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Clinical Science  |   July 1996
Ventilatory Response to Hypoxia in Humans: Influences of Subanesthetic Desflurane
Author Notes
  • (Dahan) Staff Anesthesiologist, Department of Anesthesiology, Leiden University Hospital.
  • (Sarton, van den Elsen) Resident, Department of Anesthesiology, Leiden University Hospital.
  • (van Kleef) Professor and Chairman, Department of Anesthesiology, Leiden University Hospital.
  • (Teppema) Assistant Professor of Physiology, Department of Physiology, Leiden University.
  • (Berkenbosch) Associate Professor of Physiology, Department of Physiology, Leiden University.
  • Received from the Department of Anesthesiology, Leiden University Hospital, and the Department of Physiology, Leiden University, Leiden, The Netherlands. Submitted for publication January 5, 1996. Accepted for publication March 8, 1996. Supported in part by Pharmacia Nederland B.V., Woerden, The Netherlands.
  • Address reprint requests to Dr. Dahan: Department of Anesthesiology, Leiden University Hospital, PO Box 9600, 2300 RC Leiden, The Netherlands. Address electronic mail to: dahan@rullf2.medfac.leidenuniv.nl.
Article Information
Clinical Science
Clinical Science   |   July 1996
Ventilatory Response to Hypoxia in Humans: Influences of Subanesthetic Desflurane
Anesthesiology 7 1996, Vol.85, 60-68. doi:
Anesthesiology 7 1996, Vol.85, 60-68. doi:
Key words: Anesthetics, volatile: desflurane. Methods: dynamic end-tidal forcing; isocapnia. Receptors, peripheral: carotid bodies. Ventilation: hypercapnia; hypoxic response; normocapnia. Respiration: regulation.
DESFLURANE, an inhalational anesthetic introduced in clinical practice in 1992, reduces the ventilatory response to carbon dioxide at anesthetic concentrations (minimum alveolar concentration [MAC] fraction greater or equal to 0.8). [1] At these alveolar concentrations, the regulation of breathing is affected via depression of the central neuronal respiratory drive, the peripheral drive from the carotid bodies, and/or the efferent pathways between controller and ventilatory pump. In the current study, we investigated the effects of subanesthetic desflurane (0.1 MAC) on ventilatory control, in particular on the responses mediated via the carotid bodies. Studies in humans performed in our laboratory consistently showed that halothane and isoflurane at MAC-fractions ranging from 0.05 to 0.2 reduced the ventilatory responses that originated at the carotid bodies (i.e, the hypoxic ventilatory response and the ventilatory carbon dioxide sensitivity of the peripheral chemoreceptors). [2-6] We expected that subanesthetic desflurane would behave in a similar fashion, despite its somewhat distinctive pharmacodynamic properties apparent at higher inspired concentrations that may be related to the control of breathing: airway irritation, [7] and a significant increase in sympathetic activity that occurs with rapidly increasing the MAC-fraction from 0.5 to 1.0 or 1.5. [8] .
Our main aim in the current study was to assess the influence of 0.1 MAC desflurane on the ventilatory response to hypoxia at constant normocapnic and hypercapnic levels in healthy young volunteers. This allowed us to examine the effects of desflurane on the augmentation of the hypoxic response by carbon dioxide, an effect believed to originate at the peripheral chemoreceptors.
Materials and Methods
Subjects and Apparatus
After approval by the Leiden University Committee on Medical Ethics, 14 healthy, aged 24-30 yr subjects (5 women) without a history of smoking, drug, or alcohol abuse were selected for the study. None had participated in other respiratory studies. Before the studies, subjects participated in a training session to become familiarized with the protocol and apparatus. The magnitude of the hypoxic response was not measured in these training sessions. The subjects were advised not to eat or drink for the 6 h before the study. This procedure was identical to that used in our earlier studies. [2-6] .
During the study, the subjects were in a semirecumbent position. An oronasal mask was fitted before the experiment started. The airway gas flow was measured with a pneumotachograph (Fleisch, Lausanne, Switzerland) connected to a differential pressure transducer (model 270, Hewlett Packard, Andovar, MA) and electronically integrated to yield a volume signal. This signal was calibrated with a motor-driven piston pump (stroke volume 11 at a frequency of 20 strokes/min). The pneumotachograph was connected to a T piece. One arm of the T piece received a gas mixture, with a flow of 45 l/min from a gas mixing system that consisted of four mass flow controllers (F201-F203, Bronkhorst High Tec, Veenendaal, The Netherlands) with which the flow of oxygen, carbon dioxide, nitrogen, and desflurane in nitrogen could be set individually at a desired level. Flows were calibrated with flow resistance standards (Godart, Bilthoven, The Netherlands). A Programmable Digital Processor 11/23 microcomputer (Digital Equipment Corporation, Maynard, IA) provided control signals to the mass flow controllers, so that the composition of the inspiratory gas mixture could be adjusted to force the end-tidal oxygen tension (PETO2) to follow a specific pattern in time while the end-tidal carbon dioxide tension (PETCO2) is kept constant. Part of the nitrogen (5 l/min) passed through the desflurane vaporizer (Tec 6, Ohmeda, West Yorkshire, United Kingdom). During the initial part of the study, the vaporizer was kept in the "off" position.
The oxygen and carbon dioxide concentrations of the inspired and expired gases were measured with a gas monitor (Datex Multicap, Helsinki, Finland) by paramagnetic and infrared analysis, respectively. The gas monitor was calibrated with gas mixtures of known concentrations delivered by a gas-mixing pump (Wosthoff, Bochum, Germany). The desflurane concentration was measured at the mouth with a Datex monitor (Capnomac Ultima, Helsinki, Finland). A pulse oximeter (Datex Satellite Plus, Helsinki, Finland) continuously measured the arterial hemoglobin-oxygen saturation via a finger probe (SPO2). Throughout the study, the electrocardiograph was monitored. Inspiratory minute ventilation (VI), tidal volume (VT), respiratory rate (RR), SPO2, PETCO2, and PETO2were stored on a breath-to-breath basis.
Study Design
The ventilatory responses to hypoxia at the background of normocapnia (Normocapnic Studies) and the responses at a background of hypercapnia (Hypercapnic Studies) were determined on different morning sessions, at least 1 week apart. Four hypoxic responses were obtained before and during desflurane administration at the following target end-tidal oxygen fractions: 0.10 (PETO2approximately 75 mmHg), 0.07 (PETO2approximately 53 mmHg), 0.058 (PETO2approximately 44 mmHg), and 0.050 (PETO2approximately 38 mmHg; Figure 1).
Figure 1. Schematic representation of 1 of 24 possible study sequences. The interludes between hypoxic episodes are 10-15 min.
Figure 1. Schematic representation of 1 of 24 possible study sequences. The interludes between hypoxic episodes are 10-15 min.
Figure 1. Schematic representation of 1 of 24 possible study sequences. The interludes between hypoxic episodes are 10-15 min.
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Each session started with a 30-min relaxation period. Thereafter, individual resting PETCO2was determined at the end of 10 min of steady-state VIwith no inspired carbon dioxide. Subsequently, the PETCO2was increased by 2 mmHg in the normocapnic studies and 8 mmHg in the hypercapnic studies. This level was maintained throughout the control and desflurane studies.
Hypoxia was induced with a "dynamic end-tidal forcing" system [9] : steps from normoxia (PETO2approximately 110 mmHg) into hypoxia (target PETO2level obtained within 4-8 breaths) were applied. Hypoxia was maintained for 3 min, after which normoxia was reintroduced. Between hypoxic challenges there was a 10- to 15-min interlude. For each study (control-normocapnia; control hypercapnia; desflurane-normocapnia; desflurane-hypercapnia), the subjects were allocated randomly to 1 of 24 possible study sequences (Figure 1).
The control studies always preceded the desflurane hypoxic studies. The end-tidal fraction of desflurane was brought to 0.72% (approximately 0.1 MAC) [7] within 1 min by means of an "overpressure" technique. Thereafter a 10- to 15-min equilibration period preceded the hypoxic challenges.
Data Analysis
Hypoxic sensitivity--The average V with dotIof the last 30 s of each hypoxic challenge was calculated. In addition, normoxic ventilation was determined before the hypoxic challenges longer than 30 s. This yielded 5 V with dotI-SPO2data points.
We expressed V with dotIas a linear function of arterial oxygen-hemoglobin desaturation: Equation 1where S is the hypoxic sensitivity and V with dotI(0) the ventilation at normoxia (SPO2= 98%). The parameters were determined by linear regression of V with dotIon (100 - SPO2). Similar procedures were performed for respiratory rate and tidal volume.
Inclusion Criteria
One of the investigators (AD, ES, or MvdE) continuously observed the subjects. During the study, soft music was played, but there was no visual stimulation. Experiments were performed in a normal lighted room that was sealed off from the data acquisition- and end-tidal steering-apparatus.
At the start and end of the studies, we recorded the central nervous system (CNS) arousal state of the subjects by applying a five-point scale:
0 = normal alertness;
1 = drowsy, open eyes;
2 = closed eyes, opened in response to verbal command;
3 = closed eyes, opened in response to touch; and
4 = closed eyes, unarousable.
Data were included for analysis if the subjects were in scale 0 for control and scales 0, 1, or 2 for the desflurane studies. In addition, data were discarded when a subject displayed discomfort during the study.
Statistical Analysis
To detect a significant difference (in the normocapnic and hypercapnic studies) between the control and desflurane studies, a Student's t test was performed on the S, V with dotI(0), Delta VT/Delta SPO2, Delta RR/Delta SPO2, respiratory rate at normoxia (RR(O)), and tidal volume at normoxia (VT(0)). Probability levels < 0.05 were considered significant. All values reported are mean+/-SE.
Results
All fourteen subjects completed the normocapnic studies without problems or discomfort. Two subjects did not attend the hypercapnic session for unknown reasons; three others failed to complete the hypercapnic studies because of nausea and vomiting (two subjects) or discomfort (one subject). There were no signs of airway irritation, such as coughing, from desflurane during the studies.
Normocapnic Studies
End-tidal carbon dioxide tension averaged 43+/-0.8 mmHg in the control and desflurane studies. The mean end-tidal desflurane concentration was 0.71+/-0.01% in the desflurane studies. In the control studies, the CNS arousal state of all subjects was 0 (normal alertness), and in the desflurane studies, 4 subjects were at level 1 and 10 were at level 2.
The V with dotI-SPO2relation over the SPO2range tested by us (98 to approximately 70%) was linear (Figure 2). The hypoxic sensitivities obtained from the linear regression of V with dotIon (100 - SPO2) did not differ significantly between control and desflurane studies: 0.45+/-0.07 l *symbol* min sup- 1 *symbol* % sup -1 (control) versus 0.43+/-0.09 l *symbol* min sup -1 *symbol* % sup -1 (desflurane). Inspiratory minute ventilation averaged 11.8+/-0.6 l *symbol* min sup -1 in the control studies and 10.8+/-0.8 l *symbol* min sup -1 in the desflurane studies (not significant). In Figure 3, the hypoxic sensitivities of all subjects are collected in a scatter diagram. The three subjects that had an increase of their hypoxic sensitivity with desflurane had an CNS arousal score of 2. The values of the estimated parameters are listed in Table 1.
Figure 2. The effect of 0.1 minimum alveolar concentration desflurane on the normoisocapnic ventilatory response to hypoxia in two subjects (A [(open square) in Figure 3] and B [(closed triangle) in Figure 3]). Data points were obtained at end-tidal oxygen tension levels of 110, 75, 44, and 38 mmHg. Closed circles reflect control studies, open circles reflect desflurane studies. Left: V with dotIversus end-tidal oxygen tension. To guide the eye, an exponential function of the form A[exp(-D *symbol* PO2)] + k is fitted through the data points (solid line control, dotted line desflurane). Right: Inspired minute ventilation versus arterial hemoglobin-oxygen desaturation (100 - SPO2). Solid line = linear regression of control data points; dotted line = linear regression of desflurane data points.
Figure 2. The effect of 0.1 minimum alveolar concentration desflurane on the normoisocapnic ventilatory response to hypoxia in two subjects (A [(open square) in Figure 3] and B [(closed triangle) in Figure 3]). Data points were obtained at end-tidal oxygen tension levels of 110, 75, 44, and 38 mmHg. Closed circles reflect control studies, open circles reflect desflurane studies. Left: V with dotIversus end-tidal oxygen tension. To guide the eye, an exponential function of the form A[exp(-D *symbol* PO2)] + k is fitted through the data points (solid line control, dotted line desflurane). Right: Inspired minute ventilation versus arterial hemoglobin-oxygen desaturation (100 - SPO2). Solid line = linear regression of control data points; dotted line = linear regression of desflurane data points.
Figure 2. The effect of 0.1 minimum alveolar concentration desflurane on the normoisocapnic ventilatory response to hypoxia in two subjects (A [(open square) in Figure 3] and B [(closed triangle) in Figure 3]). Data points were obtained at end-tidal oxygen tension levels of 110, 75, 44, and 38 mmHg. Closed circles reflect control studies, open circles reflect desflurane studies. Left: V with dotIversus end-tidal oxygen tension. To guide the eye, an exponential function of the form A[exp(-D *symbol* PO2)] + k is fitted through the data points (solid line control, dotted line desflurane). Right: Inspired minute ventilation versus arterial hemoglobin-oxygen desaturation (100 - SPO2). Solid line = linear regression of control data points; dotted line = linear regression of desflurane data points.
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Figure 3. Left: Scatter diagram of the normocapnic hypoxic sensitivities (S in l *symbol* min sup -1 *symbol* % sup -1) of the control (abscissa) and desflurane (ordinate) studies of the 14 individual subjects. Right: Scatter diagram of the hypercapnic hypoxic sensitivities (S in l *symbol* min sup -1 *symbol* % sup -1) of the control (abscissa) and desflurane (ordinate) studies of the nine individual subjects. Dotted lines = the line of identity. Each subject is represented by the same unique symbol in the two diagrams
Figure 3. Left: Scatter diagram of the normocapnic hypoxic sensitivities (S in l *symbol* min sup -1 *symbol* % sup -1) of the control (abscissa) and desflurane (ordinate) studies of the 14 individual subjects. Right: Scatter diagram of the hypercapnic hypoxic sensitivities (S in l *symbol* min sup -1 *symbol* % sup -1) of the control (abscissa) and desflurane (ordinate) studies of the nine individual subjects. Dotted lines = the line of identity. Each subject is represented by the same unique symbol in the two diagrams
Figure 3. Left: Scatter diagram of the normocapnic hypoxic sensitivities (S in l *symbol* min sup -1 *symbol* % sup -1) of the control (abscissa) and desflurane (ordinate) studies of the 14 individual subjects. Right: Scatter diagram of the hypercapnic hypoxic sensitivities (S in l *symbol* min sup -1 *symbol* % sup -1) of the control (abscissa) and desflurane (ordinate) studies of the nine individual subjects. Dotted lines = the line of identity. Each subject is represented by the same unique symbol in the two diagrams
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Table 1. Effects of 0.1 MAC Desflurane on the Ventilatory Response to Hypoxia at a Background of Isonormocapnia and Isohypercapnia
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Table 1. Effects of 0.1 MAC Desflurane on the Ventilatory Response to Hypoxia at a Background of Isonormocapnia and Isohypercapnia
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Hypercapnic Studies
The hypoxic experiments were performed at a mean PETCO2background of 49+/-1 mmHg, approximately 8 mmHg above resting P sub ET CO2and 6 mmHg above the PETCO2level of the normocapnic studies. The end-tidal desflurane concentration averaged 0.72 +/-0.01% in the desflurane studies. In the control studies, the CNS arousal state of all subjects was 0 (normal alertness)l; in the desflurane studies, 4 subjects were at level 1, and 5 subjects were at level 2.
The slopes of the linear regression of V with dotIon (100 - SPO2) decreased from 0.74+/-0.09 l *symbol* min sup -1 *symbol* % sup -1 (control) to 0.53+/-0.06 1 *symbol* min sup -1 *symbol* % sup -1 (desflurane; P = 0.04). In Figure 3, the individual hypoxic sensitivities are plotted. Inspiratory minute ventilation did not differ significantly between treatments: 20.7+/-1.7 1 *symbol* min sup -1 and 20.9+/-1.6 l *symbol* min sup -1 in the control and desflurane studies, respectively. See Table 1for results of all estimates.
Discussion
In the current study, we observed that subanesthetic desflurane in a group of 14 healthy volunteers did not influence significantly the ventilatory response to isocapnic hypoxia over the range of 110 to 38 mmHg (SPO298 to approximately 70%) when experiments were performed against a background of normocapnia. This indicates that desflurane at 0.1 MAC lacks the well described and pronounced effect on the carotid bodies that the other inhalational anesthetic agents (halothane, isoflurane, and enflurane) possess. [2-6,10] Still, the carotid bodies did not remain unaffected by their exposure to 0.1 MAC desflurane, because the ventilatory response to the combination of hypoxia and hypercapnia (asphyxia) was reduced by 30%.
Critique of Methods
Control of Exhaled Gas Concentrations. To study the ventilatory response to acute hypoxia (i.e., hypoxia < 5 min), we used the computer-driven dynamic end-tidal forcing technique. [9] This allowed us to perform steps in PETO2while maintaining a constant PETCO2by manipulation of the inspired gas concentrations independently of the ventilatory response. The PETCO2was set at 2 mmHg above the resting values in the normocapnic studies and at 8 mmHg above resting in the hypercapnic studies. The reason for the increase in the normocapnic studies is twofold. First, a small increase in inspired carbon dioxide concentration is necessary to control the end-tidal carbon dioxide concentrations adequately. The precision of end-tidal PCO2control was 0.6 mmHg; that is, the standard deviation of the breath-to-breath PETCO2of single periods [A or B] was 0.6 mmHg or less. A similar precision of control was obtained for PETO2in periods A and B. Second, this procedure permits the control and drug baseline PETCO2's to be similar, despite differences in level of baseline V with dotI. Differences in PETCO2between control and drug studies make the interpretation of the results difficult, and sometimes impossible, because the additive or synergistic effects of separate stimuli (for example pH, arterial PCO2and PO2, or circulating catecholamines) on the measured response differ between treatments and may offset a specific drug effect. Other noncomputer-driven systems also are able to control end-tidal gas concentrations adequately to achieve near steps in PETO2at constant PETCO2(for example, see [11]).
Mask Versus Mouthpiece. The subjects were attached to the pneumotachograph through an oronasal mask. We prefer a mask above a mouthpiece-noseclip arrangement for two reasons. It allows normal movement of mouth and lips and is less disruptive to normal breathing. The fit of the mask was loose to prevent excessive pressure on the face. However, the combination of mask and pneumotachograph increased the dead space to approximately 200 ml. This, together with the increased PETCO2level, explains the higher baseline V with dotEof the normocapnic studies compared with studies that do not use a mask and/or inspired carbon dioxide. [1-7] .
Corrections for Changes in Inspired Oxygen Concentrations. Because of the changes in oxygen concentration of the inspired air, the viscosity of the inspired gas changes and, consequently, so does the flow measured through the pneumotachograph. As in previous studies, we performed an online correction for these changes in oxygen viscosity. [2-6] .
Step Hypoxic Test. We performed 3-min hypoxic steps in this study. It is our experience that peak V with dotIis reached in the first 3 min of hypoxia, when the drop in PETO2is achieved within 4-6 breaths and the control of PETCO2is strict. We tested four levels of hypoxia for two reasons: (1) It allows the study of the hypoxic response to a broad hypoxic range (SPO2down to approximately 70%); and (2) It reduces the intra-subject response variability. In previous studies, we determined the hypoxic response at a single PETO2level (approximately 44 mmHg). [2-6] Analysis of the single step test at PETO2approximately 44 mmHg in the current study showed, however, that similar conclusions are drawn from a single test in comparison to the multiple step test. In addition, because a single step test reduces study duration, this test may be preferable above multiple step tests to study the effects of drugs on the hypoxic response.
The obtained ventilatory step responses are the sum of different factors that determine V with dotIon exposure to hypoxia: (1) the hypoxic drive from the carotid bodies; [12] (2) the depressive effects of "central" hypoxia [12]; and (3) the hypoxic effect on the ventral medullary blood flow that determines the carbon dioxide tension at the site of the central chemo-receptors. [4,6,13] After 3 min of hypoxia specially, factors 1 and 3 are thought to be involved in determining the hypoxic response. Our measured responses, therefore, include some central (depressant) effect due to the increased brain blood flow (BBF) that may not have reached a steady state within 3 min. [13] .
The complete recovery from 20 min of hypoxia requires as long as 1 h of room air breathing or 7 min of breathing 100% O2. [14] When breathing room air after sustained hypoxia, a subsequent hypoxic response will be smaller in magnitude compared with the first one. This is most probably caused by non-BBF-related hypoxic depression. [14,15] A 3-min hypoxic episode generates hypoxic depression, [16] most of which is due to an increase in ventral medullary blood flow. However, we are unable to exclude an effect of non-BBF-related hypoxic depression on a subsequent hypoxic response in our study. A bias due to this effect was not observed. We relate this to the weak potency of non-BBF-related hypoxic depression generated during 3 min of hypoxia, the random order of the hypoxic levels, and the intra-subject response variability.
Analysis of V with dot I-O2 Data. The relation between V with dotIand PETO2obtained is nonlinear and were described using either hyperbolic or exponential functions, whereas linear functions were found empirically to describe the V with dotI-SPO2relation. [17-19] There is no physiologic reason to select one over the other. However, with a linear response, the sensitivity S should in principle be independent of the level of hypoxia at which it is determined, simplifying the method. In addition, when the number of data points is limited, the linear relation between V with dotIand SPO2, with only two parameters to estimate, is preferred. Using exponential, hyperbolic, or other nonlinear functions (see below) increases the number of parameters to estimate. With limited data, this reduces the reliability of estimation.
We observed that the isocapnic semi-steady-state relation between V with dotIand PETO2was curvilinear (Figure 2). It is of interest to discuss to some extent the linearity of the V with dotI-SPO2relation. To the best of our knowledge, there are no studies in which researchers investigated the linearity of the V with dotI-SPO2relation when V with dotIdata points are obtained under (semi)-steady-state conditions. In some of our subjects, we observed a convex relation between V with dotIand SPO2(e.g., subject A of Figure 2). Although not designed for this purpose, we tested the V with dotI-SPO2relation for nonlinearity. The data of individual responses were fitted to a second-order polynomial function of the form: Equation 2where H = [100 - SPO2], epsilon is a constant, beta is a first order parameter, and gamma is a second order parameter. If the data are adequately described by a linear model, the value of gamma is not different from zero. [20] Analysis of all 46 hypoxic responses revealed that nonlinearity occurred in only 6 responses (Figure 4). Although this seems to indicate that a linear function adequately describes the (semi)-steady-state V with dotI-SPO2relation (in the S sub P O2range from 98% to approximately 70%), further studies, using multiple responses in individual subjects on one day--to increase the reliability of the estimates--are necessary to clarify this matter. The finding that some of the V with dotI-SPO2responses are nonlinear does not affect our main conclusions.
Figure 4. Inspired minute ventilation (VI) versus arterial hemoglobin-oxygen desaturation [100 - SpO2]. A polynomial function of the form VI= beta H + gamma H2+ epsilon, where H = [100 - SpO2], is fitted through the data points. Parameter gamma was significantly different from zero in the control response of subject A. The other three responses were best described by a linear function (that is, parameter gamma was not different from zero). Solid circles and line show control; open circles and dotted line show desflurane.
Figure 4. Inspired minute ventilation (VI) versus arterial hemoglobin-oxygen desaturation [100 - SpO2]. A polynomial function of the form VI= beta H + gamma H2+ epsilon, where H = [100 - SpO2], is fitted through the data points. Parameter gamma was significantly different from zero in the control response of subject A. The other three responses were best described by a linear function (that is, parameter gamma was not different from zero). Solid circles and line show control; open circles and dotted line show desflurane.
Figure 4. Inspired minute ventilation (VI) versus arterial hemoglobin-oxygen desaturation [100 - SpO2]. A polynomial function of the form VI= beta H + gamma H2+ epsilon, where H = [100 - SpO2], is fitted through the data points. Parameter gamma was significantly different from zero in the control response of subject A. The other three responses were best described by a linear function (that is, parameter gamma was not different from zero). Solid circles and line show control; open circles and dotted line show desflurane.
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Desflurane Administration. As in previous studies, the drug studies were performed at a target concentration of 0.1 MAC (in the age group 18-30 yr, the MAC of desflurane is 7.2%). [7] Hypoxic studies began after a 10- to 15-min equilibration time at the target end-tidal desflurane concentration. Although the time constant for desflurane brain uptake at a constant end-tidal concentration is not reported, data in rabbits using in vivo nuclear magnetic resonance indicate that desflurane brain uptake is 1.7 times faster than isoflurane brain uptake. [21] The time constant for brain uptake at constant isoflurane concentration is 4 min. [22] Therefore, we estimated the time constant for desflurane brain uptake at approximately 2-2.5 min. The 10-min equilibration period, therefore, constitutes 4 to 5 times the estimated time constant. A similar equilibration period was selected in our previous studies on the effects of subanesthetic isoflurane on ventilatory control. [5,6] .
Sequence of Studies. The order of experiments was fixed to control before desflurane studies. We did not want to perform control and drug studies on separate days, because day-to-day variability of the hypoxic responses is greater than within-day variability. [23] A randomized crossover design on one day was not considered, because it leads to long sessions and subject discomfort, a possible influence of a drug experiment on a subsequent control experiment, and an increased run-to-run variability. Because of the structured nature of the study design, we were unable to exclude an order or time effect on the measured responses. However, such an effect favorably outweighs the influences of a randomized crossover design on single or separate days.
Normocapnic Studies
The individual desflurane hypoxic sensitivities as fraction of the control responses ranged between 0.02 and 2.0 (mean 0.91+/-0.14; Figure 3). The coefficient of variation was 57%, indicating the "large" intersubject variability. The difference in the outcome of the normocapnic studies compared with our previous findings with halothane and isoflurane is surprising, and may not be related to methodologic differences, because in this investigation, we used identical standards, as were used in previous studies regarding subject selection and preparation, randomization of drug and control experiments, the step hypoxic test, the magnitude of the inspired carbon dioxide concentration during the studies, the CNS arousal state of the subjects, the MAC-fraction studied, and the equilibration time for desflurane brain uptake (see Methods section and [2,3,5,6,24]).
We cannot exclude the fact that our data underestimated the effects of desflurane somewhat (type II error). Eliminating the four outliers from the normocapnic data pool (the subjects with closed symbols in Figure 3: SDES/SCON= 0.02, 1.6, 1.6, and 2.0) yielded a significant 13% reduction of the hypoxic response. This reduction is still less than observed with isoflurane and halothane in our laboratory (50% or more reduction of the hypoxic response at 0.1 MAC; Figure 5). [2,6] .
Figure 5. The influences of 0.1 minimum alveolar concentration halothane, isoflurane, and desflurane on the ventilatory response to isonormocapnic hypoxia as a percentage of control response. Values are mean+/-the 95% confidence interval. Halothane data are from Dahan et al., [2] isoflurane data are from van den Elsen et al., [5,6] and desflurane data are from the current study. AHR = acute hypoxic response.
Figure 5. The influences of 0.1 minimum alveolar concentration halothane, isoflurane, and desflurane on the ventilatory response to isonormocapnic hypoxia as a percentage of control response. Values are mean+/-the 95% confidence interval. Halothane data are from Dahan et al., [2]isoflurane data are from van den Elsen et al., [5,6]and desflurane data are from the current study. AHR = acute hypoxic response.
Figure 5. The influences of 0.1 minimum alveolar concentration halothane, isoflurane, and desflurane on the ventilatory response to isonormocapnic hypoxia as a percentage of control response. Values are mean+/-the 95% confidence interval. Halothane data are from Dahan et al., [2] isoflurane data are from van den Elsen et al., [5,6] and desflurane data are from the current study. AHR = acute hypoxic response.
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Three of the subjects had a normocapnic control response < 0.2 l *symbol* min sup -1 *symbol* % sup -1 (Figure 3). The average control normocapnic hypoxic sensitivity (0.45 l *symbol* min sup -1 *symbol* % sup -1) is low in comparison to one of our earlier studies on subanesthetic halothane (S = 0.9 l *symbol* min sup -1 *symbol* % sup -1). [2] It is possible that a group with a low hypoxic response makes a type II error more likely. For this reason, some investigators select subjects with high hypoxic responses. [11] However, the control responses of the current population volunteers are of similar magnitude in comparison to those of two groups of volunteers in studies on subanesthetic isoflurane (S = 0.54 and 0.44 l *symbol* min sup -1 *symbol* % sup -1). [5,6] In these studies, 0.1 MAC isoflurane caused a reduction of approximately 50% of the hypoxic responses.
Taking into account the above, a different effect of desflurane, compared to halothane and isoflurane, should be taken into consideration (for example, on the carotid bodies or on the CNS).
The ventilatory changes due to a sudden decrease in PETO sub 2 (step hypoxic test) are caused by an increase in tidal volume and respiratory rate. Halothane and isoflurane at 0.1 MAC reduce these increases of both ventilatory components. [2,5,6] Desflurane caused a reduction in Delta VT/Delta SpO2similar to that observed with isoflurane and halothane (Table 1). This indicates that low-dose desflurane had a depressant effect on the carotid bodies with respect to tidal volume. Conversely, the somewhat higher levels of RR in periods A and B compared with control counteracted the depression of tidal volume such that their product was not significantly different in control and desflurane studies. The sustained or even increased RR in normoxia and hypoxia may be related to stimulation of specific airway, lung, or systemic (for example, at the carotid bodies or within the CNS) receptors. [25] At high inspired concentrations, stimulation of these receptors causes transient increases in sympathetic activity. [8] The integrity of the hypoxic VIresponse with low-dose desflurane may be related to the stimulation of these receptors that trigger a central mechanism that counteracts depression of the peripheral chemoreceptors in terms of VI(for instance, by affecting rythmogenesis or increasing sympathetic activity).
Hypercapnic Studies
During hypercapnia, desflurane inhalation reduced the hypoxic sensitivities of 8 of the 9 subjects (individual desflurane hypoxic sensitivities as fraction of the control responses ranged between 0.42 and 1.0; mean 0.77+/-0.08; coefficient of variation 34%; Figure 3). Desflurane reduced the carbon dioxide-induced augmentation of the hypoxic ventilatory drive: increase of S from normocapnia to hypercapnia = 65% and 23% in the studies before and during desflurane inhalation, respectively. From our data, we were able to estimate the ventilatory carbon dioxide sensitivities in normoxia and hypoxia. Remember, however, that normocapnic and hypercapnic studies were performed on separate days. Performing experiments on different days increases the run-to-run variability. [23,26] The ratio of the carbon dioxide sensitivity obtained during desflurane inhalation to the control carbon dioxide sensitivity decreased from 1.1 to 0.87 and 0.78 at an SpO2of 97.5%, 80%, and 70%, respectively. Our findings suggest that desflurane affects the carbon dioxide-induced augmentation of the hypoxic response (which is mediated by the carotid bodies) [9] more than either the hypoxic or hypercapnic responses. This may be clinically of interest because the combination of hypercapnia and hypoxia may occur more frequently in perioperative patients than does hypoxia or hypercapnia alone.
The discrepant findings in the normocapnic and hypercapnic studies suggest that the translation of the oxygen-carbon dioxide interaction into VIat the carotid bodies involves a separate mechanism from the hypoxic response at normocapnia or mild hypercapnia. To the best of our knowledge, there are no studies to support this suggestion. Because we do not conceive the hypoxic response at high inspired carbon dioxide concentrations to involve a fundamentally different mechanism from the hypoxic response at low or no inspired carbon dioxide concentrations, we relate the inability to find a significant effect of 0.1 MAC desflurane in the normocapnic studies to a type II error. Clearly, the number of volunteers was too small to detect a small effect of subanesthetic desflurane on the hypoxic response. Inflation of the hypoxic response by carbon dioxide unearthed the depressant influence of desflurane.
In conclusion, we report that, in contrast with the results on subanesthetic halothane and isoflurane, subanesthetic desflurane has only a small effect on the normocapnic ventilatory response to hypoxia in healthy volunteers. In common with the other inhalational anesthetic agents, subanesthetic desflurane decreases the ventilatory response to asphyxia.
The authors thank Dr. John W. Severinghaus for suggestions concerning the design of the study and for critical reading of the manuscript.
REFERENCES
Lockhart SH, Rampil IJ, Yasuda N, Eger II EI, Weiskopf RB: Depression of ventilation by desflurane in humans. ANESTHESIOLOGY 1991; 74:484-8.
Dahan A, van den Elsen MJLJ, Berkenbosch A, DeGoede J, Olievier ICW, van Kleef JW, Bovill JG: Effects of subanesthetic halothane on the ventilatory response to hypercapnia and acute hypoxia in healthy volunteers. ANESTHESIOLOGY 1994; 80:727-38.
Dahan A, van den Elsen MJLJ, Berkenbosch A, DeGoede J, Olievier ICW, Burm AGL, van Kleef JW: Influence of a subanesthetic concentration of halothane on the ventilatory response to step changes into and out of sustained isocapnic hypoxia in healthy volunteers. ANESTHESIOLOGY 1994; 81:850-9.
Dahan A, van den Elsen MJLJ, Berkenbosch A, DeGoede J, Olievier ICW, van Kleef JW: Halothane affects ventilatory afterdischarge in humans. Br J Anaesth 1995; 74:544-8.
van den Elsen MJLJ, Dahan A, Berkenbosch A, DeGoede J, van Kleef JW, Olievier ICW: Does subanesthetic isoflurane affect the ventilatory response to acute hypoxia in healthy volunteers? ANESTHESIOLOGY 1994; 81:860-7.
van den Elsen MJLJ, Dahan A, DeGoede J, Berkenbosch A, van Kleef JW: Influences of subanesthetic isoflurane on ventilatory control in humans. ANESTHESIOLOGY 1995; 83:478-90.
Rampil IJ, Lockhart SH, Zwass MS, Peterson N, Yasuda N, Eger II EI, Weiskopf RB, Damask MC: Clinical characteristics of desflurane in surgical patients: Minimum alveolar concentration. ANESTHESIOLOGY 1991; 74:429-33.
Ebert TJ, Muzi M: Sympathetic hyperactivity during desflurane anesthesia in healthy volunteers: A comparison with isoflurane. ANESTHESIOLOGY 1993; 79:444-53.
Dahan A, DeGoede J, Berkenbosch A, Olievier ICW: The influence of oxygen on the ventilatory response to carbon dioxide in man. J Physiol (Lond) 1990; 428:485-99.
Nagyova B, Dorrington KL, Robbins PA: Effect of low-dose enflurane on the ventilatory response to hypoxia in humans. Br J Anaesth 1994; 72:509-14.
Eriksson LI, Sato M, Severinghaus JW: Effect of a vecuronium induced partial neuromuscular block on hypoxic ventilatory response. ANESTHESIOLOGY 1993; 78:693-9.
Vizek M, Pickett CK, Weil JV: Biphasic ventilatory response of adult cats to sustained hypoxia has central origin. J Appl Physiol 1987; 63:1658-64.
Suzuki A, Nishimura M, Yamamoto H, Miyamoto K, Kishi F, Kawakami Y: No effect of brain blood flow on ventilatory depression during sustained hypoxia. J Appl Physiol 1989; 66:1674-8.
Easton PA, Slykerman LJ, Anthonisen NR: Recovery of the ventilatory response to hypoxia in normal adults. J Appi Physiol 1988; 64:521-8.
Berkenbosch A, Dahan A, DeGoede J, Olievier ICW: The ventilatory response to CO sub 2 of the peripheral and central chemoreceptor loop before and after sustained hypoxia in man. J Physiol (Lond) 1992; 456:71-83.
Dahan A, Berkenbosch A, DeGoede J, van den Elsen M, Olievier I, van Kleef J: Influence of hypoxic duration and posthypoxic inspired Oxygen sub 2 concentration on short term potentiation of breathing in humans. J Physiol (Lond) 1995; 488:803-13.
Ward SA, Robbins PA: The ventilatory response to hypoxia. Physiological Society Study Guides: 3. The Control of Breathing in Man. Edited by Whipp BJ. Manchester, Manchester University, 1987, pp 29-44.
Kronenberg K, Hamilton FN, Gabel R, Hickey R, Read DJC, Severinghaus JW: Comparison of three methods for quantifying the respiratory response to hypoxia in man. Respir Physiol 1973; 16:109-25.
Ward DS, Dahan A, Mann CB: Modelling the dynamic ventilatory response to hypoxia in humans. Ann Biomed Eng 1992; 20:181-94.
Cole DJ, Kalichman MW, Shapiro HM, Drummond JC: The nonlinear potency of sub-MAC concentrations of nitrous oxide in decreasing the anesthetic requirements of enflurane, halothane, and isoflurane in rats. ANESTHESIOLOGY 1990; 73:93-9.
Lockhart SH, Cohen Y, Yasuda N, Freire B, Laheri S, Litt L, Eger El II: Cerebral uptake and elimination of desflurane, isoflurane, and halothane from rabbit brain: An in vivo NMR study. ANESTHESIOLOGY 1991; 74:575-80.
Eger EI II: Anesthetic Uptake and Action. Baltimore, Williams and Wilkins, 1974.
Sahn SA, Zwillich CW, Dick N, McCullough RE, Lakshiminarayan S, Weil JV: Variability of ventilatory responses to hypoxia and hypercapnia. J Appl Physiol 1977; 43:1019-25.
Robotham JL: Do low-dose inhalational anesthetic agents alter ventilatory control? (editorial). ANESTHESIOLOGY 1994; 80:723-6.
Weiskopf RB, Eger EI II, Daniel M, Noorani M: Cardiovascular stimulation induced by rapid increases in desflurane concentration in humans results from activation of tracheopulmonary and systemic receptors. ANESTHESIOLOGY 1995; 83:1173-8.
Berkenbosch A, Bovill JG, Dahan A, DeGoede J, Olievier ICW: The ventilatory CO sub 2 sensitivities from Read's rebreathing method and the steady-state method are not equal in man. J Physiol (Lond) 1989; 411:367-7727.
Figure 1. Schematic representation of 1 of 24 possible study sequences. The interludes between hypoxic episodes are 10-15 min.
Figure 1. Schematic representation of 1 of 24 possible study sequences. The interludes between hypoxic episodes are 10-15 min.
Figure 1. Schematic representation of 1 of 24 possible study sequences. The interludes between hypoxic episodes are 10-15 min.
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Figure 2. The effect of 0.1 minimum alveolar concentration desflurane on the normoisocapnic ventilatory response to hypoxia in two subjects (A [(open square) in Figure 3] and B [(closed triangle) in Figure 3]). Data points were obtained at end-tidal oxygen tension levels of 110, 75, 44, and 38 mmHg. Closed circles reflect control studies, open circles reflect desflurane studies. Left: V with dotIversus end-tidal oxygen tension. To guide the eye, an exponential function of the form A[exp(-D *symbol* PO2)] + k is fitted through the data points (solid line control, dotted line desflurane). Right: Inspired minute ventilation versus arterial hemoglobin-oxygen desaturation (100 - SPO2). Solid line = linear regression of control data points; dotted line = linear regression of desflurane data points.
Figure 2. The effect of 0.1 minimum alveolar concentration desflurane on the normoisocapnic ventilatory response to hypoxia in two subjects (A [(open square) in Figure 3] and B [(closed triangle) in Figure 3]). Data points were obtained at end-tidal oxygen tension levels of 110, 75, 44, and 38 mmHg. Closed circles reflect control studies, open circles reflect desflurane studies. Left: V with dotIversus end-tidal oxygen tension. To guide the eye, an exponential function of the form A[exp(-D *symbol* PO2)] + k is fitted through the data points (solid line control, dotted line desflurane). Right: Inspired minute ventilation versus arterial hemoglobin-oxygen desaturation (100 - SPO2). Solid line = linear regression of control data points; dotted line = linear regression of desflurane data points.
Figure 2. The effect of 0.1 minimum alveolar concentration desflurane on the normoisocapnic ventilatory response to hypoxia in two subjects (A [(open square) in Figure 3] and B [(closed triangle) in Figure 3]). Data points were obtained at end-tidal oxygen tension levels of 110, 75, 44, and 38 mmHg. Closed circles reflect control studies, open circles reflect desflurane studies. Left: V with dotIversus end-tidal oxygen tension. To guide the eye, an exponential function of the form A[exp(-D *symbol* PO2)] + k is fitted through the data points (solid line control, dotted line desflurane). Right: Inspired minute ventilation versus arterial hemoglobin-oxygen desaturation (100 - SPO2). Solid line = linear regression of control data points; dotted line = linear regression of desflurane data points.
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Figure 3. Left: Scatter diagram of the normocapnic hypoxic sensitivities (S in l *symbol* min sup -1 *symbol* % sup -1) of the control (abscissa) and desflurane (ordinate) studies of the 14 individual subjects. Right: Scatter diagram of the hypercapnic hypoxic sensitivities (S in l *symbol* min sup -1 *symbol* % sup -1) of the control (abscissa) and desflurane (ordinate) studies of the nine individual subjects. Dotted lines = the line of identity. Each subject is represented by the same unique symbol in the two diagrams
Figure 3. Left: Scatter diagram of the normocapnic hypoxic sensitivities (S in l *symbol* min sup -1 *symbol* % sup -1) of the control (abscissa) and desflurane (ordinate) studies of the 14 individual subjects. Right: Scatter diagram of the hypercapnic hypoxic sensitivities (S in l *symbol* min sup -1 *symbol* % sup -1) of the control (abscissa) and desflurane (ordinate) studies of the nine individual subjects. Dotted lines = the line of identity. Each subject is represented by the same unique symbol in the two diagrams
Figure 3. Left: Scatter diagram of the normocapnic hypoxic sensitivities (S in l *symbol* min sup -1 *symbol* % sup -1) of the control (abscissa) and desflurane (ordinate) studies of the 14 individual subjects. Right: Scatter diagram of the hypercapnic hypoxic sensitivities (S in l *symbol* min sup -1 *symbol* % sup -1) of the control (abscissa) and desflurane (ordinate) studies of the nine individual subjects. Dotted lines = the line of identity. Each subject is represented by the same unique symbol in the two diagrams
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Figure 4. Inspired minute ventilation (VI) versus arterial hemoglobin-oxygen desaturation [100 - SpO2]. A polynomial function of the form VI= beta H + gamma H2+ epsilon, where H = [100 - SpO2], is fitted through the data points. Parameter gamma was significantly different from zero in the control response of subject A. The other three responses were best described by a linear function (that is, parameter gamma was not different from zero). Solid circles and line show control; open circles and dotted line show desflurane.
Figure 4. Inspired minute ventilation (VI) versus arterial hemoglobin-oxygen desaturation [100 - SpO2]. A polynomial function of the form VI= beta H + gamma H2+ epsilon, where H = [100 - SpO2], is fitted through the data points. Parameter gamma was significantly different from zero in the control response of subject A. The other three responses were best described by a linear function (that is, parameter gamma was not different from zero). Solid circles and line show control; open circles and dotted line show desflurane.
Figure 4. Inspired minute ventilation (VI) versus arterial hemoglobin-oxygen desaturation [100 - SpO2]. A polynomial function of the form VI= beta H + gamma H2+ epsilon, where H = [100 - SpO2], is fitted through the data points. Parameter gamma was significantly different from zero in the control response of subject A. The other three responses were best described by a linear function (that is, parameter gamma was not different from zero). Solid circles and line show control; open circles and dotted line show desflurane.
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Figure 5. The influences of 0.1 minimum alveolar concentration halothane, isoflurane, and desflurane on the ventilatory response to isonormocapnic hypoxia as a percentage of control response. Values are mean+/-the 95% confidence interval. Halothane data are from Dahan et al., [2] isoflurane data are from van den Elsen et al., [5,6] and desflurane data are from the current study. AHR = acute hypoxic response.
Figure 5. The influences of 0.1 minimum alveolar concentration halothane, isoflurane, and desflurane on the ventilatory response to isonormocapnic hypoxia as a percentage of control response. Values are mean+/-the 95% confidence interval. Halothane data are from Dahan et al., [2]isoflurane data are from van den Elsen et al., [5,6]and desflurane data are from the current study. AHR = acute hypoxic response.
Figure 5. The influences of 0.1 minimum alveolar concentration halothane, isoflurane, and desflurane on the ventilatory response to isonormocapnic hypoxia as a percentage of control response. Values are mean+/-the 95% confidence interval. Halothane data are from Dahan et al., [2] isoflurane data are from van den Elsen et al., [5,6] and desflurane data are from the current study. AHR = acute hypoxic response.
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Table 1. Effects of 0.1 MAC Desflurane on the Ventilatory Response to Hypoxia at a Background of Isonormocapnia and Isohypercapnia
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Table 1. Effects of 0.1 MAC Desflurane on the Ventilatory Response to Hypoxia at a Background of Isonormocapnia and Isohypercapnia
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