Anesth Analg 2005;101:1809-1811
© 2005 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000184203.52747.7D
CRITICAL CARE AND TRAUMA
The Use of Small-Dose Theophylline for the Treatment of Bradycardia in Patients with Spinal Cord Injury
Sebastian Schulz-Stübner, MD, PhD
Department of Anesthesia, University of Iowa Hospitals and Clinics, Iowa City
Address correspondence and reprint requests to Sebastian Schulz-Stübner, MD, PhD, University of Iowa Hospitals and Clinics Department of Anesthesia, 6JCP 200 Hawkins Dr., Iowa City, IA 52242. Address e-mail to sebastian-schulz-stubner{at}uiowa.edu.
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Abstract
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Small-dose theophylline can be a useful alternative in the treatment of bradycardia in patients with spinal cord injury. In this series of three cases, I describe its successful use for this indication. In one case, initiation of theophylline treatment also increased respiratory drive and minute ventilation. A possible mechanism is that theophylline increases the force of contraction of diaphragmatic muscles because of enhancement of calcium uptake through an adenosine-mediated channel. The antibradycardiac effect is probably mediated through one or more different molecular mechanisms, which seem to be mediated by inhibition of phosphodiesterase 3.
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Introduction
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Bradycardia and hypoventilation are common complications of spinal cord injuries and often require monitoring and treatment in an intensive care unit (ICU) (1). Here, three patients are presented in whom small-dose theophylline was successfully used to treat persistent bradycardia. In one of these patients, small-dose theophylline also increased respiratory rate and tidal volume and prevented hypercarbia.
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Case Reports
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Case 1
A 54-year-old woman (63 kg; 167 cm) was involved in a motor vehicle accident in which she suffered a C5 fracture with tetraparesis (American Spinal Injury Association [ASIA] impairment scale C [Table 1]). She underwent anterior spinal fusion, and her neurologic condition improved, with increased strength in the upper extremities. On postoperative Day 4, she developed sinus bradycardia, with a heart rate around 30 bpm. Intermittent asystole for up to 4 s was noticed on the monitor. Treatment attempts with intermittent bolus doses of atropine 0.4 mg and glycopyrrolate 0.2 mg were successful only over the short term. On postoperative Day 5, a 200-mg bolus dose of theophylline IV was administered, and her heart rate increased to 60–70 bpm over the following hour. The theophylline therapy was continued with 50 mg every 8 h through the Dobhoff feeding tube, and no further episodes of bradycardia were observed. Theophylline was discontinued after 6 wk, with no recurrence of bradycardic symptoms. No arrhythmogenic or central nervous side effects were observed.
Case 2
A 56-year-old man (112 kg; 191 cm) suffered a gunshot wound to the neck, with occlusion of the left vertebral artery, an intima tear of the left carotid artery, and spinal cord contusions between C6 and T1 (ASIA impairment scale A [Table 1]). The patient presented to the surgical ICU with tetraparesis after surgical repair of the tissue damage by an otolaryngologist and stenting of the left carotid artery by interventional radiology. His ICU course was complicated by respiratory failure requiring reintubation and tracheostomy for excessive secretions and adrenal insufficiency requiring hydrocortisone replacement therapy. On postoperative Day 6, he developed sinus bradycardia, with a heart rate in the low 20s to 30. Episodes of asystole lasting up to 6 s were observed on the electrocardiogram monitor. Treatment with glycopyrrolate 0.2 mg and repeated doses of atropine 0.4 mg were only temporarily successful. During the bradycardic episodes, his arterial blood pressure remained stable at approximately 110/65 mm Hg. Transcutaneous pacer electrodes were placed prophylactically. The patient then received 200 mg of theophylline bolus, and his heart rate increased to 50–60 bpm over the next hour. Theophylline therapy was continued with 100 mg every 8 h, which resulted in fewer bradycardic episodes (as slow as 40 bpm), mainly overnight. The dose was adjusted to 100 mg-100 mg-200 mg orally, and the heart rate remained in the upper 60s throughout the remainder of his ICU stay. The theophylline level showed a peak at 3.4 µg/mL 6 h after the evening dose. No arrhythmogenic or central nervous system side effects were observed. The patient was still receiving the medication after discharge from a rehabilitation facility 12 wk after the insult and then was lost for follow-up.
Case 3
A 37-year-old man (84 kg; 188 cm) was involved in a rollover motor vehicle accident and ejected from the vehicle. He suffered a C6 fracture with quadriplegia (initially AISA impairment scale A [Table 1]) and bilateral lung contusions. His ICU course was complicated by left upper extremity compartment syndrome and pneumonia. His C6 fracture was treated with halo fixation, and his neurological status improved, with some sensation down to his feet and some motor activity in his upper extremities. After placement of his halo fixation and resolving pneumonia, he was tracheally extubated on postadmission Day 5. At this point, he showed intermittent episodes of bradycardia into the low 40s. After tracheal extubation, his Paco2 increased slowly from 42 mm Hg to 48 mm Hg to 53 mm Hg with normal oxygenation. He was treated with 200 mg of theophylline for his bradycardia and also to increase his respiratory drive. His respiratory rate increased from 10 to 12 breaths/min to 15 to 18 breaths/min, and the tidal volume, measured by spirometry, increased from 540 mL to 710 mL. His heart rate increased to the high 60s and low 70s in the following hour. His Paco2 decreased to 39 mm Hg 6 h after the theophylline application. Therapy was continued with 100 mg every 8 hours, and his theophylline level reached 1.4 µg/mL 6 h after the evening dose. No further episodes of bradycardia or hypoventilation were observed, and the patient was discharged to a rehabilitation facility. No adverse side effects were observed, and therapy was terminated after 8 wk without recurrent bradycardia.
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Discussion
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This is a small case series of patients with spinal cord injury-related bradycardia who were successfully treated with small-dose theophylline. A Medline search from 1966–2005 using the key words "spinal cord injury" and "theophylline" revealed only two other cases in the literature, reported by Pasnoori and Leesar in 2004 (2).
Whereas the exact mechanism of action of theophylline is not known with certainty, studies in animals suggest that the bronchodilation is mediated by the inhibition of two isoenzymes of the phosphodiesterase (PDE3 and to a lesser extent PDE4). Nonbronchodilatory actions are probably mediated through one or more different molecular mechanisms, which seem to be mediated by inhibition of PDE 3. Whereas the recommended therapeutic serum concentrations for theophylline-induced bronchodilation are 5–20 µg/mL, in our patients, excellent clinical results for the treatment of bradycardia were achieved with much smaller serum theophylline levels (1.4–3.4 µg/mL).
Theophylline is rapidly and completely absorbed after oral administration and does not undergo any presystemic elimination. It is extensively metabolized in the liver.
Although our case reports indicate that only small doses of theophylline might be required to achieve the desired therapeutic effects, it should be considered that the absolute bioavailability of oral theophylline in patients with spinal cord injury could be impaired secondary to delayed gastric emptying, as shown by Segal et al. (3,4).
In otherwise healthy adults, the mean half-life of theophylline ranges from 6.1 to 12.8 hours according to the Physicians Desk Reference 2005. The total body clearance ranges from 0.27 to 1.03 mL · kg–1 · min–1. This long half-life makes theophylline superior to shorter-acting drugs such as atropine for the treatment of bradycardia in patients with spinal cord injury.
In our third patient, we also observed an increased respiratory rate, increased tidal volumes, and reduced hypercarbia after initiation of theophylline treatment. Theophylline increases the force of contraction of diaphragmatic muscles because of enhancement of calcium uptake through an adenosine-mediated channel. Whereas controlled trials and large case series investigating the successful use of theophylline in humans with spinal cord injury are missing, several experimental studies in rats have demonstrated increased diaphragmatic force and recovery of phrenic nerve function (5). Basura et al. (6) suggest that theophylline may induce motor recovery, likely via the adenosine A1 receptor located at the level of the spinal cord. The concurrent stimulation of converging 5-hydroxytryptamine-2-receptors may augment the response. Nantwi and Goshgarian (7) showed, in 1998, that theophylline not only induces, but also maintains recovery for prolonged periods after cervical spinal cord injury in rats. Gorini et al. (8) could show, in 1994, that theophylline increases ventilation by promoting larger tidal volumes caused by increased neural drive to inspiratory muscles in healthy volunteers. Whereas a Cochrane review by Smith et al. (9), in 2002, indicates that there are no data available to support the use of theophylline in patients with obstructed sleep apnea, the observation in our patient and the animal experimental data might promote further research into the use of theophylline to increase tidal volume and respiratory drive in patients with spinal cord injuries.
A prospective, double-blind, randomized trial is warranted to confirm our clinical experience. Further research is also required to determine the optimal serum theophylline levels and the optimal duration of treatment required in patients with bradycardia caused by spinal cord injury. In our patients, the decision to try to discontinue therapy was made purely based on clinical judgment of the overall recovery profile. In some patients with recurrent bradycardia, long-term treatment might be required.
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Footnotes
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There is no conflict of interest related to this manuscript. Dr. Schulz-Stübner received an unrestricted educational grant from ESP Pharma, USA (2004), and research grants from Verla Pharm, Germany, and Ferring Arzneimittel, Germany (2001), not related to this case series.
Accepted for publication June 14, 2005.
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References
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- Management of acute central cervical spinal cord injuries. Neurosurgery 2002;50:S166–72.[Medline]
- Pasnoori VR, Leesar MA. Use of aminophylline in the treatment of severe symptomatic bradycardia resistant to atropine. Cardiol Rev 2004;12:65–8.[Medline]
- Segal JL, Brunnemann SR. Clinical pharmacokinetics in patients with spinal cord injuries. Clin Pharmacokinet 1989;17:109–29.[Medline]
- Segal JL, Brunnemann SR, Gordon SK, Eltorai IM. The absolute bioavailability of oral theophylline in patients with spinal cord injury. Pharmacotherapy 1986;6:26–9.[Medline]
- Nantwi KD, El-Bohy A, Goshgarian HG. Actions of systemic theophylline on hemidiaphragmatic recovery in rats following cervical spinal cord hemisection. Exp Neurol 1996;140:53–9.[ISI][Medline]
- Basura GJ, Nantwi KD, Goshgarian HG. Theophylline-induced respiratory recovery following cervical spinal cord hemisection is augmented by serotonin 2 receptor stimulation. Brain Res 2002;956:1–13.[ISI][Medline]
- Nantwi KD, Goshgarian HG. Effects of chronic systemic theophylline injections on recovery of hemidiaphragmatic function after cervical spinal cord injury in adult rats. Brain Res 1998;789:126–9.[ISI][Medline]
- Gorini M, Duranti R, Misuri G, et al. Aminophylline and respiratory muscle interaction in normal humans. Am J Respir Crit Care Med 1994;149:1227–34.[Abstract]
- Smith I, Lasserson T, Wright J. Drug treatments for obstructive sleep apnoea. Cochrane Database Syst Rev 2002:CD003002.
- Aids of the investigation of peripheral nerve injuries. Medical Research Council War Memorandum No. 7, London, H. M. Stationary Office, 1942.
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Abstract
Introduction
