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Background: The N-methyl-D-aspartate receptor antagonist ketamine is metabolized in the liver into its active metabolite norketamine. No human data are available on the relative contribution of norketamine to ketamine-induced analgesia and side effects. One approach to assess the ketamine and norketamine contributions is by measuring the ketamine effect at varying ketamine and norketamine plasma concentrations using the CYP450 inducer rifampicin.Methods: In 12 healthy male volunteers the effect of rifampicin versus placebo pretreatment on S-ketamine-induced analgesia and cognition was quantified; the S-ketamine dosage was 20 mg/h for 2 h. The relative ketamine and norketamine contribution to effect was estimated using a linear additive population pharmacokinetic-pharmacodynamic model.Results: S-ketamine produced significant analgesia, psychotropic effects (drug high), and cognitive impairment (including memory impairment and reduced psychomotor speed, reaction time, and cognitive flexibility). Modeling revealed a negative contribution of S-norketamine to S-ketamine- induced analgesia and absence of contribution to cognitive impairment. At ketamine and norketamine effect concentrations of 100 ng/ml and 50 ng/ml, respectively, the ketamine contribution to analgesia is -3.8 cm (visual analog pain score) versus a contribution of norketamine of +1.5 cm, causing an overall effect of -2.3 cm. The blood-effect site equilibration half-life ranged from 0 (cognitive flexibility) to 11.8 (pain intensity) min and was 6.1 min averaged across all endpoints.Conclusions: This first observation that norketamine produces effects in the opposite direction of ketamine requires additional proof. It can explain the observation of ketamine-related excitatory phenomena (such as hyperalgesia and allodynia) upon the termination of ketamine infusions. [ABSTRACT FROM AUTHOR]

Background: Low-dose ketamine is used as analgesic for acute and chronic pain. It is metabolized in the liver to norketamine via cytochrome P450 (CYP) enzymes. There are few human data on the involvement of CYP enzymes on the elimination of norketamine and its possible contribution to analgesic effect. The aim of this study was to investigate the effect of CYP enzyme induction by rifampicin on the pharmacokinetics of S-ketamine and its major metabolite, S-norketamine, in healthy volunteers.Methods: Twenty healthy male subjects received 20 mg/70 kg/h (n = 10) or 40 mg/70 kg/h (n = 10) intravenous S-ketamine for 2 h after either 5 days oral rifampicin (once daily 600 mg) or placebo treatment. During and 3 h after drug infusion, arterial plasma concentrations of S-ketamine and S-norketamine were obtained at regular intervals. The data were analyzed with a compartmental pharmacokinetic model consisting of three compartments for S-ketamine, three sequential metabolism compartments, and two S-norketamine compartments using the statistical package NONMEM® 7 (ICON Development Solutions, Ellicott City, MD).Results: Rifampicin caused a 10% and 50% reduction in the area-under-the-curve of the plasma concentrations of S-ketamine and S-norketamine, respectively. The compartmental analysis indicated a 13% and 200% increase in S-ketamine and S-norketamine elimination from their respective central compartments by rifampicin.Conclusions: : A novel observation is the large effect of rifampicin on S-norketamine concentrations and indicates that rifampicin induces the elimination of S-ketamine's metabolite, S-norketamine, probably via induction of the CYP3A4 and/or CYP2B6 enzymes. [ABSTRACT FROM AUTHOR]

Background: Opioid-induced respiratory depression is antagonized effectively by the competitive opioid receptor antagonist naloxone. However, to fully understand the complex opioid agonist-antagonist interaction, the effects of various naloxone doses on morphine and morphine-6-glucuronide (M6G)-induced respiratory depression were studied in healthy volunteers.Methods: Twenty-four subjects received 0.15 mg/kg morphine intravenously at t = 0 followed by placebo, 200 or 400 microg naloxone at t = 30 min. Thirty-two subjects received 0.3 mg/kg M6G intravenously at t = 0 followed by placebo, 25, 100, or 400 microg naloxone at t = 55 min. There were a total of 8 subjects per treatment group. Respiration was measured on a breath-to-breath basis at constant end-tidal Pco2. A mechanism-based pharmacokinetic-pharmacodynamic model consisting of a part describing biophase equilibration and a part describing receptor association-dissociation kinetics was used to analyze the data.Results: Naloxone reversal of M6G-induced respiratory depression developed more slowly than reversal of the respiratory effect of morphine. A simulation study revealed that this was related to the slower receptor association-dissociation kinetics of M6G (koff M6G = 0.0327 +/- 0.00455 min versus morphine 0.138 +/- 0.0148 min; values are typical +/-SE). Duration of naloxone reversal was longer for M6G. This was related to the three- to fourfold greater potency of naloxone as an antagonist against M6G compared with morphine. Increasing the naloxone dose had no effect on the speed of reversal, but it did extend reversal duration.Conclusions: Naloxone reversal of the opioid effect is dependent on the receptor association-dissociation kinetics of the opioid that needs reversal with respect to the rate of reversal. The pharmacodynamics of naloxone determines reversal magnitude and duration. [ABSTRACT FROM AUTHOR]

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 x ml x min) 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 x min x Torr, and remifentanil blood effect site equilibration half-life (t(1/2)ke0) 0.53 +/- 0.2 min. Propofol caused a 20-50% reduction of C50 and G but had no effect on t(1/2)ke0. Apnea occurred during propofol infusion only. A simulation study revealed an increase in apnea duration at infusion speeds of 2.5-0.5 ng x ml x min followed by a reduction. At an infusion speed of < or = 0.31 ng x ml x min, 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. [ABSTRACT FROM AUTHOR]

Background: In previous studies, the authors reported on the absorption and disposition kinetics of levobupivacaine and ropivacaine. The current study was designed to develop a population pharmacokinetic-pharmacodynamic model capable of linking the kinetic data to the analgesic effects of these local anesthetics (i.e., sensory neural blockade).Methods: A disposition compartmental model was fitted to concentration data of the intravenously administered deuterium-labeled anesthetics, and a model consisting of two parallel absorption compartments and the identified disposition compartments was fitted to concentration data of the concomitantly epidurally administered unlabeled anesthetics. The epidural segments were modeled by individual central and peripheral absorption compartments and effect sites, which were fitted to the simultaneously acquired pinprick data. A covariate model incorporated the effects of age.Results: The threshold for epidural anesthesia increased from the lower to the higher segments. The central effect compartment equilibration half-lives were approximately 15 min for levobupivacaine and 25 min for ropivacaine. For levobupivacaine, age reduced the equilibration half-lives at all segments; for ropivacaine, age increased the anesthetic sensitivity at segments T12 and higher.Conclusions: A population pharmacokinetic-pharmacodynamic model was developed that quantitatively described sensory blockade during epidural anesthesia, including the effects of age. The model may be useful to individualize dose requirements, to predict the time course of sensory blockade, and to study new local anesthetics. [ABSTRACT FROM AUTHOR]

Background: The use of anesthetics may result in depression of the hypoxic ventilatory response. Since there are no receptor-specific antagonists for most anesthetics, there is the need for agnostic respiratory stimulants that increase respiratory drive irrespective of its cause. The authors tested whether ENA-001, an agnostic respiratory stimulant that blocks carotid body BK-channels, could restore the hypoxic ventilatory response during propofol infusion. They hypothesize that ENA-001 is able to fully restore the hypoxic ventilatory response., Methods: In this randomized, double-blind crossover trial, 14 male and female healthy volunteers were randomized to receive placebo and low- and high-dose ENA-001 on three separate occasions. On each occasion, isohypercapnic hypoxic ventilatory responses were measured during a fixed sequence of placebo, followed by low- and high-dose propofol infusion. The authors conducted a population pharmacokinetic/pharmacodynamic analysis that included oxygen and carbon dioxide kinetics., Results: Twelve subjects completed the three sessions; no serious adverse events occurred. The propofol concentrations were 0.6 and 2.0 µg/ml at low and high dose, respectively. The ENA-001 concentrations were 0.6 and 1.0 µg/ml at low and high dose, respectively. The propofol concentration that reduced the hypoxic ventilatory response by 50% was 1.47 ± 0.20 µg/ml. The steady state ENA-001 concentration to increase the depressed ventilatory response by 50% was 0.51 ± 0.04 µg/ml. A concentration of 1 µg/ml ENA-001 was required for full reversal of the propofol effect at the propofol concentration that reduced the hypoxic ventilatory response by 50%., Conclusions: In this pilot study, the authors demonstrated that ENA-001 restored the hypoxic ventilatory response impaired by propofol. This finding is not only of clinical importance but also provides mechanistic insights into the peripheral stimulation of breathing with ENA-001 overcoming central depression by propofol., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Anesthesiologists.)

Background: Oliceridine (Olinvyk) is a μ-opioid receptor agonist that in contrast to conventional opioids preferentially engages the G-protein-coupled signaling pathway. This study was designed to determine the utility function of oliceridine versus morphine based on neurocognitive tests and cold pressor test., Methods: The study had a randomized, double-blind, placebo-controlled, partial block three-way crossover design. Experiments were performed in 20 male and female volunteers. The subjects received intravenous oliceridine (1 or 3 mg; cohorts of 10 subjects/dose), morphine (5 or 10 mg; cohorts of 10 subjects/dose), or placebo on three separate occasions. Before and after dosing, neurocognitive tests, cold pressor test, and plasma drug concentrations were obtained at regular intervals. Population pharmacokinetic-pharmacodynamic analyses served as the basis for construction of a utility function, which is an objective function of probability of benefit minus probability of harm. Antinociception served as the measure of benefit, and slowing of saccadic peak velocity and increased body sway as the measures of neurocognitive harm., Results: The oliceridine and morphine C50 values, i.e., the effect-site concentrations causing 50% effect, were as follows: antinociception, 13 ± 2 and 23 ± 7 ng/ml; saccadic peak velocity, 90 ± 14 and 54 ± 15 ng/ml; and body sway, 10 ± 2 and 5.6 ± 0.8 ng/ml, respectively. The ratio oliceridine/morphine of the therapeutic indices, C50(benefit)/C50(harm), were 0.34 (95% CI, 0.17 to 0.7; P < 0.01) for saccadic peak velocity and 0.33 (0.16 to 0.50; P < 0.01) for body sway. The oliceridine utility was positive across the effect-site concentration 5 to 77 ng/ml, indicative of a greater probability of benefit than harm. The morphine utility was not significantly different from 0 from 0 to 100 ng/ml. Over the concentration range 15 to 50 ng/ml, the oliceridine utility was superior to that of morphine (P < 0.01). Similar observations were made for body sway., Conclusions: These data indicate that over the clinical concentration range, oliceridine is an analgesic with a favorable safety profile over morphine when considering analgesia and neurocognitive function., (Copyright © 2023 American Society of Anesthesiologists. All Rights Reserved.)

Opioids are effective analgesics, but they can have harmful adverse effects, such as addiction and potentially fatal respiratory depression. Naloxone is currently the only available treatment for reversing the negative effects of opioids, including respiratory depression. However, the effectiveness of naloxone, particularly after an opioid overdose, varies depending on the pharmacokinetics and the pharmacodynamics of the opioid that was overdosed. Long-acting opioids, and those with a high affinity at the µ-opioid receptor and/or slow receptor dissociation kinetics, are particularly resistant to the effects of naloxone. In this review, the authors examine the pharmacology of naloxone and its safety and limitations in reversing opioid-induced respiratory depression under different circumstances, including its ability to prevent cardiac arrest., (Copyright © 2023 American Society of Anesthesiologists. All Rights Reserved.)

Background: Balancing between opioid analgesia and respiratory depression continues to challenge clinicians in perioperative, emergency department, and other acute care settings. Morphine and hydromorphone are postoperative analgesic standards. Nevertheless, their comparative effects and side effects, timing, and respective variabilities remain poorly understood. This study tested the hypothesis that IV morphine and hydromorphone differ in onset, magnitude, duration, and variability of analgesic and ventilatory effects., Methods: The authors conducted a randomized crossover study in healthy volunteers. Forty-two subjects received a 2-h IV infusion of hydromorphone (0.05 mg/kg) or morphine (0.2 mg/kg) 1 to 2 weeks apart. The authors measured arterial opioid concentrations, analgesia in response to heat pain (maximally tolerated temperature, and verbal analog pain scores at discrete preset temperatures to determine half-maximum temperature effect), dark-adapted pupil diameter and miosis, end-expired carbon dioxide, and respiratory rate for 12 h after dosing., Results: For morphine and hydromorphone, respectively, maximum miosis was less (3.9 [3.4 to 4.2] vs. 4.6 mm [4.0 to 5.0], P < 0.001; median and 25 to 75% quantiles) and occurred later (3.1 ± 0.9 vs. 2.3 ± 0.7 h after infusion start, P < 0.001; mean ± SD); maximum tolerated temperature was less (49 ± 2 vs. 50 ± 2°C, P < 0.001); verbal pain scores at end-infusion at the most informative stimulus (48.2°C) were 82 ± 4 and 59 ± 3 (P < 0.001); maximum end-expired CO2 was 47 (45 to 50) and 48 mmHg (46 to 51; P = 0.007) and occurred later (5.5 ± 2.8 vs. 3.0 ± 1.5 h after infusion start, P < 0.001); and respiratory nadir was 9 ± 1 and 11 ± 2 breaths/min (P < 0.001), and occurred at similar times. The area under the temperature tolerance-time curve was less for morphine (1.8 [0.0 to 4.4]) than hydromorphone (5.4°C-h [1.6 to 12.1] P < 0.001). Interindividual variability in clinical effects did not differ between opioids., Conclusions: For morphine compared to hydromorphone, analgesia and analgesia relative to respiratory depression were less, onset of miosis and respiratory depression was later, and duration of respiratory depression was longer. For each opioid, timing of the various clinical effects was not coincident. Results may enable more rational opioid selection, and suggest hydromorphone may have a better clinical profile., (Copyright © 2023 American Society of Anesthesiologists. All Rights Reserved.)

Background: Oliceridine is a G protein-biased µ-opioid, a drug class that is associated with less respiratory depression than nonbiased opioids, such as morphine. The authors quantified the respiratory effects of oliceridine and morphine in elderly volunteers. The authors hypothesized that these opioids differ in their pharmacodynamic behavior, measured as effect on ventilation at an extrapolated end-tidal Pco2 at 55 mmHg, V̇E55., Methods: This four-arm double-blind, randomized, crossover study examined the respiratory effects of intravenous 0.5 or 2 mg oliceridine and 2 or 8 mg morphine in 18 healthy male and female volunteers, aged 55 to 89 yr, on four separate occasions. Participants' CYP2D6 genotypes were determined, hypercapnic ventilatory responses were obtained, and arterial blood samples were collected before and for 6 h after treatment. A population pharmacokinetic-pharmacodynamic analysis was performed on V̇E55, the primary endpoint; values reported are median ± standard error of the estimate., Results: Oliceridine at low dose was devoid of significant respiratory effects. High-dose oliceridine and both morphine doses caused a rapid onset of respiratory depression with peak effects occurring at 0.5 to 1 h after opioid dosing. After peak effect, compared with morphine, respiratory depression induced by oliceridine returned faster to baseline. The effect-site concentrations causing a 50% depression of V̇E55 were 29.9 ± 3.5 ng/ml (oliceridine) and 21.5 ± 4.6 ng/ml (morphine), the blood effect-site equilibration half-lives differed by a factor of 5: oliceridine 44.3 ± 6.1 min and morphine 214 ± 27 min. Three poor CYP2D6 oliceridine metabolizers exhibited a significant difference in oliceridine clearance by about 50%, causing higher oliceridine plasma concentrations after both low- and high-dose oliceridine, compared with the other participants., Conclusions: Oliceridine and morphine differ in their respiratory pharmacodynamics with a more rapid onset and offset of respiratory depression for oliceridine and a smaller magnitude of respiratory depression over time., (Copyright © 2023, the American Society of Anesthesiologists. All Rights Reserved.)

Background: Animal data suggest that the antidepressant and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor modulator tianeptine is able to prevent opioid-induced respiratory depression. The hypothesis was that oral or intravenous tianeptine can effectively prevent or counteract opioid-induced respiratory depression in humans., Methods: Healthy male and female volunteers participated in two studies that had a randomized, double blind, placebo-controlled, crossover design. First, oral tianeptine (37.5-, 50-, and 100-mg doses with 8 subjects) pretreatment followed by induction of alfentanil-induced respiratory depression (alfentanil target concentration, 100 ng/ml) was tested. Primary endpoint was ventilation at an extrapolated end-tidal carbon dioxide concentration of 55 mmHg (V̇E55). Next, the ability of four subsequent and increasing infusions of intravenous tianeptine (target tianeptine plasma concentrations 400, 1,000, 1,500, and 2,000 ng/ml, each given over 15 min) to counteract remifentanil-induced respiratory depression was determined in 15 volunteers. Ventilation was measured at isohypercpania (baseline ventilation 20 ± 2 l/min). The primary endpoint was minute ventilation during the 60 min of tianeptine versus placebo infusion., Results: Alfentanil reduced V̇E55 to 13.7 (95% CI, 8.6 to 18.8) l/min after placebo pretreatment and to 17.9 (10.2 to 25.7) l/min after 50-mg tianeptine pretreatment (mean difference between treatments 4.2 (-11.5 to 3.0) l/min, P = 0.070). Intravenous tianeptine in the measured concentration range of 500 to 2,000 ng/ml did not stimulate ventilation but instead worsened remifentanil-induced respiratory depression: tianeptine, 9.6 ± 0.8 l/min versus placebo 15.0 ± 0.9 l/min; mean difference, 5.3 l/min; 95% CI, 2.5 to 8.2 l/min; P = 0.001, after 1 h of treatment., Conclusions: Neither oral nor intravenous tianeptine were respiratory stimulants. Intravenous tianeptine over the concentration range of 500 to 2000 ng/ml worsened respiratory depression induced by remifentanil., (Copyright © 2022, the American Society of Anesthesiologists. All Rights Reserved.)

Background: Ketamine produces potent analgesia combined with psychedelic effects. It has been suggested that these two effects are associated and possibly that analgesia is generated by ketamine-induced dissociation. The authors performed a post hoc analysis of previously published data to quantify the pharmacodynamic properties of ketamine-induced antinociception and psychedelic symptoms. The hypothesis was that ketamine pharmacodynamics (i.e., concentration-effect relationship as well as effect onset and offset times) are not different for these two endpoints., Methods: Seventeen healthy male volunteers received escalating doses of S- and racemic ketamine on separate occasions. Before, during, and after ketamine infusion, changes in external perception were measured together with pain pressure threshold. A population pharmacokinetic-pharmacodynamic analysis was performed that took S- and R-ketamine and S- and R-norketamine plasma concentrations into account., Results: The pharmacodynamics of S-ketamine did not differ for antinociception and external perception with potency parameter (median [95% CI]) C50, 0.51 (0.38 to 0.66) nmol/ml; blood-effect site equilibration half-life, 8.3 [5.1 to 13.0] min), irrespective of administration form (racemic ketamine or S-ketamine). R-ketamine did not contribute to either endpoint. For both endpoints, S-norketamine had a small antagonistic effect., Conclusions: The authors conclude that their data support an association or connectivity between ketamine analgesia and dissociation. Given the intricacies of the study related to the pain model, measurement of dissociation, and complex modeling of the combination of ketamine and norketamine, it is the opinion of the authors that further studies are needed to detect functional connectivity between brain areas that produce the different ketamine effects., (Copyright © 2022, the American Society of Anesthesiologists. All Rights Reserved.)

Background: Several models describing the pharmacokinetics of ketamine are published with differences in model structure and complexity. A systematic review of the literature was performed, as well as a meta-analysis of pharmacokinetic data and construction of a pharmacokinetic model from raw data sets to qualitatively and quantitatively evaluate existing ketamine pharmacokinetic models and construct a general ketamine pharmacokinetic model., Methods: Extracted pharmacokinetic parameters from the literature (volume of distribution and clearance) were standardized to allow comparison among studies. A meta-analysis was performed on studies that performed a mixed-effect analysis to calculate weighted mean parameter values and a meta-regression analysis to determine the influence of covariates on parameter values. A pharmacokinetic population model derived from a subset of raw data sets was constructed and compared with the meta-analytical analysis., Results: The meta-analysis was performed on 18 studies (11 conducted in healthy adults, 3 in adult patients, and 5 in pediatric patients). Weighted mean volume of distribution was 252 l/70 kg (95% CI, 200 to 304 l/70 kg). Weighted mean clearance was 79 l/h (at 70 kg; 95% CI, 69 to 90 l/h at 70 kg). No effect of covariates was observed; simulations showed that models based on venous sampling showed substantially higher context-sensitive half-times than those based on arterial sampling. The pharmacokinetic model created from 14 raw data sets consisted of one central arterial compartment with two peripheral compartments linked to two venous delay compartments. Simulations showed that the output of the raw data pharmacokinetic analysis and the meta-analysis were comparable., Conclusions: A meta-analytical analysis of ketamine pharmacokinetics was successfully completed despite large heterogeneity in study characteristics. Differences in output of the meta-analytical approach and a combined analysis of 14 raw data sets were small, indicative that the meta-analytical approach gives a clinically applicable approximation of ketamine population parameter estimates and may be used when no raw data sets are available., (Copyright © 2020, the American Society of Anesthesiologists, Inc. All Rights Reserved.)

Background: To improve understanding of the respiratory behavior of oliceridine, a μ-opioid receptor agonist that selectively engages the G-protein-coupled signaling pathway with reduced activation of the β-arrestin pathway, the authors compared its utility function with that of morphine. It was hypothesized that at equianalgesia, oliceridine will produce less respiratory depression than morphine and that this is reflected in a superior utility., Methods: Data from a previous trial that compared the respiratory and analgesic effects of oliceridine and morphine in healthy male volunteers (n = 30) were reanalyzed. A population pharmacokinetic-pharmacodynamic analysis was performed and served as basis for construction of utility functions, which are objective functions of probability of analgesia, P(analgesia), and probability of respiratory depression, P(respiratory depression). The utility function = P(analgesia ≥ 0.5) - P(respiratory depression ≥ 0.25), where analgesia ≥ 0.5 is the increase in hand withdrawal latency in the cold pressor test by at least 50%, and respiratory depression ≥ 0.25 is the decrease of the hypercapnic ventilatory response by at least 25%. Values are median ± standard error of the estimate., Results: The two drugs were equianalgesic with similar potency values (oliceridine: 27.9 ± 4.9 ng/ml; morphine 34.3 ± 9.7 ng/ml; potency ratio, 0.81; 95% CI, 0.39 to 1.56). A 50% reduction of the hypercapnic ventilatory response by morphine occurred at an effect-site concentration of 33.7 ± 4.8 ng/ml, while a 25% reduction by oliceridine occurred at 27.4 ± 3.5 ng/ml (potency ratio, 2.48; 95% CI, 1.65 to 3.72; P < 0.01). Over the clinically relevant concentration range of 0 to 35 ng/ml, the oliceridine utility function was positive, indicating that the probability of analgesia exceeds the probability of respiratory depression. In contrast, the morphine function was negative, indicative of a greater probability of respiratory depression than analgesia., Conclusions: These data indicate a favorable oliceridine safety profile over morphine when considering analgesia and respiratory depression over the clinical concentration range.

Background: There is an ongoing need for potent opioids with less adverse effects than commonly used opioids. R-dihydroetorphine is a full opioid receptor agonist with relatively high affinity at the μ-, δ- and κ-opioid receptors and low affinity at the nociception/orphanin FQ receptor. The authors quantified its antinociceptive and respiratory effects in healthy volunteers. The authors hypothesized that given its receptor profile, R-dihydroetorphine will exhibit an apparent plateau in respiratory depression, but not in antinociception., Methods: The authors performed a population pharmacokinetic-pharmacodynamic study (Eudract registration No. 2009-010880-17). Four intravenous R-dihydroetorphine doses were studied: 12.5, 75, 125, and 150 ng/kg (infused more than 10 min) in 4 of 4, 6 of 6, 6 of 6, and 4 of 4 male subjects in pain and respiratory studies, respectively. The authors measured isohypercapnic ventilation, pain threshold, and tolerance responses to electrical noxious stimulation and arterial blood samples for pharmacokinetic analysis., Results: R-dihydroetorphine displayed a dose-dependent increase in peak plasma concentrations at the end of the infusion. Concentration-effect relationships differed significantly between endpoints. R-dihydroetorphine produced respiratory depression best described by a sigmoid EMAX-model. A 50% reduction in ventilation in between baseline and minimum ventilation was observed at an R-dihydroetorphine concentration of 17 ± 4 pg/ml (median ± standard error of the estimate). The maximum reduction in ventilation observed was at 33% of baseline. In contrast, over the dose range studied, R-dihydroetorphine produced dose-dependent analgesia best described by a linear model. A 50% increase in stimulus intensity was observed at 34 ± 11 pg/ml., Conclusions: Over the dose range studied, R-dihydroetorphine exhibited a plateau in respiratory depression, but not in analgesia. Whether these experimental advantages extrapolate to the clinical setting and whether analgesia has no plateau at higher concentrations than investigated requires further studies.

Background: The multidimensional index of nociception, the nociception level, outperforms blood pressure and heart rate in detection of nociceptive events during anesthesia. We hypothesized that nociception level-guided analgesia reduces opioid consumption and suboptimal anesthesia events such as low blood pressure and use of vasoactive medication., Methods: In this single-blinded randomized study, 80 American Society of Anesthesiologists class I-III adult patients of either sex, scheduled for major abdominal procedures under remifentanil/propofol anesthesia by target-controlled infusion, were included. During the procedure nociception level, noninvasive blood pressure, and heart rate were monitored. Patients were randomized to receive standard clinical care or nociception level-guided analgesia. In the nociception level-guided group, remifentanil concentration was reduced when index values were less than 10 or increased when values were above 25 for at least 1 min, in steps of 0.5 to 1.0 ng/ml. Propofol was titrated to bispectral index values between 45 and 55. The primary outcomes of the study were remifentanil and propofol consumption and inadequate anesthesia events., Results: Compared with standard care, remifentanil administration was reduced in nociception level-guided patients from (mean ± SD) 0.119 ± 0.033 to 0.086 ± 0.032 μg · kg · min (mean difference, 0.039 μg · kg · min; 95% CI, 0.025-0.052 μg · kg · min; P < 0.001). Among nociception level-guided patients, 2 of 40 (5%) experienced a hypotensive event (mean arterial pressure values less than 55 mm Hg) versus 11 of 40 (28%) patients in the control group (relative risk, 0.271; 95% CI, 0.08-0.77; P = 0.006). In the nociception level-guided group, 16 of 40 (40%) patients received vasoactive medication versus 25 of 40 (63%) patients in the standard care group (relative risk, 0.64; 95% CI, 0.40-0.99; P = 0.044)., Conclusions: Nociception level-guided analgesia during major abdominal surgery resulted in 30% less remifentanil consumption.

What We Already Know About This Topic: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: The pharmacokinetics of infused drugs have been modeled without regard for recirculatory or mixing kinetics. We used a unique ketamine dataset with simultaneous arterial and venous blood sampling, during and after separate S(+) and R(-) ketamine infusions, to develop a simplified recirculatory model of arterial and venous plasma drug concentrations., Methods: S(+) or R(-) ketamine was infused over 30 min on two occasions to 10 healthy male volunteers. Frequent, simultaneous arterial and forearm venous blood samples were obtained for up to 11 h. A multicompartmental pharmacokinetic model with front-end arterial mixing and venous blood components was developed using nonlinear mixed effects analyses., Results: A three-compartment base pharmacokinetic model with additional arterial mixing and arm venous compartments and with shared S(+)/R(-) distribution kinetics proved superior to standard compartmental modeling approaches. Total pharmacokinetic flow was estimated to be 7.59 ± 0.36 l/min (mean ± standard error of the estimate), and S(+) and R(-) elimination clearances were 1.23 ± 0.04 and 1.06 ± 0.03 l/min, respectively. The arm-tissue link rate constant was 0.18 ± 0.01 min, and the fraction of arm blood flow estimated to exchange with arm tissue was 0.04 ± 0.01., Conclusions: Arterial drug concentrations measured during drug infusion have two kinetically distinct components: partially or lung-mixed drug and fully mixed-recirculated drug. Front-end kinetics suggest the partially mixed concentration is proportional to the ratio of infusion rate and total pharmacokinetic flow. This simplified modeling approach could lead to more generalizable models for target-controlled infusions and improved methods for analyzing pharmacokinetic-pharmacodynamic data.

Background: Previous studies integrated opioid benefit and harm into one single function-the utility function-to determine the drug toxicity (respiratory depression) in light of its wanted effect (analgesia). This study further refined the concept of the utility function using the respiratory and analgesic effects of the opioid analgesic alfentanil as example., Methods: Data from three previous studies in 48 healthy volunteers were combined and reanalyzed using a population pharmacokinetic-pharmacodynamic analysis to create utility probability functions. Four specific conditions were defined: probability of adequate analgesia without severe respiratory depression, probability of adequate analgesia with severe respiratory depression, probability of inadequate analgesia without severe respiratory depression, and probability of inadequate analgesia with severe respiratory depression., Results: The four conditions were successfully identified with probabilities varying depending on the opioid effect-site concentration. The optimum analgesia probability without serious respiratory depression is reached at an alfentanil effect-site concentration of 68 ng/ml, and exceeds the probability of the most unwanted effect, inadequate analgesia with severe respiratory depression (odds ratio, 4.0). At higher effect-site concentrations the probability of analgesia is reduced and exceeded by the probability of serious respiratory depression., Conclusions: The utility function was successfully further developed, allowing assessment of specific conditions in terms of wanted and unwanted effects. This approach can be used to compare the toxic effects of drugs relative to their intended effect and may be a useful tool in the development of new compounds to assess their advantage over existing drugs.

Background: Esketamine is traditionally administered via intravenous or intramuscular routes. In this study we developed a pharmacokinetic model of inhalation of nebulized esketamine with special emphasis on pulmonary absorption and bioavailability., Methods: Three increasing doses of inhaled esketamine (dose escalation from 25 to 100 mg) were applied followed by a single intravenous dose (20 mg) in 19 healthy volunteers using a nebulizer system and arterial concentrations of esketamine and esnorketamine were obtained. A multicompartmental pharmacokinetic model was developed using population nonlinear mixed-effects analyses., Results: The pharmacokinetic model consisted of three esketamine, two esnorketamine disposition and three metabolism compartments. The inhalation data were best described by adding two absorption pathways, an immediate and a slower pathway, with rate constant 0.05 ± 0.01 min (median ± SE of the estimate). The amount of esketamine inhaled was reduced due to dose-independent and dose-dependent reduced bioavailability. The former was 70% ± 5%, and the latter was described by a sigmoid EMAX model characterized by the plasma concentration at which absorption was impaired by 50% (406 ± 46 ng/ml). Over the concentration range tested, up to 50% of inhaled esketamine is lost due to the reduced dose-independent and dose-dependent bioavailability., Conclusions: We successfully modeled the inhalation of nebulized esketamine in healthy volunteers. Nebulized esketamine is inhaled with a substantial reduction in bioavailability. Although the reduction in dose-independent bioavailability is best explained by retention of drug and particle exhalation, the reduction in dose-dependent bioavailability is probably due to sedation-related loss of drug into the air.

Background: Pharmacokinetic and pharmacodynamic models are used to predict and explore drug infusion schemes and their resulting concentration profiles for clinical application. Our aim was to develop a pharmacokinetic-pharmacodynamic model for remifentanil that is accurate in patients with a wide range of age and weight., Methods: Remifentanil pharmacokinetic data were obtained from three previously published studies of adults and children, one of which also contained pharmacodynamic data from adults. NONMEM was used to estimate allometrically scaled compartmental pharmacokinetic and pharmacodynamic models. Weight, age, height, sex, and body mass index were explored as covariates. Predictive performance was measured across young children, children, young adults, middle-aged, and elderly., Results: Overall, 2,634 remifentanil arterial concentration and 3,989 spectral-edge frequency observations from 131 individuals (55 male, 76 female) were analyzed. Age range was 5 days to 85 yr, weight range was 2.5 to 106 kg, and height range was 49 to 193 cm. The final pharmacokinetic model uses age, weight, and sex as covariates. Parameter estimates for a 35-yr-old, 70-kg male (reference individual) are: V1, 5.81 l; V2, 8.82 l; V3, 5.03 l; CL, 2.58 l/min; Q2, 1.72 l/min; and Q3, 0.124 l/min. Parameters mostly increased with fat-free mass and decreased with age. The pharmacodynamic model effect compartment rate constant (ke0) was 1.09 per minute (reference individual), which decreased with age., Conclusions: We developed a pharmacokinetic-pharmacodynamic model to predict remifentanil concentration and effect for a wide range of patient ages and weights. Performance exceeded the Minto model over a wide age and weight range.

Background: Cebranopadol is a novel strong analgesic that coactivates the nociceptin/orphanin FQ receptor and classical opioid receptors. There are indications that activation of the nociceptin/orphanin FQ receptor is related to ceiling in respiratory depression. In this phase 1 clinical trial, we performed a pharmacokinetic-pharmacodynamic study to quantify cebranopadol's respiratory effects., Methods: Twelve healthy male volunteers received 600 μg oral cebranopadol as a single dose. The following main endpoints were obtained at regular time intervals for 10 to 11 h after drug intake: ventilation at an elevated clamped end-tidal pressure of carbon dioxide, pain threshold and tolerance to a transcutaneous electrical stimulus train, and plasma cebranopadol concentrations. The data were analyzed using sigmoid Emax (respiration) and power (antinociception) models., Results: Cebranopadol displayed typical opioid-like effects including miosis, analgesia, and respiratory depression. The blood-effect-site equilibration half-life for respiratory depression and analgesia was 1.2 ± 0.4 h (median ± standard error of the estimate) and 8.1 ± 2.5 h, respectively. The effect-site concentration causing 50% respiratory depression was 62 ± 4 pg/ml; the effect-site concentration causing 25% increase in currents to obtain pain threshold and tolerance was 97 ± 29 pg/ml. The model estimate for minimum ventilation was greater than zero at 4.9 ± 0.7 l/min (95% CI, 3.5 to 6.6 l/min)., Conclusions: At the dose tested, cebranopadol produced respiratory depression with an estimate for minimum ventilation greater than 0 l/min. This is a major advantage over full μ-opioid receptor agonists that will produce apnea at high concentrations. Further clinical studies are needed to assess whether such behavior persists at higher doses.

Background: Respiratory depression is a potentially fatal complication of opioid use, which may be exacerbated by simultaneous ethanol intake. In this three-way sequential crossover dose-escalating study, the influence of coadministration of oral oxycodone and intravenous ethanol was assessed on resting ventilation, apneic events and the hypercapnic ventilatory response in healthy young and older volunteers., Methods: Twelve young (21 to 28 yr) and 12 elderly (66 to 77 yr) opioid-naive participants ingested one 20 mg oxycodone tablet combined with an intravenous infusion of 0, 0.5, or 1 g/l ethanol. Resting respiratory variables and the primary outcome, minute ventilation at isohypercapnia (end-tidal partial pressure of carbon dioxide of 55 mmHg or VE55), were obtained at regular intervals during treatment., Results: Oxycodone reduced baseline minute ventilation by 28% (P < 0.001 vs. control). Ethanol caused a further decrease of oxycodone-induced respiratory depression by another 19% at 1 g/l ethanol plus oxycodone (P < 0.01 vs. oxycodone). Ethanol combined with oxycodone caused a significant increase in the number of apneic events measured in a 6-min window with a median (range) increase from 1 (0 to 3) at 0 g/l ethanol to 1 (0 to 11) at 1 g/l ethanol (P < 0.01). Mean (95% CI) VE55 decreased from 33.4 (27.9 to 39.0) l/min (control) to 18.6 (15.6 to 21.6) l/min (oxycodone, P < 0.01 vs. control) and to 15.7 (12.7 to 18.6) l/min (oxycodone combined with ethanol, 1 g/l; P < 0.01 vs. oxycodone)., Conclusions: Ethanol together with oxycodone causes greater ventilatory depression than either alone, the magnitude of which is clinically relevant. Elderly participants were more affected than younger volunteers.

Introduction: Integrating opioid risk and benefit into a single function may give a useful single measure of the opioid's positive and negative effects. An explorative study on the effects of fentanyl on antinociception and respiratory depression was performed to construct fentanyl risk-benefit (utility) functions., Methods: Twelve volunteers received a 3.5-μg/kg fentanyl intravenous injection on 2 separate study days. On one occasion, ventilation at a clamped increased carbon dioxide concentration was measured and on another the pain tolerance to electrical stimulation. In both sessions, arterial plasma samples were obtained. The data were analyzed with a population pharmacokinetic-pharmacodynamic model. A simulation study was performed, using the model parameter estimates and their variances, in which simulated subjects received 3.5 μg/kg of fentanyl. The resultant distributions were used to calculate the utility functions, defined as the probability of at least 50% analgesia (an increase in pain tolerance by ≥50%) minus the probability of at least 50% respiratory depression (a reduction in ventilation by ≥50%). Utility functions were constructed in concentration and time domains., Results: Fentanyl produced significant respiratory depression and analgesia. The pharmacokinetic and pharmacodynamic models adequately described the data. The constructed utility functions were negative at effect-site concentrations of greater than 0.5 ng/ml in the first 90 min after the 3.5 μg/kg bolus infusion., Conclusions: Utility functions based on fentanyl's experimental effects on respiration and pain relief were successfully constructed. These functions are useful in multiple effect comparisons among experimental drugs. Further studies are required to assess whether this risk-benefit analysis is valuable in clinical practice.

Background: The objective of this investigation was to examine the ability of the opioid antagonist naloxone to reverse respiratory depression produced by the mu-opioid analgesic, buprenorphine, in healthy volunteers. The studies were designed in light of the claims that buprenorphine is relatively resistant to the effects of naloxone., Methods: In a first attempt, the effect of an intravenous bolus dose of 0.8 mg naloxone was assessed on 0.2 mg buprenorphine-induced respiratory depression. Next, the effect of increasing naloxone doses (0.5-7 mg, given over 30 min) on 0.2 mg buprenorphine-induced respiratory depression was tested. Subsequently, continuous naloxone infusions were applied to reverse respiratory depression from 0.2 and 0.4 mg buprenorphine. All doses are per 70 kg. Respiration was measured against a background of constant increased end-tidal carbon dioxide concentration., Results: An intravenous naloxone dose of 0.8 mg had no effect on respiratory depression from buprenorphine. Increasing doses of naloxone given over 30 min produced full reversal of buprenorphine effect in the dose range of 2-4 mg naloxone. Further increasing the naloxone dose (doses of 5 mg or greater) caused a decline in reversal activity. Naloxone bolus doses of 2-3 mg, followed by a continuous infusion of 4 mg/h, caused full reversal within 40-60 min of both 0.2 and 0.4 mg buprenorphine-induced respiratory depression., Conclusions: Reversal of buprenorphine effect is possible but depends on the buprenorphine dose and the correct naloxone dose window. Because respiratory depression from buprenorphine may outlast the effects of naloxone boluses or short infusions, a continuous infusion of naloxone may be required to maintain reversal of respiratory depression.

Background: The objective of this investigation was to characterize the pharmacokinetic-pharmacodynamic relation of buprenorphine's antinociceptive effect in healthy volunteers., Methods: Data on the time course of the antinociceptive effect after intravenous administration of 0.05-0.6 mg/70 kg buprenorphine in healthy volunteers was analyzed in conjunction with plasma concentrations by nonlinear mixed-effects analysis., Results: A three-compartment pharmacokinetic model best described the concentration time course. Four structurally different pharmacokinetic-pharmacodynamic models were evaluated for their appropriateness to describe the time course of buprenorphine's antinociceptive effect: (1) E(max) model with an effect compartment model, (2) "power" model with an effect compartment model, (3) receptor association-dissociation model with a linear transduction function, and (4) combined biophase equilibration/receptor association-dissociation model with a linear transduction function. The latter pharmacokinetic-pharmacodynamic model described the time course of effect best and was used to explain time dependencies in buprenorphine's pharmacodynamics. The model converged, yielding precise estimation of the parameters characterizing hysteresis and the relation between relative receptor occupancy and antinociceptive effect. The rate constant describing biophase equilibration (k(eo)) was 0.00447 min(-1) (95% confidence interval, 0.00299-0.00595 min(-1)). The receptor dissociation rate constant (k(off)) was 0.0785 min(-1) (95% confidence interval, 0.0352-0.122 min(-1)), and k(on) was 0.0631 ml . ng(-1) . min(-1) (95% confidence interval, 0.0390-0.0872 ml . ng(-1) . min(-1))., Conclusion: This is consistent with observations in rats, suggesting that the rate-limiting step in the onset and offset of the antinociceptive effect is biophase distribution rather than slow receptor association-dissociation. In the dose range studied, no saturation of receptor occupancy occurred explaining the lack of a ceiling effect for antinociception.

Background: To study the influence of morphine on chemical control of breathing relative to the analgesic properties of morphine, the authors quantified morphine-induced analgesia and respiratory depression in a single group of healthy volunteers. Both respiratory and pain measurements were performed over single 24-h time spans., Methods: Eight subjects (four men, four women) received a 90-s intravenous morphine infusion; eight others (four men, four women) received a 90-s placebo infusion. At regular time intervals, respiratory variables (breathing at a fixed end-tidal partial pressure of carbon dioxide of 50 mmHg and the isocapnic acute hypoxic response), pain tolerance (derived from a transcutaneous electrical acute pain model), and arterial blood samples were obtained. Data acquisition continued for 24 h. Population pharmacokinetic (sigmoid Emax)-pharmacodynamic models were applied to the respiratory and pain data. The models are characterized by potency parameters, shape parameters (gamma), and blood-effect site equilibration half-lives. All collected data were analyzed simultaneously using the statistical program NONMEM., Results: Placebo had no systematic effect on analgesic or respiratory variables. Morphine potency parameter and blood-effect site equilibration half-life did not differ significantly among the three measured effect parameters (P > 0.01). The integrated NONMEM analysis yielded a potency parameter of 32 +/- 1.4 nm (typical value +/- SE) and a blood-effect site equilibration half-life of 4.4 +/- 0.3 h. Parameter gamma was 1 for hypercapnic and hypoxic breathing but 2.4 +/- 0.7 for analgesia (P < 0.01)., Conclusions: Our data indicate that systems involved in morphine-induced analgesia and respiratory depression share important pharmacodynamic characteristics. This suggests similarities in central mu-opioid analgesic and respiratory pathways (e.g., similarities in mu-opioid receptors and G proteins). The clinical implication of this study is that after morphine administration, despite lack of good pain relief, moderate to severe respiratory depression remains possible.

Background: Morphine-6-glucuronide (M6G) is a metabolite of morphine and a micro-opioid agonist. To quantify the potency and speed of onset-offset of M6G and explore putative sex dependency, the authors studied the pharmacokinetics and pharmacodynamics of M6G in volunteers using a placebo-controlled, randomized, double-blind study design., Methods: Ten men and 10 women received 0.3 mg/kg intravenous M6G and placebo (two thirds of the dose as bolus, one third as a continuous infusion over 1 h) on separate occasions. For 7 h, pain tolerance was measured using gradually increasing transcutaneous electrical stimulation, and blood samples were obtained. A population pharmacokinetic (inhibitory sigmoid Emax)-pharmacodynamic analysis was used to analyze M6G-induced changes in tolerated stimulus intensity. The improvement in model fits by inclusion of covariate sex was tested for significance. P values less than 0.01 were considered significant. Taking into account previous morphine data, a predictive pharmacokinetic-pharmacodynamic model was constructed to determine the contribution of M6G to morphine analgesia., Results: M6G concentrations did not differ between men and women. M6G caused analgesia significantly greater than that observed with placebo (P < 0.01). The M6G analgesia data were well described by the pharmacokinetic-pharmacodynamic model. The M6G effect site concentration causing a 25% increase in current (C25) was 275 +/- 135 nm (population estimate +/- SE), the blood effect site equilibration half-life was 6.2 +/- 3.3 h, and the steepness parameter was 0.71 +/- 0.18. Intersubject variability was 167% for C25 and 218% for the effect half-life. None of the model parameters showed sex dependency., Conclusions: A cumulative dose of 0.3 mg/kg M6G, given over 1 h, produces long-term analgesia greater than that observed with placebo, with equal dynamics (potency and speed of onset-offset) in men and women. Possible causes for the great intersubject response variability, such as genetic polymorphism of the micro-opioid receptor and placebo-related phenomena, are discussed. The predictive pharmacokinetic-pharmacodynamic model was applied successfully and was used to estimate M6G analgesia after morphine in patients with normal and impaired renal function.

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 microg/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 V(i) : 12.6 +/- 3.3% and 27.7 +/- 3.5% depression at 1 microg/ml propofol and 1 ng/ml remifentanil, respectively; V(i) at fixed Petco of 55 mmHg: 44.3 +/- 3.9% and 57.7 +/- 3.5% depression at 1 microg/ml propofol and 1 ng/ml remifentanil, respectively; blood pressure: 9.9 +/- 1.8% and 3.7 +/- 1.1% depression at 1 microg/ml propofol and 1 ng/ml remifentanil, respectively). When given in combination, their effect on respiration was synergistic (greatest synergy observed for resting V(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.

Background: The authors modeled the influence of remifentanil on the dynamics of sevoflurane using three parameters derived from the electroencephalogram: 95% spectral edge frequency (SEF), canonical univariate parameter (CUP), and Bispectral Index (BIS)., Methods: Thirty-six patients with American Society of Anesthesiologists physical status class I or II were recruited, of which 12 received a target remifentanil concentration of 0 ng/ml, eight 2 ng/ml, eight 4 ng/ml, and another eight 8 ng/ml. Next (before surgery), several step-wise changes in the end-tidal sevoflurane concentration (F(ET,sevo)) were performed. A data acquisition system simultaneously recorded F(ET,sevo), the raw electroencephalogram, BIS, and SEF. The authors used a combination of an effect compartment and an inhibitory sigmoid E(MAX) model to describe the relation between F(ET,sevo) and BIS, SEF, and CUP. Model parameters (t(1/2)k(e0), E(MAX), E(MIN), C(50), gamma, CUP weight factors) were estimated using the population data analysis program NONMEM. Significant remifentanil model parameter dependencies (P < 0.01) were determined., Results: Determined from SEF, remifentanil had no effect on t(1/2)k(e0) (1.91 +/- 0.26 min [mean +/- standard error]) but caused an increase in C(50) (baseline = 1.48 +/- 0.12%; 80% increase at 8 ng/ml) and decrease in E(MIN) (baseline = 10.8 +/- 0.6 Hz; 80% reduction at 8 ng/ml). Determined from CUP, remifentanil caused a dose-dependent decrease in t(1/2)k(e0) (baseline = 4.31 +/- 1.00 min; 60% decrease at 8 ng/ml), with no effect on C(50) (baseline = 0.88 +/- 0.13%). Determined from BIS, remifentanil caused a dose-dependent decrease in t(1/2)k(e0) (baseline value = 3.11 +/- 0.32 min; 40% decrease at 8 ng/ml), without affecting C(50) (baseline = 1.12 +/- 0.05%). Median R(2) values of the pooled data set were 0.815 for SEF, 0.933 for CUP (P < 0.01 vs. SEF), and 0.952 for BIS (P < 0.01 vs. SEF and CUP). Addition of remifentanil increased the R(2) values for CUP only., Conclusions: Remifentanil accelerates sevoflurane blood-brain equilibration without affecting its hypnotic potency as determined from BIS and CUP. In terms of R(2), the authors' pharmacodynamic model describes the anesthetic-BIS relation best.

Background: Inhalational anesthetics produce dose-dependent effects on electroencephalogram-derived parameters, such as 95% spectral edge frequency (SEF) and bispectral index (BIS). The authors analyzed the relationship between end-tidal sevoflurane and isoflurane concentrations (FET) and BIS and SEF and determined the speed of onset and offset of effect (t1/2k(e0))., Methods: Twenty-four patients with American Society of Anesthesiologists physical status I or II were randomly assigned to receive anesthesia with sevoflurane or isoflurane. Several transitions between 0.5 and 1.5 minimum alveolar concentration were performed. BIS and SEF data were analyzed with a combination of an effect compartment and an inhibitory sigmoid Emax model, characterized by t1/2k(e0), the concentration at which 50% depression of the electroencephalogram parameters occurred (IC50), and shape parameters. Parameter values estimated are mean +/- SD., Results: The model adequately described the FET-BIS relationship. Values for t1/2k(e0), derived from the BIS data, were 3.5 +/- 2.0 and 3.2 +/- 0.7 min for sevoflurane and isoflurane, respectively (NS). Equivalent values derived from SEF were 3.1 +/- 2.4 min (sevoflurane) and 2.3 +/- 1.2 min (isoflurane; NS). Values of t1/2k(e0) derived from the SEF were smaller than those from BIS (P < 0.05). IC50 values derived from the BIS were 1.14 +/- 0.31% (sevoflurane) and 0.60 +/- 0.11% (isoflurane; P < 0.05)., Conclusions: The speed of onset and offset of anesthetic effect did not differ between isoflurane and sevoflurane; isoflurane was approximately twice as potent as sevoflurane. The greater values of t1/2k(e0) derived from the BIS data compared with those derived from the SEF data may be related to computational and physiologic delays.

Background: Cardiac output (CO) is likely to influence the pharmacokinetics of anesthetic drugs and should be accounted for in pharmacokinetic models. The influence of CO on the pharmacokinetic parameters of alfentanil in pigs was evaluated using compartmental and recirculatory models., Methods: Twenty-four premedicated pigs were evaluated during halothane (0.6-2%) anesthesia. They were assigned randomly to one of three groups. One group served as control. In the other groups, the baseline CO was decreased or increased by 40% by pharmacologic intervention (propranolol or dobutamine). Boluses of alfentanil (2 mg) and indocyanine green (25 mg) were injected into the right atrium. Blood samples were taken for 150 min from the right atrium and aortic root. Arterial concentration-time curves of indocyanine green and alfentanil were analyzed using compartmental models (two-stage and mixed-effects approach) and a recirculatory model, which can describe lung uptake and early distribution., Results: The CO of individual pigs varied from 1.33 to 6.44 l/min. Three-compartmental modeling showed that CO is a determinant of the central compartment volume (V1, r2 = 0.54), fast peripheral compartment volume (V2, r2 = 0.29), steady state distribution volume (Vss, r2 = 0.29), fast distribution clearance (Cl12, r2 = 0.39), and elimination clearance (Cl10, r2 = 0.51). Recirculatory modeling showed that CO is a determinant of total distribution volume (r2 = 0.48), elimination clearance (r2 = 0.54), and some distribution clearances. The pulmonary distribution volume was independent of CO., Conclusions: Cardiac output markedly influences the pharmacokinetics of alfentanil in pigs. Therefore, accounting for CO enhances the predictive value of pharmacokinetic models of alfentanil.

Background: Inhalational anesthetics depress breathing dose dependently. The authors studied the dynamics of ventilation on changes in end-tidal sevoflurane partial pressure. To learn more about the mechanisms of sevoflurane-induced respiratory depression, the authors also studied its influence on the dynamic ventilatory response to carbon dioxide., Methods: Experiments were performed in cats anesthetized with alpha chloralose-urethane. For protocol 1, step changes in end-tidal sevoflurane partial pressure were applied and inspired ventilation was measured. Breath-to-breath inspired ventilation was related to the sevoflurane concentration in a hypothetical effect compartment based on an inhibitory sigmoid Emax model. For protocol 2, step changes in the end-tidal partial pressure of carbon dioxide were applied at 0, 0.5, and 1% end-tidal sevoflurane. The inspired ventilation-end-tidal partial pressure of carbon dioxide data were analyzed using a two-compartment model of the respiratory controller, which consisted of a fast peripheral and slow central compartment. Values are the mean +/- SD., Results: In protocol 1, the effect-site half-life of respiratory changes caused by alterations in end-tidal sevoflurane partial pressure was 3.6+/-1.0 min. In protocol 2, at 0.50% sevoflurane, the central and peripheral carbon dioxide sensitivities decreased to 43+/-20% and 36+/-18% of control. At 1% sevoflurane, the peripheral carbon dioxide sensitivity decreased further, to 12+/-13% of control, whereas the central carbon dioxide sensitivity showed no further decrease., Conclusions: Steady state inspired ventilation is reached after 18 min (i.e., 5 half-lives) on stepwise changes in end-tidal sevoflurane. Anesthetic concentrations of sevoflurane have, in addition to an effect on pathways common to the peripheral and central chemoreflex loops, a selective effect on the peripheral chemoreflex loop. Sevoflurane has similar effects on ventilatory control in humans and cats.