Respiratory sites of action of propofol: absence of depression of peripheral chemoreflex loop by low-dose propofol.

BACKGROUND: Propofol has a depressant effect on metabolic ventilatory control, causing depression of the ventilatory response to acute isocapnic hypoxia, a response mediated via the peripheral chemoreflex loop. In this study, the authors examined the effect of sedative concentrations of propofol on the dynamic ventilatory response to carbon dioxide to obtain information about the respiratory sites of action of propofol. METHODS: In 10 healthy volunteers, the end-tidal carbon dioxide concentration was varied according to a multifrequency binary sequence that involved 13 steps into and 13 steps out of hypercapnia (total duration, 1,408 s). In each subject, two control studies, two studies at a plasma target propofol concentration of 0.75 microg/ml (P(low)), and two studies at a target propofol concentration of 1.5 microg/ml (P(high)) were performed. The ventilatory responses were separated into a fast peripheral component and a slow central component, characterized by a time constant, carbon dioxide sensitivity, and apneic threshold. Values are mean +/- SD. RESULTS: Plasma propofol concentrations were approximately 0.5 microg/ml for P(low) and approximately 1.3 mg/ml for P(high), Propofol reduced the central carbon dioxide sensitivity from 1.5 +/- 0.4 to 1.2 +/- 0.3 (P(low); P < 0.01 vs. control) and 0.9 +/- 0.1 l x min(-1) x mmHg(-1) (P(high); P < 0.001 vs. control). The peripheral carbon dioxide sensitivity remained unaffected by propofol (control, 0.5 +/- 0.3; P(low), 0.5 +/- 0.2; P(high), 0.5 +/- 0.2 l x min(-1) x mmHg(-1)). The apneic threshold was reduced from 36.3 +/- 2.7 (control) to 35.0 +/- 2.1 (P(low); P < 0.01 vs. control) and to 34.6 +/- 1.9 mmHg (P(high); P < 0.01 vs. control). CONCLUSIONS: Sedative concentrations of propofol have an important effect on the control of breathing, showing depression of the ventilatory response to hypercapnia. The depression is attributed to an exclusive effect within the central chemoreflex loop at the central chemoreceptors. In contrast to low-dose inhalational anesthetics, the peripheral chemoreflex loop, when stimulated with carbon dioxide, remains unaffected by propofol.

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.

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)

Influence of a subanesthetic concentration of halothane on the ventilatory response to step changes into and out of sustained isocapnic hypoxia in healthy volunteers.

BACKGROUND: In humans the ventilatory response to isocapnic hypoxia is biphasic: an initial increase in minute ventilation (VE) from baseline, the acute hypoxic response, is followed after 3-5 min by a slow ventilatory decay, the hypoxic ventilatory decline, and a new steady state, 25-40% greater than baseline VE, is reached in about 15-20 min. The transition from 20 min of isocapnic hypoxia into normoxia results in a rapid decrease in VE, the off-response. In humans, halothane, at subanesthetic concentrations, is known to decrease the acute hypoxic response. In order to investigate the effects of halothane on sustained hypoxia we quantified the effects of 0.15 minimum alveolar concentration halothane on the ventilatory response at the onset of 20 min of hypoxia and at the termination of 20 min of hypoxia by normoxia in healthy volunteers. METHODS: Step changes in end-tidal oxygen tension were performed against a background of constant mild hypercapnia (end-tidal carbon dioxide tension about 1 mmHg above individual resting values) in fourteen male subjects. The end-tidal oxygen tension was forced as follows: 5-10 min at 110 mmHg, 20 min at 44 mmHg, and 10 min at 110 mmHg. In each subject we performed one trial before and one during 0.15 minimum alveolar concentration halothane administration. RESULTS: Ten responses into hypoxia and nine out of hypoxia were considered for analysis. All control trials were performed during wakefulness. Using behavioral characteristics, the central nervous system arousal state of the subjects during halothane inhalation was defined as "anesthesia-induced hypnosis." The acute hypoxic response averaged 10.4 +/- 4.7 l/min for control versus 3.7 +/- 2.4 l/min for halothane trials (P < 0.01). The hypoxic ventilatory decline was 4.8 +/- 2.5 l/min versus 3.9 +/- 2.9 l/min (NS), the off-response was 6.7 +/- 3.2 l/min versus 3.7 +/- 3.0 l/min (P < 0.05) for control versus halothane, respectively. All values are mean +/- SD. CONCLUSIONS: Our results indicate that halothane caused VE to be less than control levels during acute and sustained hypoxia as well as when sustained hypoxia is replaced by normoxia. It is argued that the depression of VE during acute hypoxia is attributed to an effect of halothane on the peripheral chemoreceptors. During sustained hypoxia halothane had no effect on the magnitude of the hypoxic ventilatory decrease, which is probably related to an increase by halothane of inhibitory neuromodulators within the central nervous system. With halothane, the ventilatory decrease when sustained hypoxia is replaced by normoxia is related to the removal of the hypoxic drive at the site of the peripheral chemoreceptors.

Does subanesthetic isoflurane affect the ventilatory response to acute isocapnic hypoxia in healthy volunteers?

BACKGROUND: Differences in results studying the effects of subanesthetic concentrations of volatile agents on the hypoxic ventilatory response may be related to the conditions under which the subjects were tested. In this study we investigated the effects of 0.1 minimum alveolar concentration (MAC) of isoflurane on the hypoxic ventilatory response without and with audiovisual stimulation. METHODS: Step decreases in arterial hemoglobin oxygen saturation from normoxia into hypoxia (arterial hemoglobin oxygen saturation 80% +/- 2%; duration of hypoxia 5 min) were performed in ten healthy subjects. We obtained four responses per subject: one without isoflurane in a darkened, quiet room; one without isoflurane with audiovisual input (music videos); one in a darkened room at 0.1 MAC isoflurane; and one at 0.1 MAC isoflurane with audiovisual input (subjects were addressed to keep their eyes open). Experiments were performed against a background of isocapnia (end-tidal carbon dioxide tension 1-1.4 mmHg above initial resting values). RESULTS: The hypoxic responses averaged 0.54 +/- 0.09 1.min-1.%-1 (without isoflurane in a darkened, quiet room), 0.27 +/- 0.06 l-min-1.%-1 (in a darkened room at 0.1 MAC isoflurane; P < 0.01), 0.56 +/- 0.131.min-1.%-1 (without isoflurane with audiovisual input), and 0.47 +/- 0.13 l.min-1.%-1 (at 0.1 MAC isoflurane with audiovisual input). Values are means +/- SE. During 0.1 MAC isoflurane administration, all subjects showed a depressed hypoxic response when not stimulated, while with stimulation two subjects had an increased response, four a decreased response and four an unchanged response compared to control. CONCLUSIONS: We observed an important effect of the study conditions on the effects that 0.1 MAC isoflurane has on the hypoxic ventilatory response. A depressant effect of subanesthetic isoflurane was found only when external stimuli to the subjects were absent. With extraneous audiovisual stimuli the effect of isoflurane on the response to hypoxia was more variable. On the average, however, the response then was not depressed by isoflurane.

Effects of subanesthetic halothane on the ventilatory responses to hypercapnia and acute hypoxia in healthy volunteers.

BACKGROUND: The peripheral chemoreceptors are responsible for the ventilatory response to hypoxia (acute hypoxic response) and for 30% of the normoxic hypercapnic ventilatory response. To quantify the effects of subanesthetic concentrations of halothane on the respiratory control system, in particular on the peripheral chemoreceptors, we studied the response of humans to carbon dioxide and oxygen at two subanesthetic concentrations of halothane. METHODS: Square-wave changes in end-tidal carbon dioxide tension (7.5-11.3 mmHg) and step decreases in end-tidal oxygen tension (arterial hemoglobin oxygen saturation 82 +/- 2%; duration of hypoxia 5 min) were performed in nine healthy male subjects during 0, 0.05 (HA-1), and 0.1 minimum alveolar concentration (HA-2) halothane. 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. RESULTS: Fifty-six carbon dioxide responses and 27 oxygen responses were obtained. The peripheral carbon dioxide sensitivities averaged to 0.76 +/- 0.14 l.min-1.mmHg-1 (control), 0.50 +/- 0.12 l.min-1.mmHg-1 (HA-1), and 0.30 +/- 0.08 l.min-1.mmHg-1 (HA-2; P < 0.01 vs. control). The central carbon dioxide sensitivity did not differ significantly among treatment groups (control, 1.47 +/- 0.22 l.min-1.mmHg-1; HA-1, 1.41 +/- 0.51 l.min-1.mmHg-1; and HA-2, 1.23 +/- 0.30 l.min-1.mmHg-1). The time constants of the central chemoreflex loop showed a large decrease during the administration of 0.1 minimum alveolar concentration halothane. The acute hypoxic response declined from 15.0 +/- 3.9 l.min-1 to 10.9 +/- 2.9 l.min-1 (HA-1) and 4.8 +/- 1.4 l.min-1 (HA-2; P < 0.01 vs. control and HA-1). All values are means +/- SEM. CONCLUSIONS: The results show depression of the ventilatory responses to hypoxia and hypercapnia during inhalation of subanesthetic concentrations of halothane. The depression is attributed to a selective effect of halothane on the peripheral chemoreflex loop. The oxygen and carbon dioxide responses mediated by the peripheral chemoreceptors are affected proportionally. It is argued that the decrease in central time constants is caused by an effect of halothane on central neuronal dynamics.

Water-sealed spirometer for measurements in newborns and infants.

Details are given of two spirometers for use in neonates and infants < 12 mo old. The minimum volumes are 520 and 670 ml, respectively. The maximum volume changes that can be recorded are 250 and 450 ml, respectively. The minimal detectable volume changes are 0.4 and 0.6 ml, respectively. Rebreathing of dead space gas is prevented by a fan producing a flow of 6.2 and 10.2 l/min, respectively; 100% gas mixing after injecting a gas bolus in the two spirometers is achieved in 5.7 and 6.6 s, respectively. Resistance to airflow is 0.2 kPa.l-1.s (2 cmH2O.l-1.s) at 150 ml/s in both spirometers. The frequency response of both instruments is flat to 6 cycles/s. The instruments can be easily cleaned and are suitable for bedside measurements.

The ventilatory response to CO2 of the peripheral and central chemoreflex loop before and after sustained hypoxia in man.

1. The ventilatory response to sustained hypoxia is characterized by a fast increase due to the peripheral chemoreceptors followed by a slow decline. The mechanism of this decline is unknown. 2. To investigate the characteristics of the ventilatory response to sustained hypoxia ten healthy subjects were exposed to two consecutive periods of isocapnic hypoxia (arterial saturation 78%) separated by a 5 min exposure to isocapnic normoxia. 3. The acute hypoxic response to the second exposure to hypoxia (mean increase in ventilation +/- S.E.M., 7.2 +/- 0.8 l min-1) was significantly depressed (P = 0.04) compared to the first one (9.5 +/- 1.3 l min-1). 4. To investigate whether this depression was due to central or peripheral effects or both we measured, in the same ten subjects, the normoxic ventilatory response to CO2 before and after a period of 25 min of hypoxia using the technique of dynamic end-tidal forcing. 5. Each response was separated into a fast peripheral and slow central component characterized by a CO2 sensitivity, time constant, time delay and an off-set. 6. A total of thirty-six prehypoxic and thirty posthypoxic responses were analysed. The ventilatory CO2 sensitivities of the peripheral and central chemoreflex loops and the overall off-set (apnoeic threshold) after 25 min of hypoxia were somewhat larger than their prehypoxic values, but this effect was not significant. 7. We argue that the hypoxic ventilatory decline in man is due to a change in the off-set of the peripheral chemoreflex loop.

The influence of oxygen on the ventilatory response to carbon dioxide in man.

1. The ventilatory response to isoxic square-wave challenges in end-tidal PCO2 was investigated at three levels of end-tidal PO2 (PET, O2) in nine healthy male subjects. 2. Twenty-seven responses against a background of mild hypoxia (PET, O2 approximately 10 kPa), sixty-seven against a background of normoxia (PET, O2 approximately 14.5 kPa) and seventy-six against a background of hyperoxia (PET, O2 approximately 70 kPa) were collected. 3. The breath-to-breath data were partitioned into a fast and a slow ventilatory component using a two-compartment model. 4. In the normoxic and hypoxic experiments the CO2 sensitivity of the fast component averaged to about 30 and 40% of the total CO2 sensitivity, respectively. In the hyperoxic experiments three subjects had no fast component in their response while in three others the CO2 sensitivity of the fast component averaged to about 24% of the total CO2 sensitivity. In the remaining three subjects the presence of a fast component was doubtful. 5. We argue that the fast component is due to the peripheral chemoreflex loop and the slow component to the central chemoreflex loop. 6. The central CO2 sensitivity and the apnoeic threshold (extrapolated end-tidal CO2 at zero ventilation in the steady state) were 15% smaller in hyperoxia than those in normoxia and hypoxia. In normoxia and mild hypoxia the central CO2 sensitivities were not significantly different. 7. We argue, that apart from peripheral oxygen-carbon dioxide interaction, there is evidence for central oxygen-carbon dioxide interaction in human subjects. 8. We conclude that in general there is a contribution to ventilation of the peripheral chemoreceptors during hyperoxia in man.

On a pseudo-rebreathing technique to assess the ventilatory sensitivity to carbon dioxide in man.

1. The ventilatory sensitivity to carbon dioxide obtained from a step-ramp CO2 challenge was compared to the CO2 sensitivity from the steady-state method. 2. Experiments were performed in nine healthy male subjects against a background of hyperoxia and in two subjects against a background of normoxia. 3. In each subject experiments were performed in which the stepwise increase in end-tidal PCO2 above its resting value (A) was varied (range 0-2 kPa) and the subsequent rate of rise of end-tidal PCO2 in time (R) kept constant at 0.6 or 0.8 kPa min-1. 4. The results of the hyperoxic experiments show that the slope of the non-steady-state ventilatory response to CO2 (Sn) is greatly influenced by the magnitude of A. An increase of A of 1 kPa results in a 54% increase of the ratio non-steady-state ventilatory CO2 sensitivity to steady-state ventilatory CO2 sensitivity (Ss). The magnitude of R plays a minor role in determining Sn. The normoxic experiments gave similar results. 5. In experiments performed during hyperoxia Sn approximates Ss when the magnitude of A is 0.5 kPa. 6. The results are discussed and related to a physiological model. Simulations with representative values for the model parameters are in fair agreement with experimental values.

The ventilatory CO2 sensitivities from Read's rebreathing method and the steady-state method are not equal in man.

1. The ventilatory response to changes in end-tidal carbon dioxide tension during hyperoxia, obtained with Read's rebreathing method and a steady-state technique, were compared. 2. In ten young male subjects, forty successful rebreathing and thirteen steady-state experiments were performed on thirteen different morning sessions. 3. In all subjects the ventilatory CO2 sensitivities obtained with the rebreathing method (Sr) were appreciably larger than the steady-state CO2 sensitivities (Ss). The ratio Sr/Ss ranged from 1.40 to 2.59 with a mean value of 1.85. 4. We argue that these results can be explained by considering the effect of changes in cerebral blood flow upon increasing the arterial CO2 tension during rebreathing and the steady state. 5. We conclude that in general the CO2 sensitivity obtained with Read's rebreathing method does not represent the steady-state CO2 sensitivity.

Respiratory muscle force and ventilatory function in adolescents.

In 94 girls and 90 boys, aged 12.5-20.3 yr, the relationship of respiratory pressures or forces with lung volumes and ventilatory flows was studied. There was great variability in respiratory muscle performance, which helps to explain differences in lung volumes between individuals. Respiratory muscle force increases almost proportionally with thoracic dimensions, so that inspiratory and expiratory pressures generated at the level of residual volume (RV), functional residual capacity (FRC) and total lung capacity (TLC) are approximately constant with age. In the oldest boys there is evidence that the continued increase in lung volumes when they stop growing is due to a 'muscularity effect'. Boys generate larger pressures than girls at all lung volumes. Thus boys attain a larger TLC, and in spite of narrower airways, the same peak expiratory flow and a larger FIV1/FVC ratio than girls. Effort independent flows (FEV1 and MMEF), however, are larger in girls.