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

2004 ◽  
Vol 100 (2) ◽  
pp. 240-250 ◽  
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.

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

2003 ◽  
Vol 99 (4) ◽  
pp. 779-787 ◽  
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.

Pharmacokinetic-Pharmacodynamic Modeling of the Respiratory Depressant Effect of Alfentanil 

1999 ◽  
Vol 91 (1) ◽  
pp. 144-155 ◽  
Author(s):  
Thomas Bouillon ◽  
Christina Schmidt ◽  
Gudrun Garstka ◽  
Dirk Heimbach ◽  
Dieter Stafforst ◽  
...  
Keyword(s):  
Carbon Dioxide ◽  
Respiratory Depression ◽  
Pharmacodynamic Modeling ◽  
Model Parameters ◽  
Pharmacokinetic Data ◽  
Indirect Response Models ◽  
Response Model ◽  
Indirect Response Model ◽  
Indirect Response ◽  
Arterial Blood

Background Although respiratory depression is the most well-known and dangerous side effect of opioids, no pharmacokinetic-pharmacodynamic model exists for its quantitative analysis. The development of such a model was the aim of this study. Methods After institutional approval approval and informed consent were obtained, 14 men (American Society of Anesthesiologists physical status I or II; median age, 42 yr [range, 20-71 yr]; median weight, 82.5 kg [range, 68-108 kg]) were studied before they underwent major urologic surgery. An intravenous infusion of alfentanil (2.3 microg x kg(-1) x min(-1)) was started while the patients were breathing oxygen-enriched air (fraction of inspired oxygen [FIO2 = 0.5) over a tightly fitting continuous positive airway pressure mask. The infusion was discontinued when a cumulative dose of 70 microg/kg had been administered, the end-expiratory partial pressure of carbon dioxide (PE(CO2) exceeded 65 mmHg, or apneic periods lasting more than 60 s occurred During and after the infusion, frequent arterial blood samples were drawn and analyzed for the concentration of alfentanil and the arterial carbon dioxide pressure (PaCO2). A mamillary two-compartment model was fitted to the pharmacokinetic data. The PaCO2 data were described by an indirect response model The model accounted for the respiratory stimulation resulting from increasing PaCO2. The model parameters were estimated using NONMEM. Simulations were performed to define the respiratory response at steady state to different alfentanil concentrations. Results The indirect response model adequately described the time course of the PaCO2. The following pharmacodynamic parameters were estimated (population means and interindividual variability): EC50, 60.3 microg/l (32%); the elimination rate constant of carbon dioxide (Kel), 0.088 min(-1) (44%); and the gain in the carbon dioxide response, 4(28%) (fixed according to literature values). Simulations revealed the pronounced role of PaCO2 in maintaining alveolar ventilation in the presence of opioid. Conclusions The model described the data for the entire opioid-PaCo2 response surface examined. Indirect response models appear to be a promising tool for the quantitative evaluation of drug-induced respiratory depression.

The Pharmacodynamic Effect of a Remifentanil Bolus on Ventilatory Control

2000 ◽  
Vol 92 (2) ◽  
pp. 393-393 ◽  
Author(s):  
H. Daniel Babenco ◽  
Pattilyn F. Conard ◽  
Jeffrey B. Gross
Keyword(s):  
Carbon Dioxide ◽  
Respiratory Depression ◽  
Response Curve ◽  
Time Course ◽  
Ventilatory Response ◽  
Minute Ventilation ◽  
Effect Site ◽  
Ventilatory Drive ◽  
Ventilatory Depression ◽  
Carbon Dioxide Response

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.

Temperature-induced changes in blood acid-base status in the alligator, Alligator mississipiensis

1978 ◽  
Vol 45 (6) ◽  
pp. 922-926 ◽  
Author(s):  
D. G. Davies
Keyword(s):  
Carbon Dioxide ◽  
Body Temperature ◽  
Minute Ventilation ◽  
Carbon Dioxide Production ◽  
Carbon Dioxide Partial Pressure ◽  
Acid Base ◽  
Arterial Blood ◽  
Acid Base Status ◽  
Body Temperature Increase ◽  
Alligator Mississipiensis

Gas exchange and arterial blood acid-base status were measured in 13 conscious alligators, Alligator mississipiensis, at 15, 25, and 35 degrees C. Arterial pH decreased by 0.250 units (from 7.635 to 7.385) and arterial carbon dioxide partial pressure increased by 11.4 Torr (from 11.8 to 23.2) as body temperature increased from 15 to 35 degrees C. No statistically significant changes occurred in arterial bicarbonate concentration. When OH-/H+ and alpha-imidazole were compared at each temperature, more variability was observed in OH-/H+, which increased from 8.7 to 12.0 as temperature increased from 15 to 35 degrees C. alpha-Imidazole remained essentially constant (0.76 at 15 degrees C and 0.80 at 35 degrees C). Body temperature increase caused marked increases in minute ventilation (VE), oxygen consumption (VO2), and carbon dioxide production (VCO2). The relative changes in these parameters resulted in a decrease in both VE/VO2 and VE/VCO2. The data of the present study are consistent with the concept that poikilotherms regulate their alveolar ventilation with changes in body temperature in order to keep OH-/H+ or alpha-imidazole constant.

Effects of Varied Vocal Intensity on Ventilation and Energy Expenditure in Women and Men

1998 ◽  
Vol 41 (2) ◽  
pp. 239-248 ◽  
Author(s):  
Bridget A. Russell ◽  
Frank J. Cerny ◽  
Elaine T. Stathopoulos
Keyword(s):  
Carbon Dioxide ◽  
Steady State ◽  
Energy Expenditure ◽  
Minute Ventilation ◽  
Face Mask ◽  
Carbon Dioxide Production ◽  
Quiet Breathing ◽  
Energy Expenditures ◽  
Ventilatory Responses ◽  
End Tidal

This study was completed to determine how ventilatory responses change by means of speech reading at three different sound pressure levels (SPL) as compared to quiet breathing prior to each task. The energy required to alter SPL was also studied and compared to energy expenditures during a quiet breathing condition. Twenty-four adults (12 women, 12 men) were studied while reading a standard passage at low, comfortable, and high SPLs for 7 minutes with quiet breathing periods between each task to achieve respiratory steady state and serve as a control to which the reading tasks were compared. The last 2 minutes of exhaled air for all speaking and quiet breathing tasks were collected using a Hans Rudolph mouth breathing face mask. A Sensor Medics V max 29 TM series diagnostic instrument system measured all ventilatory responses and energy expenditures. Volume and timing alterations in ventilation were characterized by measuring tidal volume (V T ), inspiratory time (T I ), inspiratory flow rate (V T /T I ), and expiratory time (T E ). Average ventilation, energy expenditure, and adequacy of ventilation were measured using minute ventilation (V W E ), oxygen consumption V W O 2 ), carbon dioxide production (V W CO 2 ), and partial pressure of end-tidal carbon dioxide (end-tidal PET CO2 ). Results indicated volume, timing, ventilation, and energy expenditure values remained closest to quiet breathing values for the comfortable SPL. Volume, ventilation, and energy expenditure were significantly greater for the high SPL and lower for the low SPL, compared to the baseline steady state, indicating that the low SPL causes a ventilatory deficit that was found to be paid back at the end of the speech task during the quiet breathing period. These results demonstrate that an individual's comfortable SPL is the least energyrequiring way to speech breathe. As SPL rises above or below comfortable SPL, speech breathing requires more energy.

Indirect-response model for the time course of leukopenia with anticancer drugs*

1998 ◽  
Vol 64 (5) ◽  
pp. 511-521 ◽  
Author(s):  
Hironobu Minami ◽  
Yasutsuna Sasaki ◽  
Nagahiro Saijo ◽  
Tomoko Ohtsu ◽  
Hirofumi Fujii ◽  
...  
Keyword(s):  
Anticancer Drugs ◽  
Time Course ◽  
Response Model ◽  
Indirect Response Model ◽  
Indirect Response

Effect of obesity on ventilatory adjustment to exercise

1963 ◽  
Vol 18 (1) ◽  
pp. 19-24 ◽  
Author(s):  
J. Howland Auchincloss ◽  
John Sipple ◽  
Robert Gilbert
Keyword(s):  
Carbon Dioxide ◽  
Steady State ◽  
Treadmill Exercise ◽  
Ventilatory Response ◽  
Carbon Dioxide Production ◽  
Exercise Ventilation ◽  
Expired Gas ◽  
Obese Subjects ◽  
Oxygen Tensions ◽  
Alveolar Oxygen

The ventilatory response to treadmill exercise was studied in normal and obese subjects, with an analysis of both the steady and unsteady states of exercise. Ventilation, oxygen consumption, carbon dioxide production, respiratory quotient, and alveolar and mixed expired gas concentrations were measured directly or computed. During the steady state of exercise obese subjects increased their ventilation sufficiently to maintain normal alveolar carbon dioxide tensions. During the first 2 min of exercise hypoventilation was more pronounced in obese subjects and in certain individuals resulted in mild reductions in alveolar oxygen tensions. Obese individuals exercised less efficiently than nonobese as manifested by excessive energy expenditure in relation to weight. Steady-state exercise PaCoCo2 values were higher in those subjects previously shown to be relatively insensitive to inhalation of 5% CO2 but failed to correlate with the speed of ventilatory responsiveness.

Stimulation of ventilation in emphysema by passively induced body motion

1962 ◽  
Vol 17 (5) ◽  
pp. 771-774 ◽  
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

Potassium as a respiratory signal in humans

1990 ◽  
Vol 69 (5) ◽  
pp. 1799-1803 ◽  
Author(s):  
C. G. Newstead ◽  
G. C. Donaldson ◽  
J. R. Sneyd
Keyword(s):  
Minute Ventilation ◽  
Blood Chemistry ◽  
Carbon Dioxide Production ◽  
Renal Transplant Recipients ◽  
Transplant Recipients ◽  
Arterial Blood ◽  
Respiratory Signal ◽  
Carbon Dioxide Production Rate ◽  
The Relationship ◽  
Resting Muscle

Six renal transplant recipients underwent a series of incremental exercise experiments. Minute ventilation (VE), carbon dioxide production rate (VCO2), and arterial blood chemistry were measured at rest and while subjects exercised on a stationary bicycle. Four of the subjects performed a similar experiment while exercising on a static rowing machine. Within each subject, arterial potassium concentration ([K+]a) was linearly related to VCO2 and VE during exercise. The slope of the relationship between [K+]a and VCO2 was similar in the cycling and rowing experiments. This implies that the absorption of potassium by resting muscle does not significantly limit the arterial hyperkalemia seen during exercise. When VE, VCO2, and [K+]a were measured 1 and 5 min after the end of cycling there was no correlation, whereas VE continued to be closely correlated with VCO2. The relationship demonstrated between change in [K+]a and VCO2 in these experiments is compatible with change of [K+]a acting as a respiratory signal during exercise but not during recovery from exercise in humans.

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