Almitrine increases the steady-state hypoxic ventilatory response in hypoxic chronic air-flow obstruction

Almitrine, a peripheral chemoreceptor agonist, exerts beneficial effects on blood gases in patients with hypoxic chronic air-flow obstruction, but as these patients exhibit poor ventilatory responses to hypoxia, the mechanism for this improvement is not clear. The effect of a 100-mg dose of almitrine given orally on ventilation and the steady-state hypoxic ventilatory response (HVR) were measured in a randomized, double-blind, placebo-controlled manner in 7 patients with severe hypoxic chronic air-flow obstruction. The isocapnic HVR (delta VE/delta SaO2) was calculated from the changes in ventilation and SaO2 from breathing 60% O2 to breathing air with the addition of CO2 to maintain isocapnia (as estimated from a transcutaneous CO2 electrode). Resting ventilation while breathing air and isocapnic HVR were measured before and 3 h after almitrine or placebo. Almitrine caused no significant change in resting ventilation. There was, however, a large increase in HVR after almitrine (almitrine: -1.5 L/min/%SaO2; range, -0.5 to -3.1; control: -0.4; range, -0.3 to -1.3), but no change after placebo. Almitrine is a powerful stimulant of chemosensitivity and of the hypoxic ventilatory response in chronic hypoxemia, with potential benefit to patients with chronic air-flow obstruction in respiratory failure.     

Measuring ventilatory acclimatization to hypoxia: comparative aspects

Acclimatization to hypoxia increases the hypoxic ventilatory response (HVR) in mammals. The literature on humans shows that several protocols can quantify this increase in HVR if isocapnia is maintained, regardless of the exact level of Pa(CO(2)). In rats, the isocapnic HVR also increases with chronic hypoxia and this cannot be explained by a non-specific effect of increased ventilatory drive on the HVR. Changes in arterial pH are predicted to increase the HVR during chronic hypoxia in rats but this has not been quantified. Limitations in determining mechanisms of change in the HVR from reflex experiments are discussed. Chronic hypoxia changes some, but not all, indices of ventilatory motor output that are useful for normalization between experiments on anesthetized rats. Finally, ducks also show time-dependent increases in ventilation during chronic hypoxia and birds provide a good experimental model to study reflex interactions. However, reflexes from intrapulmonary CO(2) chemoreceptors can complicate the measurement of changes in the isocapnic HVR during chronic hypoxia in birds.     

Sleep deprivation and the control of ventilation

Sleep deprivation is common in acutely ill patients because of their underlying disease and can be compounded by aggressive medical care. While sleep deprivation has been shown to produce a number of psychological and physiologic events, the effects on respiration have been minimally evaluated. We therefore studied resting ventilation and ventilatory responses to hypoxia and hypercapnia before and after 24 h of sleeplessness in 13 healthy men. Hypoxic ventilatory responses (HVR) were measured during progressive isocapnic hypoxia, and hypercapnic ventilatory responses (HCVR) were measured using a rebreathing technique. Measures of resting ventilation, i.e., minute ventilation, tidal volume, arterial oxygen saturation, and end-tidal gas concentrations, did not change with short-term sleep deprivation. Both HVR and HCVR, however, decreased significantly after a single night without sleep. The mean hypoxic response decreased 29% from a slope of 1.20 +/- 0.22 (SEM) to 0.85 +/- 0.15 L/min/% saturation (p less than 0.02), and the slope of the HCVR decreased 24% from 2.07 +/- 0.17 to 1.57 +/- 0.15 L/min/mmHg PCO2 (p less than 0.01). These data indicate that ventilatory chemosensitivity may be substantially attenuated by even short-term sleep deprivation. This absence of sleep could therefore contribute to hypoventilation in acutely ill patients.     

The ventilatory effects of sustained isocapnic hypoxia during exercise in humans.

To investigate how the ventilatory response to isocapnic hypoxia is modified by steady-state exercise, five subjects were studied at rest and performing 70 W bicycle exercise. At rest, isocapnic hypoxia (end-tidal PO2 50 Torr) for 25 min resulted in a biphasic response: an initial increase in ventilation was followed by a subsequent decline (HVD). During exercise, an end-tidal PO2 of 55-60 Torr was used. The magnitude of the initial ventilatory response to isocapnic hypoxia was increased from a mean +/ SE of 1.43 +/- 0.323 L/min per % arterial desaturation at rest to 2.41 +/- 0.424 L/min per % during exercise (P less than 0.05), but the magnitude of the HVD was reduced from 0.851 +/- 0.149 L/min per % at rest to 0.497 +/- 0.082 L/min per % during exercise (P less than 0.05). The ratio of HVD to the acute hypoxia response was reduced from 0.696 +/- 0.124 at rest to 0.202 +/- 0.029 during exercise (P less than 0.01). We conclude that while exercise augments the ventilatory sensitivity to hypoxia, it also has a direct effect on the mechanisms by which sustained hypoxia depresses peripheral chemosensitivity.     

Effects of dopamine and domperidone on ventilation during isocapnic hypoxia in humans.

In order to investigate the role of dopamine in the ventilatory response to sustained, isocapnic hypoxia six subjects were studied three times in each of three pharmacological conditions: (1) in the absence of any drug administration, (2) during i.v. infusion of dopamine (3 micrograms.kg-1.min-1), and (3) after pretreatment with domperidone. Otherwise the experimental protocol was identical on each day and consisted of holding the subjects' end-tidal PO2 at 100 Torr for 10 min, then 50 Torr for 20 min and finally at 100 Torr again for 5 min. End-tidal PCO2 was held constant 2-3 Torr above normal throughout the experiment. Domperidone increased, and dopamine decreased the magnitudes of both the fast on- and off-responses, but neither drug affected the magnitude of the hypoxic ventilatory decline (HVD). The results of this study suggests: (1) that a peripheral dopaminergic mechanism is not involved in the genesis of HVD, and (2) the peripheral chemoreflex may be modulated peripherally to produce HVD.     

Ventilatory responses to chemosensory stimuli in quadriplegic subjects

We tested the hypothesis that interruption of motor traffic running down the spinal cord to respiratory muscle motoneurons suppresses the ventilatory response to increased chemical drive. We compared the hypoxic (HVR) and hypercapnic (HCVR) ventilatory responses, based on the rebreathing technique, before and during inspiratory flow-resistive loading in 17 quadriplegic patients with low cervical spinal cord transection and in 17 normal subjects. The ventilatory response was evaluated from minute ventilation (VE) and mouth occlusion pressure (P0.2) slopes on arterial oxygen saturation (SaO2) or on end-tidal PCO2 (PACO2), and from absolute VE values at SaO2 80% or at PACO2 55 mmHg. We found no difference in the unloaded HVR or HCVR between the quadriplegic and normal subjects. In the loaded HVR, the delta VE/delta SaO2 slope tended to decrease similarly in both groups of subjects. The delta P0.2/delta SaO2 slope was shifted upwards in normal subjects, yielding a significantly higher P0.2 at a given SaO2. In contrast, this rise in the P0.2 level during loaded HVR was absent in quadriplegics. Loaded HCVR yielded qualitatively similar results in both groups of subjects; delta VE/delta PACO2 decreased and delta P0.2/delta PACO2 increased significantly. The results show that the ventilatory chemosensory responses were unsuppressed in quadriplegics, although they displayed a disturbance in load-compensation, as reflected by occlusion pressure, in hypoxia. We conclude that the descending drive to respiratory muscle motoneurons is not germane to the operation of the chemosensory reflexes.     

Ventilatory response to hypoxia in elderly humans

In young adults the ventilatory response to 25 min of isocapnic hypoxia (SaO2 = 80%) is characterized by an initial increase in ventilation followed by a decline. The increase and decline are proportional. Because older adults have been reported to have reduced initial ventilatory responses to hypoxia, we compared responses to hypoxia in 14 older (mean age 62) and 15 younger (mean age 29) subjects. There was no difference. Both groups demonstrated a similar initial increase in ventilation with hypoxia and a similar subsequent decline due to a decline in tidal volume. In both groups the size of the initial increase was proportional to the subsequent decline. In both groups hyperoxia immediately after 25 min of hypoxia transiently depressed ventilation, while hyperoxia after room air breathing did not. We conclude that the ventilatory response to 25 min of hypoxia is independent of age in normal humans.     

Changes in dopamine D(2)-receptor modulation of the hypoxic ventilatory response with chronic hypoxia

Modulation of the hypoxic ventilatory response (HVR) by dopamine D(2)-receptors (D(2)-R) in the carotid body (CB) and central nervous system (CNS) are hypothesized to contribute to ventilatory acclimatization to hypoxia. We tested this with blockade of D(2)-R in the CB or CNS in conscious rats after 0, 2 and 8 days of hypoxia. On day 0, CB D(2)-R blockade significantly increased VI and frequency (fR) in hyperoxia (FI(O(2))=0.30), but not hypoxia (FI(O(2))=0.10). CNS D(2)-R blockade significantly decreased fR in hypoxia only. On day 2, neither CB nor CNS D(2)-R blockade affected VI or fR. On day 8, CB D(2)-R blockade significantly increased hypoxic VI and fR. CNS D(2)-R blockade significantly decreased hypoxic VI and fR. CB and CNS D(2)-R modulation of the HVR decreased after 2 days of hypoxia, but reappeared after 8 days. Changes in the opposing effects of CB and CNS D(2)-R on the HVR during chronic hypoxia cannot completely explain ventilatory acclimatization in rats.     

Effect of dichloroacetate on ventilatory response to sustained hypoxia in normal adults

In adult humans, the ventilatory response to acute sustained hypoxia is biphasic, characterized by an initial brisk increase followed by a decline to an intermediate plateau. Recently, it has been shown that hypoxic lactate formation in the brain depresses ventilation in peripherally chemodenervated animals, and postulated that this formation might mediate the hypoxic ventilatory decline observed in adult humans. To investigate this hypothesis, the ventilatory response to 25 min of acute isocapnic hypoxia (SaO2 = 80%) was evaluated in adult humans after pretreatment with intravenous dichloroacetate (DCA), a drug that crosses the blood-brain barrier and reduces lactate formation. Ten subjects were pretreated with DCA (50 mg.kg-1.h-1) or normal saline infusion on two days in a double blind manner. The infusion started 35 min before the institution of hypoxia and continued throughout the experiment. Independent of pretreatment, the ventilatory response to acute sustained hypoxia was biphasic; an increase followed by a decline. Ventilation during hypoxia declined significantly and the magnitude of the decline did not differ between the DCA and placebo pretreatments, averaging 3.32 +/- 0.45 and 3.17 +/- 0.58 L/min, respectively (mean +/- SE). With and without DCA infusion the hypoxic ventilatory decline was due to significant decrease in tidal volume and mean inspiratory flow without changes in breathing frequency. We conclude that brain lactic acidosis is unlikely to be involved in the ventilatory response to sustained hypoxia of adult humans, at least in the range of hypoxia studied.     

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 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.     

Chemoreflex drive and the dynamics of ventilation and gas exchange during exercise at hypoxia

We tested the hypothesis that the promotion of hypoxic ventilatory responsiveness (HVR) and/or hypercapnic ventilatory responsiveness (HCVR) mostly acting on the carotid body with a changing work rate can be attributed to faster hypoxic ventilatory dynamics at the onset of exercise. Eleven subjects performed a cycling exercise with two repetitions of 6 minutes while breathing at FIO(2) = 12%. The tests began with unloaded pedaling, followed by three constant work rates of 40%, 60%, and 80% of the subject's ventilatory threshold at hypoxia. Reference data were obtained at the 80% ventilatory threshold work rate during normoxia. Using three inhaled 100% O(2) breath tests, a comparison of hypoxia and normoxia revealed an augmentation of HVR in hypoxia, which then significantly increased proportionally with the increase in work rate. In contrast, HCVR using three inhaled 10% CO(2) breath tests was unaffected by the difference in work rate at hypoxia but did exceed its level at normoxia. The decrease in the half-time of hypoxic ventilation became significant with an increase in work rates and was significantly lower than at normoxia. Using a multiregression equation, HVR was found to account for 63% of the variance of hypoxic ventilatory dynamics at the onset of exercise and HCVR for 9%. O(2) uptake on-kinetics and off-kinetics under hypoxic conditions were significantly slower than under normoxic conditions, whereas they were not altered by the changing work rates at hypoxia. These results suggest that the faster hypoxic ventilatory dynamics at the onset of exercise can be mostly attributed to the augmentation of HVR with an increase in work rates rather than to HCVR. Otherwise, O(2) uptake dynamics are affected by the lower O(2), not by the changing work rates under hypoxic conditions.     

Effect of treatment with nasal continuous positive airway pressure on ventilatory response to hypoxia and hypercapnia in patients with sleep apnea syndrome

BACKGROUND: The increase in peripheral chemoreflex sensitivity in patients with obstructive sleep apnea (OSA) is associated with activation of autonomic nervous system and hemodynamic responses. Nasal CPAP (nCPAP) is an effective treatment for OSA, but little is known on its effect on chemoreflex sensitivity. OBJECTIVES: To assess the effect of nCPAP treatment or placebo (sham nCPAP) on ventilatory control in patients with OSA. SETTING: Sleep laboratory of Azienda Ospedaliera Garibaldi. PATIENTS: Twenty-five patients with moderate-to-severe OSA. DESIGN AND MEASUREMENTS: Patients were randomly assigned to either therapeutic nCPAP (use of optimal pressure, n = 15) or sham nCPAP (suboptimal pressure of 1 to 2 cm H2O, n = 10) in a double-blind fashion and treated for 1 month. A rebreathing test to assess ventilatory response to normocapnic hypoxia and normoxic hypercapnia was performed at basal condition and after 1 month of treatment. RESULTS: The use of therapeutic nCPAP or sham nCPAP did not affect daytime percentage of arterial oxygen saturation (SaO2%) or end-tidal P(CO2). The normocapnic hypoxic ventilatory response was reduced after 1 month of treatment with nCPAP (the slope was 1.08 +/- 0.02 L/min/SaO2% at basal condition and 0.53 +/- 0.07 L/min/SaO2% after 1 month of treatment, p = 0.008) [mean +/- SD], but not in patients treated with sham nCPAP (slope, 0.83 +/- 0.09 L/min/SaO2% and 0.85 +/- 0.19 L/min/SaO2% at basal condition and after 1 month, respectively). The normoxic hypercapnic ventilatory response remained unchanged after 1 month in both groups. No changes in ventilatory response to either hypoxia or hypercapnia were observed after a single night of nCPAP treatment. CONCLUSION: The ventilatory response to hypoxia is reduced during regular treatment, but not after short-term treatment, with nCPAP. Readjusted peripheral oxygen chemosensitivity during nCPAP treatment may be a side effect of both reduced sympathetic activity and increased baroreflex activity, or a possible continuous positive airway pressure-related mechanism leading to a reduced activation of autonomic nervous system per se.     

Respiratory stimulants and sleep periodic breathing at high altitude. Almitrine versus acetazolamide

We studied the effects of almitrine, acetazolamide, and placebo on the hypoxic ventilatory response (HVR), sleep periodic breathing, and arterial oxygen saturation (SaO2) in 4 healthy climbers. In a laboratory on Denali (Mt. McKinley) at 4,400 m (PB = 440 mm Hg), we used a double-blind, randomized, three-way crossover design. The HVR was measured during the waking state. Periodic breathing and SAO2% were measured during 3-h sleep studies. Almitrine and acetazolamide both increased SaO2% during sleep, although almitrine increased periodic breathing, whereas acetazolamide decreased periodic breathing. The HVR (delta VE/delta SaO2%) was doubled with almitrine (p less than 0.05), but unchanged with acetazolamide. The HVR was positively related to periodic breathing (p less than 0.05). We conclude that periodic breathing during sleep at high altitude is related to the hypoxic ventilatory response, and that acetazolamide is a superior agent to almitrine for ameliorating periodic breathing.     

Time domains of the hypoxic ventilatory response in awake ducks: episodic and continuous hypoxia

Time-dependent ventilatory responses to episodic and continuous isocapnic hypoxia were measured in unidirectionally ventilated, awake ducks. Three protocols were used: (1) ten 3-min episodes of moderate hypoxia (10% O(2)) with 5-min normoxic intervals; (2) three 3-min episodes of severe hypoxia (8% O(2)) with 5-min normoxic intervals; and (3) 30-min of continuous moderate hypoxia. Ventilation (V(I)) increased immediately within a hypoxic episode (acute response), followed by a further slow rise in V(I) (short-term potentiation). The peak V(T) response increased from the first to second moderate hypoxic episode (progressive augmentation), but was unchanged thereafter. During normoxic intervals, V(I) increased progressively (56% following the tenth episode; long term facilitation). Time-dependent changes were not observed during or following 30-min of continuous hypoxia. Although several time-dependent ventilatory responses to episodic hypoxia are observed in awake ducks, they are relatively small and biased towards facilitation versus inhibitory mechanisms.     

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 acclimatization to high altitude is prevented by CO2 breathing

The hypoxia of high altitude stimulates ventilation. If the resultant respiratory alkalosis inhibits the initial increase in ventilation, then with prevention of alkalosis, ventilation should rise immediately to a stable plateau. 4 subjects inspired CO2 (3.77%) from ambient air in a hypobaric chamber (PB = 440-455 Torr) during 100 h at high altitude. Ventilation (for given oxygen uptakes at rest and during exercise) increased promptly and remained stable. 4 control subjects exposed to high altitude without CO2 supplementation showed the expected progressive increases in ventilation with time. The hyperoxic CO2 ventilatory response curve shifted progressively to the left with time in the control subjects, but not in those given supplemental CO2. The latter group also failed to increase the ventilatory response to isocapnic hypoxia. Thus, CO2 supplementation at high altitude prevented the so-called "ventilatory acclimatization' from occurring. Prevention of respiratory alkalosis at high altitude probably permitted maintenance of [H+] at some central nervous system locus, thus allowing an uninhibited hypoxic stimulation of ventilation.     

Plasma Adenosine during Investigation of Hypoxic Ventilatory Response

Adenosine, an endogenous nucleoside, is released by hypoxic tissue, causes vasodilation, and influences ventilation. Its effects are mediated by P1-purinoceptors. We examined to what extent the plasma adenosine concentration in the peripheral venous blood correlates with hypoxic ventilatory response (HVR) and ventilatory drive P0.1 to find out whether endogenously formed adenosine has an influence on the individual ventilatory drive under hypoxic conditions. While investigating the HVR of 14 healthy subjects, the ventilatory drive P0.1 was measured with the shutter of a spirometer. Determination of the ventilatory drive P0.1(RA) started under room air conditions (21% O₂) and then inspiratory gas was changed to a hypoxic mixture of 10% O₂in N₂to determine P0.1(Hyp). At the time of the P0.1 measurements, two blood samples were taken to determine the adenosine concentrations. After removal of cellular components and proteins, samples were analyzed by high-pressure liquid chromatography (HPLC). Both adenosine concentrations in plasma under room air (r = 0.59, p< 0.05) and adenosine concentrations under hypoxia (r = 0.75, p< 0.01) correlated significantly with the ventilatory drive P0.1. In addition, plasma adenosine concentrations during hypoxic conditions showed a significant correlation with HVR on the 0.01 level (r = 0.71, p< 0.01). The results indicate a possible role of endogenous adenosine in the regulation of breathing in humans. We assume that endogenous adenosine influences the HVR and the ventilatory drive, probably by modulating the carotid body chemoreceptor response to hypoxia.     

Hypercapnic and hypoxic ventilatory responses in parents and siblings of children with congenital central hypoventilation syndrome

Children with congenital central hypoventilation syndrome (CCHS) have abnormal ventilatory responses to metabolic stimuli. As there is a genetically determined component of chemoreceptor sensitivity, parents and siblings of children with CCHS may also have blunted ventilatory responses to hypercapnea and hypoxia. To test this, we studied hypercapnic ventilatory responses and hypoxic ventilatory responses in six mothers, four fathers, and five siblings (6 to 49 yr of age) of seven children with CCHS and compared them with 15 age- and sex-matched control subjects (5 to 47 yr of age). Pulmonary function tests were not different between relatives of children with CCHS and control subjects. To measure hypercapnic ventilatory responses, subjects rebreathed 5% CO2/95% O2 until PACO2 reached 60 to 70 mm Hg. To measure hypoxic ventilatory responses (L/min/% SaO2), subjects rebreathed 14% O2/7% CO2/balance N2 at mixed venous PCO2 until SaO2 fell to 75%. All tests were completed in less than 4 min. Instantaneous minute ventilation, mean inspiratory flow (tidal volume/inspiratory time), and respiratory timing (inspiratory timing/total respiratory cycle timing) were calculated on a breath-by-breath basis. Hypercapnic ventilatory responses were 1.97 +/- 0.32 L/min/mm Hg PACO2 in children with CCHS relatives and 2.23 +/- 0.23 L/min/mm Hg PACO2 in control subjects. Hypoxic ventilatory responses were -1.99 +/- 0.37 L/min/% SaO2 in the relatives and -1.54 +/- 0.25 L/min/% SaO2 in the control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Changes in peripheral chemoreflex sensitivity during sustained, isocapnic hypoxia

One hypothesis concerning the origin of hypoxic ventilatory decline is that hypoxia acts centrally to depress peripheral chemoreflex loop activity. To investigate possible changes in peripheral chemoreflex loop activity during sustained, isocapnic hypoxia, the ventilatory responses to four one minute pulses of either extra hypoxia (45 Torr) or carbon dioxide (8 Torr above resting levels) were measured in man at minutes 2, 7, 12, and 17 of a 23 min isocapnic, hypoxic period (50 Torr). For hypoxia, the first pulse response (130%) was significantly greater (P less than 0.05) than the fourth response (74%). For CO2, pulse responses 2 and 3 (101 and 103%, respectively) were significantly greater (P less than 0.05) than the fourth response (91%). A central depression of peripheral chemoreflex loop activity should affect peripheral sensitivities to CO2 and hypoxia equally. Our results suggest that the peripheral sensitivity to hypoxia declined more than that to CO2, implying a peripheral chemoreceptor origin for hypoxic ventilatory decline.