Ventilatory responses to hypercapnia and hypoxia following chronic hypercapnia in the rat

This study investigated the effects of an 18 week exposure to 10% CO(2) in air on minute ventilation (V(E)), breathing pattern and the chemoresponiveness of rats to hypoxic and hyperoxic stimuli. We found that V(E) remained elevated over the 18 weeks. Nonetheless, the breathing pattern changed significantly. Tidal volume increased and the durations of inspiration and the total cycle decreased. After the sustained hypercapnia the mean Pa(CO(2)) was 72.0+/-5.1 (S. D.) mmHg. Every 6 weeks the chemoresponiveness of the CO(2)-exposed rats was tested by an acute exposure sequentially to room air, then a 6% O(2), 10% CO(2) and 84% N(2) gas mixture, and finally a 90% O(2) in 10% CO(2) mixture. On either room air or the hyperoxic-hypercapnic mixture V(E) fell to its pre-hypercapnic level. On the hypoxic-hypercapnic mixture V(E) increased significantly. These results demonstrate that the initial stimulating effect of 10% CO(2) on V(E) persisted for the entire 18 weeks without altering hypoxic or hyperoxic ventilatory responses.     

Ventilatory responses of aged male and female rats to hypercapnia and to hypoxia

Ventilatory parameters such as tidal volume, minute ventilation (VE), and inspiratory flow rate decrease in 24- vs. 12-month-old male and female rats. Differences between male and female values are maintained with age. Ventilatory response male and female rats exhibit to hypercapnia is altered by a decrease of the intercept, but not the slope value. The pattern of breathing exhibited by young females and males in response to hypercapnia (i.e. an increase of VT and f) is different than that noted in old males and females (i.e. an increase in VT only). In contrast, the ventilatory response both of slope and intercept male rats show by 24 months is decreased compared to the 12-month value; but the slope value is actually increased in the older vs. younger female rats in response to hypoxia.     

Central sleep apnea in stable methadone maintenance treatment patients

STUDY OBJECTIVES: Methadone, a long-acting mu-opioid agonist, is an effective treatment for heroin addiction. Our previous data show that 6 of 10 methadone maintenance treatment (MMT) patients had central sleep apnea (CSA). This study aims to confirm these results and to investigate the pathogenesis of the CSA. METHODS: Twenty-five male and 25 female MMT patients and 20 age-, sex-, and body mass index (BMI)-matched normal subjects were tested with polysomnography, blood toxicology, and ventilatory responses to hypoxia and hypercapnia. Resting cardiorespiratory tests were performed in the MMT group RESULTS: MMT patients and normal subjects were 35 +/- 9 years old (mean +/- SD), and BMI values were 27 +/- 6 kg/m2 and 27 +/- 5 kg/m2, respectively. Thirty percent of MMT patients had a central apnea index (CAI) > 5, and 20% had a CAI > 10. All normal subjects had a CAI < 1, and no difference was found in obstructive apnea-hypopnea index between the two groups. Methadone blood concentration was the only significant variable (t = 2.33, p = 0.025) associated with CAI and explains 12% of the variance. Awake Pa(CO2), antidepressant use, reduced ventilatory response to hypercapnia, and widened awake alveolar-arterial oxygen pressure gradient together explain a further 17% of the CAI variance. CONCLUSIONS: Thirty percent of stable MMT patients have CSA, a minority of which can be explained by blood methadone concentration. Other physiologic variables may also play a role in the pathogenesis of CSA in MMT patients, and further research is indicated in this area.     

Ventilatory and respiratory muscle responses to hypercapnia in patients with paraplegia

To evaluate ventilatory and respiratory muscle responses to hypercapnia in patients with paraplegia with paralysis of abdominal muscles, we studied seven patients with complete transection of the midthoracic cord (Th6-Th7) and six normal subjects. Minute ventilation (V E) and mean inspiratory flow responses to hypercapnia were similar in normal subjects and patients with paraplegia, but in the latter, at any given level of end-tidal CO(2) partial pressure (PET(CO(2))), tidal volume (VT) was reduced and frequency was increased. In normal subjects during hypercapnia, end-expiratory transpulmonary pressure (PL) and abdominal volume at end expiration decreased markedly, whereas end-expiratory volume of the rib cage (Vrc,E) remained constant, suggesting progressive recruitment of abdominal muscles. In patients with paraplegia compared to normal subjects the decrease in end-expiratory PL was reduced, and it was associated with a decrease in Vrc,E, suggesting recruitment of rib cage expiratory muscles. For a PET(CO(2)) of 70 mm Hg the estimated expiratory muscle contribution to VT was 10.3 and 28.4% (p < 0.02) in patients with paraplegia and normal subjects, respectively. We conclude that the V E-CO(2) relationship is preserved in patients with paraplegia with the development of a rapid and shallow pattern of breathing. This suggests that expiratory muscle paralysis elicits adaptation of the ventilatory control system similar to that observed in patients with generalized respiratory muscle weakness.     

Ventilatory and occlusion pressure responses to hypercapnia in patients with chronic renal failure

Little is known of the effect of chronic renal failure (CRF) on ventilatory regulation. In 38 subjects (19 healthy, 19 with CRF before and after dialysis), we performed measurements of ventilation (VE) and occlusion pressure (P0.1) while the subjects were breathing air and hypercapnic gas mixtures. The results have shown that (1) during air ventilation, CRF patients exhibited lower values of VE and P0.1, which returned to normal after dialysis; (2) during hypercapnic ventilation, CRF patients had the same response as healthy subjects for VE but higher P0.1; hemodialysis induced an upward shift of the CO2 response curve in CRF patients. A twofold mechanism is probably involved: pulmonary edema, which reduces lung elasticity, and neuromuscular hypoexcitability, both implying a stronger central command.     

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.     

Cardiac responses to hypoxia and hypercapnia in spinal man

The purpose of this study was to evaluate the effect of interruptionof the descending supraspinal sympathetic outflow on heart ratecontrol during exposures to chemical stimuli. We investigatedthe heart rate responses to progressive isocapnic hypoxia andhyperoxic hypercapnia using the rebreathing technique and quantifiedthe relationship between heart rate (HR), oxygen saturation(SaO₂), alveolar PCO₂ (P_ACO₂), and minute ventilation (V_E) in16 chronic tetraplegic subjects with low cervical spinal cordtransection. The HR responses were determined from the linearslopes of HR on SaO₂ and HR on P_ACO₂. We found that mean restingheart rate was within normal range; 66 ±3 (SEM) beatsmin^–1. HR increased as oxygenation fell or CO₂ tensionrose. The mean tetraplegic HR/SaO₂ was 0.83 ± 0.14 beatsmin^–1 per 1% fall in SaO₂ and that of HR/P_ACO₂ was 0.30± 0.13 beats min^–1 per mmHG rise in P_ACO₂. TheHR and V_E responses to either hypoxia or hypercapnia were relatedin the tetraplegic subjects. We conclude that the stimulatoryHR reponses to chemical stimuli are not suppressed by cervicalspinal cord transection. Thus, the descending sympathetic activitydoes not underlie the HR acceleration by chemical stimuli.     

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.     

Respiratory and cerebrovascular responses to hypoxia and hypercapnia in familial dysautonomia

Although cardiorespiratory complications contribute to the high morbidity/mortality of familial dysautonomia (FD), the mechanisms remain unclear. We evaluated respiratory, cardiovascular, and cerebrovascular control by monitoring ventilation, end-tidal carbon dioxide (CO2-et), oxygen saturation, RR interval, blood pressure (BP), and midcerebral artery flow velocity (MCFV) during progressive isocapnic hypoxia, progressive hyperoxic hypercapnia, and during recovery from moderate hyperventilation (to simulate changes leading to respiratory arrest) in 22 subjects with FD and 23 matched control subjects. Subjects with FD had normal ventilation, higher CO2-et, lower oxygen saturation, lower RR interval, and higher BP. MCFV was also higher but depended on the higher baseline CO2-et. In the FD group, whereas hyperoxic hypercapnia induced normal cardiovascular and ventilatory responses, progressive hypoxia resulted in blunted increases in ventilation, paradoxical decreases in RR interval and BP, and lack of MCFV increase. Hyperventilation induced a longer hypocapnia-induced apneic period (51.5 +/- 9.9 versus 11.2 +/- 5.5 seconds, p < 0.008) with profound desaturation (to 75.8 +/- 3.5%), marked BP decrease, and RR interval increase. Subjects with FD develop central depression in response to even moderate hypoxia with lack of expected change in cerebral circulation, leading to hypotension, bradycardia, hypoventilation, and potentially respiratory arrest. Higher resting BP delays occurrence of syncope during hypoxia. Therapeutic measures preventing hypoxia/hypocapnia may correct cardiovascular accidents in patients with FD.     

Peripheral chemoreceptor control of fetal renin responses to hypoxia and hypercapnia

The renin response to hypoxia in late gestation fetal sheep has been well characterized. However, the renin response to asphyxia--the combination of hypoxia and hypercapnia--has not been extensively studied. The purpose of this study was to determine 1) the interaction of hypoxia and hypercapnia in the control of renin secretion in late gestation fetal sheep and 2) the role of peripheral arterial chemoreceptors therein. Chronically catheterized fetal sheep (intact or sinoaortic denervated) were exposed to hypoxia and/or hypercapnia for 30 minutes. Hypercapnia alone had no effect on plasma renin activity or aldosterone but did result in a significant increase in angiotensin II. Hypercapnia combined with hypoxia resulted in a significant increase in renin activity, angiotensin II, and aldosterone. Sinoaortic denervation attenuated the renin and angiotensin II responses to hypercapnia plus hypoxia. The increase in renin and angiotensin II in response to hypercapnia with or without concomitant hypoxia strongly correlated with the magnitude of the decrease in arterial pH in intact fetuses only. Hypoxia alone and in concert with hypercapnia increased mean arterial pressure and decreased heart rate in intact but not sinoaortic denervated fetuses. We conclude that 1) hypercapnia more potently increases plasma renin activity than does hypoxia in late gestation fetal sheep, 2) arterial pH may be the relevant signal perceived by the peripheral arterial chemoreceptors for the control of the renin-angiotensin system during asphyxia, and 3) the cardiovascular response to hypoxia is mediated, in part, by peripheral arterial chemoreceptors.     

Differing responses to hypercapnia and hypoxia following pneumotaxic center ablation.

The respiratory responses of 21 cats were examined upon exposure to hypercapnia and isocapnic hypoxia. Animals having bilateral electrolytic lesions localized in the pontile pneumotaxic center exhibited hypercapnia-induced minute volumes which were significantly less than those of unlesioned control cats. The hypoxia-induced minute volumes of pneumotaxic lesioned animals, examined at isocapnic alveolar gas partial pressures, were likewise significantly less than control animals at end-expired oxygen partial pressures (PAO2) in excess of 65.0 mm Hg. At PAO2 levels below 65.0 mmHg. the minute volume of experimental animals rose sharply and became statistically indistinguishable from that of the unlesioned cats. The placement of control brain stem lesions typically produced no significant alterations in the respiratory responses to hypoxia or hypercapnia. It was concluded that the pneumotaxic center constitutes an integral component of the central chemoreceptor CO1-H+ CONTROLLING SUBSYSTEM. The concept of differing anatomical sites within the brain stem serving integrative functions for central chemoreceptor and peripheral chemoreceptor afferent stimuli is also supported.     

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.     

Prenatal cigarette smoke exposure and postnatal respiratory responses to hypoxia and hypercapnia

Prenatal cigarette smoke (CS) exposure, in combination with hypoxia and/or hyperthermia can lead to gasping and attenuated recovery from hypoxia in 7 days old rat pups. We studied 95 unanesthetized spontaneously breathing 14 days old rat pups to investigate if the destabilizing effects of increased ambient temperature and prenatal CS exposure on respiratory control observed in 7 days old rats were still evident at day 14. This postnatal age was selected as it is beyond the analogous risk period for SIDS in human. Furthermore, we investigated if the breathing responses to hypercapnia are affected by prenatal CS exposure. Since high ambient (HA) temperature can lead to gasping and aberrant respiratory control, we recorded respiratory patterns at low (24-25°C) and high (29-30°C) ambient temperatures, and under hypoxic or hypercapnic states. No gasping was observed in 14 days old rat pups. During hypoxia, breathing frequency increased in the CS-exposed group under low and HA temperatures. Rectal temperature decreased only in the sham group in response to low ambient temperature hypoxia. At HA temperature, breathing frequency increased in both sham and CS-exposed groups during hypercapnia, however, it remained elevated during washout period only in the sham group. We demonstrate that prenatal CS exposure continues to have profound effects on respiratory and thermoregulatory responses to hypoxia and hypercapnia at day 14. The attenuated respiratory and thermoregulatory responses to acute hypoxia and hypercapnia on day 14 demonstrate a strong interaction between CS exposure, respiratory control, and thermoregulation during postnatal maturation.     

Developmental changes in cardio-respiratory responses to hypoxia and hypercapnia in anesthetized low-birth-weight rats

The present study compared the developmental changes in the cardio-respiratory responses to hypoxia and hypercapnia between full-term low-birth-weight (LBW) and control rats during the postnatal period. The heart rate (HR), respiratory frequency (fR) and amplitude (aR) were measured during hypoxia (10% O(2) for 10 min) and hypercapnia (5% CO(2) for 10 min) in rats aged 7, 14 and 21 days, anesthetized with urethane. During hypoxia, HR was not significantly modified in the younger rats of both groups. In the older rats, aged 14 and 21 days, HR was markedly diminished, with a more pronounced decrease in LBW rats. The HR recovery was never observed in the older LBW rats. The fR and aR showed an age-related increase in both groups: a biphasic fR pattern observed on day 7 was replaced by a sustained increase on days 14 and 21. In contrast to controls, LBW rats never displayed a fR recovery during reoxygenation. In controls, aR shifted from a biphasic pattern in the younger rats to a sustained increase in the older ones. The LBW rats only displayed a decrease of aR in the younger, while in the older ones, a transient and slight increase preceded this decrease. During hypercapnia, the only significant difference detected between these two groups was that aR increased in LBW rats to a greater extent than in controls on days 14 and 21. Altogether, our results revealed a markedly attenuated cardio-respiratory response to hypoxia in LBW rats, but no such effect in response to hypercapnia.