Hypoxic Ventilatory Sensitivity Research Articles

Carbonic anhydrase inhibition and chemoreflex control of breathing: A litmus test for methazolamide as a viable alternative to acetazolamide.

Carbonic anhydrase inhibition and chemoreflex control of breathing: A litmus test for methazolamide as a viable alternative to acetazolamide.

Model-based characterization of ventilatory stability using spontaneous breathing

Cyclic ventilatory instabilities are widely attributed to an increase in the sensitivity or loop gain of the chemoreflex feedback loop controlling ventilation. A major limitation in the conventional characterization of this feedback loop is the need for labor-intensive methodologies. To overcome this limitation, we developed a method based on trivariate autoregressive modeling using ventilation, end-tidal Pco(2) and Po(2); this method provides for estimation of the overall "loop gain" of the respiratory control system and its components, chemoreflex gain and plant gain. Our method was applied to recordings of spontaneous breathing in 15 anesthetized, tracheostomized, newborn lambs before and after administration of domperidone (a dopamine D(2)-receptor antagonist that increases carotid body sensitivity). We quantified the known increase in hypoxic ventilatory sensitivity in response to domperidone; controller gain for O(2) increased from 0.06 (0.03, 0.09) l·min(-1)·mmHg(-1) to 0.09 (0.08, 0.13) l·min(-1)·mmHg(-1); median (interquartile-range). We also report that domperidone increased the loop gain of the control system more than twofold [0.14 (0.12, 0.22) to 0.40 (0.15, 0.57)]. We observed no significant changes in CO(2) controller gain, or plant gains for O(2) and CO(2). Furthermore, our estimate of the cycle duration of periodic breathing compared favorably with that observed experimentally [measured: 7.5 (7.2, 9.1) vs. predicted: 7.9 (7.0, 9.2) breaths]. Our results demonstrate that model-based analysis of spontaneous breathing can 1) characterize the dynamics of the respiratory control system, and 2) provide a simple tool for elucidating an individual's propensity for ventilatory instability, in turn allowing potential therapies to be directed at the underlying mechanisms.

Determinants of blood oxygenation during pregnancy in Andean and European residents of high altitude

High altitude decreases birth weight, but this effect is diminished in long vs. short-resident, high-altitude populations. We asked whether women from long vs. short-resident, high-altitude populations had higher arterial oxygenation levels by comparing 42 Andean and 26 European residents of La Paz, Bolivia (3,600 m), serially during pregnancy (weeks 20, 30, and 36) and again 4 mo postpartum. Pregnancy raised hypoxic ventilatory sensitivity threefold, resting ventilation (.Ve), and arterial O(2) saturation (Sa(O2)) in both groups. Ancestry, as identified using 81 genetic markers, correlated with respiratory pattern, such that greater Andean ancestry was associated with higher respiratory frequency and lower tidal volume. Pregnancy increased total blood and plasma volume approximately 40% in both groups without changing red blood cell mass relative to body weight; hence, hemoglobin fell. The hemoglobin decline was compensated for by the rise in .Ve and Sa(O2) with the result that arterial O2 content (Ca(O2)) was maintained near nonpregnant levels in both groups. Birth weights were similar for all Andean and European babies, but after adjusting for variation in gestational age, maternal height and parity, Andeans weighed 209 g more than Europeans. Babies with heavier birth weights and greater ponderal indices were born to Andean women with higher Ve during pregnancy. We concluded that while maternal .Ve and arterial oxygenation were important, some factor other than higher Ca(O2) was responsible for protecting Andeans from altitude-associated reductions in fetal growth.

Peripheral chemoreceptors in health and disease.

Peripheral chemoreceptors (carotid and aortic bodies) detect changes in arterial blood oxygen and initiate reflexes that are important for maintaining homeostasis during hypoxemia. This mini-review summarizes the importance of peripheral chemoreceptor reflexes in various physiological and pathophysiological conditions. Carotid bodies are important for eliciting hypoxic ventilatory stimulation in humans and in experimental animals. In the absence of carotid bodies, compensatory upregulation of aortic bodies as well as other chemoreceptors contributes to the hypoxic ventilatory response. Peripheral chemoreceptors are critical for ventilatory acclimatization at high altitude. They also contribute in part to the exercise-induced hyperventilation, especially with submaximal and heavy exercise. During pregnancy, hypoxic ventilatory sensitivity increases, perhaps due to the actions of estrogen and progesterone on chemoreceptors. Augmented peripheral chemoreceptors have been implicated in early stages of recurrent apneas, congestive heart failure, and certain forms of hypertension. It is likely that chemoreceptors tend to maintain oxygen homeostasis and act as a defense mechanism to prevent the progression of the morbidity associated with these diseases. Experimental models of recurrent apneas, congestive heart failure, and hypertension offer excellent opportunities to unravel the cellular mechanisms associated with altered chemoreceptor function.

Geriatric Men at Altitude: Hypoxic Ventilatory Sensitivity and Blood Dopamine Changes

Background: Short-term exposure to high-altitude hypoxia increases hypoxic ventilatory sensitivity (HVS) in healthy humans. Dopamine (DA) is the implicated neurotransmitter in carotid body (CB) chemoreceptor response, and the microenvironmental conditions in CB tissue are comparable to blood. Continuous DA infusion affected ventilation in animals and humans. Age-related oscillations in blood DA levels may influence peripheral chemoreflexes. Objective: Hypoxic ventilatory responses (HVR) relative to blood DA concentration and its precursor, dihydroxyphenylalanine (DOPA) was measured in young and elderly men during short-term altitude adaptation. Methods: Nine elderly climbers (group 1: 61 ± 1.4 years) and 7 young healthy subjects (group 2: 23 ± 2 years) were tested at sea level on day 0, on day 3 after passive transport to 2,200 m, and on day 14 after climbing to 4,200 and 5,642 m. Results: Sea level HVR in group 1 was 47% lower than in group 2, accompanied by higher blood DOPA (300%) and DA (37%) content. Initial DA and DOPA concentrations showed a negative correlation with initial HVR but a positive correlation with age. Passive transport to middle altitude (2,200 m) increased HVS, doubling HVR slopes in groups 1 and 2 and producing increased maximum expired minute ventilation during isocapnic rebreathing (29 and 28%, respectively). Day 3 2,200-meter blood DOPA content decreased by 22% in group 1 and increased by 300% in group 2. DA increased in both groups. Conclusion: The relationship between HVR and the reciprocal DA and DOPA values seen in both groups is associated with age, producing decreased DA receptor sensitivity and enhanced DA reuptake during adaptation to high altitude.

Intermittent hypoxia (IH) improves hypoxic ventilatory sensitivity and blood dopamine (DA) in patients with Parkinson's disease (PD)

Recent lines of inquiry indicate that sedatives can influence the immune system, leading to the concept of sedative-induced immunomodulation. It has been hypothesized that sedatives may alter immune responses by modulating the sympathetic nervous system, however, little information is known regarding the effects of sedatives on regulation of splenic sympathetic nerve discharge (SND), a significant omission based on the functional role that changes in splenic SND exert on splenic cytokine gene expression. The present investigation determined the effect of systemic Dexmedetomidine (Dex) administration on the level of directly-recorded splenic SND and tested the hypothesis that the intravenous administration of Dex would inhibit splenic SND in anesthetized rats. The present results demonstrate for the first time that intravenous Dex administration significantly reduces splenic sympathetic nerve outflow in baroreceptor-intact and sinoaortic-denervated rats, indicating that Dex administration alters the central regulation of splenic SND. The present results provide new information regarding the effect of a centrally-acting alpha2-adrenergic agonist on the level of sympathetic nerve outflow to a secondary lymphoid organ that plays a critical role in peripheral immune responses.

Ventilatory responses to acute and sustained hypoxia during isoflurane anesthesia.

In the awake state, isocapnic hypoxic ventilatory responses (HVRs) are biphasic, with an acute response within 5 min of hypoxic stimulation followed by a less pronounced sustained response. In this study, we investigated the influence of isoflurane anesthesia (end-tidal concentration 1.1 kPa) on acute and sustained isocapnic HVRs in eight healthy women at pulse oximetry arterial saturations of 75%-80%. The aims were to determine whether HVR (20 min of hypoxia) during anesthesia was biphasic and to quantify ventilatory responses. Pneumotachography and in-line infrared capnometry were used. A biphasic HVR was found both in awake and anesthetized patients. Of the subjects, six had decreased and two had increased acute and sustained isocapnic HVRs in the anesthetized, compared with the awake state, which resulted in an approximately 50% reduction in both acute and sustained HVRs. In addition, the ventilatory response pattern was altered by anesthesia. Awake HVR was accomplished by increased tidal volumes while respiratory rates were unchanged. The opposite occurred during anesthesia. The underlying mechanisms for this biological action of inhaled anesthetics remains to be elucidated. In conclusion, this study clearly demonstrates the persistence of hypoxic ventilatory sensitivity during clinical anesthesia. We studied the ventilatory effects of 20 min of breathing air with low oxygen content (hypoxic) in eight women, before and during anesthesia with inhaled isoflurane. We demonstrated a persistent but blunted hypoxic ventilatory response during clinical anesthesia.

Ventilatory Responses to Acute and Sustained Hypoxia During Isoflurane Anesthesia

In the awake state, isocapnic hypoxic ventilatory responses (HVRs) are biphasic, with an acute response within 5 min of hypoxic stimulation followed by a less pronounced sustained response.In this study, we investigated the influence of isoflurane anesthesia (endtidal concentration 1.1 kPa) on acute and sustained isocapnic HVRs in eight healthy women at pulse oximetry arterial saturations of 75%-80%. The aims were to determine whether HVR (20 min of hypoxia) during anesthesia was biphasic and to quantify ventilatory responses. Pneumotachography and in-line infrared capnometry were used. A biphasic HVR was found both in awake and anesthetized patients. Of the subjects, six had decreased and two had increased acute and sustained isocapnic HVRs in the anesthetized, compared with the awake state, which resulted in an approximately 50% reduction in both acute and sustained HVRs. In addition, the ventilatory response pattern was altered by anesthesia. Awake HVR was accomplished by increased tidal volumes while respiratory rates were unchanged. The opposite occurred during anesthesia. The underlying mechanisms for this biological action of inhaled anesthetics remains to be elucidated. In conclusion, this study clearly demonstrates the persistence of hypoxic ventilatory sensitivity during clinical anesthesia. Implications: We studied the ventilatory effects of 20 min of breathing air with low oxygen content (hypoxic) in eight women, before and during anesthesia with inhaled isoflurane. We demonstrated a persistent but blunted hypoxic ventilatory response during clinical anesthesia. (Anesth Analg 1998;86:403-9)

Effects of carotid body hypocapnia during ventilatory acclimatization to hypoxia.

Hypoxic ventilatory sensitivity is increased during ventilatory acclimatization to hypoxia (VAH) in awake goats, resulting in a time-dependent increase in expired ventilation (VE). The objectives of this study were to determine whether the increased carotid body (CB) hypoxic sensitivity is dependent on the level of CB CO2 and whether the CB CO2 gain is changed during VAH. Studies were carried out in adult goats with CB blood gases controlled by an extracorporeal circuit while systemic (central nervous system) blood gases were regulated independently by the level of inhaled gases. Acute VE responses to CB hypoxia (CB PO2 40 Torr) and CB hypercapnia (CB PCO2 50 and 60 Torr) were measured while systemic normoxia and isocapnia were maintained. CB PO2 was then lowered to 40 Torr for 4 h while the systemic blood gases were kept normoxic and normocapnic. During the 4-h CB hypoxia, VE increased in a time-dependent manner. Thirty minutes after return to normoxia, the ventilatory response to CB hypoxia was significantly increased compared with the initial response. The slope of the CB CO2 response was also elevated after VAH. An additional group of goats (n = 7) was studied with a similar protocol, except that CB PCO2 was lowered throughout the 4-h CB hypoxic exposure to prevent reflex hyperventilation. CB PCO2 was progressively lowered throughout the 4-h CB hypoxic period to maintain VE at the control level. After the 4-h CB hypoxic exposure, the ventilatory response to hypoxia was also significantly elevated. However, the slope of the CB CO2 response was not elevated after the 4-h hypoxic exposure. These results suggest that CB sensitivity to both O2 and CO2 is increased after 4 h of CB hypoxia with systemic isocapnia. The increase in CB hypoxic sensitivity is not dependent on the level of CB CO2 maintained during the 4-h hypoxic period.

Prematurity alters hypoxic and hypercapnic ventilatory responses in developing lambs

We have determined the effects of preterm birth on the postnatal development of ventilatory responses to progressive hypoxia and hypercapnia in awake lambs. Hypoxic and hypercapnic rebreathing tests were performed at weekly intervals in 5 preterm (born at 135 ± 0.5 d) and 5 term (born at 146 ± 0.2 d) lambs up to 6–7 weeks after birth. Term lambs were also studied at 25 weeks after birth. During rebreathing tests, we measured arterial P O 2 and P CO 2 and related them to minute ventilation (V̇ i). Owing to variability in resting Pa O 2 , hypoxic sensitivity was defined as the percentage increase in V̇ i when Pa O 2 fell to 60% of resting values. Hypoxic sensitivities of preterm lambs did not change with age (68.9 ± 24.4%), whereas values for term lambs more than doubled over the first 6 weeks (day 2, 73.9 ± 15.8%; week 6, 227.4 ± 24.9%) but returned to early postnatal values by week 25 (87.0 ± 21.2%). Hypercapnic sensitivities (ml min −1 kg −1 mmHg CO −1 2) of preterm lambs were lower than those of term lambs between day 2 and week 2, but reached values in term lambs thereafter. We conclude that preterm birth abolishes the normal postnatal maturation of hypoxic ventilatory sensitivity, and temporarily depresses hypercapnic sensitivity.

Ventilatory response to hypoxia in humans. Influences of subanesthetic desflurane.

At low dose, the halogenated anesthetic agents halothane, isoflurane, and enflurane depress the ventilatory response to isocapnic hypoxia in humans. In the current study, the influence of subanesthetic desflurane (0.1 minimum alveolar concentration [MAC]) on the isocapnic hypoxic ventilatory response was assessed in healthy volunteers during normocapnia and hypercapnia. A single hypoxic ventilatory response was obtained at each of 4 target end-tidal partial pressure of oxygen concentrations: 75, 53, 44, and 38 mmHg, before and during 0.1 MAC desflurane administration. Fourteen subjects were tested at a normal end-tidal partial pressure of carbon dioxide (43 mmHg), with 9 subjects tested at an end-tidal carbon dioxide concentration of 49 mmHg (hypercapnia). The hypoxic sensitivity (S) was computed as the slope of the linear regression of inspired minute ventilation (V1) on (100-SPO2). Values are mean +/- SE. Sensitivity was unaffected by desflurane during normocapnia (control: S = 0.45 +/- 0.07 l.min-1.%-1 vs. 0.1 MAC desflurane: S = 0.43 +/- 0.09 l.min-1.%-1). With hypercapnia S decreased by 30% during desflurane inhalation (control: S = 0.74 +/- 0.09 l.min-1.%-1 vs. 0.1 MAC desflurane: S = 0.53 +/- 0.06 l.min-1.%-1; P < 0.05). On the basis of the data, subanesthetic desflurane has no detectable effect on the normocapnic hypoxic ventilatory response sensitivity. However, the carbon dioxideinduced augmentation of the hypoxic response was reduced. This indicates that subanesthetic desflurane effects the chemoreceptors at the carotid bodies.

Scaling of hypercapnic ventilatory responsiveness in birds and mammals

The possible relationship between CO 2 responsiveness and body mass in birds was explored using newly acquired ventilatory data from the barn swallow, Hirundo rustica, and the pigeon, Columbia livia, and that from the literature on four other species. Ventilatory responsiveness (%ΔV̇) of birds to 5% inspired CO 2 is scaled to body mass to the 0.145 power (%ΔV̇ ∝ Mb 0.145). A similar allometric relationship exists for data on 7 species of eutherian mammals taken from the literature (%ΔV̇ ∝ Mb 0.130). The reduced responsiveness to CO 2 in small birds and mammals may be related to an elevated hypoxic ventilatory sensitivity, as demonstrated in mammals (Boggs and Tenney, Respir. Physiol. 58: 245–251, 1984). These scaling relationships may reflect a mechanism for minimizing the inhibition of ventilation resulting from excessive loss of CO 2 which thereby permits a higher hypoxic ventilatory response in small species. Other mechanisms, however, could include size related differences in mechanics or alveolar ventilation.

Increased hypoxic ventilatory sensitivity during exercise in man: are neural afferents necessary?

1. The acute ventilatory response to 3 min periods of hypoxia (AHR) was examined in nine patients with clinically complete spinal cord transection (T4-T7) during (a) rest and (b) electrically induced leg exercise (EEL). 2. EEL was produced by surface electrode stimulation of the quadriceps muscles so as to cause the legs to extend at the knee against gravity. End-tidal PCO2 was held constant 1-2 mmHg above resting values throughout both protocols. 3. On exercise, the average increase in metabolic CO2 production (VCO2 +/- S.E.M.) was 41 +/- 5 ml min-1. Venous lactate levels did not rise with exercise. 4. Baseline euoxic ventilation did not increase significantly with EEL, but there was a consistent and highly significant increase in the ventilatory response to hypoxia during EEL (mean delta AHR +/- S.E.M. of 1.6 +/- 0.21 min-1). 5. We conclude that an increase in hypoxic sensitivity during exercise can occur in the absence of volitional control of exercise and in the absence of afferent neural input from the limbs.

Exercise endurance and arterial desaturation in normobaric hypoxia with increased chemosensitivity

We studied whether exercise endurance under normobaric hypoxia can be enhanced by increasing hypoxic ventilatory sensitivity with almitrine bismesylate (ALM). On both ALM and placebo (PL) days, resting subjects breathed a hypoxic gas mixture (an inspired O2 fraction of 10.4-13.2%), which lowered resting arterial O2 saturation (SaO2) to 80%. After 15 min of rest there was a 3-min warm-up period of exercise at 50 W (light) on a cycle ergometer, followed by a step increase in load to 60% of the previously determined maximum power output with room-air breathing (moderate), which was maintained until exhaustion. With PL, SaO2 decreased rapidly with the onset of exercise and continued to fall slowly during moderate exercise, averaging 71.0 +/- 1.8% (SE) at exhaustion. With ALM, saturation did not differ from PL during air breathing but significantly exceeded SaO2 with PL, by 3.4% during resting hypoxia, by 4.0% at the start of exercise, and by 5.9% at exhaustion. Ventilation was not affected by ALM during air breathing and was slightly, although not significantly, increased during hypoxic rest and exercise. ALM was associated with an increased heart rate during room air breathing but not during hypoxia. Endurance time was 20.6 +/- 1.6 min with ALM and 21.3 +/- 0.9 min with PL. During hypoxic exercise, the potential benefit of greater saturation with ALM is apparently offset by other unidentified factors.

Ventilatory responses to chemoreceptor stimulation after hypoxic acclimatization in awake goats

Our objective was to test the hypothesis that exposure to prolonged hypoxia results in altered responsiveness to chemoreceptor stimulation. Acclimatization to hypoxia occurs rapidly in the awake goat relative to other species. We tested the sensitivity of the central and peripheral chemoreceptors to chemical stimuli before and after 4 h of either isocapnic or poikilocapnic hypoxia (arterial PO2 40 Torr). We confirmed that arterial PCO2 decreased progressively, reaching a stable value after 4 h of hypoxic exposure (poikilocapnic group). In the isocapnic group, inspired minute ventilation increased over the same time course. Thus, acclimatization occurred in both groups. In goats, isocapnic hypoxia did not result in hyperventilation on return to normoxia, whereas poikilocapnic hypoxia did cause hyperventilation, indicating a different mechanism for acclimatization and the persistent hyperventilation on return to normoxia. Goats exposed to isocapnic hypoxia exhibited an increased slope of the CO2 response curve. Goats exposed to poikilocapnic hypoxia had no increase in slope but did exhibit a parallel leftward shift of the CO2 response curve. Neither group exhibited a significant change in response to bolus NaCN injections or dopamine infusions after prolonged hypoxia. However, both groups demonstrated a similar significant increase in the ventilatory response to subsequent acute exposure to isocapnic hypoxia. The increase in hypoxic ventilatory sensitivity, which was not dependent on the modality of hypoxic exposure (isocapnic vs. poikilocapnic), reinforces the key role of the carotid chemoreceptors in ventilatory acclimatization to hypoxia.

Effects of CO2 breathing on ventilatory response to sustained hypoxia in normal adults

The relationship between CO2 and ventilatory response to sustained hypoxia was examined in nine normal young adults. At three different levels of end-tidal partial pressure of CO2 (PETCO2, approximately 35, 41.8, and 44.3 Torr), isocapnic hypoxia was induced for 25 min and after 7 min of breathing 21% O2, isocapnic hypoxia was reinduced for 5 min. Regardless of PETCO2 levels, the ventilatory response to sustained hypoxia was biphasic, characterized by an initial increase (acute hypoxic response, AHR), followed by a decline (hypoxic depression). The biphasic response pattern was due to alteration in tidal volume, which at all CO2 levels decreased significantly (P less than 0.05), without a significant change in breathing frequency. The magnitude of the hypoxic depression, independent of CO2, correlated significantly (r = 0.78, P less than 0.001) with the AHR, but not with the ventilatory response to CO2. The decline of minute ventilation was not significantly affected by PETCO2 [averaged 2.3 +/- 0.6, 3.8 +/- 1.3, and 4.5 +/- 2.2 (SE) 1/min for PETCO2 35, 41.8, and 44.3 Torr, respectively]. This decay was significant for PETCO2 35 and 41.8 Torr but not for 44.3 Torr. The second exposure to hypoxia failed to elicit the same AHR as the first exposure; at all CO2 levels the AHR was significantly greater (P less than 0.05) during the first hypoxic exposure than during the second. We conclude that hypoxia exhibits a long-lasting inhibitory effect on ventilation that is independent of CO2, at least in the range of PETCO2 studied, but is related to hypoxic ventilatory sensitivity.