J Cardiol 2007 Feb; 49（2）: 91 – 96

Sequential Use of Aminophylline
and Theophylline for the Treatmentof Atropine-Resistant Bradycardia
After Spinal Cord Injury: A Case
ReportTomohiro

SAKAMOTO,MD＊

Tsuneaki SADANAGA, MDTomoki

OKAZAKI, MD

Abstract ─────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────
A 66-year-old Japanese man was brought to our emergency department after he was accidentally compressed into a lateral groove. Physical examination revealed pinprick sensory level of T4 and motor levelof C7. On the 4th hospital day, electrocardiography suddenly showed sinus bradycardia of 33 beats/min.
Bolus injection of 0.5 mg of atropine sulphate was not effective. Bolus injection of aminophylline wasadministered followed by continuous infusion. His heart rate increased and remained stable at 60 to 70
beats/min. Therapy was switched from aminophylline to oral theophylline and continued for about 5weeks, with no recurrence of bradycardia. Use of xanthine derivatives is thought to be an effective, safe
and simple treatment for spinal cord injury-induced bradycardia.
──────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────J Cardiol 2007 Feb; 49（2）: 91−96

Key Words
Bradycardia aminophylline, theophylline

INTRODUCTION
Bradycardia and cardiac arrest are complications
observed in the acute phase of cervical spinal cord
injury.1,2）The bradycardia is self-limited, disappearing within 3−5 weeks after the onset of paraplegia, and usually does not require implantation ofa permanent pacemaker.3）However, medical treatment for the disorder often fails and temporarytransvenous ventricular pacing is required. 4,5）
Previously, oral theophylline therapy was found tobe beneficial in patients with sick sinus syndrome.6）
However, whether this therapy is also effective intreating bradycardia associated with spinal cord
injury was unclear. Recently, the use of aminophylline7）or theophylline8）was reported as a usefulalternative treatment for severe symptomatic brady-Antiarrhythmia atropine

cardia in patients with spinal cord injury from theU.S. and Germany, respectively. In this report wedescribe a Japanese case of cervical spinal cord
injury complicated with atropine-resistant severe
bradycardia, which was managed by sequential
administration of both aminophylline and theophylline.
CASE REPORT
A 66-year-old Japanese man with no significant
medical history was brought to our emergency
department after he was accidentally compressed
into a lateral groove. He had symptoms of neckpain, inability to move his legs, and lack of sensation below his breast. His vital signs were stable onadmission, and physical examination revealed pinprick sensory level of T4 and motor level of C8──────────────────────────────────────────────
健康保険八代総合病院 循環器科 : 〒 866−8660 熊本県八代市松江城町 2−26 ; ＊（現）済生会熊本病院心臓血管センター 内科 :〒 861−4193 熊本県熊本市近見 5−3−1
Department of Cardiovascular Medicine, Health Insurance Yatsushiro General Hospital, Kumamoto ; ＊（present）Division of Cardiology,
Cardiovascular Center, Saiseikai Kumamoto Hospital, Kumamoto
Address for correspondence : SAKAMOTO T, MD, Division of Cardiology, Cardiovascular Center, Saiseikai Kumamoto Hospital,Chikami 5−3−1, Kumamoto, Kumamoto 861−4193 ; E-mail : tom@kumamoto-u.ac.jp
Manuscript received September 13, 2006 ; revised October 30, 2006 ; accepted November 2, 200691

92

Sakamoto, Sadanaga, Okazaki

Fig. 1 Magnetic resonance images of the thoracic and cervical spinal cord
Fresh compression fracture of the T6（left, white arrow）and spinal canal stenosis at C5/6 and C6/7 withabnormal signal of the cervical spinal cord（right, white line）were observed.

Fig. 2 Three lead electrocardiogram
Sinus bradycardia（33 beats/min）was recorded at the time of symptom onset.

（American Spinal Association Impairment Scale,9）Class A-Central Cord）. Magnetic resonance imaging revealed compression fracture at T6 and spinal
canal stenosis at C5/6 and C6/7 with intramedullary
abnormal signals（Fig. 1）. The patient was considered to have cervical spinal cord injury induced bystrong traumatic stress at pre-existing cervicalspondylosis. Methylprednisolone 30 mg/kg wasadministered intravenously for 15 min followed 45
min later by continuous infusion（5.4 mg/kg/hr）forthe next 23 hr.
On the 4th hospital day, he suddenly complainedof chest discomfort, cold, and diaphoresis.
Electrocardiography（ECG）revealed sinus bradycardia of 33 beats/min and his blood pressure
dropped to 60 mmHg systolic during this episode（Fig. 2）. There were no significant ischemic ST-T
changes or new bundle branch block in the 12-lead
ECG. Bolus injection of atropine sulphate 0.5 mg
was not effective to increase his heart rate
（Fig. 3）.
Bolus injection of aminophylline（ 250 mg）wasadministered followed by continuous infusion（0.5 mg/kg/hr）. His heart rate increased within 1 hr
and remained stable at 60 to 70 beats/min during
J Cardiol 2007 Feb; 49（2）: 91 – 96

Spinal Cord Injury-Induced Bradycardia

93

Pre

Post

Fig. 3 Bedside electrocardiograms before and after atropine injection
Administration of intravenous atropine（0.5 mg）was not effective to increase the heart rate.

Aminophylline drip infusion (1 week after onset)

Theophylline oral administration (3 weeks after onset)

els）. The chart of his heart rate and blood pressureduring the entire clinical course is shown in
response to the treatment（Fig. 5）. The drug levelsin the blood were 11.2μg/ml during aminophylline
infusion and 9.7μg/ml after switching to oral theophylline.
DISCUSSION

Theophylline cessation (5 weeks after onset)

Fig. 4 Comparison of lead Ⅱ of 12-lead electrocardiogram during aminophylline and theophylline
therapy
Heart rate was 57 beats/min during drip infusion ofaminophylline（upper）, 63 beats/min during oral administration of theophylline（middle）, and 58 beats/minwith no medications（lower）.

the infusion（Fig. 4, upper panel）. On the 19th hospital day, intravenous aminophylline therapy was
switched to oral theophylline（400 mg/day）and discontinued after the 38th hospital day with no recurrence of bradycardia（Fig. 4, middle and lower panJ Cardiol 2007 Feb; 49（2）: 91 – 96

This Japanese patient with spinal cord injuryrelated severe bradycardia was successfully managed with aminophylline administered intravenously during the acute phase followed by oral theophylline. The correction of the bradycardia wasmost likely due to the drugs, although the naturalcourse of the disease may have been responsible.
Cardiovascular abnormalities associated withacute spinal cord injury are observed more oftenwith severe cervical cord injury compared withmilder cervical cord injury or thoracolumbar cord
trauma.1）Persistent bradycardia defined as mean
heart rate for at least 1 day ＜ 60 beats/min wasobserved in all of 31 patients with severe cervical
cord injury and mean heart rate ＜ 45 beats/min in
71%. The occurrence of persistent bradycardia
peaked 4 days after injury. The onset period ofsevere sinus bradycardia in the present case wasconsistent with that report.
The cardiac abnormality underlying cervical cord
injury-induced bradycardia may be due to the acute94

Sakamoto, Sadanaga, Okazaki

Fig. 5 Chart of heart rate and blood pressure during the clinical course● : PR（pulse rate）. ▽, △ : BP（blood pressure）.

autonomic imbalance imposed on the heart by acervical cord lesion. Sympathetic innervation exits
the spinal cord in preganglionic fibers at the 1stthrough 4th thoracic levels. On the other hand,parasympathetic control is exerted through thevagus nerve, which originates at the level of themedulla oblongata. Therefore, injury to the cervical
cord could completely disrupt the cardiac sympathetic influences from higher centers whereas theparasympathetic control remains intact. This might
be the reason why the use of atropine, which relatively activates sympathetic tone by reducing
parasympathetic activity, was not effective toincrease heart rate.
Besides atropine, 0.5 mg repeated to a total doseof 3 mg, epinephrine（2−10μg/min）or dopamine（2−10μg/kg/min）infusions are recommended forthe management of symptomatic bradycardia withpoor perfusion in the setting of cardiopulmonary
resuscitation and emergency cardiovascular care.10）
However, in contrast to bradycardia associated withacute coronary syndromes, which is promptly
reversed by effective reperfusion with percutaneous
coronary intervention, the bradycardia observedwith spinal cord injury lasts 3 to 5 weeks. 3）
Therefore, the use of dopamine or epinephrine is
not suitable in this clinical setting because of theirpotential hazardous effects on the heart and vasculature in extended use. In some cases of atropineresistant bradycardia due to spinal cord injury,transvenous ventricular pacing is used.4,5）However,extended use of a transvenously inserted pacemakerlead should be avoided if at all possible because of
the risk of deep vein thrombosis due to prolonged
bed rest. Furthermore, the sinus bradycardia after
spinal cord injury is self-limiting in its naturalcourse.1）Taking these factors into consideration,
we tried to use xanthine derivatives in this specificJapanese patient instead of catecholamines or apacemaker in accordance with the previously treated Caucasian patients.7,8）
Xanthine derivatives such as aminophylline andtheophylline exert positive chronotropic effects on
the sinoatrial and atrioventricular node cells.
Possible mechanisms of the xanthine derivatives
include antagonism of the negative chronotoropic
effects of adenosine by competitive blocking ofextracellular adenosine receptors, 11）release ofendogenous catecholamines from sympathetic
nerve endings and adrenergic medulla,12）and inhibition of phosphodiesterase（ PDE）leading to anincrease in cyclic adenosine monophosphate with asubsequent rise in catecholamines.13）The ischemicmetabolite adenosine was unlikely to be involvedin our case, and higher serum concentration of thedrug of as much as 10 −5 to 10 − 4 mol/l is needed torelease endogenous catecholamine, 14） so wehypothesized that the xanthine derivatives worked
mainly by inhibiting PDE. Extended use of xanthine derivatives might also be somehow harmful
because of the PDE inhibition. Tremor, seizure,nausea, and hyperventilation are all typical adverse
J Cardiol 2007 Feb; 49（2）: 91 – 96

Spinal Cord Injury-Induced Bradycardia

effects of the drugs.
These agents have been used to treat bradycardia
associated with acute myocardial ischemia, especially with inferior myocardial infarction15,16）andsick sinus syndrome.6）In addition, the effects of a
relatively large dose of aminophylline（ 300 mg
bolus followed by 5 mg/kg/hr）and a mild dose oftheophylline（ 200 mg p.o. followed by 100 mg
every 8 hr）on spinal cord injury-induced bradycardia were also reported.7,8）In our case, 0.5 mg/kg/hr
of continuous infusion of aminophylline after an
intravenous loading dose of 250 mg was effective inincreasing the heart rate to 57 beats/min. The blood
drug concentration achieved in our patient was similar to those achieved when these agents are used
for bronchodilation. The initial intravenous infusion of aminophylline was switched to oral administration of a sustained-release theophylline tablet（200 mg twice daily）. The same blood concentration was obtained and bradycardia did not recur
要95

after this change of agent. Although theophylline isan effective drug to treat bradycardia related tospinal cord injury, the therapeutic dose of the drug
could vary by race, and the level and extent ofspinal cord injury. This therapy appears to be aseffective in Japanese as in Caucasians. Our casesuggests that the initial doses of xanthine derivatives are similar to those used in the treatment ofbronchial asthma. We need further experience oflower doses of the drugs for this purpose.
In summary, bradycardia which is associatedwith acute spinal cord injury can be successfully
treated in Japanese patients with the serial use ofaminophylline and theophylline. This therapy may
be an effective alternative to transvenous ventricular pacing or extended use of catecholamine inpatients with atropine-resistant bradycardia. A randomized, controlled trial is needed to validate thewidespread use of xanthine derivatives in this common but serious clinical setting.
約

頸部脊椎損傷後アトロピン耐性高度徐脈におけるアミノフィリン
およびテオフィリン投与の有効性
坂本知浩

定永恒明

岡崎智樹

症例は 66 歳の男性．歩行中に側溝に転落して動けなくなっているところを発見され，救急搬送された．来院時のバイタルは正常であったが，T4 レベルの感覚障害および C7 レベルの運動機能障害を呈していた．頸部脊椎損傷の診断によりメチルプレドニゾロンの持続投与が行われた．第 4 病日，冷汗を伴う胸部苦悶が出現し，モニター心電図上，心拍数 33/min の洞性徐脈を呈した．硫酸アトロピンが無効であったため，アミノフィリン 250 mg の静注に引き続き 0.5 mg/kg/hr の持続投与を行ったところ，心拍数は 60−70/min に上昇し症状も消失した．第 19 病日に経口のテオフィリン（400 mg）に切り替えられ，第 38 病日に中止されたが，再発を認めなかった．静注および経口での薬物血中濃度はそれぞれ 11.2 および 9.7μg/ml であった．キサンチン誘導体投与は，頸部脊椎損傷後の徐脈に対し有効，安全かつ簡便な治療法であると考えられた．

J Cardiol 2007 Feb; 49（2）: 91−96

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