Selected contribution: chemoreflex responses to CO2 before and after an 8-h exposure to hypoxia in humans.

The ventilatory sensitivity to CO2, in hyperoxia, is increased after an 8-h exposure to hypoxia. The purpose of the present study was to determine whether this increase arises through an increase in peripheral or central chemosensitivity. Ten healthy volunteers each underwent 8-h exposures to 1) isocapnic hypoxia, with end-tidal PO2 (PET(O2)) = 55 Torr and end-tidal PCO2 (PET(CO2)) = eucapnia; 2) poikilocapnic hypoxia, with PET(O2) = 55 Torr and PET(CO2) = uncontrolled; and 3) air-breathing control. The ventilatory response to CO2 was measured before and after each exposure with the use of a multifrequency binary sequence with two levels of PET(CO2): 1.5 and 10 Torr above the normal resting value. PET(O2) was held at 250 Torr. The peripheral (Gp) and the central (Gc) sensitivities were calculated by fitting the ventilatory data to a two-compartment model. There were increases in combined Gp + Gc (26%, P < 0.05), Gp (33%, P < 0.01), and Gc (23%, P = not significant) after exposure to hypoxia. There were no significant differences between isocapnic and poikilocapnic hypoxia. We conclude that sustained hypoxia induces a significant increase in chemosensitivity to CO2 within the peripheral chemoreflex.     

Cerebral vasoreactivity during hypercapnia is reset by augmented sympathetic influence

Sympathetic nerve activity influences cerebral blood flow, but it is unknown whether augmented sympathetic nerve activity resets cerebral vasoreactivity to hypercapnia. This study tested the hypothesis that cerebral vasodilation during hypercapnia is restrained by lower-body negative pressure (LBNP)-stimulated sympathoexcitation. Cerebral hemodynamic responses were assessed in nine healthy volunteers [age 25 yr (SD 3)] during rebreathing-induced increases in partial pressure of end-tidal CO(2) (Pet(CO(2))) at rest and during LBNP. Cerebral hemodynamic responses were determined by changes in flow velocity of middle cerebral artery (MCAV) using transcranial Doppler sonography and in regional cerebral tissue oxygenation (ScO(2)) using near-infrared spectroscopy. Pet(CO(2)) values during rebreathing were similarly increased from 41.9 to 56.5 mmHg at rest and from 40.7 to 56.0 mmHg during LBNP of -15 Torr. However, the rates of increases in MCAV and in ScO(2) per unit increase in Pet(CO(2)) (i.e., the slopes of MCAV/Pet(CO(2)) and ScO(2)/Pet(CO(2))) were significantly (P ≤0.05) decreased from 2.62 ± 0.16 cm·s(-1)·mmHg(-1) and 0.89 ± 0.10%/mmHg at rest to 1.68 ± 0.18 cm·s(-1)·mmHg(-1) and 0.63 ± 0.07%/mmHg during LBNP. In conclusion, the sensitivity of cerebral vasoreactivity to hypercapnia, in terms of the rate of increases in MCAV and in ScO(2), is diminished by LBNP-stimulated sympathoexcitation.     

Transcranial Doppler estimation of cerebral blood flow and cerebrovascular conductance during modified rebreathing.

Clinical transcranial Doppler assessment of cerebral vasomotor reactivity (CVMR) uses linear regression of cerebral blood flow velocity (CBFV) vs. end-tidal CO(2) (Pet(CO(2))) under steady-state conditions. However, the cerebral blood flow (CBF)-Pet(CO(2)) relationship is nonlinear, even for moderate changes in CO(2). Moreover, CBF is increased by increases in arterial blood pressure (ABP) during hypercapnia. We used a modified rebreathing protocol to estimate CVMR during transient breath-by-breath changes in CBFV and Pet(CO(2)). Ten healthy subjects (6 men) performed 15 s of hyperventilation followed by 5 min of rebreathing, with supplemental O(2) to maintain arterial oxygen saturation constant. To minimize effects of changes in ABP on CVMR estimation, cerebrovascular conductance index (CVCi) was calculated. CBFV-Pet(CO(2)) and CVCi-Pet(CO(2)) relationships were quantified by both linear and nonlinear logistic regression. In three subjects, muscle sympathetic nerve activity was recorded. From hyperventilation to rebreathing, robust changes occurred in Pet(CO(2)) (20-61 Torr), CBFV (-44 to +104% of baseline), CVCi (-39 to +64%), and ABP (-19 to +23%) (all P < 0.01). Muscle sympathetic nerve activity increased by 446% during hypercapnia. The linear regression slope of CVCi vs. Pet(CO(2)) was less steep than that of CBFV (3 vs. 5%/Torr; P = 0.01). Logistic regression of CBF-Pet(CO(2)) (r(2) = 0.97) and CVCi-Pet(CO(2)) (r(2) = 0.93) was superior to linear regression (r(2) = 0.91, r(2) = 0.85; P = 0.01). CVMR was maximal (6-8%/Torr) for Pet(CO(2)) of 40-50 Torr. In conclusion, CBFV and CVCi responses to transient changes in Pet(CO(2)) can be described by a nonlinear logistic function, indicating that CVMR estimation varies within the range from hypocapnia to hypercapnia. Furthermore, quantification of the CVCi-Pet(CO(2)) relationship may minimize the effects of changes in ABP on the estimation of CVMR. The method developed provides insight into CVMR under transient breath-by-breath changes in CO(2).     

Changes in respiratory control in humans induced by 8 h of hyperoxia.

In humans, 8 h of isocapnic hypoxia causes a progressive rise in ventilation associated with increases in the acute ventilatory responses to hypoxia (AHVR) and hypercapnia (AHCVR). To determine whether 8 h of hyperoxia causes the converse of these effects, three 8-h protocols were compared in 14 subjects: 1) poikilocapnic hyperoxia, with end-tidal PO(2) (PET(O(2))) = 300 Torr and end-tidal PCO(2) (PET(CO(2))) uncontrolled; 2) isocapnic hyperoxia, with PET(O(2)) = 300 Torr and PET(CO(2)) maintained at the subject's normal air-breathing level; and 3) control. Ventilation was measured hourly. AHVR and AHCVR were determined before and 0.5 h after each exposure. During isocapnic hyperoxia, after an initial increase, ventilation progressively declined (P < 0.01, ANOVA). After exposure to hyperoxia, 1) AHVR declined (P < 0.05); 2) ventilation at fixed PET(CO(2)) decreased (P < 0.05); and 3) air-breathing PET(CO(2)) increased (P < 0.05); but 4) no significant changes in AHCVR or intercept were demonstrated. In conclusion, 8 h of hyperoxia have some effects opposite to those found with 8 h of hypoxia, indicating that there may be some "acclimatization to hypoxia" at normal sea-level values of PO(2).     

Hypercapnic cerebral vascular reactivity is decreased, in humans, during sleep compared with wakefulness.

During wakefulness, increases in the partial pressure of arterial CO(2) result in marked rises in cortical blood flow. However, during stage III-IV, non-rapid eye movement (NREM) sleep, and despite a relative state of hypercapnia, cortical blood flow is reduced compared with wakefulness. In the present study, we tested the hypothesis that, in normal subjects, hypercapnic cerebral vascular reactivity is decreased during stage III-IV NREM sleep compared with wakefulness. A 2-MHz pulsed Doppler ultrasound system was used to measure the left middle cerebral artery velocity (MCAV; cm/s) in 12 healthy individuals while awake and during stage III-IV NREM sleep. The end-tidal Pco(2) (Pet(CO(2))) was elevated during the awake and sleep states by regulating the inspired CO(2) load. The cerebral vascular reactivity to CO(2) was calculated from the relationship between Pet(CO(2)) and MCAV by using linear regression. From wakefulness to sleep, the Pet(CO(2)) increased by 3.4 Torr (P < 0.001) and the MCAV fell by 11.7% (P < 0.001). A marked decrease in cerebral vascular reactivity was noted in all subjects, with an average fall of 70.1% (P = 0.001). This decrease in hypercapnic cerebral vascular reactivity may, at least in part, explain the stage III-IV NREM sleep-related reduction in cortical blood flow.     

Upper airway muscle responsiveness to rising PCO(2) during NREM sleep.

Although pharyngeal muscles respond robustly to increasing PCO(2) during wakefulness, the effect of hypercapnia on upper airway muscle activation during sleep has not been carefully assessed. This may be important, because it has been hypothesized that CO(2)-driven muscle activation may importantly stabilize the upper airway during stages 3 and 4 sleep. To test this hypothesis, we measured ventilation, airway resistance, genioglossus (GG) and tensor palatini (TP) electromyogram (EMG), plus end-tidal PCO(2) (PET(CO(2))) in 18 subjects during wakefulness, stage 2, and slow-wave sleep (SWS). Responses of ventilation and muscle EMG to administered CO(2) (PET(CO(2)) = 6 Torr above the eupneic level) were also assessed during SWS (n = 9) or stage 2 sleep (n = 7). PET(CO(2)) increased spontaneously by 0.8 +/- 0.1 Torr from stage 2 to SWS (from 43.3 +/- 0.6 to 44.1 +/- 0.5 Torr, P < 0.05), with no significant change in GG or TP EMG. Despite a significant increase in minute ventilation with induced hypercapnia (from 8.3 +/- 0.1 to 11.9 +/- 0.3 l/min in stage 2 and 8.6 +/- 0.4 to 12.7 +/- 0.4 l/min in SWS, P < 0.05 for both), there was no significant change in the GG or TP EMG. These data indicate that supraphysiological levels of PET(CO(2)) (50.4 +/- 1.6 Torr in stage 2, and 50.4 +/- 0.9 Torr in SWS) are not a major independent stimulus to pharyngeal dilator muscle activation during either SWS or stage 2 sleep. Thus hypercapnia-induced pharyngeal dilator muscle activation alone is unlikely to explain the paucity of sleep-disordered breathing events during SWS.     

糖尿病植物神经病变病人心率变异的非线性定量分析

目的：研究糖尿病人植物神经病变与心率变异的关系。对象：正常对照组和根据临床有无糖尿病神经病变（ＤＡＮ）分组的糖尿病病人,方法：应用２４小时动态心电图对正常和糖尿病人进行心率变异的线性,非线性散点图和非线性定量参数分析,结果：单纯糖尿病组ＳＤＮＮ,ＳＤＡＮＮ和ＰＮＮ５０低于正常组（Ｐ〈０．０５）;糖尿病＋ＤＡＮ组各项线性时域分析指标均低于正常和单纯糖尿病组（Ｐ〈０．０１－０．００１）,散点图分析结果     

Cerebral and myocardial blood flow responses to hypercapnia and hypoxia in humans

In humans, cerebrovascular responses to alterations in arterial Pco(2) and Po(2) are well documented. However, few studies have investigated human coronary vascular responses to alterations in blood gases. This study investigated the extent to which the cerebral and coronary vasculatures differ in their responses to euoxic hypercapnia and isocapnic hypoxia in healthy volunteers. Participants (n = 15) were tested at rest on two occasions. On the first visit, middle cerebral artery blood velocity (V(P)) was assessed using transcranial Doppler ultrasound. On the second visit, coronary sinus blood flow (CSBF) was measured using cardiac MRI. For comparison with V(P), CSBF was normalized to the rate pressure product [an index of myocardial oxygen consumption; normalized (n)CSBF]. Both testing sessions began with 5 min of euoxic [end-tidal Po(2) (Pet(O(2))) = 88 Torr] isocapnia [end-tidal Pco(2) (Pet(CO(2))) = +1 Torr above resting values]. Pet(O(2)) was next held at 88 Torr, and Pet(CO(2)) was increased to 40 and 45 Torr in 5-min increments. Participants were then returned to euoxic isocapnia for 5 min, after which Pet(O(2)) was decreased from 88 to 60, 52 and 45 Torr in 5-min decrements. Changes in V(P) and nCSBF were normalized to isocapnic euoxic conditions and indexed against Pet(CO(2)) and arterial oxyhemoglobin saturation. The V(P) gain for euoxic hypercapnia (%/Torr) was significantly higher than nCSBF (P = 0.030). Conversely, the V(P) gain for isocapnic hypoxia (%/%desaturation) was not different from nCSBF (P = 0.518). These findings demonstrate, compared with coronary circulation, that the cerebral circulation is more sensitive to hypercapnia but similarly sensitive to hypoxia.     

Modulation of the corticospinal control of ventilation by changes in reflex respiratory drive.

We have determined whether changes in PCO(2) above and below eucapnia modulate the precision of the voluntary control of breathing. Twelve trained subjects performed a compensatory tracking task in which they had to maintain the position of a cursor (perturbed by a variable triangular forcing function) on a fixed target by breathing in and out of a spirometer (ventilatory tracking; at 10 l/min). Before each task, subjects hyperventilated for 5 min, and the end-tidal PCO(2) (PET(CO(2))) was controlled; tracking was then performed separately at hypocapnia, eucapnia, and hypercapnia (PET(CO(2)) approximately 25, 37, and 43 Torr, respectively). Ventilatory tracking error was unchanged during hypocapnia (P > 0.05) but was significantly worse during hypercapnia (P < 0.003), compared with eucapnia; arm tracking error, performed as a control, was not significantly affected by PET(CO(2)) (P > 0. 05). In conclusion, ventilatory tracking performance is unaffected by the eucapnic PCO(2). From this, we suggest that resting breathing in awake humans may be independent of chemical drives and of the prevailing PCO(2).     

Cardiovascular and cerebrovascular responses to acute isocapnic and poikilocapnic hypoxia in humans

We examined the cardiovascular and cerebrovascular responses to acute isocapnic (IH) and poikilocapnic hypoxia (PH) in 10 men (25.7 +/- 4.2 yr, mean +/- SD). Heart rate (HR), mean arterial pressure (MAP), and mean peak middle cerebral artery blood flow velocity (Vp) were measured continuously during two randomized protocols of 20 min of step IH and PH (45 Torr). HR was elevated during both IH (P < 0.01) and PH (P < 0.01), with no differences observed between conditions. MAP was modestly elevated across all time points during IH but only became elevated after 5 min during PH. During IH, Vp was elevated from baseline throughout the exposure with a consistent hypoxic sensitivity of approximately 0.34 cm x s(-1).%desaturation(-1) (P < 0.05). The Vp response to PH was biphasic with an initial decrease from baseline occurring at 79 +/- 23 s, followed by a subsequent elevation, becoming equivalent to the IH response by 10 min. The nadir of the PH response exhibited a hypoxic sensitivity of -0.24 cm x s(-1) x % desaturation(-1). When expressed in relation to end-tidal Pco2, a sensitivity of -1.08 cm x s(-1).Torr(-1) was calculated, similar to previously reported sensitivities to euoxic hypocapnia. Cerebrovascular resistance (CVR) was not changed during IH. During PH, an initial increase in CVR was observed. However, CVR returned to baseline by 20 min of PH. These data show the cerebrovascular response to PH consists of an early hypocapnia-mediated response, followed by a secondary increase, mediated predominantly by hypoxia.     

Improvement of cardiovascular autonomic reflexes after amelioration of metabolic control in insulin-dependent diabetic subjects with severe autonomic neuropathy

To evaluate the influence of good metabolic equilibrium on Diabetic Autonomic Neuropathy (DAN), cardiovascular autonomic reflexes were monitored in 9 male insulin-dependent diabetic patients with DAN, treated with Continuous Subcutaneous Insulin Infusion (CSII) by pump: 9 for 10 days, 4 for 1 year and 2 for 20 months. Autonomic neuropathy was assessed evaluating 5 cardiovascular autonomic tests: Valsalva Manoeuvre (VR), Deep Breathing (DB), Lying-to-Standing (L-S), Sustained Handgrip (SHG), and Postural Hypotension (PH). Metabolic control was assessed evaluating the mean daily plasma glucose, glucosuria and glycosylated hemoglobin. Ten days of CSII treatment induced a normalization of glucose balance and a slight but significant improvement in some parasympathetic cardiovascular tests (VR: from 1.09 +/- 0.01 to 1.13 +/- 0.02; P less than 0.05). After 4-8 months of CSII treatment a significant improvement in VR (P less than 0.05); DB (P less than 0.01) and L-S (P less than 0.05) was recorded. The long-term treatment with CSII did not seem to induce a further amelioration in cardiovascular autonomic reflexes. These results show that the slight improvement induced by good metabolic balance in the cardiovascular autonomic response could be related to functional-metabolic rather than structural changes in the nerves.     

Relationship of ovarian hormones to hypoxemia in women residents of 4,300 m

Prevalence of excessive erythrocytosis, the main sign of chronic mountain sickness (CMS), is greater in postmenopausal Andean women than in premenopausal women. It is uncertain whether this greater prevalence is related to the decline in female hormones and ventilatory function after the occurrence of the menopause. To study this, we compared the physiological variables involved in the physiopathology of CMS [end-tidal CO(2) (PET(CO(2)), Torr) and end-tidal O(2) (PET(O(2)), Torr), arterial oxygen saturation (Sa(O(2)), %), and Hb concentration (g/dl)] and progesterone and estradiol levels between postmenopausal and premenopausal women, both in the luteal and follicular phases. Women residing in Cerro de Pasco (n = 33; 4,300 m) aged 26--62 yr were studied. Postmenopausal women compared with premenopausal women in the luteal phase had lower PET(O(2)) (48 +/- 4 vs. 53 +/- 2 Torr, P = 0.005) and Sa(O(2)) levels (82 +/- 12 vs. 88 +/- 12%, P < 0.005) and higher PET(CO(2)) (34 +/- 2 vs. 29 +/- 3 Torr, P = 0.005) and Hb concentration (19 +/- 1 vs. 14 +/- 2 g/dl, P < 0.005). In addition, plasma progesterone was negatively correlated with PET(CO(2)) and positively correlated with PET(O(2)) and Sa(O(2)). No clear relationship was found among the cycle phases between estradiol and the variables studied. In conclusion, our results reveal that, before menopause, there is better oxygenation and lower Hb levels in women long residing at altitude, and this is associated with higher levels of progesterone in the luteal phase of the cycle.     

Peripheral chemoreceptor contributions to sympathetic and cardiovascular responses during hypercapnia

We tested the hypothesis that integrated sympathetic and cardiovascular reflexes are modulated by systemic CO2 differently in hypoxia than in hyperoxia (n = 7). Subjects performed a CO2 rebreathe protocol that equilibrates CO2 partial pressures between arterial and venous blood and that elevates end tidal CO2 (PET(CO2)) from approximately 40 to approximately 58 mmHg. This test was repeated under conditions where end tidal oxygen levels were clamped at 50 (hypoxia) or 200 (hyperoxia) mmHg. Heart rate (HR; EKG), stroke volume (SV; Doppler ultrasound), blood pressure (MAP; finger plethysmograph), and muscle sympathetic nerve activity (MSNA) were measured continuously during the two protocols. MAP at 40 mmHg PET(CO2) (i.e., the first minute of the rebreathe) was greater during hypoxia versus hyperoxia (P < 0.05). However, the increase in MAP during the rebreathe (P < 0.05) was similar in hypoxia (16 +/- 3 mmHg) and hyperoxia (17 +/- 2 mmHg PET(CO2)). The increase in cardiac output (Q) at 55 mmHg PET(CO2) was greater in hypoxia (2.61 +/- 0.7 L/min) versus hyperoxia (1.09 +/- 0.44 L/min) (P < 0.05). In both conditions the increase in Q was due to elevations in both HR and SV (P < 0.05). Systemic vascular conductance (SVC) increased to similar absolute levels in both conditions but rose earlier during hypoxia (> 50 mmHg PET(CO2)) than hyperoxia (> 55 mmHg). MSNA increased earlier during hypoxic hypercapnia (> 45 mmHg) compared with hyperoxic hypercapnia (> 55 mmHg). Thus, in these conscious humans, the dose-response effect of PET(CO2) on the integrated cardiovascular responses was shifted to the left during hypoxic hypercapnia. The combined data indicate that peripheral chemoreceptors exert important influence over cardiovascular reflex responses to hypercapnia.     

Regulation of ANP secretion in insulin-dependent diabetes mellitus and the influence of autonomic neuropathy.

In order to determine the effect of diabetic autonomic neuropathy (DAN) on the atrial natriuretic peptide (ANP) response to dynamic stimuli, we studied the ANP response to 60 degrees head-up and 60 degrees leg-up tilt in diabetic subjects with (DAN + ve, n = 8) and without (DAN - ve, n = 8) evidence of autonomic neuropathy and seven matched non-diabetic controls. Mean baseline plasma ANP concentrations were similar in all three groups. Head-up tilt was associated with a fall in plasma ANP in all seven healthy controls (21.8 (16.8-30.7) to 16.8 (7.1-29.1), P = 0.06, mean (range)), seven of the eight DAN - ve (16.9 (6.5-33.7) to 8.5 (3.0-21.1), P = 0.015) and all eight DAN + ve subjects (27.3 (8.5-101.5) to 15.4 (1.0-67.6), P = 0.044). Leg-up tilt caused a rise in plasma ANP in six of the seven healthy controls (17.6 (7.5-27.9) to 22.4 (15.2-48.1), P = 0.041), six of the eight DAN - ve (12.5 (7.8-27.8) to 15.5 (7.3-31.3), P = 0.054) and seven of the eight DAN + ve subjects (18.2 (2.8-55.1) to 25.1 (4.5-92.8), P = 0.013). There was no significant difference in the fall in plasma ANP during head-up tilt or in the rise in plasma ANP during leg-up tilt between the three groups. We conclude that the regulation of ANP secretion is normal in diabetes mellitus, and is unaffected by the presence of autonomic neuropathy.     

Cerebrovascular responsiveness to steady-state changes in end-tidal CO2 during passive heat stress.

This study tested the hypothesis that passive heat stress alters cerebrovascular responsiveness to steady-state changes in end-tidal CO(2) (Pet(CO(2))). Nine healthy subjects (4 men and 5 women), each dressed in a water-perfused suit, underwent normoxic hypocapnic hyperventilation (decrease Pet(CO(2)) approximately 20 Torr) and normoxic hypercapnic (increase in Pet(CO(2)) approximately 9 Torr) challenges under normothermic and passive heat stress conditions. The slope of the relationship between calculated cerebrovascular conductance (CBVC; middle cerebral artery blood velocity/mean arterial blood pressure) and Pet(CO(2)) was used to evaluate cerebrovascular CO(2) responsiveness. Passive heat stress increased core temperature (1.1 +/- 0.2 degrees C, P < 0.001) and reduced middle cerebral artery blood velocity by 8 +/- 8 cm/s (P = 0.01), reduced CBVC by 0.09 +/- 0.09 CBVC units (P = 0.02), and decreased Pet(CO(2)) by 3 +/- 4 Torr (P = 0.07), while mean arterial blood pressure was well maintained (P = 0.36). The slope of the CBVC-Pet(CO(2)) relationship to the hypocapnic challenge was not different between normothermia and heat stress conditions (0.009 +/- 0.006 vs. 0.009 +/- 0.004 CBVC units/Torr, P = 0.63). Similarly, in response to the hypercapnic challenge, the slope of the CBVC-Pet(CO(2)) relationship was not different between normothermia and heat stress conditions (0.028 +/- 0.020 vs. 0.023 +/- 0.008 CBVC units/Torr, P = 0.31). These results indicate that cerebrovascular CO(2) responsiveness, to the prescribed steady-state changes in Pet(CO(2)), is unchanged during passive heat stress.     

Splanchnic hemodynamics and gut mucosal-arterial PCO(2) gradient during systemic hypocapnia.

The effects of hypocapnia [arterial PCO(2) (Pa(CO(2))) 15 Torr] on splanchnic hemodynamics and gut mucosal-arterial P(CO(2)) were studied in seven anesthetized ventilated dogs. Ileal mucosal and serosal blood flow were estimated by using laser Doppler flowmetry, mucosal PCO(2) was measured continuously by using capnometric recirculating gas tonometry, and serosal surface PO(2) was assessed by using a polarographic electrode. Hypocapnia was induced by removal of dead space and was maintained for 45 min, followed by 45 min of eucapnia. Mean Pa(CO(2)) at baseline was 38.1 +/- 1.1 (SE) Torr and decreased to 13.8 +/- 1.3 Torr after removal of dead space. Cardiac output and portal blood flow decreased significantly with hypocapnia. Similarly, mucosal and serosal blood flow decreased by 15 +/- 4 and by 34 +/- 7%, respectively. Also, an increase in the mucosal-arterial PCO(2) gradient of 10.7 Torr and a reduction in serosal PO(2) of 30 Torr were observed with hypocapnia (P < 0.01 for both). Hypocapnia caused ileal mucosal and serosal hypoperfusion, with redistribution of flow favoring the mucosa, accompanied by increased PCO(2) gradient and diminished serosal PO(2).     

Respiratory effects in humans of a 5-day elevation of end-tidal PCO2 by 8 Torr.

The aims of this study were to determine 1) whether ventilatory adaptation occurred over a 5-day exposure to a constant elevation in end-tidal PCO2 and 2) whether such an exposure altered the sensitivity of the chemoreflexes to acute hypoxia and hypercapnia. Ten healthy human subjects were studied over a period of 13 days. Their ventilation, chemoreflex sensitivities, and acid-base status were measured daily before, during, and after 5 days of elevated end-tidal PCO2 at 8 Torr above normal. There was no major adaptation of ventilation during the 5 days of hypercapnic exposure. There was an increase in ventilatory chemosensitivity to acute hypoxia (from 1.35 +/- 0.08 to 1.70 +/- 0.07 l/min/%; P < 0.01) but no change in ventilatory chemosensitivity to acute hypercapnia. There was a degree of compensatory metabolic alkalosis. The results do not support the hypothesis that the ventilatory adaptation to chronic hypercapnia would be much greater with constant elevation of alveolar PCO2 than with constant elevation of inspired PCO2, as has been used in previous studies and in which the feedback loop between ventilation and alveolar PCO2 is left intact.     

Carotid body denervation in dogs: eupnea and the ventilatory response to hyperoxic hypercapnia.

We assessed the time course of changes in eupneic arterial PCO(2) (Pa(CO(2))) and the ventilatory response to hyperoxic rebreathing after removal of the carotid bodies (CBX) in awake female dogs. Elimination of the ventilatory response to bolus intravenous injections of NaCN was used to confirm CBX status on each day of data collection. Relative to eupneic control (Pa(CO(2)) = 40 +/- 3 Torr), all seven dogs hypoventilated after CBX, reaching a maximum Pa(CO(2)) of 53 +/- 6 Torr by day 3 post-CBX. There was no significant recovery of eupneic Pa(CO(2)) over the ensuing 18 days. Relative to control, the hyperoxic CO(2) ventilatory (change in inspired minute ventilation/change in end-tidal PCO(2)) and tidal volume (change in tidal volume/ change in end-tidal PCO(2)) response slopes were decreased 40 +/- 15 and 35 +/- 20% by day 2 post-CBX. There was no recovery in the ventilatory or tidal volume response slopes to hyperoxic hypercapnia over the ensuing 19 days. We conclude that 1) the carotid bodies contribute approximately 40% of the eupneic drive to breathe and the ventilatory response to hyperoxic hypercapnia and 2) there is no recovery in the eupneic drive to breathe or the ventilatory response to hyperoxic hypercapnia after removal of the carotid chemoreceptors, indicating a lack of central or aortic chemoreceptor plasticity in the adult dog after CBX.     

Postevent ventilation as a function of CO(2) load during respiratory events in obstructive sleep apnea.

Maintenance of eucapnia during sleep in obstructive sleep apnea (OSA) requires a balance between CO(2) loading during apnea and CO(2) elimination. This study examines individual respiratory events and relates magnitude of postevent ventilation to CO(2) load during the preceding respiratory event in 14 patients with OSA (arterial PCO(2) 42-56 Torr). Ventilation and expiratory CO(2) and O(2) fractions were measured on a breath-by-breath basis during daytime sleep. Calculations included CO(2) load during each event (metabolic CO(2) production - exhaled CO(2)) and postevent ventilation in the 10 s after an event. In 12 of 14 patients, a direct relationship existed between postevent ventilation and CO(2) load during the preceding event (P < 0.05); the slope of this relationship varied across subjects. Thus the postevent ventilation is tightly linked to CO(2) loading during each respiratory event and may be an important mechanism that defends against development of acute hypercapnia in OSA. An inverse relationship was noted between this postevent ventilatory response slope and the chronic awake arterial PCO(2) (r = 0.90, P < 0.001), suggesting that this mechanism is impaired in patients with chronic hypercapnia. The link between development of acute hypercapnia during respiratory events asleep and maintenance of chronic awake hypercapnia in OSA remains to be further investigated.     

Influence of arterial O2 on the susceptibility to posthyperventilation apnea during sleep.

To investigate the contribution of the peripheral chemoreceptors to the susceptibility to posthyperventilation apnea, we evaluated the time course and magnitude of hypocapnia required to produce apnea at different levels of peripheral chemoreceptor activation produced by exposure to three levels of inspired P(O2). We measured the apneic threshold and the apnea latency in nine normal sleeping subjects in response to augmented breaths during normoxia (room air), hypoxia (arterial O2 saturation = 78-80%), and hyperoxia (inspired O2 fraction = 50-52%). Pressure support mechanical ventilation in the assist mode was employed to introduce a single or multiple numbers of consecutive, sigh-like breaths to cause apnea. The apnea latency was measured from the end inspiration of the first augmented breath to the onset of apnea. It was 12.2 +/- 1.1 s during normoxia, which was similar to the lung-to-ear circulation delay of 11.7 s in these subjects. Hypoxia shortened the apnea latency (6.3 +/- 0.8 s; P < 0.05), whereas hyperoxia prolonged it (71.5 +/- 13.8 s; P < 0.01). The apneic threshold end-tidal P(CO2) (Pet(CO2)) was defined as the Pet(CO2)) at the onset of apnea. During hypoxia, the apneic threshold Pet(CO2) was higher (38.9 +/- 1.7 Torr; P < 0.01) compared with normoxia (35.8 +/- 1.1; Torr); during hyperoxia, it was lower (33.0 +/- 0.8 Torr; P < 0.05). Furthermore, the difference between the eupneic Pet(CO2) and apneic threshold Pet(CO2) was smaller during hypoxia (3.0 +/- 1.0 Torr P < 001) and greater during hyperoxia (10.6 +/- 0.8 Torr; P < 0.05) compared with normoxia (8.0 +/- 0.6 Torr). Correspondingly, the hypocapnic ventilatory response to CO2 below the eupneic Pet(CO2) was increased by hypoxia (3.44 +/- 0.63 l.min(-1).Torr(-1); P < 0.05) and decreased by hyperoxia (0.63 +/- 0.04 l.min(-1).Torr(-1); P < 0.05) compared with normoxia (0.79 +/- 0.05 l.min(-1).Torr(-1)). These findings indicate that posthyperventilation apnea is initiated by the peripheral chemoreceptors and that the varying susceptibility to apnea during hypoxia vs. hyperoxia is influenced by the relative activity of these receptors.