Phenylephrine-induced hypertension acutely decreases genioglossus EMG activity in awake humans ERIK GARPESTAD, ROBERT C. BASNER, JACK RINGLER, JENNIFER LILLY, RICHARD SCHWARTZSTEIN, STEVEN E. WEINBERGER, AND J. WOODROW WEISS Charles A. Dana Institute and Harvard-Thorndike Laboratory of Beth Israel Hospital, Beth Israel Hospital Sleep Disorders Center, and Departments of Medicine, Beth Israel Hospital and Harvard Medical School, Boston, Massachusetts 02115 GARPESTAD, ERIK, ROBERT C. BASNER, JACK RINGLER, JENNIFER LILLY, RICHARD SCHWARTZSTEIN, STEVEN E. WEINBERGER, AND J. WOODROW WEISS. PhenyZephrine-induced hypertension acutely decreases genioglossus EMG activity in awake humans. J. Appl. Physiol. 72(l): 110-115, 1992.-To investigate the relationship between systemic blood pressure (BP) and upper airway dilator muscle activity, we recorded genioglossuselectromyograms(EMGgg) during pharmacologically induced acute increasesin BP in five healthy humans (ages27-40 yr). EMGgg was measured with perorally placed fine-wire electrodes; phasic EMGgg was expressedas percentage of baselineactivity. Subjects were studied supine, awake, and breathing through a face mask with their mouths taped. End-tidal PCU~ wasmonitored with a massspectrometer; minute ventilation was measuredwith a pneumotachograph.Digital BP was monitored continuously with the Penaz method (Finapres, Ohmeda).Mean arterial pressure(MAP) at baseline was 89 t 6 (SD) mmHg. Phenylephrine wasinfused until MAP reached15-25 mmHg above baseline(107 t 7 mmHg). Recording was continued until MAP returned to baseline (90 t 7 mmHg). Elevated BP was associatedwith a significantly decreasedphasic EMGgg (P < 0.005). With return of MAP to baseline,phasic EMGgg returned toward normal (P < 0.01). Minute ventilation and end-tidal Pcoz did not differ among conditions. Genioglossusactivity appearsto be influenced by acute changesin systemicBP. We speculatethat BP elevations accompanying obstructive apneas during sleep may decrease upper airway tone and facilitate subsequentapneas.
muscle activity in awake humans, just as occurs in animals. Because obstructive apneas during sleep are associated with substantial BP elevations (27), such a relationship between BP and UA muscle activity in humans could have pathogenetic significance for sleep-related UA obstruction. METHODS
affect output of respiratory muscles, with increases in blood pressure producing decreases in diaphragm activity and total ventilation (20, 25, 28). However, the relationship between BP and upper airway (UA) muscle function is less well defined. In anesthetized dogs, activity of the hypoglossal nerve, which innervates the genioglossus, selectively decreases in response to sudden mechanically induced increases in systemic blood pressure (25). Similarly, in cats, electromyographic (EMG) activity of the posterior cricoarytenoid muscle, another UA dilator, declines with pharmacological elevations of arterial pressure (20). However, no similar data exist in hu-
Subjects. Eleven healthy nonsmoking males were studied (mean age 31 yr, range 27-40 yr). None was obese or had a history of sleep disorders or snoring. Informed consent was obtained from all subjects in accordance with the guidelines of the Committee on Clinical Investigations of Beth Israel Hospital. Subjects were included in the data analysis if they met two criteria: I) phasic genioglossus electromyographic activity (EMGgg) evident during unstimulated breathing and 2) an increase of 1525 mmHg in mean arterial pressure (MAP) duringphenylephrine infusion. Electromyography. To quantify UA dilator muscle activity, we recorded EMGgg using fine-wire electrodes. Four percent lidocaine was applied to the floor of the mouth as local anesthetic; excess was expectorated. Teflon-coated stainless steel fine-wire bipolar electrodes were inserted perorally with a 24.gauge needle into the genioglossus muscle, following the method of Sauerland and Harper (26). The wires were securely taped into place after removal of the needle and attached to copper spring clips soldered to the free ends of the amplifier lead-in wires (1). All signals were amplified (Tektronix AM 504), band-pass filtered between 10 and 1,000 Hz, rectified, and electronically integrated with a leak time constant of 150 ms (7). Respiratory measurements. Subjects were studied supine, awake, and breathing through a face mask (Bird) with their mouths taped to ensure nose breathing (2). The face mask was connected to a low-resistance oneway valve (Hans Rudolph). Inspiratory flow was measured with a pneumotachograph (Fleisch no. 2) positioned in the inspiratory side of the breathing circuit. The flow signal was integrated by a respiratory integrator (Hewlett-Packard model 8815a) for determination of inspired minute ventilation (VI). End-tidal PCO,
mans. On the basis of these observations, we hypothe-
(PET~~Jwas continuously monitored at the mask with a
sized that baroreceptor stimulation produced by increases in arterial pressure would selectively reduce UA
mass spectrometer (Medical Elmer, Pomona, CA).
obstructive sleep apnea; hemodynamics; baroreflex; upper airway CHANGESin systemic blood pressure (BP) are known to
110
Gas Analyzer 1100, Perkin-
0161-7567/92 $2.00 Copyright 0 1992 the American Physiological Society
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Resktance measurements. Supraglottic resistance (Rua) was measured by the method of Hudgel and colleagues (14). A 50-cm length of polyethylene tubing (PE200) was passed through the nares. The tip of the catheter was held in the esophagus by a 3-cm latex balloon. The catheter was occluded with nontoxic glue 20 cm from the esophageal end. Seven 18-gauge needle perforations were made in the catheter 1 cm above the occlusion. The catheter was inserted so that the perforations were positioned 17 cm from the nares, just posterior to the epiglottis (14). To prevent occlusion of the perforations by secretions, a O,2 l/s bias flow of air was maintained through the catheter by a Y-connector. The proximal end of the catheter was attached to one side of a differential pressure transducer (Validyne MP45-18, t5.0 cmH,O). The other side of the transducer was connected to the inside of the face mask with polyethylene tubing of identical length and diameter. After mechanical calibration with a rotameter, inspiratory flow through the UA was measured with a pneumotachograph (Fleisch no. 2). Rua was calculated at peak inspiratory flow (14). Systemic blood pressure. Arterial BP was measured continuously and noninvasively with a Finapres blood pressure monitor (Ohmeda). This instrument uses the volume clamp method originally devised by Penaz (see Ref. XI), with blood volume measured by digital photoplethysmography. MAP was calculated as one-third of the pulse pressure plus diastolic pressure. prOtocoZ. After giving their informed consent, subjects were seated, and EMG electrodes were inserted as described. Subjects were then placed supine, their mouths were taped to ensure nose breathing, and the face mask was secured. Absence of an air leak around the mask was confirmed by the use of a CO, probe. An intravenous catheter was inserted in a forearm vein, and an infusion of 5% dextrose in water (D5W, 25 ml/h) was begun. The Finapres monitor was applied, and digital BP was measured continuously. After the subject had had 5-7 min of quiet breathing, an infusion of phenylephrine (40 mg in 250 ml of D5W) was initiated at 0.5 pg. kg-l. min? The rate was increased at 1-min intervals to 1.0, 2.0, and 4.0 pg kg-l. min-l until MAP increased to between 15 and 25 mmHg above the baseline level. When the target BP was reached, the infusion was ended, but recording was continued until MAP returned to baseline. Infusion rates were controlled by a mechanical infusion pump (IVAC). To assess the possible confounding influence on EMGgg of intravenous phenylephrine-induced changes in Rua, we measured EMGgg in four of the subjects before and after 2 ml nebulized phenylephrine (0.5%) was applied to the nasal mucosa bilaterally. All subjects, after this regimen, noted a subjective decrease in nasal resistance similar to what they had felt with the intravenous infusion of phenylephrine. In two of these subjects, we also measured the effect of both nasal and intravenous phenylephrine on Rua. In these two subjects, Rua was measured on a second study day during phenylephrine infusion at doses similar to those on the first study day. On an additional day, the genioglossus electrodes were reinserted, and Rua (2 subjects) and EMGgg (4 subjects) were recorded before and after the topical phenylephrine was applied. During the studies of topical phenylephrine, l
GENIOGLOSSUS
111
EMG
BP was continuously recorded via the Finapres Monitor as it was during the intravenous infusion. Data analysis. All data were continuously displayed on a strip-chart recorder (Hewlett-Packard 7758A) for subsequent analysis. Integrated phasic EMGgg were quantified as the deflection from the beginning of inspiration to the peak of inspiratory activity, expressed in arbitrary units, and analyzed as percentage of the baseline value. Statistical analysis was performed on the Core Laboratory Computer Facilities of the Beth Israel Hospital. A blocked Newman-Keuls test (data normally distributed) was used to compare mean EMGgg, VI, and PET,,, under the different study conditions (32). Data from each subject were analyzed during three noncontinuous periods. The first period consisted of all continuous segments of breaths not obscured by artifact during the period of stable breathing immediately before the intravenous infusion of phenylephrine (baseline). Baseline thus ranged from 2 to 5 min per subject, depending on the amount of artifact. The second period included all breaths occurring while the MAP was between 15 and 25 mmHg above the baseline level (increased MAP). This period ranged from 1.3 to 3.5 min, depending on the length of time the MAP remained elevated. The third period consisted of all breaths not obscured by artifact in the first 4 min after the BP returned to baseline (return to baseline; range 1.3-3.3 min). The time until the MAP returned to baseline varied among subjects from 5 to 19 min after the phenylephrine infusion was discontinued. RESULTS
In five of the subjects we obtained clear phasic EMGgg activity. Unstimulated activity was not present in an additional four subjects; these subjects were therefore excluded from further study, generating no data. In one subject we could not achieve the targeted increase in BP, and another subject had excess salivation during phenylephrine infusion, so that swallowing artifact precluded accurate measurement of the EMG signal. These subjects also were excluded from further study, generating no data. For the group (Fig. 1, Table 1), mean values of EMGgg were decreased.during the period of increased MAP compared with baseline (from 100 to 53%). This change in EMGgg is significant (P < 0.005). With return of MAP to baseline level, the EMGgg signal returned toward normal in all subjects (from 53 to 86%). This rise in EMGgg from increased MAP to return to baseline is also significant (P < 0:Ol). There was no significant difference in ~~~~~~ or in VI among these three periods. Additionally, VI was analyzed in terms of respiratory rate (f) and tidal volume (VT); there was no significant difference in these variables among the three periods. Individual EMGgg data are displayed in Fig. 1, and group data are displayed in Table 1. A polygraph record of a representative subject is displayed in Fig. 2. In two subjects we measured Rua during the intravenous infusion of phenylephrine. From baseline to increased MAP, the Rua decreased by 1.93 cmH,O 1-l. s in the first subject (from 4.11 to 2.18 cmH,O 1-l s) and by l
l
l
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112
INDUCED
HYPERTENSION
DECREASES
n=5 0
1 BASELINE
I INCREASED MAP
I RETURN TO BASELINE
FIG. 1. Mean phasic inspiratory electromyographic activity of genioglossus (EMGgg) for each subject in arbitrary units during baseline recording before phenylephrine infusion (Baseline), with increased mean arterial pressure (Increased MAP) from phenylephrine infusion, and after phenylephrine infusion when MAP has returned to baseline levels (Return to baseline). All subjects display decreased EMGgg during increased MAP and increased EMGgg to baseline or near baseline levels during return-to-baseline period.
1.63 cmH,O 1-l. s in the second subject (from 3.47 to 1.84 cmH,O* 1-l. s). In these same subjects, Rua decreased after phenylephrine nasal spray by 2.75 cmH,O l 1-l. s in the first subject (from 4.36 to 1.61 cmH,O s) and by 0.95 cmH,O 1-l s in the second subject (from 1.76 to 0.81 cmH,O 1-l s). In the first subject, EMGgg increased after nasal phenylephrine to 143% of baseline; in the second subject, EMGgg increased after nasal phenylephrine to 162% of baseline. EMGgg was also measured in two other subjects before and after nasal phenylephrine; Rua was not measured in these two subjects. In these subjects the EMGgg decreased to 91% of baseline in one and increased to 124% of baseline in the other. MAP did not change by >lO mmHg in any of the subjects after nasal phenylephrine; similarly, PETITE did not vary by ~4 mmHg in any subject before and after nasal phenylephrine. VI did not vary by >0.4 l/min in two of the subjects and increased by 1.4 and 3.6 l/min, respectively, in the other two subjects after nasal phenylephrine. A polygraph record of a representative subject before and after nasal phenylephrine is displayed in Fig. 3. l
al-l
l
l
l
l
l
DISCUSSION
This study demonstrates a relationship between systemic BP and EMGgg in humans. In awake normal subjects, a pharmacologically induced increase in MAP was associated with a decrease in EMGgg, without a change in VI or PET,,,. These data suggest a differential response of UA and respiratory pumping muscles to changes in arterial pressure. There is considerable evidence that arterial pressure may influence the output of the respiratory system (13). Large boluses of intravenous epinephrine or norepinephrine have been demonstrated to cause dramatic reductions in VI; the most striking of these responses has been termed “epinephrine apnea” (16). Increases in arterial BP reduce ventilation, and decreases in arterial BP stim-
GENIOGLOSSUS
EMG
ulate ventilation (10). Heymans and Bouckaert (12) and Winder (31) were among the first to describe this interaction. Heymans and Bouckaert (12) showed that the respiratory response could be eliminated by denervation of the carotid sinus. Winder (31) showed that the effects of BP depended on a baroreflex mechanism rather than on altered blood flow only. In cats, Grunstein et al. (9) studied the acute respiratory response to bar loreceptor stimulation produced by transient inflation of a balloon placed in the descending aorta and demonstrated a decrease in VT, a prolongation of the duration of inspiration, and a decrease in f. Although the authors attributed the change in VT to baroreceptor stimulation, they concluded that the effect on f was from a vagally mediated Hering-Breuer reflex. Heistad et al. (10) used dogs to study how the ventilatory responses to chemoreceptor stimu lation are modulated by concomitant baroreceptor stimulation and showed that aortic occlusion decreased baseline VI. Trelease et al. (28) and Bishop (3) both demonstrated that baroreceptor stimulation reduced diaphragmatic EMG activity. The respiratory baroreflex is not as well documented in humans, although it is generally accepted (6, 11). Because EMGgg activity parallels ventilation in general, a decrease in ventilation resulting from BP elevation in our subjects could have been responsible for the primary finding. If ventilation fell as BP rose, the diminished EMGgg could not be ascribed to a direct effect on the UA. In fact, decreased ventilation of any cause would confound our results. For this reason J we monitored VI and PETITE, neither of which sh.owed a sign Scant change with experimental alterations of BP. Additionally, 01 was analyzed in terms of f and VT; again, there was no significant change in these parameters among the three periods. Because EMGgg fell without a change in other ventilatory parameters, our fin .dings suggest th .at there may be a qu .antitative difference between UA and respiratory pumping muscle responses to baroreceptor stimulation in humans, with relatively low levels of baroreceptor stimulation selectively decreasing UA muscle activity. Our findings of selective reduction in EMG activity of an UA dilator muscle relative to ventilatory activity with acute elevations in BP are consistent with previous work TABLE 1. Genioglossus and ventilator-y responses
to acute changes in MAP Increased
MAP
Baseline (89+6
EMGgg, %baseline VI, llmin f, breaths/min VT, liters PETS*, , Torr
mmHg)
100
6t2 13s 0.6kO.3 37t2
(107-t7
mmHg)
53t26 7t2 1344 0.6-t-0.3 36t2
Rehrn
to
Baseline (90-+7
mmHg)
86+16 6t3 13t4 0.5t0.3 37t2
Values are means t SD of 5 subjs. EMGgg, phasic inspiratory genioglossus electromyographic activity; VI, inspired minute ventilation; f, respiratory rate; VT, tidal volume; PETITE, end-tidal Pco~. Baseline, recording period before phenylephrine infusion; Increased MAP, recording during and just after phenylephrine infusion; Return to Baseline, recording after phenylephrine infusion, EMGgg is significantly decreased with increased MAP (P < 0.005); increase in EMGgg from increased MAP to return to baseline is also significant (P < 0.01).
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INDUCED
HYPERTENSION
DECREASES
113
EMG
INCREASED
BASELINE Blood Pressure
GENIOGLOSSUS
MAP
200-
“:I
EMwl
(Integrated)
EMGWI (Raw) 0
V ISec
H
FIG. 2. Polygraph record of a representative subject displaying systemic blood pressure (Blood pressure) in mmHg and raw and integrated EMGgg during baseline recording and with increased MAP. Inspiratory flow tracing (V) is displayed for reference. Increased MAP is associated with a decrease in EMGgg.
in animals. Salamone et al. (25) showed in anesthetized dogs that acute elevations in BP produced by balloon inflation in the aorta caused a greater inhibitory effect on the respiratory activity of the hypoglossal nerve than on the activity of the phrenic nerve. Marks and Harper (20) transiently elevated arterial pressure by intravenous infusions of phenylephrine in intact freely moving cats during sleep and wakefulness to determine arterial pressure effects on diaphragmatic and laryngeal abductor EMG activity. They concluded that pharmacological increases in BP differentially inhibited activity of the posterior cricoarytenoid muscle relative to diaphragm activity. Those findings and the data reported here indicate that acute BP elevation must be included in the list of stimuli
BASELINE
that confer differential reduction of upper vs. lower respiratory muscle activity. This differential reduction, previously demonstrated in response to hypercapnia (4), hypoxia (29), sedative drugs (19), alcohol (17), and sleep (26), is the basis for the hypothesis that UA collapse in obstructive sleep apnea (OSA) is a result of differential control of the UA and respiratory pumping muscles (22). Although Salamone et al. (25) observed a decrease in UA nerve activity with mechanically induced increases in arterial pressure, we, as well as Marks and Harper (20), used pharmacological methods to raise arterial pressure. Thus a possible explanation for the decrease in EMGgg in our subjects is an action of phenylephrine separate from its hypertensive effect. For example, changes in
NASAL PHENYLEPHRINE
EMGgg (Integrated)
FIG. 3. Polygraph record of a representative subject displaying integrated EMGgg and systemic blood pressure (BP), inspiratory flow, and pharyngeal pressure (Pph) tracings during baseline recording before nasal phenylephrine (Baseline) and after nasal phenylephrine (Nasal phenylephrine). Decreasedpharyngeal resistance with nasalphenylephrine is associated with an increase in EMGgg.
BP (mmHg)
lnspiratory Flow (L/S)
PPh kmH20)
10 . -
o -10I
-
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114
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DECREASES
Rua may alter UA muscle activity. Topical phenylephrine is marketed as a nasal decongestant. Therefore we felt it was important to assess the potential contribution of decreased Rua to the diminished genioglossus signal during increased MAP with systemic phenylephrine. For this reason, we measured Rua during the phenylephrine infusion in two of our subjects. Intravenous phenylephrine infusions were, in fact, associated with small decreases in Rua, -1.75 cmH,O 1-l. s in the two subjects studied. However, because nasal phenylephrine produced similar decreases in Rua without a decrease in EMGgg, we believe our findings are not likely attributable to any phenylephrine-induced mucosal constriction. We determined Rua at peak inspiratory flow as the most meaningful and consistent measure of dynamic airflow resistance, given the alinear pressure-flow relationship across the UA (14). We also determined Rua at an isoflow of 0.35 l/s to have another reference point within each breath. The changes in Rua calculated at isoflow were similar with intravenous and nasal phenylephrine. We cannot explain why the EMGgg signal increased in three of the four subjects after nasal phenylephrine; uncovering of nasal flow receptors, which may reflexly augment EMGgg, is one possible explanation (2). Alternately, increased VI may have contributed to the EMGgg changes observed during this part of the protocol. Although these findings suggest that EMGgg did not decrease as a consequence of decreased Rua, we have not ruled out other systemic effects of parenteral phenylephrine as potential contributors to the EMGgg response. This is an important consideration because at least one central a-agonist, cx-methyldopa, has been demonstrated to decrease UA EMG activity (18). However, a-methyldopa is an Lu,-agonist (24), whereas phenylephrine is an al-agonist (30). ar,-Agonists depress sympathetic activity (5), whereas al-agonists are sympathomimetic (30). In addition, phenylephrine would be expected to have minimal central nervous system effects in the doses used in this investigation (30). Interestingly, four of our five subjects volunteered that they felt %timulated” during the phenylephrine infusion. While this may have reflected an unanticipated central effect of phenylephrine, Fewell and Johnson (8) have presented evidence that hypertension induced in lambs by balloon inflation in the aorta can produce arousal from sleep. Those data suggest that baroreceptor stimulation without pharmacological manipulation causes excitation of the central nervous system, possibly accounting for the symptoms in our subjects. Whether the increased level of arousal was a consequence of baroreceptor stimulation or direct central action of phenylephrine, we would have expected that it would produce an increase in UA muscle activity, because UA activity appears to be influenced directly by activity in the reticular activating system (21). But in all trials, EMGgg was least when the subjective level of alertness was greatest. Therefore, although we believe that a peripheral action of increased BP rather than a direct central action of phenylephrine is more likely to explain our results, we must emphasize that our experimental protocol does not definitely distinguish between these two alternative explanations of our findings. The results of the present study suggest that a nonunil
GENIOGLOSSUS
EMG
form response of the respiratory muscles to baroreceptor stimulation exists in humans. Would such a hemodynamic-respiratory interaction have clinical implications with regard to patients with repetitive OSAs? In a previous study, we found that apnea termination in such patients is associated with brief transient elevation of BP (MAP commonly rises by 230 mmHg), which occurs 2-7 s after resumption of ventilation (23). BP and heart rate fall rapidly during the first few seconds of the next apnea, a response likely mediated by the cardiovascular baroreflex. Although apnea onset is also accompanied by other potential influences, including behavioral state change, the BP elevations that follow obstructive apneas could contribute to decreased UA tone that, in turn, might facilitate the ensuing apnea. The current study supports only speculation about such a sequence. We studied awake normal subjects and raised their BP over minutes; thus the timing of the stimulus and the influence of behavioral state could not be analyzed critically. Nevertheless, this study provides evidence of a reflex in humans connecting acute changes in BP with activity of an UA dilator muscle. This interaction, previously demonstrated in animal models, may prove to have a role in the pathogenesis of OSA. This study was supported by National Heart, Lung, and tute Training Grant HL-07633 and Pulmonary Specialized Research Grant HL-19170 and by a grant from the Jack Freeman Foundation.
Blood InstiCenter
of
and Pauline
This work was presented in part at the Annual Meeting of the American Thoracic
Society,
Boston,
MA,
May
1990.
Address for reprint requests: J. W. Weiss, Pulmonary Israel
Hospital,
Received
330 Brookline
4 October
Ave.,
1990; accepted
Boston, in final
MA form
Div., Beth
02215. 9 August
1991.
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C., S. L. KNUTH, R. C. KROL, AND D. BARTLETT, JR. The effect of diazepam on genioglossal muscle activity in normal human subjects. Am. Rev. Respir. Dis. 132: 216-219, 1985. 20. MARKS, J. D., AND R. M. HARPER. Differential inhibition of the diaphragm and posterior cricoarytenoid muscles induced by transient hypertension across sleep states in intact cats. Exp. Neural. 95: 730-742,
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115
ANCH. Pathogenesis of upper airway occlusion during sleep. J. Appl. Physiol. 44: 931-938, 1978. RINGLER, J., R. C. BASNER, R. SHANNON, R. SCHWARTZSTEIN, H. MANNING, S, E. WEINBERGER, AND J. W. WEISS. Hypoxemia alone does not explain blood pressure elevations after obstructive apneas. J. Appl. Physiol. 69: 2143-2148, 1990. RUDD, P., AND T. F. BLASCHKE. Antihypertensive agents and the drug therapy of hypertension.In: The Pharmacological Basis of Therapeutics, edited by A. G. Gilman, L. S. Goodman, T. W. Rall, and F. Murad. New York: Macmillan, 1985, p. 788-790. SALAMONE, J. A., K. P. STROHL, D. M. WEINER, J. MITRA, AND N. S. CHERNIACK. Cranial and phrenic nerve responses to changes in systemic blood pressure. J. Appl. Physiol. 55: 61-68, 1983. SAUERLAND, E. K., AND R. M. HARPER. The human tongue during sleep: electromyographic activity of the genioglossus muscle. Exp. Neural. 51: 160-170, 1976. TILKIAN, A. G., C. GUILLEMINAULT, J. S. SCHROEDER, K. L. LEHRMAN, F. B. SIMMONS, AND W. DEMENT. Hemodynamics in sleepinduced apnea. Ann. Intern. Med. 85: 714-719,1976. TRELEASE, R. B., G. C. SIECK, J. D. MARKS, AND R. M. HARPER. Respiratory inhibition induced by transient hypertension during sleep in unrestrained cats. Exp. Neural. 90: 173-186, 1985. WEINER, D., J. MITRA, J. SALAMONE, AND N. S. CHERNIACK. Effect of chemical stimuli on nerves supplying upper airway muscles. J. Appl. Physiol. 52: 530-536, 1982. WEINER, N. Norepinephrine, epinephrine, and the sympathomimetic amines. In: The Pharmacological Basis of Therapeutics, edited by A. G. Gilman, L. S. Goodman, T. W. Rail, and F. Murad. New York: Macmillan, 1985, p. 170-171. WINDER, C. V. Isolation of the carotid sinus pressoreceptive respiratory reflex. Am. J. Physiol. 122: 306-318, 1938. ZAR, J. H. Biostutistical Analysis. Englewood Cliffs, NJ: PrenticeHall, 1974.
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muscle activity in awake humans, just as occurs in animals. Because obstructive apneas during sleep are associated with substantial BP elevations (27), such a relationship between BP and UA muscle activity in humans could have pathogenetic significance for sleep-related UA obstruction. METHODS
affect output of respiratory muscles, with increases in blood pressure producing decreases in diaphragm activity and total ventilation (20, 25, 28). However, the relationship between BP and upper airway (UA) muscle function is less well defined. In anesthetized dogs, activity of the hypoglossal nerve, which innervates the genioglossus, selectively decreases in response to sudden mechanically induced increases in systemic blood pressure (25). Similarly, in cats, electromyographic (EMG) activity of the posterior cricoarytenoid muscle, another UA dilator, declines with pharmacological elevations of arterial pressure (20). However, no similar data exist in hu-
Subjects. Eleven healthy nonsmoking males were studied (mean age 31 yr, range 27-40 yr). None was obese or had a history of sleep disorders or snoring. Informed consent was obtained from all subjects in accordance with the guidelines of the Committee on Clinical Investigations of Beth Israel Hospital. Subjects were included in the data analysis if they met two criteria: I) phasic genioglossus electromyographic activity (EMGgg) evident during unstimulated breathing and 2) an increase of 1525 mmHg in mean arterial pressure (MAP) duringphenylephrine infusion. Electromyography. To quantify UA dilator muscle activity, we recorded EMGgg using fine-wire electrodes. Four percent lidocaine was applied to the floor of the mouth as local anesthetic; excess was expectorated. Teflon-coated stainless steel fine-wire bipolar electrodes were inserted perorally with a 24.gauge needle into the genioglossus muscle, following the method of Sauerland and Harper (26). The wires were securely taped into place after removal of the needle and attached to copper spring clips soldered to the free ends of the amplifier lead-in wires (1). All signals were amplified (Tektronix AM 504), band-pass filtered between 10 and 1,000 Hz, rectified, and electronically integrated with a leak time constant of 150 ms (7). Respiratory measurements. Subjects were studied supine, awake, and breathing through a face mask (Bird) with their mouths taped to ensure nose breathing (2). The face mask was connected to a low-resistance oneway valve (Hans Rudolph). Inspiratory flow was measured with a pneumotachograph (Fleisch no. 2) positioned in the inspiratory side of the breathing circuit. The flow signal was integrated by a respiratory integrator (Hewlett-Packard model 8815a) for determination of inspired minute ventilation (VI). End-tidal PCO,
mans. On the basis of these observations, we hypothe-
(PET~~Jwas continuously monitored at the mask with a
sized that baroreceptor stimulation produced by increases in arterial pressure would selectively reduce UA
mass spectrometer (Medical Elmer, Pomona, CA).
obstructive sleep apnea; hemodynamics; baroreflex; upper airway CHANGESin systemic blood pressure (BP) are known to
110
Gas Analyzer 1100, Perkin-
0161-7567/92 $2.00 Copyright 0 1992 the American Physiological Society
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INDUCED
HYPERTENSION
DECREASES
Resktance measurements. Supraglottic resistance (Rua) was measured by the method of Hudgel and colleagues (14). A 50-cm length of polyethylene tubing (PE200) was passed through the nares. The tip of the catheter was held in the esophagus by a 3-cm latex balloon. The catheter was occluded with nontoxic glue 20 cm from the esophageal end. Seven 18-gauge needle perforations were made in the catheter 1 cm above the occlusion. The catheter was inserted so that the perforations were positioned 17 cm from the nares, just posterior to the epiglottis (14). To prevent occlusion of the perforations by secretions, a O,2 l/s bias flow of air was maintained through the catheter by a Y-connector. The proximal end of the catheter was attached to one side of a differential pressure transducer (Validyne MP45-18, t5.0 cmH,O). The other side of the transducer was connected to the inside of the face mask with polyethylene tubing of identical length and diameter. After mechanical calibration with a rotameter, inspiratory flow through the UA was measured with a pneumotachograph (Fleisch no. 2). Rua was calculated at peak inspiratory flow (14). Systemic blood pressure. Arterial BP was measured continuously and noninvasively with a Finapres blood pressure monitor (Ohmeda). This instrument uses the volume clamp method originally devised by Penaz (see Ref. XI), with blood volume measured by digital photoplethysmography. MAP was calculated as one-third of the pulse pressure plus diastolic pressure. prOtocoZ. After giving their informed consent, subjects were seated, and EMG electrodes were inserted as described. Subjects were then placed supine, their mouths were taped to ensure nose breathing, and the face mask was secured. Absence of an air leak around the mask was confirmed by the use of a CO, probe. An intravenous catheter was inserted in a forearm vein, and an infusion of 5% dextrose in water (D5W, 25 ml/h) was begun. The Finapres monitor was applied, and digital BP was measured continuously. After the subject had had 5-7 min of quiet breathing, an infusion of phenylephrine (40 mg in 250 ml of D5W) was initiated at 0.5 pg. kg-l. min? The rate was increased at 1-min intervals to 1.0, 2.0, and 4.0 pg kg-l. min-l until MAP increased to between 15 and 25 mmHg above the baseline level. When the target BP was reached, the infusion was ended, but recording was continued until MAP returned to baseline. Infusion rates were controlled by a mechanical infusion pump (IVAC). To assess the possible confounding influence on EMGgg of intravenous phenylephrine-induced changes in Rua, we measured EMGgg in four of the subjects before and after 2 ml nebulized phenylephrine (0.5%) was applied to the nasal mucosa bilaterally. All subjects, after this regimen, noted a subjective decrease in nasal resistance similar to what they had felt with the intravenous infusion of phenylephrine. In two of these subjects, we also measured the effect of both nasal and intravenous phenylephrine on Rua. In these two subjects, Rua was measured on a second study day during phenylephrine infusion at doses similar to those on the first study day. On an additional day, the genioglossus electrodes were reinserted, and Rua (2 subjects) and EMGgg (4 subjects) were recorded before and after the topical phenylephrine was applied. During the studies of topical phenylephrine, l
GENIOGLOSSUS
111
EMG
BP was continuously recorded via the Finapres Monitor as it was during the intravenous infusion. Data analysis. All data were continuously displayed on a strip-chart recorder (Hewlett-Packard 7758A) for subsequent analysis. Integrated phasic EMGgg were quantified as the deflection from the beginning of inspiration to the peak of inspiratory activity, expressed in arbitrary units, and analyzed as percentage of the baseline value. Statistical analysis was performed on the Core Laboratory Computer Facilities of the Beth Israel Hospital. A blocked Newman-Keuls test (data normally distributed) was used to compare mean EMGgg, VI, and PET,,, under the different study conditions (32). Data from each subject were analyzed during three noncontinuous periods. The first period consisted of all continuous segments of breaths not obscured by artifact during the period of stable breathing immediately before the intravenous infusion of phenylephrine (baseline). Baseline thus ranged from 2 to 5 min per subject, depending on the amount of artifact. The second period included all breaths occurring while the MAP was between 15 and 25 mmHg above the baseline level (increased MAP). This period ranged from 1.3 to 3.5 min, depending on the length of time the MAP remained elevated. The third period consisted of all breaths not obscured by artifact in the first 4 min after the BP returned to baseline (return to baseline; range 1.3-3.3 min). The time until the MAP returned to baseline varied among subjects from 5 to 19 min after the phenylephrine infusion was discontinued. RESULTS
In five of the subjects we obtained clear phasic EMGgg activity. Unstimulated activity was not present in an additional four subjects; these subjects were therefore excluded from further study, generating no data. In one subject we could not achieve the targeted increase in BP, and another subject had excess salivation during phenylephrine infusion, so that swallowing artifact precluded accurate measurement of the EMG signal. These subjects also were excluded from further study, generating no data. For the group (Fig. 1, Table 1), mean values of EMGgg were decreased.during the period of increased MAP compared with baseline (from 100 to 53%). This change in EMGgg is significant (P < 0.005). With return of MAP to baseline level, the EMGgg signal returned toward normal in all subjects (from 53 to 86%). This rise in EMGgg from increased MAP to return to baseline is also significant (P < 0:Ol). There was no significant difference in ~~~~~~ or in VI among these three periods. Additionally, VI was analyzed in terms of respiratory rate (f) and tidal volume (VT); there was no significant difference in these variables among the three periods. Individual EMGgg data are displayed in Fig. 1, and group data are displayed in Table 1. A polygraph record of a representative subject is displayed in Fig. 2. In two subjects we measured Rua during the intravenous infusion of phenylephrine. From baseline to increased MAP, the Rua decreased by 1.93 cmH,O 1-l. s in the first subject (from 4.11 to 2.18 cmH,O 1-l s) and by l
l
l
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112
INDUCED
HYPERTENSION
DECREASES
n=5 0
1 BASELINE
I INCREASED MAP
I RETURN TO BASELINE
FIG. 1. Mean phasic inspiratory electromyographic activity of genioglossus (EMGgg) for each subject in arbitrary units during baseline recording before phenylephrine infusion (Baseline), with increased mean arterial pressure (Increased MAP) from phenylephrine infusion, and after phenylephrine infusion when MAP has returned to baseline levels (Return to baseline). All subjects display decreased EMGgg during increased MAP and increased EMGgg to baseline or near baseline levels during return-to-baseline period.
1.63 cmH,O 1-l. s in the second subject (from 3.47 to 1.84 cmH,O* 1-l. s). In these same subjects, Rua decreased after phenylephrine nasal spray by 2.75 cmH,O l 1-l. s in the first subject (from 4.36 to 1.61 cmH,O s) and by 0.95 cmH,O 1-l s in the second subject (from 1.76 to 0.81 cmH,O 1-l s). In the first subject, EMGgg increased after nasal phenylephrine to 143% of baseline; in the second subject, EMGgg increased after nasal phenylephrine to 162% of baseline. EMGgg was also measured in two other subjects before and after nasal phenylephrine; Rua was not measured in these two subjects. In these subjects the EMGgg decreased to 91% of baseline in one and increased to 124% of baseline in the other. MAP did not change by >lO mmHg in any of the subjects after nasal phenylephrine; similarly, PETITE did not vary by ~4 mmHg in any subject before and after nasal phenylephrine. VI did not vary by >0.4 l/min in two of the subjects and increased by 1.4 and 3.6 l/min, respectively, in the other two subjects after nasal phenylephrine. A polygraph record of a representative subject before and after nasal phenylephrine is displayed in Fig. 3. l
al-l
l
l
l
l
l
DISCUSSION
This study demonstrates a relationship between systemic BP and EMGgg in humans. In awake normal subjects, a pharmacologically induced increase in MAP was associated with a decrease in EMGgg, without a change in VI or PET,,,. These data suggest a differential response of UA and respiratory pumping muscles to changes in arterial pressure. There is considerable evidence that arterial pressure may influence the output of the respiratory system (13). Large boluses of intravenous epinephrine or norepinephrine have been demonstrated to cause dramatic reductions in VI; the most striking of these responses has been termed “epinephrine apnea” (16). Increases in arterial BP reduce ventilation, and decreases in arterial BP stim-
GENIOGLOSSUS
EMG
ulate ventilation (10). Heymans and Bouckaert (12) and Winder (31) were among the first to describe this interaction. Heymans and Bouckaert (12) showed that the respiratory response could be eliminated by denervation of the carotid sinus. Winder (31) showed that the effects of BP depended on a baroreflex mechanism rather than on altered blood flow only. In cats, Grunstein et al. (9) studied the acute respiratory response to bar loreceptor stimulation produced by transient inflation of a balloon placed in the descending aorta and demonstrated a decrease in VT, a prolongation of the duration of inspiration, and a decrease in f. Although the authors attributed the change in VT to baroreceptor stimulation, they concluded that the effect on f was from a vagally mediated Hering-Breuer reflex. Heistad et al. (10) used dogs to study how the ventilatory responses to chemoreceptor stimu lation are modulated by concomitant baroreceptor stimulation and showed that aortic occlusion decreased baseline VI. Trelease et al. (28) and Bishop (3) both demonstrated that baroreceptor stimulation reduced diaphragmatic EMG activity. The respiratory baroreflex is not as well documented in humans, although it is generally accepted (6, 11). Because EMGgg activity parallels ventilation in general, a decrease in ventilation resulting from BP elevation in our subjects could have been responsible for the primary finding. If ventilation fell as BP rose, the diminished EMGgg could not be ascribed to a direct effect on the UA. In fact, decreased ventilation of any cause would confound our results. For this reason J we monitored VI and PETITE, neither of which sh.owed a sign Scant change with experimental alterations of BP. Additionally, 01 was analyzed in terms of f and VT; again, there was no significant change in these parameters among the three periods. Because EMGgg fell without a change in other ventilatory parameters, our fin .dings suggest th .at there may be a qu .antitative difference between UA and respiratory pumping muscle responses to baroreceptor stimulation in humans, with relatively low levels of baroreceptor stimulation selectively decreasing UA muscle activity. Our findings of selective reduction in EMG activity of an UA dilator muscle relative to ventilatory activity with acute elevations in BP are consistent with previous work TABLE 1. Genioglossus and ventilator-y responses
to acute changes in MAP Increased
MAP
Baseline (89+6
EMGgg, %baseline VI, llmin f, breaths/min VT, liters PETS*, , Torr
mmHg)
100
6t2 13s 0.6kO.3 37t2
(107-t7
mmHg)
53t26 7t2 1344 0.6-t-0.3 36t2
Rehrn
to
Baseline (90-+7
mmHg)
86+16 6t3 13t4 0.5t0.3 37t2
Values are means t SD of 5 subjs. EMGgg, phasic inspiratory genioglossus electromyographic activity; VI, inspired minute ventilation; f, respiratory rate; VT, tidal volume; PETITE, end-tidal Pco~. Baseline, recording period before phenylephrine infusion; Increased MAP, recording during and just after phenylephrine infusion; Return to Baseline, recording after phenylephrine infusion, EMGgg is significantly decreased with increased MAP (P < 0.005); increase in EMGgg from increased MAP to return to baseline is also significant (P < 0.01).
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INDUCED
HYPERTENSION
DECREASES
113
EMG
INCREASED
BASELINE Blood Pressure
GENIOGLOSSUS
MAP
200-
“:I
EMwl
(Integrated)
EMGWI (Raw) 0
V ISec
H
FIG. 2. Polygraph record of a representative subject displaying systemic blood pressure (Blood pressure) in mmHg and raw and integrated EMGgg during baseline recording and with increased MAP. Inspiratory flow tracing (V) is displayed for reference. Increased MAP is associated with a decrease in EMGgg.
in animals. Salamone et al. (25) showed in anesthetized dogs that acute elevations in BP produced by balloon inflation in the aorta caused a greater inhibitory effect on the respiratory activity of the hypoglossal nerve than on the activity of the phrenic nerve. Marks and Harper (20) transiently elevated arterial pressure by intravenous infusions of phenylephrine in intact freely moving cats during sleep and wakefulness to determine arterial pressure effects on diaphragmatic and laryngeal abductor EMG activity. They concluded that pharmacological increases in BP differentially inhibited activity of the posterior cricoarytenoid muscle relative to diaphragm activity. Those findings and the data reported here indicate that acute BP elevation must be included in the list of stimuli
BASELINE
that confer differential reduction of upper vs. lower respiratory muscle activity. This differential reduction, previously demonstrated in response to hypercapnia (4), hypoxia (29), sedative drugs (19), alcohol (17), and sleep (26), is the basis for the hypothesis that UA collapse in obstructive sleep apnea (OSA) is a result of differential control of the UA and respiratory pumping muscles (22). Although Salamone et al. (25) observed a decrease in UA nerve activity with mechanically induced increases in arterial pressure, we, as well as Marks and Harper (20), used pharmacological methods to raise arterial pressure. Thus a possible explanation for the decrease in EMGgg in our subjects is an action of phenylephrine separate from its hypertensive effect. For example, changes in
NASAL PHENYLEPHRINE
EMGgg (Integrated)
FIG. 3. Polygraph record of a representative subject displaying integrated EMGgg and systemic blood pressure (BP), inspiratory flow, and pharyngeal pressure (Pph) tracings during baseline recording before nasal phenylephrine (Baseline) and after nasal phenylephrine (Nasal phenylephrine). Decreasedpharyngeal resistance with nasalphenylephrine is associated with an increase in EMGgg.
BP (mmHg)
lnspiratory Flow (L/S)
PPh kmH20)
10 . -
o -10I
-
t i 10 Set Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (161.023.084.010) on August 29, 2018. Copyright © 1992 American Physiological Society. All rights reserved.
114
INDUCED
HYPERTENSION
DECREASES
Rua may alter UA muscle activity. Topical phenylephrine is marketed as a nasal decongestant. Therefore we felt it was important to assess the potential contribution of decreased Rua to the diminished genioglossus signal during increased MAP with systemic phenylephrine. For this reason, we measured Rua during the phenylephrine infusion in two of our subjects. Intravenous phenylephrine infusions were, in fact, associated with small decreases in Rua, -1.75 cmH,O 1-l. s in the two subjects studied. However, because nasal phenylephrine produced similar decreases in Rua without a decrease in EMGgg, we believe our findings are not likely attributable to any phenylephrine-induced mucosal constriction. We determined Rua at peak inspiratory flow as the most meaningful and consistent measure of dynamic airflow resistance, given the alinear pressure-flow relationship across the UA (14). We also determined Rua at an isoflow of 0.35 l/s to have another reference point within each breath. The changes in Rua calculated at isoflow were similar with intravenous and nasal phenylephrine. We cannot explain why the EMGgg signal increased in three of the four subjects after nasal phenylephrine; uncovering of nasal flow receptors, which may reflexly augment EMGgg, is one possible explanation (2). Alternately, increased VI may have contributed to the EMGgg changes observed during this part of the protocol. Although these findings suggest that EMGgg did not decrease as a consequence of decreased Rua, we have not ruled out other systemic effects of parenteral phenylephrine as potential contributors to the EMGgg response. This is an important consideration because at least one central a-agonist, cx-methyldopa, has been demonstrated to decrease UA EMG activity (18). However, a-methyldopa is an Lu,-agonist (24), whereas phenylephrine is an al-agonist (30). ar,-Agonists depress sympathetic activity (5), whereas al-agonists are sympathomimetic (30). In addition, phenylephrine would be expected to have minimal central nervous system effects in the doses used in this investigation (30). Interestingly, four of our five subjects volunteered that they felt %timulated” during the phenylephrine infusion. While this may have reflected an unanticipated central effect of phenylephrine, Fewell and Johnson (8) have presented evidence that hypertension induced in lambs by balloon inflation in the aorta can produce arousal from sleep. Those data suggest that baroreceptor stimulation without pharmacological manipulation causes excitation of the central nervous system, possibly accounting for the symptoms in our subjects. Whether the increased level of arousal was a consequence of baroreceptor stimulation or direct central action of phenylephrine, we would have expected that it would produce an increase in UA muscle activity, because UA activity appears to be influenced directly by activity in the reticular activating system (21). But in all trials, EMGgg was least when the subjective level of alertness was greatest. Therefore, although we believe that a peripheral action of increased BP rather than a direct central action of phenylephrine is more likely to explain our results, we must emphasize that our experimental protocol does not definitely distinguish between these two alternative explanations of our findings. The results of the present study suggest that a nonunil
GENIOGLOSSUS
EMG
form response of the respiratory muscles to baroreceptor stimulation exists in humans. Would such a hemodynamic-respiratory interaction have clinical implications with regard to patients with repetitive OSAs? In a previous study, we found that apnea termination in such patients is associated with brief transient elevation of BP (MAP commonly rises by 230 mmHg), which occurs 2-7 s after resumption of ventilation (23). BP and heart rate fall rapidly during the first few seconds of the next apnea, a response likely mediated by the cardiovascular baroreflex. Although apnea onset is also accompanied by other potential influences, including behavioral state change, the BP elevations that follow obstructive apneas could contribute to decreased UA tone that, in turn, might facilitate the ensuing apnea. The current study supports only speculation about such a sequence. We studied awake normal subjects and raised their BP over minutes; thus the timing of the stimulus and the influence of behavioral state could not be analyzed critically. Nevertheless, this study provides evidence of a reflex in humans connecting acute changes in BP with activity of an UA dilator muscle. This interaction, previously demonstrated in animal models, may prove to have a role in the pathogenesis of OSA. This study was supported by National Heart, Lung, and tute Training Grant HL-07633 and Pulmonary Specialized Research Grant HL-19170 and by a grant from the Jack Freeman Foundation.
Blood InstiCenter
of
and Pauline
This work was presented in part at the Annual Meeting of the American Thoracic
Society,
Boston,
MA,
May
1990.
Address for reprint requests: J. W. Weiss, Pulmonary Israel
Hospital,
Received
330 Brookline
4 October
Ave.,
1990; accepted
Boston, in final
MA form
Div., Beth
02215. 9 August
1991.
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C., AND J. J. BOUC-KAERT. Sinus caroticus and respiratory reflexes. J. physiol. Lo&. 69: 254-266,193O. 13. HEYMANS, C., AND E. NEIL. Refkogenic Areas of the Cardiovascular System. Boston, MA: Little, Brown, 1958, p. 95-97. 14. HUDGEL, D. W., R. J. MARTIN, B. JOHNSON, AND P. HILL. Mechanics of the respiratory system and breathing pattern during sleep in normal humans. J. Appl. Physiol. 56: 133-137, 1984. 15. IMHOLZ, B. P. M., G. A. VAN MONTFRANS, J. J. SETTELS, G. M. A. VAN DER HOEVEN, J. M. KAREMAKER, AND W. WEILING. Continuous non-invasive blood pressure monitoring: reliability of fmapres device during the Valsalva manoeuvre. Cdrdiouosc. Res. 22: 39012. HEYMANS,
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C., S. L. KNUTH, R. C. KROL, AND D. BARTLETT, JR. The effect of diazepam on genioglossal muscle activity in normal human subjects. Am. Rev. Respir. Dis. 132: 216-219, 1985. 20. MARKS, J. D., AND R. M. HARPER. Differential inhibition of the diaphragm and posterior cricoarytenoid muscles induced by transient hypertension across sleep states in intact cats. Exp. Neural. 95: 730-742,
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GENIOGLOSSUS
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