Analgesic Efficacy of Oxycodone in Postoperative Dressings after Surgical Treatment of Burn Wounds: A Randomised Controlled Trial.

INTRODUCTION: This study aimed to assess the analgesic efficacy of oxycodone at doses of 10 mg and 20 mg in dressings after surgery of burn wounds. MATERIAL AND METHODS: Twenty adult patients who underwent surgical treatment of third-degree burn wounds under general anaesthesia were included. Burn wounds were treated with dressings, to which oxycodone was added at 20 mg in Group 1 and 10 mg in Group 2. After the surgery, plasma oxycodone and noroxycodone concentrations were assayed, and pain intensity was assessed with Numerical Rating Scale (NRS). RESULTS: In Group 1, no patient reported pain; in Group 2, four patients reported pain. The pain intensity, according to NRS, was 1-8. Plasma concentration of oxycodone in the blood serum was in the range of 1.24-3.15 ng/mL and 1.09-1.28 ng/mL in Group 1 and Group 2, respectively. Noroxycodone was not detected in the plasma. Adverse effects were not observed in any of the treated patients. CONCLUSIONS: Oxycodone in dressings provides patients with adequate and safe analgesia.

THC-Reduced Cannabis sativa L.-How Does the Solvent Determine the Bioavailability of Cannabinoids Given Orally?

The bioavailability levels of cannabidiol (CBD) and tetrahydrocannabinol (THC) determine their pharmacological effects. Therefore, for medical purposes, it is essential to obtain extracts containing the lowest possible content of the psychogenic component THC. In our extract, the CBD/THC ratio was 16:1, which is a high level compared to available medical preparations, where it is, on average, 1:1. This study assessed the bioavailability and stability of CBD and THC derived from Cannabis sativa L. with reduced THC content. The extract was orally administered (30 mg/kg) in two solvents, Rapae oleum and Cremophor, to forty-eight Wistar rats. The whole-blood and brain concentrations of CBD and THC were measured using liquid chromatography coupled with mass spectrometry detection. Much higher concentrations of CBD than THC were observed for both solvents in the whole-blood and brain after oral administration of the Cannabis sativa extract with a decreased THC content. The total bioavailability of both CBD and THC was higher for Rapae oleum compared to Cremophor. Some of the CBD was converted into THC in the body, which should be considered when using Cannabis sativa for medical purposes. The THC-reduced hemp extract in this study is a promising candidate for medical applications.

Population Pharmacokinetic-Pharmacodynamic Modeling and Probability of Target Attainment Analysis of Rocuronium and Sugammadex in Children Undergoing Surgery.

BACKGROUND AND OBJECTIVES: Probability of target attainment (PTA) curves are commonly used to support dose recommendations of antibiotics for different patient groups. In this study we propose PTA analysis to optimize sugammadex dosing in children. METHODS: This study involved data from an observational cohort study of 30 American Society of Anesthesiologists (ASA) Physical Status I and II children undergoing surgery requiring muscle relaxation. All patients received 0.6 mg/kg rocuronium, with sugammadex administered at the end of surgery in three different doses (0.5, 1.0, and 2.0 mg/kg) to reverse the neuromuscular blockade. RESULTS: The data were analyzed using a population Bayesian-based approach. The developed model was used to simulate pharmacokinetic-pharmacodynamic profiles for different patient groups and dosing regimens before the PTA analysis was performed to translate these simulations into a clinically useful measure. The target was defined as neuromuscular blockade reversal measured by Train-of-Four (TOF ratio > 90%) at 1.5, 3, and 5 min post sugammadex dose. The sugammadex doses leading to 90% PTA were determined for different patients' body weights, rocuronium doses, and time gaps between rocuronium and sugammadex administration assuming the model, priors, and gathered data. For comparison, PTA curves for a range of clinical scenarios are provided to illustrate the usefulness of PTA analysis in selecting the appropriate dose for a given patient. CONCLUSIONS: The proposed PTA analysis is useful to support the sugammadex dose selection in different clinical scenarios. TRIAL REGISTRATION: The study was registered by ClinicalTrials.gov under number NCT04851574 on 21 April 2021.

Analgesic Efficacy and Safety of Spinal Oxycodone in Total Hip Arthroplasty: A Preliminary Study.

AIM: The aim of this study was to assess the analgesic efficacy and safety of 1 mg and 0.5 mg oxycodone administration in a spinal block procedure for a total hip arthroplasty (THA). PATIENTS AND METHODS: Forty-two THA patients aged 59-81 with American Society Anesthesiology (ASA) II-III were included. All patients received anesthesia using spinal blockade, with bupivacaine 0.5% spinal heavy 2.5 ml, with 0.5 ml oxycodone hydrochloride 1.0 mg (group A; n = 28) or 0.5 mg (group B; n = 14). During surgery, each patient was sedated with 2-4 mg/kg/h intravenous propofol infusion. They received 100 mg intravenous ketoprofen at the end of the surgery at 8 pm and 8 am, with recommended doses every 12 h thereafter. Subcutaneous morphine 5 mg was used as a rescue analgesic, and the time to morphine use was recorded. After surgery, pain intensity (at the moment of patient report) was assessed using an 11-point numerical rating scale (NRS). The incidence of adverse effects was monitored. Blood samples were taken for assays of serum oxycodone, noroxycodone and bupivacaine levels. RESULTS: The time to rescue analgesia was 9.6 ± 5.6 h in group A and 7.3 ± 1.9 h in group B, and it did not differ between patient groups (P = 0.179). The mean NRS pain score was 4.5 in group A and 4.2 in group B. Three group A patients had detectable oxycodone levels: two < 7.1 ng/ml and in 1 spinal block induced anesthesia was unsuccessful and so he/she underwent general anesthesia (this patient was excluded from the analysis). Four group B patients had single values < 5 ng/ml. Noroxycodone levels were in all patients undetectable, and bupivacaine levels were 70-300 ng/ml. Regarding adverse effects, one patient had hypotension, one had bradycardia, and one had pruritus. CONCLUSION: Oxycodone in spinal block prolongs analgesia period, does not cause serious adverse effects and seems to be safe and effective opioid for patients undergoing THA.

The influence of cardiac output on propofol and fentanyl pharmacokinetics and pharmacodynamics in patients undergoing abdominal aortic surgery.

Cardiac output (CO) is expected to affect elimination and distribution of highly extracted and perfusion rate-limited drugs. This work was undertaken to quantify the effect of CO measured by the pulse pressure method on pharmacokinetics and pharmacodynamics of propofol and fentanyl administrated during total intravenous anesthesia (TIVA). The data were obtained from 22 ASA III patients undergoing abdominal aortic surgery. Propofol was administered via target-controlled infusion system (Diprifusor) and fentanyl was administered at a dose of 2-3 µg/kg each time analgesia appeared to be inadequate. Hemodynamic measurements as well as bispectral index were monitored and recorded throughout the surgery. Data analysis was performed by using a non-linear mixed-effect population modeling (NONMEM 7.4 software). Three compartment models that incorporated blood flows as parameters were used to describe propofol and fentanyl pharmacokinetics. The delay of the anesthetic effect, with respect to plasma concentrations, was described using a biophase (effect) compartment. The bispectral index was linked to the propofol and fentanyl effect site concentrations through a synergistic Emax model. An empirical linear model was used to describe CO changes observed during the surgery. Cardiac output was identified as an important predictor of propofol and fentanyl pharmacokinetics. Consequently, it affected the depth of anesthesia and the recovery time after propofol-fentanyl TIVA infusion cessation. The model predicted (not observed) CO values correlated best with measured responses. Patients' age was identified as a covariate affecting the rate of CO changes during the anesthesia leading to age-related difference in individual patient's responses to both drugs.

Population analysis to assess the influence of age and body weight on pharmacokinetics and pharmacodynamics of dexmedetomidine in New Zealand White rabbits.

The purpose of this work was i) to develop a population pharmacokinetic (PK) and pharmacodynamic (PD) model of dexmedetomidine (DEX) in New Zealand White rabbits, ii) to investigate the influence of the age and weight of the animals on the model parameters, and iii) to assess the linearity of DEX PKs in the examined dose range. This was a prospective, crossover study, using a total of 18 New Zealand White rabbits. DEX was administered as a single intravenous bolus injection in the doses from 25 to 300 µg kg-1 . Each New Zealand White rabbit was given the same dose of drug in its three developmental stages. To determine the DEX PK, seven blood samples were taken from each animal. The pedal withdrawal reflex was the PD response used to assess the degree of sedation. Nonlinear mixed effects modelling was used for the population PK/PD analysis. The typical value of elimination clearance was 0.061 L min-1 and was 35% higher in younger New Zealand White rabbits compared with older animals. The PK of DEX was linear in the examined concentration range. Age-related changes in sensitivity to DEX were not detected. The results suggest that due to the pharmacokinetics, younger animals will have lower DEX concentrations and a shorter duration of sedation than older animals given the same doses of DEX per kg of body weight.

Population Pharmacokinetic Model of Dexmedetomidine in a Heterogeneous Group of Patients.

Dexmedetomidine is a hepatically eliminated drug with sedative, anxiolytic, sympatholytic, and analgesic properties that has been increasingly used for various indications in the form of a short or continuous intravenous infusion. This study aimed to propose a population pharmacokinetic (PK) model of dexmedetomidine in a heterogeneous group of intensive care unit patients, incorporating 29 covariates potentially linked with dexmedetomidine PK. Data were collected from 70 patients aged between 0.25 and 88 years and treated with dexmedetomidine infusion for various durations at 1 of 4 medical centers. Statistical analysis was performed using a nonlinear mixed-effect model. Categorical and continuous covariates including demographic data, hemodynamic parameters, biochemical markers, and 11 single-nucleotide polymorphisms were tested. A 2-compartment model was used to describe dexmedetomidine PK. An allometric/isometric scaling was used to account for body weight difference in PK parameters, and the Hill equation was used to describe the maturation of clearance. Typical values of the central and peripheral volume of distribution and the systemic and distribution clearance for a theoretical adult patient were central volume of distribution = 22.50 L, peripheral volume of distribution = 86.1 L, systemic clearance = 34.7 L/h, and distribution clearance = 40.8 L/h. The CYP1A2 genetic polymorphism and noradrenaline administration were identified as significant covariates for clearance. A population PK model of dexmedetomidine was successfully developed. The proposed model is well calibrated to the observed data. The identified covariates account for <5% of interindividual variability and consequently are of low clinical significance for the purpose of dose adjustment.

Rectal enema of bupivacaine in cancer patients with tenesmus pain - case series.

Introduction: Rectal tenesmus pain in cancer patients most frequently appears in patients with colon cancer, and as a consequence of radiotherapy of the hypogastrium region. Treatment with opioids and adjuvant analgesics is often ineffective. Patients and methods: Here, we report on two female patients diagnosed with colon and ovary cancer, respectively, who had very severe tenesmus pain (numerical rating scale 8-10) despite using high doses of opioids, including methadone with corticosteroids, anticonvulsants, antidepressants and ketamine. Results: In both patients, bupivacaine was administered via a rectal enema. In the first patient, bupivacaine was administered at a dose of 100 mg 0.1% (100 mL), and subsequently 100 mg 0.2% (50 mL), leading to effective analgesia for 8 and 12 hrs, respectively. In the second patient, 100 mg 0.1% (100 mL) was initially administered, followed by 100 mg 0.2% (50 mL), leading to effective analgesia for 12 and 17 hrs, respectively, with only dull abdominal pain reported that was relieved by 100 mg IV ketoprofen and complete disappearance of tenesmus pain. Rectal bupivacaine administration did not cause neurologic adverse effects, heart function disturbances or decreased blood pressure. A volume of 50 mL was enough to cover a painful area in the colon. Initial bupivacaine concentrations in the blood serum did not exceed 50 ng/mL and eventually dropped to 20 ng/mL and below. Conclusions: Administration of 100 mg bupivacaine as a rectal enema is safe and provides effective analgesia, and this procedure may be conducted in hospital departments and out-patient clinics. Furthermore, this procedure in the case of pain recurrence, can be repeated, and by providing effective pain relief often allows time for the patient to be transferred to a specialized pain center.

Pharmacokinetics of dexmedetomidine during analgosedation in ICU patients.

Dexmedetomidine (DEX) is a fairly new alfa2-agonist which has been increasingly used in recent years for analgosedation, mostly because it offers a unique ability of providing both moderate level of sedation and analgesia without respiratory depression. Despite of many papers published, there are still only a few concerning the PK of the drug given as long-term infusion in ICU patients. The aim of this work was to characterize the population pharmacokinetics of dexmedetomidine and to investigate the potential benefits of individualization of drug dosing based on patient characteristics in the heterogeneous group of medical and surgical patients staying in intensive care unit. This study was performed in the group of 17 males and 10 females patients with a median age of 59.5 years and median body weight of 75 kg. Blood samples for dexmedetomidine assay were collected from arterial catheter, during and after discontinuation of a standard infusion, that ranged from 24 to 102 h. The following covariates were examined to influence dexmedetomidine PK: age, sex, body weight, patients' health status described by Sequential Organ Failure Assessment Score (SOFA), inotropes usage, and infusion duration. The dexmedetomidine PK was best described by a two-compartment model. The typical values of PK parameters were estimated as 27 L for the volume of the central compartment, 87.6 L for the volume of the peripheral compartment, 38.5 L/h (9.2 mL/min/kg for a 70 kg patient) for systemic clearance and 46.4 L/h for the distribution clearance. Those values are consistent with literature findings. We were unable to show any significant relationship between collected covariates and dexmedetomidine PK. This study does not provide sufficient evidence to support the individualization of dexmedetomidine dosing based on age, sex, body weight, SOFA, and infusion duration.

Analgesic efficacy and safety of epidural oxycodone in patients undergoing total hip arthroplasty: a pilot study.

BACKGROUND AND OBJECTIVES: Oxycodone is poorly studied as an adjuvant to central blockades. The aim of this pilot study was to assess the efficacy and safety of oxycodone hydrochloride in epidural blockade among patients undergoing total hip arthroplasty (THA). PATIENTS AND METHODS: In 11 patients (American Society of Anesthesiologists physical status classification system II/III, age range: 59-82 years), THA was conducted with an epidural blockade using 15 mL 0.25% bupivacaine (37.5 mg) with 5 mg oxycodone hydrochloride and sedation with propofol infusion at a dose of 3-5 mg/kg/h. After the surgery, patients received ketoprofen at a dose of 100 mg twice daily. In the first 24 hours postoperative period, pain was assessed by numerical rating scale at rest and on movement; adverse effects (AEs) were recorded; and plasma concentrations of oxycodone, noroxycodone, and bupivacaine were measured. RESULTS: The administration of epidural oxycodone at a dose of 5 mg in patients undergoing THA provided analgesia for a mean time of 10.3±4.89 h. In one patient, mild pruritus was observed. Oxycodone did not evoke other AEs. Plasma concentrations of oxycodone while preserving analgesia were >2.9 ng/mL. Noroxycodone concentrations in plasma did not guarantee analgesic effect. CONCLUSION: The administration of epidural oxycodone at a dose of 5 mg prolongs the analgesia period to ~10 hours in patients after THA. Oxycodone may evoke pruritus. A 5 mg dose of oxycodone hydrochloride used in an epidural blockade seems to be a safe drug in patients after THA.

Flip-Flop Phenomenon in Epidural Sufentanil Pharmacokinetics: A Population Study in Children and Infants.

The aims of this study were to develop a population pharmacokinetic model of sufentanil coadministered with 0.2% ropivacaine as an epidural infusion in infants and describe the sufentanil absorption profile from epidural space. Data from 2 previously published studies were merged for analysis-20 infants aged 3-36 months receiving sufentanil as an epidural infusion and 41 children 0-17 years old receiving sufentanil as a long-term intravenous infusion. A population nonlinear mixed-effects model was built in NONMEM. Sufentanil pharmacokinetics were described by a 2-compartment model with first-order absorption. The effect of body size on all volume and clearance parameters was included in the model according to allometric scaling with theoretical exponents. The maturation process of metabolic clearance was described by the Hill model. During the model-building process the population was divided into 2 fractions with different typical values of metabolic clearance (CL1 and CL2). The typical values of systemic clearance scaled to a 70-kg patient for the 2 subpopulations were CL1 = 52.6 L/h and CL2 = 158 L/h. The parameters of the Hill function were 54.9 weeks for the postmenstrual age of 50% clearance maturation and 0.802 for the Hill coefficient. The typical values of distribution clearance and volumes of the central and peripheral compartments for a patient with a weight of 70 kg were Q = 40.5 L/h, VC = 7.63 L, and VT = 473 L, respectively. The value of the absorption rate constant from the epidural space was 0.0459/h, which suggests flip-flop pharmacokinetics of sufentanil after epidural administration.

HPLC-MS/MS method for dexmedetomidine quantification with Design of Experiments approach: application to pediatric pharmacokinetic study.

AIM: The purpose of this work was to develop and validate a rapid and robust LC-MS/MS method for the determination of dexmedetomidine (DEX) in plasma, suitable for analysis of a large number of samples. METHOD: Systematic approach, Design of Experiments, was applied to optimize ESI source parameters and to evaluate method robustness, therefore, a rapid, stable and cost-effective assay was developed. The method was validated according to US FDA guidelines. LLOQ was determined at 5 pg/ml. The assay was linear over the examined concentration range (5-2500 pg/ml), Results: Experimental design approach was applied for optimization of ESI source parameters and evaluation of method robustness. The method was validated according to the US FDA guidelines. LLOQ was determined at 5 pg/ml. The assay was linear over the examined concentration range (R2 > 0.98). The accuracies, intra- and interday precisions were less than 15%. The stability data confirmed reliable behavior of DEX under tested conditions. CONCLUSION: Application of Design of Experiments approach allowed for fast and efficient analytical method development and validation as well as for reduced usage of chemicals necessary for regular method optimization. The proposed technique was applied to determination of DEX pharmacokinetics in pediatric patients undergoing long-term sedation in the intensive care unit.

Influence of the Time of Intravenous Administration of Paracetamol on its Pharmacokinetics and Ocular Disposition in Rabbits.

BACKGROUND AND OBJECTIVES: Paracetamol is one of the most common analgesics and antipyretics applied in health care. The aim of the study was to investigate the influence of the time-of-day administration on the paracetamol pharmacokinetics and its penetration into aqueous humour (AH). METHODS: Rabbits were divided into three groups: I-receiving paracetamol at 08.00 h, II-receiving paracetamol at 16.00 h, and III-receiving paracetamol at 24.00 h. Paracetamol was administered intravenously at a single dose of 35 mg/kg. The concentrations of paracetamol and its metabolite (paracetamol glucuronide) in the plasma, as well as in AH were measured with the validated HPLC-UV method. RESULTS: No significant differences in the pharmacokinetic parameters of paracetamol was observed. When the drug was administered at 24.00 h,  elimination half-life (t 1/2kel) of paracetamol glucuronide was longer than when the drug was administered 08.00 h (P = 0.0193). In addition, a statistically significant increase in the paracetamol glucuronide/paracetamol ratio was observed when the drug was administered at 08.00 vs. 16.00 h (P ≤ 0.0001) and 24.00 h (P ≤ 0.0001). CONCLUSIONS: There was no chronobiological effect on the pharmacokinetic parameters of paracetamol.

The pharmacokinetics of propofol in ICU patients undergoing long-term sedation.

The aim of this study was to characterize the pharmacokinetics (PK) of propofol in ICU patients undergoing long-term sedation and to assess the influence of routinely collected covariates on the PK parameters. Propofol concentration-time profiles were collected from 29 patients. Non-linear mixed-effects modelling in NONMEM 7.2 was used to analyse the observed data. The propofol pharmacokinetics was best described with a three-compartment disposition model. Non-parametric bootstrap and a visual predictive check were used to evaluate the adequacy of the developed model to describe the observations. The typical value of the propofol clearance (1.46 l/min) approximated the hepatic blood flow. The volume of distribution at steady state was high and was equal to 955.1 l, which is consistent with other studies involving propofol in ICU patients. There was no statistically significant covariate relationship between PK parameters and opioid type, SOFA score on the day of admission, APACHE II, predicted death rate, reason for ICU admission (sepsis, trauma or surgery), gender, body weight, age, infusion duration and C-reactive protein concentration. The population PK model was developed successfully to describe the time-course of propofol concentration in ICU patients undergoing prolonged sedation. Despite a very heterogeneous group of patients, consistent PK profiles were observed. Copyright © 2016 John Wiley & Sons, Ltd.

The pharmacokinetics of dexmedetomidine during long-term infusion in critically ill pediatric patients. A Bayesian approach with informative priors.

The purpose of this study was to assess the pharmacokinetics of dexmedetomidine in the ICU settings during the prolonged infusion and to compare it with the existing literature data using the Bayesian population modeling with literature-based informative priors. Thirty-eight patients were included in the analysis with concentration measurements obtained at two occasions: first from 0 to 24 h after infusion initiation and second from 0 to 8 h after infusion end. Data analysis was conducted using WinBUGS software. The prior information on dexmedetomidine pharmacokinetics was elicited from the literature study pooling results from a relatively large group of 95 children. A two compartment PK model, with allometrically scaled parameters, maturation of clearance and t-student residual distribution on a log-scale was used to describe the data. The incorporation of time-dependent (different between two occasions) PK parameters improved the model. It was observed that volume of distribution is 1.5-fold higher during the second occasion. There was also an evidence of increased (1.3-fold) clearance for the second occasion with posterior probability equal to 62 %. This work demonstrated the usefulness of Bayesian modeling with informative priors in analyzing pharmacokinetic data and comparing it with existing literature knowledge.

Pharmacokinetics and pharmacodynamics of propofol and fentanyl in patients undergoing abdominal aortic surgery - a study of pharmacodynamic drug-drug interactions.

Propofol is routinely combined with opioid analgesics to ensure adequate anesthesia during surgery. The aim of the study was to assess the effect of fentanyl on the hypnotic effect of propofol and the possible clinical implications of this interaction. The pharmacokinetic/pharmacodynamic (PK/PD) data were obtained from 11 patients undergoing abdominal aortic surgery, classified as ASA III. Propofol was administered by a target-controlled infusion system. Fentanyl 2-3 µg/kg was given whenever insufficient analgesia occurred. The bispectral index (BIS) was used to monitor the depth of anesthesia. A population PK/PD analysis with a non-linear mixed-effect model (NONMEM 7.2 software) was conducted. Two-compartment models satisfactorily described the PK of propofol and fentanyl. The delay of the anesthetic effect in relation to PK was described by the effect compartment. The BIS was linked to propofol and fentanyl effect-site concentrations through an additive Emax model. Context-sensitive decrement times (CSDT) determined from the final model were used to assess the influence of fentanyl on the recovery after anesthesia. The population PK/PD model was successfully developed to describe simultaneously the time course and variability of propofol and fentanyl concentrations and BIS. Additive propofol-fentanyl interactions were observed and quantitated. The duration of the fentanyl infusion had minimal effect on CSDT when it was shorter than the duration of the propofol infusion. If the fentanyl infusion was longer than the propofol infusion, an almost two-fold increase in CSDT occurred. Additional doses of fentanyl administered after the cessation of the propofol infusion result in lower BIS values, and can prolong the time of recovery from anesthesia. Copyright © 2016 John Wiley & Sons, Ltd.

Analysis of the gene polymorphism of aldosterone synthase (CYP11B2) and atrial natriuretic peptide (ANP) in women with preeclampsia.

OBJECTIVE: Preeclampsia (PE) is a major cause of mortality of mothers, fetuses and newborns around the world. The etiology of preeclampsia has not yet been clarified, but many studies indicate a multifactorial basis of PE. Aldosterone synthase (CYP11B2) is responsible for synthesis of aldosterone responsible for regulating blood pressure. Similarly, natriuretic peptide (ANP) regulates blood pressure through a variety of mechanisms affecting the sodium concentration and the amount of extracellular fluid. Currently, attention is paid to the role of the polymorphisms in the expression level of these genes. The aim of the study was to determine the frequencies of genotypes and alleles for polymorphisms of -344C>T CYP11B2 gene and 2238T>C ANP gene in women with preeclampsia and healthy pregnant women from the Caucasian population. STUDY DESIGN: The study included a group of 165 pregnant women (59 women with preeclampsia and 109 healthy pregnant women). DNA was extracted from peripheral blood. Determination of the polymorphism of -344C>T CYP11B2 gene and 2238T>C ANP gene was performed by PCR-RFLP method. RESULTS: The results showed that the frequencies of the TC and CC genotypes of 2238T>C polymorphism in ANP gene were significantly higher in patients with PE compared to control group. For -344C>T polymorphism of CYP11B2 gene, the frequency of TT genotype was significantly higher in patients with hypertension than in controls (32.2% vs. 23.58%). CONCLUSIONS: Our findings showed that gene polymorphism of CYP11B2 (-344C>T) and ANP (2238T>C) may be associated with developing PE during pregnancy.

Pharmacokinetics of sufentanil during long-term infusion in critically ill pediatric patients.

The aim of this study was to develop a population pharmacokinetic model of sufentanil and to assess the influence of covariates in critically ill children admitted to a pediatric intensive care unit. After institutional approval, 41 children were enrolled in the study. Blood samples for pharmacokinetic (PK) assessment were collected from routinely placed arterial catheters during and after discontinuation of infusion. Population nonlinear mixed-effects modeling was performed using NONMEM. A 2-compartment model described sufentanil PK sufficiently. Typical values of the central and peripheral volume of distribution and the metabolic and intercompartmental clearance for a theoretical patient weighing 70 kg were VC = 7.90 l, VT = 481 L, Cl = 5.3 L/h, and Q = 38.3 L/h, respectively. High interindividual variability of all PK parameters was noted. Allometric/isometric principles to scale sufentanil PK revealed that to achieve the same steady-state sufentanil concentrations in plasma for pediatric patients of different body weights, the infusion rate should follow the formula (infusion rate for a 70-kg adult patient, µg/h) × (body weight/70 kg)(0.75). Severity of illness described by PRISM score, the monitored physiological and laboratory parameters, and coadministered drugs such as vasopressors were not found to be significant covariates.

Pharmacokinetics and pharmacodynamics of propofol in cancer patients undergoing major lung surgery.

Despite the growing number of cancer cases and cancer surgeries around the world, the pharmacokinetics (PK) and pharmacodynamics (PD) of anesthetics used in this population are poorly understood. Patients operated due to cancer are usually in severe state and often require chemotherapy. It might affect the PK/PD of drugs used in this population. Therefore, in this study we explored the PK/PD of propofol in cancer patients having a major lung surgery. 23 patients that underwent a propofol-fentanyl total intravenous anesthesia were included in the analysis. A large set of demographic, biochemical and hemodynamic parameters was collected for the purpose of covariate analysis. Nonlinear mixed effect modeling in NONMEM was used to analyze the collected data. A three-compartment model was sufficient to describe PK of propofol. The anesthetic effect (AAI index) was linked to the propofol effect site concentrations through a sigmoidal E max model. A slightly higher value of clearance, a lower value of distribution clearance, and a decreased volume of peripheral compartment were observed in our patients, as compared with the literature values reported for healthy volunteers by Schnider et al. and by Eleveld et al. Despite these differences, both models led to a clinically insignificant bias of -8 and -1 % in concentration predictions, as reflected by the median performance error. The C e50 and propofol biophase concentration at the time of postoperative orientation were low and equaled 1.40 and 1.13 mg/L. The population PK/PD model was proposed for cancer patients undergoing a major lung surgery. The large body of studied covariates did not affect PK/PD of propofol significantly. The modification of propofol dosage in the group of patients under study is not necessary when TCI-guided administration of propofol by means of the Schnider model is used.

Melatonin and clonidine premedication has similar impact on the pharmacokinetics and pharmacodynamics of propofol target controlled-infusions.

Recently oral melatonin has been proposed as an agent for premedication. In this study, we compared melatonin with clonidine, considering its anxiolytic properties as well as the influence of both agents on the pharmacokinetic, hypnotic, and hemodynamic effects of propofol during propofol-remifentanil total intravenous anesthesia (TIVA). The dataset under analysis included 32 patients scheduled for a functional endoscopic sinus surgery. The population pharmacokinetic modeling was done with NONMEM. The PK of propofol was described with a two-compartment disposition model, whereas the BIS and AAI were described with a sigmoidal Emax model linked with the propofol concentration via the biophase compartment. The anxiolytic effect was assessed by means of the visual analog scale for anxiety (VAS-A). The population PK/PD model was successfully developed to describe the data. No significant differences in the PK/PD of propofol were noted due to the premedication with clonidine and melatonin. Melatonin was less effective than clonidine in reducing patients' anxiety at the induction of anesthesia, whereas clonidine premedication was associated with greater decrease in heart rate and blood pressure. A decreased EC50 (2.47 vs. 3.17 mg/L) and increased slope (2.71 vs. 1.30) of the sigmoidal Emax relationship was observed for the AAI index, as compared with the BIS measurements.