Mechanisms of acute cardiovascular response to periodic apneas in sedated pigs.

This study was designed to evaluate the importance of sympathoadrenal activation in the acute cardiovascular response to apneas and the role of hypoxemia in this response. In addition, we evaluated the contribution of the vagus nerve to apnea responses after chemical sympathectomy. In six pigs preinstrumented with an electromagnetic flow probe and five nonpreinstrumented pigs, effects of periodic nonobstructive apneas were tested under the following six conditions: room air breathing, 100% O2 supplementation, both repeated after administration of hexamethonium (Hex), and both repeated again after bilateral vagotomy in addition to Hex. With room air apneas, during the apnea cycle, there were increases in mean arterial pressure (MAP; from baseline of 108 +/- 4 to 124 +/- 6 Torr, P < 0.01), plasma norepinephrine (from 681 +/- 99 to 1,825 +/- 578 pg/ml, P < 0.05), and epinephrine (from 191 +/- 67 to 1,245 +/- 685 pg/ml, P < 0.05) but decreases in cardiac output (CO; from 3.3 +/- 0.6 to 2.4 +/- 0.3 l/min, P < 0.01) and cervical sympathetic nerve activity. With O2 supplementation relative to baseline, apneas were associated with small increases in MAP (from 112 +/- 4 to 118 +/- 3 Torr, P < 0.01) and norepinephrine (from 675 +/- 97 to 861 +/- 170 pg/ml, P < 0.05). After Hex, apneas with room air were associated with small increases in MAP (from 103 +/- 6 to 109 +/- 6 Torr, P < 0.05) and epinephrine (from 136 +/- 45 to 666 +/- 467 pg/ml, P < 0.05) and decreases in CO (from 3.6 +/- 0.4 to 3.2 +/- 0. 5 l/min, P < 0.05). After Hex, apneas with O2 supplementation were associated with decreased MAP (from 107 +/- 5 to 100 +/- 5 Torr, P < 0.05) and no other changes. After vagotomy + Hex, with room air and O2 supplementation, apneas were associated with decreased MAP (from 98 +/- 6 to 76 +/- 7 and from 103 +/- 7 to 95 +/- 6 Torr, respectively, both P < 0.01) but increased CO [from 2.7 +/- 0.3 to 3. 2 +/- 0.4 l/min (P < 0.05) and from 2.4 +/- 0.2 to 2.7 +/- 0.2 l/min (P < 0.01), respectively]. We conclude that sympathoadrenal activation is the major pressor mechanism during apneas. Cervical sympathetic nerve activity does not reflect overall sympathoadrenal activity during apneas. Hypoxemia is an important but not the sole trigger factor for sympathoadrenal activation. There is an important vagally mediated reflex that contributes to the pressor response to apneas.     

Effects of vagotomy on cardiovascular response to periodic apneas in sedated pigs.

There are few studies investigating the influence of vagally mediated reflexes on the cardiovascular response to apneas. In 12 sedated preinstrumented pigs, we studied the effects of vagotomy during apneas, controlling for apnea periodicity and thoracic mechanical effects. Nonobstructive apneas were produced by paralyzing and mechanically ventilating the animals, then turning the ventilator off and on every 30 s. Before vagotomy, relative to baseline, apnea caused increased mean arterial pressure (MAP; +19 +/- 25%, P < 0.05), systemic vascular resistance (SVR; +33 +/- 16%, P < 0.0005), and heart rate (HR; +5 +/- 6%, P < 0.05) and decreased cardiac output (CO) and stroke volume (SV; -16 +/- 10% P < 0.001). After vagotomy, no significant change occurred in MAP, SVR, and SV during apneas, but CO and HR increased relative to baseline. HR was always greater ( approximately 14%, P < 0.01) during the interapneic interval compared with during apnea. We conclude that vagally mediated reflexes are important mediators of the apneic pressor response. HR increases after apnea termination are related, at least in part, to nonvagally mediated reflexes.     

Repetitive apneas reduce nonlinear dynamical complexity of the human cardiovascular control system.

We tested the hypothesis that intermittent apneas performed by awake subjects simulate obstructive sleep apnea (OSA) and change dynamic complexity of the cardiovascular control system by repetitive short time stimulation of arterial chemoreceptors. Correlation dimension (CD) and reccurent plot quantification calculated as ratio % determinism versus % recurrence (RDR) were used.as indices of chaotic dynamics. Thirty three normotensive subjects of mean age 21,58 +/- 4,1 performed 10 voluntary apneas 1 min. each separated by 1 min free breathing period. Systolic (SYS), diastolic (DIAS) arterial blood pressure was continuously recorded by finger volume clamp. Stroke volume (SV) was estimated by pulse pressure analysis. Cardiac output (CO) and total peripheral resistance (TPR) were calculated by Portapress system. Cardiac inter-beat interval (IBI) was measured from R-R intervals of ECG. Standard deviation (SD), an index of linear variability, was calculated in 1 min epoch. Dynamics of cardiovascular variables was computed in each subject during 20 min. rest (C), 20 min. of 10 apneas, 1 min each, separated by 1 min free breathing (A), and in 20 min. recovery free breathing (R). In A period CD of all circulatory variables was significantly reduced and RDR augmented. In 23 out of 33 subjects decreased nonlinear dynamics of TPR was carried over from A to R. In contrast, SD increased significantly in A. In conclusion, intermittent brief chemoreflex stimulations by repetitive apneas increase blood pressure and TPR and decrease chaotic behaviour and complexity of the cardiovascular autonomic control system, presumably by inhibition of some regulatory loops such as baroreflex, less vital for survival at oxygen deprivation. Reduced complexity could be implicated in the mechanism of arterial hypertension linked with OSA.     

Active glottal closure during central apneas limits oxygen desaturation in premature lambs.

Our laboratory previously reported that active glottal closure was present in 90% of spontaneous central apneas in premature lambs while maintaining a high-apneic lung volume (Renolleau S, Letourneau P, Niyonsenga T, and Praud JP. Am J Respir Crit Care Med 159: 1396-1404, 1999.) The present study aimed at testing whether this mechanism limits postapnea oxygen desaturation. Four premature lambs were instrumented for recording states of alertness, thyroarytenoid muscle and diaphragm electromyographic (EMG) activity, nasal airflow, lung volume changes, and pulse oximetry. One thousand four hundred fifty-two spontaneous central apneas (isolated or during periodic breathing) were analyzed in nonsedated lambs. Apneas, with high lung volume maintained by active glottal closure, were compared with apneas, with a tracheostomy opened at apnea onset. Oxygen desaturation slopes were lower when high-apneic lung volume was actively maintained during both wakefulness and quiet sleep. Furthermore, oxygen desaturation slopes were lower after isolated apneas with continuous thyroarytenoid EMG during wakefulness, compared with apneas with noncontinuous thyroarytenoid EMG (= glottis opened shortly after apnea onset). These results highlight the importance of maintaining high-alveolar oxygen stores during central apneas by active glottal closure to limit desaturation in newborns.     

Changes in cardiovascular function during the sleep onset period in young adults.

Blood pressure (BP) and heart rate (HR) are influenced by the sleep-wake cycle, with relatively abrupt falls occurring in association with sleep onset (SO). However, the pattern and rate of fall in BP and HR during SO and the processes that contribute to the fall in these variables have not been fully identified. Continuous BP and HR recordings were collected beginning 1 h before lights out (LO) until the end of the first non-rapid eye movement sleep period in 21 young, healthy participants maintained in a supine position. Five consecutive phases were defined: 1) the 30 min of wakefulness before LO; 2) LO to stage 1 sleep; 3) stage 1 to stage 2 sleep; 4) stage 2 sleep to the last microarousal before stable sleep; and 5) the first 30 min of undisturbed stable sleep. The data were analyzed on a beat-by-beat basis and reported as 2-min periods for phases 1 and 5 and 10% epochs for phases 2, 3, and 4 (as participants had variable time periods in these phases). The level of baroreflex (BR) activity was assessed by the sequence technique and an autoregressive multivariate model. Furthermore, during phases 3 and 4, the BP and HR responses to arousal from sleep were determined. There were substantial falls in BP and HR after LO before the initial onset of theta;-activity (phase 3) and again after the onset of stable sleep after the cessation of spontaneous arousals. During phases 3 and 4 when there were repeated arousals from sleep, the fall in both variables was retarded. Furthermore, both the rate and magnitude of the fall in BP were negatively associated with the number of arousals during phases 3 and 4. There was a small increase in the sensitivity of the BR and indirect evidence of a substantial fall in its set point.     

Systemic and myocardial hemodynamics during periodic obstructive apneas in sedated pigs

The effects of periodic obstructive apneas onsystemic and myocardial hemodynamics were studied in ninepreinstrumented sedated pigs under four conditions: breathing room air(RA), breathing 100% O₂,breathing RA after critical coronary stenosis (CS) of the left anteriordescending coronary artery, and breathing RA after autonomic blockadewith hexamethonium (Hex). Apneas with RA increased mean arterialpressure (MAP; from baseline 103.0 ± 3.5 to late apnea 123.6 ± 7.0 Torr, P < 0.001) and coronary blood flow (CBF; late apnea 193.9 ± 22.9% of baseline,P < 0.001) but decreased cardiacoutput (CO; from baseline 2.97 ± 0.15 to late apnea 2.39 ± 0.19 l/min, P < 0.001). Apneas withO₂ increased MAP (from baseline105.1 ± 4.6 to late apnea 110.7 ± 4.8 Torr, P < 0.001). Apneas with CS producedsimilar increases in MAP as apneas with RA but greater decreases in CO(from baseline 3.03 ± 0.19 to late apnea 2.1 ± 0.15 l/min,P < 0.001). In LAD-perfused myocardium, there was decreased segmental shortening (baseline 11.0 ± 1.5 to late apnea 7.6 ± 2.0%,P < 0.01) and regionalintramyocardial pH (baseline 7.05 ± 0.03 to late apnea 6.72 ± 0.11, P < 0.001) during apneas withCS but under no other conditions. Apneas with Hex increased to the sameextent as apneas with RA. Myocardial O₂ demand remained unchangedduring apnea relative to baseline. We conclude that obstructiveapnea-induced changes in left ventricular afterload and CO aresecondary to autonomic-mediated responses to hypoxemia. Increased CBFduring apneas is related to regional metabolic effects of hypoxia andnot to autonomic factors. In the presence of limited coronary flowreserve, decreased O₂ supply during apneas can lead to myocardial ischemia, which in turnadversely affects left ventricular function.

     

Diving response and arterial oxygen saturation during apnea and exercise in breath-hold divers.

This study addressed the effects of apnea in air and apnea with face immersion in cold water (10 degrees C) on the diving response and arterial oxygen saturation during dynamic exercise. Eight trained breath-hold divers performed steady-state exercise on a cycle ergometer at 100 W. During exercise, each subject performed 30-s apneas in air and 30-s apneas with face immersion. The heart rate and arterial oxygen saturation decreased and blood pressure increased during the apneas. Compared with apneas in air, apneas with face immersion augmented the heart rate reduction from 21 to 33% (P < 0.001) and the blood pressure increase from 34 to 42% (P < 0.05). The reduction in arterial oxygen saturation from eupneic control was 6.8% during apneas in air and 5.2% during apneas with face immersion (P < 0.05). The results indicate that augmentation of the diving response slows down the depletion of the lung oxygen store, possibly associated with a larger reduction in peripheral venous oxygen stores and increased anaerobiosis. This mechanism delays the fall in alveolar and arterial PO(2) and, thereby, the development of hypoxia in vital organs. Accordingly, we conclude that the human diving response has an oxygen-conserving effect during exercise.     

Expiratory threshold loading impairs cardiovascular function in health and chronic heart failure during submaximal exercise.

We determined the effects of augmented expiratory intrathoracic pressure (P(ITP)) production on cardiac output (Q(TOT)) and blood flow distribution in healthy dogs and dogs with chronic heart failure (CHF). From a control expiratory P(ITP) excursion of 7 +/- 2 cmH2O, the application of 5, 10, or 15 cmH2O expiratory threshold loads increased the expiratory P(ITP) excursion by 47 +/- 23, 67 +/- 32, and 118 +/- 18% (P < 0.05 for all). Stroke volume (SV) rapidly decreased (onset <10 s) with increases in the expiratory P(ITP) excursion (-2.1 +/- 0.5%, -2.4 +/- 0.9%, and -3.6 +/- 0.7%, P < 0.05), with slightly smaller reductions in Q(TOT) (0.8 +/- 0.6, 1.0 +/- 1.1, and 1.8 +/- 0.8%, P < 0.05) owing to small increases in heart rate. Both Q(TOT) and SV were restored to control levels when the inspiratory P(ITP) excursion was augmented by the addition of an inspiratory resistive load during 15 cmH2O expiratory threshold loading. The highest level of expiratory loading significantly reduced hindlimb blood flow by -5 +/- 2% owing to significant reductions in vascular conductance (-7 +/- 2%). After the induction of CHF by 6 wk of rapid cardiac pacing at 210 beats/min, the expiratory P(ITP) excursions during nonloaded breathing were not significantly changed (8 +/- 2 cmH2O), and the application of 5, 10, and 15 cmH2O expiratory threshold loads increased the expiratory P(ITP) excursion by 15 +/- 7, 23 +/- 7, and 31 +/- 7%, respectively (P < 0.05 for all). Both 10 and 15 cmH2O expiratory threshold loads significantly reduced SV (-3.5 +/- 0.7 and -4.2 +/- 0.7%, respectively) and Q(TOT) (-1.7 +/- 0.4 and -2.5 +/- 0.4%, P < 0.05) after the induction of CHF, with the reductions in SV predominantly occurring during inspiration. However, the augmentation of the inspiratory P(ITP) excursion now elicited further decreases in SV and Q(TOT). Only the highest level of expiratory loading significantly reduced hindlimb blood flow (-4 +/- 2%) as a result of significant reductions in vascular conductance (-5 +/- 2%). We conclude that increases in expiratory P(ITP) production-similar to those observed during severe expiratory flow limitation-reduce cardiac output and hindlimb blood flow during submaximal exercise in health and CHF.     

Changes in heart rate during breathing interrupted by recurrent apneas in humans

Heart rate varies with breathing patterns, especially in sleep apnea. To assess the effects on heart rate of recurrent apneas interrupting tidal breathing, we studied five normal awake male subjects. These subjects voluntarily changed their breathing pattern from regular tidal breathing to tidal breathing interrupted by breath holding at end expiration. This recurrent apneic breathing pattern did not change mean heart rate but increased its variance significantly. In addition, the variations in heart rate formed a cyclic pattern of oscillation with a mean cycle length identical to both arterial O2 saturation (SaO2) (R = 0.95; P less than 0.01) and ventilation (R = 0.92; P less than 0.01). Cyclic changes in either SaO2 or ventilation reproduced the oscillatory patterns of heart rate seen with tidal breathing interrupted by multiple apneas, but the amplitude of the variance in heart rate was smaller. Finally, preventing the cyclic declines in SaO2 with supplemental O2 did not significantly alter the heart rate changes seen in tidal breathing interrupted by apneas.     

Calcium metabolism and cardiovascular function after spaceflight.

To determine the influence of dietary calcium on spaceflight-induced alterations in calcium metabolism and blood pressure (BP), 9-wk-old spontaneously hypertensive rats, fed either high- (2%) or low-calcium (0.02%) diets, were flown on an 18-day shuttle flight. On landing, flight animals had increased ionized calcium (P < 0.001), elevated parathyroid hormone levels (P < 0.001), reduced calcitonin levels (P < 0.05), unchanged 1,25(OH)(2)D(3) levels, and elevated skull (P < 0.01) and reduced femur bone mineral density. Basal and thrombin-stimulated platelet free calcium (intracellular calcium concentration) were also reduced (P < 0.05). There was a tendency for indirect systolic BP to be reduced in conscious flight animals (P = 0.057). However, mean arterial pressure was elevated (P < 0.001) after anesthesia. Dietary calcium altered all aspects of calcium metabolism (P < 0.001), as well as BP (P < 0.001), but the only interaction with flight was a relatively greater increase in ionized calcium in flight animals fed low- compared with high-calcium diets (P < 0.05). The results indicate that 1) flight-induced disruptions of calcium metabolism are relatively impervious to dietary calcium in the short term, 2) increased ionized calcium did not normalize low-calcium-induced elevations of BP, and 3) parathyroid hormone was paradoxically increased in the high-calcium-fed flight animals after landing.     

Dehydration markedly impairs cardiovascular function in hyperthermic endurance athletes during exercise

González-Alonso, José, RicardoMora-Rodríguez, Paul R. Below, and Edward F. Coyle.Dehydration markedly impairs cardiovascular function inhyperthermic endurance athletes during exercise. J. Appl. Physiol. 82(4): 1229-1236, 1997.Weidentified the cardiovascular stress encountered by superimposingdehydration on hyperthermia during exercise in the heat and themechanisms contributing to the dehydration-mediated stroke volume (SV)reduction. Fifteen endurance-trained cyclists [maximalO₂ consumption(O_{2 max}) = 4.5 l/min] exercised in the heat for 100-120 min and either became dehydrated by 4% body weight or remained euhydrated by drinkingfluids. Measurements were made after they continued exercise at 71%O_{2 max} for 30 minwhile 1) euhydrated with anesophageal temperature (T_es) of38.1-38.3°C (control); 2)euhydrated and hyperthermic (39.3°C);3) dehydrated and hyperthermic withskin temperature (T_sk) of34°C; 4) dehydrated withT_es of 38.1°C and T_sk of 21°C; and5) condition4 followed by restored blood volume. Compared withcontrol, hyperthermia (1°C T_esincrease) and dehydration (4% body weight loss) each separatelylowered SV 7-8% (11 ± 3 ml/beat;P < 0.05) and increased heart ratesufficiently to prevent significant declines in cardiac output.However, when dehydration was superimposed on hyperthermia, thereductions in SV were significantly (P < 0.05) greater (26 ± 3 ml/beat), and cardiac output declined 13% (2.8 ± 0.3 l/min). Furthermore, mean arterialpressure declined 5 ± 2%, and systemic vascular resistanceincreased 10 ± 3% (both P < 0.05). When hyperthermia wasprevented, all of the decline in SV with dehydration was due to reducedblood volume (~200 ml). These results demonstrate that thesuperimposition of dehydration on hyperthermia during exercise in theheat causes an inability to maintain cardiac output and blood pressurethat makes the dehydrated athlete less able to cope with hyperthermia.

     

Cardiac output and muscle blood flow during rest-associated apneas of elephant seals

In order to evaluate hemodynamics and blood flow during rest-associated apnea in young elephant seals (Mirounga angustirostris), cardiac outputs (CO, thermodilution), heart rates (HR), and muscle blood flow (MBF, laser Doppler flowmetry) were measured. Mean apneic COs and HRs of three seals were 46% and 39% less than eupneic values, respectively (2.1+/-0.3 vs. 4.0+/-0.1 mL kg(-1) s(-1), and 54+/-6 vs. 89+/-14 beats min(-1)). The mean apneic stroke volume (SV) was not significantly different from the eupneic value (2.3+/-0.2 vs. 2.7+/-0.5 mL kg(-1)). Mean apneic MBF of three seals was 51% of the eupneic value. The decline in MBF during apnea was gradual, and variable in both rate and magnitude. In contrast to values previously documented in seals during forced submersions (FS), CO and SV during rest-associated apneas were maintained at levels characteristic of previously published values in similarly-sized terrestrial mammals at rest. Apneic COs of such magnitude and incomplete muscle ischemia during the apnea suggest that (1) most organs are not ischemic during rest-associated apneas, (2) the blood O(2) depletion rate is greater during rest-associated apneas than during FS, and (3) the blood O(2) store is not completely isolated from muscle during rest-associated apneas.     

Dynamics of respiratory drive and pressure during NREM sleep in patients with occlusive apneas

To study the dynamics of respiratory drive and pressure in patients with occlusive apneas, diaphragmatic electromyogram (EMGdi), esophageal pressure (Pes), and genioglossal electromyogram (EMGge) were monitored during nocturnal sleep in five patients. Both EMGs were analyzed as peak moving time average, and Pes was quantitated as the peak inspiratory change from base line. During the ventilatory phase both EMGs decreased proportionally. The decrease in Pes was less than the decrease observed in EMGdi, and Pes generated for a given EMGdi increased during the preapneic phase in spite of the proportional decrease in EMGdi and EMGge during this period. We conclude that negative inspiratory pressures which lead to the passive collapse of oropharyngeal walls are dependent on both respiratory and upper airway muscle activity and that occlusive apneas of non-rapid-eye-movement (NREM) sleep do occur in spite of proportional changes observed in the activity of both muscle groups. The preapneic increase in negative inspiratory pressures generated for a given respiratory muscle activity is most likely due to the decrease in upper airway muscle activity that is associated with an increase in oropharyngeal resistance.     

Effects of exhaustive submaximal exercise on cardiovascular function during sleep

The influence of an afternoon bout of exhaustive submaximal exercise on cardiovascular function and catecholamine excretion during sleep was examined in five female and four male subjects. Subjects walked on a treadmill for successive 50-min periods at 50, 60, and 70% maximal O2 consumption, separated by 10-min rest periods. Exercise terminated with volitional exhaustion. Following an adaptation night, electroencephalographic and impedance cardiographic measures were obtained during three successive nights of sleep, with exercise preceding night 3. Relative to the base-line night (night 2), exhaustive exercise resulted in a sustained elevation of heart rate and cardiac output throughout the entire night's sleep. The magnitude of these elevations was unaffected by sleep stage but decreased over the night. The typical pattern of circadian decline in cardiac output was unaltered. However, the decline in heart rate with sleep onset was greater on the exercise night. Changes in impedance dZ/dt and R-Z interval suggested an enhanced myocardial contractility during the first 3 h of sleep postexercise. Analysis of morning urine samples revealed that in seven of nine subjects norepinephrine excretion increased, epinephrine excretion decreased, and dopamine excretion was unchanged during sleep on the exercise night. It is suggested that these cardiac changes reflect a sustained increase in myocardial beta-receptor activity.