Determinants of poststimulus potentiation in humans during NREM sleep M. SAFWAN BADR, JAMES B. SKATRUD, AND JEROME A. DEMPSEY (With the Technical Assistance of James D. Lookabaugh and Dominic S. Puleo) Medical Service, William S. Middleton Memorial Veterans Hospital, and John Runkin Laboratory of Preventive Medicine, Departments of Medicine and Preventive Medicine, University of Wisconsin, Madison, Wisconsin 53702 BADR, M. SAFWAN,JAMES B. SKATRUD, AND JEROME A. DEMPSEY. Determinants of poststimulus potentiatim in humans during NREM sleep. J. Appl. Physiol. 73(5): 1958-1971, 1992.-To test whether active hyperventilation activates the

“afterdischarge” mechanism during non-rapid-eye-movement (NREM) sleep, we investigated the effect of abrupt termination of active hypoxia-induced hyperventilation in normal subjects during NREM sleep. Hypoxia was induced for 15 s, 30 s, 1 min, and 5 min. The last two durations were studied under both isocapnic and hypocapnic conditions. Hypoxia was abruptly terminated with 100% inspiratory 0, fraction. Several room airto-hyperoxia transitions were performed to establish a control period for hyperoxia after hypoxia transitions. Transient hyperoxia alone was associated with decreased expired ventilation (iTE) to 90 t 7% of room air. Hyperoxic termination of 1 min of isocapnic hypoxia [end-tidal PO, (PET* ) 63 t 3 Torr] was associated with TE persistently above the hyperoxic control for four to six breaths. In contrast, termination of 30 s or 1 min of hypocapnic hypoxia [PET,, 49 t 3 and 48 t 2 Torr, respectively; end-tidal PCO, (PETITE) decreased by 2.5 or 3.8 Torr, respectively] resulted in hypoventilation for 45 s and prolongation of expiratory duration (TE) for 18 s. Termination of 5 min of isocapnic hypoxia (PETE, 63 t 3 Torr) wa; associated with central apnea (longest TE 200% of room air); VE remained below the hyperoxic control for 49 s. Termination of 5 min of hypocapnic hypoxia (PET,~ 64 t 4 Torr, PETIT, decreased by 2.6 Torr) was also associated with central apnea (longest TE 500% of room air). VE remained below the hyperoxic control for 88 s. We conclude that I) poststimulus hyperpnea occurs in NREM sleep as long as hypoxia is brief and arterial PCO~ is maintained, suggesting the activation of the afterdischarge mechanism; 2) transient hypocapnia overrides the potentiating effects of afterdischarge, resulting in hypoventilation; and 3) sustained hypoxia abolishes the potentiating effects of afterdischarge, resulting in central apnea. These data suggest that the inhibitory effects of sustained hypoxia and hypocapnia may interact to cause periodic breathing. afterdischarge mechanism; hypoxia; central apnea; periodic breathing; hypoventilation

DURING non-rapid-eye-movement (NREM) sleep, termination of passive hyperventilation is followed by central apnea if arterial PCO~ (Pa,,,) is lowered below a highly sensitive, hypocapnic apneic threshold (9,38). However, evidence in the literature would question the relevance of such a finding to breathing instability because it has been demonstrated after passive rather than active hyperventilation (14,44). The difference in response between pas-

sive and active hyperventilation has been attributed to the activation of a central nervous system phenomenon referred to as poststimulus potentiation or “afterdischarge” (14-19), which maintains ventilation after cessation of a stimulus despite hypocapnic inhibition. Several studies have shown that voluntary hyperventilation (41) and active, hypoxically induced hyperventilation during wakefulness (21) are not followed by ventilatory inhibition, presumably because of the development of afterdischarge. The afterdischarge phenomenon has not yet been demonstrated in sleeping humans. The first purpose of this study was to determine whether afterdischarge could be activated in humans during NREM sleep and whether it could stabilize ventilation in the presence of hypocapnia. The use of hypoxia to induce hyperventilation adds a confounding variable related to the possibility of hypoxic brain depression (34). Several studies in animals (4, 31, 43) and humans (12, 13, 23) have shown that sustained hypoxia may be associated with hypoxic ventilatory depression, which may attenuate or abolish afterdischarge. Thus the second purpose of this study was to determine whether the occurrence of posthyperventilation apnea is affected by the duration of the preceding hypoxia. METHODS

Subject Selection Twelve healthy nonsnoring subjects were studied. Four subjects were studied during both wakefulness and NREM sleep, and eight were studied during NREM sleep only. Five additional subjects were studied during wakefulness only, with a protocol involving simultaneous measurement of arterial blood gases and end-tidal gases. All subjects were free of daytime hypersomnolence and any sleep-related breathing disorder. The study protocol was approved by the Human Subjects Committee in our institution. Subjects were instructed to restrict their sleep to a total sleep time of 4-6 h the night before the study. The study was done during regular sleep hours. Breathing

Circuit

The subject was connected to the circuit with an airtight silicone rubber mask strapped and glued to the face

to prevent leaks. The mask was attached to a unidirec-

1958 Downloaded from www.physiology.org/journal/jappl at Univ of Cincinnati (129.137.005.042) on February 12, 2019.

HYPOXIA

AND AFTERDISCHARGE

tional low-resistance valve with a heated pneumotachometer on the inspiratory line. The combined dead space of the mask and valve was -125 ml. The valve allowed inspiration either from ambient air or from one of three tubes connected to large gas bags containing N,, 8% inspiratory 0, fraction (FI,J, or 100% FI,,. To maintain isocapnia, three similar bags with supplemental CO, were attached in parallel with the non-CO,-containing bags by manual two-way valves. Two proximal attachments allowed variable bleed of O2 or CO, in the circuit. Protocol Brief isocapnic hypoxia. This trial was done to investigate whether afterdischarge is activated by brief hypoxia. Ten subjects were studied (54 trials). Hypoxia was rapidly induced by the subject’s breathing several breaths of N, (range 4-7) supplemented with CO, [inspiratory CO, fraction (FI,,J 2.0~2.5%], followed by 8% FI,, supplemented with CO, (FI,,, 2.5-3.5%). The total duration of hypoxia did not exceed 1 min. Care was taken to ensure isocapnia; trials that were not isocapnic were excluded from this analysis. Hypoxia was abruptly terminated with 100% F1ep. We assumed that the first two hyperoxic breaths were likely to be hypoxic at the chemoreceptor level because ventilation remained at the room-air level during hyperoxic transitions from room air (see below). This is also supported by previous data showing a lungto-chemoreceptor circulation time of -6 s (25, 28). Therefore isocapnia was maintained for the first two hyperoxic breaths, followed by hyperoxia without supplemental CO,. Brief hypocapnic hypoxia. This trial was done to determine whether afterdischarge could be manifested in the presence of hypocapnic inhibition. Nine subjects were studied during NREM sleep; four of them were studied during wakefulness as well. Brief hypoxia was abruptly induced with six breaths of N,, followed by six breaths of 8% Frq:!. The number of breaths was empirically adjusted to achreve 0, saturation of 80%. Hypoxia was abruptly terminated with 100% Froz. Three durations of hypoxia were chosen: 1 min (67 trials), 30 s (53 trials), and 15 s (28 trials). Brief hypocapnic hypoxia trials were performed during both wakefulness and NREM sleep. During awake trials, subjects lay supine watching a television show and were instructed to keep their eyes open at all times. An opaque screen was placed between the subjects and the experimental apparatus, preventing them from anticipating an intervention. Sustained isocapnic hypoxia. This trial was performed to determine the effect of sustained hypoxia on the development of afterdischarge. Four subjects were studied. Hypoxia was induced and maintained for 5 min (range 4-7 min) as in the sustained hypocapnic hypoxia trials. A variable bleed valve allowed precise control of end-tidal PCO, and PO, (PETIT, and PET*,)to maintain isocapnic hypoxia. Hypoxia was abruptly terminated with 100% FI,,. Isocapnia was maintained for the first two breaths as described above. A total of 20 trials was performed. Sustained hypocuptic hypoxia. This was performed to determine the combined effect of sustained hypoxia and hypocapnia on afterdischarge and the development of posthyperventilation apnea. Four subjects were studied

1959

with this protocol. Hypoxia was induced and maintained by the subject’s breathing a low-oxygen mixture (FI,,, 12%) for 5 min (range 4-7 min). Variable-bleed 0, was utilized to maintain 0, saturation close to 80%. Hypoxia was terminated with 100% Fr,. A total of 15 trials was performed. Room air to hyperoxia. To isolate the effects of hyperoxia alone, we performed several trials of room air-to-hyperoxia transitions in nine subjects. A total of 31 trials was performed. All these subjects underwent brief isocapnic and hypocapnic hypoxia trials, and four underwent sustained hypoxic trials. Awake hypoxia with PaCo, and PETITE measurements. To confirm isocapnic and hypocapnic conditions during our study, we measured Pace, and PETIT, in five subjects. Isocapnic and hypocapnic hypoxia were induced during supine wakefulness. An arterial line was placed in the right radial artery and continuously flushed with heparinized saline. During isocapnic trials, isocapnic hypoxia was accomplished rapidly as in the brief isocapnic protocol and maintained for 5 min. During hypocapnic hypoxia protocol, hypoxia was rapidly induced and maintained without CO, supplementation for 5 min. 0, saturation was maintained at 80% during both types of hypoxia. Five arterial blood gas samples were drawn during the control room-air period. During hypoxia, five arterial blood gas samples were drawn slowly at 1-min intervals. Arterial blood gas samples were analyzed using a radiometer frequently calibrated with tonometered blood of known arterial PO, and Pa,,,. Repeated measurements were performed on every sample. Measurements Ventilation was measured by inductance plethysmography (Respitrace, Ambulatory Monitoring) (n = 5) or from integrated flow signal (n = 5). The inductance plethysmography output was calibrated by the isovolume technique of Konno and Mead (26) in conjunction with a rolling seal spirometer (model 800, Ohio). Volumes measured with the plethysmograph showed close correlation with volumes measured from the integrated flow signal (R = 0.96-0.98). Respiratory cycle timing was measured using the inductance plethysmograph signal. Inspiratory muscle electromyogram (EMG,,,) was recorded using two bipolar electrodes (3M Red Dot) placed 2-4 cm above the right costal margin in the anterior axillary line. One pair was positioned at the percussed dullness at total lung capacity, and another was positioned at the point of percussed dullness at functional residual capacity. The pair with no expiratory contamination was chosen for analysis. Raw EMG signals were amplified, band-pass filtered from 5 to 10,000 Hz (Grass model 7-D polygraph), full wave rectified, and integrated with a Paynter filter with a time constant of 100 ms, We used the method of Ledlie et al. (29) to quantitate EMG; the area beneath the moving time average curve was obtained by computerized integration, divided by the duration of muscle activity, and expressed in arbitrary units. This quantity, the mean amplitude, was used to quantitate muscle activity in a way independent of changes in duration or shape of integrated activity. PETIT, was measured breath by breath (model LB-2, Beckman, Fullerton, CA).

Downloaded from www.physiology.org/journal/jappl at Univ of Cincinnati (129.137.005.042) on February 12, 2019.

1960

HYPOXIA

AND AFTERDISCHARGE

PET,,was measured breath by breath with an 0, analyzer (OM 11, Beckman). Electroencephalogram, chin EMG, and electrooculogram were recorded during both awake and NREM sleep trials (Grass model 7-D). Sleep stage was analyzed according to the criteria of Rechtschaffen and Kales (37). Trials were included in the analysis if sleep state remained constant throughout the trial. Data Analysis

The control room-air period was determined by the mean of the 10 breaths immediately preceding hypoxia. This was compared with the mean of the last 5 hypoxic breaths in the brief hypoxia trials and with the last 10 hypoxic breaths in the sustained hypoxia trials. A mean of all trials was obtained for room air and hypoxia under each study condition. A paired t test was utilized to compare room air with hypoxia for every study condition. To analyze the effect of abrupt hyperoxic termination of hypoxia, we made a comparison breath by breath with hyperoxia after room air, which allowed us to eliminate the effect of hyperoxia alone on ventilation. Hyperoxic breaths 3-10 were determined for every study condition, and a mean of all similar trials was obtained for every subject. Comparison was made to breaths 3-10 of hyperoxia after room air, which were used as control values, on a breath-by-breath basis. Hyperoxic breaths 1 and 2 were excluded from the analysis because they were likely not to be true hyperoxic breaths at the chemoreceptor level, given a lung-chemoreceptor circulation time of ~6 s (25, 28). Our data in the transition from room air to hyperoxia confirm this assumption (see below). Two-way analysis of variance was used to compare, breath by breath, the hyperoxic period after each condition with the hyperoxic period after room air and to compare breaths 3-10 under each condition. RESULTS

kkdity of PETcoz measurements. The results of simultaneous Pacoz vs.PETIT,measurements during hypoxia are shown in Fig. 1. During room-air breathing, PacOg was slightly higher than PETIT,in the majority of trials. During hypocapnic hypoxia both Pace, and PETIT decreased (Fig. 1B) without demonstrable change in the arterial end-tidal difference. However, when end-tidal isocapnia was maintained (Fro*, 253.5%; Fig. lA), Paco2 decreased slightly, resulting in a small negative arterial end-tidal difference (LO-l.5 Torr) that remained essentially constant throughout the hypoxic period. In other words, isocapnic hypoxia by end-tidal measurements may have overestimated Paco2 by 1.0-1.5 Torr. During hypocapnic hypoxia, PETIT,tracked Pa,, well; thus end-tidal hypocapnic hypoxia was likely to be true hypocapnic hypoxia by Paco2 measurements. Ventilution and timing during hyperuxiu. The transition from room air to hyperoxia is shown breath by breath in Fig. 2. Note that ventilation (TE) decreased to 90 t 7% after 10 s of hyperoxia (4th hyperoxic breath) and reached a nadir of 89 + 4% after 18 s of hyperoxia (6th hyperoxic breath). In most trials, hyperoxic inhibition was apparent on the third hyperoxic breath, which represented the first breath during which significant hy-

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1. Comparison between end-tidal PCO~ (PET~~J and arterial PCO~ (Pa,,,) during hypoxia (n = 5). A: isocapnic hypoxia. Note negative arterial end-tidal difference. B: hypocapnic hypoxia. PETITE tracked Pacog throughout hypoxia. RA, room air. FIG.

peroxic inhibition reached the peripheral chemoreceptars. Similarly, EMGinsp decreased with hyperoxia (n = 3), reaching a nadir of 79 t 7% of room air. Because all trials involved transitions to hyperoxia, the room air-tohyperoxia trials were considered as the control period for all trials, starting at the third hyperoxic breath. Hyperoxic

termination

of brief

isocupnic hypoxia. Iso-

capnic hypoxia was induced and maintained for 1 min (PET,,63 t 3 Torr). Isocapnia was maintained during hypoxia (PETIT,44.3 t 1.2 vs. 43.9 t 1.2 Torr during an$ VE were constant during room air). PET*,,PETITE, the last few hypoxic breaths. VEincreased from 6.8 t 0.4 to 11.6 t 1.1 l/min. An example of brief isocapnic hypoxia is shown in Fig. 3A. Hypoxia was abruptly terminated with 100% FIEF, and isocapnia was maintained for the first two hyperoxic breaths. Tidal volume (VT) and EMGins gradually decreased. Note that VTand TE were elevate d above room air level for the first two hyperoxic breaths (7.5 s), confirming that peripheral chemoreceptors were still hypoxic. Both VT and VE decreased gradually, starting on the third hyperoxic breath, but remained higher than the hyperoxic control. The results of the group are shown, breath by breath, in Fig. 3B. Note that VE and VT remained above the room air-preceded hyperoxic control (the shaded area) for several breaths after termination of hypoxia with hyperoxia and were never below the hyperoxic control. VE reached a nadir (99 t 5% of room air) after 30 s of hyperoxia (8th hyper-

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HYPOXIA

AND

1961

AFTERDISCHARGE

3). Central apnea (TE prolongation >200% of room air) occurred infrequently; 26 trials were associated with hypocapnia of >4 Torr relative to room air, and 6 of them resulted in central apnea (Fig. 5). VE and VT returned to the hyperoxic control range after 45 s of hyperoxia (12th hyperoxic breath). Note the earlier return of TE to the hyperoxic control range after 18 s of hyperoxia. In summary, abrupt termination of brief hypocapnic hypoxia was associated with decreased VE and VT and prolongation of TE. The effect of shorter periods of hypocapnic hypoxia was less pronounced. Hypocapnic hypoxia was induced for 30 s (PETIT 49 t 3 Torr). PET,,, dropped from 45.5 t 1.9 to 43.0 t 1.6 Torr. VE increased from 7.9 t 0.7 to 10.5 t 1.0 Urnin. PET,,,, PETIT, and VT remained stable for the last few breaths of hypoxia. After termination of 30-s hypocapnic hypoxia triais (Fig. 6A), TjE remained elevated above room air for 9 s (2 hyperoxic breaths) and then decreased gradually, starting on the third hyperoxic breath, reaching a nadir (71.2t 9.2%) after 26 s of hyperoxia (7th hyperoxic breath). VE and VT remained below the hyperoxic control for 18 s (5 breaths) (P < 0.05), returning to the hyperoxic range on the ninth hyperoxic breath. TE remained within the hyperoxic control range throughout the hyperoxic transition. Mild hypocapnic hypoxia was induced for 15 s by the subject’s breathing four breaths of N, (PET,, 73.2 t 6.1 Torr). PET,,, dropped from 44.8 t 0.8 to 44.1 t 0.9 Torr. VE increased from 8.0 t 0.4 to 9.4 t 1.4 Urnin. On termination of 15-s hypoxia, VT and VE remained above the hyperoxic control for 8 s (2 breaths) but were not followed by ventilatory inhibition relative to the hyperoxic control (P > 0.05), because VE, VT, and TE remained within the hyperoxic control range (Fig. 6B). Hyperoxic

0

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100

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HYPERUXIA

2. Effect breath-by-breath subjects. VT, tidal VT and prolonged FIG.

of hyperoxia on ventilation (iTE) and timing on a basis (n = 9). Each point represents mean value of all volume; TE, expiratory time. Note decreased VE and

TE.

oxic breath). In summary, abrupt, hyperoxic termination of brief isocapnic hypoxia was associated with increased VE above the hyperoxic

control preceded by room air.

of brief hypocupnic hypoxia. A representative example of brief hypocapnic hypoxia is shown in Fig. 4A. Hypocapnic hypoxia was induced for 1 min (PETE, 48 t 2.5 Torr). PET,,, dropped from 43.9 t 0.8 to 40.1 t 0.8 Torr. TE increased from 8.6 t 0.6 to 12.0 k 1.0 l/min. PETCO,, PET,,, and VT remained stable for the last few breaths of hypoxia. The breath-by-breath findings are shown in Fig. 4B. Note that VE remained elevated above room air for 9 s (2 hyperoxic breaths) and gradually decreased below the hyperoxic control, starting on the third hyperoxic breath, reaching a nadir (64 t 5%) after 22 s of hyperoxia (6th hyperoxic breath). Expiratory duration (TE) was prolonged, reaching a peak of 128 t 8% of room air after 13 s of hyperoxia. Similarly, EMGi,sp decreased to a nadir of 66 t 9% of room air (n = Hyperoxic

termination

termination

of sustained

isocapnic hypoxia.

Mild hypoxia (PETE 63 t 3 Torr) was maintained for 5 min. PET,,, during h ypoxia (43 t 1.4 Torr) was essentially unchanged relative to room air (43.1 t 1.3). PET~?~, PET,, t and VE remained steady for the last 2 mm of each trial. VE increased from 6.9 t 0.45 to 10.1t 0.65 l/min. Hypoxia was abruptly terminated with 100% FIEF. An example of sustained isocapnic hypoxia is shown in Fig. 7A, Note that hyperoxic termination of isocapnic hypoxia was followed by central apnea. The results of the group are shown breath by breath in Fig. 7B. VE remained above room air for two breaths, followed by central apnea after 7.5 s of hyperoxia. VE remained below the hyperoxic control for 49 s (9 breaths) (P < O.OOl), whereas TE remained above the hyperoxic control for 43 S. Similarly, EMGi,sp (II = 2) decreased to a nadir of 43% of room-air control. Thus hyperoxic termination of sustained isocapnic hypoxia was associated with ventilatory inhibition manifested by decreased VT and prolongation of TE. Hyperoxic termination

of sustuined hypocapnic hypoxia.

Mild hypoxia (PETIT 64 t 4 Torr) was maintained for 5 min. VE increased from 7.3 t 0.76 to 9.6 t 0.89 Urnin. PET,,, dropped from 43.7 t 1.2 Torr during room air to 41.1 t 1.3 Torr (-2.6 Torr), Hypoxia was abruptly terminated with 100% FI,,. An example of sustained hypocapnit hypoxia is shown in Fig. 8A. Note that hyperoxic termination of hypocapnic hypoxia was followed by central apnea. The group findings are shown breath by breath in

Downloaded from www.physiology.org/journal/jappl at Univ of Cincinnati (129.137.005.042) on February 12, 2019.

1962

HYPOXIA

NOffNhJ

Isocapnic

AND AFTERDISCHARGE

Hyperoxio

Hypoxia

FIG. 3. Effect of abrupt termination of 1 min of isocapnic hypoxia on iTE (n = 10). A: representative polygraph record in 1 subj. PET,,, end-tidal POT; 0 2sat,oxyhemoglobin saturation; EMGdi, surface inspiratory EMC. VT during hyperoxia after hypoxia is higher than mean VT during room air-to-hyperoxia transition, as represented by dots within VT tracing. B: group data on breath-by-breath basis (means t SE; n = 9). Vertical dashed line, hyperoxic transition; hatched area, hyperoxia after room air. VE and VT remained above hyperoxic control until 9th hyperoxic breath. TE was not prolonged relative to hyperoxic control. See Fig. 2 for definitions of abbreviations.

80

i

il

Breath #

HYQOXIA

HYPEROXIA

Seconds

Fig. 8B. After termination of sustained hypocapnic hypoxia, ifE remained elevated above room air for the first hyperoxic breath, which was followed by central apnea after 3.5 s of hyperoxia. Similarly, EMGinsp (n = 2) de-

creased to a nadir of 38% of room-air control. VE and VT remained below the hyperoxic control for 88 s (19 hyperoxic breaths) (P < O.OOl),and TE was prolonged relative to the hyperoxic control for 50 s (8 breaths) (P < 0.01). In

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HYPOXIA

A

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30sec

AND AFTERDISCHARGE

1963

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FIG. 4. Effect of abrupt termination of 1 min of hypocapnic hypoxia (n = 9). A: representative polygraph record. See Fig. 3A for definitions of abbreviations. Note decreased VT and EMGdi after transition to hyperoxia. 23:group data on breath-by-breath basis. See Fig. 2 for definitions of abbreviations. Hatched area and vertical dashed line as in Fig. 3B. VE and VT decreased below hyperoxic control (n = 9) starting on 3rd hyperoxic breath. Note also different duration of inhibition for ventilation and timing.

80

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HYPOXIA

HYPEROXIA

summary, hyperoxic termination of sustained hypocapnit hypoxia was associated with prolonged poststimulus ventilatory inhibition.

Hyperoxic termination of brief hypocupnic hypoxia during wakefulness. Brief hypocapnic hypoxia was induced in four subjects for 30 or 60 s. PETITE decreased by 2.5 t

Downloaded from www.physiology.org/journal/jappl at Univ of Cincinnati (129.137.005.042) on February 12, 2019.

1964

HYPOXIA

pM-[,

AND

I

AFTERDISCHARGE

t

Normoxia Hypocapnic Hypoxia FIG. 5. Polygraph record depicting central apnea after termination definitions of abbreviations.

0.1 and 2.6 t 0.4, respectively. Individual results are shown breath by breath in Fig. 9. Note that the responses to hyperoxia and hyperoxic termination of hypoxia were highly variable; no evidence of poststimulus inhibition or potentiation was noted in the hyperoxic recovery period. Furthermore, no difference was noted between the two hypoxic durations. Wakefulness was confirmed by conventional electroencephalogram at all times. DISCUSSION

We have shown that abrupt termination of brief isocapnic hypoxia is associated with preservation of VE above the hyperoxic control, suggesting that hypoxia activated afterdischarge during NREM sleep. Hypocapnia, however, had a significant inhibitory influence on VE during the post-hypoxia period despite the activation of afterdischarge. Ventilatory inhibition during brief (15 to 60-s) hypocapnic trials was influenced by the duration of hypoxia and the magnitude of hypocapnia. Termination of mild sustained hypoxia, both hypocapnic and isocapnit, was associated with significant ventilatory inhibition and often with central apnea, suggesting the absence of afterdischarge. Critique of methods. To properly interpret our data, we have to address several limitations of our methods and design. First, we do not know precisely when the stimulus to the carotid body was removed with hyperoxia. We estimated that two breaths were sufficient for most of the hypoxic stimulus to be removed, on the basis of the findings of room air-to-hyperoxia transitions and previous estimates of lung-carotid body circulation time of 6 s (21, 25, 28). However, we cannot determine the beginning of hyperoxic inhibition as precisely as in animal studies utilizing electrical stimulation of the carotid sinus nerve. Second, we must qualify the term isocapnic hypoxia for the I- and 5-min isocapnia trials. We were able to maintain end-tidal isocapnia during hypoxia and for two breaths after transition to hyperoxia. However, the

Hyperoxia of 1 min of hypocapnic hypoxia. See Fig. 3A for

Pa C02-P~~C02difference was slightly negative during isocapnic hypoxia; thus it is likely that our isocapnic trials were actually hypocapnic by -1.0-1.5 Torr and that we underestimated the magnitude of afterdischarge. We also allowed PET,*~ to fall after the first two hyperoxic breaths, which may further underestimate afterdischarge. The presence of mild arterial hypocapnia is unlikely to alter our conclusions for the brief isocapnic trials, because we were able to confirm the activation of afterdischarge, but it may have contributed to ventilatory inhibition after sustained isocapnic hypoxia. The hypoxic increase in cerebral blood flow may also decrease medullary PCO~ despite arterial isocapnia (30). Obviously, we could neither control nor determine medullary Pco,, although it is doubtful that such mild hypoxia would cause a major increase in cerebral blood flow in humans (9; see below). Finally, the decrease in VE after termination of hypoxia may reflect an increase in upper airway resistance leading to hypoventilation and not a decrease in ventilatory drive. This is unlikely in our nonsnoring subjects, who are less likely to have a collapsible upper airway. We also noted that the decrease in VE was associated with decreased EMGinsp 9 suggesting a decrease in ventilatory drive. Our preliminary data confirm the absence of increased upper airway resistance after termination of brief or sustained hypocapnic hypoxia (1). Brief hypox;ia alzd after&charge. The maintenance of VE after termination of brief isocapnic hypoxia suggests that hypoxia activated afterdischarge, thus driving VE for several breaths after cessation of the hypoxic stimulus. Our data agree with previous studies suggesting the activation of afterdischarge with active hyperventilation in humans (21, 41). In addition, our data show that the activation of afterdischarge is preserved during NREM sleep in humans, confirming its independence of behavioral or conscious influences. During wakefulness, we found no systematic effect of hyperoxic termination of brief hypocapnic trials. In other

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HYPOXIA

1965

AND AFTERDISCHARGE i

i I

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FIG. 6. A: effect of abrupt hyperoxic termination of 30 s of hypocapnic hypoxia (n = 5) relative to room air-to-hyperoxia transitions (n = 5), See Fig. 2 for definitions of abbreviations. Note decreased VT and irE below hyperoxic control. TE remained within hyperoxic control range. B: effect of abrupt hyperoxic termination of 15 s of hypocapnic hypoxia (n = 4) relative to room air-to-hyperoxia transitions (n = 5). VE, VT, and TE: remained within hyperoxic range. Hatched area and vertical dashed line as in Fig. 3B.

words, we found no evidence of poststimulus ventilatory inhibition or p&r&i&ion. In contrast, Georgopolpus et al. (21) demonstrated in a similar protocol that VE remains above room air for several breaths after termination of brief (40 s) hypocapnic hypoxia during wakefulness. In their study, VE increased by 40% and PETITE decreased by 1.8 Torr in response to brief hypocapnic hypoxia. In our awake trials, VE increased by 34% and PETIT, decreased by 2.5 Torr in response to 30 s of hypocapnic hypoxia. It is also notable that our findings were more variable, potentially masking a poststimulus potentiation or inhibition. During NREM sleep, our data demonstrated the presence of hypocapnic inhibition, leading to decreased VT

and ifs and prolonged TE, even if afterdischarge is activated. The unmasking of hypcxapnic inhibition after active hyperventilation during NREM sleep is analogous to the unmasking of the apneic threshold after passive hyperventilation (10,38). The presence of ventilatory inhibition after termination of 1 min of hypocapnic hypoxia suggests that afterdischarge was either abolished or overridden by hypocapnic inhibition. Our data do not permit us to distinguish between these two possibilities or to determine whether afterdischarge prevented a more profound ventilatory inhibition. The gradual decline of VE to a nadir is consistent with the speculation that afterdischarge was still present, albeit overridden by hypocapnic inhibition.

Downloaded from www.physiology.org/journal/jappl at Univ of Cincinnati (129.137.005.042) on February 12, 2019.

1966

HYPOXIA

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AND AFTERDISCHARGE

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P t ,001 FIG, 7. Effect of abrupt hyperoxic termination of 5 min of isocapnic hypoxia (n = 4), relative to room air-to-hyperoxia transitions (n. = 4). A: representative polygraph record. See Fig. 3A for definitions of abbreviations. Note occurrence of central apnea on transition to hyperoxia. Sleep state remained constant. B: group data on breath-by-breath basis. See Fig. 2 for definitions of abbreviations. iiE decreased to a nadir (40% of room air), and TE was prolonged to 200% of room air. Note similar duration of inhibition for VT, VE, and TE. Hatched area and vertical dashed line as in Fig. 3B.

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1968

HYPOXIA

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9. Effect of abrupt hyperoxic termination on TjE during wakefulness on breath-by-breath basis in each subject and corresponding room air-to-hyperoxia transition in each subject (shaded area). 0, 30-s trials; 0, 60-s trials. Note variability in response and absence of poststimulus potentiation. FIG.

A definitive answer requires direct comparison between the effects of similar levels of hypocapnia induced by passive and active hyperventilation. In a previous study, Skatrud and Dempsey (38) demonstrated that hypocapnia of 4 Torr after 3 min of passive hyperventilation was consistently followed by central apnea of 5 s duration or TE prolongation averaging -200% of control. In our study, hypocapnia of >4 Torr (-4 to -7 Torr) was achieved in 26 brief (30- to 60-s) hypocapnic hypoxia trials during NREM sleep; only 6 of these trials were associated with TE prolongation ~200% of room air. For the group, PET,,, decreased by 3.8 Torr and resulted in an average TE prolongation of 123%. On the basis of this active vs. passive comparison, we would hypothesize that afterdischarge did minimize the hypocapnic inhibition. Unfortunately, the duration of hyperventilation was quite different in the active and passive hyperventilation protocols, limiting our ability to draw firm conclusions. A direct comparison between active and passive hyperventilation of similar durations and magnitude of hypocapnia is essential to quantify the effect of afterdischarge under hypocapnic conditions. The balance between the excitatory effects of afterdischarge and the inhibitory influences of hypocapnia may determine the magnitude of ventilatory inhibition on termination of brief hypocapnic hypoxia. For example, termination of brief isocapnic hypoxia was associated with clearly identifiable ventilatory potentiation, despite mild arterial hypocapnia of - 1.0-1.5 Torr. Termination of transient (15-s) hypocapnic hypoxia was not associated with either ventilatory potentiation or inhibition, suggesting that afterdischarge and hypocapnic inhibition were sufficiently weak to offset each other. Finally, termi-

nation of 30 s or 1 min of hypocapnic hypoxia was associated with significant ventilatory inhibition, indicating that hypocapnic inhibition overrode the potentiating effects of afterdischarge. Our data are consistent with those of Engwall et al. (ZO), who performed hypoxic stimulation of the isolated carotid body in awake goats. They found a clear poststimulus potentiation of VE immediately after isocapnic hypoxia and ventilatory inhibition after mild (-2 Torr) hypocapnic hypoxia. A decrease in the magnitude of poststimulus potentiation by hypocapnia was also noted by Eldridge (US), who used electrical carotid sinus nerve stimulation at different levels of PCO, in anesthetized cats. However, Eldridge also found that afterdischarge could still be manifested even after PCO, was lowered by as much as 9 Torr below the apneic threshold and that apnea did not occur until Pm2 was lowered by 12 Torr below the apneic threshold. In contrast, we demonstrated that hypocapnia, with an average decrease in PETIT, of ~4 Torr below eupneic breathing, consistently resulted in ventilatory inhibition and on six occasions resulted in apnea (Fig. 5). The manifestation of afterdischarge could also be influenced by the magnitude and duration of the preceding hyperpnea. One may speculate that the difference in VE after termination of hypocapnic hypoxia relative to VE after termination of isocapnic hypoxia could be attributed, in part, to the difference in the preceding hyperpnea. In Eldridge’s studies (14-19), electrical stimulation of the carotid sinus nerve is probably a more powerful stimulus than the mild hypoxia used in our study, with a more potent afterdischarge, thus maintaining VE despite profound hypocapnia. Finally, we noted that the duration of inhibition was

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HYPOXIA

AND AFTERDISCHARGE

different between TE and VT, and hence VE. For example, VT and VE remained below the hyperoxic control for 39 s after termination of 1 min of hypocapnic hypoxia, whereas TE remained below the hyperoxic control for only 18 s. The reason for the difference is not clear, but the difference may represent a preferential inhibitory effect of hypocapnia on rhythm generation relative to switching mechanisms. In summary, we believe that hypocapnic inhibition is a potent counterinfluence to the excitatory effects of afterdischarge. We do not believe that activation of afterdischarge and development of apnea are mutually exclusive; the net effect of hypocapnia vs. afterdischarge depends on the balance between these opposing influences. Thus afterdischarge may not prevent the occurrence of an apnea but may shorten its duration. What is the site of hypocapnic inhibition? Recent studies in awake goats have shown that decreased carotid body PCO, alone, with normal (or even elevated) central nervous system Pco,, causes ventilatory inhibition when a hyperoxic background is present (6). Data in awake dogs (3) also demonstrate a strong inhibitory effect of reduced carotid body PCO, on TE prolongation. Conversely, Engwall et al. (20) have shown in awake goats, with isolated carotid body perfusion, that medullary hypocapnia alone is sufficient to override afterdischarge after carotid body stimulation with hypoxia. Thus hypocapnia may exert its inhibitory influences on either central or peripheral chemoreceptors; our data do not permit us to determine their relative contribution. Sustained hypoxia and afterdischarge. The occurrence of central apnea after termination of sustained hypocapnit or isocapnic hypoxia suggests that active hyperventilation may be followed by a posthyperventilation apnea and that afterdischarge was either abolished or overridden in this setting. One potential cause of ventilatory inhibition after sustained hypoxia is the increase in cerebral blood flow leading to medullary hypocapnia (4, 7, 29). However, evidence in the literature casts doubt on the magnitude of decreased medullary Pco,, after hypoxia. Suzuki et al. (40) demonstrated the presence of biphasic ventilatory response to sustained hypoxia in awake humans. However, jugular venous Pco~, presumed representative of cerebral Pco,, remained constant after the initial decrease within 80 s of hypoxia. Similarly, Javaheri and Teppema (22) showed, in anesthetized cats, that decreased TE during sustained hypoxia occurred without change in ventral medullary PCO, or pH. Finally, Dempsey et al. (9) have shown that 1 h of exposure to moderate hypoxia (arterial PO, 48-53 Torr) did not produce a consistent change in arterial-jugular venous difference for Pco,. They concluded that global cerebral blood flow remained unchanged during the 1st h of hypoxia. In contrast, Neubauer and Edelman (33) demonstrated that increased cerebral blood flow in response to hypoxia is not uniform in anesthetized cats, being highest in the caudal brain stem relative to the cortex. Thus we cannot determine the contribution of increased brain blood flow to ventilatory inhibition. It is likely that increased medullary blood flow leads to decreased medullary PQ; however, it is unlikely to be the sole cause of ventilatory depression.

1969

The development of posthyperventilation apnea may be a consequence of central hypoxic depression (5,12,31, 34). A direct neuronal inhibition by hypoxia is unlikely, given the mild degree of hypoxia during our sustained hypoxia trials. However, sustained hypoxia may lead to the accumulation of inhibitory neuromodulators, resulting in central hypoxic depression, either by inhibiting central respiratory neurons or by abolishing afterdischarge. In humans (12), sustained hypoxia for 20-25 min is associated with ventilatory depression, attributed to central hypoxic depression. In our study, brief (l-min) hypocapnic hypoxia was associated with a more profound hypocapnia (-3.8 Torr compared with -2.6 Torr in the sustained hypocapnic hypoxia trials), yet ventilatory inhibition was less pronounced. Sustained hypoxia may have abolished afterdischarge, allowing unmitigated hypocapnic ventilatory inhibition, whereas hyperoxia may have unmasked central hypoxic depression earlier. We are in agreement with Holtby et al. (23), who were able to unmask ventilatory inhibition after 5 min of isocapnic hypoxia in awake humans; when hypoxia was terminated after 20 min, a more profound ventilatory inhibition occurred. However, in our study, ventilatory inhibition after termination of sustained hypoxia was a result of decreased VT and breathing frequency, in contrast to the predominant decrease in VT seen in our brief trials and in previous studies suggesting the occurrence of hypoxic depression in humans. Younes (44) has suggested that hypoxia may impair the neural switching mechanism from expiration to inspiration, thereby producing expiratory central apnea. Whether central apneas in our subjects resulted from inhibition of the rhythm generator or whether they represent delayed switching is not addressed by our data. We emphasize that cerebral hypoxic ventilatory depression and its apparent dependence on duration of hypoxia exposure are incompletely understood. For example, VE is depressed by cerebral hypoxia in some studies (5, 12, 13, 23, 24, 31, 43) but not others (39). In humans, sustained hypoxia for 20 min is associated with an initial increase in VE followed by a gradual decrease to a plateau, which has been attributed to hypoxic brain depression (12). Recent data in carotid body-resected humans also suggest that sustained hypoxia of several minutes’ duration has a central inhibitory influence on TE, manifested by a downward shift of the hypercapnic ventilatory response during hypoxia relative to hyperoxia (24). However, the difference in response between hypoxia and hyperoxia was minimal in two of five subjects, which precludes drawing any firm conclusions about the role of hypoxic brain depression in these carotid body-resected individuals. In contrast, truly prolonged hypoxia of 12-24 h in humans (8,9,36), or even 6-8 h in goats (27, 37,39) or rats (35), produces quite different aftereffects. Under these chronic circumstances, restoration of normoxia or brief hyperoxia results in continued hyperventilation at only a slightly reduced level compared with chronic hypoxia, which persists for several days. This paradoxic hypoxic effect is very intriguing; the mechanisms and adaptive objectives of such a response are poorly understood. Given the complexity of our model, it is difficult to attribute posthyperventilation apnea after termination

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1970

HYPOXIA

AND AFTERDISCHARGE

of sustained hypoxia to a single mechanism. We believe that hypocapnia, both arterial and medullary, is a powerful ventilatory inhibitor. Central hypoxic depression (secondary to accumulation of inhibitory neuromodulators?) abolishes afterdischarge and interacts with hypocapnia to cause posthyperventilation apnea. Implicutions for periodic breathing. Our findings are directly relevant to the etiology of periodic breathing during sleep, especially that induced by hypoxia. Two important questions emerge. First, does transient hyperventilation lead to breathing instability? Second, what is the relative contribution of afterdischarge in minimizing instability vs. the inhibitory influences of hypocapnia and sustained hypoxemia? Under carefully controlled circumstances during NREM sleep, such as during our brief isocapnic or very mildly hypocapnic (~2 Torr) hypoxia, afterdischarge played a clearly stabilizing role in VE, as shown by the persistent hyperpnea above control levels for several breaths after hyperoxic termination of hypoxia. It is conceivable that brief augmentation of ventilatory drive in the presence of isocapnia (or even slight hypocapnia) might occur in subjects with high upper airway resistance during sleep; but in most cases, transient hyperpnea would be accompanied by hypocapnia. Our data suggest that 30 or 60 s of transient mild hypocapnia (3-5 Torr) induced by “active” hyperventilation causes instability of VE and ventilatory pattern in the poststimulus period. The interpretation of the magnitude of the ventilatory inhibition depends on the definition of “instability” or “apnea.” Clearly, transient hyperventilation was never followed by a potentiation of ventilatory output during NREM sleep and was always followed by significant prolongation of TE, decreased reduced VT, and hypoventilation. Thus hypoEMGim3* 9 capnia was clearly a cause of ventilatory depression and instability. In fact, a few trials were associated with central apnea, suggesting that hypocapnia overrode the potentiating effects of afterdischarge (Fig. 5). It is likely, however, that afterdischarge prevented a more profound ventilatory inhibition; in its absence, central apnea would be more frequent and perhaps longer. In summary, we would e?pect hypocapnia to cause a transient destabilization of VE regardless of the cause of hyperventilation. Sustained moderate hypoxia during NREM sleep was also followed by marked ventilatory inhibition independent of systemic Pco,, suggesting that afterdischarge was abolished by sustained hypoxia. As Younes (44) suggested, this effect may, in part, explain why periodic breathing requires several minutes of hypoxic exposure to develop (2,42). It is likely that sustained hypoxia and hypocapnia, even of moderate severity, have an interactive effect on breathing stability, as manifested by more profound decrease in VT and more profound hypoventilation after 5 min of hypocapnic hypoxia. Finally, as hypoxia is greatly prolonged over many days, the magnitude of periodic breathing during NREM sleep is significantly reduced or abolished. This stabilization of breathing pattern coincides with the emergence of a strong and sustained posthypoxic hyperpnea (8) and may signal that the hypoxic depressant effect on the poststimulus potentiation mechanism has been replaced, during the accli-

matization period, with a powerful excitatory mechanism(s). Finally, we note that the inhibitory effects of hypocapnia and sustained hypoxia may not be sufficient to explain the development of periodic breathing and the marked individual variability of its manifestation (2,42). For example, periodic breathing is noted more often during NREM sleep than during wakefulness or REM sleep, suggesting that sleep state per se facilitates the development of breathing instability. Likewise, a dynamically changing sleep state, upper airway resistance, or metabolic rate may also contribute to breathing instability during NREM sleep (11). In contrast, a constantly high upper airway resistance may stabilize VE by minimizing hypocapnia in the face of increased ventilatory drive. In conclusion, we have demonstrated that brief hypoxia activates afterdischarge. Hypocapnic inhibition and sustained hypoxia may override or abolish afterdischarge. This is a destabilizing factor that may contribute to breathing disorders during sleep. The authors thank Carol Steinhart for excellent editorial assistance. This work was supported by the Medical Research Service of the Department of Veterans Affairs and by National Heart, Lung, and Blood Institute Specialized Center of Research Grant HL-42242 and Clinical Investigator Award HL-02588 (M. S. Badr). Address for reprint requests: M. S. Badr, H6/380 Clinical Science Center, 600 Highland Ave., Madison, WI 53702. Received 31 May 1991; accepted in final form 25 May 1992. REFERENCES 1. BADR, S., J. SKATRUD, AND J. DEMPSEY. Effect of fluctuating ventilatory drive on total pulmonary resistance during NREM sleep. (Abstract). Am. Rev. Respir. Dis. 43: A792, 1991. A., J. DEMPSEY, C. IBER, J. SKATRUD, AND P. 2. BERSSENBRUGGE, WILSON. Mechanisms of hypoxia-induced periodic breathing during sleep in humans. J. Physiol. Land. 343: 507-524, 1983. 3. BOWES, G., S. M. ANDREY, L. F. KOZAR, AND E. A. PHILLIPSON. Carotid chemoreceptor regulation of expiratory duration. J. Appl. Physiol. 54: 1195-1201, 1983. 4. BROWN, D. L., AND E. E. LAWSON. Brain stem extracellular fluid pH and respiratory drive during hypoxia in newborn pigs. J. Appl. Physiol. 64: 1055-1059, 1988. M. HIRAI, T. KURIYAMA, Y. SAGAWA, 5. CHIN, K., 0. MOTOHARU, AND K. KUNO. Breathing during sleep with mild hypoxia. J. Appl. Physiol. 67: 1198-1207, 1989. L., A. D. BERSSENBRUGGE, M. J. ENGWALL, AND 6. DARISTOTLE, G. E. BISGARD. The effects of carotid body hypocapnia on ventilation in goats. Respir. Physiol. 79: 123-136, 1990. 7. DARNALL, R. A., G. GREEN, L. PINTO, AND N. HART. Effect of brief hypoxia on respiration and brain stem blood flow in the piglet. J. Appl. Physiol. 70: 251-259, 1991. 8. DEMPSEY, J. A., AND H. V. FORSTER. Mediation of ventilatory adaptations. Physiol. Rev. 62: 262-346, 1982, 9. DEMPSEY, J. A., H. V. FORSTER, AND G. A. DOPICO. Ventilatory acclimatization to moderate hypoxemia in man: the role of spinal fluid [H+]. J. Clin. Inuest. 53: 1091-1100, 1974. 10. DEMPSEY, J. A., AND J. B. SKATRUD. A sleep-induced apneic threshold and its consequences. Am. Rev. Respir. Dis. 133: 1163-1170, 1986. 11. DEMPSEY, J. A., J. B. SKATRUD, M. S. BADR, AND K. G. HENKE. Effects of sleep on the regulation of breathing and respiratory muscle function. In: The Lung: Scientific Foundations, edited by R. G. Crystal1 and J. B. West. New York: Raven, 1991, p. 1615-1629. 12. EASTON, P. A., L. J. SLYKERMAN, AND N. R. ANTHONISEN. Ventilatory response to sustained hypoxia in normal adults. J. Appl. Physiol. 61: 906-911, 1986. 13. EDELMAN, N. H., P. E. EPSTEIN, S. LAHIRI, AND N. S. CHERNIACK. Ventilatory responses to transient hypoxia and hypercapnia in man. Respir. Physiol. 17: 302-314, 1973.

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central apnea and periodic 1989.

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Determinants of poststimulus potentiation in humans during NREM sleep.

To test whether active hyperventilation activates the "afterdischarge" mechanism during non-rapid-eye-movement (NREM) sleep, we investigated the effec...
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