Ventilatory Response Curve Research Articles

The acetazolamide analogue N‐methyl acetazolamide does not alter the ventilatory response to hypoxia but reduces the hypercapnic response in the anesthetized cat

Acetazolamide (AZ) may have cardiorespiratory effects independently from inhibition of carbonic anhydrase (CA). In contrast to methazolamide, it impairs respiratory muscle function in rabbits and reduces the hypoxic ventilatory response in cats. In rat pulmonary arterial smooth muscle cells, AZ inhibits the hypoxia‐induced rise in [Ca2+]i, an effect that is shared by N‐methyl acetazolamide (NMA), an AZ analogue devoid of inhibiting effects on CA. We have studied the effect of NMA on the ventilatory response to hypoxia and hypercapnia in 7 anesthetized cats. NMA, (20 mg.kg−1, i.v.) did not influence the hypoxic response measured at a constant end‐tidal PCO2 of about 6 kPa, described with the exponential equation Vi (inspired ventilation) = G.{(exp) − DPO2} + R, with G = hypoxic sensitivity, D = shape factor and R = ventilation in hyperoxia. Mean values of G, D and R were not different in control and following NMA. Surprisingly however, the ventilatory CO2 response curve described with Vi = S(PCO2−B) with the CO2 sensitivity S and the extrapolated X‐intercept (apneic threshold) B underwent dramatic changes: S and B decreased by 60 and 72%, respectively. Whether these effects of NMA may be due to vascular effects remains to be examined.

Arterial [H+] and the ventilatory response to hypoxia in humans: influence of acetazolamide-induced metabolic acidosis

In this study, we investigated possible separate effects of H+ ions and CO2 on hypoxic sensitivity in humans. We also examined whether hypoxic sensitivity, conventionally defined as the ratio of (hypoxic - normoxic) ventilation over (hypoxic - normoxic) Hb oxygen saturation can also be estimated by taking the ratio (hypoxic - normoxic) ventilation over (logPa(O2) hypoxia - logPa(O2) normoxia), enabling one to measure the hypoxic response independently from potential confounding influences of changes in position of the Hb oxygen saturation curve. We used acetazolamide to induce a metabolic acidosis. To determine the acute hypoxic response (AHR), we performed step decreases in end-tidal Po2 to approximately 50 Torr lasting 5 min each at three different constant end-tidal Pco2 levels. Nine subjects ingested 250 mg of acetazolamide or placebo every 8 h for 3 days in a randomized double-blind crossover design. The metabolic acidosis was accompanied by a rise in ventilation, a substantial fall in Pa(CO2), and a parallel leftward shift of the ventilatory CO2 response curve. In placebo, CO2 induced equal relative increases in hypoxic sensitivity (O2-CO2 interaction) regardless of the way it was defined. Acetazolamide shifted the response line representing the relationship between hypoxic sensitivity and arterial [H+] ([H+](a)) to higher values of [H+](a) without altering its slope, indicating that it did not affect the O2-CO2 interaction. So, in contrast to an earlier belief, CO2 and H+ have separate effects on hypoxic sensitivity. This was also supported by the finding that infusion of bicarbonate caused a leftward shift of the hypoxic sensitivity-[H+](a) response lines in placebo and acetazolamide. A specific inhibitory effect of acetazolamide on hypoxic sensitivity was not demonstrated.

Respiratory depression by tramadol in the cat: involvement of opioid receptors.

Tramadol hydrochloride (tramadol) is a synthetic opioid analgesic with a relatively weak affinity at opioid receptors. At analgesic doses, tramadol seems to cause little or no respiratory depression in humans, although there are some conflicting data. The aim of this study was to examine whether tramadol causes dose-dependent inhibitory effects on the ventilatory carbon dioxide response curve and whether these are reversible or can be prevented by naloxone. Experiments were performed in cats under alpha-chloralose-urethane anesthesia. The effects of tramadol and naloxone were studied by applying square-wave changes in end-tidal pressure of carbon dioxide (Petco2; 7.5-11 mmHg) and by analyzing the dynamic ventilatory responses using a two-compartment model with a fast peripheral and a slow central component, characterized by a time constant, carbon dioxide sensitivity, time delay, and a single offset (apneic threshold). In five animals 1, 2, and 4 mg/kg tramadol (intravenous) increased the apneic threshold (control: 28.3 +/- 4.8 mmHg [mean +/- SD]; after 4 mg/kg: 36.7 +/- 7.1 mmHg; P < 0.05) and decreased the total carbon dioxide sensitivity (control: 109.3 +/- 41.3 ml x min(-1) x mmHg(-1) ) by 31, 59, and 68%, respectively, caused by proportional equal reductions in sensitivities of the peripheral and central chemoreflex loops. Naloxone (0.1 mg/kg, intravenous) completely reversed these effects. In five other cats, 4 mg/kg tramadol caused an approximately 70% ventilatory depression at a fixed Pet co2 of 45 mmHg that was already achieved after 15 min. A third group of five animals received the same dose of tramadol after pretreatment with naloxone. At a fixed Petco of 45 mmHg, naloxone prevented more than 50% of the expected ventilatory depression in these animals. Because naloxone completely reversed the inhibiting effects of tramadol on ventilatory control and it prevented more than 50% of the respiratory depression after a single dose of tramadol, the authors conclude that this analgesic causes respiratory depression that is mainly mediated by opioid receptors.

Effects of Acetazolamide and Furosemide on Ventilation and Cerebral Blood Volume in Normocapnic and Hypercapnic Patients With COPD

Effects of chronic metabolic alkalosis and acidosis and their relation to central chemoregulation may differ between normocapnic and chronic hypercapnic patients with COPD. The relationship between responses of inspired ventilation (VI), mouth occlusion pressure (P(0.1)), and cerebral blood volume (CBV), to short-term changes in arterial PCO(2) was measured. Seventeen patients with chronic hypercapnia and COPD (PaCO(2) > 6.0 kPa) and 16 normocapnic patients with COPD (PaCO(2) < or = 6.0 kPa) [FEV(1) 27% predicted] were studied under baseline metabolic conditions and after 1 week of treatment with oral furosemide, 40 mg/d, or acetazolamide, 500 mg/d. Hypercapnia (change in end-tidal carbon dioxide > 1 kPa) was induced by administering adequate amounts of carbon dioxide in the inspired air. CBV was measured using near-infrared spectroscopy. Compared with baseline metabolic condition, chronic metabolic acidosis and alkalosis did not change ventilatory (Delta VI/Delta PaCO(2)) and cerebrovascular (Delta CBV/Delta PaCO(2)) reactivity. Base excess (BE) decreased by 6.8 +/- 1.1 mEq/L and 6.9 +/- 1.6 mEq/L, respectively, in the normocapnic and chronic hypercapnic COPD groups during metabolic acidosis, resulting in a not-quite-significant leftward shift of both the ventilatory and cerebrovascular carbon dioxide response curve. BE increased by 2.3 +/- 1.2 mEq/L and 1.2 +/- 1.3 mEq/L, respectively, during chronic metabolic alkalosis in both COPD groups, without concomitant shift. Poor correlations between ventilatory and cerebrovascular carbon dioxide responsiveness (Delta CBV/Delta PaCO(2) and Delta VI/Delta PaCO(2), Delta CBV/Delta PaCO(2) and Delta P(0.1)/Delta PaCO(2), respectively) were found irrespective of baseline, respiratory condition, and induced metabolic state. Normocapnic and chronic hypercapnic COPD patients have the same ventilatory and cerebrovascular carbon dioxide responsiveness irrespective of induced metabolic state.

The Effects on Hypercarbic Ventilatory Response of Sameridine Compared to Morphine and Placebo

Sameridine, a novel molecule, has both local anesthetic and partial μ-opioid receptor properties. The aim of this single, blinded, randomized, four-way cross-over study was to investigate the hypercarbic ventilatory response (HCVR) in 12 healthy volunteers. A 20-min IV infusion of two doses of sameridine 0.15 mg/kg (S-Small) and 0.73 mg/kg (S-Large) were compared with 0.10 mg/kg of morphine and placebo. Ventilation was studied repeatedly for 2 h by pneumotachography and inline capnography. The hypercarbic ventilatory response was measured after addition of 4% CO2 to inspired air until steady state. A visual analog scale followed sedation. After drug infusion there was a significant rightward shift (on average 4.5 mm Hg) of the ventilatory response curve (HCVR = Δ&OV0312;e/ΔETCO2) in the S-Large group. There were no changes of HCVR in the other groups. On a molar basis, the S-Large dose was 6.5 times the morphine dose, and such a dose would have been expected to cause a 12 mm Hg rightward shift. This discrepancy in effect is most likely a result of the partial μ-agonist effect of sameridine. Sedation was most pronounced after S-Large and morphine infusions. The authors concluded that a large IV dose of sameridine depressed the hypercarbic ventilatory response, whereas a smaller, clinical dose did not. Implications A novel molecule, sameridine, produces both a local anesthetic blockade and a partial μ-agonist action. In large doses, the ventilatory CO2 response was depressed, which was not the case when the recommended clinical dose was used.

The neuronal nitric oxide synthase inhibitor 7-nitroindazole (7-NI) and morphine act independently on the control of breathing

Inhibitors of nitric oxide synthase (NOS) have analgesic properties and reduce opioid tolerance and dependency. To investigate a possible interaction of NOS inhibitors with the respiratory depressant action of morphine, we determined the effects of the neuronal NOS inhibitor 7-nitroindazole (7-NI) on the ventilatory carbon dioxide response curve; subsequently, we studied the effects of additional morphine application. Finally, using naloxone, we investigated a possible interaction (at the opioid receptor) between the effects of 7-NI and morphine. The effects of 7-NI 50 mg kg-1 i.p., morphine 0.1 mg kg-1 i.v. and naloxone 0.1 mg kg-1 i.v. were studied using dynamic end-tidal carbon dioxide forcing in eight cats under alpha-choralose-urethane anaesthesia. Data analysis was performed using a two-compartment model comprising a fast peripheral and a slow central component characterized by carbon dioxide sensitivities and a single offset B (apnoeic threshold). 7-NI decreased the mean apnoeic threshold from 4.27 (SD 0.87) to 2.59 (1.71) kPa. Peripheral and central carbon dioxide sensitivities were reduced from 0.56 (0.22) to 0.26 (0.09) litre min-1 kPa-1 and from 0.09 (0.05) to 0.04 (0.03) litre min-1 kPa-1, respectively. Morphine increased the apnoeic threshold by 0.5 kPa and reduced carbon dioxide sensitivity by a further 35%. Naloxone reversed the ventilatory effects of morphine but not those induced by 7-NI. We conclude that the respiratory effects of 7-NI and morphine are mediated independently and that the effects of 7-NI do not result from interaction with opioid receptors.

Effect of low-dose acetazolamide on the ventilatory CO2 response during hypoxia in the anaesthetized cat.

Acetazolamide, a carbonic anhydrase inhibitor, is used in patients with chronic obstructive pulmonary diseases and central sleep apnoea syndrome and in the prevention and treatment of the symptoms of acute mountain sickness. In these patients, the drug increases minute ventilation (V'E), resulting in an improvement in arterial oxygen saturation. However, the mechanism by which it stimulates ventilation is still under debate. Since hypoxaemia is a frequently observed phenomenon in these patients, the effect of 4 mg x kg(-1) acetazolamide (i.v.) on the ventilatory response to hypercapnia during hypoxaemia (arterial oxygen tension (Pa,O2)=6.8+/-0.8 kPa, mean+/-SD) was investigated in seven anaesthetized cats. The dynamic end-tidal forcing (DEF) technique was used, enabling the relative contributions of the peripheral and central chemoreflex loops to the ventilatory response to a step change in end-tidal carbon dioxide tension, (PET,CO2) to be separated. Acetazolamide reduced the CO2 sensitivities of the peripheral (Sp) and central (Sc) chemoreflex loops from 0.22+/-0.08 to 0.11+/-0.03 L x min(-1) x kPa(-1) (mean+/-SD) (p<0.01) and from 0.74+/-0.32 to 0.40+/-0.10 L x min(-1) x kPa(-1) (p<0.01), respectively. The apnoeic threshold B (x-intercept of the ventilatory CO2 response curve) decreased from 2.88+/-0.97 to 0.95+/-0.92 kPa (p<0.01). The net result was a stimulation of ventilation at PET,CO2 <5 kPa. The effect of acetazolamide is possibly due to a direct effect on the peripheral chemoreceptors as well as to an effect on the cerebral blood flow regulation. Possible clinical implications of these results are discussed.

Hypoxic Ventilatory Responses and Gas Exchange in Patients with Parkinson’s Disease

Ventilatory responses to isocapnic, progressive hypoxic rebreathing (HVR), in supine and sitting positions, lung ventilation and gas exchange while breathing air and during 5 min of breathing 11% O₂ in N₂ were studied in 12 healthy young (20–28 years), 5 old (57–73 years) male subjects, and in 7 male patients with Parkinson’s disease (PD) aged 55–67 years. The piecewise linear approximation technique was used for evaluation of the ventilatory response curves, which allowed a separate analysis of slopes during minor and severe hypoxia. It has been shown that body position affected HVR. In the range of P_ETO₂ from 60 to 35 mm Hg, the ventilatory response in the sitting position was higher than supine: in young persons by 43%, in healthy old persons by 76%, and in the PD patients by 211%. No significant differences in HVR to minor hypoxia (P_ETO₂ from 100 to 60 mm Hg) were found in the 3 groups. During severe hypoxia (P_ETO₂ from 60 to 35 mm Hg) the slope of minute ventilation versus O₂ was 4.6 (supine) and 2.6 (sitting) times greater in healthy old men than PD patients’ slopes. PD patients compared to old controls had 32% lower alveolar ventilation, 10% lower P_ETO₂ and 15% elevation of P_ETCO₂ while breathing air; similar differences were found while the patients were breathing 11% O₂. The reduced alveolar ventilation under severe hypoxia in patients with PD could not be attributed to mechanical restriction of lung function. We suggest that the discrepancy in HVR under minor and severe hypoxia results from dysfunction in chemoreception associated with Parkinsonism.

Changes in the period of no respiratory sensation and total breath-holding time in successive breath-holding trials.

1. Immediately after breath-holding at end-expiratory level, there is a certain period of no particular respiratory sensation which is terminated by the onset of an unpleasant sensation and followed by progressive discomfort during breath-holding. This period, defined as the time from the start of voluntary breath-holding to the point where the onset of an unpleasant sensation occurs, is designated "the period of no respiratory sensation'. Although it has been shown that the maximum breath-holding performance is improved with successive trials, it is not clear whether this training effect exerts a similar influence on the period of no respiratory sensation during breath-holding. 2. Since the training effect seems to be associated with the stresses of breath-holding, we hypothesized that the initial period of no respiratory sensation during breath-holding might be less influenced by the training effect. 3. We studied 13 normal subjects who performed repeated breath holds while continuously rating their respiratory discomfort using a visual analogue scale. In addition, we measured the hypercapnic ventilatory response of each individual and obtained the relationship between the slope of the hypercapnic response curve and breath-holding periods. 4. Our results showed that there was little training effect on the period of no respiratory sensation and that the period of no sensation during breath-holding is inversely related to the slope of the hypercapnic ventilatory response curve. 5. The period of no respiratory sensation was also measured in eight patients with chronic obstructive pulmonary disease. The values of the period of no respiratory sensation in patients with chronic obstructive pulmonary disease were apparently lower than those obtained in normal subjects. 6. These findings suggest that measurement of the period of no respiratory sensation can be a useful clinical test for the study of genesis of dyspnoea.

The effect of low-dose acetazolamide on the ventilatory CO2 response curve in the anaesthetized cat.

1. The effect of 4 mg kg-1 acetazolamide (I.V.) on the slope (S) and intercept on the Pa,CO2 axis (B) of the ventilatory CO2 response curve of anaesthetized cats with intact or denervated carotid bodies was studied using the technique of dynamic end-tidal forcing. 2. This dose did not induce an arterial-to-end-tidal PCO2 (P(a-ET),CO2) gradient, indicating that erythrocytic carbonic anhydrase was not completely inhibited. Within the first 2 h after administration, this small dose caused only a slight decrease in mean standard bicarbonate of 1.8 and 1.7 mmol l-1 in intact (n = 7) and denervated animals (n = 7), respectively. Doses of acetazolamide larger than 4 mg kg-1 (up to 32 mg kg-1) caused a significant increase in the P(a-ET),CO2 gradient. 3. In carotid body-denervated cats, 4 mg kg-1 acetazolamide caused a decrease in the CO2 sensitivity of the central chemoreflex loop (Sc) from 1.52 +/- 0.42 to 0.96 +/- 0.32 l min-1 kPa-1 (mean +/- S.D.) while the intercept on the Pa,CO2 axis (B) decreased from 4.5 +/- 0.5 to 4.2 +/- 0.7 kPa. 4. In carotid body-intact animals, 4 mg kg-1 acetazolamide caused a decrease in the CO2 sensitivity of the peripheral chemoreflex loop (Sp) from 0.28 +/- 0.18 to 0.19 +/- 0.12 l min-1 kPa-1. Se and B decreased from 1.52 +/- 0.55 to 0.84 +/- 0.21 l min-1 kPa-1, and from 4.0 +/- 0.5 to 3.0 +/- 0.6 kPa, respectively, not significantly different from the changes encountered in the denervated animals. 5. It is argued that the effect of acetazolamide on the CO2 sensitivity of the peripheral chemoreflex loop in intact cats may be caused by a direct effect on the carotid bodies. Both in intact and in denervated animals the effects of the drug on Sc and B may not be due to a direct action on the central nervous system, but rather to an effect on cerebral vessels resulting in an altered relationship between brain blood flow and brain tissue PCO2.

Source of respiratory drive during periodic breathing in lambs

In order to investigate the mechanisms underlying periodic breathing (PB), we studied the initiation of breathing after passive hyperventilation in 14 anaesthetised 10–20 day old lambs. Eight of the lambs exhibited PB following post-hyperventilation apnea (PHA), with an epoch duration of 82.4 ± 14.2 sec (mean ± SEM), a cycle duration of 9.7 ± 0.7 sec and a ratio of ventilatory duration to apnea duration (V-A ratio) of 1.24 ± 0.32. The remaining lambs showed stable breathing patterns following PHA. The ventilatory response to isocapnic hypoxia was significantly greater in the group that had PB (−7.2 ± 1.0 ml min −1 %Sa −1 O 2 kg −1) than in the animals that did not (−2.5 ± 1.0 ml min −1 %Sa −1 O 2 kg −1). Using experimentally determined ventilatory response curves to O 2 and CO 2 we calculated that the swings in Sa O 2 and Pa CO 2 during PB generated chemical drive that accounted for only 16.2% of the ventilatory oscillations observed during PB. Much of the remaining drive appeared to originate in the ‘switch-on’ characteristics of the respiratory controller; in lambs that exhibited periodic breathing, when breathing began after PHA ventilation jumped abruptly from zero to 55.1% of the eupneic ventilation. The magnitude of this jump in ventilation accounted for 51.9% of the amplitude of ventilatory oscillations that occur during PB. We speculate that this previously unrecognised feature of the respiratory controller, together with an elevated sensitivity to hypoxaemia, play crucial roles in generating PB in the infant.

Maximal breath-holding time and immediate tissue CO2 storage capacity during head-out immersion in humans.

This study tested three possible mechanisms that could explain the prolonged breath-holds (BH) previously observed in humans during submersion in 35 degrees C (thermoneutral) water, including a reduced metabolism, a decreased CO2 sensitivity, and an increased CO2 storage capacity. During immersed BH (n = 13), maximal BH time was prolonged by 20.3% (P < 0.05), the rate of rise of end tidal partial pressure of carbon dioxide (PETCO2) was slower (P < 0.05) by 31% (compatible with increased CO2 storage capacity), but the breaking-point PETCO2 (CO2 sensitivity) and the rate of decrease of end tidal partial pressure of oxygen (metabolism) were unchanged. During air breathing (n = 5), immersion resulted in a significant decrease in tidal volume (11%), but did not affect O2 uptake, CO2 elimination (VCO2), or respiratory exchange ratio (R). During a 4-min CO2-rebreathing (n = 9), the slope of the hypercapnic ventilatory response curve (CO2 sensitivity index) was unchanged by immersion, but the significantly decreased VCO2, R, and rate of rise in PETCO2 during immersed rebreathing indicated an increase in the acute CO2 storage capacity (SC). The estimated SC (n = 9), based on an assumed cellular respiratory quotient of 0.8, were 0.52 (SEM 0.03) ml.kg-1.mmHg-1 for control and 0.66 (SEM 0.04) ml.kg-1.mmHg-1 for immersion. A proposed mechanism for the increased SC during immersed BH and during immersed rebreathing is that immersion accelerated CO2 redistribution in the body by increasing perfusion to some low-perfused, low-metabolism, and high-capacity tissues, such as resting skeletal muscle. The increased SC during immersion, however, did not correlate with the prolonged BH duration (n = 9, P > 0.05). The mechanism of the latter remains unclear.

Carbonic anhydrase and control of breathing: different effects of benzolamide and methazolamide in the anaesthetized cat.

1. The effect of inhibition of erythrocyte carbonic anhydrase on the ventilatory response to CO2 was studied by administering benzolamide (70 mg kg-1, i.v.), an inhibitor which does not cross the blood-brain barrier, to carotid body denervated cats which were anaesthetized with chloralose-urethane. 2. In the same animals the effect on the ventilatory response to CO2 of subsequent inhibition of central nervous system (CNS) carbonic anhydrase was studied by infusing methazolamide (20 mg kg-1), an inhibitor which rapidly penetrates into brain tissue. 3. The results show that inhibition of erythrocyte carbonic anhydrase by benzolamide leads to a decrease in the slope of the normoxic CO2 response curve, and a decrease of the extrapolated arterial PCO2 at zero ventilation. 4. Inhibition of CNS carbonic anhydrase by methazolamide results in an increase in slope and alpha-intercept of the ventilatory CO2 response curve. 5. Using a mass balance equation for CO2 of a brain compartment, it is argued that inhibition of erythrocyte carbonic anhydrase results in a decrease in slope of the in vivo CO2 dissociation curve, which can explain the effects of benzolamide. 6. The changes in slope and intercept induced by methazolamide are discussed in relation to effects on neurones containing carbonic anhydrase, which may include central chemoreceptors.

Diphenhydramine enhances the interaction of hypercapnic and hypoxic ventilatory drive.

Although diphenhydramine is frequently used to treat pruritus and nausea in patients who have received neuraxial opioids, there are no data regarding its effect on ventilatory control. We conducted the current study to evaluate the effects of diphenhydramine on hypercapnic and hypoxic ventilatory control in healthy volunteers. First, we measured the steady-state ventilatory response to carbon dioxide during hyperoxia with an end-tidal carbon dioxide tension of 46 or 54 mmHg (alternate subjects) in eight healthy volunteers. We then determined the hypoxic ventilatory response during isocapnic rebreathing at the same carbon dioxide tension. After a 10-min recovery period, we repeated the steady-state and hypoxic ventilatory response measurements at the other carbon dioxide tension (54 or 46 mmHg). Ten minutes after subjects received diphenhydramine 0.7 mg.kg-1 intravenously, we repeated this sequence of ventilatory measurements. Under hyperoxic conditions (inspired oxygen fraction > 0.5) diphenhydramine did not affect the ventilatory response to hypercapnia. Similarly, at an end-tidal carbon dioxide tension of 46 mmHg, neither the slope nor the position of the hypoxic ventilatory response curve changed significantly after diphenhydramine. However, at an end-tidal carbon dioxide tension of 54 mmHg, the slope of the hypoxic ventilatory response increased from 1.28 +/- 0.33 to 2.13 +/- 0.61 l.min-1.%SpO2(-1) (mean +/- standard error), and VE at an arterial hemoglobin oxygen saturation of 90% increased from 31.2 +/- 3.1 to 43.1 +/- 5.4 l.min-1). We conclude that although it did not affect the ventilatory response to carbon dioxide during hyperoxia or the ventilatory response to hypoxia at an end-tidal carbon dioxide tension of 46 mmHg diphenhydramine augmented the hypoxic response under conditions of hypercapnia in our young healthy volunteers. Although these findings may help to explain the apparent safety of diphenhydramine, they may not be applicable to debilitated patients or those who have received systemic or neuraxial ventilatory depressants.

Propofol Depresses the Hypoxic Ventilatory Response during Conscious Sedation and Isohypercapnia

Propofol infusion at subanesthetic doses provides reliable conscious sedation. However, the ventilatory effects of sedative doses of propofol have not been established. The current study was conducted to determine the effects of propofol sedation on the hypoxic ventilatory response. Eight healthy, male volunteers received 1 mg.kg-1 propofol followed by a propofol infusion adjusted to maintain a constant, subanesthetic level of sedation. Hypoxic ventilatory response was measured using an isocapnic rebreathing technique: while keeping PETCO2 constant (approximately 6 mmHg above prestudy baseline), the authors continuously recorded minute ventilation and tidal volume, as oxygen saturation (SpO2) decreased from 98 to 70%. Hypoxic response determinations were performed before and during propofol infusion, as well as 30 and 60 min after termination of the propofol infusion. The slope of the hypoxic ventilatory response curve (VE vs. SpO2) decreased from 0.88 +/- 0.15 to 0.17 +/- 0.03 l.min-1.%SpO2 -1 during propofol sedation (mean +/- SE). Thirty minutes after discontinuation of the propofol infusion, slope returned to its prepropofol value. In addition, minute ventilation at SpO2 = 90% decreased during propofol sedation, from 16.1 +/- 0.8 to 8.7 +/- 0.4 l.min-1, accompanied by a similar decrease in tidal volume at SpO2 = 90%, from 1,099 +/- 87 to 523 +/- 21 ml. Thirty minutes after discontinuation of the propofol infusion, these variables also returned to their prepropofol values. The authors concluded that propofol infusion for conscious sedation significantly decreases the slope and causes a downward shift of the hypoxic ventilatory response curve measured during isohypercapnia.

Hyperosmolality alters the ventilatory response to acute hypercapnia and hypoxia

Acute hyperosmolality in the Pekin duck results in an extracellular acidosis and hypercarbia without any stimulation of ventilation. The development of the extracellular acidosis is accompanied by the concurrent development of an intracellular alkalosis systematically which has been hypothesized to depress ventilation (Kasserra et al., J. Appl. Physiol., 1993). In order to investigate this apparent suppression of ventilation, the ventilatory response to various respiratory challenges (CO 2, O 2, K +) was studied both before (normosmotic) and after (hyperosmotic) hypertonic sucrose infusion. Increased plasma osmolality caused a significant drop in arterial pH of 0.06 ± 0.01 units and a 4 Torr increase in Pa CO 2 , yet did not stimulate any significant increase in ventilation despite a significant increase in oxygen consumption. Acute hyperosmolality increased the Pa CO 2 associated with resting ventilation, and decreased the magnitude of the ventilatory response to a given increase in Pa CO 2 , compared with the response to the same ventilatory challenge in normosmotic animals. Acute hyperosmolality increased the ventilatory response to hypoxia and K + compared with normosmotic animals. The opposite effect of hyperosmolality on the ventilatory responses to hypercapnia compared with hypoxia suggests that the mechanisms of chemoreception for hypercapnia and hypoxia are different. The depressed ventilatory response curve to increased Pa CO 2 and decreased arterial pH during hyperosmolality, both alone and during the hypercapnic challenge, suggests that the peripheral chemoreceptor response to pH and CO 2 is suppressed. It is hypothesized that the suppression results from the intracellular alkalosis occurring during acute hyperosmolality.

The Effect of Flumazenil on Midazolam-induced Depression of the Ventilatory Response to Hypoxia during Isohypercarbia

While flumazenil reverses benzodiazepine-induced sedation, its ability to antagonize the ventilatory depressant effects of benzodiazepines has not been fully established. A randomized, double-blind study was conducted to determine whether flumazenil effectively reverses midazolam-induced depression of the hypoxic ventilatory response. Twelve healthy male volunteers received intravenous midazolam 0.12 +/- 0.01 mg.kg-1 followed by either flumazenil 1.0 mg or placebo. Hypoxic ventilatory response was measured using an isocapnic rebreathing technique: as Spo2 decreased to 70% VE and tidal volume were continuously recorded. Hypoxic response determinations were performed before and after midazolam, as well as 3, 30, 60, 120, and 180 min after flumazenil or placebo. After midazolam, the slope of the hypoxic ventilatory response curve (VE vs. SpO2) decreased to 0.59 +/- 0.05 (means +/- SE) times its premidazolam baseline; likewise, at Spo2 = 90%, minute ventilation (VE90) and tidal volume (TV90) decreased to 0.70 +/- 0.04 and 0.62 +/- 0.03 times baseline, respectively. Three minutes after flumazenil, the slope increased to 1.10 +/- 0.13 times baseline (P < 0.05 vs. postmidazolam), while following placebo, it was only 0.81 +/- 0.09 times baseline (P = NS vs. postmidazolam, P < 0.05 between treatments). VE90 and TV90, after flumazenil, increased to 1.45 +/- 0.15 and 1.27 +/- 0.09 times baseline, respectively (P < 0.05 vs. postmidazolam); these increases were significantly greater than the corresponding changes observed after placebo (P < 0.05 between treatments). It was concluded that, after sedation with midazolam, flumazenil causes a greater increase in hypoxic ventilatory response during isohypercarbic conditions than does placebo, and may, therefore, be useful in the treatment of midazolam-induced ventilatory depression.

Respiratory interaction after spinal anesthesia and sedation with midazolam.

The combined use of midazolam and spinal anesthesia is common in clinical practice. Despite the known potential for each to alter ventilation, the effect of their interaction has not been examined. Nineteen healthy volunteers were studied to assess the impact of intravenous midazolam (0.05 or 0.075 mg/kg), spinal anesthesia (T3-T8; mean level, T6), and their combination on resting ventilation and ventilatory responses to progressive hyperoxic hypercapnia. Resting ventilatory pattern was altered significantly by each condition. Midazolam caused a 29% decrease in resting tidal volume and a 24% decrease in mean inspiratory flow rate, while respiratory frequency increased by 14% and minute ventilation remained unchanged. By contrast, spinal anesthesia alone caused a 32% increase in tidal volume, a 24% increase in mean inspiratory flow rate, and a 13% increase in minute ventilation accompanied by a 14% decrease in respiratory frequency. The combination of midazolam and spinal anesthesia caused a significant decrease in minute ventilation (19%), tidal volume (28%), and mean inspiratory flow rate (27%), all of which were significantly more than the predicted sum of the individual interventions. Midazolam and spinal anesthesia each produced a significant decrease in hypercapnic ventilatory response slope, whereas their combination provoked no net change in hypercapnic ventilatory response slope. Interpretation of the hypercapnic ventilatory response data was complicated by shifts in the position of the ventilatory response curve, particularly under the spinal anesthesia condition. It is concluded that intravenous midazolam depresses resting ventilation, spinal anesthesia stimulates resting ventilation, and their combination has a modest synergistic effect of depressing resting ventilation.

Effects of a 1-yr stay at altitude on ventilation, metabolism, and work capacity.

The hypoxic and hypercapnic ventilatory drive, gas exchange, blood lactate and pyruvate concentrations, acid-base balance, and physical working capacity were determined in three groups of healthy males: 17 residents examined at sea level (group I), 24 sea-level natives residing at 1,680-m altitude for 1 yr and examined there (group II), and 17 sea-level natives residing at 3,650-m altitude for 1 yr and examined there (group III). The piecewise linear approximation technique was used to study the ventilatory response curves, which allowed a separate analysis of slopes during the first phase of slow increase in ventilation and the second phase of sharp increase. The hypoxic ventilatory response for both isocapnic and poikilocapnic conditions was greater in group II and even greater in group III. The first signs of consciousness distortion in sea-level residents appeared at an end-tidal O2 pressure level (4.09 +/- 0.56 kPa) higher than that of temporary residents of middle (3.05 +/- 0.12) and high altitude (2.90 +/- 0.07). The hypercapnic response was also increased, although to a lesser degree. Subjects with the highest hypoxic respiratory sensitivity at high altitude demonstrated greater O2 consumption at rest, greater ventilatory response to exercise, higher physical capacity, and a less pronounced anaerobic glycolytic flux but a lower tolerance to extreme hypoxia. That is, end-tidal O2 pressure that caused a distortion of the consciousness was higher in these subjects than in those with lower hypoxic sensitivity. Two extreme types of adaptation strategy can be distinguished: active, with marked reactions of "struggle for oxygen," and passive, with reduced O2 metabolism, as well as several intermediate types.(ABSTRACT TRUNCATED AT 250 WORDS)

Central chemoreceptor drive to breathing in unanesthetized toads, Bufo paracnemis

Central chemoreceptor drive to breathing was studied in unanesthetized toads, equipped with face masks to measure pulmonary ventilation and arterial catheters to analyze blood gases. Two series of experiments were performed. Expt. 1: The fourth cerebral ventricle was perfused with solutions of mock CSF, adjusted to stepwise decreasing pH values. Concomitant perfusion-induced increases of pulmonary ventilation, pHa and Pa O 2 were measured. Expt. 2: Inspiration of hypercapnic gas mixtures was applied to stimulate both central and peripheral chemoreceptors. Subsequently, only peripheral chemoreceptors were stimulated. This was accomplished by repeating the hypercapnic conditions while the fourth ventricle was perfused with mock CSF at pH 7.7. This procedure reduced the slope of the ventilatory response curve by about 80%. Taken together, the experiments suggest a highly dominant role of central chemoreceptors in the ventilatory acid-base regulation of the toad.