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Theophylline Therapy for Cheyne-Stokes Respiration During Sleep in a 41-Year-Old Man With Refractory Arterial HypertensionBP and Theophylline for Cheyne-Stokes Respiration FREE TO VIEW

Jacek Wolf, MD, PhD; Ewa Świerblewska, MD, PhD; Hanna Jasiel-Wojculewicz, MD, PhD; Krzysztof Gockowski, MD, PhD; Bogdan Wyrzykowski, MD, PhD; Virend K. Somers, MD, PhD, FCCP; Krzysztof Narkiewicz, MD, PhD
Author and Funding Information

From the Department of Hypertension and Diabetology (Drs Wolf, Świerblewska, Jasiel-Wojculewicz, Gockowski, Wyrzykowski, and Narkiewicz) Medical University of Gdańsk, Gdańsk, Poland; the Division of Cardiovascular Diseases (Dr Somers), Mayo Clinic, Rochester MN; and the Department of Cardiovascular Diseases (Drs Wolf and Narkiewicz), International Clinical Research Center, St. Anne’s University Hospital in Brno (FNUSA), Brno, Czech Republic.

Correspondence to: Jacek Wolf, MD, PhD, Medical University of Gdańsk, Department of Hypertension and Diabetology, Dębinki 7C, 80-952 Gdańsk, Poland; e-mail: lupus@gumed.edu.pl


Funding/Support: Dr Somers is supported by the National Institutes of Health [Grant NIH R01 HL65176]. Drs Wolf and Narkiewicz are supported by the European Regional Development Fund, Project FNUSA-ICRC [Grant CZ.1.05/1.1.00/02.0123] and by the REGPOT ICRC-ERA Human Bridge [Grant 316345] provided by the European Union.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;146(1):e8-e10. doi:10.1378/chest.13-2897
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We report a case of a 41-year-old man who was noted to have position-dependent Cheyne-Stokes respiration with central sleep apnea (CSA) during sleep. The patient had multiple cardiovascular risk factors and target organ damages, including a history of two myocardial infarctions, transient ischemic attack, and chronic kidney disease. His hypertension was refractory to a number of antihypertensive medicines, however, a complete elimination of sleep-disordered breathing with oral theophylline treatment was paralleled by a significant BP fall with a subsequent need for reduction of antihypertensive drugs. Following these surprising observations we decided to withdraw theophylline from treatment (in-clinic). Theophylline discontinuation resulted in a gradual increase in BP and an urgent call for antihypertensive treatment modification. These observations suggest a potent hypotensive action of oral theophylline via Cheyne-Stokes respiration with CSA elimination. Our data suggest that CSA may be a mechanism that raises BP even during the daytime.

Figures in this Article

Cheyne-Stokes respiration (CSR) with central sleep apnea (CSA) is frequently encountered in pathologic conditions (eg, neurologic dysfunction or congestive heart failure), where it may be implicated in increased morbidity and mortality.1-3 Although sleep apnea has been linked to arterial hypertension, only the obstructive type of sleep apnea, and not CSA, is believed to be a causative factor in developing hypertension.4-6 In this case report, we show that attenuation of CSR-CSA during sleep with oral theophylline treatment in a patient with hypertensive heart failure (left ventricular ejection fraction [LVEF] = 45%) significantly improved BP control.

A 41-year-old man with a longstanding history of complicated, essential hypertension refractory to seven antihypertensives was noted to have CSR-CSA during sleep (Fig 1), exclusively in the supine position. His BP control was poor and showed measurements up to 280/180 mm Hg on home and office measurements and up to 200/140 mm Hg without nocturnal BP dip on 24-h ambulatory BP. The patient had an atherogenic lipid profile, was overweight (BMI = 28), smoked cigarettes, frequently drank alcohol to excess, and had a strong family history of cardiovascular disease. He had left ventricle hypertrophy with segmental contractility impairment, a history of two non-ST segment elevation myocardial infarctions, transient ischemic attack (TIA), retinopathy, and chronic kidney disease (plasma creatinine level, 150 μmol/L). The patient was free of diabetes mellitus. Several forms of secondary hypertension (renovascular, hormonal, vasculitis) as well as noncompliance with medications were excluded.

Figure Jump LinkFigure 1. A 10-min epoch sample taken from the baseline study. Curves represent (from top to bottom) blood oxygen saturation, ECG, pulse, position (supine), airflow, and respiratory movements.Grahic Jump Location
Sleep-Related History

Despite poor sleep quality for approximately 20 years, the patient did not seek professional medical help for this particular problem; however, he occasionally used hypnotics. Diagnostic sleep study revealed CSR-CSA in the supine position (apnea/hypopnea index [AHI] = 16.6; AHI supine = 49.3; oxygen saturation by pulse oximetry [Spo2] = 93.4%).

Intervention

The patient was administered sustained-release oral theophylline 250 mg bid (serum concentration < 10 μg/mL). A sleep study while on theophylline therapy showed marked attenuation of CSR-CSA (AHI = 0.6; AHI supine = 4.1; Spo2 = 95.3%). These changes were associated with not only a marked improvement in subjective sleep quality and sleep prolongation but also a remarkable BP fall confirmed by 24-h ambulatory BP (103/68 mm Hg). Following these observations, two antihypertensive drugs were discontinued, and dosages of three other medications were reduced. Since theophylline administration was the only treatment change coinciding with the BP fall, we decided to assess the effects of a period of withdrawal. On the morning of the third day after theophylline discontinuation, BP increased substantially, and the patient developed TIA (Fig 2). At the time, we decided to resume theophylline therapy, and a progressive improvement in the patient’s BP control was noted over the next few days.

Figure Jump LinkFigure 2. Office SBP and DBP recordings before, during, and after theophylline was administered. On the first day of theophylline therapy experimental withdrawal the theophylline level equalled 8.4 mg/dL, and on the morning of day 3, plasma theophylline concentration was 0 mg/dL. On the third day of the experiment, the patient developed TIA, and radical hypotensive drug modifications were implemented, including theophylline resumption. Data are shown as mean ± SD. DBP = diastolic BP; SBP = systolic BP; THEO = theophylline; TIA = transient ischemic attack.Grahic Jump Location
Follow-up

BP control was satisfactory, and no substantial change in antihypertensive drug therapy was required over the next year. At 1-year follow-up visit, mean plasma theophylline level was 3.4 μg/mL, and sleep monitoring revealed AHI = 1.8, AHI supine = 3.8, and Spo2 = 95.1%.

Theophylline has been previously suggested as a possible therapy for CSR-CSA both in patients with systolic heart failure and in those with normal LVEF.7,8 Most studies of theophylline in CSA examined subjects with concomitant advanced systolic heart failure.9,10 These patients in general are hypotensive. However, this patient had an LVEF of 45% and still had extremely high BP. A major effect of sleep apnea on the cardiovascular system is sympathetic excitation.10 Since we had previously sought to alleviate effects of neurohormonal activation in this patient (two β-blockers, angiotensin-converting enzyme inhibitor, and angiotensin receptor blocker), we then gave priority to eliminating CSR during sleep.

There are peripheral and central mechanisms of theophylline actions that may result eventually in BP lowering, including endothelium-dependent and -independent vasorelaxation,11,12 a diuretic effect, and central apnea elimination via adenosine antagonism resulting in attenuation of hypoxemias and hypercapnias.7 Other potential factors contributing to our findings include pharmacologic interactions between the antihypertensive drugs and theophylline and a history of smoking and regular alcohol consumption. In the reported case, during theophylline discontinuation the rise in BP was not linear, as drug concentration was decreasing over time but was more dependent on that level of BP that was set after a nighttime sleep (Fig 2). This suggests a central mechanism of action of theophylline in BP regulation, namely via the alleviation of sleep-disordered breathing, improvement in sleep quality, and blood gas chemistry. Although a direct influence of theophylline on vascular tone cannot be entirely disregarded, our data suggest that this is unlikely to be of major relevance.

In conclusion, we report a potent antihypertensive action of oral theophylline therapy in a unique patient diagnosed with position-dependent CSR-CSA. These data suggest that CSA may be a mechanism that raises BP even during the daytime.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Drs Wolf and Narkiewicz have received lectures fees from ResMed. Dr Somers has served as a consultant for Neu Pro; Respicardia, Inc; Sorin Inc; Price Waterhouse; and ResMed and has received grant support from Philips-Respironics Foundation. Mayo Foundation has received a gift from the Philips-Respironics Foundation for the study of sleep apnea and cardiovascular disease.

Role of sponsors: The contents of the manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health.

Other contributions:CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.

AHI

apnea-hypopnea index

CSA

central sleep apnea

CSR

Cheyne-Stokes respiration

LVEF

left ventricular ejection fraction

Spo2

oxygen saturation by pulse oximetry

TIA

transient ischemic attack

Javaheri S. Sleep disorders in systolic heart failure: a prospective study of 100 male patients. The final report. Int J Cardiol. 2006;106(1):21-28. [PubMed]
 
Hanly PJ, Zuberi-Khokhar NS. Increased mortality associated with Cheyne-Stokes respiration in patients with congestive heart failure. Am J Respir Crit Care Med. 1996;153(1):272-276. [PubMed]
 
Lanfranchi PA, Braghiroli A, Bosimini E, et al. Prognostic value of nocturnal Cheyne-Stokes respiration in chronic heart failure. Circulation. 1999;99(11):1435-1440. [PubMed]
 
Kales A, Bixler EO, Cadieux RJ, et al. Sleep apnoea in a hypertensive population. Lancet. 1984;2(8410):1005-1008. [PubMed]
 
Young T, Peppard P, Palta M, et al. Population-based study of sleep-disordered breathing as a risk factor for hypertension. Arch Intern Med. 1997;157(15):1746-1752. [PubMed]
 
Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med. 2000;342(19):1378-1384. [PubMed]
 
Javaheri S, Parker TJ, Wexler L, Liming JD, Lindower P, Roselle GA. Effect of theophylline on sleep-disordered breathing in heart failure. N Engl J Med. 1996;335(8):562-567. [PubMed]
 
Pesek CA, Cooley R, Narkiewicz K, Dyken M, Weintraub NL, Somers VK. Theophylline therapy for near-fatal Cheyne-Stokes respiration. A case report. Ann Intern Med. 1999;130(5):427-430. [PubMed]
 
Andreas S, Reiter H, Lüthje L, et al. Differential effects of theophylline on sympathetic excitation, hemodynamics, and breathing in congestive heart failure. Circulation. 2004;110(15):2157-2162. [PubMed]
 
Spaak J, Egri ZJ, Kubo T, et al. Muscle sympathetic nerve activity during wakefulness in heart failure patients with and without sleep apnea. Hypertension. 2005;46(6):1327-1332. [PubMed]
 
Karsten AJ, Derouet H, Ziegler M, Eckert RE. Involvement of cyclic nucleotides in renal artery smooth muscle relaxation. Urol Res. 2003;30(6):367-373. [PubMed]
 
Lo YC, Tsou HH, Lin RJ, et al. Endothelium-dependent and -independent vasorelaxation by a theophylline derivative MCPT: roles of cyclic nucleotides, potassium channel opening and phosphodiesterase inhibition. Life Sci. 2005;76(8):931-944. [PubMed]
 

Figures

Figure Jump LinkFigure 1. A 10-min epoch sample taken from the baseline study. Curves represent (from top to bottom) blood oxygen saturation, ECG, pulse, position (supine), airflow, and respiratory movements.Grahic Jump Location
Figure Jump LinkFigure 2. Office SBP and DBP recordings before, during, and after theophylline was administered. On the first day of theophylline therapy experimental withdrawal the theophylline level equalled 8.4 mg/dL, and on the morning of day 3, plasma theophylline concentration was 0 mg/dL. On the third day of the experiment, the patient developed TIA, and radical hypotensive drug modifications were implemented, including theophylline resumption. Data are shown as mean ± SD. DBP = diastolic BP; SBP = systolic BP; THEO = theophylline; TIA = transient ischemic attack.Grahic Jump Location

Tables

References

Javaheri S. Sleep disorders in systolic heart failure: a prospective study of 100 male patients. The final report. Int J Cardiol. 2006;106(1):21-28. [PubMed]
 
Hanly PJ, Zuberi-Khokhar NS. Increased mortality associated with Cheyne-Stokes respiration in patients with congestive heart failure. Am J Respir Crit Care Med. 1996;153(1):272-276. [PubMed]
 
Lanfranchi PA, Braghiroli A, Bosimini E, et al. Prognostic value of nocturnal Cheyne-Stokes respiration in chronic heart failure. Circulation. 1999;99(11):1435-1440. [PubMed]
 
Kales A, Bixler EO, Cadieux RJ, et al. Sleep apnoea in a hypertensive population. Lancet. 1984;2(8410):1005-1008. [PubMed]
 
Young T, Peppard P, Palta M, et al. Population-based study of sleep-disordered breathing as a risk factor for hypertension. Arch Intern Med. 1997;157(15):1746-1752. [PubMed]
 
Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med. 2000;342(19):1378-1384. [PubMed]
 
Javaheri S, Parker TJ, Wexler L, Liming JD, Lindower P, Roselle GA. Effect of theophylline on sleep-disordered breathing in heart failure. N Engl J Med. 1996;335(8):562-567. [PubMed]
 
Pesek CA, Cooley R, Narkiewicz K, Dyken M, Weintraub NL, Somers VK. Theophylline therapy for near-fatal Cheyne-Stokes respiration. A case report. Ann Intern Med. 1999;130(5):427-430. [PubMed]
 
Andreas S, Reiter H, Lüthje L, et al. Differential effects of theophylline on sympathetic excitation, hemodynamics, and breathing in congestive heart failure. Circulation. 2004;110(15):2157-2162. [PubMed]
 
Spaak J, Egri ZJ, Kubo T, et al. Muscle sympathetic nerve activity during wakefulness in heart failure patients with and without sleep apnea. Hypertension. 2005;46(6):1327-1332. [PubMed]
 
Karsten AJ, Derouet H, Ziegler M, Eckert RE. Involvement of cyclic nucleotides in renal artery smooth muscle relaxation. Urol Res. 2003;30(6):367-373. [PubMed]
 
Lo YC, Tsou HH, Lin RJ, et al. Endothelium-dependent and -independent vasorelaxation by a theophylline derivative MCPT: roles of cyclic nucleotides, potassium channel opening and phosphodiesterase inhibition. Life Sci. 2005;76(8):931-944. [PubMed]
 
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