Medroxyprogesterone acetate with acetazolamide stimulates breathing in cats.

Both medroxyprogesterone acetate (MPA) and acetazolamide (ACET) increase ventilation. Combined administration of these agents could result in an additional improvement of blood gases, for example in patients with chronic obstructive pulmonary diseases. The aim of this study in anaesthetized female (ovariohysterectomized, pre-treated with 17-beta-estradiol) cats was to compare the effects on the CO2 response curve of MPA alone (4 microg kg(-1), i.v.) with those after MPA followed by ACET (4 mg kg(-1) i.v.). We performed dynamic end-tidal CO2 forcing and analysed the data with a two-compartment model comprising a fast peripheral and slow central compartment, characterized by CO2 sensitivities (Sp and Sc, respectively) and a single offset (the apnoeic threshold B). MPA reduced Sp from 0.22 +/- 0.09 (mean +/- S.D.) to 0.13 +/- 0.06 L min(-1) kPa(-1) (P < 0.01) and Sc from 1.01 +/- 0.38 to 0.88 +/- 0.32 L min(-1) kPa(-1) (P < 0.01). B decreased from 4.02 +/- 0.27 to 3.64 +/- 0.42 kPa (P < 0.01). Subsequent administration of ACET reduced Sp and Sc further to 0.09 +/- 0.06 and to 0.70 +/- 0.49 L min(-1) kPa(-1) (P < 0.01), respectively. The apnoeic threshold decreased further to 2.46 +/- 1.50 kPa (P < 0.01). Because both treatments reduced ventilatory CO2 sensitivity, we conclude that a simulating effect on ventilation is due to a decrease in the apnoeic threshold. Combined administration of MPA and ACET may lead to larger increases in ventilation than treatment with either drugs alone.

Influence of 0.1 minimum alveolar concentration of sevoflurane, desflurane and isoflurane on dynamic ventilatory response to hypercapnia in humans.

To assess the effects and site of action of a sub-anaesthetic concentration of isoflurane, desflurane and sevoflurane (0.1 minimum alveolar concentration (MAC)) on respiratory control, we measured the ventilatory response to square wave changes in PE1CO2 against a background of normoxia. Using the computer steered "end-tidal forcing system", 2 min of steady state ventilation were followed by a step increase in PE1CO2 (1-1.5 kPa). This level was maintained for 8 min, followed by a step decrease to the original value for another 8 min. Each hypercapnic response was separated into a fast, peripheral component and a slow, central component, characterized by a time constant, carbon dioxide sensitivity, time delay and off-set. We studied 25 healthy volunteers; they performed 2-3 studies without and 2-3 studies during inhalation of the anaesthetic agent. Level of sedation was scored using a subjective seven-point scale from 0 (= alert and awake) to 6 (unrousable). In the isoflurane (16 subjects, 33 control, 37 drug studies) and sevoflurane (15 subjects, 40 control, 41 drug studies) studies, peripheral carbon dioxide sensitivity was reduced by approximately 45% and approximately 27% (ANOVA, P < 0.05 vs control), respectively, without affecting central carbon dioxide sensitivity or apnoeic threshold. In the desflurane study (16 subjects, 36 control, 37 drug studies), no significant effect was observed for any of the variables measured. A significant relation was observed between sedation score and change from control in central carbon dioxide sensitivities in the isoflurane and desflurane studies and in the change in the ratio peripheral carbon dioxide sensitivity over total carbon dioxide sensitivity in the sevoflurane studies. At the highest level of sedation observed (score 3-arousal state comparable with "light sleep"--in three subjects) these latter variables differed significantly from those in the other observed sedation levels (scores 1 and 2-a state of drowsiness). We conclude that 0.1 MAC of isoflurane and sevoflurane depressed the peripheral chemoreflex loop, without affecting the central chemoreflex loop. Desflurane at the same MAC showed no effect on peripheral and central carbon dioxide sensitivity. When the level of sedation was considered, our data suggested that at levels of sedation comparable with sleep, a depressive effect of all three anaesthetics was observed on the central chemoreflex loop.

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.

Expression of c-fos in the rat brainstem after exposure to hypoxia and to normoxic and hyperoxic hypercapnia.

In this study, Fos immunohistochemistry was used to map brainstem neuronal pathways activated during hypercapnia and hypoxia. Conscious rats were exposed to six different gas mixtures: (a) air; (b) 8% CO2 in air; (c) 10% CO2 in air; (d) 15% CO2 in air; (e) 15% CO2 + 60% O2, balance N2; (f) 9% O2, balance N2. Double-staining was performed to show the presence of tyrosine hydroxylase. Hypercapnia, in a dose-dependent way caused Fos expression in the following areas: caudal nucleus tractus solitarius (NTS), with few labeled A2 noradrenergic neurons; noradrenergic A1 cells and noncatecholaminergic neurons in the caudal ventrolateral medulla; raphe magnus and gigantocellular nucleus pars alpha (GiA); many noncatecholaminergic (and relatively few C1) neurons in the lateral paragigantocellular nucleus (PGCl), and in the retrotrapezoid nucleus (RTN); locus coeruleus (LC), external lateral parabrachial and Kölliker-Fuse nuclei, and A5 noradrenergic neurons at pontine level; and in caudal mesencephalon, the ventrolateral column of the periaqueductal gray (vlPAG). In most of these nuclei, hypoxia also induced Fos expression, albeit generally less than after hypercapnia. However, hypoxia did not cause labeling in RTN, juxtafacial PGCl, GiA, LC, or vlPAG. After normoxic hypercapnia, more labeled cells were present in NTS and PGCl than after hyperoxic hypercapnia. Part of the observed labeling could be caused by stress- or cardiovascular-related sequelae of hypoxia and hypercapnia. Possible implications for the neural control of breathing are also discussed, particularly with regard to the finding that several nuclei, not belonging to the classical brainstem respiratory centres, contained labeled cells.

Influence of acute pain induced by activation of cutaneous nociceptors on ventilatory control.

BACKGROUND: Although many studies show that pain increases breathing, they give little information on the mechanism by which pain interacts with ventilatory control. The authors quantified the effect of experimentally induced acute pain from activation of cutaneous nociceptors on the ventilatory control system. METHODS: In eight volunteers, the influence of pain on various stimuli was assessed: room air breathing, normoxia (end-tidal pressure of carbon dioxide (PET(CO2)) clamped, normoxic and hyperoxic hypercapnia, acute hypoxia, and sustained hypoxia (duration, 15-18 min; end-tidal pressure of oxygen, approximately 53 mmHg). Noxious stimulation was administered in the form of a 1-Hz electric current applied to the skin over the tibial bone. RESULTS: While volunteers breathed room air, pain increased ventilation (V(I)) from 10.9 +/- 1.7 to 12.9 +/- 2.5 l/min(-1) (P < 0.05) and reduced PET(CO2) from 38.3 +/- 2.3 to 36.0 +/- 2.3 mmHg (P < 0.05). The increase in V(I) due to pain did not differ among the different stimuli. This resulted in a parallel leftward-shift of the V(I)-carbon dioxide response curve in normoxia and hyperoxia, and in a parallel shift to higher V(I) levels in acute and sustained hypoxia. CONCLUSIONS: These data indicate that acute cutaneous pain of moderate intensity interacted with the ventilatory control system without modifying the central and peripheral chemoreflex loop and the central modulation of the hypoxia-related output of the peripheral chemoreflex loop. Pain causes a chemoreflex-independent tonic ventilatory drive.

Influences of morphine on the ventilatory response to isocapnic hypoxia.

BACKGROUND: The ventilatory response to hypoxia is composed of the stimulatory activity from peripheral chemoreceptors and a depressant effect from within the central nervous system. Morphine induces respiratory depression by affecting the peripheral and central carbon dioxide chemoreflex loops. There are only few reports on its effect on the hypoxic response. Thus the authors assessed the effect of morphine on the isocapnic ventilatory response to hypoxia in eight cats anesthetized with alpha-chloralose-urethan and on the ventilatory carbon dioxide sensitivities of the central and peripheral chemoreflex loops. METHODS: The steady-state ventilatory responses to six levels of end-tidal oxygen tension (PO2) ranging from 375 to 45 mmHg were measured at constant end-tidal carbon dioxide tension (P[ET]CO2, 41 mmHg) before and after intravenous administration of morphine hydrochloride (0.15 mg/kg). Each oxygen response was fitted to an exponential function characterized by the hypoxic sensitivity and a shape parameter. The hypercapnic ventilatory responses, determined before and after administration of morphine hydrochloride, were separated into a slow central and a fast peripheral component characterized by a carbon dioxide sensitivity and a single offset B (apneic threshold). RESULTS: At constant P(ET)CO2, morphine decreased ventilation during hyperoxia from 1,260 +/- 140 ml/min to 530 +/- 110 ml/ min (P < 0.01). The hypoxic sensitivity and shape parameter did not differ from control. The ventilatory response to carbon dioxide was displaced to higher P(ET)CO2 levels, and the apneic threshold increased by 6 mmHg (P < 0.01). The central and peripheral carbon dioxide sensitivities decreased by about 30% (P < 0.01). Their ratio (peripheral carbon dioxide sensitivity:central carbon dioxide sensitivity) did not differ for the treatments (control = 0.165 +/- 0.105; morphine = 0.161 +/- 0.084). CONCLUSIONS: Morphine depresses ventilation at hyperoxia but does not depress the steady-state increase in ventilation due to hypoxia. The authors speculate that morphine reduces the central depressant effect of hypoxia and the peripheral carbon dioxide sensitivity at hyperoxia.

Effect of N omega-nitro-L-arginine on ventilatory response to hypercapnia in anesthetized cats.

The effect of intravenous administration of 40 mg/kg N omega-nitro-L-arginine (L-NNA), an inhibitor of the synthesis of nitric oxide (NO), on the ventilatory response to CO2 was studied in anesthetized cats. The ventilatory response to CO2 was assessed during normoxia by applying square-wave changes in end-tidal PCO2 of approximately 1 kPa. Each CO2 response was separated into a fast peripheral and slow central component characterized by a CO2 sensitivity (Sp and Sc, respectively), time constant, time delay, and an offset (apneic threshold). L-NNA reduced Sp, Sc, and the apneic threshold significantly by approximately 30%. However, the ratio Sp/Sc was not changed. It is argued that the reduction in Sp and Sc, Sp/Sc remaining constant, may be due to a potent inhibitory action of L-NNA on the brain stem respiratory-integrating centers and on the neuromechanical link between these centers and respiratory movements. It is concluded that NO plays an important role in the control of breathing.

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.

Influence of reduced carotid body drive during sustained hypoxia on hypoxic depression of ventilation in humans.

To evaluate whether the intact hypoxic drive from the carotid bodies during sustained hypoxia is required for the generation of hypoxic depression of ventilation (VE), 16 volunteers were exposed to two consecutive periods of isocapnic hypoxia (first period 20 min; second period 5 min; end-tidal PO2 45 Torr) separated by 6 min of normoxia. In study A, saline was given. In study B, 3 micrograms.kg-1.min-1 i.v. dopamine (DA), a carotid body inhibitor, was given during the first hypoxic exposure followed by saline during normoxia and the second hypoxic exposure. In study C, 20 min of normoxia with DA preceded 6 min of normoxia and 5 min of hypoxia without DA. The first peak hypoxic VE (PHV) in study A was approximately 100% above normoxic VE. After 20 min of hypoxia, VE declined to 60% above normoxic VE. The second PHV in study A was only 60% of the first PHV. We relate this delayed recovery from hypoxia to "ongoing" effects of hypoxic depression. During DA infusion, the changes in VE due to sustained hypoxia were insignificant (study B). The second PHV in study B was not different from the PHV after air breathing in studies A and C. This indicates that the recovery from sustained hypoxia with a suppressed carotid body drive was complete within 6 min. Our results show that despite central hypoxia the absence of ventilatory changes during 20 min of isocapnic hypoxia due to intravenous DA prevented the generation of central hypoxic depression and the depression of a subsequent hypoxic response.

Acute pain and central nervous system arousal do not restore impaired hypoxic ventilatory response during sevoflurane sedation.

BACKGROUND: To quantify the effects of acute pain on ventilatory control in the awake and sedated human volunteer, the acute hypoxic ventilatory response was studied in the absence and presence of noxious stimulation before and during 0.1 minimum alveolar concentration sevoflurane inhalation. METHODS: Step decreases in end-tidal partial pressure of oxygen from normoxia into hypoxia (approximately 50 mmHg) were performed in 11 healthy volunteers. Four acute hypoxic ventilatory responses were obtained per subject: one in the absence of pain and sevoflurane (C), one in the absence of sevoflurane with noxious stimulation in the form of a 1-Hz electrical current applied to the skin over the tibial bone (C + P), one in the absence of pain during the inhalation of 0.1 minimum alveolar concentration sevoflurane (S), and one during 0.1 minimum alveolar concentration sevoflurane with noxious stimulation (S + P). The end-tidal partial pressure of carbon dioxide was held constant at a value slightly greater than baseline (44 mmHg). To assess the central nervous system arousal state, the bispectral index of the electroencephalogram was monitored. Values are mean +/- SE. RESULTS: Pain caused an increase in prehypoxic baseline ventilation before and during sevoflurane inhalation: C = 13.7 +/- 0.9 l.min-1, C + P = 16.0 +/- 1.0 l.min-1 (P < 0.05 vs. C and S), S = 12.7 +/- 1.2 l.min-1, and S + P = 15.9 +/- 1.1 l.min-1 (P < 0.05 vs. C and S). Sevoflurane decreased the acute hypoxic ventilatory response in the absence and presence of noxious stimulation: C = 0.69 +/- 0.20 l.min-1 (% change in arterial hemoglobin-oxygen saturation derived from pulse oximetry [SpO2])-1, C + P = 0.64 +/- 0.13 l.min-1.%SpO2(-1), S = 0.48 +/- 0.15 l.min-1.%SpO2(-1) (P < 0.05 vs. C and C + P) and S + P = 0.46 +/- 0.21 l.min-1.%SpO2(-1) (P < 0.05 vs. C and C + P). The bispectral indexes were C = 96.2 +/ 0.7, C + P = 97.1 +/- 0.4, S = 86.3 +/- 1.3 (P < 0.05), and S + P = 95.0 +/- 1.0. CONCLUSIONS: The observation that acute pain caused an increase in baseline ventilation with no effect on the acute hypoxic ventilatory response indicates that acute pain interacted with ventilatory control without modifying the effect of low-dose sevoflurane on the peripheral chemoreflex loop. Acute pain increased the level of arousal significantly during sevoflurane inhalation but did not restore the approximately 30% depression of the acute hypoxic ventilatory response by sevoflurane. The central nervous system arousal state per se did not contribute to the impairment of the acute hypoxic ventilatory response by sevoflurane.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Slow ventilatory dynamics after isocapnic hypoxia and voluntary hyperventilation in humans: effects of isoflurane.

Short-term potentiation (STP) of breathing refers to respiratory activity that persists at termination of a primary stimulus and is not related just to the dynamics of chemoreceptors. In humans, STP is activated by brief episodes of hypoxia and voluntary hyperventilation (VHV). STP exerts a stabilizing influence on breathing pattern. To investigate the effects of a subanaesthetic concentration of isoflurane on STP, we studied recovery from mild and moderate hypoxic hyperpnoea and VHV. Experiments were performed in eight healthy volunteers. If necessary, subjects were aroused to maintain a state of wakefulness. In the hypoxic studies, a control study involved 1 min of isocapnic hypoxia (end-tidal PO2 (PE'O2 6.1) kPa) followed by sudden transition to normoxia. In the isoflurane studies, 1 min of mild hypoxia (Iso-1 study: PE'O2 6.2 kPa) and 1 min of moderate hypoxia (Iso-2 study: PE'O2 5.7 kPa) were followed by sudden transition to normoxia during inhalation of 0.1 minimum alveolar concentration (MAC) of isoflurane. PE'CO2 was maintained at 5.9 kPa. In the VHV study, ventilatory recovery from 1 min of normoxic VHV was monitored before and during inhalation of 0.1 MAC of isoflurane. Subjects performed multiple transitions in each study. In the hypoxic studies, peak ventilation after 1 min of hypoxic stimulation did not differ between treatments. The averaged responses reached normoxic baseline after 56.3 (SEM 10.7) s in the control study (n = 47 transitions), 18.0 (3.3) s in the Iso-1 study (n = 41; P < 0.05 vs control) and 15.3 (2.4) s in the Iso-2 study (n = 23; P < 0.05 vs control). In the VHV studies, VE at termination of VHV was not different from baseline after 36 s in the control study. An immediate reduction to less than baseline ventilation, lasting 24 s, was present in the isoflurane study. We believe that shortening of the time required to reach baseline in the hypoxic studies, and hypoventilation at cessation of VHV in the isoflurane studies, are related to the inability to activate STP of breathing via an effect of isoflurane on respiratory neurones in the brain stem. Increasing the stimulus intensity during isoflurane inhalation (Iso-2 study) did not (re)-activate STP.

Strength of the Breuer-Hering inflation reflex in term and preterm infants.

The effect of the presence of the respiratory distress syndrome (RDS) or related factors (static compliance of the respiratory system and transcutaneous blood gases) and gestational age on the strength of the Breuer-Hering inflation reflex (BHIR) was studied in three groups of infants. Twenty-six ventilated preterm infants with and without RDS were studied 6 h after birth (group 1). In 24 preterm infants, we followed the development of reflex strength during the first year of life (group 2). Twenty-one healthy nonintubated term infants were studied within the first week of life (group 3). The BHIR was initiated by end-inspiratory occlusions, and the strength was characterized by the ratio of expiratory time after and without preceding airway occlusion. The static compliance of the respiratory system in ventilated infants was assessed by the multiple-occlusion technique. In group 1, reflex strength declined with increasing gestational age; in the presence of RDS or low respiratory compliance, the decline was less. Transcutaneous blood gases did not affect reflex strength. At term age, reflex strength was similar in spontaneously breathing preterm (group 2) and term infants (group 3). The BHIR decreased in strength during the first year after preterm birth. We conclude that 1) the strength of the BHIR decreases with increasing gestational and postnatal ages and 2) RDS, due to changes in respiratory system mechanics, causes an increase in reflex strength.

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.

Influence of hypoxic duration and posthypoxic inspired O2 concentration on short term potentiation of breathing in humans.

1. Short term potentiation (STP) of breathing refers to respiratory activity at a higher level than expected just from the dynamics of the peripheral and central chemoreceptors. In humans STP is activated by hypoxic stimulation. 2. To investigate the effects of the duration of hypoxia and the posthypoxic inspired O2 concentration on STP, the ventilatory responses to 30 s and 1, 3 and 5 min of hypoxia (end-tidal PO2, P(ET.O2) approximately 6.5 kPa) followed by normoxia (P(ET.O2) approximately 14.5 kPa) and hyperoxia (P(ET.O2) approximately 70 kPa) were studied in ten healthy subjects. End-tidal PCO2 (P(ET.CO2)) was clamped during hypoxic and recovery periods at 5.7 kPa. 3. Steady-state ventilation (VE) was 13.7 +/- 0.6 l min-1 during normoxia and increased to 15.5 +/- 0.3 l min-1 during hyperoxia (P < 0.05) due to the reduced Haldane effect and some decrease in cerebral blood flow (CBF). 4. The mean responses following hypoxia reached normoxic baseline after 69, 54, 12 and 12 s when 30 s and 1, 3 and 5 min of hypoxia, respectively, were followed by normoxia. An undershoot of 10 and 20% below hyperoxic baseline was observed when 3 and 5 min of hypoxia, respectively, were followed by hyperoxia. Hyperoxic VE reached hyperoxic baseline after 9, 15, 12 and 9 s at the termination of 30 s and 1, 3 and 5 min of hypoxia, respectively. 5. Normoxic recovery from 30 s and 1 min of hypoxia displayed a fast and subsequent slow decrease towards normoxic baseline. The fast component was attributed to the loss of the hypoxic drive at the site of the peripheral chemoreceptors, and the slow component to the decay of the STP that had been activated centrally by the stimulus. A slow decrease at the termination of 30 s and 1 min of hypoxia by hyperoxia was not observed since this component was cancelled by the increase in ventilatory output due to the reduced Haldane effect and some decrease of CBF. 6. Decay of the STP was not apparent in the normoxic recovery from 3 and 5 min of hypoxia as a slow component since it cancelled against the slow ventilatory increase related to the increase of brain tissue PCO2 due to the reduction of CBF at the relief of hypoxia. The undershoot observed when hyperoxia followed 3 and 5 min of hypoxia reflects the stimulatory effects of hyperoxia on VE. 7. The manifestation of the STP as a slow ventilatory decrease depends on the duration of hypoxia and the subsequent inspired oxygen concentration. We argue that STP is not abolished by the central depressive effects of hypoxia, although the manifestation of the STP may be overridden or counteracted by other mechanisms.

Influences of subanesthetic isoflurane on ventilatory control in humans.

BACKGROUND: The purpose of this study was to quantify in humans the effects of subanesthetic isoflurane on the ventilatory control system, in particular on the peripheral chemoreflex loop. Therefore we studied the dynamic ventilatory response to carbon dioxide, the effect of isoflurane wash-in upon sustained hypoxic steady-state ventilation, and the ventilatory response at the onset of 20 min of isocapnic hypoxia. METHODS: Study 1: Square-wave changes in end-tidal carbon dioxide tension (7.5-11.5 mmHg) were performed in eight healthy volunteers at 0 and 0.1 minimum alveolar concentration (MAC) isoflurane. Each hypercapnic response was separated into a fast, peripheral component and a slow, central component, characterized by a time constant, carbon dioxide sensitivity, time delay, and off-set (apneic threshold). Study 2: The ventilatory changes due to the wash-in of 0.1 MAC isoflurane, 15 min after the induction of isocapnic hypoxia, were studied in 11 healthy volunteers. Study 3: The ventilatory responses to a step decrease in end-tidal oxygen (end-tidal oxygen tension from 110 to 44 mmHg within 3-4 breaths; duration of hypoxia 20 min) were assessed in eight healthy volunteers at 0, 0.1, and 0.2 MAC isoflurane. RESULTS: Values are reported as means +/- SF. Study 1: The peripheral carbon dioxide sensitivities averaged 0.50 +/- 0.08 (control) and 0.28 +/- 0.05 l.min-1.mmHg-1 (isoflurane; P < 0.01). The central carbon dioxide sensitivities (control 1.20 +/- 0.12 vs. isoflurane 1.04 +/- 0.11 l.min-1.mmHg-1) and off-sets (control 36.0 +/- 0.1 mmHg vs. isoflurane 34.5 +/- 0.2 mmHg) did not differ between treatments. Study 2: Within 30 s of exposure to 0.1 MAC isoflurane, ventilation decreased significantly, from 17.7 +/- 1.6 (hypoxia, awake) to 15.0 +/- 1.5 l.min-1 (hypoxia, isoflurane). Study 3: At the initiation of hypoxia ventilation increased by 7.7 +/- 1.4 (control), 4.1 +/- 0.8 (0.1 MAC; P < 0.05 vs. control), and 2.8 +/- 0.6 (0.2 MAC; P < 0.05 vs. control) l.min-1. The subsequent ventilatory decrease averaged 4.9 +/- 0.8 (control), 3.4 +/- 0.5 (0.1 MAC; difference not statistically significant), and 2.0 +/- 0.4 (0.2 MAC; P < 0.05 vs. control) l.min-1. There was a good correlation between the acute hypoxic response and the hypoxic ventilatory decrease (r = 0.9; P < 0.001). CONCLUSIONS: The results of all three studies indicate a selective and profound effect of subanesthetic isoflurane on the peripheral chemoreflex loop at the site of the peripheral chemoreceptors. We relate the reduction of the ventilatory decrease of sustained hypoxia to the decrease of the initial ventilatory response to hypoxia.

Halothane affects ventilatory afterdischarge in humans.

In awake humans, when ventilatory stimulation is suddenly removed, the subsequent change in minute ventilation (which remains at higher levels for longer times than expected from the dynamics of the chemoreceptors) is termed ventilatory after discharge. In this study we investigated the effects of subanaesthetic concentrations of halothane on afterdischarge. The ventilatory pattern after sudden termination of brief periods (90-180 s) of isocapnic hypoxia (PE'cO2 approximately 0.1 kPa above initial resting values; PE'O2 6.5 kPa) by normoxia (PE'O2 14 kPa) was determined in healthy volunteers. Six subjects underwent 13 studies without halothane (control) and six others 10 studies during inhalation of 0.22% halothane. Isocapnic hypoxia caused a mean increase in ventilation of 10.8 (SD 2.4) litre min-1 in the control and 4.2 (2.4) litre min-1 in the halothane studies (P < 0.01). The transition to normoxia caused a slow ventilatory decay in the control and a fast decay in the halothane groups: the interval that occurred between the "last hypoxic" breath and the time required for ventilation to return to 110% of baseline was 60.7 (23) s for the control and 12.3 (6.0) s for the halothane studies (P < 0.05). Taking into consideration the different factors that determine the pattern of breathing immediately after termination of a brief period of hypoxia by normoxia (PE'O2 waveform, transport delay time between lungs and carotid bodies, time constant of the peripheral chemoreflex loop and afterdischarge), the faster ventilatory decay observed with halothane is probably related to suppression of afterdischarge.(ABSTRACT TRUNCATED AT 250 WORDS)