Ventilatory response to 2-h sustained hypoxia in humans

We used two protocols to determine if hypoxic ventilatory decline (HVD) involves changes in slope and/or intercept of the isocapnic HVR (hypoxic ventilatory response, expressed as the increase in VI per percentage decrease in SaO2). Isocapnia was defined as 1.5 mmHg above hyperoxic PET(CO2). HVD was recorded in protocol I during two sequential 25 min exposures to isocapnic hypoxia (85 and 75% SaO2, n=7) and in protocol II during 14 min of isocapnic hypoxia (90% SaO2, FIO2=0.13, n=15), extended to 2 h of hypoxia with CO2-uncontrolled in eight subjects. HVR was measured by the step reduction to sequentially lower levels of SaO2 in protocol I and by 3 min steps to 80% SaO2 at 8, 14 and 120 min in protocol II. The intercept of the HVR (VI predicted at SaO2=100%) decreased after 14 and 25 min in both protocols (P<0.05). Changes in slope were observed only in protocol I at SaO2=75%, suggesting that the slope of the HVR is more sensitive to depth than duration of hypoxic exposure. After 2 h of hypoxia the HVR intercept returned toward control value (P<0.05) with still no significant changes in the HVR slope. We conclude that HVD in humans involves a decrease in hyperoxic ventilatory drive that can occur without significant change in slope of the HVR. The partial reversal of the HVD after 2 h of hypoxia may reflect some components of ventilatory acclimatization to hypoxia.     

Ventilatory and arousal responses to hypoxia in sleeping humans

We measured ventilatory and arousal responses to progressive eucapnic hypoxia during wakefulness, nonrapid-eye-movement (NREM) sleep, and rapid-eye-movement (REM) sleep using a progressive isocapnic rebreathing method. Nine healthy adults (4 female, 5 male) slept with a mask glued to the face with medical silicone rubber and breathed from a closed valveless biased flow circuit, including an in-line bag-in-box and a variable soda-lime absorber. Progressive hypoxia was induced by consumption of oxygen and by gradual replacement of circuit volume with nitrogen. Tidal volume was measured by electrical integration of the flow signal from a pneumotach on the box. Arterial hemoglobin oxygen saturation (SaO2) was measured with an ear oximeter and end-tidal CO2 tension (PetCO2) was measured continuously and kept constant by variable absorption. Sleep state was identified using standard criteria with 2 channels each of EEG, submental EMG, and EOG. There was marked variability in arousal level both in NREM and REM sleep, with subjects failing to awaken by 70% SaO2, our previously agreed safety limit, on 12 of 26 NREM tests, and 7 of 15 REM tests. During wakefulness, the mean slope +/- SEM of the ventilatory response to hypoxia was 0.68 +/- 0.07 L/min% SaO2 (n = 36, mean PetCO2 = 37.0 mmHg). In NREM sleep, this response decreased to a mean of 0.42 +/- 0.06 L/min/% SaO2 (n = 26, mean PetCO2 = 37.2 mmHg). In REM sleep, the average ventilatory response was further decreased to 0.33 +/- 0.06 L/min/% SaO2 (n = 15, mean PetCO2 = 37.8 mmHg). Analysis of variance showed a significant state-dependent effect on ventilatory response (p less than 0.01). The wake-NREM and wake-REM differences were significantly different (p less than 0.05), but the NREM-REM difference was not (p greater than 0.2). In REM sleep, breath-to-breath variability was marked, and in 2 cases, the response was not significantly different from zero. In all 3 states, the entire ventilatory response was due to increments in tidal volume. We conclude that (1) at normal alveolar CO2 tension, hypoxia is a poor arousal stimulus in humans, both in NREM and REM sleep, and (2) the eucapnic hypoxic response is reduced but present in NREM sleep and similarly reduced but not always present in REM sleep.     

Ventilatory response of the newborn infant to mild hypoxia

The transition from an immature (biphasic) to a mature (sustained hyperpneic) response to a brief period of sustained hypoxia is believed to be well advanced by postnatal day 10 for newborn infants. However, a review of the supporting evidence convinced us that this issue warranted further, more systematic investigation. Seven healthy term infants aged 2 days to 8 weeks were studied. The ventilatory response (VR) elicited by 5 min breathing of 15% O₂ was measured during quiet sleep. Arterial S_aO2 (pulse oximeter) and minute ventilation (expressed as a change from control, ΔV′_i) were measured continuously. Infants were wrapped in their usual bedding and slept in open cots at room temperature (23°–25°). Infants aged 2–3 days exhibited predominately a sustained hypopnea during the period of hypoxia (ΔV′_i = −2% at 1 min, −13% at 5 min). At 8 weeks of age, the mean response was typically biphasic (ΔV′_i = +9% at 1 min, −4% at 5 min). This age-related difference between responses was statistically significant (two-way ANOVA by time and age-group; interaction P < 0.05). These data reveal that term infants studied under ambient conditions during defined quiet sleep may exhibit an immature VR to mild, sustained hypoxia for at least 2 months after birth. This suggests that postnatal development of the O₂ chemoreflex is slower than previously thought. Pediatr. Pulmonol. 1997; 24:163–172. © 1997 Wiley-Liss, Inc.     

Ventilatory response to sustained eucapnic hypoxia in the adult conscious dog.

The ventilatory response to 20 min sustained isocapnic hypoxia (SaO2, 80 +/- 2%) was examined in 5 trained unanesthetized adult dogs breathing through an endotracheal tube. End tidal PCO2 was maintained at the resting levels. The dogs' conscious status was monitored by recording EEG and EOG on a chart recorder. The room temperature was kept between 19 and 21 degrees C. All tests were repeated in each dog on 2 occasions: (1) unloaded tracheal breathing or (2) resistive loaded breathing. During unloaded tracheal breathing, the average ventilation in response to sustained hypoxia rose from a control of 5.1 +/- 0.3 L/min (mean +/- within-dog SE) to 19.2 +/- 1.1 L/min at the initial stage of hypoxia. Ventilation remained at 20.7 +/- 1.3 L/min at 10 min, and then 19.7 +/- 1.4 L/min at the completion of the 20 min hypoxic exposure. There was no ventilatory adaptation observed (P greater than 0.05). After release from hypoxia, the ventilation fell abruptly to 7.6 +/- 0.8 L/min, which was higher than the resting baseline level (P less than 0.05), and then gradually returned to the resting baseline within 10 min. Experiments exposing the dogs to 40 min sustained hypoxia also failed to elicit significant adaptation. During resistive loading, the pattern of average ventilation in response to sustained hypoxia was similar to that observed in unloaded breathing tests. But the ventilatory recovery was longer than unloaded breathing, returning to the resting baseline within 20 min. Again, there was no ventilatory adaptation observed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ventilatory response to sustained hypoxia: effect of methysergide and verapamil

The biphasic nature of the ventilatory response to sustained (30 min) hypoxia may be explained by the central accumulation of a neurochemical with net inhibitory effect or, alternatively, peripheral chemoreceptor adaptation. To determine the role of serotonin (a putative central neuroinhibitor) and calcium ions (a putative peripheral neurotransmitter) in this response we measured VI and breathing pattern during 30 min of sustained isocapnic hypoxia in 11 normal adults 1 h after the double blind administration of either 2 mg methysergide (serotonin antagonist), 80 mg verapamil (calcium channel blocker), or placebo. Each subject was studied once a day for three days. After placebo the mean VI peaked at 12.5 +/- 3.4 L/min (176% of resting room air VI). VI then declined to a mean of 9.8 +/- 2.3 L/min (138% of room air VI) during 25 min of constant hypoxia. VI during hypoxia was always greater than VI during room air breathing (p less than 0.01), and peak VI during hypoxia was greater than final VI during hypoxia (p less than 0.05). The hypoxic response was not significantly affected by either pharmaceutical. At their maximal safe dosage in humans, methysergide and verapamil suggest no role for serotonin and calcium ions. Not excluded is the possibility that drug levels were inadequate to effect meaningful blockade.     

Ventilatory response to CO2 and hypoxia during cold exposure in awake rats

Recently, we have described the effects of hypoxia and of hypercapnia on the metabolic (V̇_O2) and ventilatory responses to cold in unanesthetized intact and carotid body-denervated (CBD) rats (Gautier et al., J. Appl. Physiol. 73: 847–854, 1992 and 75: 2570–2579, 1993). In the present paper, we have reanalyzed the above results for a more detailed study of the interactions of hypoxia (Fi_O2 = 0.12), hypercapnia (Fi_CO2 = 0.04) and changes in V̇_O2 with the ventilatory control. The results show that: (1) Compared to normoxia, in hypoxia increments in V̇ and Vt are proportional to V̇_O2 whereas in hypercapnia increments in ventilation (V̇) and tidal volume (Vt) are independent of V̇_O2. In both hypoxia and hypercapnia, increases in respiratory frequency (fr) are independent of V̇_O2; and (2) Interactions of hypoxia, hypercapnia and V̇_O2 with control of V̇ persist in CBD rats but, for a given V̇_O2, V̇, Vt and fr are lower than in intact rats. These interactions are essentially similar to those observed during muscular exercise performed in normoxia, hypoxia or hypercapnia. It is suggested that during cold exposure or muscular exercise, resulting both in increased V̇_O2, there are common integrative structures probably located in the hypothalamus which are involved in the control of breathing.     

Ventilatory response to hypoxia and hypercapnia in the torpid bat, Eptesicus fuscus.

Ventilatory pattern and ventilatory responses to hypercapnia and hypoxia were investigated in torpid big brown bats at body temperatures of 5, 10, 20, 30 and 37 degrees C. The pattern of breathing at temperatures below 30 degrees C was intermittent, consisting of rhythmic breathing bouts separated by apneic periods with occasional sporadic, non-rhythmic breathing episodes. Overall ventilation (Ve) was matched consistently to overall oxygen consumption (MO2) over the entire range of temperatures with a mean air convection requirement (Ve/MO2) of 1.28 L/mmol. However, calculating the air convection requirement using only oxygen uptake acquired during ventilation yielded an ectotherm-like temperature relationship. Ventilation was stimulated at all temperatures by either increased inspired CO2 or decreased inspired O2. At 20 degrees C, graded hypercapnic stimulation increased the duration of the rhythmic bouts and decreased the duration of apneas until at high CO2 (greater than 3%) breathing was continuous. Hypoxic stimulation below about 7% O2 increased ventilation by selectively increasing the non-rhythmic ventilations and decreasing rhythmic bouts.     

Ventilatory adaptation to hypoxia occurs in serotonin-depleted rats

To test the hypothesis that serotonin mediated respiratory activity is involved in ventilatory adaptation to hypoxia, rats were treated with parachlorophenylalanine (PCPA), a potent, long-acting inhibitor of tryptophan hydroxylase, the rate-limiting enzyme in the biosynthesis of serotonin. In normoxia, a single, intraperitoneal injection of 300 mg PCPA/kg body weight decreased the Paco2 from a control level at 39.1 +/- 0.6 Torr (mean +/- 95% confidence limits) to 34.0 +/- 0.6 Torr measured during a period from 1 to 48 h following PCPA treatment. This PCPA-produced hyperventilation corresponds to an increase of 3.7 +/- 0.5 in the VA (BTPS)/Vco2 (STPD) ratio. Hyperventilation during ventilatory adaptation to hypoxia (PIO2 approximately equal to 90 Torr) was superimposed in an additive fashion on the underlying hyperventilation due to PCPA pretreatment. Specifically, PCPA pretreatment caused an average 3.5 +/- 1.2 increase in the VA/VCO2 ratio determined in acute (1 h) hypoxia, chronic (24 h) hypoxia and acute return to normoxia following chronic hypoxia. Since ventilatory adaptation to hypoxia occurred in rats treated with PCPA, the prolonged, serotonin mediated respiratory activity described by Millhorn et al. (1980b) is probably not important in ventilatory acclimatization to - or deacclimatization from - hypoxia.     

Ventilatory response in metabolic acidosis and cerebral blood volume in humans

The relationship between alterations in cerebral blood volume (CBV) and central chemosensitivity regulation was studied under neutral metabolic conditions and during metabolic acidosis. Fifteen healthy subjects (56+/-10 years) were investigated. To induce metabolic acidosis, ammonium chloride (NH(4)Cl) was given orally. CBV was measured using Near Infrared Spectroscopy during normo- and hypercapnia and related to inspired ventilation (V(i)). A mean acute metabolic acidosis of Delta pH - 0.04 was realized with a mean decreased arterialized capillary PCO(2) (P(c)CO(2)) of 0.20 kPa (1.5 mmHg) (both P<0.001). During normocapnia, CBV was 3.51+/-0.71 and 3.65+/-0.56 ml 100 g(-1) (mean+/-S.D.), measured under neutral metabolic conditions and during acute metabolic acidosis, respectively (ns). Corresponding values of V(i) were 7.6+/-1.4 and 10.0+/-2.4 l min(-1) (P<0.01), respectively. The slopes of the CO(2)-responsiveness (DeltaCBV/DeltaP(c)CO(2) and DeltaV(i)/DeltaP(c)CO(2)), were not significantly different during both metabolic conditions. A significant correlation between DeltaCBV/DeltaP(c)CO(2) and DeltaV(i)/DeltaP(c)CO(2) was found during metabolic acidosis (P<0.01), but not under neutral metabolic conditions. CBV does not contribute in a predictable way to the regulation of central chemoreceptors.     

Naloxone increases ventilatory response to hypercapnic hypoxia in healthy adult humans

The ventilatory response to hypercapnic progressive hypoxia and the breathing pattern during steady-state hypercapnic hypoxia were compared before and after intravenous infusion of 3 mg of naloxone in a relatively large number of healthy adults (n = 21). In addition, the withdrawal response from hypercapnic hypoxia (modified transient O2 test) was measured to investigate the possible role of endogenous opioids in the peripheral chemoreceptors. The average ventilatory response (delta VE/delta SaO2) increased significantly from 0.51 +/- SD 0.26 to 0.65 +/- 0.42 L/min/% (p less than 0.05) after naloxone infusion, whereas there were no significant changes between two tests with normal saline in the control study (n = 7). Because there was considerable interindividual variation in the response to naloxone administration, we selected "high responders" (n = 8) who showed larger increases with naloxone than the upper limit of the 95% confidence interval for the change with the second saline in the control study. They showed greater delta VE/delta SaO2 (p less than 0.01), respiratory frequency (p less than 0.01), and mean inspiratory flow (p less than 0.01) during hypercapnic hypoxia before naloxone infusion than did the other subjects. There was no significant change in the withdrawal response before and after naloxone infusion, even in such high responders. We conclude that endogenous opioids participate in the control of breathing in normal adults during hypercapnic hypoxia. This may be particularly true for those subjects who exhibit greater chemosensitivity to hypercapnic hypoxia. Endogenous opioids appear to act centrally rather than peripherally.     

Ventilatory response of goats to transient changes in CO2 and O2 during acute hypoxia.

The authors assessed the relative sensitivity of the peripheral chemoreceptors of 4 goats to a transient decrease in inspired CO2 using a 2-breath test. This test provides a steady-state background of hypoxia and hypercapnia and then, for 2 breaths, an equally hypoxic gas mixture containing no CO2. Another type of 2-breath test, providing 2 breaths of a hyperoxic gas mixture against a background of hypoxia, was used to establish the time course of a response known to come from peripheral chemoreceptors. Seven human subjects were studied in a similar fashion to establish the validity of the procedure. Except for 2 responses, the author's human data agree with those reported previously by others. All 4 goats resembled man in responding to removal of hypoxia with a significant decrease in ventilation, but 3 of the 4 goats, unlike man, showed no significant decrease in ventilation when CO2 was removed. The authors conclude that the peripheral chemoreceptors of goats are commonly insensitive to transient changes in inspired CO2 during acute hypoxia.     

Ventilatory control in normal man following five minutes' exposure to hypoxia

Ventilatory control was studied in normal subjects following brief (5 min) exposure to hypoxia (inhalation 7-8% O2). The ventilatory response to rebreathing CO2 (hyperoxic) was assessed 20 min before and after 5 min exposure to (a) 7-8% O2, (b) 7-8% O2 rebreathing CO2, (c) rebreathing CO2 during hyperoxia, and (d) 10% O2, normocapnic. The slope of the V-PCO2 response (S) was increased for up to 40 min following (a) and (b) by 25-34%, but was unchanged following (c) and (d). Resting ventilation was unchanged throughout. The ventilatory response to normocapnic progressive hypoxia was measured as the slope of the V-Hb% SaO2 relationship (H); this was increased by 26%. The mechanism underlying this change in ventilatory control in man is unknown; it may relate to the process of acclimatization to hypoxia whereby chronic hypoxia is a greater stimulus to ventilation than acute hypoxia.     

Ventilatory responses to hypoxia nullify hypoxic tracheal constriction in awake dogs

Three awake dogs with chronic tracheostomies were used to study the effects of hypoxia (12% O2) on tracheal smooth muscle tone. Pressure changes within a water-filled cuff in an isolated portion of the cervical trachea reflected changes in tracheal tone. During spontaneous ventilation, hypoxia produced hyperventilation, but no significant change in tracheal tone. If hypocapnia was prevented with inspired CO2 during hypoxia, one of three dogs increased tracheal tone, and all dogs increased ventilation beyond that measured with hypoxia alone. When the awake dogs were ventilated mechanically to prevent changes in ventilation, hypoxia always increased tracheal tone. We made independent changes in ventilation and CO2 similar to the spontaneous responses to hypoxia to test these effects on tracheal tone. When the dogs were ventilated mechanically first with 2% CO2, and then with no CO2, the resulting drop in end-tidal CO2 always decreased tone. When the tidal volume on the ventilator was increased under hyperoxic, isocapnic conditions, tracheal tone always decreased. We conclude that the normal ventilatory response to hypoxia opposes the bronchoconstrictor effect of hypoxia, resulting in no net change in tracheal smooth muscle tone.