Hypoxic Responsiveness Research Articles

VENTILATORY FLOW LIMITATION CONFOUNDS THE INFLUENCE OF RESTING CHEMORESPONSIVENESS ON SaO2

1083 Traditionally the capacity of the pulmonary system has been thought to be too large to limit exercise. However, it has been suggested that some athletes attain a mechanical limit to ventilatory flow generation during intense exercise (Johnson, Saupe, and Dempsey, 1992). In order to test the hypothesis that ventilatory flow limitation has an effect on oxygen delivery during exercise, 16 elite male runners were grouped based on the degree of expired flow limitation observed in flow volume loops collected during the final minute of an incremental progressive test to exhaustion. Eight flow limited(FL) (VO2max 75.85 ± 2.39 ml • kg-1 • min-1; 47.30 ± 20.4% expiratory flow limited) and eight non-flow limited subjects (NFL) (VO2max 75.55 ± 4.76 ml • kg-1 • min-1; 0.30 ± 0.80% expiratory flow limited) were tested for hypoxic ventilatory responsiveness (HVR). Independent groups ANOVA revealed no significant differences between FL and NFL for VO2max, VEmax (136.20 ± 16.03 vs. 137.49 ± 21.551• min-1), VE/VO2 (28.40 ± 3.19 vs. 27.64± 2.891 • IO2-1), HVR (0.23 ± 0.19 vs. 0.25± 0.14), or SaO2 at max (89.06 ± 2.39 vs. 86.62± 4.11%). A significant relationship was observed between HVR and SaO2 (r = 0.92, p ≤ 0.001) in NFL that was not present in FL. Also, a significant relationship between VE/VO2 and SaO2 (r = 0.79, ≤ 0.019) was observed in FL but not NFL. These relationships suggest that SaO2 is influenced by resting chemoresponsiveness in the NFL subjects, but this relationship is confounded by flow limitation in the FL subjects.

The Respiratory Effects of the Cytokine Regulating Agent HP 228 Alone and in Combination with Morphine in Human Volunteers

HP 228 is a synthetic heptapeptide analog of alpha-MSH that attenuates the production and release of inflammatory cytokines. The purpose of this study was to define HP 228’s effects, alone and in combination with morphine, on resting ventilation and the ventilatory response to hypoxia and hypercarbia. Six healthy nonsmoking young adult males completed the four-session experiment. Subjects first underwent an initial training session. During subsequent sessions, each subject was tested for the respiratory effects of intravenous HP 228 (30 μg/kg), morphine (0.15 mg/kg), or HP 228 (30 μg/kg) plus morphine (0.15 mg/kg) in a double-blind placebo-controlled randomized balanced within-subjects experimental design. Sessions began with baseline measurement of resting ventilation, oxygen consumption, the isocapnic hypoxic ventilatory response (HVR), and normoxic hypercapnic ventilatory response (HCVR). A second set of respiratory measurements were obtained 10 min after completion of HP 228 or placebo infusion. Morphine or placebo was then administered and ventilatory responses were determined 15 and 40 min postinfusion. HP 228 produced cutaneous flushing, but had no significant effect on respiration or hemodynamics. Morphine significantly decreased metabolism, resting ventilation, and hypoxic and hypercarbic ventilatory responsiveness, independent of prior HP 228 administration. A seventh subject experienced a significant cardiac arrhythmia upon exposure to hypoxia after receiving both HP 228 and morphine and was withdrawn from further study. In conclusion, in this early Phase I clinical trial, HP 228 was found to neither depress ventilation nor augment morphine-induced respiratory depression in healthy young males.

Human adaptation to high altitude: regional and life-cycle perspectives.

Studies of the ways in which persons respond to the adaptive challenges of life at high altitude have occupied an important place in anthropology. There are three major regions of the world where high-altitude studies have recently been performed: the Himalayas of Asia, the Andes of South America, and the Rocky Mountains of North America. Of these, the Himalayan region is larger, more geographically remote, and likely to have been occupied by humans for a longer period of time and to have been subject to less admixture or constriction of its gene pool. Recent studies of the physiological responses to hypoxia across the life cycle in these groups reveal several differences in adaptive success. Compared with acclimatized newcomers, lifelong residents of the Andes and/or Himalayas have less intrauterine growth retardation, better neonatal oxygenation, and more complete neonatal cardiopulmonary transition, enlarged lung volumes, decreased alveolar-arterial oxygen diffusion gradients, and higher maximal exercise capacity. In addition, Tibetans demonstrate a more sustained increase in cerebral blood flow during exercise, lower hemoglobin concentration, and less susceptibility to chronic mountain sickness (CMS) than acclimatized newcomers. Compared to Andean or Rocky Mountain high-altitude residents, Tibetans demonstrate less intrauterine growth retardation, greater reliance on redistribution of blood flow than elevated arterial oxygen content to increase uteroplacental oxygen delivery during pregnancy, higher levels of resting ventilation and hypoxic ventilatory responsiveness, less hypoxic pulmonary vasoconstriction, lower hemoglobin concentration, and less susceptibility to CMS. Several of the distinctions demonstrated by Tibetans parallel the differences between natives and newcomers, suggesting that the degree of protection or adaptive benefit relative to newcomers is enhanced for the Tibetans. We thus conclude that Tibetans have several physiological distinctions that confer adaptive benefit consistent with their probable greater generational length of high-altitude residence. Future progress is anticipated in achieving a more integrated view of high-altitude adaptation, incorporating a sophisticated understanding of the ways in which levels of biological organization are articulated and a recognition of the specific genetic variants contributing to differences among high-altitude groups.

Effect of chronic resistive loading on hypoxic ventilatory responsiveness.

Depression of ventilation mediated by endogenous opioids has been observed acutely after resistive airway loading. We evaluated the effects of chronically increased airway resistance on hypoxic ventilatory responsiveness shortly after load imposition and 6 wk later. A circumferential tracheal band was placed in 200-g rats, tripling tracheal resistance. Sham surgery was performed in controls. Ventilation and the ventilatory response to hypoxia were measured by using barometric plethysmography at 2 days and 6 wk postsurgery in unanesthetized rats during exposure to room air and to 12% O2-5% CO2-balance N2. Trials were performed with and without naloxone (1 mg/kg i.p.). Room air arterial blood gases demonstrated hypercapnia with normoxia in obstructed rats at 2 days and 6 wk postsurgery. During hypoxia, a 30-Torr fall in PO2 occurred with no change in PCO2. Hypoxic ventilatory responsiveness was suppressed in obstructed rats at 2 days postloading. Naloxone partially reversed this suppression. However, hypoxic responsiveness at 6 wk was not different from control levels. Naloxone had a small effect on ventilatory pattern at this time with no overall effect on hypoxic responsiveness. This was in contrast to previously demonstrated long-term suppression of CO2 sensitivity in this model, which was partially reversible by naloxone only during the immediate period after load imposition. Endogenous opioids apparently modulate ventilatory control acutely after load imposition. Their effect wanes with time despite persistence of depressed CO2 sensitivity.

Prenatal cocaine: effect on hypoxic ventilatory responsiveness in neonatal rats

The effects of prenatal (embryonic days 7–21) cocaine (30 mg/kg b.i.d., s.c.) exposure on postnatal respiratory and behavioral responsiveness to acute hypoxia were investigated in 5-day-old (P5) rat pups. Control and cocaine-exposed pups were subjected to 20 min of 0.21 FI O 2 followed by 20 min of 0.08 FI O 2 . Although all pups demonstrated the characteristic biphasic response to hypoxia, cocaine-exposed pups exhibited a blunted, initial response in minute ventilation ( p < 0.05) and inspiratory drive ( p < 0.05) as compared with control pups who showed increases in these measures ( p < 0.01 and p < 0.05, respectively). The consequence of this apparent blunted ventilatory response was reflected in blood gas data gathered after 20 min of 0.08 FI O 2 : P CO 2 ( p < 0.05) and base-excess ( p < 0.05) were increased and HCO − 3 ( p < 0.05) and S O 2 ( p < 0.01) were decreased relative to control pups. Cocaine-exposed pups also exhibited behavioral evidence of decreased struggling ( p < 0.001) in response to the hypoxic challenge. These data in the rat confirm our previous findings of altered ventilatory responsiveness to inspired hypoxia in the rabbit and extend our observations of a decreased ability to successfully compensate and behaviorally arouse following prenatal cocaine-exposure, thus underscoring the potential vulnerability of infants so exposed.

Development of ventilatory responsiveness to progressive hypoxia and hypercapnia in low-birth-weight lambs.

Our aim was to determine the effects of low birth weight on ventilatory responses to progressive hypoxia and hypercapnia during early postnatal life. Seven low-birth-weight (2.7 +/- 0.3 kg) and five normal-birth-weight (4.8 +/- 0.2 kg) lambs, all born at term, underwent weekly rebreathing tests during wakefulness while arterial PO2, PCO2, and pH were measured. Hypoxic ventilatory responsiveness (HOVR; percent increase in ventilation when arterial PO2 fell to 605 of resting values) increased in normal lambs from 86.6 +/- 7.1% at week 1 to 227.4 +/- 24.9% at week 6. In low-birth-weight lambs, HOVR was not significantly different at week 1 (60.1 +/- 18.7%) from that of normal lambs but did not increase with postnatal age (56.6 +/- 19.3% at week 6). HOVR of all lambs at 6 wk was significantly correlated with birth weight (r2 = 0.8). Hypercapnic ventilatory responsiveness (gradient of ventilation vs. arterial PCO2) did not change with age and was not significantly different between groups [84.7 +/- 7.5 (low-birth-weight lambs) vs. 89.4 +/- 6.6 ml.min-1.kg-1.mmHg-1 (normal lambs)]. We conclude that intrauterine conditions that impair fetal growth lead to the failure of HOVR to increase with age.

Attenuation of the hypoxic ventilatory response in adult rats following one month of perinatal hyperoxia.

1. This study was designed to test the hypothesis that perinatal suppression of peripheral arterial chemoreceptor inputs attenuates the hypoxic ventilatory response in adult rats. Perinatal suppression of peripheral chemoreceptor activity was achieved by exposing rats to hyperoxia throughout the first month of life. 2. Late-gestation pregnant rats were housed in a 60% O2 environment, exposing the pups to hyperoxia from several days prior to birth until they were returned to normoxia on postnatal day 28. These perinatally treated rats were then reared to adulthood (3-5 months old) in normoxia. In addition to the mother rats, adult male rats were also exposed to hyperoxia, creating an adult-treated control group. Two to four months after the hyperoxic exposure, treated rats were compared with untreated male rats of similar age. 3. A whole-body, flow-through plethysmograph was used to measure hypoxic and hypercapnic ventilatory responses of the unanaesthetized adult rats. In moderate hypoxia (arterial oxygen partial pressure, Pa,O2 approximately 48 mmHg). VE (minute ventilation) and the ratio VE/VCO2 (ventilation relative to CO2 production) increased by 16.7 +/- 4.0 and 35.4 +/- 3.4%, respectively, in perinatal-treated rats (means +/- S.E.M.), but increased more in untreated control rats (51.4 +/- 2.8 and 83.1 +/- 4.3%; both P < 10(-6)). 4. In contrast to the impaired hypoxic ventilatory response, ventilatory responses to hypercapnia (5% CO2) were similar between untreated control and perinatal-treated rats. 5. Impaired hypoxic responsiveness was unique to the perinatal-treated rats since hypoxic ventilatory responses were not attenuated in adult-treated rats. 6. The results indicate that ventilatory responses to hypoxaemia are greatly attenuated in adult rats that had experienced hyperoxia during their first month of life, and suggest that normal hypoxic ventilatory control mechanisms are susceptible to developmental plasticity.

Hypoxic ventilatory responses in Tibetan residents of 4400 m compared with 3658 m

Lifelong Tibetan residents of 3658 m ventilate as much and have hypoxic and hypercapnic ventilatory responsiveness as least as great as acclimatized newcomers, and likely greater than lifelong North or South American high-altitude residents. To determine whether Tibetans residing at altitudes > 3658 m maintained similar levels of ventilation, hypoxic and hypercapnic ventilatory responses, we transported 20 lifelong residents of ≥ 4400 m to 3658m for comparison with 27 similarly-aged male Tibetan residents of 3658 m. At 3658 m, the 4400 m compared with the 3658 m Tibetans had similar levels of minute ventilation and arterial O 2 saturation, higher respiratory quotients but lower hypoxic ventilatory responses. We concluded that Tibetan residents of ≥ 4400 m ventilate as much as Tibetan residents of 3658 m despite an altitude-associated blunting of their hypoxic ventilatory responses. Thus, factors other than hypoxic ventilatory chemosensitivity are likely to be important contributors to resting ventilation among Tibetan high altitude residents.

Diuretic effect of acute hypoxia in humans: relationship to hypoxic ventilatory responsiveness and renal hormones

ARTICLESDiuretic effect of acute hypoxia in humans: relationship to hypoxic ventilatory responsiveness and renal hormonesA. HonigA. HonigPublished Online:01 Feb 1995https://doi.org/10.1152/jappl.1995.78.2.375MoreSectionsPDF (488 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat "Diuretic effect of acute hypoxia in humans: relationship to hypoxic ventilatory responsiveness and renal hormones." Journal of Applied Physiology, 78(2), pp. 375–376 Previous Back to Top Next Download PDF FiguresReferencesRelatedInformation More from this issue > Volume 78Issue 2February 1995Pages 375-376 Copyright & PermissionsCopyright © 1995 the American Physiological Societyhttps://doi.org/10.1152/jappl.1995.78.2.375PubMed7759404History Published online 1 February 1995 Published in print 1 February 1995 Metrics

Effects of testosterone on hypoxic ventilatory and carotid body neural responsiveness.

Hypoxic (HVR) and hypercapnic ventilatory responses (HCVR) are known to be influenced by the administration of testosterone, but whether the hormone acts centrally or peripherally is unknown. To determine whether testosterone alters HVR, HCVR, and carotid sinus nerve (CSN) responsiveness to hypoxia, we compared the ventilatory and CSN responses of neutered male cats treated with testosterone with those of placebo-treated cats. Testosterone treatment increased resting ventilation and CO2 production but did not change end-tidal or arterial PCO2, implying that alveolar ventilation per unit CO2 production was unaltered. Testosterone treatment raised the HVR shape parameter A value 63% in the awake animals (from 16.9 +/- 4.2 to 28 +/- 4, p < 0.05) and 69% in the anesthetized cats (from 22.4 +/- 0.9 to 37.8 +/- 3.7, p < 0.05). Testosterone also augmented the HCVR slope S in awake cats (from 0.17 +/- 0.02 to 0.25 +/- 0.04, p < 0.05). Placebo treatment did not change HVR or HCVR. The CSN response to hypoxia was greater in the testosterone-treated than in the placebo-treated animals (A = 53.6 +/- 7.1 versus 27.1 +/- 5.5 respectively, p < 0.05). The crossplot of the simultaneously measured CSN activity and ventilation during progressive hypoxia showed that the central nervous system translation of CSN output into ventilation was similar in the hormone- and placebo-treated groups. Unilateral, proximal sectioning of the CSN decreased the ventilatory and the CSN responses to hypoxia in the testosterone-treated animals but not in the placebo group. These results indicated that testosterone increased hypoxic and hypercapnic ventilatory responsiveness and increased hypoxic sensitivity of the carotid body.(ABSTRACT TRUNCATED AT 250 WORDS)

Increase of cerebral blood flow at high altitude: its possible relation to AMS.

CBF increases with acute hypoxia despite the opposing vasoconstrictor effects of the drop in pCO2 caused by hyperventilation. Maintaining normocapnia by adding CO2 the hypoxic CBF responsiveness about doubles. As we have shown recently by this test, the hypoxic CBF response is not blunted but rather somewhat sharpened over five days at almost 4000 meters of altitude. This, along with other evidence, shows that CBF does not in itself adapt to chronic hypoxia. Nevertheless, a decrease in CBF is seen over days at constant altitude primarily due to increase in the hematocrit. The cerebral vasodilatation cannot explain the usual (mild) form of AMS. But it may well be involved in the pathogenesis of the rare but severe cerebral form of AMS, as prolonged increased capillary pressure in vasodilated areas could lead to vasogenic cerebral edema.

Hypoxic ventilatory response and carotid endarterectomy

Carotid endarterectomy is reported to abolish hypoxic ventilatory responsiveness. This effect is thought to be due to denervation or destruction of the carotid bodies by surgical exposure. The technique of carotid endarterectomy, however, does not require the sacrifice of these structures. Six patients who had bilateral carotid endarterectomy with careful preservation of the carotid bodies and their innervation were studied pre- and postoperatively with respect to hypoxic ventilatory responsiveness and the latter was taken as a measure of chemoreceptor activity. Five patients showed a weak or absent response to hypoxia before surgery. In four of these there was a significant increase in reactivity after the procedure (p less than 0.01 in one case, p less than 0.05 in three others). The fifth patient had a non-significant increase and the sixth had a normal response before and after surgery. Thus, loss of chemoreceptor function after bilateral carotid endarterectomy was not observed in this group of patients with preserved carotid bodies. The low ventilatory hypoxic sensitivity before surgery and its occasional increase after removal of the plaque suggests that atherosclerosis might well impair the microscopic blood supply to the carotid bodies, inducing sensor dysfunction but this hypothesis requires further investigation.

Decreased Ventilation and Hypoxic Ventilatory Responsiveness Are Not Reversed by Naloxone in Lhasa Residents with Chronic Mountain Sickness

Persons with chronic mountain sickness (CMS) hypoventilate and are more hypoxemic than normal individuals, but the cause of the hypoventilation is unclear. Studies of 14 patients with CMS and 11 healthy age-matched control subjects residing in Lhasa, Tibet, China (3,658 m) were conducted to test the hypothesis that hypoventilation, blunted hypoxic ventilatory responsiveness (HVR), and hypoxic ventilatory depression of CMS were due to increased endogenous opioid production. Patients with CMS compared with control subjects exhibited hypoventilation (end-tidal carbon dioxide pressure [PETCO2] = 36.6 +/- 1.0 versus 31.5 +/- 0.5 mm Hg, p less than 0.05), lower tidal volume (VT = 0.54 +/- 0.02 versus 0.61 +/- 0.02 ml BTPS, p less than 0.05), blunted HVR (shape parameter A = 17 +/- 8 versus 114 +/- 22 mm Hg/L BTPS/min, p less than 0.05), and a depressant effect of ambient hypoxia on ventilation (delta PETCO2 with acute hyperoxia = -3.5 +/- 0.5 versus -1.0 +/- 0.6 mm Hg, p less than 0.05). Reduced forced expiratory volume in 1 s to vital capacity ratios (FEV1/VC) and a higher proportion of cigarette smokers in the group of patients with CMS compared with control subjects suggested that at least some patients with CMS had mild airway obstructive lung disease. Naloxone infusion (0.14 mg/kg) to six patients with CMS did not change resting VT, PETCO2, HVR, or SaO2.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of estrogen and progesterone on carotid body neural output responsiveness to hypoxia

Pregnancy increases ventilatory and carotid body neural output (CBNO) responsiveness to hypoxia in cats (J. Appl. Physiol. 67: 797-803, 1989). To determine whether progesterone and estrogen stimulated hypoxic ventilatory and CBNO responsiveness, we studied 24 castrated male cats before and after 1 wk of placebo, estrogen, progesterone, or estrogen plus progesterone treatment. Estrogen plus progesterone treatment decreased end-tidal PCO2 (-3.8 +/- 0.8 Torr) and increased hypoxic ventilatory responsiveness, whereas estrogen or progesterone alone had no effect. Animals receiving progesterone alone or in combination with estrogen had higher CBNO responsiveness than placebo or estrogen-treated animals (shape parameter A = 45 +/- 7 vs. 27 +/- 4, P less than 0.05). However, the group treated with estrogen plus progesterone did not have greater CBNO responsiveness to hypoxia than the group receiving progesterone alone. The cross plot of the simultaneously measured CBNO and ventilation during progressive hypoxia revealed a greater slope in the estrogen-treated than in the placebo animals, suggesting that estrogen treatment increased central nervous system transduction of CBNO into ventilation. Thus the data taken together suggested that progesterone and estrogen had a combination of peripheral (carotid body) and central sites of action such that the administration of both hormones together had a more consistent stimulatory effect on hypoxic ventilatory responsiveness than either hormone alone.

VENTILATORY RESPONSES TO HYPOXIA AND HYPERCAPNIA IN ASTHMATICS WITH PREVIOUS RESPIRATORY FAILURE

The ventilatory response to hypoxia and the ventilatory and mouth occlusion pressure response to hypercapnia was measured in 13 subjects who had previously developed respiratory failure or respiratory arrest during an acute asthma attack. In 11 of 12 subjects tested there was a normal response to hypercapnia. Six of the 13 subjects had an impaired response to hypoxia. Impaired hypoxic responsiveness may contribute to the early onset of hypercapnic respiratory failure during acute severe asthma.

Relation of TXA2 and PGI2 to the difference in hypoxic pulmonary vasoconstriction between different strains of rats

TXB2 and 6-keto-PGF1 alpha levels in arterial and venous plasma of Wistar and Hilltop rats during hypoxia were measured to investigate the roles of TXA2 and PGI2 in hypoxic pulmonary vasoconstriction (HPV) and responsiveness difference of pulmonary vessels to hypoxia between different strains of rats. The results showed that PGI2 might play an important role in maintaining the low resistance in pulmonary circulation of these two strains of rats. Increased TXA2 during hypoxia may partially mediate HPV in Wistar rats, while augmented PGI2 during hypoxia may modulate HPV in Wistar rats. This might be the important mechanism responsible for more intensive responsiveness of pulmonary vessels to hypoxia in Hilltop rats than in Wistar rats.

Hypoxic and hypercapnic ventilatory responses in awake children with congenital central hypoventilation syndrome.

Congenital central hypoventilation syndrome (CCHS) has been thought to be a disorder of central chemoreceptor responsiveness. Previous studies in CCHS have shown decreased or absent ventilatory responsiveness to both hypercarbia and hypoxia. However, hypoxic responsiveness during wakefulness has not been systematically studied. We studied hypoxic and hypercapnic ventilatory responses during wakefulness in five children with CCHS (6 to 11 yr of age). To measure the hypercapnic response, the children rebreathed a hyperoxic hypercapnic mixture until PaCO2 reached 56 to 69 mm Hg. For the hypoxic response, the children rebreathed a hypoxic gas mixture, at mixed venous PCO2, until SaO2 had fallen to less than 78%. We found that the ventilatory responses to hypercapnia and hypoxia were very variable (linear correlation coefficients ranging from -0.44 to +0.63 for hypercapnic responses and from -0.15 to +0.77 for hypoxic responses), with no significant change from baseline in response to either stimulus. There was no evidence of progressive ventilatory stimulation despite increasing stimulus. Additionally, these children had no subjective sensation of dyspnea or discomfort. This establishes that hypoxic and hypercapnic ventilatory control is absent during wakefulness. Chemoreceptor control (peripheral and central) is, therefore, defective in all states in children with CCHS. We speculate that the defect in CCHS lies in central integration of the central and peripheral chemoreceptor signals.

Ethanol-induced depression of hypoxic drive and reversal by naloxone--a sex difference.

The effects of ethanol ingestion and subsequent intravenously administered naloxone on the ventilatory response to hypercapnic hypoxia in 8 normal males and 8 normal females were examined. The responses of controls were lower in the females (-0.63 +/- 0.07 L/min/% SaO2) than the males (-1.11 +/- 0.18 L/min/% SaO2). Alcohol depressed the male response to a mean of -0.50 +/- 0.08 L/min/%SaO2 (p less than 0.01) but increased the mean female response to -0.87 +/- 0.11 L/min/%SaO2 (p less than 0.01). Naloxone reversed the ethanol-induced depression of the hypercapnic hypoxic response in males, but had no effect on the female response. In males there was a direct correlation between the magnitude of the initial hypoxic response and the extent of depression by ethanol; the higher the response the greater the depression. Females showed a significant direct correlation between the blood alcohol and the increase in hypercapnic hypoxic slope, whereas males showed a weaker inverse correlation to blood alcohol level. These results demonstrate that ethanol depresses male but not female hypoxic ventilatory responsiveness and suggest that this is mediated by opioid-like mechanisms. Because the alcohol-induced depression was seen in subjects with a high control hypoxic response, the male-female difference might simply reflect initially lower control responses in females. This suggests a qualitative difference in hypoxic ventilatory control mechanisms between sexes.

Prediction and reversal of blunted ventilatory responsiveness in patients with hypothyroidism

To define the prevalence of impaired ventilatory responses in hypothyroidism, clinical and chemical parameters predicting their presence, and the potential for their acute reversal, ventilatory responses to hypercapnia and hypoxia were studied in 38 hypothyroid patients before treatment, and after short-term (seven days) and long-term (12 to 24 weeks) thyroid hormone therapy. Before treatment, hypercapnic ventilatory responses were blunted in 10 of 29 patients (34 percent), whereas hypoxic ventilatory responses were abnormal in eight of 30 patients (27 percent). Hypothyroid women and patients with marked pretreatment elevation of the serum thyrotropin concentration (greater than 90 mU/liter) were significantly more likely to have impaired ventilatory responses. In patients with an abnormal pretreatment response, parenteral thyroid hormone therapy (25 to 50 μg of L-triiodothyronine or 100 μg of L-thyroxine per day for seven days) significantly enhanced hypercapnic (0.75 ± 0.06 to 1.19 ± 0.16 liters/minute/mm Hg, p <0.05) and hypoxic (93 ± 12 to 176 ± 31 liters · mm Hg/minute, p <0.05) ventilatory responsiveness acutely. In seven of nine patients with abnormal pretreatment hypercapnic responses, and six of eight patients with abnormal hypoxic responses, normal ventilatory responsiveness was restored after one week of therapy. It is concluded that: (1) a subset of hypothyroid patients have blunted ventilatory responses to hypercapnia and/or hypoxia; (2) hypothyroid women and patients with a serum thyrotropin greater than 90 mU/liter more often manifest this abnormality; and (3) thyroid hormone therapy for one week reverses impaired ventilatory responses in hypothyroidism.

Low acute hypoxic ventilatory response and hypoxic depression in acute altitude sickness

Persons with acute altitude sickness hypoventilate at high altitude compared with persons without symptoms. We hypothesized that their hypoventilation was due to low initial hypoxic ventilatory responsiveness, combined with subsequent blunting of ventilation by hypocapnia and/or prolonged hypoxia. To test this hypothesis, we compared eight subjects with histories of acute altitude sickness with four subjects who had been asymptomatic during prior altitude exposure. At a simulated altitude of 4,800 m, the eight susceptible subjects developed symptoms of altitude sickness and had lower minute ventilations and higher end-tidal PCO2's than the four asymptomatic subjects. In measurements made prior to altitude exposure, ventilatory responsiveness to acute hypoxia was reduced in symptomatic compared to asymptomatic subjects, both when measured under isocapnic and poikolocapnic (no added CO2) conditions. Diminution of the poikilocapnic relative to the isocapnic hypoxic response was similar in the two groups. Ventilation fell, and end-tidal PCO2 rose in both groups during 30 min of steady-state hypoxia relative to values observed acutely. After 4.5 h at 4,800 m, ventilation was lower than values observed acutely at the same arterial O2 saturation. The reduction in ventilation in relation to the hypoxemia present was greater in symptomatic than in asymptomatic persons. Thus the hypoventilation in symptomatic compared to asymptomatic subjects was attributable both to a lower acute hypoxic response and a subsequent greater blunting of ventilation at high altitude.