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E Olofsen

Publications and source records attributed to E Olofsen.

At least 19 recordsLinked to original sources
PubMed2007

Mechanism-based PK/PD modeling of the respiratory depressant effect of buprenorphine and fentanyl in healthy volunteers.

The objective of this study was to characterize the pharmacokinetic/pharmacodynamic (PK/PD) relationship of buprenorphine and fentanyl for the respiratory depressant effect in healthy volunteers. Data on the time course of the ventilatory response at a fixed P(ET)CO(2) of 50 mm Hg and P(ET)O(2) of 110 mm Hg following intravenous administration of buprenorphine and fentanyl were obtained from two phase I studies (50 volunteers received buprenorphine: 0.05-0.6 mg/70 kg and 24 volunteers received fentanyl: 0.075-0.5 mg/70 kg). The PK/PD correlations were analyzed using nonlinear mixed effects modeling. A two- and three-compartment pharmacokinetic model characterized the time course of fentanyl and buprenorphine concentration, respectively. Three structurally different PK/PD models were evaluated for their appropriateness to describe the time course of respiratory depression: (1) a biophase distribution model with a fractional sigmoid E(max) pharmacodynamic model, (2) a receptor association/dissociation model with a linear transduction function, and (3) a combined biophase distribution-receptor association/dissociation model with a linear transduction function. The results show that for fentanyl hysteresis is entirely determined by the biophase distribution kinetics, whereas for buprenorphine hysteresis is caused by a combination of biophase distribution kinetics and receptor association/dissociation kinetics. The half-time values of biophase equilibration (t(1/2, k(eo))) were 16.4 and 75.3 min for fentanyl and buprenorphine, respectively. In addition, for buprenorphine, the value of k(on) was 0.246 ml/ng/min and the value of k(off) was 0.0102 min(-1). The concentration-effect relationship of buprenorphine was characterized by a ceiling effect at higher concentrations (intrinsic activity alpha=0.56, 95% confidence interval (CI): 0.50-0.62), whereas fentanyl displayed full respiratory depressant effect (alpha=0.91, 95% CI: 0.19-1.62).

Adult↗
PubMed2006

Buprenorphine induces ceiling in respiratory depression but not in analgesia.

BACKGROUND: We measured the effect of two weight adjusted i.v. doses (0.2 mg per 70 kg and 0.4 mg per 70 kg) of the potent opioid buprenorphine on analgesia and respiratory depression in healthy volunteers. The aim of the study was to compare buprenorphine's behaviour with respect to the occurrence of ceiling (or apparent maximum) in these typical micro-opioid protein-(MOP) receptor effects. METHODS: Ten subjects (5 males) received 0.2 mg per 70 kg, 10 others (5 males) 0.4 mg per 70 kg i.v. buprenorphine. Steady-state inspired minute ventilation at a fixed end-tidal Pco(2) of 7 kPa was measured before drug infusion and at regular intervals after drug infusion. Experimental pain was induced using transcutaneous electrical stimulation and a gradually increasing current. Pain tolerance was measured at regular intervals before and after drug infusion. The studies lasted 8 h. RESULTS: After infusion of the drug ventilation showed a rapid decline and reached peak depression between 150 and 180 min after drug administration. This effect was dose-independent with respect to timing and magnitude. At peak respiratory depression minute ventilation was 13.1 (sd 1.8) litre min(-1) in the 0.2 mg group vs 12.0 (sd 1.3) litre min(-1) in the 0.4 mg group (n.s.). At buprenorphine 0.2 mg a small short-lived analgesic effect was observed with a maximum increase in pain tolerance current of 6.7 (sd 2.8) mA occurring at 75 min after drug administration. Peak analgesic effect was 29% above baseline current. In contrast, buprenorphine 0.4 mg caused a large and long-lived analgesic effect with a maximum increase in pain tolerance current of 23.8 (sd 7.4) mA occurring at 130 min after drug administration. Peak analgesic effect was 160% above baseline current (0.4 vs 0.2 mg, P<0.01). CONCLUSIONS: While buprenorphine's analgesic effect increased significantly, respiratory depression was similar in magnitude and timing for the two doses tested. We conclude that over the dose range tested buprenorphine displays ceiling in respiratory effect but none in analgesic effect.

Adult↗
PubMed2005

Comparison of the respiratory effects of intravenous buprenorphine and fentanyl in humans and rats.

BACKGROUND: There is evidence from animal studies suggesting the existence of a ceiling effect for buprenorphine-induced respiratory depression. To study whether an apparent ceiling effect exists for respiratory depression induced by buprenorphine, we compared the respiratory effects of buprenorphine and fentanyl in humans and rats. METHODS: In healthy volunteers, the opioids were infused i.v. over 90 s and measurements of minute ventilation at a fixed end-tidal PCO2 of 7 kPa were obtained for 7 h. Buprenorphine doses were 0.7, 1.4, 4.3 and 8.6 microg kg(-1) (n=20 subjects) and fentanyl doses 1.1, 2.1, 2.9, 4.3 and 7.1 microg kg(-1) (n=21). Seven subjects received placebo. In rats, both opioids were infused i.v. over 20 min, and arterial PCO2 was measured 5, 10, 15 and 20 min after the start of fentanyl infusion and 30, 150, 270 and 390 min after the start of buprenorphine infusion. Doses tested were buprenorphine 0, 100, 300, 1000 and 3000 microg kg(-1) and fentanyl 0, 50, 68 and 90 microg kg(-1). RESULTS: In humans, fentanyl produced a dose-dependent depression of minute ventilation with apnoea at doses > or = 2.9 microg kg(-1); buprenorphine caused depression of minute ventilation which levelled off at doses > or = 3.0 microg kg(-1) to about 50% of baseline. In rats, the relationship of arterial PCO2 and fentanyl dose was linear, with maximum respiratory depression at 20 min (maximum PaCO2 8.0 kPa). Irrespective of the time at which measurements were obtained, buprenorphine showed a non-linear effect on PaCO2, with a ceiling effect at doses > 1.4 microg kg(-1). The effect on PaCO2 was modest (maximum value measured, 5.5 kPa). CONCLUSIONS: Our data confirm a ceiling effect of buprenorphine but not fentanyl with respect to respiratory depression.

Adult↗
PubMed2001

Recirculatory pharmacokinetics and pharmacodynamics of rocuronium in patients: the influence of cardiac output.

BACKGROUND: Recirculatory models are capable of accurately describing first-pass pharmacokinetics and the influence of cardiac output (CO), which is important for drugs with a fast onset of effect. The influence of CO on pharmacokinetic and pharmacodynamic parameters of rocuronium in patients was evaluated using a recirculatory pharmacokinetic model. METHODS: Fifteen patients were included to study rocuronium pharmacokinetics and pharmacodynamics. Bolus doses of rocuronium (0.35 mg/kg) and indocyanine green (25 mg) were injected simultaneously via a peripheral intravenous catheter. Blood samples were taken for 240 min from the radial artery. The force of contraction of the adductor pollicis after a train-of-four at 2 Hz every 12 s was measured. Arterial concentration-time curves of rocuronium and indocyanine green were analyzed using a recirculatory model. Pharmacodynamics were described using a sigmoid maximum effect (Emax) model. RESULTS: The CO of the patients varied from 2.43 to 5.59 l/min. Total distribution volume of rocuronium was 17.3 +/- 4.8 l (mean +/- SD). The CO showed a correlation with the fast tissue clearance (Cl(T_f); r2 = 0.51), with the slow tissue clearance (Cl(T_s); r2 = 0.31) and with the mean transit times of rocuronium except for the mean transit time of the slow tissue compartment. The blood-effect site equilibration constant (k(e0)) was strongly correlated with CO (r2 = 0.70). CONCLUSIONS: Cardiac output influences the pharmacokinetics, including k(e0), for rocuronium in patients. For drugs with a fast onset of effect, a recirculatory model, which includes CO, can give a good description of the relation between concentration and effect, in contrast to a conventional compartmental pharmacokinetic model.

Adult↗
PubMed2001

Modeling population pharmacokinetics of lidocaine: should cardiac output be included as a patient factor?

BACKGROUND: Inclusion of cardiac output and other physiologic parameters, in addition to or instead of, demographic variables might improve the population pharmacokinetic modeling of lidocaine. METHODS: Thirty-one patients were included in a population pharmacokinetic study of lidocaine. After bolus injection of lidocaine (1 mg/kg), 22 or 10 blood samples per patient were taken from a radial artery. During the experiment, cardiac output was measured using a thoracic electrical bioimpedance method. The following four population pharmacokinetic models were constructed and their performances investigated: a model with no covariates, a model with cardiac output as covariate, a model with demographic covariates, and a model with both cardiac output and demographic characteristics as covariates. Model discrimination was performed with the likelihood ratio test. RESULTS: Inclusion of cardiac output resulted in a significant improvement of the pharmacokinetic model, but inclusion of demographic covariates was even better. However, the best model was obtained by inclusion of both demographic covariates and cardiac output in the pharmacokinetic model. CONCLUSIONS: When population pharmacokinetic models are used for individualization of dosing schedules, physiologic covariates, e.g., cardiac output, can improve their ability to predict the individual kinetics.

Adult↗
PubMed2001

Propofol alters the pharmacokinetics of alfentanil in healthy male volunteers.

BACKGROUND: The influence of propofol on the pharmacokinetics of alfentanil is poorly understood. The authors therefore studied the effect of a pseudo-steady state concentration of propofol on the pharmacokinetics of alfentanil. METHODS: The pharmacokinetics of alfentanil was studied on two occasions in eight male volunteers in a randomized crossover manner with a 3-week interval. While breathing 30% O2 in air, 12.5 microg/kg intravenous alfentanil was given in 2 min, followed by 25 microg.kg(-1).h(-1) for 58 min (sessions A and B). During session B, a target controlled infusion of propofol (target concentration, 1.5 microg/ml) was given from 10 min before the start until 6 h after termination of the alfentanil infusion. Blood pressure, cardiac output, electrocardiogram, respiratory rate, oxygen saturation, and end-tidal carbon dioxide were monitored. Venous blood samples for determination of the plasma alfentanil concentration were collected until 6 h after termination of the alfentanil infusion. Nonlinear mixed-effects population pharmacokinetic models examining the influence of propofol and mean arterial pressure were constructed. RESULTS: A three-compartment model, including a lag time accounting for the venous blood sampling, adequately described the concentration-time curves of alfentanil Propofol decreased the elimination clearance of alfentanil by 15%, rapid distribution clearance by 68%, slow distribution clearance by 51%, and lag time by 62%. Mean arterial pressure and systemic vascular resistance were significantly lower in the presence of propofol. Scaling the pharmacokinetic parameters to the mean arterial pressure instead of propofol improved the model. CONCLUSIONS: Propofol alters the pharmacokinetics of alfentanil. Hemodynamic changes induced by propofol may have an important influence on the pharmacokinetics of alfentanil.

Adult↗
PubMed2001

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 (approximately 50 mmHg) at constant end-tidal partial pressure of carbon dioxide (approximately 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 (Vi), HR, hypoxic Vi, 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 Vi and resting HR. Depression of Vi 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 Vi and HR responses and BIS. Depression of the hypoxic Vi 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 Vi and HR than does the summed effect of each drug administered separately. The effects of combining alfentanil and sevoflurane on hypoxic Vi 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.

Adolescent↗
PubMed2000

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

BACKGROUND: Animal 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. METHODS: Young 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). RESULTS: The 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. CONCLUSIONS: These 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.

Adult↗
PubMed1999

A procedure of multiple period searching in unequally spaced time-series with the Lomb-Scargle method.

Periodogram analysis of unequally spaced time-series, as part of many biological rhythm investigations, is complicated. The mathematical framework is scattered over the literature, and the interpretation of results is often debatable. In this paper, we show that the Lomb-Scargle method is the appropriate tool for periodogram analysis of unequally spaced data. A unique procedure of multiple period searching is derived, facilitating the assessment of the various rhythms that may be present in a time-series. All relevant mathematical and statistical aspects are considered in detail, and much attention is given to the correct interpretation of results. The use of the procedure is illustrated by examples, and problems that may be encountered are discussed. It is argued that, when following the procedure of multiple period searching, we can even benefit from the unequal spacing of a time-series in biological rhythm research.

Body Temperature↗
PubMed1999

Speed of onset and offset and mechanisms of ventilatory depression from sevoflurane: an experimental study in the cat.

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.

Anesthetics, Inhalation↗
PubMed1999

Recirculatory and compartmental pharmacokinetic modeling of alfentanil in pigs: the influence of cardiac output.

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.

Alfentanil↗
PubMed1999

The dynamic relationship between end-tidal sevoflurane and isoflurane concentrations and bispectral index and spectral edge frequency of the electroencephalogram.

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.

Adolescent↗
PubMed1999

Searching for biological rhythms: peak detection in the periodogram of unequally spaced data.

The classical power spectrum, computed in the frequency domain, outranks traditionally used periodograms derived in the time domain (such as the chi2 periodogram) regarding the search for biological rhythms. Unfortunately, classical power spectral analysis is not possible with unequally spaced data (e.g., time series with missing data). The Lomb-Scargle periodogram fixes this shortcoming. However, peak detection in the Lomb-Scargle periodogram of unequally spaced data requires some careful consideration. To guide researchers in the proper evaluation of detected peaks, therefore, a novel procedure and a computer program have recently become available. It is recommended that the Lomb-Scargle periodogram be the default method of periodogram analysis in future biomedical applications of rhythm investigation.

Computer Simulation↗