Respiratory Sites of Action of Propofol

2001 ◽  
Vol 95 (4) ◽  
pp. 889-895 ◽  
Author(s):  
Diederik Nieuwenhuijs ◽  
Elise Sarton ◽  
Luc J. Teppema ◽  
Erik Kruyt ◽  
Ida Olievier ◽  
...  
Keyword(s):  
Carbon Dioxide ◽  
Ventilatory Response ◽  
Binary Sequence ◽  
Total Duration ◽  
Carbon Dioxide Concentration ◽  
Central Component ◽  
End Tidal ◽  
Sites Of Action ◽  
Peripheral Chemoreflex ◽  
Carbon Dioxide Sensitivity

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.

Influences of Subanesthetic Isoflurane on Ventilatory Control in Humans

1995 ◽  
Vol 83 (3) ◽  
pp. 478-490. ◽  
Author(s):  
Maarten van den Elsen ◽  
Albert Dahan ◽  
Jacob DeGoede ◽  
Aad Berkenbosch ◽  
Jack van Kleef
Keyword(s):  
Carbon Dioxide ◽  
Healthy Volunteers ◽  
Ventilatory Response ◽  
Carbon Dioxide Tension ◽  
Central Component ◽  
Ventilatory Control ◽  
Ventilatory Responses ◽  
End Tidal ◽  
Peripheral Chemoreflex ◽  
Ventilatory Response To Hypoxia

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.

Effect of intravenous dopamine on hypercapnic ventilatory response in humans

1983 ◽  
Vol 55 (5) ◽  
pp. 1418-1425 ◽  
Author(s):  
D. S. Ward ◽  
J. W. Bellville
Keyword(s):  
Carbon Dioxide ◽  
Ventilatory Response ◽  
Carbon Dioxide Concentration ◽  
Carbon Dioxide Tension ◽  
Model Parameters ◽  
Loop Gain ◽  
Loop Contribution ◽  
Dopamine Infusion ◽  
Hypercapnic Ventilatory Response ◽  
End Tidal

This study assessed the effect of low-dose intravenous dopamine (3 micrograms X kg-1 X min-1) on the hypercapnic ventilatory response in humans. Six normal healthy subjects were studied. By manipulating the inspired carbon dioxide concentration, the end-tidal carbon dioxide tension was raised in a stepwise fashion from 41 to 49 Torr and held at this level for 4 min. The end-tidal CO2 tension was then lowered back to 41 Torr in a stepwise fashion. The end-tidal O2 tension was held constant at 106 Torr throughout the experiment. The ventilatory response to this normoxic hypercapnic stimulus was analyzed by fitting two exponential functions, allowing the response to be separated into slow and fast chemoreflex loops. Each loop is described by a gain, time constant, and time delay. A single eupneic threshold was used for both loops. Nine control experiments and eight experiments performed during dopamine infusion were analyzed. The dopamine infusion caused the fast loop gain to be significantly (P less than 0.05) reduced from 0.64 to 0.19 l X min-1 X Torr-1, while the slow loop gain was unchanged. The fast loop contribution was reduced from 28 to 11% of the total ventilatory response. None of the other model parameters were significantly affected by the dopamine infusion. Exogenously administered dopamine substantially reduces the sensitivity of the fast chemoreflex loop to carbon dioxide.

The Ventilatory Response to Hypoxia Below the Carbon Dioxide Threshold

1997 ◽  
Vol 22 (1) ◽  
pp. 23-36 ◽  
Author(s):  
Theodore Rapanos ◽  
James Duffin
Keyword(s):  
Carbon Dioxide ◽  
Partial Pressure ◽  
Ventilatory Response ◽  
Pressure Threshold ◽  
Partial Pressures ◽  
Progressive Hypoxia ◽  
End Tidal ◽  
Peripheral Chemoreflex ◽  
Ventilatory Response To Hypoxia ◽  
Lower Carbon

The ventilatory response to acute progressive hypoxia below the carbon dioxide threshold using rebreathing was investigated. Nine subjects rebreathed after 5 min of hyperventilation to lower carbon dioxide stores. The rebreathing bag initially contained enough carbon dioxide to equilibrate alveolar and arterial partial pressures of carbon dioxide to the lowered mixed venous partial pressure (≈ 30 mmHg), and enough oxygen to establish a chosen end-tidal partial pressure (50-70 mmHg), within one circulation time. During rebreathing, end-tidal partial pressure of carbon dioxide increased while end-tidal partial pressure of oxygen fell. Ventilation increased linearly with end-tidal carbon dioxide above a mean end-tidal partial pressure threshold of 39 ± 2.7 mmHg. Below this peripheral-chemoreflex threshold, ventilation did not increase, despite a progressive fall in end-tidal oxygen partial pressure to a mean of 37 ± 4.1 mmHg. In Conclusion, hypoxia does not stimulate ventilation when carbon dioxide is below its peripheral-chemoreflex threshold. Key words: peripheral chemoreflex, rebreathing technique, hyperventilation

Influences of Morphine on the Ventilatory Response to Isocapnic Hypoxia 

1997 ◽  
Vol 86 (6) ◽  
pp. 1342-1349 ◽  
Author(s):  
Aad Berkenbosch ◽  
Luc J. Teppema ◽  
Cees N. Olievier ◽  
Albert Dahan
Keyword(s):  
Carbon Dioxide ◽  
Steady State ◽  
Shape Parameter ◽  
Ventilatory Response ◽  
Depressant Effect ◽  
Ventilatory Responses ◽  
Before And After ◽  
End Tidal ◽  
Ventilatory Response To Hypoxia ◽  
Carbon Dioxide Sensitivity

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.

Selected Contribution: Chemoreflex responses to CO2 before and after an 8-h exposure to hypoxia in humans

2001 ◽  
Vol 90 (4) ◽  
pp. 1607-1614 ◽  
Author(s):  
Marzieh Fatemian ◽  
Peter A. Robbins
Keyword(s):  
Ventilatory Response ◽  
Binary Sequence ◽  
Compartment Model ◽  
Breathing Control ◽  
Central Chemosensitivity ◽  
Two Compartment Model ◽  
Before And After ◽  
End Tidal ◽  
Peripheral Chemoreflex ◽  
Sustained Hypoxia

The ventilatory sensitivity to CO2, in hyperoxia, is increased after an 8-h exposure to hypoxia. The purpose of the present study was to determine whether this increase arises through an increase in peripheral or central chemosensitivity. Ten healthy volunteers each underwent 8-h exposures to 1) isocapnic hypoxia, with end-tidal Po2 (Pet O2 ) = 55 Torr and end-tidal Pco2 (Pet CO2 ) = eucapnia; 2) poikilocapnic hypoxia, with Pet O2 = 55 Torr and Pet CO2 = uncontrolled; and 3) air-breathing control. The ventilatory response to CO2 was measured before and after each exposure with the use of a multifrequency binary sequence with two levels of Pet CO2 : 1.5 and 10 Torr above the normal resting value. Pet O2 was held at 250 Torr. The peripheral (Gp) and the central (Gc) sensitivities were calculated by fitting the ventilatory data to a two-compartment model. There were increases in combined Gp + Gc (26%, P < 0.05), Gp (33%, P < 0.01), and Gc (23%, P = not significant) after exposure to hypoxia. There were no significant differences between isocapnic and poikilocapnic hypoxia. We conclude that sustained hypoxia induces a significant increase in chemosensitivity to CO2 within the peripheral chemoreflex.

Speed of Onset and Offset and Mechanisms of Ventilatory Depression from Sevoflurane 

1999 ◽  
Vol 90 (4) ◽  
pp. 1119-1128 ◽  
Author(s):  
Albert Dahan ◽  
Erik Olofsen ◽  
Luc Teppema ◽  
Elise Sarton ◽  
Cees Olievier
Keyword(s):  
Carbon Dioxide ◽  
Partial Pressure ◽  
Compartment Model ◽  
Central Compartment ◽  
Effect Compartment ◽  
Emax Model ◽  
End Tidal ◽  
Alpha Chloralose ◽  
Peripheral Chemoreflex ◽  
Carbon Dioxide Sensitivity

Background Inhalational anesthetics depress breathing dose dependently. The authors studied the dynamics of ventilation on changes in end-tidal sevoflurane partial pressure. To learn more about the mechanisms of sevoflurane-induced respiratory depression, the authors also studied its influence on the dynamic ventilatory response to carbon dioxide. Methods Experiments were performed in cats anesthetized with alpha chloralose-urethane. For protocol 1, step changes in end-tidal sevoflurane partial pressure were applied and inspired ventilation was measured. Breath-to-breath inspired ventilation was related to the sevoflurane concentration in a hypothetical effect compartment based on an inhibitory sigmoid Emax model. For protocol 2, step changes in the end-tidal partial pressure of carbon dioxide were applied at 0, 0.5, and 1% end-tidal sevoflurane. The inspired ventilation-end-tidal partial pressure of carbon dioxide data were analyzed using a two-compartment model of the respiratory controller, which consisted of a fast peripheral and slow central compartment. Values are the mean +/- SD. Results In protocol 1, the effect-site half-life of respiratory changes caused by alterations in end-tidal sevoflurane partial pressure was 3.6+/-1.0 min. In protocol 2, at 0.50% sevoflurane, the central and peripheral carbon dioxide sensitivities decreased to 43+/-20% and 36+/-18% of control. At 1% sevoflurane, the peripheral carbon dioxide sensitivity decreased further, to 12+/-13% of control, whereas the central carbon dioxide sensitivity showed no further decrease. Conclusions Steady state inspired ventilation is reached after 18 min (i.e., 5 half-lives) on stepwise changes in end-tidal sevoflurane. Anesthetic concentrations of sevoflurane have, in addition to an effect on pathways common to the peripheral and central chemoreflex loops, a selective effect on the peripheral chemoreflex loop. Sevoflurane has similar effects on ventilatory control in humans and cats.

Sex Differences in Morphine-induced Ventilatory Depression Reside within the Peripheral Chemoreflex Loop 

1999 ◽  
Vol 90 (5) ◽  
pp. 1329-1338 ◽  
Author(s):  
Elise Sarton ◽  
Luc Teppema ◽  
Albert Dahan
Keyword(s):  
Carbon Dioxide ◽  
Sex Differences ◽  
Minute Ventilation ◽  
Carbon Dioxide Tension ◽  
Central Component ◽  
Men And Women ◽  
Ventilatory Depression ◽  
End Tidal ◽  
Peripheral Chemoreflex ◽  
Sustained Hypoxia

Background This study gathers information in humans on the sites of sex-related differences in ventilatory depression caused by the mu-opioid receptor agonist morphine. Methods Experiments were performed in healthy young men (n = 9) and women (n = 7). Dynamic ventilatory responses to square-wave changes in end-tidal carbon dioxide tension (7.5-15 mmHg) and step decreases in end-tidal oxygen tension (step from 110 to 50 mmHg, duration of hypoxia 15 min) were obtained before and during morphine infusion (intravenous bolus dose 100 microg/kg, followed by 30 microg x kg(-1) x h(-1)). Each hypercapnic response was separated into a fast peripheral and slow central component, which yield central (Gc) and peripheral (Gp) carbon dioxide sensitivities. Values are mean +/- SD. Results In carbon dioxide studies in men, morphine reduced Gc from 1.61 +/- 0.33 to 1.23 +/- 0.12 l x min(-1) x mmHg(-1) (P &lt; 0.05) without affecting Gp (control, 0.41 +/- 0.16 and morphine, 0.49 +/- 0.12 l x min(-1) x mmHg(-1), not significant). In carbon dioxide studies in women, morphine reduced Gc, from 1.51 +/- 0.74 to 1.17 +/- 0.52 l x min(-1) x mmHg(-1) (P &lt; 0.05), and Gp, from 0.54 +/- 0.19 to 0.39 +/- 0.22 l x min(-1) x mmHg(-1) (P &lt; 0.05). Morphine-induced changes in Gc were equal in men and women; changes in Gp were greater in women. In hypoxic studies, morphine depressed the hyperventilatory response at the initiation of hypoxia more in women than in men (0.54 +/- 0.23 vs. 0.26 +/- 0.34 l x min(-1) x %(-1), respectively; P &lt; 0.05). The ventilatory response to sustained hypoxia (i/e., 15 min) did not differ between men and women. Conclusions The data indicate the existence of sex differences in morphine-induced depression of responses mediated via the peripheral chemoreflex pathway, with more depression in women, but not of responses mediated via the central chemoreflex pathway. In men and women, morphine did not change the translation of the initial hyperventilatory response to short-term hypoxia into the secondary decrease in inspired minute ventilation (Vi) caused by sustained hypoxia.

scholarly journals Differential Effect of Morphine and Morphine-6-glucuronide on the Control of Breathing in the Anesthetized Cat

2008 ◽  
Vol 109 (4) ◽  
pp. 689-697 ◽  
Author(s):  
Luc J. Teppema ◽  
Eveline van Dorp ◽  
Babak Mousavi Gourabi ◽  
Jack W. van Kleef ◽  
Albert Dahan
Keyword(s):  
Carbon Dioxide ◽  
Respiratory Depression ◽  
Carbon Dioxide Concentration ◽  
Compartment Model ◽  
Central Component ◽  
Depressant Effect ◽  
End Tidal Carbon Dioxide ◽  
Mu Opioids ◽  
End Tidal ◽  
Anesthetized Cat

Background Morphine's metabolite, morphine-6-glucuronide (M6G), activates the mu-opioid receptor. Previous data suggest that M6G activates a unique M6G receptor that is selectively antagonized by 3-methoxynaltrexome (3mNTX). The authors compared the effects of M6G and morphine on breathing in the anesthetized cat and assessed whether 3mNTX reversal was selective for M6G. Methods Step changes in end-tidal carbon dioxide concentration were applied in cats anesthetized with alpha-chloralose-urethane. In study 1, the effect of the 0.15 mg/kg morphine followed by 0.2 mg/kg 3mNTX and next 0.8 mg/kg M6G was assessed in six cats. In study 2, the effect of 0.8 mg/kg M6G followed by 0.2 mg/kg 3mNTX and 0.15 mg/kg morphine was tested in another six cats. The ventilatory carbon dioxide responses were analyzed with a two-compartment model of the ventilatory controller, which consists of a fast peripheral and a slow central component. Results Both opioids shifted the ventilatory carbon dioxide responses to higher end-tidal carbon dioxide levels. Morphine had a preferential depressant effect within the central chemoreflex loop. In contrast, M6G had a preferential depressant effect within the peripheral chemoreflex loop. Irrespective of the opioid, 3mNTX caused full reversal of and prevented respiratory depression. Conclusions In anesthetized cats, the mu-opioids morphine and M6G induce respiratory depression at different sites within the ventilatory control system. Because 3mNTX caused full reversal of the respiratory depressant effects of both opioids, it is unlikely that a 3mNTX-sensitive unique M6G receptor is the cause of the differential respiratory behavior of morphine and M6G.

Ventilatory Response to Hypoxia in Humans

1996 ◽  
Vol 85 (1) ◽  
pp. 60-68 ◽  
Author(s):  
Albert Dahan ◽  
Elise Sarton ◽  
Maarten van den Elsen ◽  
Jack van Kleef ◽  
Luc Teppema ◽  
...  
Keyword(s):  
Carbon Dioxide ◽  
Partial Pressure ◽  
Ventilatory Response ◽  
Minute Ventilation ◽  
Carbon Dioxide Concentration ◽  
Detectable Effect ◽  
Hypoxic Ventilatory Response ◽  
Anesthetic Agents ◽  
Carotid Bodies ◽  
End Tidal

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 &lt; 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.

Cerebrovascular time constant: dependence on cerebral perfusion pressure and end-tidal carbon dioxide concentration

2012 ◽  
Vol 34 (1) ◽  
pp. 17-24 ◽  
Author(s):  
Marek Czosnyka ◽  
Hugh K Richards ◽  
Matthias Reinhard2 ◽  
Luzius A Steiner3 ◽  
Karol Budohoski ◽  
...  
Keyword(s):  
Carbon Dioxide ◽  
Cerebral Perfusion Pressure ◽  
Time Constant ◽  
Cerebral Perfusion ◽  
Perfusion Pressure ◽  
Carbon Dioxide Concentration ◽  
End Tidal Carbon Dioxide ◽  
End Tidal
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