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Intravenous Theophylline — An Alternative to Temporary Pacing in the

Management of Bradycardia Secondary to AV Nodal Block

Article  in  Annals of Pharmacotherapy · April 2001

DOI: 10.1345/aph.10106 · Source: PubMed

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Intravenous Theophylline —
An Alternative to Temporary Pacing in the Management of
Bradycardia Secondary to AV Nodal Block

Michael J Cawley, Abdulrazaq S Al-Jazairi, and Elizabeth A Stone

OBJECTIVE: To report a case of bradycardia secondary to atrioventricular nodal block (AVNB) successfully treated with intravenous
theophylline. Intravenous theophylline was used as an alternative to temporary pacing in a patient with sepsis secondary to thermal
injury.
CASE SUMMARY: A 79-year-old white woman with significant cardiac history was admitted with 14.5% total body surface area burns
after a house fire. Cardiac events included intermittent episodes of sinus bradycardia complicated by the development of second-
degree AVNB and periods of sinus arrest. Intravenous theophylline initiation maintained normal sinus rhythm without further
episodes of sinus bradycardia or heart block, thus preventing the need for cardiac pacemaker placement.
DISCUSSION: This is the first case published in the English-language literature describing the use of intravenous theophylline as an
alternative therapy to temporary pacing in a patient with sepsis secondary to thermal injury. Bradyarrhythmic events in sepsis
patients have been associated with catecholamine production increasing adenosine formation. High concentrations of adenosine in
the areas of the sinoatrial or atrioventricular nodal regions may induce sinus bradycardia or AVNB. Theophylline, an adenosine
antagonist, has been identified as a treatment option for such bradyarrhythmic events.
CONCLUSIONS: Theophylline, a methylxanthine derivative, may represent an alternative to other pharmacologic therapies and
temporary pacing in the treatment of bradycardia secondary to AVNB. These agents may represent a pharmacologic alternative in
patients in whom other pharmacologic strategies or cardiac pacemaker insertion may be contraindicated.
KEY WORDS: adenosine, atrioventricular nodal block, bradycardia, theophylline.

Ann Pharmacother 2001;35:303-7.

atients with clinical instability arising from atrioven-
P tricular nodal block (AVNB) and bradycardia can pre-
sent a clinical dilemma. The dilemma may escalate due to
medical complications that limit treatment choices. Clini-
cal interventions for AVNB and bradycardia may consist
of intravenous atropine and isoproterenol or, beyond these
pharmacologic approaches, temporary external or transve-
nous pacing. If the arrhythmia persists, the insertion of a
permanent cardiac pacemaker may be indicated.1 Howev-
er, some patients may not qualify as surgical candidates or
may refuse pacemaker placement. Issues that must be con-
sidered include risks of the surgical procedure, costs related
to occupation of an intensive-care bed, intensity of patient
monitoring, and mechanical or infectious complications.
Author information provided at the end of the text.
Therefore, alternatives that minimize surgical intervention
and provide patient comfort must be sought.
Theophylline, a methylxanthine derivative primarily in-
dicated for pharmacologic management of bronchospasm,
has also been investigated for use in cardiac rhythm distur-
bances. Cardiac uses have included atropine-resistant AVNB
during and after myocardial infarction, neonatal apnea–
bradycardia, atrial fibrillation with slow ventricular response,
sick-sinus syndrome, and sinus node dysfunction in human
heart transplant recipients.2-7 Theophylline has been shown
to affect cardiac performance at specific serum concentra-
tions; concentrations between 5 and 15 mg/L have en-
hanced biventricular function, increased resting heart rate
in healthy subjects, and provided positive chronotropic ef-
fects on symptomatic recurrent bradycardia.8,9
Bradyarrhythmias may be associated with myocardial
ischemia, hypoxia, sepsis, or other conditions affecting

www.theannals.com The Annals of Pharmacotherapy ■ 2001 March, Volume 35 ■ 303

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MJ Cawley et al.

atrioventricular nodal conduction. Pharmacologic strate-
gies for the treatment of this condition have included oral
anticholinergics and sympathomimetics. Anticholinergics
have shown a potential for intolerance by causing ortho-
static hypotension and sympathomimetics by increasing
myocardial consumption, which may exacerbate the ar-
rhythmia.10,11 Adenosine, a product of cardiac vascular en-
dothelium and cardiomyocytes, has been associated with
negative inotropic and chronotropic effects. Methylxan-
thine derivatives such as theophylline and aminophylline
have shown antagonism against adenosine and have been
identified as an alternative therapy in patients with AVNB
and bradycardia.2,3,10,12-14
We report a case of bradycardia secondary to AVNB
successfully treated with intravenous theophylline as an al-
ternative to temporary pacing in a patient with sepsis sec-
ondary to thermal injury.
CASE REPORT
A 79-year-old, 50-kg, white woman with a history of hyperten-
sion, coronary artery disease with triple-vessel percutaneous
coronary angioplasty in 1995, hypothyroidism, and gastroesoph-
ageal reflux disease was admitted to our burn treatment center
with 14.5% total body surface area burns after a house fire. Burns
included 5% full thickness of the posterior neck and back and
9.5% partial thickness of the upper chest and face; she also had
inhalation injury requiring intubation, mechanical ventilation,
and hemodynamic stabilization. Multiple surgical debridement
and split-thickness skin-grafting procedures were performed for
thermal injuries during hospitalization. Two weeks after admis-
sion, the patient developed systemic inflammatory response syn-
drome manifested as BP 75/50 mm Hg, T 38.5 ˚C, RR 20–25
breaths/min, and white blood cell count 13 × 103 cells/mm3 with
13% bands. Multiple blood cultures identified group D Entero-
coccus and coagulase-negative staphylococci. Sputum cultures
identified Staphylococcus aureus and Acinetobacter baumanii.
Antibiotics were tailored based on sensitivities of the organisms
and included vancomycin, chloramphenicol, imipenem/cilastatin,
and amikacin. Other medications initiated during hospitalization
were dopamine, lorazepam, morphine sulfate, heparin, sucralfate,
nystatin, Metamucil, docusate sodium, and levothyroxine.
Approximately three weeks after admission, the patient devel-
oped intermittent episodes of sinus bradycardia with an HR of 55
beats/min (admission HR 75 beats/min). Intermittent sinus brady-
cardia continued for five days, which was further complicated by
the development of second-degree AVNB, Mobitz type I, with
periods of 2:1 conduction and HR of 34 beats/min. AVNB was
occasionally associated with marked sinus arrest of up to 10–12
seconds of asystole and hypotension responding to 1 mg intra-
venous atropine and recovering to sinus rhythm of 80 beats/min
with 1:1 atrioventricular conduction (Table 1). Less than 24
hours later, a similar arrhythmia occurred, again responding to in-
travenous atropine 1 mg. Electrolyte disorders, active ischemia,
hypoxia, hypothyroidism, drug therapy (lorazepam, morphine
sulfate, heparin, sucralfate, nystatin, Metamucil, docusate sodi-
um, levothyroxine), and other nonpharmacologic interventions
(i.e., endotracheal suctioning, burn wound debridement) that may
change sympathetic or vagal tone were excluded as etiologies for
the bradycardia. Temporary and permanent pacemaker insertion
was considered, but sepsis, extent and location of thermal injury
(i.e., chest), and comorbid disease states placed her at high infec-
tious risk for both interventions. Further pharmacologic interven-
tions with a continuous infusion of a positive chronotrope were
dismissed due to the concern for adverse cardiac effects associat-
ed with the patient’s cardiac history.
As an alternative to atropine, isoproterenol, or permanent or
temporary pacing, treatment with intravenous theophylline was
initiated. A loading dose of 450 mg followed by a maintenance

Table 1. Pharmacologic Treatment of Bradycardia Secondary to AVNB

Cardiac Rhythm Lowest HR Average BP
Date/Time (beats/min) (mm Hg) Pharmacologic Treatment Result

4/1 1300 34 (2:1 AV conduction), 2˚ AVNB; 95/35 atropine 1 mg × 1 converted SR 1:1 AV conduction
10–12 sec of asystole
4/1 0200 52 101/48 none maintained SR 1:1 AV conduction

4/2 1000 36 (2:1 AV conduction), 2˚ AVNB; 80/50 atropine 1 mg × 1 converted SR 1:1 AV conduction
10–12 sec of asystole
4/2 2100 54 90/40 theophylline 450 mg iv LD maintained SR 1:1 AV conduction
over 30 min, then MD 19 mg/h
4/3 2100 64 145/53 theophylline MD 19 mg/h maintained SR 1:1 AV conduction;
theophylline concentration 6.7 mg/L

4/4 0800 65 130/70 theophylline MD 19 mg/h maintained SR 1:1 AV conduction

4/5 1300 68 136/74 theophylline MD 19 mg/h maintained SR 1:1 AV conduction

4/6 1900 62 131/78 theophylline MD 19 mg/h maintained SR 1:1 AV conduction

4/7 0400 67 139/82 theophylline MD 19 mg/h maintained SR 1:1 AV conduction

4/8 2300 68 141/84 DC theophylline maintained SR 1:1 AV conduction

4/9–4/15 68a 132/72a none maintained SR 1:1 AV conduction

AV = atrioventricular; AVNB = atrioventricular nodal block; DC = discontinued; LD = loading dose; MD = maintenance dose; SR = sinus rhythm.
a
HR and BP for duration of transitional care while off theophylline infusion until discharge.

304 ■ The Annals of Pharmacotherapy ■ 2001 March, Volume 35 www.theannals.com


infusion of 19 mg/h (9 mg/kg/d) was initiated. The patient expe-
rienced two documented episodes of sinus bradycardia with an
HR <60 beats/min within the first 24 hours of the theophylline
infusion. After approximately 24 hours of initiating the infusion,
the theophylline concentration was 6.7 mg/L. Normal sinus
rhythm continued with no further documented episodes of sinus
bradycardia or heart block. The theophylline drip was discontin-
ued after six days based on a response including normal HR and
BP. The patient remained in the burn treatment center for an ad-
ditional six days with no further episodes of bradycardia or
AVNB and was discharged home with instructions for cardiovas-
cular and burn wound care follow-up.
Discussion
Our findings demonstrate that theophylline, an adeno-
sine antagonist, is a pharmacologic alternative treatment
for bradycardia and an alternative to temporary pacing. Al-
though there are data advocating the use of methylxanthine
derivatives for the treatment of bradyarrhythmias,2,3,5,6,9,11
no reports have recommended the use of these agents as an
alternative to temporary pacing or pacemaker insertion in
patients with sepsis.
Pharmacologic and nonpharmacologic management of
bradyarrhythmia includes intravenous atropine or isopro-
terenol, temporary external or transvenous pacing, or per-
manent cardiac pacemaker implantation. Insertion of an
implantable pacemaker may lead to complications such as
a need for pacemaker lead revision or infection, which will
increase morbidity and cost. Theophylline may represent
another pharmacologic strategy in patients facing an unac-
ceptable surgical risk or refusing pacemaker insertion.
Although the exact molecular mechanism for cardiac
and hemodynamic activity of methylxanthines is unknown,
there are proposed mechanisms. The most widely studied
methylxanthine derivative, theophylline, has undergone a
clinical analysis of proposed mechanism for its positive
chronotropic effects. Theories include stimulation of sinoa-
trial or atrioventricular nodes by indirectly increasing cir-
culatory catecholamines,15 inhibition of phosphodiesterase
resulting in an increased concentration of cyclic adenosine
monophosphate, and translocation of intracellular calcium.16
Current studies12,13,17-19 suggest that theophylline’s positive
chronotropic activity is predominantly due to blockage of
myocardial adenosine receptor subtype A1, which occurs at
therapeutic concentrations of 10–50 µM.
Adenosine, an endogenous metabolite, has been shown
to have potent effects on the cardiovascular system. In the
heart, adenosine is primarily a vasoactive agent, but it has
also been shown to have other cardiovascular properties
such as depression of sinoatrial and atrioventricular node
activity, reduction of atrial contractility, attenuation of the
stimulatory actions of catecholamines primarily in the ven-
tricular myocardium, and decreases of ventricular auto-
maticity.19,20 These specific properties are expressed by two
cell-surface receptor subtypes, A1 and A2. A1 is primarily
responsible for inhibition of positive chronotropic, inotrop-
ic, and dromotropic effects of catecholamines19; A2 receptor
subtypes are present in endothelial and vascular smooth-
muscle cells, mediating vasodilatation.19 Adenosine may
www.theannals.com The Annals of Pharmacotherapy
Case Reports
also prevent calcium influx into the myocardium, which
may decrease intracellular calcium concentrations, lead to
slowing of myocardial conduction, and result in brady-
arrhythmias and AVNB.19
Thermal injury resulting in sepsis can lead to suppres-
sion of the immune function, although the true mechanism
of action is still elusive. Early biochemical events in sepsis
involve an initial elevation of endotoxin, which may trig-
ger the production of pro-inflammatory cytokines (e.g., tu-
mor necrosis factor alfa [TNF-α] and interleukin 1). TNF-
α is commonly believed to be the most important mediator
of sepsis-induced myocardial dysfunction.21 The mecha-
nism by which TNF-α causes myocardial dysfunction in-
cludes direct cytotoxicity, oxidant stress, disruption of ex-
citation–contraction coupling, myocyte apoptosis, and other
mechanisms.22 Other mediators besides pro-inflammatory
cytokines involved in myocardial dysfunction include lipo-
polysaccharides, free radicals, prostanoids, nitric oxide,
catecholamines, and endotoxin.21,23 These mediators all
promote different effects on cardiac contractility and must
be considered a part of the etiology of cardiac bradyar-
rhythmias in the sepsis patient.
Although our patient experienced atropine-responsive
bradycardia, it was determined that theophylline was an
acceptable option for treatment of her bradyarrhythmias
based on the supporting literature, because the mechanism
underlying her AVNB may have been the result of unop-
posed adenosine activity. The infectious risk associated
with thermal injury wounds precluded her from pacemaker
placement. Theophylline dosing in our patient was based
on previous data obtained from treatment of elderly pa-
tients (>65 y old) with hemodynamically compromising
bradyarrhythmias. Patients received theophylline 8–12
mg/kg/d to achieve steady-state concentrations between 5
and 10 mg/L. Theophylline did show positive effects fol-
lowing both short- and long-term treatment on both HR
and hemodynamic stability.11
The theophylline concentration of 6.7 mg/L in our pa-
tient was determined approximately 24 hours after the
loading dose, suggesting a pre-steady-state theophylline
concentration based on degree of renal function (serum
creatinine 0.8 mg/dL) and pharmacokinetic estimation. At
this time, the patient did show hemodynamic improvement,
which is consistent with the supporting literature.8,9,11,15
Theophylline may be used for short- or long-term mainte-
nance therapy for bradyarrhythmias. Dose recommenda-
tions would depend on the specific arrhythmia and contin-
ued subjective and objective assessment of the patient to
determine an end point for treatment.
Summary
The bradyarrhythmic events in our patient may have
been associated with increased adenosine formation through
sepsis-mediated catecholamine production. If the concen-
tration of adenosine is high enough in the sinoatrial and/or
atrioventricular nodal regions, sinus bradycardia or AVNB
may occur. The most physiologic therapy would be to de-
■ 2001 March, Volume 35 ■ 305
MJ Cawley et al.
liver an adenosine antagonist. The positive response to in-
travenous theophylline in our patient supports this hypoth-
esis.
Although data supporting the use of methylxanthine
derivatives for bradyarrhythmias exist, they are only an al-
ternative to other pharmacologic therapies and temporary
pacing in the treatment of bradycardia secondary to AVNB.
Methylxanthine derivatives can be used for patients in
whom other pharmacologic strategies or cardiac pacemak-
er insertion may be contraindicated. Our case supports the
use of adenosine receptor antagonists for treatment of pa-
tients with bradyarrhythmias.
Michael J Cawley PharmD, Assistant Professor of Clinical Phar-
macy, Department of Pharmacy Practice and Pharmacy Adminis-
tration, Philadelphia College of Pharmacy, University of the Sciences
in Philadelphia, Philadelphia, PA
Abdulrazaq S Al-Jazairi PharmD, at time of writing, Cardiovas-
cular Pharmacotherapy Resident, Department of Pharmacy Prac-
tice and Pharmacy Administration, Philadelphia College of Phar-
macy, University of the Sciences in Philadelphia; now, Clinical
Pharmacy Specialist, Cardiology, King Faisal Specialist Hospital and
Research Center, Riyadh, Saudi Arabia
Elizabeth A Stone PharmD, at time of writing, PharmD Student,
Philadelphia College of Pharmacy, University of the Sciences in
Philadelphia; now, Pharmacy Practice Resident, Saint Barnabas
Medical Center, Livingston, NJ
Reprints: Michael J Cawley PharmD, Department of Pharmacy
Practice and Pharmacy Administration, Philadelphia College of Phar-
macy, University of the Sciences in Philadelphia, 600 S. 43rd St.,
Philadelphia, PA 19104-4495, FAX 215/596-8586, E-mail m.cawley
@usip.edu
References
1. British Pacing and Electrophysiology Group. Recommendations for
pacemaker prescription for symptomatic bradycardia. Br Heart J 1991;
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2. Wesley RC Jr, Lerman BB, DiMarco JP, Berne RM, Belardinelli L.
Mechanism of atropine resistant atrioventricular block during inferior
myocardial infarction: possible role of adenosine. J Am Coll Cardiol
1986;8:1232-4.
3. Bertolet BD, McMurtrie EB, Hill JA, Belardinelli L. Theophylline for
the treatment of atrioventricular block after myocardial infarction. Ann
Intern Med 1995;123:509-11.
4. Shannon DC, Gotay F, Stein IM, Roger MC, Todres ID, Moylan FMB.
Prevention of apnea and bradycardia in low-birthweight infants. Pedi-
atrics 1975;55:589-94.
5. Alboni P, Ratto B, Scarfo S, Rossi P, Cappato R, Paparella N. Dromo-
tropic effects of oral theophylline in patients with atrial fibrillation and
slow ventricular response. Eur Heart J 1991;12:630-4.
6. Alboni P, Menozzi C, Brignole M, Paparella N, Gaggioli G, Lolli G, et
al. Effects of permanent pacemaker and oral theophylline in sick sinus
syndrome. Circulation 1997;96:260-6.
7. Redmond JM, Zehr KJ, Gillinov MA, Baughman KL, Augustine SM,
Cameron DE, et al. Use of theophylline for treatment of prolonged sinus
node dysfunction in human orthotopic heart transplantation. J Heart
Lung Transplant 1993;12:133-8.
8. Ogilvie RJ, Fernandez PG, Winsberg F. Cardiovascular response to in-
creasing theophylline concentrations. Eur J Clin Pharmacol 1977;12:
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9. Benditt DG, Benson DW Jr, Kreitt J, Dunnigan A, Pritzker MR, Crouse
L, et al. Electrophysiological effects of theophylline in young patients
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12. Bertolet BD, Eagle DA, Conti JB, Mills RM, Belardinelli L. Bradycardia
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EXTRACTO
OBJETIVO: Reportar un caso de bradicardia secondaria a un bloqueo del
nudo aurículoventricular tratado exitosamente con teofilina intravenosa.
La teofilina intravenosa fue usada como una alternativa al uso de un
marcapasos en un paciente con sepsis secondaria a una quemadura del
cuerpo.
RESUMEN DEL CASO: Una mujer blanca de 79 años de edad con historial
cardíaco fue admitida al hospital con quemaduras en un 14.5% de su
cuerpo causadas por un fuego en su domicilio. Durante la
hospitalización, la paciente tuvo varios episodios de bradicardia
causados por un bloqueo del nudo aurículoventricular y períodos de
paro senoauricular. El uso de teofilina intravenosa ayudó a mantener un
ritmo cardíaco normal evitando la necesidad de usar un marcapasos.
DISCUSIÓN: Este es el primer caso publicado en la literatura de habla
inglesa que describe el uso de teofilina intravenosa como una alternativa
al marcapasos cardíaco. Los episodios de bradicardia senoauricular en
pacientes con sepsis han sido asociados con la producción de
catecolaminas lo cual aumenta la producción de adenosina.
Concentraciones altas de adenosina en el área de la región
aurículoventricular o senoauricular puede inducir bradicardia o bloqueo
aurículoventricular. Teofilina, un antagonista de adenosina, ha sido
identificado como una opción de tratamiento para tratar eventos de
bradiarrítmias.
CONCLUSIONES: Teofilina, un derivado de metilxantina, puede
representar una alternativa al uso de otros productos farmacológicos o al
uso de un marcapasos en el tratamiento de bradicardia secondaria a un
bloqueo del nudo aurículoventricular.
Magaly Rodríguez de Bittner
RÉSUMÉ
OBJECTIF: Rapporter un cas de bradycardie suite à un bloc auriculo-
ventriculaire (AV), ce dernier ayant été traité avec succès à l’aide de
théophylline administrée par voie intraveineuse. La théophylline
intraveineuse a été employée comme alternative à la stimulation
www.theannals.com
 Case Reports

cardiaque électrique temporaire chez un patient septique, admis pour
brûlures.
RÉSUMÉ DU CAS: Suite à l’incendie de son domicile, une femme de race
blanche, âgée de 79 ans, et présentant une histoire de maladie
coronarienne, fut admise pour le traitement de brûlures sur 14.5% de sa
surface corporelle totale. Approximativement trois semaines après son
admission, la patiente a présenté des épisodes intermittents de
bradycardie sinusale, compliqués par le développement d’un bloc AV
du second degré et de périodes d’arrêt sinusal. L’initiation de
théophylline intraveineuse a permis le maintien du rythme sinusal
normal, sans aucun autre épisode de bradycardie sinusale ou de bloc
cardiaque, éliminant ainsi le besoin d’implanter un pacemaker
cardiaque.
DISCUSSION: Il s’agit ici du premier cas publié en anglais décrivant
l’emploi de théophylline intraveineuse comme alternative à la
stimulation cardiaque électrique temporaire chez une patiente septique à
la suite de brûlures. Les épisodes de bradycardie chez les patients
septiques sont peut-être reliés à la production de catécholamines, celles-
ci augmentant la synthèse d’adénosine. Des concentrations d’adénosine
suffisamment élevées dans la région des noeuds sino-auriculaire ou AV
peuvent induire de la bradycardie sinusale ou un bloc AV. La
théophylline, un antagoniste de l’adénosine, a été identifiée comme une
option thérapeutique lors de telles bradyarythmies.
CONCLUSIONS: La théophylline, un dérivé méthylxanthine, peut
représenter une alternative aux autres mesures pharmacologiques ou à la
stimulation cardiaque électrique temporaire dans le traitement de la
bradycardie secondaire au bloc AV. Les dérivés méthylxanthines
représentent une alternative pour les patients chez qui les autres
alternatives pharmacologiques ou l’insertion d’un pacemaker sont
contre-indiqués.
Pierre Martineau

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