CO2 Ventilatory Response Research Articles

AltitudeOmics: enhanced cerebrovascular reactivity and ventilatory response to CO2 with high-altitude acclimatization and reexposure

The present study is the first to examine the effect of high-altitude acclimatization and reexposure on the responses of cerebral blood flow and ventilation to CO2. We also compared the steady-state estimates of these parameters during acclimatization with the modified rebreathing method. We assessed changes in steady-state responses of middle cerebral artery velocity (MCAv), cerebrovascular conductance index (CVCi), and ventilation (V(E)) to varied levels of CO2 in 21 lowlanders (9 women; 21 ± 1 years of age) at sea level (SL), during initial exposure to 5,260 m (ALT1), after 16 days of acclimatization (ALT16), and upon reexposure to altitude following either 7 (POST7) or 21 days (POST21) at low altitude (1,525 m). In the nonacclimatized state (ALT1), MCAv and V(E) responses to CO2 were elevated compared with those at SL (by 79 ± 75% and 14.8 ± 12.3 l/min, respectively; P = 0.004 and P = 0.011). Acclimatization at ALT16 further elevated both MCAv and Ve responses to CO2 compared with ALT1 (by 89 ± 70% and 48.3 ± 32.0 l/min, respectively; P < 0.001). The acclimatization gained for V(E) responses to CO2 at ALT16 was retained by 38% upon reexposure to altitude at POST7 (P = 0.004 vs. ALT1), whereas no retention was observed for the MCAv responses (P > 0.05). We found good agreement between steady-state and modified rebreathing estimates of MCAv and V(E) responses to CO2 across all three time points (P < 0.001, pooled data). Regardless of the method of assessment, altitude acclimatization elevates both the cerebrovascular and ventilatory responsiveness to CO2. Our data further demonstrate that this enhanced ventilatory CO2 response is partly retained after 7 days at low altitude.

Cardiorespiratory effects of gap junction blockade in the locus coeruleus in unanesthetized adult rats

The locus coeruleus (LC) plays an important role in central chemoreception. In young rats (P9 or younger), 85% of LC neurons increase firing rate in response to hypercapnia vs. only about 45% of neurons from rats P10 or older. Carbenoxolone (CARB – gap junction blocker) does not affect the % of LC neurons responding in young rats but it decreases the % responding by half in older animals. We evaluated the participation of gap junctions in the CO2 ventilatory response in unanesthetized adult rats by bilaterally microinjecting CARB (300μM, 1mM or 3mM/100nL), glycyrrhizic acid (GZA, CARB analog, 3mM) or vehicle (aCSF – artificial cerebrospinal fluid) into the LC of Wistar rats. Bilateral gap junction blockade in LC neurons did not affect resting ventilation; however, the increase in ventilation produced by hypercapnia (7% CO2) was reduced by ∼25% after CARB 1mM or 3mM injection (1939.7±104.8mLkg−1min−1 for the aCSF group and 1468.3±122.2mLkg−1min−1 for 1mM CARB, P<0.05; 1939.7±104.8mLkg−1min−1 for the aCSF group and 1540.9±68.4mLkg−1min−1 for the 3mM CARB group, P<0.05) due largely to a decrease in respiratory frequency. GZA injection or CARB injection outside the LC (peri-LC) had no effect on ventilation under any conditions. The results suggest that gap junctions in the LC modulate the hypercapnic ventilatory response of adult rats.

Clinical, morphological and functional features of primary ciliary dyskinesia children in southeast Spain

Introduction: Congenital central hypoventilation syndrome (CCHS) is a disorder of the respiratory center at medulla oblongata. Responsiveness of the respiratory center is measured by relating the increase in minute ventilation induced by an increase in inhaled CO2, known as the Ventilatory Response to CO2 (VRCO2). The VRCO2 is useful because it can be evaluated quantitatively. We measured the VRCO2 in CCHS and compared the results with normal children. Method: Records of VRCO2 in 6 children with CCHS between January 1989 and December 2012 were reviewed. Demographic data, time of diagnosis and type of PHOX2B gene abnormality were analyzed. The VRCO2 was measured using a pulmonary function measuring system made by Aivision Japan and Read’s rebreathing technique in which a mixture of 95% O2 and 5% CO2 was inhaled in a closed circuit. Result: The VRCO2 was measured 7 times. Five measurements were taken in infancy, others in adolescence. The average VRCO2 was 0.037ml/mm/min/mmHg (−0.035 to 0.013). It was extremely low compared with normal children (0.64±0.23) at our institution. In a child with repeated measurements at 5 months and 18 years of age, the VRCO2 did not improve. There was no correlation between the VRCO2, type of PHOX2B gene abnormality, and time of diagnosis. Conclusion: These data demonstrate that the VRCO2 in CCHS is extremely low compared with normal children and does not improve with age. Therefore, the VRCO2 is very useful in the diagnosis of CCHS.

Gap junction blockade in the locus coeruleus (LC) decreases the hypercapnic ventilatory response

The LC has an important role in central chemoreception and its contribution decreases with development. In neurons from young rats (P9 or younger), the % of LC neurons that increase firing rate in response to hypercapnia is 85% while it is only about 45% in neurons from rats P10 or older. Carbenoxolone (CARB ‐ gap junction blocker) has very little effect on this response in neurons from the youngest rats, with the % responding dropping only to 70% in the presence of CARB. However, CARB decreases the % responding by half in older animals, dropping it to 21%. We evaluated the participation of gap junctions in the CO2 ventilatory response in conscious adult rats by bilaterally microinjecting CARB (1mM or 3mM / 0.1 μL) or vehicle (artificial cerebrospinal fluid) into the LC of Wistar rats. Bilateral gap junction blockade in LC neurons did not affect resting ventilation. However, the increase in ventilation produced by hypercapnia (7% CO2) was reduced by 20% after CARB injection (1904.5 ± 95.2 in vehicle group vs 1518.0 ± 76.1 mL/kg/min in CARB 3mM group and 1468.3 ± 122.2 mL/kg/min in CARB 1mM) due largely to a decrease in respiratory frequency. The results suggest that gap junctions modulate the hypercapnic ventilatory response, but that they are not involved in respiratory control during normocapnia, in the LC of rats older than P10.Financial support: INCT‐Fisiologia Comparada, FAPESP, CNPq, and NIH Grant HL56683.

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.

Chronic ethanol exposure disrupts neuroventilation and responses to hypoxia in bullfrog tadpoles

Chronic early developmental ethanol (EtOH) exposure is a sudden infant death syndrome risk factor and impairs neonatal rat hypoxic ventilatory responses. 10‐wk EtOH exposure impairs tadpole CO2 ventilatory responses. We hypothesized that tadpole hypoxic ventilatory responses would be impaired by EtOH. Neurocorrelates of lung and gill ventilation were recorded from in vitro brainstems of control and 10‐wk EtOH‐exposed tadpoles during normoxia and hypoxia. The tadpole central hypoxic ventilatory response was a reduced lung burst frequency and an increased lung burst duration, and these responses became more pronounced over development. Early‐stage tadpoles also increased gill burst amplitude late in hypoxia. 10‐wk EtOH exposure depressed baseline lung burst frequency and the hypoxia‐induced changes in lung burst duration and gill burst amplitude. Across development, chronic EtOH destabilized neuroventilation. The more marked impairments in late‐stage tadpoles suggest developmentally increased EtOH sensitivity or a disrupted maturation of the hypoxic ventilatory response. Thus, the ventilatory consequences of developmental EtOH exposure are an impaired hypoxic and hypercapnic responses.

Effects of theophylline on ventilatory regulation in patients with chronic obstructive pulmonary disease

The effects and the mechanism of single and long-term administration of theophylline on ventilatory regulation were investigated in patients with chronic obstructive pulmonary disease (COPD). The ventilatory and mouth occlusion pressure (P0.1) responses during CO2 rebreathing were measured before and 4 hours after oral, single administration of theophylline in 15 patients with pulmonary emphysema, 15 patients with asthma and 10 healthy subjects. Ventilatory response to CO2 (VE/PCO2) was increased in patients with asthma and P0.1 response to CO2 (P0.1/PaCO2) was increased in patients with pulmonary emphysema after single theophylline administration. In patients with pulmonary emphysema, the increase in P0.1 was more marked than that in maximum inspiratory pressure static (MIPS). The effect of long-term administration of theophylline was studied in 8 patients with COPD and 8 patients with restrictive lung disease. In patients with COPD, P0.1/PaCO2 was significantly increased and the increase was maintained until three months later. These findings suggest that theophylline is effective in improving ventilatory and occlusion pressure responses to CO2 in patients with asthma probably by its bronchodilating effect, and in patients with pulmonary emphysema by its direct effect on the ventilatory control system.

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.

A Comparison of the Effects on Respiratory Carbon Dioxide Response, Arterial Blood Pressure, and Heart Rate of Dexmedetomidine, Propofol, and Midazolam in Sevoflurane-Anesthetized Rabbits

Dexmedetomidine, propofol, and midazolam are commonly used sedative-hypnotic drugs. Using a steady-state method, we examined the CO2 ventilatory response, mean arterial blood pressure (MAP) and heart rate (HR) effects of these three drugs in sevoflurane-anesthetized rabbits. New Zealand white rabbits weighing 2.9 +/- 0.2 kg (mean +/- SD) were used. After anesthetic induction and tracheostomy, the animals inhaled 2% sevoflurane to ensure a stable level of sedation throughout the experiment. After preparation, the rabbits were randomly assigned to four groups (n = 10 x 4) and received the following drugs: Group C, control; Group D, dexmedetomidine infused at 2 microg x kg(-1) x h(-1); Group P, propofol with the plasma concentration maintained at 15 microg/mL; Group M, midazolam initial IV 0.3 mg/kg bolus dose, followed by infusion at 1.86 mg x kg(-1) x h(-1). At 15 minutes after the start of infusion, for 20 min periods, in random sequences, gas including 0%, 1%, 2%, 3%, 4%, or 5% of CO2 was delivered to each animal. Fraction of inspired oxygen was maintained at 0.9. We did intergroup comparisons of minute ventilation (MV), respiratory rate, MAP, and HR during the final minute of each inspiratory carbon dioxide concentration (FiCO2) period. For Groups P and M, the rightward shift of plots for MV against FiCO2 indicated significant respiratory depression compared with Group C. There was also significantly more depression than in Group D. We found no significant differences between Groups P and M or between Groups C and D in the plots of MV against FiCO2. No significant differences among the four groups were apparent for respiratory rate. PaCO2-MV response plots were derived from linear regression analysis of data for mean MV and mean PaCO2 at each FiCO2 to compute apneic CO2 thresholds and CO2 sensitivities. The apneic CO2 thresholds of Groups P and M were larger than those of Groups C and D. The CO2 sensitivities of Group D were slightly lower than in Group C. No similar significant difference between the CO2 sensitivities of other group pairs was apparent. MAP in Group D was lower than in Groups C and M. In Group D, HR was lower than in Groups C, P, and M. The major finding is that, during sevoflurane anesthesia in rabbits, dexmedetomidine slightly altered the ventilatory response to CO2. It decreased MAP more than propofol and midazolam, which both significantly depressed the ventilatory response to CO2.

Involvement of the Nucleus Raphe Obscurus (ROb) on CO2 ventilatory response

Background: Several brainstem regions have been recognized as central CO2/pH chemoreceptors, including the medullary raphe region. The specific role of the Nucleus Raphe Obscurus (ROb) in the ventilatory responses to hypercapnia is uncertain, but a prior study suggest that the ROb does not by itself contribute to chemoreception directly, but it has a modulatory role (Li et al., 2006). In the present study, we investigated the involvement of ROb in the ventilatory responses to CO2 by nonspecific lesioning of this nucleus. Methods: Seven days before the experiments, male Wistar rats received microinjections of ibotenic acid (0.4 ìg/0.2 ìL) or vehicle (PBS, 50 mM, pH 7.4) into the ROb. Measurements of ventilation (VE) were performed by the body plethysmograph. Animals were exposed first to humidified room air, followed by 30 min of hypercapnia exposure (7% CO2). Results: Hypercapnia caused hyperventilation and in all groups. ROb lesions decreased ventilatory response to hypercapnia up to 15% [1341.1±67.7 mL.kg-1.min-1 (ibotenic acid) vs 1647.8±47.7 mL.kg-1.min-1 (vehicle)] due to lower tidal volume (VT) and respiratory frequency (f). Conclusion: The results suggest that ROb exerts an excitatory modulation in CO2-drive to breathing, acting on VT and f. Financial Support: FAPESP, FAEPA, USP.

The “Silver Hut” Expedition— A Commentary 40 Years Later

The “Silver Hut” Expedition— A Commentary 40 Years Later

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.

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.

Role of nucleus isthmi in the ventilatory response to hypoxia of Bufo paracnemis.

Nucleus isthmi (NI) is a mesencephalic structure of the amphibian brain that has recently been reported to participate in CO2-ventilatory response. The present study was designed to test the hypothesis that NI is also involved in hypoxia-induced hyperventilation and in the breathing pattern of the toad Bufo paracnemis. Pulmonary ventilation was directly measured by pneumotachography method in control, sham-operated and NI-lesioned toads exposed to normoxia and hypoxia (7 and 5% inspired O2). Under normoxic conditions, NI lesion caused no significant change in the ventilatory pattern or in the pulmonary ventilation. Hypoxia caused a significant (P < 0.05) increase in ventilation in control and sham-operated animals mainly due to an elevated VT. The hypoxia-induced hyperventilation was greater (P < 0.05) in the NI-lesioned toads, due to increases in both fR and VT. Such increased fR under hypoxia was due to a higher number of breaths per burst. The data indicate that NI plays no role under normoxic conditions but is involved in the ventilatory response to hypoxia, exercising an inhibitory modulation on pulmonary ventilation.

Ventilatory response to CO2 in children with obstructive sleep apnea from adenotonsillar hypertrophy.

We measured the ventilatory response to CO2 as an indicator of respiratory control dysfunction in children with obstructive sleep apnea (OSA) scheduled for adenotonsillectomy. Measurements were performed in unpremedicated children via an endotracheal tube under 0.4%-0.5% end-tidal halothane anesthesia. Mean ventilatory CO2 response slopes for 11 children with OSA requiring adenotonsillectomy (Group I) were compared with those for 14 children without OSA requiring adenotonsillectomy (Group II) and 15 children without OSA requiring nonairway surgery (Group III). The mean ventilatory slope corrected for body surface area for Groups I, II, and III were 539 +/- 338, 828 +/- 234, and 850 +/- 380 mL.min-1.mm Hg ETCO2(-1).m-2, respectively (P < 0.05, Group I versus Groups II and III). Historical data--including snoring, apneic episodes > 10 s, daytime hypersomnolence, and nocturnal enuresis--defined those with OSA. Obesity occurred more frequently in patients with OSA and with depressed ventilatory responses (P < 0.001). Children with OSA from adenotonsillar hypertrophy have a diminished ventilatory response to CO2 stimulation, compared with those without OSA symptoms. The depressed response may account, in part, for the reported increased risk of perioperative respiratory complications in this population. Children with obstructive sleep apnea undergoing adenotonsillar surgery are at risk of postoperative respiratory compromise. We found that patients with a clinical history suggesting obstructive sleep apnea have a diminished ventilatory response to CO2 rebreathing, compared with controls.

Ventilatory Response to CO2 in Children with Obstructive Sleep Apnea from Adenotonsillar Hypertrophy

We measured the ventilatory response to CO2 as an indicator of respiratory control dysfunction in children with obstructive sleep apnea (OSA) scheduled for adenotonsillectomy.Measurements were performed in unpremedicated children via an endotracheal tube under 0.4%-0.5% end-tidal halothane anesthesia. Mean ventilatory CO2 response slopes for 11 children with OSA requiring adenotonsillectomy (Group I) were compared with those for 14 children without OSA requiring adenotonsillectomy (Group II) and 15 children without OSA requiring nonairway surgery (Group III). The mean ventilatory slope corrected for body surface area for Groups I, II, and III were 539 +/- 338, 828 +/- 234, and 850 +/- 380 mL [middle dot] min-1 [middle dot] mm Hg ETCO2-1 [middle dot] m-2, respectively (P < 0.05, Group I versus Groups II and III). Historical data-including snoring, apneic episodes >10 s, daytime hypersomnolence, and nocturnal enuresis-defined those with OSA. Obesity occurred more frequently in patients with OSA and with depressed ventilatory responses (P < 0.001). Children with OSA from adenotonsillar hypertrophy have a diminished ventilatory response to CO2 stimulation, compared with those without OSA symptoms. The depressed response may account, in part, for the reported increased risk of perioperative respiratory complications in this population. Implications: Children with obstructive sleep apnea undergoing adenotonsillar surgery are at risk of postoperative respiratory compromise. We found that patients with a clinical history suggesting obstructive sleep apnea have a diminished ventilatory response to CO2 rebreathing, compared with controls. (Anesth Analg 1999;89:328-32)

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.

Hypercapnia enhances the development of coughing during continuous infusion of water into the pharynx.

We investigated the effects of increasing CO2 ventilatory drive on the coordination of respiration and reflex swallowing elicited by continuous infusion of distilled water into the pharynx (2.5 ml/min) in 11 normal subjects. Ventilation was monitored using a pneumotachograph and swallowing was recorded by submental electromyogram. The CO2 ventilatory drive was increased by addition of external dead space, while ventilation, the frequency of swallows, and the timing of swallows in relation to the phases of the respiratory cycle were measured at steady-state conditions. We found that the CO2 ventilatory response is not influenced by continuous reflex swallowing but that hypercapnia influences the timing and frequency of these swallows. Signs of aspiration were never observed during continuous infusion of water at eucapnia, but seven of 11 subjects showed laryngeal irritation and/or pending aspiration during hypercapnia, and the incidence of laryngeal irritation was higher the greater the PCO2. Detailed analysis of laryngeal irritations consisting of single coughs in seven subjects revealed that the majority of laryngeal irritations occurred when swallows coincided with expiratory-inspiratory transition or when swallows coincided with inspiration, whereas laryngeal irritation after an expiratory swallow was never observed. These results suggest that the automatic respiratory control system is not influenced by continuous swallowing but that the coordination of swallowing and respiration may be compromised during hypercapnia.

Effect of posture change on control of ventilation.

To clarify the control mechanism of ventilation during posture change, ventilatory parameters, PETCO2, and ventilatory response to CO2 were examined in 11 healthy male subjects at supine (0 degrees) and 75 degrees head-up tilt positions. Minute expiratory ventilation (V.E), tidal volume (VT), respiratory frequency (f), end-tidal and transcutaneous PCO2 and CO2 output (V.CO2), and ventilatory response to CO2 were measured during a steady state condition. V.E (V.A) and VT increased significantly at 75 degrees tilt with significant decrease in PETCO2 from 40.1 mmHg (0 degrees) to about 36.1 mmHg (75 degrees). Transcutaneous PCO2 also decreased during tilt, by 3.3 mmHg. Physiological dead space (VD/VT) and V.CO2, however, remained unchanged, and ventilatory equivalent (V.E/V.CO2, V.A/V.CO2) increased significantly. The CO2-ventilatory response curve shifted upward (or leftward) without significant change in the response slope. At 75 degrees tilt, EMG activity of gastro-cnemius muscle increased. These findings suggested that PETCO2 decreased because of increased V.E (V.A) with a leftward shift of CO2-ventilatory response curve. Various signals such as afferents from lower extremities might have net stimulatory effects on a CO2-ventilation control system to reset the controlled level of PETCO2 to a lower range, but without significant change in CO2-ventilatory response during upright position.

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.