterium tuberculosis complex in respiratory that expand upon that initial experience of Love and
specimens. Eur J Clin Microbiol Infect Dis 1994; 13:
Howell.1 This report summarizes that experience.
827-29
Case Reports
18 Dilworth JP, Goyal M, Young DB, et al. Comparison of
polymerase chain reaction for IS6110 and AMPLICOR in the Presented are nine cases of symptomatic bradycardia collected
diagnosis of tuberculosis. Thorax 1996; 51:320-22 as a convenience sample from July 1996 to March 1997. All those
receiving glucagon therapy for symptomatic bradycardia during
19 Pfyffer GE, Kissling P, Wirth R, et al. Direct detection of this period are included in this report. As best as can be
Mycobacterium tuberculosis complex in respiratory speci¬ determined, only one patient meeting our criteria (noted further
mens by a target-amplified test system. J Clin Microbiol 1994; on) did not receive glucagon. This patient was receiving throm-
*From the Department of Emergency Medicine, Georgetown
32:918-23 University Hospital (Drs. Love, Sachdeva, Curtis, and Howell),
Washington, DC, and Johns Hopkins School of Medicine (Dr.
20 Jonas V, Alden MJ, Curry JI, et al. Detection and identifica¬
tion of Mycobacterium tuberculosis directly from sputum Bessman), Baltimore, Md.
sediments by amplification of rRNA. J Clin Microbiol 1993;
Manuscript received June 18, 1997; revision accepted December
'
2, 1997.
31:2410-16
Reprint requests: Jeffrey N. Love, MD, Department ofEmergency
21 Abe C, Hirano K, Wada M, et al. Detection of Mycobacte¬ Medicine, Georgetown University Hospital, 3800 Reservoir Rd,
rium tuberculosis in clinical specimens by polymerase chain NW, Washington, DC 20007
reaction and Gen-Probe amplified Mycobacterium tubercu¬
CHEST / 114 / 1 / JULY, 1998 323
losis direct test. J Clin Microbiol 1993; 31:3270-74

22 Manterola JM, Gamboa F, Lonca J, et al. Inhibitory effect of
sodium dodecyl sulfate in detection of Mycobacterium tuber¬
culosis by amplification of rRNA. J Clin Microbiol 1995;

33:3338-40

23 American Thoracic Society Workshop (Medical Section of the
American Lung Association). Rapid diagnostic tests for tuber¬
culosis: what is the appropriate use? Am J Respir Crit Care

Med 1997; 155:1804-14

24 Moore DF, Curry JI, Knott CA, et al. Amplification of rRNA
for assessment of treatment response of pulmonary tubercu¬
losis patients during antimicrobial therapy. J Clin Microbiol

1996; 34:1745-49

25 Shafran SD, Singer J, Zarowny DP, et al. A comparison of two

regimens for the treatment of Mycobacterium avium complex
bacteremia in AIDS: rifabutin, ethambutol, and clarithromy¬
cin versus rifampin, ethambutol, clofazimine, and ciprofloxa¬
cin. N Engl J Med 1996; 335:377-83
26 Barnes PF. Rapid diagnostic tests for tuberculosis: progress
but no gold standard. Am J Respir Crit Care Med 1997;

155:1497-98

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bolytic therapy for an acute myocardial infarction. Glucagon was cardiovascular status improved with 3 mg of glucagon. Calcium
withheld due to concern over predicting its effects in an unstable therapy was added after clinical improvement. Glucagon infu¬
patient receiving multiple cardioactive medications simulta¬ sion, 3 mg/h, was discontinued after 6V2 h.
neously (eg, thrombolytics, nitrates, dobutamine). All patients
presented with bradycardia (heart rate of less than 60 beats/min), Patient 5
systolic blood pressure less than 100 mm Hg, and symptoms
consistent with decreased end-organ perfusion. All received a An 82-year-old man complained of weakness, nausea, and
minimum of 1.0 mg of atropine intravenously and were consid¬ shortness of breath upon his arrival. Long-term medications
ered by the treating physicians to require further therapy because included digoxin and enalapril maleate. No change in cardiovas¬
of an inadequate response. Subsequently, each patient was given
glucagon intravenously (Eli Lilly; Indianapolis). If other thera¬ cular symptoms or vital signs was noted with administration of 3
peutic modalities were utilized, they are noted.
mg of glucagon. Both improved with digoxin-specific Fab frag¬
Patient 1
ments.
A 69-year-oid woman presented with weakness, fatigue, and
dizziness. On examination, she appeared lethargic and confused. Patient 6
Her medications included metoprolol tartrate. Her heart rate and
BP improved within 5 min of receiving 3 mg of glucagon and A 68-year-old woman had chief complaints of weakness and
mental status improved to baseline within 1 h. Glucagon infusion nausea. She appeared lethargic. Her family was concerned that
at 3 mg/h was continued for another 14 h. Calcium chloride was she may have taken extra verapamil. The patient's mental status,
chief complaints, and cardiovascular status improved 5 min after
added after improvement in vital signs. 3.0 mg of glucagon was administered; a maintenance infusion was
initiated, and no other therapy was required.
Patient 2
Patient 7
A 65-year-old woman presented after a syncopal episode with
A 46-year-old woman presented with lethargy and shallow
nausea and shortness of breath. Her medications included vera¬ respirations. The paramedics reported that she may have taken
someone else's propranolol hydrochloride. Cardiovascular status
pamil and atenolol. Her symptoms and vital signs improved improved with administration of 7.0 mg of glucagon. Mainte¬
dramatically within 10 min of receiving 3 mg intravenous gluca¬ nance glucagon infusion at 5 mg/h was continued for 6 h.
gon. An infusion at 3 mg/h was continued for 11 h. No other
therapeutic intervention was required. Patient 8

Patient 3 A 77-year-old man who complained of feeling poorly for
several days had a syncopal episode. In the emergency depart¬
A 73-year-old woman presented with altered mental status. ment, he was poorly responsive with hypotension and bradycardia
Her medications included atenolol. An initial 1-mg bolus of despite administration of high-dose dopamine and norepineph¬
glucagon improved her BP and pulse rate. She had two further rine. Glucagon, 3.0 mg, was given, and improvement in vital signs
episodes of hypotension and bradycardia, which responded to
subsequent 1-mg boluses of glucagon. Her hemodynamics re¬ at 5 and 10 min was noted.
mained stable on a 3 mg/h glucagon infusion. Upon arrival at the
ICU, the glucagon administration was discontinued and dopa¬ Patient 9
mine therapy was initiated. The patient again became brady-
cardic and hypotensive and remained confused until the follow¬ A 65-year-old man developed nausea, vomiting, and abdominal
ing day when her symptoms and \ital signs spontaneously pain within 12 h of presentation. Metoprolol therapy was report¬
improved. edly initiated 5 days prior for hypertension. The heart rate was 44

Patient 4 beats/min and BP was 94/55 mm Hg. After atropine and with

A 51-year-old man presented with fatigue and weakness and dopamine at 40 |jLg/kg/min, the heart rate was 74 beats/min and
appeared confused 2 weeks after therapy with verapamil and BP was 67/41 mm Hg. Within 10 min of intravenous glucagon (10
methyldopa for hypertension was started. Mental status and mg) administration, his BP dramatically improved, and the
patient's condition appeared to stabilize on a maintenance infu¬
sion 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.

Table 1.Data Associated With Nine Cases of Symptomatic Bradycardia*

Heart Rate, BP, mm Hg

beats/min

Case Age/Sex Rhythm QRS, s Atropine, mg BG AG BG AG Cause

69/F J 0.096 2.0 37 52 49/22 132/78 AE

65/F J 0.068 1.0 45 59 82/41 136/85 AE

73/F S 0.102 1.0 37 54 77/32 137/57 AE

51/M J 0.092 1.0 65 71 73/57 92/62 AE

82/M J/s 0.100 1.0 48 44 90/P 90/46 AE

68/F J 0.144 1.0 56 77 70/P 117/47 AE/OD

46/F s 0.104 1.0 59 68 81/52 120/71 OD

77/M s 0.148 3.5 50 76 76/50 102/62 MI

9 65/M J 0.156 1.0 74 98 67/41 117/58 Uncertain

*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.

324 Selected Reports

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Table 2.Long-term Drug Therapy That Potentially sulting from calcium channel blocker ingestion. In the
Contributed to Cases of Symptomatic Bradycardia presence of beta-blocker intoxication, glucagon avoids the
use of high-dose catecholamines that are required to
Serum competitively overcome beta-receptor blockade and the
Level at complications that can result from other unopposed car¬
diovascular effects (eg, alpha activity). Aggregate clinical
Case Oral Medication Presentation Therapeutic Level data3 and canine studies45 suggest that glucagon improves
bradycardia, myocardial contractility, hypotension, and
1 Metoprolol 940 ng/mL 28 to 340 ng/mL end-organ hypoperfusion resulting from beta-blocker in¬
Diltiazem hydrochloride 0 ng/mL toxication. The peripheral vasodilatory properties of glu¬
2 Atenolol 600 ng/mL 200 to 500 ng/mL cagon may be responsible for that minority ofpatients who
remain hypotensive with therapy. This appears to be more
Verapamil 580 ng/mL 200 ng/mL likely in the presence of a second vasodilating medication.6
3 Atenolol
Symptomatic bradycardia is a relatively common emer¬
4 Verapamil 800 ng/mL 200 ng/mL gency department presentation particularly among elderly
Methyldopa
5 Digoxin 4.12 ng/mL <2.0 ng/mL patients. Beta-blockers and calcium channel blockers are
6 Verapamil
7 Propranolol frequently implicated as the cause, while their presence
8 Nadolol 390 ng/mL 40 to 210 ng/mL complicates treatment alternatives. As demonstrated by
these nine cases, a history of therapeutic beta-blocker use
Timolol maleate 0 ng/mL as well as the cause of symptomatic bradycardia often are
not readily apparent at presentation. Consequently, gluca¬
Diltiazem 0 ng/mL
gon may be a safer and more effective treatment alterna¬
9 Metoprolol 0 ng/mL
tive to catecholamines in symptomatic bradycardia pa¬
Comment
tients.
Further details for each patient are provided in Table 1.
The associated cardiac rhythm was determined to be To date, no controlled studies have examined the effect
junctional in five, sinus jn three, and uncertain in one. The
of glucagon on symptomatic bradycardia. We previously
heart rates and BP after atropine administration and again reported three geriatric patients in whom the need for a
temporary pacemaker was avoided by administering glu¬
5 to 10 min after the glucagon bolus are reported in Table cagon.1 In this follow-up report, 8 of 9 additional patients
1. The pulse increased in all but one instance; in six experienced improvement in key cardiovascular parame¬
ters within 5 to 10 min of glucagon administration. It
patients, the increase was greater than 11 beats/min. The appears that the positive inotropic action of glucagon is

systolic pressure also increased by 19 to 81 mm Hg in all often as important to clinical improvement as is its positive
but one patient. Two of eight patients whose vital signs
improved were intubated (cases 8 and 9), making symp¬ chronotropic activity.1
Four of these cases were thought to be the result of an
tom evaluation difficult. Of the remaining six patients, five
demonstrated associated improvement in presenting com¬ adverse drug effect, and one each resulted from acute
overdose of beta-blockers, acute anterior myocardial in¬
plaints by patient and physician assessment.
All nine patients were receiving long-term therapy with farction, and unknown cause (case 9). The one treatment

either a beta-blocker (six patients), a calcium channel failure was a case of digoxin toxicity. It is unclear whether
blocker (five patients), or digoxin (one patient). In six, this represents a circumstance in which glucagon therapy
medication levels were done and are reported in Table 2. is ineffective. Previous clinical work suggests that glu¬
Discharge diagnoses were "adverse drug effect" in six,
acute overdose in one, acute myocardial infarction in one, cagon may be an inconsistent inotrope in the presence

and uncertain cause in one. of chronic ventricular dysfunction.7 Glucagon is an
Discussion endogenous polypeptide hormone with no serious side
effects. Its only common adverse effects are nausea and
Glucagon acts on the cellular membrane at a site vomiting, which are usually self-limited and easily con¬
distinct from the beta-adrenergic receptor. Glucagon in¬ trolled by antiemetics if needed.18 Although glucagon
creases intracellular cyclic adenosine monophosphate lev¬ increases serum glucose and decreases serum potas¬
sium, these effects do not appear to be clinically
els and alters the flux of calcium ions. Its cardiovascular significant in this setting.7 Peak clinical effects occur 5

effects include directly increasing automaticity at the to 10 min after intravenous administration and are gone

sinoatrial and atrioventricular nodes, as well as increasing by 30 min. An initial bolus of 50 |JLg/kg is generally
recommended,1 though higher doses may provide addi¬
myocardial contractility and peripheral vasodilation. Stud¬ tional effects.9 A maintenance infusion of 1 to 10 mg/h
ies on healthy canines have shown that glucagon is capable generally is considered necessary due to a short half-
of "changing the escape pacemaker to a higher focus in the life.3-910 According to the experience from this study,
conducting system and converting an escape mechanism increasing the maintenance infusion during the first
originating below the AV nodal regions to a rhythm hour or using multiple glucagon boluses may be neces¬
sary to maintain serum levels until a steady state is
originating at or above the AV node."2 reached. Hospital supplies of glucagon tend to be
limited; this problem can and often does pose difficul-
Glucagon generally is considered the drug of choice for
cardiovascular depression resulting from beta-blocker CHEST / 114 / 1 / JULY, 1998 325
overdose. Glucagon also is effective for hypotension re¬

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ties in emergency circumstances.9 The radiology depart¬ Commotio Cordis*
ment may be an additional source of glucagon, where it
is used to relax gastrointestinal smooth muscle during Cardiovascular Manifestations of a
imaging procedures. When a clinician administers glu¬ Rare Survivor
cagon, he or she should know that the diluent provided
for clinical reconstitution contains 2 mg/mL of phenol. Mark S. Link, MD; Sally H. Ginsburg, MD;
Consequently, when glucagon is reconstituted as rec¬ Paul J. Wang, MD; James B. Kirchhojfer, MD;
ommended, large doses place the patient at risk for
phenol toxicity.11 For this reason, glucagon was recon¬ Charles I. Bend, MD; N. A. Mark Estes III, MD; and
Yvonne M. Paris, MD
stituted in 0.9% NaCl or 5% dextrose in water in this
Death due to low-energy chest wall trauma, commo¬
series. tio cordis, may occur in young athletes. Death is
sudden and usually refractory to even immediate
Theoretically, the profile of cardiovascular actions resuscitation efforts. Herein are described the clini¬
would appear to make glucagon useful in the treatment
of symptomatic bradycardia. The nine cases reported cal, angiographic, and hemodynamic data of a rare
here and the three previously reported1 demonstrate survivor. These observations suggest that commotio
that glucagon therapy may "buy time" for more defini¬ cordis not only may be secondary to ventricular
tive therapy, such as pacemaker placement, or obviate fibrillation, but also may be associated with coronary
the need for further therapy altogether. The most vasospasm or segmental changes in myocardial
obvious advantage to glucagon therapy is in the pres¬ contractility. (CHEST 1998; 114:326-328)
ence of beta-blocker therapy, which may contribute to
Key words: sports injuries; sudden death; ventricular fibrillation
the patient's illness. Both this and a broader spectrum

of causes for symptomatic bradycardia deserve closer
scrutiny by controlled studies.

References /^ ommotio cordis was first described in 1932 by
^^ Schlomka and Schmitz1 who separated chest wall
1 Love JN, Howell JM. Glucagon therapy in the treatment of
symptomatic bradycardia. Ann Emerg Med 1997; 29: trauma induced injury into commotio cordis (with little or

181-83 no evident cardiac damage) and contusio cordis (with
evident myocardial damage). In the current era, commotio
2 Lipski JI, Kaminsky D, Donoso E, et al. Electrophysiological
effects of glucagon on the normal canine heart. Am J Physiol cordis has been defined as a condition of those individuals

1972; 222:1107-12 who suffer sudden death with a relatively minor (typically

3 Weinstein RS. Recognition and management of poisoning a thrown or batted baseball) chest wall injury and whose
autopsies show no evidence of structural cardiac abnor¬
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13:1123-31 sudden death.2 Annually, two to four deaths due to
commotio cordis are reported in baseball.3 Survival after
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amrinone and glucagon therapy for cardiovascular depression be seen with prompt resuscitation.4 Commotio cordis is
associated with propranolol toxicity in a canine model. J
thought to result from ventricular fibrillation which occurs
Toxicol Clin Toxicol 1992; 30:399-412
when chest wall trauma coincides with the cardiac T
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asystole, neurocardiogenic, hypervagatonia, and the long
6 Love JN, Leasure JA, Mundt DJ. A comparison of combined QT syndrome.5 We describe a case of commotio cordis in
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Emerg Med 1993; 11:360-63
including immediate ECGs, a coronary angiogram, a left
7 Armstrong PW, Gold HK, Daggett WM, et al. Hemodynamic ventriculogram, and echocardiography. These clinical de¬
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lation 1971; 44:67-73 argue that the mechanism of commotio cordis may be

8 Lvoff R, Wilcken DEL. Glucagon in heart failure and in more complex than solely ventricular fibrillation.
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*From The Cardiac Arrhythmia Service, New England Medical
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811

11 Mofenson HC, Caraccio TR, Laudano J. Glucagon for pro¬
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326

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