René Mooren

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.

S(+)-ketamine Effect on Experimental Pain and Cardiac Output: A Population Pharmacokinetic-Pharmacodynamic Modeling Study in Healthy Volunteers

Background:Low-dose ketamine behaves as an analgesic in the treatment of acute and chronic pain. To further understand ketamine’s therapeutic profile, the authors performed a population pharmacokinetic-pharmacodynamic analysis of the S(+)-ketamine analgesic and nonanalgesic effects in healthy volunteers. Methods:Ten men and ten women received a 2-h S(+)-ketamine infusion. The infusion was increased at 40 ng/ml per 15 min to reach a maximum of 320 ng/ml. The following measurements were made: arterial plasma S(+)-ketamine and S(+)-norketamine concentrations, heat pain intensity, electrical pain tolerance, drug high, and cardiac output. The data were modeled by using sigmoid Emax models of S(+)-ketamine concentration versus effect and S(+)-ketamine + S(+)-norketamine concentrations versus effect. Results:Sex differences observed were restricted to pharmacokinetic model parameters, with a 20% greater elimination clearance of S(+)-ketamine and S(+)-norketamine in women resulting in higher drug plasma concentrations in men. S(+)-ketamine produced profound drug high and analgesia with six times greater potency in the heat pain than the electrical pain test. After ketamine-infusion, analgesia rapidly dissipated; in the heat pain test but not the electrical pain test, analgesia was followed by a period of hyperalgesia. Over the dose range tested, ketamine produced a 40–50% increase in cardiac output. A significant consistent contribution of S(+)-norketamine to overall effect was detected for none of the outcome parameters. Conclusions:S(+)-ketamine displays clinically relevant sex differences in its pharmacokinetics. It is a potent analgesic at already low plasma concentrations, but it is associated with intense side effects.

Alfentanil and placebo analgesia : No sex differences detected in models of experimental pain

Background:To assess whether patient sex contributes to the interindividual variability in alfentanil analgesic sensitivity, the authors compared male and female subjects for pain sensitivity after alfentanil using a pharmacokinetic–pharmacodynamic modeling approach. Methods:Healthy volunteers received a 30-min alfentanil or placebo infusion on two occasions. Analgesia was measured during the subsequent 6 h by assaying tolerance to transcutaneous electrical stimulation (eight men and eight women) of increasing intensity or using visual analog scale scores during treatment with noxious thermal heat (five men and five women). Sedation was concomitantly measured. Population pharmacokinetic–pharmacodynamic models were applied to the analgesia and sedation data using NONMEM. For electrical pain, the placebo and alfentanil models were combined post hoc. Results:Alfentanil and placebo analgesic responses did not differ between sexes. The placebo effect was successfully incorporated into the alfentanil pharmacokinetic–pharmacodynamic model and was responsible for 20% of the potency of alfentanil. However, the placebo effect did not contribute to the analgesic response variability. The pharmacokinetic–pharmacodynamic analysis of the electrical and heat pain data yielded similar values for the potency parameter, but the blood–effect site equilibration half-life was significantly longer for electrical pain (7–9 min) than for heat pain (0.2 min) or sedation (2 min). Conclusions:In contrast to the ample literature demonstrating sex differences in morphine analgesia, neither sex nor subject expectation (i.e., placebo) contributes to the large between-subject response variability with alfentanil analgesia. The difference in alfentanil analgesia onset and offset between pain tests is discussed.

An observational study on the effect of S+-ketamine on chronic pain versus experimental acute pain in Complex Regional Pain Syndrome type 1 patients.

Aims The aim of the study was to explore the analgesic effect of the N‐methyl‐d‐aspartate receptor (NMDAR) antagonist ketamine in acute experimental versus chronic spontaneous pain in Complex Regional Pain Syndrome type 1 (CRPS‐1) patients.

Effect of rifampicin on S-ketamine and S-norketamine plasma concentrations in healthy volunteers after intravenous S-ketamine administration.

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-ketamines metabolite, S-norketamine, probably via induction of the CYP3A4 and/or CYP2B6 enzymes.

Absence of long-term analgesic effect from a short-term S-ketamine infusion on fibromyalgia pain: A randomized, prospective, double blind, active placebo-controlled trial

To assess the analgesic efficacy of the N‐methyl‐D‐aspartate receptor antagonist S(+)‐ketamine on fibromyalgia pain, the authors performed a randomized double blind, active placebo‐controlled trial. Twenty‐four fibromyalgia patients were randomized to receive a 30‐min intravenous infusion with S(+)‐ketamine (total dose 0.5 mg/kg, n=12) or the active placebo, midazolam (5 mg, n =12). Visual Analogue Pain Scores (VAS) and ketamine plasma samples were obtained for 2.5‐h following termination of treatment; pain scores derived from the fibromyalgia impact questionnaire (FIQ) were collected weekly during an 8‐week follow‐up. Fifteen min after termination of infusion the number of patients showing a reduction in pain scores >50% was 8 vs. 3 (P<0.05), at t=180 min 6 vs. 2 (ns), at the end of week‐1 2 vs. 0 (ns) and at end of week‐8 2 vs. 2 in the ketamine and midazolam groups, respectively. Ketamine effect on VAS closely followed ketamine plasma concentrations. For VAS and FIQ scores no significant differences in treatment effects were observed in the 2.5‐h following infusion or during the 8‐week follow‐up. Side effects as measured by the Bowdle questionnaire (which scores for 13 separate psychedelic symptoms) were mild to moderate in both study groups and declined rapidly, indicating adequate blinding of treatments. Efficacy of ketamine was limited and restricted in duration to its pharmacokinetics. The authors argue that a short‐term infusion of ketamine is insufficient to induce long‐term analgesic effects in fibromyalgia patients.

Pulse dye densitometry and indocyanine green plasma disappearance in ASA physical status I-II patients.

BACKGROUND: Indocyanine green plasma disappearance rate (ICG-PDR) is used to evaluate hepatic function. Although hepatic failure is generally said to occur with an ICG-PDR <18%/min, ICG disappearance rate is poorly defined in the healthy population, and a clear cutoff value of ICG-PDR that discriminates between normal hepatic function and hepatic failure has not yet been described. We therefore defined the ICG disappearance rate in an otherwise healthy patient population. In addition, we evaluated the noninvasive measurement of ICG-PDR (transcutaneously by pulse dye densitometry [PDD] at the finger and the nose) and compared these with the simultaneously performed invasive measurements of ICG-PDR (in arterial blood). METHODS: In patients without signs of liver disease, scheduled for elective nonhepatic surgery, 10 mg ICG was administered IV and ICG-PDR measured by PDD (DDG-2001, Nihon Kohden, Tokyo, Japan). In a subset of patients, arterial blood samples were gathered to compare PDD with invasive ICG measurements. Methods were compared using Bland-Altman analysis. The results of our study and reported studies on discriminative use of ICG-PDR in assessing liver failure were used to construct receiver operating characteristic curves. RESULTS: Forty-one patients were studied: 33 using the finger probe and 8 using the nose probe. The mean ± sd noninvasive ICG-PDR in this patient population is 23.1% ± 7.9%/min (n = 41) with a range of 9.7% to 43.2%/min. Bias (±2 sd, limits of agreement) for ICG-PDR measured by PDD compared with those measured in arterial blood were 1.6%/min (−5.2% to 8.3%/min) for the finger probe and −6.0%/min (−15.5% to 3.4%/min) for the nose probe. CONCLUSION: ICG-PDR values in a population without liver failure ranged well below 18%/min, cited as the cutoff value for hepatic failure. This cutoff value needs reconsideration. In addition, we conclude that the ICG concentration is adequately determined noninvasively by PDD.

Arterial and venous pharmacokinetics of morphine-6-glucuronide and impact of sample site on pharmacodynamic parameter estimates.

BACKGROUND: In pharmacokinetic–pharmacodynamic modeling studies, venous plasma samples are sometimes used to derive pharmacodynamic model parameters. In the current study the extent of arteriovenous concentration differences of morphine-6-glucuronide (M6G) was quantified. We used simulation studies to estimate possible biases in pharmacodynamic model parameters when linking venous versus arterial concentrations to effect. METHODS: Seventeen healthy volunteers received an IV 90-second infusion of 0.3 mg/kg morphine-6-glucuronide (M6G). Arterial and venous blood samples, from the radial artery and cubital vein, respectively, were obtained. An extended pharmacokinetic model was constructed linking arterial and venous compartments. The extent of bias in pharmacodynamic model parameter estimates was explored in simulation studies with NONMEM, simulating M6G effect using first-order effect-compartment–inhibitory sigmoid EMAX models. M6G effect was simulated at various values for the arterial blood-effect-site equilibration half-lifes (t½kE0), ranging from 5 to 240 minutes. RESULTS: Arteriovenous concentration differences were apparent, with higher arterial plasma concentrations just after infusion, whereas at later times (>60 minutes) venous M6G concentrations exceeded arterial concentrations. The extended pharmacokinetic model adequately described the data and consisted of 3 arterial compartments, 1 central venous compartment, and 1 peripheral venous compartment. The simulation studies revealed large biases in model parameters derived from venous concentration data. The biases were dependent on the value of t½kE0. Assuming that the true values of M6G t½kE0 range from 120 to 240 minutes (depending on the end point measured), we would have underestimated t½kE0 by 30%, whereas the potency parameter would have been overestimated by about 40%, when using venous plasma samples. CONCLUSIONS: Because of large arteriovenous differences in M6G plasma, concentration biases in pharmacodynamic model parameters will occur when linking venous concentration to effect, using a traditional effect-compartment model.

Cardiovascular Monitoring by Pulse Dye Densitometry or Arterial Indocyanine Green Dilution

BACKGROUND: Noninvasive cardiac output (CO) monitoring is possible by indocyanine green (ICG) dilution measured by pulse dye densitometry (PDD). To validate the precision of this method, we compared hemodynamic variables derived from PDD (DDG-2001, Nihon Kohden, Japan) with those derived from simultaneously taken arterial blood ICG concentrations. METHODS: In 20 patients (6 M/14 F), ASA I or II, 36 sessions were performed (n = 24 with the PDD-finger probe, n = 10 with the PDD-nose probe). After IV administration of 10 mg ICG, 34 arterial blood samples were taken during each session, with 20 samples taken during the first 2 min. CO, central blood volume (CBV), and total blood volume (TBV) were calculated independently from ICG and PDD and the results compared between methods using Bland-Altman analysis. The results are reported as mean difference (bias) and limits of agreement (LOA = ± 2 sd). RESULTS: PDD using the finger probe underestimated CO (LOA) by 5% (−56% and 47%); overestimated CBV by 21% (−54% and 96%) and underestimated TBV by −15% (−38% and 8%). PDD using the nose probe overestimated CO (LOA) by 30% (−67% and 127%); CBV by 48% (−98% and 193%) and underestimated TBV by −10% (−47% and 27%). CONCLUSION: Despite the permissible bias, the wide LOA of the PDD-derived hemodynamic variables CO and CBV, compared with those simultaneously obtained by invasive arterial ICG measurements, suggest that PDD is unsuitable for evaluation of cardiovascular variables in the individual patient. Hence, the reliability and clinical use of this method seem limited.

The dose-dependent effect of S(+)-ketamine on cardiac output in healthy volunteers and complex regional pain syndrome type 1 chronic pain patients.

BACKGROUND: Ketamine is used as an analgesic for treatment of acute and chronic pain. While ketamine has a stimulatory effect on the cardiovascular system, little is known about the concentration–effect relationship. We examined the effect of S(+)-ketamine on cardiac output in healthy volunteers and chronic pain patients using a pharmacokinetic–pharmacodynamic modeling approach. METHODS: In 10 chronic pain patients (diagnosed with complex regional pain syndrome type 1 [CRPS1] with a mean age 43.2 ± 13 years, disease duration 8.4 years, range 1.1 to 21.7 years) and 12 healthy volunteers (21.3 ± 1.6 years), 7 increasing IV doses of S(+)-ketamine were given over 5 minutes at 20-minute intervals starting with 1.5 mg with 1.5-mg increments. Cardiac output (CO) was calculated from the arterial pressure curve obtained from an arterial catheter in the radial artery. Ketamine and norketamine plasma concentrations were measured. A novel pharmacokinetic–pharmacodynamic model was constructed to quantify the direct stimulatory effect of ketamine on CO and the following adaptation/inhibition. RESULTS: Significant differences in pharmacokinetic estimates were observed between study groups with 15% and 40% larger S(+)-ketamine S(+)-norketamine concentrations in healthy volunteers compared to CRPS1 patients. S(+)-ketamine had a dose-dependent stimulatory effect on CO in patients and volunteers. After infusion an inhibitory effect on CO was observed. Pharmacodynamic model parameters did not differ between CRPS1 patients and healthy volunteers. The concentration of S(+)-ketamine causing a 1 L/min increase in CO was 243 ± 54 ng/mL with an onset/offset half-life of 1.3 ± 0.21 minutes. The inhibitory component was slow (time constant of 67.2 ± 17.0 minutes). CONCLUSIONS: S(+)-ketamine pharmacokinetics but not pharmacodynamics differed between study populations, related to differences in disease state (CRPS1 or not) or age. The dose-dependent effect of S(+)-ketamine on CO was well described by the biphasic dynamic model. The effect of S(+)-ketamine on CO was similar between study groups with respect to its stimulatory and inhibitory components, despite group differences in age and health.