The Pharmacodynamic Effect of a Remifentanil Bolus on Ventilatory Control

Background In doses typically administered during conscious sedation, remifentanil may be associated with ventilatory depression. However, the time course of ventilatory depression after an initial dose of remifentanil has not been determined previously. Methods In eight healthy volunteers, the authors determined the time course of the ventilatory response to carbon dioxide using the dual isohypercapnic technique. Subjects breathed via mask from a to-and-fro circuit with variable carbon dioxide absorption, allowing the authors to maintain end-tidal pressure of carbon dioxide (PET(CO2)) at approximately 46 or 56 mm Hg (alternate subjects). After 6 min of equilibration, subjects received 0.5 microg/kg remifentanil over 5 s, and minute ventilation (V(E)) was recorded during the next 20 min. Two hours later, the study was repeated using the other carbon dioxide tension (56 or 46 mm Hg). The V(E) data were used to construct two-point carbon dioxide response curves at 30-s intervals after remifentanil administration. Using published pharmacokinetic values for remifentanil and the method of collapsing hysteresis loops, the authors estimated the effect-site equilibration rate constant (k(eo)), the effect-site concentration producing 50% respiratory depression (EC50), and the shape parameter of the concentration-response curve (gamma). Results The slope of the carbon dioxide response decreased from 0.99 [95% confidence limits 0.72 to 1.26] to a nadir of 0.27 l x min(-1) x mm Hg(-1) [-0.12 to 0.66] 2 min after remifentanil (P<0.001); within 5 min, it recovered to approximately 0.6 l x min(-1) x mm Hg(-1), and within 15 min of injection, slope returned to baseline. The computed ventilation at PET = 50 mm Hg (VE50) decreased from 12.9 [9.8 to 15.9] to 6.1 l/min [4.8 to 7.4] 2.5 min after remifentanil injection (P<0.001). This was caused primarily by a decrease in tidal volume rather than in respiratory rate. Estimated pharmacodynamic parameters based on computed mean values of VE50 included k(eo) = 0.24 min(-1) (T1/2 = 2.9 min), EC50 = 1.12 ng/ml, and gamma = 1.74. Conclusions After administration of 0.5 microg/kg remifentanil, there was a decrease in slope and downward shift of the carbon dioxide ventilatory response curve. This reached its nadir approximately 2.5 min after injection, consistent with the computed onset half-time of 2.9 min. The onset of respiratory depression appears to be somewhat slower than previously reported for the onset of remifentanil-induced electroencephalographic slowing. Recovery of ventilatory drive after a small dose essentially was complete within 15 min.

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Diphenhydramine Increases Ventilatory Drive during Alfentanil Infusion

Anesthesiology ◽

10.1097/00000542-199809000-00013 ◽

1998 ◽

Vol 89 (3) ◽

pp. 642-647. ◽

Cited By ~ 8

Author(s):

H. Daniel Babenco ◽

Robert T. Blouin ◽

Pattilyn F. Conard ◽

Jeffrey B. Gross

Keyword(s):

Carbon Dioxide ◽

Ventilatory Response ◽

Minute Ventilation ◽

Blood Levels ◽

Ventilatory Responses ◽

Ventilatory Drive ◽

Before And After ◽

End Tidal ◽

Carbon Dioxide Response ◽

Ventilatory Response To Hypoxia

Background Diphenhydramine is used as an antipruritic and antiemetic in patients receiving opioids. Whether it might exacerbate opioid-induced ventilatory depression has not been determined. Methods The ventilatory response to carbon dioxide during hyperoxia and the ventilatory response to hypoxia during hypercapnia (end-tidal pressure of carbon dioxide [PETCO2] is approximately equal to 54 mmHg) were determined in eight healthy volunteers. Ventilatory responses to carbon dioxide and hypoxia were calculated at baseline and during an alfentanil infusion (estimated blood levels approximately equal to 10 ng/ml) before and after diphenhydramine 0.7 mg/kg. Results The slope of the ventilatory response to carbon dioxide decreased from 1.08+/-0.38 to 0.79+/-0.36 l x min(-1) x mmHg(-1) (x +/- SD, P < 0.05) during alfentanil infusion; after diphenhydramine, the slope increased to 1.17+/-0.28 l x min(-1) x mmHg(-1) (P < 0.05). The minute ventilation (VE) at PETCO2 approximately equal to 46 mmHg (VE46) decreased from 12.1+/-3.7 to 9.7+/-3.6 l/min (P < 0.05) and the VE at 54 mmHg (VE54) decreased from 21.3+/-4.8 to 16.6+/-4.7 l/min during alfentanil (P < 0.05). After diphenhydramine, (VE46 did not change significantly, remaining lower than baseline at 9.9+/-2.9 l/min (P < 0.05), whereas VE54 increased significantly to 20.5+/-3.0 l/min. During hypoxia, VE at SpO2 = 90% (VE90) decreased from 30.5+/-9.7 to 23.1+/-6.9 l/min during alfentanil (P < 0.05). After diphenhydramine, the increase in VE90 to 27.2+/-9.2 l/min was not significant (P = 0.06). Conclusions Diphenhydramine counteracts the alfentanil-induced decrease in the slope of the ventilatory response to carbon dioxide. However, at PETCO2 = 46 mmHg, it does not significantly alter the alfentanil-induced shift in the carbon dioxide response curve. In addition, diphenhydramine does not exacerbate the opioid-induced depression of the hypoxic ventilatory response during moderate hypercarbia.

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Factors Determining the Ventilatory Response to Carbon Dioxide in Chronic Obstructive Airways Disease

Clinical Science ◽

10.1042/cs0390653 ◽

1970 ◽

Vol 39 (5) ◽

pp. 653-662 ◽

Cited By ~ 5

Author(s):

T. K. C. King ◽

D. Yu

Keyword(s):

Carbon Dioxide ◽

Response Curve ◽

Ventilatory Response ◽

Chronic Obstructive ◽

Co2 Response ◽

Arterial Pco2 ◽

Obstructive Airways Disease ◽

End Tidal ◽

Chronic Obstructive Airways Disease ◽

Carbon Dioxide Response

1. The ventilatory response to carbon dioxide was measured in a group of patients with chronic obstructive airways disease using a rebreathing method. 2. The slope of the carbon dioxide response curve was obtained by plotting the ventilation at successive half minutes against the corresponding mean end tidal Pco2. 3. The slope of the carbon dioxide response curve was positively correlated with (a) the FEV1 and (b) the reciprocal of the resting arterial Pco2, both these correlations being statistically significant. 4. Reference to FEV1 alone could explain more than 80% of the variation in the slope of the CO2 response curve. This explained variation was not significantly improved by the additional consideration of the resting arterial Pco2. 5. It was suggested that whatever the underlying complex mechanisms that determine the response to CO2, the FEV1 can be used as an empirical factor for the prediction of this response in patients with chronic obstructive airways disease.

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A Model of the Ventilatory Depressant Potency of Remifentanil in the Non–steady State

Anesthesiology ◽

10.1097/00000542-200310000-00007 ◽

2003 ◽

Vol 99 (4) ◽

pp. 779-787 ◽

Cited By ~ 50

Author(s):

Thomas Bouillon ◽

Joergen Bruhn ◽

Lucian Radu-Radulescu ◽

Corina Andresen ◽

Carol Cohane ◽

...

Keyword(s):

Carbon Dioxide ◽

Steady State ◽

Time Course ◽

Minute Ventilation ◽

Infusion Pump ◽

Hill Coefficient ◽

Bolus Administration ◽

Indirect Response Model ◽

Arterial Blood ◽

Ventilatory Depression

Background The C50 of remifentanil for ventilatory depression has been previously determined using inspired carbon dioxide and stimulated ventilation, which may not describe the clinically relevant situation in which ventilatory depression occurs in the absence of inspired carbon dioxide. The authors applied indirect effect modeling to non-steady state Paco2 data in the absence of inspired carbon dioxide during and after administration of remifentanil. Methods Ten volunteers underwent determination of carbon dioxide responsiveness using a rebreathing design, and a model was fit to the end-expiratory carbon dioxide and minute ventilation. Afterwards, the volunteers received remifentanil in a stepwise ascending pattern using a computer-controlled infusion pump until significant ventilatory depression occurred (end-tidal carbon dioxide [Peco2] > 65 mmHg and/or imminent apnea). Thereafter, the concentration was reduced to 1 ng/ml. Remifentanil pharmacokinetics and Paco2 were determined from frequent arterial blood samples. An indirect response model was used to describe the Paco2 time course as a function of remifentanil concentration. Results The time course of hypercarbia after administration of remifentanil was well described by the following pharmacodynamic parameters: F (gain of the carbon dioxide response), 4.30; ke0 carbon dioxide, 0.92 min-1; baseline Paco2, 42.4 mmHg; baseline minute ventilation, 7.06 l/min; kel,CO2, 0.08 min-1; C50 for ventilatory depression, 0.92 ng/ml; Hill coefficient, 1.25. Conclusion Remifentanil is a potent ventilatory depressant. Simulations demonstrated that remifentanil concentrations well tolerated in the steady state will cause a clinically significant hypoventilation following bolus administration, confirming the acute risk of bolus administration of fast-acting opioids in spontaneously breathing patients.

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Mixed-effects Modeling of the Intrinsic Ventilatory Depressant Potency of Propofol in the Non-steady State

Anesthesiology ◽

10.1097/00000542-200402000-00010 ◽

2004 ◽

Vol 100 (2) ◽

pp. 240-250 ◽

Cited By ~ 24

Author(s):

Thomas Bouillon ◽

Joergen Bruhn ◽

Lucian Radu-Radulescu ◽

Corina Andresen ◽

Carol Cohane ◽

...

Keyword(s):

Carbon Dioxide ◽

Steady State ◽

Time Course ◽

Minute Ventilation ◽

Carbon Dioxide Production ◽

Response Model ◽

Indirect Response Model ◽

Indirect Response ◽

Arterial Blood ◽

Ventilatory Depression

Background Despite the ubiquitous use of propofol for anesthesia and conscious sedation and numerous publications about its effect, a pharmacodynamic model for propofol-induced ventilatory depression in the non-steady state has not been described. To investigate propofol-induced ventilatory depression in the clinically important range (at and below the metabolic hyperbola while carbon dioxide is accumulating because of drug-induced ventilatory depression), the authors applied indirect effect modeling to Paco2 data at a fraction of inspired carbon dioxide of 0 during and after administration of propofol. Methods Ten volunteers underwent determination of their carbon dioxide responsiveness by a rebreathing design. The parameters of a power function were fitted to the end-expiratory carbon dioxide and minute ventilation data. The volunteers then received propofol in a stepwise ascending pattern with use of a target-controlled infusion pump until significant ventilatory depression occurred (end-tidal pressure of carbon dioxide > 65 mmHg and/or imminent apnea). Thereafter, the concentration was reduced to 1 microg/ml. Propofol pharmacokinetics and the Paco2 were determined from frequent arterial blood samples. An indirect response model with Bayesian estimates of the pharmacokinetics and carbon dioxide responsiveness in the absence of drug was used to describe the Paco2 time course. Because propofol reduces oxygen requirements and carbon dioxide production, a correction factor for propofol-induced decreasing of carbon dioxide production was included. Results The following pharmacodynamic parameters were found to describe the time course of hypercapnia after administration of propofol (population mean and interindividual variability expressed as coefficients of variation): F (gain of the carbon dioxide response), 4.37 +/- 36.7%; ke0, CO2, 0.95 min-1 +/- 59.8%; baseline Paco2, 40.9 mmHg +/- 12.8%; baseline minute ventilation, 6.45 l/min +/- 36.3%; kel, CO2, 0.11 min-1 +/- 34.2%; C50,propofol, 1.33 microg/ml +/- 49.6%; gamma, 1.68 +/- 21.3%. Conclusion Propofol at common clinical concentrations is a potent ventilatory depressant. An indirect response model accurately described the magnitude and time course of propofol-induced ventilatory depression. The indirect response model can be used to optimize propofol administration to reduce the risk of significant ventilatory depression.

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Effect of Flumazenil on Ventilatory Drive during Sedation with Midazolam and Alfentanil

Anesthesiology ◽

10.1097/00000542-199610000-00005 ◽

1996 ◽

Vol 85 (4) ◽

pp. 713-720 ◽

Cited By ~ 35

Author(s):

Jeffrey B. Gross ◽

Robert T. Blouin ◽

Shaul Zandsberg ◽

Pattilyn F. Conard ◽

Jurgen Haussler

Keyword(s):

Carbon Dioxide ◽

Respiratory Depression ◽

Minute Ventilation ◽

Study Drug ◽

Double Blind ◽

Ventilatory Responses ◽

Ventilatory Drive ◽

To Receive ◽

Blind Crossover Study ◽

Double Blind Crossover Study

Background Patients who receive a combination of a benzodiazepine and an opioid for conscious sedation are at risk for developing respiratory depression. While flumazenil effectively antagonizes the respiratory depression associated with a benzodiazepine alone, its efficacy in the presence of both a benzodiazepine and an opioid has not been established. This study was designed to determine whether flumazenil can reverse benzodiazepine-induced depression of ventilatory drive in the presence of an opioid. Methods Twelve healthy volunteers completed this randomized, double-blind, crossover study. Ventilatory responses to carbon dioxide and to isocapnic hypoxia were determined during four treatment phases: (1) baseline, (2) alfentanil infusion; (3) combined midazolam and alfentanil infusions, and (4) combined alfentanil, midazolam, and "study drug" (consisting of either flumazenil or flumazenil vehicle) infusions. Subjects returned 2-6 weeks later to receive the alternate study drug. Results Alfentanil decreased the slope of the carbon dioxide response curve from 2.14 +/- 0.40 to 1.43 +/- 0.19 l.min-1.mmHg-1 (x +/- SE, P < 0.05), and decreased the minute ventilation at P(ET)CO2 = 50 mmHg (VE50) from 19.7 +/- 1.2 to 14.8 +/- 0.9l.min-1 (P < 0.05). Midazolam further reduced these variables to 0.87 +/- 0.17 l.min-1.mmHg-1 (P < 0.05) and 11.7 +/- 0.8 l.min-1 (P < 0.05), respectively. With addition of flumazenil, slope and VE50 increased to 1.47 +/- 0.37 l.min-1.mmHg-1 (P < 0.05) and 16.4 +/- 2.0l.min-1 (P < 0.05); after placebo, the respective values of 1.02 +/- 0.19 l.min-1.mmHg-1 and 12.5 +/- 1.2 l.min-1 did not differe significantly from their values during combined alfentanil and midazolam administration. The effect of flumazenil differed significantly from that of placebo (P < 0.05). Both the slope and the displacement of the hypoxic ventilatory response, measured at P(ET)CO2 = 46 +/- 1 mmHG, were affected similarly, with flumazenil showing a significant improvement compared to placebo. Conclusions Flumazenil effectively reverses the benzodiazepine component of ventilatory depression during combined administration of a benzodiazepine and an opioid.

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Ventilatory responses to carbon dioxide at low and high levels of oxygen are elevated after episodic hypoxia in men compared with women

Journal of Applied Physiology ◽

10.1152/japplphysiol.00541.2004 ◽

2004 ◽

Vol 97 (5) ◽

pp. 1673-1680 ◽

Cited By ~ 48

Author(s):

Chris Morelli ◽

M. Safwan Badr ◽

Jason H. Mateika

Keyword(s):

Carbon Dioxide ◽

Ventilatory Response ◽

Minute Ventilation ◽

High Oxygen ◽

Set Point ◽

Ventilatory Responses ◽

Episodic Hypoxia ◽

Before And After ◽

Oxygen Gas ◽

End Tidal

We hypothesized that the acute ventilatory response to carbon dioxide in the presence of low and high levels of oxygen would increase to a greater extent in men compared with women after exposure to episodic hypoxia. Eleven healthy men and women of similar race, age, and body mass index completed a series of rebreathing trials before and after exposure to eight 4-min episodes of hypoxia. During the rebreathing trials, subjects initially hyperventilated to reduce the end-tidal partial pressure of carbon dioxide (PetCO2) below 25 Torr. Subjects then rebreathed from a bag containing a normocapnic (42 Torr), low (50 Torr), or high oxygen gas mixture (150 Torr). During the trials, PetCO2 increased while the selected level of oxygen was maintained. The point at which minute ventilation began to rise in a linear fashion as PetCO2 increased was considered to be the carbon dioxide set point. The ventilatory response below and above this point was determined. The results showed that the ventilatory response to carbon dioxide above the set point was increased in men compared with women before exposure to episodic hypoxia, independent of the oxygen level that was maintained during the rebreathing trials (50 Torr: men, 5.19 ± 0.82 vs. women, 4.70 ± 0.77 l·min−1·Torr−1; 150 Torr: men, 4.33 ± 1.15 vs. women, 3.21 ± 0.58 l·min−1·Torr−1). Moreover, relative to baseline measures, the ventilatory response to carbon dioxide in the presence of low and high oxygen levels increased to a greater extent in men compared with women after exposure to episodic hypoxia (50 Torr: men, 9.52 ± 1.40 vs. women, 5.97 ± 0.71 l·min−1·Torr−1; 150 Torr: men, 5.73 ± 0.81 vs. women, 3.83 ± 0.56 l·min−1·Torr−1). Thus we conclude that enhancement of the acute ventilatory response to carbon dioxide after episodic hypoxia is sex dependent.

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Hypoxic-hypercapnic interaction in subjects with bilateral cerebral dysfunction

Journal of Applied Physiology ◽

10.1152/jappl.1963.18.6.1139 ◽

1963 ◽

Vol 18 (6) ◽

pp. 1139-1145 ◽

Cited By ~ 10

Author(s):

Fred Plum ◽

Harold W. Brown

Keyword(s):

Carbon Dioxide ◽

Brain Damage ◽

Pyramidal Tract ◽

Ventilatory Response ◽

Cerebral Dysfunction ◽

Tract Disease ◽

The Brain ◽

Carbon Dioxide Response ◽

Ventilatory Response To Hypoxia ◽

Respiratory Responses

To analyze cerebral influences modifying autonomic respiratory responses, we compared normals and patients with bilateral pyramidal tract disease for their ventilatory response to hypoxia and hypoxia-hypercapnia. During eucapnia, the two groups showed similar hypoxic responses. During hypercapnia, the ventilatory response to hypoxia was greater in the brain-damaged subjects. This apparent augmentation, however, was due entirely to anoxia interacting with an abnormally facilitated carbon dioxide sensitivity: compared with normals, brain-damaged patients at PaOO2 90–100 mm Hg showed an 85% greater CO2 response, and at PaOO2 50 mm Hg showed a 79% greater CO2 response. Since cerebral dysfunction facilitated the ventilatory response to hypoxia-hypercapnia combined but not the response to hypoxia alone, the results imply that the two respiratory stimuli interact centrally rather than peripherally. respiration; brain damage; interaction; carbon dioxide response; forebrain effects; ventilation with CNS disease Submitted on February 18, 1963

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Stimulation of ventilation in emphysema by passively induced body motion

Journal of Applied Physiology ◽

10.1152/jappl.1962.17.5.771 ◽

1962 ◽

Vol 17 (5) ◽

pp. 771-774 ◽

Cited By ~ 3

Author(s):

Herman F. Froeb

Keyword(s):

Carbon Dioxide ◽

Technical Assistance ◽

Ventilatory Response ◽

Minute Ventilation ◽

Blood Gases ◽

Body Motion ◽

Therapeutic Tool ◽

Arterial Blood ◽

Weak Muscle ◽

Normal Males

The ventilatory stimulation arising from two different forms of passively induced body motion was chosen for study of 14 male emphysematous subjects with hypercapnia and impaired ventilatory response to carbon dioxide. Nine normal males served as controls. The object of the study was to determine whether the stimulus to ventilation from passive body motion was intact in diseased subjects and whether it could serve as a therapeutic tool by bringing about a reduction in blood carbon dioxide. The results revealed that the stimulus to ventilation was mild and comparable in both groups but was associated with two to three times more oxygen per extra liter of minute ventilation in the diseased subjects. There were no significant changes in the arterial blood gases. It was concluded that the stimulus to ventilation from passive body motion arises from weak muscle action and has no therapeutic application in emphysematous subjects as a means of lowering the PaCOCO2. Note: (With the Technical Assistance of Mabel Pearson, Roy Engstrom, Christa McReynolds, and Carol Kennedy) Submitted on March 5, 1962

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