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Clinical Science  |   October 2001
Respiratory Sites of Action of Propofol: Absence of Depression of Peripheral Chemoreflex Loop by Low-dose Propofol
Author Affiliations & Notes
  • Diederik Nieuwenhuijs, M.D.
    *
  • Elise Sarton, M.D., Ph.D.
  • Luc J. Teppema, Ph.D.
  • Erik Kruyt, M.Sc.
  • Ida Olievier, R.A.
    §
  • Jack van Kleef, M.D., Ph.D.
  • Albert Dahan, M.D., Ph.D.
    #
  • *NWO Research Associate, †Staff Anesthesiologist, #Associate Professor, Departments of Anesthesiology and Physiology, ‡Associate Professor, §Research Assistant, Department of Physiology, ∥Professor and Chairman, Department of Anesthesiology.
  • Received from the Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands.
Article Information
Clinical Science
Clinical Science   |   October 2001
Respiratory Sites of Action of Propofol: Absence of Depression of Peripheral Chemoreflex Loop by Low-dose Propofol
Anesthesiology 10 2001, Vol.95, 889-895. doi:
Anesthesiology 10 2001, Vol.95, 889-895. doi:
PROPOFOL is frequently used as a monoanesthetic–sedative for various diagnostic or small surgical procedures in patients who breathe spontaneously or is combined with regional anesthesia techniques for larger surgical procedures. Therefore, knowledge of the ventilatory effects of this agent is of importance. Although it is known that propofol has a depressant effect on metabolic ventilatory control, reducing the ventilatory response to hypoxia 1,2 and causing hypercapnia and sometimes even apnea, 3 the site of action of propofol within the ventilatory control system remains unknown. Propofol may affect breathing at peripheral sites (e.g.  , peripheral chemoreceptors, lung, diaphragm), at central sites (e.g.  , central chemoreceptors, respiratory centers), or at both sites. All halogenated volatile anesthetics, already at subanesthetic concentrations (0.05–0.2 minimum alveolar concentration [MAC]; Bispectral Index values ∼70–80), cause a selective depression of oxygen (O2) and carbon dioxide (CO2) responses mediated by the peripheral chemoreceptors (selective with regard to responses mediated by the central chemoreceptors, which remain unaffected). 4–8 In this study, we investigated whether propofol has effects on the peripheral CO2response similar to those of the inhalational anesthetics. We studied the influence of two concentrations of propofol on the dynamic ventilatory response to hypercapnia in healthy volunteers. Using the dynamic end-tidal CO2forcing technique, the ventilatory responses were separated into a fast component originating at the peripheral chemoreceptors and a slow component at the central chemoreceptors. 9,10 Note that hypoxic studies are unable to resolve the issue of effect-site of a certain agent—anesthetic or analgesic—within the ventilatory control system. The dynamic end-tidal CO2forcing technique is especially developed to quantify the contributions of the peripheral and central chemoreflex loops to inspired minute ventilation (V̇i) in a noninvasive fashion and has been validated extensively in cats and humans. 9–11 
We made two important adaptations in comparison with our earlier studies on the influences of anesthetics and opioids on the dynamic ventilatory response to carbon dioxide. First, to cause a more potent stimulus to the peripheral chemoreceptors, we performed experiments at the background of moderate hypoxia (oxygen saturation, 85–90%). 10 Second, to increase the precision of the estimation of parameters related to the peripheral chemoreflex loop, we used a multifrequency binary sequence (MFBS) in end-tidal partial pressure of carbon dioxide (PETco2) input involving 13 steps into and 13 steps out of hypercapnia. 12 
Methods
Ten healthy volunteers aged 18–25 yr (7 men and 3 women) participated in the protocols after approval was obtained from the local Human Ethics Committee (Leiden, The Netherlands). The subjects were healthy and did not have a history of tobacco or illicit drug abuse.
After arrival at the laboratory, two intravenous catheters were inserted in the left and right cubital veins (one for propofol administration and one for blood sampling). Subsequently, electrodes for electroencephalographic measurement (BisSensor; Aspect Medical Systems, Newton, MA) were placed on the head as specified by the manufacturer, and the subjects rested for 20–30 min. The subjects breathed through a face mask (Vital Signs, Totowa, NJ). Gas flows were measured with a pneumotachograph connected to a pressure transducer and were electronically integrated to yield a volume signal. Corrections were made for the changes in gas viscosity caused by changes in oxygen concentration of the inhaled gas mixtures. The inspired gas mixture was set via  a system of mass-flow controllers (Bronkhorst High-Tec, Veenendaal, The Netherlands), which received control signals from a personal computer. This allows the forcing of end-tidal partial pressure of oxygen (PETo2) and PETco2according to a specified pattern in time, independent of the ventilatory response. Inspired and expired O2and CO2concentrations and arterial hemoglobin–O2saturation (Spo2) were measured with a Datex Multicap gas monitor (near the mouth) and Datex Satellite Plus pulse oximeter, respectively (Datex-Engstrom, Helsinki, Finland). PETo2, PETco2, tidal volume, respiratory frequency, V̇i, and Spo2were collected and stored on disc for further analysis.
The electroencephalogram was recorded using an Aspect A-2000 EEG monitor (Aspect Medical Systems; software version 3.3). The BIS values were averaged over 1-min intervals.
Study Design
End-tidal partial pressure of carbon dioxide was varied according to an MFBS that involved 13 steps into and 13 steps out of fixed PETco2levels (low and high CO2: 2 mmHg and 12 mmHg above the subjects’ normal air breathing values for PETco2), altogether lasting 1,408 s (23 min 28 s). Figure 1shows a schematic diagram of the PETco2input function. The MFBS experiments were performed at a background of moderate hypoxia (PETo2= 70 mmHg) and started 20 min after the initiation of hypoxia. This was done to allow time for hypoxic ventilatory decline to develop before investigating the response to CO2.
Fig. 1. The end-tidal partial pressure of carbon dioxide (PETco2) multifrequency binary sequence. The y-axis represents the increase in PETco2above the individual subjects’ resting PETco2values.
Fig. 1. The end-tidal partial pressure of carbon dioxide (PETco2) multifrequency binary sequence. The y-axis represents the increase in PETco2above the individual subjects’ resting PETco2values.
Fig. 1. The end-tidal partial pressure of carbon dioxide (PETco2) multifrequency binary sequence. The y-axis represents the increase in PETco2above the individual subjects’ resting PETco2values.
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Drug Administration and Sampling
A Psion palm-top computer (London, England) programmed with a three-compartment propofol pharmacokinetic data set was used to control a Becton Dickinson infusion pump (St. Etienne, France) for intravenous administration of propofol. 13 Each subject performed two control MFBS experiments, two during low-dose propofol infusion (Plow; target plasma concentration, 0.75 μg/ml) and two during high-dose propofol infusion (Phigh; target plasma concentration, 1.5 μg/ml). Control studies preceded propofol studies, and low-dose propofol experiments preceded high-dose propofol experiments. MFBS studies started 15 min after plasma target concentrations had been reached. The duration of propofol infusion was 150 min (75 min for Plowand 75 min for Phigh).
Six venous propofol samples were obtained before and after each of the MFBS experiments. The samples were collected in syringes containing potassium oxalate, and propofol concentrations were determined by reverse-phase high-performance liquid chromatography.
Data Analysis
The data were analyzed by fitting the breath-to-breath ventilatory responses to a two-compartment model, as described previously. 9–11,14 The steady-state relation of V̇ito PETco2at constant PETo2in humans is described by:
where GP= the carbon dioxide sensitivity of the peripheral chemoreflex loop, GC= the carbon dioxide sensitivity of the central chemoreflex loop, and B = the apneic threshold or extrapolated PETco2of the steady-state ventilatory response to carbon dioxide at 0 V̇i. The sum of GPand GCis the total carbon dioxide sensitivity (GTOT). To describe the delay in effect and dynamics of the peripheral and central ventilatory responses to CO2, time delays (T) and time constants (τ) are incorporated in the model. The deterministic model parameters are as follows: B; GC; GP; time constant of the peripheral chemoreflex loop (τP); time constant of on-response of the central chemoreflex loop, i.e.  , at high PETco2ON); time constant of the off-response of the central chemoreflex loop, i.e.  , at low PETco2OFF); time delays of the central and peripheral chemoreflex loops (TCand TP); and a linear trend term. 10 The noise corrupting the data was modeled through an external pathway with first-order dynamics. 10 Estimation of the parameters was performed with a one-step prediction error method. 15 
Sensitivity Analysis
We performed an a posteriori  sensitivity analysis. Sensitivity analysis enabled us to determine whether the parameter values could be estimated with finite precision from the actual data. 16–18 The analysis was performed by fixing one parameter (i.e.  , by not allowing it to be estimated) at a time to a series of values (−100% to +100%) around the “optimum” value (in terms of the “cost” function or residual sum of squares of the difference between measured and estimated ventilation). The other parameters were estimated by minimizing the residual sum of squares. The shape of the relation between parameter and residual sum of squares informed us of whether parameters were estimable using the specific PETco2and PETo2inputs. 16–18 Furthermore, because we performed the sensitivity analysis on actual data (and not on simulated data), we were informed of whether local minima existed.
Statistical Analysis
The estimated parameters of control and propofol experiments were subjected to a one-way analysis of variance and post hoc  least significant differences tests. P  values less than 0.05 were considered to be significant. All values reported are mean ± SD.
Results
All subjects terminated the protocol without side effects. Because of propofol, the arousal state of the subjects decreased with Bispectral Index values of 84 ± 8 at low-dose propofol infusion and 67 ± 14 at high-dose propofol infusion. The concentration of propofol remained constant over time during the two infusion schemes (table 1). Examples of a control and a propofol MFBS experiment (propofol target = 1.5 μg/ml) and model fits of one subject are given in figure 2. Only the deterministic part of the model is shown. It shows a large effect of propofol on the output of the central chemoreflex loop (a 55% reduction of GC) with only a minor effect on the output of the peripheral chemoreflex loop (a 12% reduction of GP).
Table 1. Estimated Model Parameters, Propofol Concentrations, and Bispectral Index (BIS) Values
Image not available
Table 1. Estimated Model Parameters, Propofol Concentrations, and Bispectral Index (BIS) Values
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Fig. 2. Control (left  ) and propofol (right  ) ventilatory responses to carbon dioxide of one subject. (Top  ) End-tidal partial pressure of carbon dioxide (PETco2) input function is shown and is varied according to a multifrequency binary sequence that involved 13 steps into and 13 steps out of hypercapnia. (Bottom  ) Each circle represents one breath. The thick line through the breaths is the deterministic part of the model, which is the sum of the outputs of the peripheral (P) and central (C) chemoreflex loops and a trend term. Estimated control parameter values are as follows: B, 36.8 mmHg; GP, 0.40 l · min1· mmHg1; and GC, 1.61 l · min1mmHg1. Estimated propofol parameter values are as follows: B, 36.5 mmHg; GP, 0.35 l · min1· mmHg1; and GC, 0.75 l · min1· mmHg1. V̇i= inspired minute ventilation.
Fig. 2. Control (left 
	) and propofol (right 
	) ventilatory responses to carbon dioxide of one subject. (Top 
	) End-tidal partial pressure of carbon dioxide (PETco2) input function is shown and is varied according to a multifrequency binary sequence that involved 13 steps into and 13 steps out of hypercapnia. (Bottom 
	) Each circle represents one breath. The thick line through the breaths is the deterministic part of the model, which is the sum of the outputs of the peripheral (P) and central (C) chemoreflex loops and a trend term. Estimated control parameter values are as follows: B, 36.8 mmHg; GP, 0.40 l · min−1· mmHg−1; and GC, 1.61 l · min−1mmHg−1. Estimated propofol parameter values are as follows: B, 36.5 mmHg; GP, 0.35 l · min−1· mmHg−1; and GC, 0.75 l · min−1· mmHg−1. V̇i= inspired minute ventilation.
Fig. 2. Control (left  ) and propofol (right  ) ventilatory responses to carbon dioxide of one subject. (Top  ) End-tidal partial pressure of carbon dioxide (PETco2) input function is shown and is varied according to a multifrequency binary sequence that involved 13 steps into and 13 steps out of hypercapnia. (Bottom  ) Each circle represents one breath. The thick line through the breaths is the deterministic part of the model, which is the sum of the outputs of the peripheral (P) and central (C) chemoreflex loops and a trend term. Estimated control parameter values are as follows: B, 36.8 mmHg; GP, 0.40 l · min1· mmHg1; and GC, 1.61 l · min1mmHg1. Estimated propofol parameter values are as follows: B, 36.5 mmHg; GP, 0.35 l · min1· mmHg1; and GC, 0.75 l · min1· mmHg1. V̇i= inspired minute ventilation.
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The averaged model parameters are collected in table 1. At all three treatment levels, the estimated model parameters did not differ between the first and second CO2response. Propofol reduced the total CO2sensitivity (GTOT) by approximately 20% at a propofol target of 0.75 μg/ml and by approximately 34% at a target of 1.5 μg/ml. At both propofol concentrations, the reduction of GTOTwas caused by a reduction of the output of the central chemoreflex loop by 20% and 40% at low- and high-dose propofol, respectively, without affecting the output of the peripheral chemoreflex loop. As a consequence, the ratio GPto GCis increased relative to the control state (fig. 3). The apneic threshold (B) showed a small but significant reduction during propofol infusion (table 1). The time constants and time delays of both chemoreflex loops remained unaffected by propofol (data not shown).
Fig. 3. Influence of propofol on the ventilatory carbon dioxide (CO2) sensitivities relative to control values for peripheral CO2sensitivity (GP), central CO2sensitivity (GC), and total CO2sensitivity (GTOT). Values are mean ± SD.
Fig. 3. Influence of propofol on the ventilatory carbon dioxide (CO2) sensitivities relative to control values for peripheral CO2sensitivity (GP), central CO2sensitivity (GC), and total CO2sensitivity (GTOT). Values are mean ± SD.
Fig. 3. Influence of propofol on the ventilatory carbon dioxide (CO2) sensitivities relative to control values for peripheral CO2sensitivity (GP), central CO2sensitivity (GC), and total CO2sensitivity (GTOT). Values are mean ± SD.
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Figure 4shows the results of the sensitivity analysis of the model parameters in one subject. A well-defined minimum of the residual sum of squares was observed for all parameters, indicating that they could be identified with acceptable accuracy (including parameters TPand TP, not shown). The most accurately estimated parameters were B and GP, as shown by the steepness of the increase in residual sum of squares at parameter values above and below the optimum. The shape of the curves for GC, τP, τON, and τOFFare markedly asymmetric, indicating that the estimation may be less accurate at values higher than the optimum. As expected, the steepness of the increase in the residual sum of squares of GPis less when this parameter is estimated from the single-step CO2input function (broken line in fig. 4). This indicates that GPis estimated with greater accuracy from an MFBS input function relative to a single-step input. GCis well-estimated from an MFBS and step input. However, the analysis indicates somewhat greater accuracy using a single CO2step for values above its optimum and an MFBS input for values below its optimum.
Fig. 4. Results of the sensitivity analysis for the model parameters of the empirical carbon dioxide model of the ventilatory controller in one subject. The data are control data obtained using a multifrequency binary sequence input function (continuous lines). For comparative reasons, we added the sensitivity analysis on GPand GCobtained from a single step input function of the same subject (subject 936; broken lines). The x-axis gives the optimal parameter value (100%) ± 100%; the y-axis gives the increase in residual sum of squares (Δresidual SSQ) from the optimal value (residual SSQ set at 0).
Fig. 4. Results of the sensitivity analysis for the model parameters of the empirical carbon dioxide model of the ventilatory controller in one subject. The data are control data obtained using a multifrequency binary sequence input function (continuous lines). For comparative reasons, we added the sensitivity analysis on GPand GCobtained from a single step input function of the same subject (subject 936; broken lines). The x-axis gives the optimal parameter value (100%) ± 100%; the y-axis gives the increase in residual sum of squares (Δresidual SSQ) from the optimal value (residual SSQ set at 0).
Fig. 4. Results of the sensitivity analysis for the model parameters of the empirical carbon dioxide model of the ventilatory controller in one subject. The data are control data obtained using a multifrequency binary sequence input function (continuous lines). For comparative reasons, we added the sensitivity analysis on GPand GCobtained from a single step input function of the same subject (subject 936; broken lines). The x-axis gives the optimal parameter value (100%) ± 100%; the y-axis gives the increase in residual sum of squares (Δresidual SSQ) from the optimal value (residual SSQ set at 0).
×
Discussion
We used a multifrequency binary sequence in PETco2to quantify the effect of propofol on ventilatory control. The MFBS was designed by Pedersen et al.  12 to spread its power over the frequency range of interest for identification of both peripheral and central chemoreflex responses and to optimize identification of the peripheral chemoreflex response. Using a single step, the peripheral response is determined from only a limited portion of the data (2 min of the 15–20 min of a CO2study). Using an MFBS, this increases significantly (19.5 min of a 24-min experiment). Consequently, the precision of estimation parameters related to the peripheral chemoreflex loop is greater when derived from MFBS compared with single steps. Indeed, our sensitivity analysis indicates the improvement of the estimation of the peripheral CO2sensitivity compared with a step PETco2function, without compromising the accuracy of estimation of central CO2sensitivity (fig. 4).
We used a target-controlled infusion system to administer propofol. Fifteen minutes after target plasma concentrations of propofol were attained, the respiratory studies started. Estimation of the effect-site propofol concentration indicated that this time was ample for equilibrium between blood and effect site. We measured venous propofol concentrations, which may not reflect arterial or effect-site concentrations. However, we observed no time effect on venous propofol concentrations or on parameter estimates at Plowor Phigh. This indicates stable arterial and effect-site propofol concentrations and suggests a small gradient between venous and arterial propofol concentrations.
With respect to the control of breathing, propofol may have an effect at the central or peripheral chemoreceptors, at the respiratory centers in the brainstem, at the neuromechanical link between brainstem and ventilation (V̇i), or at sites in the central nervous system involved in behavioral state control. The exact location of the central chemoreceptors is unknown, but they are probably located in the dorsomedial medulla, the rostroventrolateral medulla, or both. 19 The peripheral chemoreceptors are located in the carotid bodies, which are strategically situated at the bifurcation of the common carotid arteries and have an important role in oxygen delivery to the brain. The peripheral chemoreceptors respond to changes in arterial oxygen tension (Pao2) and arterial carbon dioxide tension (Paco2). 20,21 
We observed that propofol, at doses causing a decrease in Bispectral Index to approximately 70, has an important effect on the control of breathing. Specifically, propofol reduced GCbut had little influence on GP. This indicates the absence of a (selective) effect of low-dose propofol on the peripheral chemoreflex loop. In this respect, propofol stands in sharp contrast to the modern volatile halogenated anesthetics. 5–8 Our findings are in agreement with studies from the literature. Dow and Goodman 22 showed in humans that during propofol anesthesia, the carotid bodies retain their ability to respond to hyperoxia. In anesthetized cats, propofol displayed an inhibitory effect on areas of the dorsomedial and ventrolateral medulla, which possibly contain the central chemoreceptors. 19,23 Evidently, our data do not preclude some depressant effect of higher doses of propofol than used by us on the carotid bodies or its afferent pathways. For example, animal data show that high-dose propofol infusion, 18–35 mg · kg1· h1, causes the cessation of carotid body chemoreceptor activity. 24 
Effect of Propofol on Peripheral CO2versus  O2Responses
Our finding of the absence of an effect of propofol up to plasma concentrations of 1.25 μg/ml on the peripheral CO2response seems in disagreement with our previous observation of a 50% depression of the acute hypoxic V̇iresponse by 0.6 μg/ml propofol. 2 Because the acute hypoxic ventilatory response originates at the peripheral chemoreceptors of the carotid bodies, 25 some depression of the peripheral CO2response was anticipated from our earlier results. Apart from the possibility that O2and CO2sensing at the carotid bodies are differentially affected by propofol, there are three conceivable explanations for this discrepancy.
First, carotid body depression by anesthetics is dependent on stimulus intensity. For example, Ponte and Sadler 26 showed that relative to a mild hypoxic stimulus, a more intense stimulus (partial pressure of oxygen [Po2] < 40 mmHg) is able to overcome volatile anesthetic-induced depression of the carotid bodies. In analogy, the stimulus in this study (a hypercapnic–hypoxic stimulus of a PETco2of 13 mmHg above resting and an Spo2of 88–90%) may offset depression of the carotid bodies by propofol as observed previously using a less-intense hypoxic stimulus (a hypercapnic–hypoxic stimulus of a PETco2of 5 mmHg above resting and an Spo2of ∼87%). Interestingly, when assessing the effect of low-dose volatile anesthetics on ventilatory control, we observed depression of carotid body–mediated responses even when intense stimuli, such as used in this study, were applied. 6,8 This suggests a difference in stimulus intensity needed to overcome carotid body depression caused by propofol and volatile anesthetics.
Second, in cats, Berkenbosch et al.  21 studied the peripheral V̇iresponse dynamics to hypoxic stimulation while the Pao2of the medulla oblongata was kept constant using the technique of artificial brainstem perfusion. Mathematically, the responses were best described by two components: a fast component with a time constant of approximately 2 s and a slow component with a time constant of approximately 73 s. The fast component was considered to originate at the carotid bodies, whereas it was argued that the slow component was due to central modulation of the carotid body response (i.e.  , neuronal dynamics). 21 Interestingly, in the same animal preparation, the response of the peripheral chemoreflex pathway to changes in PETco2does not show a slow component. 21 This indicates that although peripheral hypoxic stimulation activates central neuronal dynamics, peripheral hypercapnic stimulation does not. Also, in humans, the hyperventilatory response to hypoxia is well-described by a fast and a slow component. 27 We previously studied the effect of 0.6 μg/ml propofol on the ventilatory responses to 3 min hypoxic pulses 2 and reanalyzed the data using the two-component model as described by Berkenbosch et al.  21 All control curves were best described by two components as judged by the Akaike criterion, 28 with time constants of 3 and 100 s for the fast and slow components, respectively. Propofol did not affect the gain (i.e.  , hypoxic sensitivity) of the fast component (Gpropofol/Gcontrol= 0.95), but caused a significant reduction of the gain of the slow component (Gpropofol/Gcontrol= 0.45;P  < 0.05). If we assume that the fast response reflects the carotid body response to hypoxia and the slow component central neuronal dynamics, 21,29 these results suggest that propofol affects central neuronal dynamics but has little effect on the carotid bodies or their output, and thus does not reduce Gp. This is in contrast to the effect of inhalational anesthetics. We previously studied the effect of sevoflurane, 0.25% end-tidal (∼0.15 MAC), on the ventilatory responses to 3-min hypoxic pulses 8 and reanalyzed the data using the two-component model as described above. Sevoflurane reduced the fast and slow component by 25 and 60%, respectively (P  < 0.05), an indication for an effect of sevoflurane on the carotid bodies and on central neuronal dynamics.
Third, apart from a stimulatory effect at the carotid bodies, hypoxia causes depression of ventilation via  central mechanisms, i.e.  , within the central nervous system. 30 The central effect of hypoxia on V̇iis already apparent after 1 min of hypoxic exposure 29; therefore, any measured hypoxic V̇iresponse is the mixture of carotid body and central effects on V̇i. Because propofol enhances the magnitude of the central depressant effects of hypoxia in humans, 2 greater depression by propofol of the measured ventilatory response to hypoxia relative to the measured peripheral CO2response is expected.
These three mechanisms should be taken into account when comparing our current results on the effect of propofol on the peripheral and central chemoreflex loops with studies from the literature on the effect of propofol on the ventilatory response to acute 2,31 and subacute hypoxia. 32 
Influence of Propofol versus  Inhalational Anesthetics on Peripheral CO2Response
The discrepant effects of propofol and sevoflurane on the carotid body response to CO2is striking and may be explained by differences in molecular sites of action of intravenous and halogenated inhalational anesthetics. We believe that propofol, like inhalational anesthetics, affects breathing through enhancement of γ-aminobutyric acid–mediated transmission and reduction of glutamatergic activity in the brainstem. 2,33 This may have induced the depression of GCin our study. Furthermore, inhalational anesthetics activate background K+channels in the peripheral and central nervous system. 34–36 These channels are involved in tonic inhibition of cellular excitability, and activation by volatile anesthetics may be the cause of some major side effects, such as depression of cardiac function and respiratory depression. Buckler et al.  36 recently showed the existence of an oxygen-, acid-, and inhalational anesthetic (halothane)–sensitive background K+channel in the carotid body chemoreceptor cells, which possibly is an important link in the cascade leading to CO2and O2sensing in the carotid bodies and the selective site of inhalational anesthetic depression of carotid body function. Further studies are needed to show how anesthetics (including propofol) modulate the pH–Po2sensitivity of these background channels.
References
Blouin RT, Conrad PF, Gross JB: Time course of ventilatory depression following induction of propofol and thiopental. A nesthesiology 1991; 75: 940–4Blouin, RT Conrad, PF Gross, JB
Nieuwenhuijs D, Sarton E, Teppema L, Dahan A: Propofol for monitored anesthesia care: Implications on hypoxic control of cardiorespiratory responses. A nesthesiology 2000; 92: 46–54Nieuwenhuijs, D Sarton, E Teppema, L Dahan, A
Goodman NW, Black AMS, Carter JA: Some ventilatory effects of propofol as a sole anaesthetic agent. Br J Anaesth 1987; 59: 1497–503Goodman, NW Black, AMS Carter, JA
Knill RL, Clement JL: Site of selective action of halothane on the peripheral chemoreflex pathway in humans. A nesthesiology 1984; 61: 121–6Knill, RL Clement, JL
Dahan A, van den Elsen M, Berkenbosch A, DeGoede J, Olievier I, van Kleef J, Bovill J: Effects of subanesthetic halothane on the ventilatory response to hypercapnia and acute hypoxia in healthy volunteers. A nesthesiology 1994; 80: 727–38Dahan, A van den Elsen, M Berkenbosch, A DeGoede, J Olievier, I van Kleef, J Bovill, J
Dahan A, Sarton E, van den Elsen M, van Kleef J, Teppema L, Berkenbosch A: Ventilatory response to hypoxia: Influences of subanesthetic desflurane. A nesthesiology 1996; 85: 60–8Dahan, A Sarton, E van den Elsen, M van Kleef, J Teppema, L Berkenbosch, A
van den Elsen M, Sarton E, Teppema L, Berkenbosch A, Dahan A: Influences of 0.1 minimum alveolar concentration of sevoflurane, desflurane and isoflurane on the dynamic ventilatory response to hypercapnia in humans. Br J Anaesth 1998; 80: 174–82van den Elsen, M Sarton, E Teppema, L Berkenbosch, A Dahan, A
Sarton E, van der Wal M, Nieuwenhuijs D, Teppema L, Robotham J, Dahan A: Sevoflurane-induced reduction of hypoxic drive is sex-independent. A nesthesiology 1999; 90: 1288–93Sarton, E van der Wal, M Nieuwenhuijs, D Teppema, L Robotham, J Dahan, A
Bellville JW, Whipp BJ, Kaufman RD, Swanson GD, Aqleh KA, Wiberg DM: Central and peripheral chemoreflex loop gain in normal and carotid body resected subjects. J Appl Physiol 1979; 46: 843–53Bellville, JW Whipp, BJ Kaufman, RD Swanson, GD Aqleh, KA Wiberg, DM
Dahan A, DeGoede J, Berkenbosch A, Olievier ICW: Influence of oxygen on the ventilatory response to carbon dioxide in man. J Physiol (Lond) 1990; 428: 485–99Dahan, A DeGoede, J Berkenbosch, A Olievier, ICW
DeGoede J, Berkenbosch A, Ward DS, Bellville JW, Olievier CN: Comparison of chemoreflex gains obtained with two different methods in cats. J Appl Physiol 1985; 59: 179–89DeGoede, J Berkenbosch, A Ward, DS Bellville, JW Olievier, CN
Pedersen MEF, Fatemian M, Robbins PA: Identification of fast and slow ventilatory responses to carbon dioxide under hypoxic and hyperoxic conditions in humans. J Physiol (Lond) 1999; 521: 273–87Pedersen, MEF Fatemian, M Robbins, PA
Gepts E, Camu F, Cockshott ID, Douglas EJ: Disposition of propofol administered as constant rate intravenous infusions in humans. Anesth Analg 1987; 66: 1256–63Gepts, E Camu, F Cockshott, ID Douglas, EJ
Sarton E, Teppema L, Dahan A: Sex differences in morphine-induced ventilatory depression reside with the peripheral chemoreflex loop. A nesthesiology 1999; 90: 1329–38Sarton, E Teppema, L Dahan, A
Ljung L: System Identification: Theory for the User. Englewood Cliffs, New Jersey, Prentice-Hall, 1987, pp 214–8
Dahan A: The Influence of Oxygen on the Ventilatory Response to Carbon Dioxide: Methods and Implications [Ph.D. thesis]. Leiden: Leiden University; 1990. pp 29–44
Ward DS, Mann CB, Dahan A: Modeling the dynamic ventilatory response to hypoxia in humans. Ann Biomed Eng 1992; 20: 181–94Ward, DS Mann, CB Dahan, A
Dahan A, Olofsen E, Teppema L, Sarton E, Olievier CN: Speed of onset and offset of ventilatory depression from sevoflurane: An experimental study in the cat. A nesthesiology 1999; 90: 1119–28Dahan, A Olofsen, E Teppema, L Sarton, E Olievier, CN
Teppema LJ, Veening JG, Kronenberg A, Dahan A, Berkenbosch A, Olievier C: Expression of c-fos  in the rat brainstem after exposure to hypoxia and hyperoxic hyeprcapnia. J Comp Neurol 1997; 388: 169–90Teppema, LJ Veening, JG Kronenberg, A Dahan, A Berkenbosch, A Olievier, C
Berkenbosch A, DeGoede J, Ward D, Olievier C, vanHartevelt J: Dynamic response of peripheral chemoreflex loop to changes in end-tidal CO2. J Appl Physiol 1988; 64: 1779–85Berkenbosch, A DeGoede, J Ward, D Olievier, C vanHartevelt, J
Berkenbosch A, DeGoede J, Ward D, Olievier C, vanHartevelt J: Dynamic response of peripheral chemoreflex loop to changes in end-tidal O2. J Appl Physiol 1991; 71: 1123–28Berkenbosch, A DeGoede, J Ward, D Olievier, C vanHartevelt, J
Dow AC, Goodman NW: Effect of hyperoxia on breathing in patients anesthetized with propofol. Br J Anaesth 1993; 70: 532–5Dow, AC Goodman, NW
Yang CY, Luk HN, Chen SY, Wu CW, Chai CY: Propofol inhibits medullary pressor mechanisms in cats. Can J Anaesth 1997; 44: 775–81Yang, CY Luk, HN Chen, SY Wu, CW Chai, CY
Ponte J, Sadler CL: Effect of thiopentone, etomidate and propofol for carotid body activity in the rabbit and the cat. Br J Anaesth 1989; 62: 41–5Ponte, J Sadler, CL
Vizek M, Pickett CK, Weil J: Bipahasic ventilatory response of adult cats to sustained hypoxia has central origin. J Appl Physiol 1987; 63: 1658–64Vizek, M Pickett, CK Weil, J
Ponte J, Sadler CL: Effect of halothane, enflurane and isoflurane on carotid body chemoreceptor activity in the rabbit and cat. Br J Anaesth 1989; 62: 33–40Ponte, J Sadler, CL
Kirby TP, Wraith PK, DeCort SC, Airlie MAA, Hill JE, Carson ER, Flenley DC, Warren PM: Modelling the dynamic ventilatory response to hypoxia in normal subjects. J Theor Biol 1994; 166: 135–47Kirby, TP Wraith, PK DeCort, SC Airlie, MAA Hill, JE Carson, ER Flenley, DC Warren, PM
Akaike H: A new look at the statistical model identification. IEEE Trans Automat Contr 1974; 19: 716–23Akaike, H
Dahan A, Berkenbosch A, DeGoede J, van den Elsen M, Olievier I, van Kleef J: Influence of hypoxic duration and posthypoxic O2concentration on short term potentiation of breathing in humans. J Physiol (Lond) 1995; 488: 803–13Dahan, A Berkenbosch, A DeGoede, J van den Elsen, M Olievier, I van Kleef, J
Dahan A, Ward DS, van den Elsen M, Temp J, Berkenbosch A: Influence of reduced carotid body drive during sustained hypoxia on hypoxic depression of ventilation in humans. J Appl Physiol 1996; 81: 565–72Dahan, A Ward, DS van den Elsen, M Temp, J Berkenbosch, A
Nagyova B, Dorrington KL, Gill EW, Robbins PA: Comparison of subhypnotic concentrations of propofol and halothane on the acute ventilatory response to hypoxia. Br J Anaesth 1995; 75: 713–8Nagyova, B Dorrington, KL Gill, EW Robbins, PA
Blouin RT, Seifert HA, Babenco HD, Conrad PF, Gross JB: Propofol depresses the hypoxic ventilatory response during conscious sedation and isohypercapnia. A nesthesiology 1994; 80: 739–50Blouin, RT Seifert, HA Babenco, HD Conrad, PF Gross, JB
Stuth EAE, Krolo M, Stucke AG, Tonkovic-Capin M, Tonkovic-Capin V, Hopp FA, Kampine JP, Zuperku EJ: Effects of halothane on medullary expiratory neurons in a decerebrate dog model. A nesthesiology 2000; 91: 1474–81Stuth, EAE Krolo, M Stucke, AG Tonkovic-Capin, M Tonkovic-Capin, V Hopp, FA Kampine, JP Zuperku, EJ
Patel AJ, Honoré E, Lesage F, Fink M, Romey G, Lazdunski M: Inhalational anesthetics activate two-pore-domain background K+channels. Nat Neurosci 1999; 2: 422–6Patel, AJ Honoré, E Lesage, F Fink, M Romey, G Lazdunski, M
Sirois LE, Lie Q, Talley EM, Lynch C, Bayliss DA: The TASK-1 two-pore domain K+channel is a molecular substrate for neuronal effects of inhalational anesthetics. J Neurosci 2000; 201: 6347–54Sirois, LE Lie, Q Talley, EM Lynch, C Bayliss, DA
Buckler KJ, Williams BA, Honore E: An oxygen-, acid- and anaesthetic-sensitive TASK-like background potassium channel in rat arterial chemoreceptor cells. J Physiol (Lond) 2000; 525: 135–42Buckler, KJ Williams, BA Honore, E
Fig. 1. The end-tidal partial pressure of carbon dioxide (PETco2) multifrequency binary sequence. The y-axis represents the increase in PETco2above the individual subjects’ resting PETco2values.
Fig. 1. The end-tidal partial pressure of carbon dioxide (PETco2) multifrequency binary sequence. The y-axis represents the increase in PETco2above the individual subjects’ resting PETco2values.
Fig. 1. The end-tidal partial pressure of carbon dioxide (PETco2) multifrequency binary sequence. The y-axis represents the increase in PETco2above the individual subjects’ resting PETco2values.
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Fig. 2. Control (left  ) and propofol (right  ) ventilatory responses to carbon dioxide of one subject. (Top  ) End-tidal partial pressure of carbon dioxide (PETco2) input function is shown and is varied according to a multifrequency binary sequence that involved 13 steps into and 13 steps out of hypercapnia. (Bottom  ) Each circle represents one breath. The thick line through the breaths is the deterministic part of the model, which is the sum of the outputs of the peripheral (P) and central (C) chemoreflex loops and a trend term. Estimated control parameter values are as follows: B, 36.8 mmHg; GP, 0.40 l · min1· mmHg1; and GC, 1.61 l · min1mmHg1. Estimated propofol parameter values are as follows: B, 36.5 mmHg; GP, 0.35 l · min1· mmHg1; and GC, 0.75 l · min1· mmHg1. V̇i= inspired minute ventilation.
Fig. 2. Control (left 
	) and propofol (right 
	) ventilatory responses to carbon dioxide of one subject. (Top 
	) End-tidal partial pressure of carbon dioxide (PETco2) input function is shown and is varied according to a multifrequency binary sequence that involved 13 steps into and 13 steps out of hypercapnia. (Bottom 
	) Each circle represents one breath. The thick line through the breaths is the deterministic part of the model, which is the sum of the outputs of the peripheral (P) and central (C) chemoreflex loops and a trend term. Estimated control parameter values are as follows: B, 36.8 mmHg; GP, 0.40 l · min−1· mmHg−1; and GC, 1.61 l · min−1mmHg−1. Estimated propofol parameter values are as follows: B, 36.5 mmHg; GP, 0.35 l · min−1· mmHg−1; and GC, 0.75 l · min−1· mmHg−1. V̇i= inspired minute ventilation.
Fig. 2. Control (left  ) and propofol (right  ) ventilatory responses to carbon dioxide of one subject. (Top  ) End-tidal partial pressure of carbon dioxide (PETco2) input function is shown and is varied according to a multifrequency binary sequence that involved 13 steps into and 13 steps out of hypercapnia. (Bottom  ) Each circle represents one breath. The thick line through the breaths is the deterministic part of the model, which is the sum of the outputs of the peripheral (P) and central (C) chemoreflex loops and a trend term. Estimated control parameter values are as follows: B, 36.8 mmHg; GP, 0.40 l · min1· mmHg1; and GC, 1.61 l · min1mmHg1. Estimated propofol parameter values are as follows: B, 36.5 mmHg; GP, 0.35 l · min1· mmHg1; and GC, 0.75 l · min1· mmHg1. V̇i= inspired minute ventilation.
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Fig. 3. Influence of propofol on the ventilatory carbon dioxide (CO2) sensitivities relative to control values for peripheral CO2sensitivity (GP), central CO2sensitivity (GC), and total CO2sensitivity (GTOT). Values are mean ± SD.
Fig. 3. Influence of propofol on the ventilatory carbon dioxide (CO2) sensitivities relative to control values for peripheral CO2sensitivity (GP), central CO2sensitivity (GC), and total CO2sensitivity (GTOT). Values are mean ± SD.
Fig. 3. Influence of propofol on the ventilatory carbon dioxide (CO2) sensitivities relative to control values for peripheral CO2sensitivity (GP), central CO2sensitivity (GC), and total CO2sensitivity (GTOT). Values are mean ± SD.
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Fig. 4. Results of the sensitivity analysis for the model parameters of the empirical carbon dioxide model of the ventilatory controller in one subject. The data are control data obtained using a multifrequency binary sequence input function (continuous lines). For comparative reasons, we added the sensitivity analysis on GPand GCobtained from a single step input function of the same subject (subject 936; broken lines). The x-axis gives the optimal parameter value (100%) ± 100%; the y-axis gives the increase in residual sum of squares (Δresidual SSQ) from the optimal value (residual SSQ set at 0).
Fig. 4. Results of the sensitivity analysis for the model parameters of the empirical carbon dioxide model of the ventilatory controller in one subject. The data are control data obtained using a multifrequency binary sequence input function (continuous lines). For comparative reasons, we added the sensitivity analysis on GPand GCobtained from a single step input function of the same subject (subject 936; broken lines). The x-axis gives the optimal parameter value (100%) ± 100%; the y-axis gives the increase in residual sum of squares (Δresidual SSQ) from the optimal value (residual SSQ set at 0).
Fig. 4. Results of the sensitivity analysis for the model parameters of the empirical carbon dioxide model of the ventilatory controller in one subject. The data are control data obtained using a multifrequency binary sequence input function (continuous lines). For comparative reasons, we added the sensitivity analysis on GPand GCobtained from a single step input function of the same subject (subject 936; broken lines). The x-axis gives the optimal parameter value (100%) ± 100%; the y-axis gives the increase in residual sum of squares (Δresidual SSQ) from the optimal value (residual SSQ set at 0).
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Table 1. Estimated Model Parameters, Propofol Concentrations, and Bispectral Index (BIS) Values
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Table 1. Estimated Model Parameters, Propofol Concentrations, and Bispectral Index (BIS) Values
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