Cardiovascular changes associated with obstructive sleep apnea syndrome RICCARDO

STOOHS

AND

CHRISTIAN

GUILLEMINAULT

Sleep Disorders Clinic and Research Center, Stanford University School of Medicine, Stanford, California 94305 STOOHS,RICCARDO,AND CHRISTIANGUILLEMINAULT.Curdiovascular changes associated with obstructive sleep apnea syndrome. J. Appl. Physiol. 72(Z): 583~589,1992.-Five men free of lung or cardiovascular diseasesand with severe obstructive sleepapneaparticipated in a study on the impact of sleepstates on cardiovascular variables during sleepapneas.A total of 128 obstructive apneas[72 from stage 2 non-rapid-eye-movement (NREM) sleepand 56 from rapid-eye-movement (REM) sleep] were analyzed. Each apnea was comprised of an obstructive period (OP) followed by a hyperventilation period, which was normally associatedwith an arousal. Heart rate (HR), stroke volume (SV), cardiac output (CO) (determined with an electrical impedance system), radial artery blood pressures (BP), esophagealpressure nadir, and arterial 0, saturation during each OP and hyperventilation period were calculated for NREM and REM sleep.During stage2 NREM sleep,the lowest HR always occurred during the first third of the OP, and the highest wasalways seenduring the last third. In contrast, during REM sleepthe lowest HR wasalways noted during the last third of the OP. There was an inverse correlation when the percentage of change in HR over the percentage of change in SV during an OP was considered. The HR and SV changes during NREM sleepallowed maintenance of a near-stable CO during OPs. During REM sleep, absenceof a compensatory changein SV led to a significant drop in CO. Systolic, diastolic, and mean BP always increasedduring the studied OPs. Stepwise regression analysis indicated that HR variation during OPs was dependent on the initial HR at the beginning of the OP, the percentage of change in SV, the degreeof hypoxemia, and the age of the subject (a minor factor). SV variation was dependenton the peak esophagealpressurenadir, the SV measuredat the beginning of the OP, the percentage of HR change during the OP, and the age of the subject. Despite a trend toward slight decreaseof CO during NREM sleep and toward significant decreasein CO during REM sleep,the increase in BP indicates an increase in total peripheral resistance during the monitored OPs. heart rate; stroke volume; cardiac output; blood pressure;total peripheral resistance;sleepstates

OBSTRUCTIVESLEEP APNEA (OSA)syndromeischarac-

terized polygraphically by the recurrent cessation of airflow during sleep, which induces hypoxemia. Several studies, mainly conducted during wakefulness, have investigated the influence of lack of air exchange on the cardiac function of humans (6, 7, 9, 12, 16). It has been reported that hypoxemia leads to cardioacceleration in humans, even when respiratory rate and tidal breathing are controlled and when a steady state is maintained (12,

16). However, sleep investigations

have produced different findings. Zwillich et al. (19) stated that “obstructive sleep apnea (OSA) leads to bradycardia i.n almost all apneas. ” In addition, investigations have found th .at left ventricular stroke volume (LVSV) decreases during OSA in association with the ventricular interdependence phenomenon, which is influenced by increased systemic venous return during obstructed breathing (15) and by abrupt increase in pulmonary vascular resistance. Both bradycardia and reduction in LVSV can impair hemodynamic functions during sleep. To further investigate the cardiovascular changes associated with obstructed breathing during sleep and, specifically, to examine the different effects of different (NREM) vs. sleep states [non-rapid-eye-movement rapid-eye-movement (REM)], we investigated five subjects who h ad been diagno lsed wi .th OSA syndrome during sleep. We evaluated the roles of both sleep states on heart rate (HR) change during an obstructive apnea, and we also evaluated the LVSV and cardiac output (CO) changes associated with a specific HR variation. Our findings indicate that HR response to an OSA will not necessarily be bradycardia, as has often been suggested. HR may increase or decrease during an OSA, and stroke volume (SV) may not change sufficiently for maintenance of stable CO. METHODS Subjects

Five men with a mean age of 46 t 15.3 yr and a mean body mass index (BMI) of 28.0 t 3.1 kg/m2 participated in the study. All signed informed consents were approved by the Stanford University Committee on Protection of Human Subjects in Medical Research. Each subject presented clinical symptoms of OSA syndrome, including daytime somnolence. They had a mean respiratory disturbance index, or number of disturbances per hour of sleep, of 76.9 t 4.5. Although presenting with a moderately severe to severe syndrome, none of the subjec ts was morbidly obese, smoked, had lung disease, or had a cardiovascular pathology, as determined by clinical histories and pulmonary function tests. None took medication on a chronic basis. Recordings and Monitored Variables

All studies were conducted in the same soundproofed sleep laboratory room. Subjects lay supine with the head

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584

CARDIOVASCULAR

VARIABLES

and/or neck at an 8-loo angle. An orthopedic bed provided controlled elevation of the head to prevent position changes during the total data collection period. The following variables were monitored: electroencephalogram (C,/A,-&/A, - 0,/O, from the lo-20 international electrode placement system), chin electromyogram, and electrooculogram to determine states of alertness. Respiratory movements were monitored with uncalibrated abdominal and thoracic respiratory inductive plethysmography. Airflow was monitored by oronasal thermistors, and arterial oxygen saturation (Sa,,) was monitored continuously with pulse oximetry (Ohmeda Biox III). Esophageal pressure (Pes) was measured with an esophageal balloon; the technique described by Baydur et al. (4) was used to place and calibrate the balloon. The cardiac variables, HR, SV, and CO, were monitored beat by beat with the use of a previously validated noninvasive electrical impedance method (BoMed NCCOM3, Irvine, CA), which has reliably monitored changes in LVSV in different populations, including OSA syndrome patients without cardiac lesions (a population similar to our subjects) (2,5,8,10,13,X3). Systolic and diastolic pressures, mean blood pressure (BP), and pulse pressure (PP) were monitored with invasive arterial BP recordings. The radial artery of the nondominant arm was cannulated with a Microseld Seldinger catheter from INTRA (Saarbruecken, Germany), which measured 110 X 1.0 mm. Variables were recorded simultaneously on a Grass model 7B polygraph at a 10 mm/s paper speed and on an IBM personal computer. Data Collection and Analysis

We systematically eliminated hypopneas (i.e., persistence of some airflow) from the analysis and analyzed only apneas with complete airway occlusion (i.e., no airflow). We divided each abnormal breathing event into two segments: the obstructive period (OP) and the hyperventilation period (HP), which is observed at the resumption of air exchange. We determined these segments with the data from all the polygraphic channels, both those monitoring respiration and those monitoring arousal, to pinpoint as accurately as possible the start of ventilation. We performed independent analyses on each segment, with more extensive analyses on the OPs. As some OPs were associated with a decrease in HR, whereas others were associated with an increase in HR, we analyzed HR changes for each subject. Also, because some subjects presented both HR increases and HR decreases in different OPs, we performed intrasubject analyses of HR changes patient per patient. In our patient population, all OPs with HR increase (called OP type A) were seen during NREM sleep, whereas all OPs with HR decrease (called OP type B) were noted during REM sleep. We analyzed a total of 128 randomly selected OPs (72 from NREM sleep) and the HR changes occurring during each of them. HR was found with a modified V, lead, and each RR interval was identified. These 128 OPs came from four different NREM and three different REM periods per patient. We determined the lowest HR (HRL) and the highest (peak) HR (HRH) associated

AND

SLEEP

APNEA

with each apnea with the use of a moving average of three heartbeats. Once the HRL and HRH during the OP had been identified, the times at which the slowest and fastest RRs were noted were calculated as percentages of the total OP time. The slopes of the change of HR, SV, CO, BP, PP, Pes nadir, and Sao, during an OP were determined with trend analysis, i.e., regression analysis over time (17). Mean values and SD of HR, SV, CO, BP, PP, Pes nadir (obtained by measuring the changes in Pes with each respiratory event), and Sa,, during each OP and HP were calculated. One-way analysis of variance was performed to determine the significance of the changes, and multiple regression analysis was performed to determine the dependence between variables. We used linear regression over time (trend analysis) to determine the changes in the above variables during each OP and to determine the slopes of the changes over time. Sleep/ wake was scored by the use of international criteria (l4), and arousal at the end of the OP was determined by 2-s epoch analysis using electroencephalogram, electrooculogram, and electromyogram leads. Additional Test: Valsalva (VAL) Maneuver During Wakefulness

Four subjects (age = 49.5 t 15.2 yr; BMI = 27.6 t 3.4 kg/m2) performed VAL maneuvers while awake in bed at a 40’ angle, following the technique described by Bannister (3, 11). The maneuver was performed by use of a mouthpiece connected to a modified sphingometer. Subjects were asked to maintain a pressure of +40 cmH,O. Subjects performed the maneuver with all the monitoring equipment fitted to them, and all maneuvers were performed at about the same time of day (2100 h). RESULTS

NREM

Sleep

The mean duration of the investigated OPs (n = 72) was 26.5 t 11.6 (SD) s. The mean peak Pes nadir of the OPs was -24.2 t 14.8 cmH,O. The extreme ranges of Pes nadir (all apneas combined), when the beginning of an OP and peak Pes during an OP were calculated, were -4 and -92 cmH20, i.e., there was a differential of 88 cmH,O. Overall, Pes nadir became a mean of 3.29fold (-28.5 cmH,O) more negative during the course of the OPs. Sa,, decreased by a mean of 9.2 t 4.6% until the end of the OPs. The HRL always occurred during the first third of the OP (after a mean of 23.3% of the total OP time), whereas HRH was always seen in the last third. Figure 1 (top) shows the HR evolution during a representative OP, i.e., the apneic part of the NREM sleep abnormal breathing event. Overall, despite the initial HR decrease, HR increased 10.2 t 9.1% from the beginning to the end of the OP, whereas SV decreased 10.3 t 10.5%. CO did not change significantly. The mean BP, however, increased 19.5 t lO.4%, which we interpret to be a reflection of an increase in total peripheral resistance (TPR) during the OP. PP increased 4.8%.

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CARDIOVASCULAR NREM

APNEA

(obstructed

period

VARIABLES

only)

AND SLEEP

TABLE

585

APNEA

1. Average HR values for each OP Variable

- 1

CARDIAC

Urnin

OUTPUT

HR Min Max Delta Mean HR During first third of OF During last third of OP

STROKE VOLUME

m ml

NREM

REM

NS