Diederik Nieuwenhuijs

Sex differences in morphine analgesia: an experimental study in healthy volunteers.

BackgroundAnimal and human studies indicate the existence of important sex-related differences in opioid-mediated behavior. In this study the authors examined the influence of morphine on experimentally induced pain in healthy male and female volunteers. MethodsYoung healthy men and women (10 of each sex) received intravenous morphine (bolus 0.1-mg/kg dose followed by an infusion of 0.030 mg · kg−1 · h−1 for 1 h). Pain threshold and pain tolerance in response to a gradual increase in transcutaneous electrical stimulation, as well as plasma concentrations of morphine and its major metabolites (morphine-6-glucuronide and morphine-3-glucuronide) were determined at regular intervals up to 7 h after the start of morphine infusion. A population pharmacodynamic model was used to analyze the morphine-induced changes in stimulus intensity. The improvement of the model fits by inclusion of covariates (sex, age, weight, lean body mass) was tested for significance. The model is characterized by baseline current, a rate constant for equilibrium between plasma and effect-site morphine concentrations (ke0), and analgesic potency (AC50, or the morphine concentration causing a 100% increase in stimulus intensity for response). ResultsThe inclusion of the covariates age, weight, and lean body mass did not improve the model fits for any of the model parameters. For both pain threshold and tolerance, a significant dependency on sex was observed for the parameters ke0 (pain threshold: 0.0070 ± 0.0013 (± SE) min−1 in men vs. 0.0030 ± 0.0005 min−1 in women; pain tolerance: 0.0073 ± 0.0012 min−1 in men vs. 0.0024 ± 0.0005 min−1 in women) and AC50 (pain threshold: 71.2 ± 10.5 nm in men vs. 41.7 ± 8.4 nm in women; pain tolerance: 76.5 ± 7.4 nm in men vs. 32.9 ± 7.9 nm in women). Baseline currents were similar for both sexes: 21.4 ± 1.6 mA for pain threshold and 39.1 ± 2.3 mA for pain tolerance. Concentrations of morphine, morphine-3-glucuronide, and morphine-6-glucuronide did not differ between men and women. ConclusionsThese data show sex differences in morphine analgesia, with greater morphine potency but slower speed of onset and offset in women. The data are in agreement with observations of sex differences in morphine-induced respiratory depression and may explain higher postoperative opioid consumption in men relative to women.

Bispectral index values and spectral edge frequency at different stages of physiologic sleep.

Bispectral index (BIS) and spectral edge frequency (SEF) are used as measures of depth of anesthesia and sedation. We tested whether these signals could predict physiologic sleep stages, by taking processed electroencephalogram measurements and recording full polysomnography through a night’s sleep in 10 subjects being investigated for mild sleep apnea/hypopnea syndrome. Computerized polysomnograph signals were analyzed manually according to standard criteria, classifying each 30-s epoch as a specific sleep stage. The BIS and SEF values were taken at the end of each period of sleep when the same stage had lasted for at least 2 min. Before sleep, median values for BIS were 97 ± 12.1 and for SEF 23 ± 4.2 Hz. After sleep initiation, the median BIS values for arousal, light, slow wave, and rapid eye movement sleep were 67 ± 20.2, 50 ± 16.5, 42 ± 11.2, and 48 ± 7.1, respectively, and the median SEF values were 20 ± 4.7, 15 ± 3.6, 10 ± 2.6, and 19 ± 4.1 Hz, respectively. Although both BIS and SEF decreased with increasing sleep depth, the distribution of values at each sleep depth was considerable, with overlap between each sleep stage. Neither BIS nor SEF reliably indicated conventionally determined sleep stages. In addition, the response of the BIS was slow and patients could arouse with low BIS values, which then took some time to increase.

Response surface modeling of remifentanil-propofol interaction on cardiorespiratory control and bispectral index.

Background Since propofol and remifentanil are frequently combined for monitored anesthesia care, we examined the influence of the separate and combined administration of these agents on cardiorespiratory control and bispectral index in humans. Methods The effect of steady-state concentrations of remifentanil and propofol was assessed in 22 healthy male volunteer subjects. For each subject, measurements were obtained from experiments using remifentanil alone, propofol alone, and remifentanil plus propofol (measured arterial blood concentration range: propofol studies, 0–2.6 &mgr;g/ml; remifentanil studies, 0–2.0 ng/ml). Respiratory experiments consisted of ventilatory responses to three to eight increases in end-tidal Pco2 (Petco2). Invasive blood pressure, heart rate, and bispectral index were monitored concurrently. The nature of interaction was assessed by response surface modeling using a population approach with NONMEM. Values are population estimate plus or minus standard error. Results A total of 94 responses were obtained at various drug combinations. When given separately, remifentanil and propofol depressed cardiorespiratory variables in a dose-dependent fashion (resting &OV0312;i: 12.6 ± 3.3% and 27.7 ± 3.5% depression at 1 &mgr;g/ml propofol and 1 ng/ml remifentanil, respectively; &OV0312;i at fixed Petco2 of 55 mmHg: 44.3 ± 3.9% and 57.7 ± 3.5% depression at 1 &mgr;g/ml propofol and 1 ng/ml remifentanil, respectively; blood pressure: 9.9 ± 1.8% and 3.7 ± 1.1% depression at 1 &mgr;g/ml propofol and 1 ng/ml remifentanil, respectively). When given in combination, their effect on respiration was synergistic (greatest synergy observed for resting &OV0312;i). The effects of both drugs on heart rate and blood pressure were modest, with additive interactions when combined. Over the dose range studied, remifentanil had no effect on bispectral index even when combined with propofol (inert interaction). Conclusions These data show dose-dependent effects on respiration at relatively low concentrations of propofol and remifentanil. When combined, their effect on respiration is strikingly synergistic, resulting in severe respiratory depression.

Anesthetic potency and influence of morphine and sevoflurane on respiration in μ-opioid receptor knockout mice

Background The involvement of the &mgr;-opioid receptor (&mgr;OR) system in the control of breathing, anesthetic potency, and morphine- and anesthesia-induced respiratory depression was investigated in mice lacking the &mgr;OR. Methods Experiments were performed in mice lacking exon 2 of the &mgr;OR gene (&mgr;OR−/−) and their wild-type littermates (&mgr;OR+/+). The influence of saline, morphine, naloxone, and sevoflurane on respiration was measured using a whole body plethysmographic method during air breathing and elevations in inspired carbon dioxide concentration. The influence of morphine and naloxone on anesthetic potency of sevoflurane was determined by tail clamp test. Results Relative to wild-type mice, &mgr;OR-deficient mice displayed approximately 15% higher resting breathing frequencies resulting in greater resting ventilation levels. The slope of the ventilation–carbon dioxide response did not differ between genotypes. In &mgr;OR+/+ but not &mgr;OR−/− mice, a reduction in resting ventilation and slope, relative to placebo, was observed after 100 mg/kg morphine. Naloxone increased resting ventilation and slope in both genotypes. Sevoflurane at 1% inspired concentration induced similar reductions in resting ventilation and slope in the two genotypes. Anesthetic potency was 20% lower in mutant relevant to wild-type mice. Naloxone and morphine caused an increase and decrease, respectively, in anesthetic potency in &mgr;OR+/+ mice only. Conclusions The data indicate the importance of the endogenous opioid system in the physiology of the control of breathing with only a minor role for the &mgr;OR. The &mgr;OR gene is the molecular site of action of the respiratory effects of morphine. Anesthetic potency is modulated by the endogenous &mgr;-opioid system but not by the &kgr;- and &dgr;-opioid systems.

The involvement of the μ-opioid receptor in ketamine-induced respiratory depression and antinociception

N-methyl-d-aspartate receptor antagonism probably accounts for most of ketamine’s anesthetic effects; its analgesic properties are mediated partly via N-methyl-d-aspartate and partly via opioid receptors. We assessed the involvement of the &mgr;-opioid receptor in S(+) ketamine-induced respiratory depression and antinociception by performing dose-response curves in exon 2 &mgr;-opioid receptor knockout mice (MOR−/−) and their wild-type littermates (WT). The ventilatory response to increases in inspired CO2 was measured with whole body plethysmography. Two antinociceptive assays were used: the tail-immersion test and the hotplate test. S(+) ketamine (0, 10, 100, and 200 mg/kg intraperitoneally) caused a dose-dependent respiratory depression in both genotypes, with greater depression observed in WT relative to MOR−/− mice. At 200 mg/kg, S(+) ketamine reduced the slope of the hypercapnic ventilatory response by 93% ± 15% and 49% ± 6% in WT and MOR−/− mice, respectively (P < 0.001). In both genotypes, S(+) ketamine produced a dose-dependent increase in latencies in the hotplate test, with latencies in MOR−/− mice smaller compared with those in WT animals (P < 0.05). In contrast to WT mice, MOR−/− mice displayed no ketamine-induced antinociception in the tail-immersion test. These results indicate that at supraspinal sites S(+) ketamine interacts with the &mgr;-opioid system. This interaction contributes significantly to S(+) ketamine-induced respiratory depression and supraspinal antinociception.

Propofol for monitored anesthesia care: implications on hypoxic control of cardiorespiratory responses.

Background Hypoxia has a dual effect on ventilation: an initial period of hyperventilation, the acute hypoxic response, is followed after 3–5 min by a slow decline, the hypoxic ventilatory decline. Because of hypoxic ventilatory decline, subsequent acute hypoxic responses are depressed. In this study, the influence of a sedative concentration of propofol on ventilation was studied if hypoxia was sustained and intermittent. Methods Ten healthy young male volunteers performed two hypoxic tests without and with a target controlled infusion of propofol. The sustained hypoxic test consisted of 15 min of isocapnic hypoxia followed by 2 min of normoxia and 3 min of hypoxia. The test of hypoxic pulses involved six subsequent exposures to 3 min hypoxia followed by 2 min of normoxia. The bispectral index of the electroencephalogram was measured to obtain an objective measure of sedation. Results Blood propofol concentrations varied among subjects but were stable over time (mean blood concentration 0.6 &mgr;g/ml). The sustained hypoxic test showed that propofol decreased acute hypoxic response by ∼50% and that the magnitude of hypoxic ventilatory decline relative to acute hypoxic response was increased by > 50%. Propofol increased the depression of the acute hypoxic response after 15 min of hypoxia by ∼25%. In control and propofol studies, no hypoxic ventilatory decline was generated during exposure to hypoxic pulses. The bispectral index–acute hypoxic response data suggest that subjects were either awake (with minimal effect on acute hypoxic response) or sedated (with 50–60% reduction of acute hypoxic response). Conclusions The depression of acute hypoxic response results from an effect of propofol at peripheral or central sites involved in respiratory control or secondary to the induction of sedation or hypnosis by propofol. The relative increase in hypoxic ventilatory decline is possibly related to propofol’s action at the &ggr;-aminobutyric acid A (GABAA) receptor complex, causing increased GABAergic inhibition of ventilation during sustained (but not intermittent) hypoxia.

Response Surface Modeling of Alfentanil-Sevoflurane Interaction on Cardiorespiratory Control and Bispectral Index

Background Respiratory depression is a serious side effect of anesthetics and opioids. The authors examined the influence of the combined administration of sevoflurane and alfentanil on ventilatory control, heart rate (HR), and Bispectral Index (BIS) in healthy volunteers. Methods Step decreases in end-tidal partial pressure of oxygen from normoxia into hypoxia (∼50 mmHg) at constant end-tidal partial pressure of carbon dioxide (∼48 mmHg) were performed in nine male volunteers at various concentrations of alfentanil and sevoflurane, ranging from 0 to 50 ng/ml for alfentanil and from 0 to 0.4 end-tidal concentration (ET%) for sevoflurane, and with various combinations of alfentanil and sevoflurane. The alfentanil–sevoflurane interactions on normoxic resting (hypercapnic) ventilation (&OV0312;i), HR, hypoxic &OV0312;i, and HR responses and BIS were assessed by construction of response surfaces that related alfentanil and sevoflurane to effect using a population analysis. Results Concentration–effect relations were linear for alfentanil and sevoflurane. Synergistic interactions were observed for resting &OV0312;i and resting HR. Depression of &OV0312;i by 25% occurred at 38 ± 11 ng/ml alfentanil (population mean ± SE) and at 0.7 ± 0.4 ET% sevoflurane. One possibility for 25% reduction when alfentanil and sevoflurane are combined is 13.4 ng/ml alfentanil plus 0.12 ET% sevoflurane. Additive interactions were observed for hypoxic &OV0312;i and HR responses and BIS. Depression of the hypoxic &OV0312;i response by 25% occurred at 16 ± 1 ng/ml alfentanil and 0.14 ± 0.05 ET% sevoflurane. The effect of sevoflurane on the BIS (25% reduction of BIS occurred at 0.45 ± 0.08 ET%) was independent of the alfentanil concentration. Conclusions Response surface modeling was used successfully to analyze the effect of interactions between two drugs on respiration. The combination of alfentanil and sevoflurane causes more depression of &OV0312;i and HR than does the summed effect of each drug administered separately. The effects of combining alfentanil and sevoflurane on hypoxic &OV0312;i and HR responses and BIS could be predicted from the separate dose–response curves. Over the dose range tested, the hypoxic response is more sensitive to the effects of anesthetics and opioids relative to resting ventilation.

Respiratory sites of action of propofol : absence of depression of peripheral chemoreflex loop by low-dose propofol

BackgroundPropofol has a depressant effect on metabolic ventilatory control, causing depression of the ventilatory response to acute isocapnic hypoxia, a response mediated via the peripheral chemoreflex loop. In this study, the authors examined the effect of sedative concentrations of propofol on the dynamic ventilatory response to carbon dioxide to obtain information about the respiratory sites of action of propofol. MethodsIn 10 healthy volunteers, the end-tidal carbon dioxide concentration was varied according to a multifrequency binary sequence that involved 13 steps into and 13 steps out of hypercapnia (total duration, 1,408 s). In each subject, two control studies, two studies at a plasma target propofol concentration of 0.75 &mgr;g/ml (Plow), and two studies at a target propofol concentration of 1.5 &mgr;g/ml (Phigh) were performed. The ventilatory responses were separated into a fast peripheral component and a slow central component, characterized by a time constant, carbon dioxide sensitivity, and apneic threshold. Values are mean ± SD. ResultsPlasma propofol concentrations were approximately 0.5 &mgr;g/ml for Plow and approximately 1.3 mg/ml for Phigh. Propofol reduced the central carbon dioxide sensitivity from 1.5 ± 0.4 to 1.2 ± 0.3 (Plow;P < 0.01 vs. control) and 0.9 ± 0.1 l · min−1 · mmHg−1 (Phigh;P < 0.001 vs. control). The peripheral carbon dioxide sensitivity remained unaffected by propofol (control, 0.5 ± 0.3; Plow, 0.5 ± 0.2; Phigh, 0.5 ± 0.2 l · min−1 · mmHg−1). The apneic threshold was reduced from 36.3 ± 2.7 (control) to 35.0 ± 2.1 (Plow;P < 0.01 vs. control) and to 34.6 ± 1.9 mmHg (Phigh;P < 0.01 vs. control). ConclusionsSedative concentrations of propofol have an important effect on the control of breathing, showing depression of the ventilatory response to hypercapnia. The depression is attributed to an exclusive effect within the central chemoreflex loop at the central chemoreceptors. In contrast to low-dose inhalational anesthetics, the peripheral chemoreflex loop, when stimulated with carbon dioxide, remains unaffected by propofol.

Modeling the Non–Steady State Respiratory Effects of Remifentanil in Awake and Propofol-sedated Healthy Volunteers

Background:Few studies address the dynamic effect of opioids on respiration. Models with intact feedback control of carbon dioxide on ventilation (non–steady-state models) that correctly incorporate the complex interaction among drug concentration, end-tidal partial pressure of carbon dioxide concentration, and ventilation yield reliable descriptions and predictions of the behavior of opioids. The authors measured the effect of remifentanil on respiration and developed a model of remifentanil-induced respiratory depression. Methods:Ten male healthy volunteers received remifentanil infusions with different infusion speeds (target concentrations: 4–9 ng/ml; at infusion rates: 0.17–9 ng · ml−1 · min−1) while awake and at the background of low-dose propofol. The data were analyzed with a nonlinear model consisting of two additive linear parts, one describing the depressant effect of remifentanil and the other describing the stimulatory effect of carbon dioxide on ventilation. Results:The model adequately described the data including the occurrence of apnea. Most important model parameters were as follows: C50 for respiratory depression 1.6 ± 0.03 ng/ml, gain of the respiratory controller (G) 0.42 − 0.1 l · min−1 · Torr−1, and remifentanil blood effect site equilibration half-life (t½ke0) 0.53 ± 0.2 min. Propofol caused a 20–50% reduction of C50 and G but had no effect on t½ke0. Apnea occurred during propofol infusion only. A simulation study revealed an increase in apnea duration at infusion speeds of 2.5–0.5 ng · ml−1 · min−1 followed by a reduction. At an infusion speed of ≤ 0.31 ng · ml−1 · min−1, no apnea was seen. Conclusions:The effect of varying remifentanil infusions with and without a background of low-dose propofol on ventilation and end-tidal partial pressure of carbon dioxide concentration was described successfully using a non–steady-state model of the ventilatory control system. The model allows meaningful simulations and predictions.

Antioxidants prevent depression of the acute hypoxic ventilatory response by subanaesthetic halothane in men

We studied the effect of the antioxidants (AOX) ascorbic acid (2 g, I.V.) and α‐tocopherol (200 mg, P.O.) on the depressant effect of subanaesthetic doses of halothane (0.11 % end‐tidal concentration) on the acute isocapnic hypoxic ventilatory response (AHR), i.e. the ventilatory response upon inhalation of a hypoxic gas mixture for 3 min (leading to a haemoglobin saturation of 82 ± 1.8 %) in healthy male volunteers. In the first set of protocols, two groups of eight subjects each underwent a control hypoxic study, a halothane hypoxic study and finally a halothane hypoxic study after pretreatment with AOX (study 1) or placebo (study 2). Halothane reduced the AHR by more than 50 %, from 0.79 ± 0.31 to 0.36 ± 0.14 l min−1 %−1 in study 1 and from 0.79 ± 0.40 to 0.36 ± 0.19 l min−1 %−1 in study 2, P < 0.01 for both. Pretreatment with AOX prevented this depressant effect of halothane in the subjects of study 1 (AHR returning to 0.77 ± 0.32 l min−1 %−1, n.s. from control), whereas placebo (study 2) had no effect (AHR remaining depressed at 0.36 ± 0.27 l min−1 %−1, P < 0.01 from control). In a second set of protocols, two separate groups of eight subjects each underwent a control hypoxic study, a sham halothane hypoxic study and finally a sham halothane hypoxic study after pretreatment with AOX (study 3) or placebo (study 4). In studies 3 and 4, sham halothane did not modify the control hypoxic response, nor did AOX (study 3) or placebo (study 4). The 95 % confidence intervals for the ratio of hypoxic sensitivities, (AOX + halothane) : halothane in study 1 and (AOX ‐ sham halothane) : sham halothane in study 3, were [1.7, 2.6] and [1.0, 1.2], respectively. Because the antioxidants prevented the reduction of the acute hypoxic response by halothane, we suggest that this depressant effect may be caused by reactive species produced by a reductive metabolism of halothane during hypoxia or that a change in redox state of carotid body cells by the antioxidants prevented or changed the binding of halothane to its effect site. Our findings may also suggest that reactive species have an inhibiting effect on the acute hypoxic ventilatory response.