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Electrophysiologic evaluation of sinus node function and atrioventricular conduction in patients with prolonged ventricular asystole during obstructive sleep apnea
Electrophysiologic Evaluation of Sinus Node Function and Atrioventricular Conduction in Patients With Prolonged Ventricular Asystole During Obstructive Sleep Apnea Wolfram
Grimm, MD, Jiirgen Hoffmann, MD, Volker Menz, MD, Ulrich K6hler, J&g Heitmann, MD, J&-g H. Peter, MD, and Bernhard Maisch, MD
MD,
In 15 patients with ventricular asystole of 8.5 -+ 3.5 seconds (range 5.0 to 16.8) occurring exclusively during obstructive sleep apnea, electrophysiologic study of sinus node function and atrioventricular conduction before and after administration of intravenous atropine (0.02 mg/kg) was performed. Electrophysiologic parameters of sinus node function were normal in 12 of 15 patients (80%) and atrioventricular (AV) nodal function was normal in 7 patients (47%). Almost all abnormal findings of sinus node function and AV nodal function were reversible by administration of atropine. The His-
Purkinje system function was normal in 6 patients (40%). Prolonged HV intervals (57 to 73 ms) were found in 9 patients (60%). Intra- or infra-His block was not observed in any patient. In summary, electrophysiologic parameters of sinus node function and AV conduction were normal or only slightly abnormal in all 15 study patients, which suggests that prolonged ventricular asystole during obstructive sleep apnea is not due to fixed or anatomic disease of the sinus node or the AV conduction system. (Am J Cardiol 1996;77: 13 lo- 13 14)
xtreme bradycardia with ventricular asystole lastE ing 2 10 seconds has been well described in patients with obstructive sleep apnea.‘-‘(’ To date, how-
cardiogram, echocardiogram, and bicycle ergometry. No patient received digoxin, /? blockers, verapamil, or class I or III antiarrhythmic agents during polysomnography or before electrophysiologic evaluation.
ever, it is still unknown whether fixed or anatomic abnormalities of the sinus node and the atrioventricular ( AV) conduction system have a role in the genesis of ventricular asystole during obstructive sleep apnea in addition to increased parasympathetic tone and hypoxia. This study assesseselectrophysiologic parameters of sinus node function and AV conduction before and after administration of atropine in patients with prolonged ventricular asystole occurring exclusively during obstructive sleep apnea.
Review polysomnography with nasal continuous positive airway pressure therapy: After electrophysiologic
study was performed, the 15 study patients underwent full-night polysomnography and Holter monitoring with nasal continuous positive airway pressure therapy, with pressure levels ranging from 5 to 20 cm of water. Electrophysiologic study protocol: The study protocol was reviewed and approved by the institutional research committee, and written informed consent was obtained from all study patients. ElectrophysMETHODS iologic studies were performed in the postabsortive, Patients: A total of 15 patients with ventricular asystole r5 seconds’ duration occurring exclusively nonsedated state. After local anesthesia had been obduring obstructive sleep apnea on diagnostic poly- tained using 2% procaine hydrochloride, three 6Fr somnography with simultaneous 2-channel Holter quadripolar electrode catheters were inserted percumonitoring were recruited from the Marburg Sleep taneously through the femoral veins and advanced Disorder Clinic from October 1993 to July 1995 (Ta- to the high lateral right atrium, across the tricuspid ble I). In addition to full-night polysomnography valve to record the His bundle electrogram, and to and 24-hour Holter monitoring, the following studies the right ventricular apex. Surface electrograms from were performed or data obtained for all 15 patients: leads I to III, V’ , and V6, and intracardiac recordings medical history, physical examination, detailed neu- from high right atrium, proximal and distal His bunrologic and otolaryngologic evaluation, routine lab- dle, and right ventricle were displayed simultaoratory tests, chest x-ray, standard 12-lead electro- neously on a computer screen. Measurements of time intervals were performed manually at a screen speed of 200 mm/s. From the Department of Cardiology and the Department of Sleep Research, Phllipps-University Marburg, Morburg, Germany. ManuThe methods of electrophysiologic evaluation of script received November 6, 1995; revised manuscript received and sinus node function and AV conduction properties accepted February 9, 1996. have been described in detail elsewhere.‘3-‘6 Briefly, Address for reprints: Wolfram Grimm, MD, Philipps-University evaluation of sinus node function included heart Marburg, Department of Cardiology, Baldlngerstrasse 1, 35033 Marburg, Germany. rate-corrected sinus node recovery time, I3916sino1310
0 1996 by Excerpta Medico, All rights reserved.
Inc.
0002-9 149/96/$15.00 PII SOOO2-9149(96)00197-X
TABLE
I Clnical
Women Men
Characteristics
of
15
Study
(no.)
1 (7%) 1A
(93%) A9+ 14
[no.)
Mean
age
(yr)
Range Body
Patients
21-71
weight
[kg)
110?20
Range
81-150
Height
17425
(cm)
Range
162-l
Apnea
index
50
Range
10-152
Hypopnea
index
36
-+ 30
A-95
Range Underlying
heart
Systemic
disease
(no.)
hypertension
Coronary No
79 i- 52
artery
structural
5 (33%)
disease
heart
2 (13%)
disease
(54%)
8
Medication Angiotensinconverting Calcium
enzyme
inhibitors
2 (13%)
antagonists
2 (13%)
Diuretics
1 (7%)
Alpha-receptor Maximal
blockers
duration
OSA
2 (13%)
of ventricular
asystole
during
Range Cause
8.5
t
3.5
(s) 5.0-16.8 of ventricular
Complete SA block Complete
AV
during
OSA
(no.)
block
or sinus AV
asystole
block
AV = atrioventriculor;
8 (53%) arrest
5 (33%)
and
SA block
OSA
= obstructive
or sinus
arrest
sleep apnea;
2
(14%)
SA = sinootrial.
atria1 conduction times using the methods described by Strauss et alI4 and Narula et al, I5 and the chronotropic response of sinus rate to atropine administration. An increase in sinus rate of 225% from baseline sinus rate to 290 beats/min was considered appropriate after intravenous administration of atropine (0.02 mg/kg). Heart rate-corrected sinus node recovery times were assessedat various atria1 pacing rates for periods of 30 seconds each. Atria1 pacing cycle lengths started just below sinus cycle lengths, with decrements in steps of 100 ms until an atria1 pacing cycle length of 300 ms was reached. Assessment of AV conduction included measurements of AH and HV intervals, and determination of AV and ventriculoatrial block cycle length using incremental atria1 and ventricular pacing, respectively. AH intervals of 60 to 125 ms and AV block cycle length of <505 ms were considered normal.13 AV nodal effective refractory periods were determined by the extrastimulus technique (S, , S,) after regular atria1 pacing at a drive cycle length of 600 and 400 ms for 8 beats. The extrastimulus was introduced beginning at a coupling interval of 480 and 380 ms, with decrements of 10 ms until atria1 refractoriness was reached. AV nodal refractroy periods of ~425 ms were considered norma1.13 After completion of this study protocol, a bolus of atropine (0.02 mg/kg) was administered intravenously and the whole study protocol was repeated. All results are reported as mean Ifi SD unless otherwise specified.
RESULTS Characteristics tive sleep apnea:
of ventricular
asystole during obstruc-
Baseline diagnostic polysomnogra-
phy revealed ventricular asystole not associated with any form of ventricular escape rhythm during obstructive sleep apnea of 8.5 -+ 3.5 seconds (range 5.0 to 16.8) (Table I and Figures 1 and 2). Sinus arrest or sinoatrial block was present during asystole in 5 patients (33%)) sinus bradycardia with complete AV block was noted in 8 patients (53%), and both sinus arrest or sinoatrial block and sinus bradycardia with complete AV block were seen in 2 patients ( 14%). Sinus node function: Parameters of sinus node function were completely normal in 12 of 15 study patients (80% ) (Table II). Sinoatrial conduction times before administration of atropine were prolonged in 2 patients ( 13%) at 130 and 160 ms, respectively. Sinoatrial conduction times normalized in both patients after atropine administration to 55 and 80 ms, respectively. Rate-corrected sinus node recovery time was normal in all 15 study patients. An adequate decrease of sinus cycle length in response to atropine administration was observed in 14 of 15 study patients (93%). One patient (7%) had an inadequate chronotropic response after atropine, with a maximal sinus rate increase to 75 beats/min. Atrioventricular nodal function: AH intervals, AV block cycle lengths, and AV nodal effective refractory periods were completely normal in 7 of 15 study patients (47%) before and after atropine administration (Table II). Baseline AH intervals were prolonged in 5 patients (33%; range 135 to 164 ms). AH intervals normalized in all but 1 patient (7%) after atropine administration. Baseline AV block cycle length was prolonged in 4 patients (27%; range 540 to 730 ms), and baseline AV nodal refractory periods were prolonged in 6 patients, from 500 to 620 ms. AV block cycle lengths and AV nodal effective refractory periods normalized after atropine administration in all study patients. His-Purkinje system function: His-Purkinje system function was found to be normal in 6 patients (40%). A total of 8 patients (53%) had slightly prolonged HV intervals (range 57 to 63 ms) ; 1 patient (7%) had an HV interval of 73 ms. Intra- or infra-His block during incremental atria1 pacing was not observed in any patient (Table II). Effect of nasal continuous treatment: Nasal continuous
positive
airway
pressure
positive airway pressure treatment abolished all episodes of ventricular asystole in 13 of 15 study patients (87%). In 1 patient (7%) asystolic episodes of 5 seconds’ duration persisted despite nasal continuous positive airway pressure treatment, and insertion of a permanent pacemaker was recommended. Another patient (7%) with ventricular asystole of 16.8 seconds during baseline polysomnography had already had a permanent pacemaker inserted at the time of review sleep study with nasal continuous positive airway pressure therapy. The pacemaker in this patient was programmed to the VVI mode with a pacing rate of 30 beats/min. Polysomnography with nasal continuous positive airway pressure therapy revealed episodes of severe sinus bradycardia with initiation of
ARRHYTHMIAS AND CONDUCTION
DlSTURBANCES/ASYSTOLE
DURING SLEEPAPNEA
1311
derlying mechanisms of these findings. Slightly pro-longed HV intervals of 57 to 73 ms in 60% of patients in our study are unlikely to have a cause-effect relation with ventricular asystole during obstructive sleep apnea, because intra- or infra-His block was not observed even at fast atria1 pacing rates. Thus, the results of our study do not support the hypothesis that fixed or anatomic abnormalities of sinus node function and atrioventricular conduction have a major role in the development of asystole during obstructive sleep apnea. The findings of our study confirm the results of Tilkian et al,’ who previously demonstrated normal sinus node recovery times and HV intervals during electrophysiologic study in 5 patients with bradyarrhythmias during obstructive sleep apnea. However, in contrast to our study, only 2 of 5 patients studied by Tilkian et al had asystolic episodes of 3 to 6 seconds’ duration during obstructive sleep apnea. To date, the precise mechanism of ventricular asystole ---, during obstructive sleep apnea Abdomen remains unknown.‘,3-59 ’ Tilkl---f+Thne J I ’ ’ 7 I 1 ian et al’ proposed that even in wW.5 o&l cam predominantly obstructive apnea, central nervous system FIGURE 1. A, 2-minute segment of diagnostic polygraphic recording showing 3 episodes dysfunction initiates geniogof obstructive sleep apnea characterized by cessation of nasal airflow despite continuous thoracic and abdominal respiratory efforts. Note that ventricular asystole of 8.7 seconds lossus atonia and upper airway occurred toward the end of the first a nea episode [arrow), whereas bradycardia but no obstruction, leading to alveolar asystole occurred toward the end of ii e second and third apnea episodes. After 30 sechypoventilation with hypoxia onds of apnea, ventilation resumed briefly during an arousal and sinus speeding ocand respiratory acidosis. The curred with resumption of 1: 1 atrioventricular conduction. After approximately 10 seconds, apnea returned and the cycle repeated itself continuously. B, enlargement of the hypoxemia, in turn, results first apnea episode of the diagnostic polygraphic recording of (A/. Arrows depict nonconin a vigorous inspiratory efducted P waves with ventricular asystole of 8.7 seconds. Note the cessation of nasal airfort against the closed airway flow despite continuous thoracic and abdominal respiratory efforts before an arousal oc(Mueller’s maneuver), which curred and ventilation resumed. ECG=electrocardiogram. increases parasympathetic tone leading to bradycardia or asysventricular pacing at the programmed rate of 30 tole. When an arousal occurs, the airway obstrucbeats/min. tion is relieved and ventilation resumes with a marked decrease in parasympathetic tone and subsequent sinus node acceleration (Figure 1). The DISCUSSION The present study in 15 patients with prolonged observation of Tilkian et al that sinus bradycardia ventricular asystole occurring exclusively during ob- and asystole during sleep apnea can be prevented structive sleep apnea revealed normal electrophys- by administration of atropine despite persisting iologic findings of sinus node function and AV con- apnea episodes also supports the concept that induction in most patients. Mildly abnormal findings creased parasympathetic tone is the underlying of sinus node function and AV nodal conduction dur- mechanism of asystole during obstructive sleep ing electrophysiologic study were reversible by ad- apnea. Zwilich et al4 demonstrated that in addiministration of atropine in almost all patients, which tion to increased parasympathetic tone, hypoxia suggests enhanced vagal tone rather than structural has an important role in the development of abnormalities of the sinus and AV nodes as the un- bradycardia and asystole during sleep apnea. 1312
THE AMERICAN JOURNAL OF CARDIOLOGY@
VOL. 77
JUNE 15, 1996
FIGURE 2. A, 2-channel Holter recording obtained at a paper speed of 25 mm/s showing complete heart block with ventricular asystole of 9.2 seconds during obstructive sleep apnea. The P waves are marked with arrows. 6,2-channel Holter recording obtained at a paper speed of 25 mm/s showing ventricular asystole of 6.0 seconds resulting from sinus arrest or sinoatrial block during obstructive sleep apnea. The P waves are marked with arrows.
TABLE II Results of Electrophysiologic
Study in 15 Patients With Ventricular Before Mean
Sinus node function Sinus cycle length (ms) Rate corrected SNRT [ms) Sinoatrial conduction time (ms) AV nodal function AH interval (ms) AV block cycle length (ms) AV nodal ERP (ms) His-Purkinie system function HV interval (ms) Intro- or infraHis block l
After intravenous
AV block recovery
administration
= atrioventricular
block;
Obstructive
Sleep Apnea After Atropine*
Range
Mean
+ SD
Range
907 t 123 346 + 73 98 f 26
650-1,170 280-530 68-l 60
606 + 81 226 2 82 652 14
500-800
109 t 29 419 2 124 368 -+ 135
67-l 64 290-730 200-600
85 t 23 296 2 71 239 +- 53
54-140 200-430 180-340
57 k 7
43-73
in Q dose of 0.02
ERP = effective
During
Atropine
2 SD
58 -+ 6
of &opine
Asystole
refractory
45-73
mg/kg
period
120-390 45-80
body weight.
determined
at atria1 drive cycle length
of 400
ms; SN = sinus node;
SNRT = sinus node
time.
To date, the prognostic significance of prolonged asystole in patients with obstructive sleep apnea is unclear. Although increased mortality and sudden deaths have been reported in patients with severe sleep apnea syndrome, 3,7,8a cause-effect relation for asystolic episodes during obstructive sleep apnea has not been established. However, aborted sudden death due to neurally mediated prolonged cardiac asystole in patients without obstructive sleep apnea, with normal conventional invasive electrophysiologic evaluation, has been described.” Nasal continuous positive airway pressure therapy is currently recommended as first-line therapy for patients with sleep apnea syndrome.‘2,‘9 Of note, nasal continuous positive airway pressure treatment abolished all episodes of ventricular asystole during review polysomnography in 87% of patients in our study. This is consistent with the results of Becker et al,” who reported complete reversal of severe bradyarrhythmias by nasal continuous positive airway pressure treatment in 8 of 10 patients. Similarly, Tilkian et al ’ found that extreme sinus bradycardia and AV block during obstructive sleep apnea completely disappeared after tracheostomy and reapARRHMHMIAS
peared during sleep when the tracheostomy site was occluded. Obesity has been shown to be a predisposing factor for obstructive sleep apnea syndrome.” Consistent with other published series of patients with severe obstructive sleep apnea, 1,2s~6~8~9 13 of 15 patients (87%) in the present study were obese. Previous studies in patients with severe bradyarrhythmias and asystole associated with obstructive sleep apnea have demonstrated that normalization of body weight can result in significant improvement or disappearance of both obstructive sleep apnea and nocturnal bradyarrhythmias.*~” 1. Tilkian AC, Guilleminault C, Schroeder JS, Lehrman KL, Simmons FB, Demerit WC. Sleep induced apnea syndrome-prevalence of cardiac arrhythmias and their reversal after tracheostomy. Am .I Med 1977;63:348358. 2. Shaw TRD, Corral1 RJM, Craib IA. Cardiac and respiratory standstill during sleep. Br Heart J 1978;40:1055-1058. 3. Miller WP. Cardiac arrhythmias and conduction disturbances in the sleep apnea syndrome. Prevalence and significance. Am J Med 1982;73: 317-321. 4. Zwilich C, D&in T, White D, Douglas N, Weil J, Martin R. Bradycardia during sleep apnea-characteristics and mechanism. J Clin Invest 1982;69: 1286-1292.
AND CONDUCTION
DISTURBANCES/ASYSTOlE
DURING SLEEP APNEA
1313
5. Guilleminault C, Connolly SJ, Winkle RA. Cardiac arrhythmia and conduction disturbances during sleep in 400 patients with sleep apnea syndrome. Am J Cardiol 1983;52:490-494. 6. Balm-Audorff U, Koehler U, Becker E, Fuchs E, Maimer K, Peter HJ, van Wichert P. Nocturnal cardiac arrhythmias in the sleep apnea syndrome. Drsch Med Wochenschr 1984;109:853-856. 7. Otsuka K. Sadakane N, Ozawa T. Arrhytbmogenic properties of disordered breathing during sleep in patients with cardiovascular disorders. Clin Cardiol 1987;10:771-782. 8. Shepard JW Jr. Hypertension, cardiac arrhythmias, myocardial infarction, and stroke in relation to obstructive sleep apnea. Clin Chest Med 1992;13:437-458. 9. Flemons WW, Remmers JE, Gillis AM. Sleep apnea and cardiac arrhythmias. Is there a relationship’? Am Rev Respir Dis 1993;148:618-621. 10. Rama PR, Satish CS. Sleep apnea and complete heart block. C/in Cardiol 1994;17:675-677. 11. Douglas NJ, Polo 0. Pathogenesis of obstructive sleep apnoea/hypopnoea syndrome. Lancer 1994;344:653-655. 12. Polo 0, Berthon-Jones M, Douglas NJ, Sullivan CE. Management of obstructive sleep apnoea/hypopnoea syndrome. Lmcet 1994;344:656-660. 13. Josephson ME. Clinical Cardiac Electrophysiology-Techniques and lnterpretations. 2nd ed. Philadelphia: Lea & Febiger;1993:71- 116.
1314
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14. Strauss HC, Bigger JT, Saroff AL, Giardina EGV. Electrophysiologic evaluation of sinus node function in patients with sinus node dysfunction. Circulation 1976;53:763-776. 15. Narula OS, Shanto N, Vasquez M, Towne WD. Linhart JW. A new method for measurement of sinoatrial conduction time. Circulation 1978; 58:706-714. 16. Breithardt G, Seipel L, Loogen F. Sinus node recovery time and calculated sinoatrial conduction time in normal subjects and patients with sinus node dysfunction. Circulation 1977;56:43. 17. Becker H, Brandenburg U, Conradt R, Koehler U, Peter JH, Ploch T, van Wichert P. Influence of nCPAP therapy on bradycardic arrhythmias in sleep apnea. Pneumo/ogir 1993;47(suppl4):706-710. 18. Peiser J, Ovnat A, Uwyyed K, Lavie P. Charuzi I. Cardiac arrhythmias during sleep in morbidly obese sleep-apneic patients before and after gastric bypass surgery. Clin Cardiol 1985:8:519-521. 19. Engleman HM, Martin SE, Deary IJ, Douglas NJ. Effect of continuous positive airway pressure treatment on daytime function in sleep apnea/hypopnea syndrome. Lancer 1994;343:572-575. 20. Milstein S, Buetinkofer J, Lesser J. Goldenberg JF, Benditt DG, Gomick C, Reyes WI. Cardiac asystole: a manifestation of neurally mediated hypotension-bradycardia. J Am Coil Curdiol 1989;14: 1626-1632.
JUNE 15, 1996
Grimm, MD, Jiirgen Hoffmann, MD, Volker Menz, MD, Ulrich K6hler, J&g Heitmann, MD, J&-g H. Peter, MD, and Bernhard Maisch, MD
MD,
In 15 patients with ventricular asystole of 8.5 -+ 3.5 seconds (range 5.0 to 16.8) occurring exclusively during obstructive sleep apnea, electrophysiologic study of sinus node function and atrioventricular conduction before and after administration of intravenous atropine (0.02 mg/kg) was performed. Electrophysiologic parameters of sinus node function were normal in 12 of 15 patients (80%) and atrioventricular (AV) nodal function was normal in 7 patients (47%). Almost all abnormal findings of sinus node function and AV nodal function were reversible by administration of atropine. The His-
Purkinje system function was normal in 6 patients (40%). Prolonged HV intervals (57 to 73 ms) were found in 9 patients (60%). Intra- or infra-His block was not observed in any patient. In summary, electrophysiologic parameters of sinus node function and AV conduction were normal or only slightly abnormal in all 15 study patients, which suggests that prolonged ventricular asystole during obstructive sleep apnea is not due to fixed or anatomic disease of the sinus node or the AV conduction system. (Am J Cardiol 1996;77: 13 lo- 13 14)
xtreme bradycardia with ventricular asystole lastE ing 2 10 seconds has been well described in patients with obstructive sleep apnea.‘-‘(’ To date, how-
cardiogram, echocardiogram, and bicycle ergometry. No patient received digoxin, /? blockers, verapamil, or class I or III antiarrhythmic agents during polysomnography or before electrophysiologic evaluation.
ever, it is still unknown whether fixed or anatomic abnormalities of the sinus node and the atrioventricular ( AV) conduction system have a role in the genesis of ventricular asystole during obstructive sleep apnea in addition to increased parasympathetic tone and hypoxia. This study assesseselectrophysiologic parameters of sinus node function and AV conduction before and after administration of atropine in patients with prolonged ventricular asystole occurring exclusively during obstructive sleep apnea.
Review polysomnography with nasal continuous positive airway pressure therapy: After electrophysiologic
study was performed, the 15 study patients underwent full-night polysomnography and Holter monitoring with nasal continuous positive airway pressure therapy, with pressure levels ranging from 5 to 20 cm of water. Electrophysiologic study protocol: The study protocol was reviewed and approved by the institutional research committee, and written informed consent was obtained from all study patients. ElectrophysMETHODS iologic studies were performed in the postabsortive, Patients: A total of 15 patients with ventricular asystole r5 seconds’ duration occurring exclusively nonsedated state. After local anesthesia had been obduring obstructive sleep apnea on diagnostic poly- tained using 2% procaine hydrochloride, three 6Fr somnography with simultaneous 2-channel Holter quadripolar electrode catheters were inserted percumonitoring were recruited from the Marburg Sleep taneously through the femoral veins and advanced Disorder Clinic from October 1993 to July 1995 (Ta- to the high lateral right atrium, across the tricuspid ble I). In addition to full-night polysomnography valve to record the His bundle electrogram, and to and 24-hour Holter monitoring, the following studies the right ventricular apex. Surface electrograms from were performed or data obtained for all 15 patients: leads I to III, V’ , and V6, and intracardiac recordings medical history, physical examination, detailed neu- from high right atrium, proximal and distal His bunrologic and otolaryngologic evaluation, routine lab- dle, and right ventricle were displayed simultaoratory tests, chest x-ray, standard 12-lead electro- neously on a computer screen. Measurements of time intervals were performed manually at a screen speed of 200 mm/s. From the Department of Cardiology and the Department of Sleep Research, Phllipps-University Marburg, Morburg, Germany. ManuThe methods of electrophysiologic evaluation of script received November 6, 1995; revised manuscript received and sinus node function and AV conduction properties accepted February 9, 1996. have been described in detail elsewhere.‘3-‘6 Briefly, Address for reprints: Wolfram Grimm, MD, Philipps-University evaluation of sinus node function included heart Marburg, Department of Cardiology, Baldlngerstrasse 1, 35033 Marburg, Germany. rate-corrected sinus node recovery time, I3916sino1310
0 1996 by Excerpta Medico, All rights reserved.
Inc.
0002-9 149/96/$15.00 PII SOOO2-9149(96)00197-X
TABLE
I Clnical
Women Men
Characteristics
of
15
Study
(no.)
1 (7%) 1A
(93%) A9+ 14
[no.)
Mean
age
(yr)
Range Body
Patients
21-71
weight
[kg)
110?20
Range
81-150
Height
17425
(cm)
Range
162-l
Apnea
index
50
Range
10-152
Hypopnea
index
36
-+ 30
A-95
Range Underlying
heart
Systemic
disease
(no.)
hypertension
Coronary No
79 i- 52
artery
structural
5 (33%)
disease
heart
2 (13%)
disease
(54%)
8
Medication Angiotensinconverting Calcium
enzyme
inhibitors
2 (13%)
antagonists
2 (13%)
Diuretics
1 (7%)
Alpha-receptor Maximal
blockers
duration
OSA
2 (13%)
of ventricular
asystole
during
Range Cause
8.5
t
3.5
(s) 5.0-16.8 of ventricular
Complete SA block Complete
AV
during
OSA
(no.)
block
or sinus AV
asystole
block
AV = atrioventriculor;
8 (53%) arrest
5 (33%)
and
SA block
OSA
= obstructive
or sinus
arrest
sleep apnea;
2
(14%)
SA = sinootrial.
atria1 conduction times using the methods described by Strauss et alI4 and Narula et al, I5 and the chronotropic response of sinus rate to atropine administration. An increase in sinus rate of 225% from baseline sinus rate to 290 beats/min was considered appropriate after intravenous administration of atropine (0.02 mg/kg). Heart rate-corrected sinus node recovery times were assessedat various atria1 pacing rates for periods of 30 seconds each. Atria1 pacing cycle lengths started just below sinus cycle lengths, with decrements in steps of 100 ms until an atria1 pacing cycle length of 300 ms was reached. Assessment of AV conduction included measurements of AH and HV intervals, and determination of AV and ventriculoatrial block cycle length using incremental atria1 and ventricular pacing, respectively. AH intervals of 60 to 125 ms and AV block cycle length of <505 ms were considered normal.13 AV nodal effective refractory periods were determined by the extrastimulus technique (S, , S,) after regular atria1 pacing at a drive cycle length of 600 and 400 ms for 8 beats. The extrastimulus was introduced beginning at a coupling interval of 480 and 380 ms, with decrements of 10 ms until atria1 refractoriness was reached. AV nodal refractroy periods of ~425 ms were considered norma1.13 After completion of this study protocol, a bolus of atropine (0.02 mg/kg) was administered intravenously and the whole study protocol was repeated. All results are reported as mean Ifi SD unless otherwise specified.
RESULTS Characteristics tive sleep apnea:
of ventricular
asystole during obstruc-
Baseline diagnostic polysomnogra-
phy revealed ventricular asystole not associated with any form of ventricular escape rhythm during obstructive sleep apnea of 8.5 -+ 3.5 seconds (range 5.0 to 16.8) (Table I and Figures 1 and 2). Sinus arrest or sinoatrial block was present during asystole in 5 patients (33%)) sinus bradycardia with complete AV block was noted in 8 patients (53%), and both sinus arrest or sinoatrial block and sinus bradycardia with complete AV block were seen in 2 patients ( 14%). Sinus node function: Parameters of sinus node function were completely normal in 12 of 15 study patients (80% ) (Table II). Sinoatrial conduction times before administration of atropine were prolonged in 2 patients ( 13%) at 130 and 160 ms, respectively. Sinoatrial conduction times normalized in both patients after atropine administration to 55 and 80 ms, respectively. Rate-corrected sinus node recovery time was normal in all 15 study patients. An adequate decrease of sinus cycle length in response to atropine administration was observed in 14 of 15 study patients (93%). One patient (7%) had an inadequate chronotropic response after atropine, with a maximal sinus rate increase to 75 beats/min. Atrioventricular nodal function: AH intervals, AV block cycle lengths, and AV nodal effective refractory periods were completely normal in 7 of 15 study patients (47%) before and after atropine administration (Table II). Baseline AH intervals were prolonged in 5 patients (33%; range 135 to 164 ms). AH intervals normalized in all but 1 patient (7%) after atropine administration. Baseline AV block cycle length was prolonged in 4 patients (27%; range 540 to 730 ms), and baseline AV nodal refractory periods were prolonged in 6 patients, from 500 to 620 ms. AV block cycle lengths and AV nodal effective refractory periods normalized after atropine administration in all study patients. His-Purkinje system function: His-Purkinje system function was found to be normal in 6 patients (40%). A total of 8 patients (53%) had slightly prolonged HV intervals (range 57 to 63 ms) ; 1 patient (7%) had an HV interval of 73 ms. Intra- or infra-His block during incremental atria1 pacing was not observed in any patient (Table II). Effect of nasal continuous treatment: Nasal continuous
positive
airway
pressure
positive airway pressure treatment abolished all episodes of ventricular asystole in 13 of 15 study patients (87%). In 1 patient (7%) asystolic episodes of 5 seconds’ duration persisted despite nasal continuous positive airway pressure treatment, and insertion of a permanent pacemaker was recommended. Another patient (7%) with ventricular asystole of 16.8 seconds during baseline polysomnography had already had a permanent pacemaker inserted at the time of review sleep study with nasal continuous positive airway pressure therapy. The pacemaker in this patient was programmed to the VVI mode with a pacing rate of 30 beats/min. Polysomnography with nasal continuous positive airway pressure therapy revealed episodes of severe sinus bradycardia with initiation of
ARRHYTHMIAS AND CONDUCTION
DlSTURBANCES/ASYSTOLE
DURING SLEEPAPNEA
1311
derlying mechanisms of these findings. Slightly pro-longed HV intervals of 57 to 73 ms in 60% of patients in our study are unlikely to have a cause-effect relation with ventricular asystole during obstructive sleep apnea, because intra- or infra-His block was not observed even at fast atria1 pacing rates. Thus, the results of our study do not support the hypothesis that fixed or anatomic abnormalities of sinus node function and atrioventricular conduction have a major role in the development of asystole during obstructive sleep apnea. The findings of our study confirm the results of Tilkian et al,’ who previously demonstrated normal sinus node recovery times and HV intervals during electrophysiologic study in 5 patients with bradyarrhythmias during obstructive sleep apnea. However, in contrast to our study, only 2 of 5 patients studied by Tilkian et al had asystolic episodes of 3 to 6 seconds’ duration during obstructive sleep apnea. To date, the precise mechanism of ventricular asystole ---, during obstructive sleep apnea Abdomen remains unknown.‘,3-59 ’ Tilkl---f+Thne J I ’ ’ 7 I 1 ian et al’ proposed that even in wW.5 o&l cam predominantly obstructive apnea, central nervous system FIGURE 1. A, 2-minute segment of diagnostic polygraphic recording showing 3 episodes dysfunction initiates geniogof obstructive sleep apnea characterized by cessation of nasal airflow despite continuous thoracic and abdominal respiratory efforts. Note that ventricular asystole of 8.7 seconds lossus atonia and upper airway occurred toward the end of the first a nea episode [arrow), whereas bradycardia but no obstruction, leading to alveolar asystole occurred toward the end of ii e second and third apnea episodes. After 30 sechypoventilation with hypoxia onds of apnea, ventilation resumed briefly during an arousal and sinus speeding ocand respiratory acidosis. The curred with resumption of 1: 1 atrioventricular conduction. After approximately 10 seconds, apnea returned and the cycle repeated itself continuously. B, enlargement of the hypoxemia, in turn, results first apnea episode of the diagnostic polygraphic recording of (A/. Arrows depict nonconin a vigorous inspiratory efducted P waves with ventricular asystole of 8.7 seconds. Note the cessation of nasal airfort against the closed airway flow despite continuous thoracic and abdominal respiratory efforts before an arousal oc(Mueller’s maneuver), which curred and ventilation resumed. ECG=electrocardiogram. increases parasympathetic tone leading to bradycardia or asysventricular pacing at the programmed rate of 30 tole. When an arousal occurs, the airway obstrucbeats/min. tion is relieved and ventilation resumes with a marked decrease in parasympathetic tone and subsequent sinus node acceleration (Figure 1). The DISCUSSION The present study in 15 patients with prolonged observation of Tilkian et al that sinus bradycardia ventricular asystole occurring exclusively during ob- and asystole during sleep apnea can be prevented structive sleep apnea revealed normal electrophys- by administration of atropine despite persisting iologic findings of sinus node function and AV con- apnea episodes also supports the concept that induction in most patients. Mildly abnormal findings creased parasympathetic tone is the underlying of sinus node function and AV nodal conduction dur- mechanism of asystole during obstructive sleep ing electrophysiologic study were reversible by ad- apnea. Zwilich et al4 demonstrated that in addiministration of atropine in almost all patients, which tion to increased parasympathetic tone, hypoxia suggests enhanced vagal tone rather than structural has an important role in the development of abnormalities of the sinus and AV nodes as the un- bradycardia and asystole during sleep apnea. 1312
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FIGURE 2. A, 2-channel Holter recording obtained at a paper speed of 25 mm/s showing complete heart block with ventricular asystole of 9.2 seconds during obstructive sleep apnea. The P waves are marked with arrows. 6,2-channel Holter recording obtained at a paper speed of 25 mm/s showing ventricular asystole of 6.0 seconds resulting from sinus arrest or sinoatrial block during obstructive sleep apnea. The P waves are marked with arrows.
TABLE II Results of Electrophysiologic
Study in 15 Patients With Ventricular Before Mean
Sinus node function Sinus cycle length (ms) Rate corrected SNRT [ms) Sinoatrial conduction time (ms) AV nodal function AH interval (ms) AV block cycle length (ms) AV nodal ERP (ms) His-Purkinie system function HV interval (ms) Intro- or infraHis block l
After intravenous
AV block recovery
administration
= atrioventricular
block;
Obstructive
Sleep Apnea After Atropine*
Range
Mean
+ SD
Range
907 t 123 346 + 73 98 f 26
650-1,170 280-530 68-l 60
606 + 81 226 2 82 652 14
500-800
109 t 29 419 2 124 368 -+ 135
67-l 64 290-730 200-600
85 t 23 296 2 71 239 +- 53
54-140 200-430 180-340
57 k 7
43-73
in Q dose of 0.02
ERP = effective
During
Atropine
2 SD
58 -+ 6
of &opine
Asystole
refractory
45-73
mg/kg
period
120-390 45-80
body weight.
determined
at atria1 drive cycle length
of 400
ms; SN = sinus node;
SNRT = sinus node
time.
To date, the prognostic significance of prolonged asystole in patients with obstructive sleep apnea is unclear. Although increased mortality and sudden deaths have been reported in patients with severe sleep apnea syndrome, 3,7,8a cause-effect relation for asystolic episodes during obstructive sleep apnea has not been established. However, aborted sudden death due to neurally mediated prolonged cardiac asystole in patients without obstructive sleep apnea, with normal conventional invasive electrophysiologic evaluation, has been described.” Nasal continuous positive airway pressure therapy is currently recommended as first-line therapy for patients with sleep apnea syndrome.‘2,‘9 Of note, nasal continuous positive airway pressure treatment abolished all episodes of ventricular asystole during review polysomnography in 87% of patients in our study. This is consistent with the results of Becker et al,” who reported complete reversal of severe bradyarrhythmias by nasal continuous positive airway pressure treatment in 8 of 10 patients. Similarly, Tilkian et al ’ found that extreme sinus bradycardia and AV block during obstructive sleep apnea completely disappeared after tracheostomy and reapARRHMHMIAS
peared during sleep when the tracheostomy site was occluded. Obesity has been shown to be a predisposing factor for obstructive sleep apnea syndrome.” Consistent with other published series of patients with severe obstructive sleep apnea, 1,2s~6~8~9 13 of 15 patients (87%) in the present study were obese. Previous studies in patients with severe bradyarrhythmias and asystole associated with obstructive sleep apnea have demonstrated that normalization of body weight can result in significant improvement or disappearance of both obstructive sleep apnea and nocturnal bradyarrhythmias.*~” 1. Tilkian AC, Guilleminault C, Schroeder JS, Lehrman KL, Simmons FB, Demerit WC. Sleep induced apnea syndrome-prevalence of cardiac arrhythmias and their reversal after tracheostomy. Am .I Med 1977;63:348358. 2. Shaw TRD, Corral1 RJM, Craib IA. Cardiac and respiratory standstill during sleep. Br Heart J 1978;40:1055-1058. 3. Miller WP. Cardiac arrhythmias and conduction disturbances in the sleep apnea syndrome. Prevalence and significance. Am J Med 1982;73: 317-321. 4. Zwilich C, D&in T, White D, Douglas N, Weil J, Martin R. Bradycardia during sleep apnea-characteristics and mechanism. J Clin Invest 1982;69: 1286-1292.
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5. Guilleminault C, Connolly SJ, Winkle RA. Cardiac arrhythmia and conduction disturbances during sleep in 400 patients with sleep apnea syndrome. Am J Cardiol 1983;52:490-494. 6. Balm-Audorff U, Koehler U, Becker E, Fuchs E, Maimer K, Peter HJ, van Wichert P. Nocturnal cardiac arrhythmias in the sleep apnea syndrome. Drsch Med Wochenschr 1984;109:853-856. 7. Otsuka K. Sadakane N, Ozawa T. Arrhytbmogenic properties of disordered breathing during sleep in patients with cardiovascular disorders. Clin Cardiol 1987;10:771-782. 8. Shepard JW Jr. Hypertension, cardiac arrhythmias, myocardial infarction, and stroke in relation to obstructive sleep apnea. Clin Chest Med 1992;13:437-458. 9. Flemons WW, Remmers JE, Gillis AM. Sleep apnea and cardiac arrhythmias. Is there a relationship’? Am Rev Respir Dis 1993;148:618-621. 10. Rama PR, Satish CS. Sleep apnea and complete heart block. C/in Cardiol 1994;17:675-677. 11. Douglas NJ, Polo 0. Pathogenesis of obstructive sleep apnoea/hypopnoea syndrome. Lancer 1994;344:653-655. 12. Polo 0, Berthon-Jones M, Douglas NJ, Sullivan CE. Management of obstructive sleep apnoea/hypopnoea syndrome. Lmcet 1994;344:656-660. 13. Josephson ME. Clinical Cardiac Electrophysiology-Techniques and lnterpretations. 2nd ed. Philadelphia: Lea & Febiger;1993:71- 116.
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14. Strauss HC, Bigger JT, Saroff AL, Giardina EGV. Electrophysiologic evaluation of sinus node function in patients with sinus node dysfunction. Circulation 1976;53:763-776. 15. Narula OS, Shanto N, Vasquez M, Towne WD. Linhart JW. A new method for measurement of sinoatrial conduction time. Circulation 1978; 58:706-714. 16. Breithardt G, Seipel L, Loogen F. Sinus node recovery time and calculated sinoatrial conduction time in normal subjects and patients with sinus node dysfunction. Circulation 1977;56:43. 17. Becker H, Brandenburg U, Conradt R, Koehler U, Peter JH, Ploch T, van Wichert P. Influence of nCPAP therapy on bradycardic arrhythmias in sleep apnea. Pneumo/ogir 1993;47(suppl4):706-710. 18. Peiser J, Ovnat A, Uwyyed K, Lavie P. Charuzi I. Cardiac arrhythmias during sleep in morbidly obese sleep-apneic patients before and after gastric bypass surgery. Clin Cardiol 1985:8:519-521. 19. Engleman HM, Martin SE, Deary IJ, Douglas NJ. Effect of continuous positive airway pressure treatment on daytime function in sleep apnea/hypopnea syndrome. Lancer 1994;343:572-575. 20. Milstein S, Buetinkofer J, Lesser J. Goldenberg JF, Benditt DG, Gomick C, Reyes WI. Cardiac asystole: a manifestation of neurally mediated hypotension-bradycardia. J Am Coil Curdiol 1989;14: 1626-1632.
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