Estimation of the Loading Dose for Target-Controlled Infusion of Dexmedetomidine. Reply to Eleveld et al. Comment on "Morse et al. A Universal Pharmacokinetic Model for Dexmedetomidine in Children and Adults. J. Clin. Med. 2020, 9, 3480".

The parameters for a three-compartment model described by Morse and colleagues [...].

A Universal Pharmacokinetic Model for Dexmedetomidine in Children and Adults.

A universal pharmacokinetic model was developed from pooled paediatric and adult data (40.6 postmenstrual weeks, 70.8 years, 3.1-152 kg). A three-compartment pharmacokinetic model with first-order elimination was superior to a two-compartment model to describe these pooled dexmedetomidine data. Population parameter estimates (population parameter variability%) were clearance (CL) 0.9 L/min/70 kg (36); intercompartmental clearances (Q2) 1.68 L/min/70 kg (63); Q3 0.62 L/min/70 kg (90); volume of distribution in the central compartment (V1) 25.2 L/70 kg (103.9); rapidly equilibrating peripheral compartment (V2) 34.4 L/70 kg (41.8); slow equilibrating peripheral compartment (V3) 65.4 L/70 kg (62). Obesity was best described by fat-free mass for clearances and normal fat mass for volumes with a factor for fat mass (FfatV) of 0.293. Models describing dexmedetomidine pharmacokinetics in adults can be applied to children by accounting for size (allometry) and age (maturation). This universal dexmedetomidine model is applicable to a broad range of ages and weights: neonates through to obese adults. Lean body weight is a better size descriptor for dexmedetomidine clearance than total body weight. This parameter set could be programmed into target-controlled infusion pumps for use in a broad population.

Pharmacokinetic and pharmacodynamic considerations of general anesthesia in pediatric subjects.

Introduction: The target concentration strategy uses PKPD information for dose determination. Models have also quantified exposure-response relationships, improved understanding of developmental pharmacokinetics, rationalized dose prescription, provided insight into the importance of covariate information, explained drug interactions and driven decision-making and learning during drug development.Areas covered: The prime PKPD consideration is parameter estimation and quantification of variability. The main sources of variability in children are age (maturation) and weight (size). Model use is mostly confined to pharmacokinetics, partly because anesthesia effect models in the young are imprecise. Exploration of PK and PD covariates and their variability hold potential to better individualize treatment.Expert opinion: The ability to model drugs using computer-based technology is hindered because covariate data required to individualize treatment using these programs remain lacking. Target concentration intervention strategies remain incomplete because covariate information that might better predict individualization of dose is absent. Pharmacogenomics appear a valuable area for investigation for pharmacodynamics and pharmacodynamics. Effect measures in the very young are imprecise. Assessment of the analgesic component of anesthesia is crude. While neuromuscular monitoring is satisfactory, depth of anaesthesia EEG interpretation is inadequate. Closed loop anesthesia is possible with better understanding of EEG changes.

Differential frontal alpha oscillations and mechanisms underlying loss of consciousness: a comparison between slow and fast propofol infusion rates.

Mechanisms underlying loss of consciousness following propofol administration remain incompletely understood. The objective of this study was to compare frontal lobe electroencephalography activity and brainstem reflexes during intravenous induction of general anaesthesia, in patients receiving a typical bolus dose (fast infusion) of propofol compared with a slower infusion rate. We sought to determine whether brainstem suppression ('bottom-up') predominates over loss of cortical function ('top-down'). Sixteen ASA physical status-1 patients were randomly assigned to either a fast or slow propofol infusion group. Loss of consciousness and brainstem reflexes were assessed every 30 s by a neurologist blinded to treatment allocation. We performed a multitaper spectral analysis of all electroencephalography data obtained from each participant. Brainstem reflexes were present in all eight patients in the slow infusion group, while being absent in all patients in the fast infusion group, at the moment of loss of consciousness (p = 0.010). An increase in alpha band power was observed before loss of consciousness only in participants allocated to the slow infusion group. Alpha band power emerged several minutes after the loss of consciousness in participants allocated to the fast infusion group. Our results show a predominance of 'bottom-up' mechanisms during fast infusion rates and 'top-down' mechanisms during slow infusion rates. The underlying mechanisms by which propofol induces loss of consciousness are potentially influenced by the speed of infusion.

Pharmacokinetics of levobupivacaine with epinephrine in transversus abdominis plane block for postoperative analgesia after Caesarean section.

BACKGROUND: Transversus abdominis plane block is increasingly used for post-Caesarean section analgesia. Cases of toxicity and the limited pharmacokinetic information during pregnancy motivated this study. The objective of the study was to characterise and compare the pharmacokinetics of levobupivacaine with epinephrine in tranversus abdominis plane block, in post-Caesarean section patients and healthy volunteers. METHODS: After approval by the Ethics Committee, we collected data from 12 healthy parturients after elective Caesarean section (Study 1) and data from 11 healthy male volunteers from a previous study (Study 2). Transversus abdominus plane block was performed under ultrasound guidance. The following injectates were used: levobupivacaine 0.25%, 20 ml with epinephrine 5 µg ml-1 (Study 1) per side; 20 ml of the same solution (unilateral block) (study 2). The plasma venous concentration of levobupivacaine was measured serially for 90 min. Pharmacokinetic parameters (volume of distribution, clearance, and absorption half-life) were estimated using a non-linear mixed effects model (NONMEM). Simulation in 1000 patients estimated the maximum concentration and the time to reach it after bilateral transversus abdominis plane block. RESULTS: Venous concentrations were below toxic levels (2.62 mg L-1). Levobupivacaine volume of distribution after Caesarean section was higher than in healthy volunteers [172 L (70 kg)-1 (95% confidence interval: 137-207) vs 94.3 L (70 kg)-1 (95% CI: 62-128); P<0.01]. Clearance and absorption half-life were similar. The simulation showed that maximum levobupivacaine concentration is lower and occurs later in postpartum patients (P<0.01). Postoperative analgesia was effective. CONCLUSIONS: Postpartum women reached relatively low plasma concentrations of levobupivacaine after transversus abdominal plane block given a volume of distribution 80% higher than volunteers, which could confer a greater margin of safety. CLINICAL TRIAL REGISTRATION: NCT02852720.

Dexmedetomidine metabolic clearance is not affected by fat mass in obese patients.

BACKGROUND: Obesity has been associated with reduced dexmedetomidine clearance, suggesting impaired hepatic function or reduced hepatic blood flow. The aim of this study was to clarify the effect of obesity in dexmedetomidine metabolic clearance. METHODS: Forty patients, ASA I-III, 18-60 yr old, weighing 47-126 kg, scheduled for abdominal laparoscopic surgery, were enrolled. Anaesthetic agents (propofol, remifentanil, and dexmedetomidine) were dosed based on lean body weight measured by dual X-ray absorptiometry. Serial venous samples were drawn during and after dexmedetomidine infusion. A pharmacokinetic analysis was undertaken using non-linear mixed-effect models. In the modelling approach, the total body weight, lean body weight, and adjusted body weight were first tested as size descriptors for volumes and clearances. Hepatic blood flow, liver histopathology, liver enzymes, and gene expression of metabolic enzymes (UGT2B10 and UGT1A4) were tested as covariates of dexmedetomidine metabolic clearance. A decrease in NONMEM objective function value (ΔOFV) of 3.84 points, for an added parameter, was considered significant at the 0.05 level. RESULTS: A total of 637 dexmedetomidine serum samples were obtained. A two-compartmental model scaled to measured lean weight adequately described the dexmedetomidine pharmacokinetics. Liver blood flow was a covariate for dexmedetomidine clearance (ΔOFV=-5.878). Other factors, including fat mass, histopathological damage, and differential expression of enzymes, did not affect the dexmedetomidine clearance in the population studied (ΔOFV<3.84). CONCLUSIONS: We did not find a negative influence of obesity in dexmedetomidine clearance when doses were adjusted to lean body weight. Liver blood flow showed a significant effect on dexmedetomidine clearance. CLINICAL TRIAL REGISTRATION: NCT02557867.

Levobupivacaine absorption pharmacokinetics with and without epinephrine during TAP block: analysis of doses based on the associated risk of local anaesthetic toxicity.

PURPOSE: Cases of local anaesthetic systemic toxicity (LAST) periodically occur following transversus abdominal plane (TAP) blocks. The aim of this study was to characterize levobupivacaine absorption pharmacokinetics, with and without epinephrine, and estimate the risk of LAST, based on a previously reported toxic threshold. METHODS: Previously reported data from 11 volunteers receiving ultrasound-guided TAP blocks with and without epinephrine on two independent occasions were analysed. Serial venous concentrations were measured for 90 min. A pharmacokinetic analysis was performed using the NONMEM statistical programme. The use of epinephrine in the solution was included in the analysis of covariates. The associated risk of LAST symptoms associated with different levobupivacaine dose schemes with and without epinephrine was estimated in 1000 simulated subjects. RESULTS: A one-compartment first-order input and elimination model adequately fit the levobupivacaine data. Epinephrine prolonged the levobupivacaine absorption half-life {4.22 [95 % confidence interval (CI) 2.53-6.50] vs. 7.02 [95 % CI 3.74-14.1]; p < 0.05} and reduced its relative bioavailability (0.84; 95 % CI 0.72-0.97; p < 0.05) The derived model predicts that levobupivacaine dose schemes should be halved from 3 mg kg(-1) body weight with epinephrine to 1.5 mg kg(-1) without epinephrine to obtain a comparable risk of anaesthetic toxicity symptoms of approximately 0.1 %. CONCLUSIONS: Our results strongly support the addition of epinephrine to the local anaesthetic solution, especially when doses of levobupivacaine of >1.5 mg kg(-1) are required. Recommendations regarding the maximum allowable doses of local anaesthetics should consider population analysis to determine safer dosage ranges.

Comparison of the Cortínez and the Schnider models with a targeted effect-site TCI of 3 mcg/ml in biophase in healthy volunteers. / Comparación del modelo de Cortínez y de Schnider en perfusión de propofol controlada por objetivo de 3 mcg/ml, a biofase, en voluntarios sanos.

OBJECTIVE: To compare the Cortínez and Schnider models in effect-site TCI mode (3 mcg/ml) in healthy volunteers. METHODS: Ten healthy volunteers were prospectively studied on 2 occasions. Propofol was administered with the Cortínez or the Schnider models, as randomly assigned. Times and predicted concentrations at the time of loss and recovery of consciousness (LOC and ROC), mass of drug administered, BIS, and haemodynamic variables were compared. Statistical analysis was with paired Wilcoxon test. A P<.05 was considered significant. RESULTS: The propofol bolo was higher (1.4 [1.3-1.6] versus 0.9 [0.7-1.3] mg/kg, P=.005) and the LOC occurred earlier (1.33 [0.67-6.83] versus 3.87 [1.66-11.08] minutes, P=.02) with the Cortínez model compared to the Schnider model. With the Cortínez model, LOC occurred at an effect site concentrations of 2.6 (1.65-3.0) mcg/ml. With the Schnider model, LOC occurred at 3.87 min (1.66-11.8) after reaching the target of 3 mcg/ml. (P=.001). BIS values, infusion rates, and haemodynamic variables were similar between models after 20minutes of infusion (P>.5). Recovery (ROC) was longer with the Cortínez model (11.6 [8.1-16.2] vs. 8.5 [4.7-15.5] min, P=.003). CONCLUSIONS: The Cortínez model is a good alternative to the Schnider model for use in effect-site TCI mode in normal weight subjects. With the target used in this study (3 mcg/ml), the slower Ke0 incorporated into the Cortínez model better discriminated the LOC time.

Post-operative cognitive dysfunction at 3 months in adults after non-cardiac surgery: a qualitative systematic review.

BACKGROUND: Post-operative cognitive dysfunction is defined as a decline in cognitive functions that occurs after surgery, but different diagnostic criteria and incidences have been reported in medical literature. Our aim was to determine incidence of post-operative cognitive dysfunction 3 months after non-cardiac surgery in adults. METHODS: A systematic review of available evidence was performed by PRISMA guidelines. A search was done in May-July 2015 on PubMed, EMBASE, CINAHL, LILACS, Scielo, Clinical Trials, and Grey Literature Reports. Inclusion criteria were prospective design studies with patients over 18 years old, surgery under general or regional anesthesia, follow-up for 3 months, and use of a neurocognitive battery for diagnosis. We excluded studies made on cardiac or brain surgery patients. Risk of bias was assessed using tools from National Heart Lung and Blood Institute. RESULTS: We selected 24 studies. Average age was 68 years. Only five studies reported incidence of cognitive decline for a non-surgical control group. Median number of tests used was 5 (range 3-13). Pooled incidence of post-operative cognitive dysfunction at 3 months was 11.7% [95% CI 10.9-12.5] but with several methodological differences between studies. Increasing age was the most consistent risk factor identified (seven studies). CONCLUSIONS: Post-operative cognitive dysfunction in patients is frequent, especially in patients over 60 years old. Limitations include methodological differences in studies. Efforts must be made to reach a consensus in definition and diagnosis for future research.

Rocuronium pharmacokinetics and pharmacodynamics in the adductor pollicis and masseter muscles.

BACKGROUND: The aim of this study was to characterize the dose-effect relationship of rocuronium at the adductor pollicis and masseter muscles. METHODS: Ten, ASA I, adult patients, received a bolus dose of rocuronium 0.3 mg/kg during propofol based anesthesia. Train-of-four (TOF) was simultaneously monitored at the masseter and the adductor pollicis muscles until recovery. Rocuronium arterial serum concentrations were measured during 120 min. The first twitch of the TOF response was used to characterize the time-effect profile of both muscles using pharmacokinetic-pharmacodynamic analysis in NONMEM. A decrease in NONMEM objective function (∆OFV) of 3.84 points for an added parameter was considered significant at the 0.05 level. RESULTS: Onset time at the masseter (mean ± SD, 1.5 ± 0.9 min) was faster than at the adductor pollicis (2.7 ± 1.4 min, P < 0.05). Recovery, measured as the time to TOF ratio = 0.9 was similar between muscles 29.9 ± 6.7 (adductor pollicis) vs. 29.3 ± 8.1 (masseter). (P = 0.77). The estimated pharmacodynamic parameters [mean (95% CI)] of the adductor pollicis muscle and the masseter muscle were; plasma effect-site equilibration half-time (teq) 3.25 (2.34, 3.69) min vs. 2.86 (1.83, 3.29) min, (∆OFV 383.665); Ce50 of 1.24 (1.13, 1.56) mg/l vs. 1.19 (1.00, 1.21) mg/l, (∆OFV 184.284); Hill coefficient of 3.97 (3.82, 5.62) vs. 4.68 (3.83, 5.71), (∆OFV 78.906). CONCLUSIONS: We found that the masseter muscle has faster onset of blockade and similar recovery profile than adductor pollicis muscle. These findings were best, explained by a faster plasma effect-site equilibration of the masseter muscle to rocuronium.

Effect of intravenous fluid therapy on postoperative vomiting in children undergoing tonsillectomy.

BACKGROUND: Postoperative vomiting (POV) is one of the most frequent complications of tonsillectomy in children. The aim of this study was to evaluate the antiemetic effect of super-hydration with lactated Ringer's solution in children undergoing elective otorhinolaryngological surgery. METHODS: One hundred ASA I-II children, aged 1-12 yr, undergoing elective tonsillectomy, with or without adenoidectomy, under general anaesthesia were studied. Induction and maintenance of anaesthesia were standardized with fentanyl, mivacurium, and sevoflurane in N(2)O/O(2). Subjects were assigned to one of the two groups: 10 ml kg(-1) h(-1) lactated Ringer's solution or 30 ml kg(-1) h(-1) lactated Ringer's solution. A multivariable logistic regression was used for assessing the effects of super-hydration on POV (defined as the presence of retching, vomiting, or both). A value of P<0.05 was considered statistically significant. RESULTS: During the first 24 h postoperative, the incidence of POV decreased from 82% to 62% (relative reduction of 24%, P=0.026). In the adjusted logistic regression model, subjects in the 10 ml kg(-1) h(-1) group had an odds ratio of POV that was 2.92 (95% confidence interval: 1.14, 7.51) for POV compared with subjects in the 30 ml kg(-1) h(-1) group. CONCLUSIONS: Intraoperative administration of 30 ml kg(-1) h(-1) lactated Ringer's solution significantly reduced the incidence of POV during the first 24 h postoperative. Our results support the use of super-hydration during tonsillectomy, as an alternative way to decrease the risk of POV in children.

Evaluation of the effect of intravenous lidocaine on propofol requirements during total intravenous anaesthesia as measured by bispectral index.

BACKGROUND: I.V. lidocaine is increasingly used as an adjuvant during general anaesthesia. The aim of this study was to evaluate the effect of i.v. lidocaine in reducing propofol anaesthetic requirements during total i.v. anaesthesia (TIVA) maintenance and to evaluate its effect on early recovery from anaesthesia. METHODS: Forty adult patients undergoing elective laparoscopic cholecystectomy under TIVA were randomly allocated into the lidocaine group (administered 1.5 mg kg(-1) i.v. lidocaine over 5 min followed by 2 mg kg(-1) h(-1)) and the control group (administered an equal volume of saline). Propofol was administered using a target-controlled infusion to maintain the bispectral index values between 40 and 60. After surgery, all infusions were discontinued and the time to extubation was recorded. Serial arterial blood samples were drawn to assess drug plasma levels. RESULTS: The maintenance dose of propofol was significantly lower in the lidocaine group [6.00 (0.97) mg kg(-1) h(-1)] vs the control group [7.25 (1.13) mg kg(-1) h(-1); P=0.01]. Propofol plasma levels measured at the end of the infusion were 3.71 (0.89) µg ml(-1) in the lidocaine group and 3.67 (1.28) µg ml(-1) in the control group (P=0.91). The median time to extubation was longer (11.0 min; range: 10.0-21.0) in the lidocaine group vs the control group (8.3 min; range: 5.5-12.5; P=0.02). CONCLUSIONS: I.V. lidocaine reduces propofol requirements during the maintenance phase of TIVA, particularly during surgical stimulation. This sparing effect is associated with an increased time to extubation. Owing to its effect on early recovery from anaesthesia, i.v. lidocaine should be taken into account when used as a component of i.v. anaesthesia.

Nitrous oxide (N(2)O) reduces postoperative opioid-induced hyperalgesia after remifentanil-propofol anaesthesia in humans.

BACKGROUND: The aim of this study was to test if intraoperative administration of N(2)O during propofol-remifentanil anaesthesia prevented the onset of postoperative opioid-induced hyperalgesia (OIH). METHODS: Fifty adult ASA I-II patients undergoing elective open septorhinoplasty under general anaesthesia were studied. Anaesthesia was with propofol, adjusted to bispectral index (40-50), and remifentanil (0.30 µg kg(-1) min(-1)). Patients were assigned to one of the two groups: with N(2)O (70%) and without N(2)O (100% oxygen). Mechanical pain thresholds were measured before surgery and 2 and 12-18 h after surgery. Pain measurements were performed on the arm using hand-held von Frey filaments. A non-parametric analysis of variance was used in the von Frey data analysis. P<0.05 was considered statistically significant. RESULTS: Baseline pain thresholds to mechanical stimuli were similar in both groups, with mean values of 69 [95% confidence interval (CI): 50.2, 95.1] g in the group without N(2)O and 71 (95% CI: 45.7, 112.1) g in the group with N(2)O. Postoperative pain scores and cumulative morphine consumption were similar between the groups. The analysis revealed a decrease in the threshold value in both groups. However, post hoc comparisons showed that at 12-18 h after surgery, the decrease in mechanical threshold was greater in the group without N(2)O than the group with N(2)O (post hoc analysis with Bonferroni's correction, P<0.05). CONCLUSIONS: Intraoperative 70% N(2)O administration significantly reduced postoperative OIH in patients receiving propofol-remifentanil anaesthesia.

Performance evaluation of paediatric propofol pharmacokinetic models in healthy young children.

BACKGROUND: The performance of eight currently available paediatric propofol pharmacokinetic models in target-controlled infusions (TCIs) was assessed, in healthy children from 3 to 26 months of age. METHODS: Forty-one, ASA I-II children, aged 3-26 months were studied. After the induction of general anaesthesia with sevoflurane and remifentanil, a propofol bolus dose of 2.5 mg kg(-1) followed by an infusion of 8 mg kg(-1) h(-1) was given. Arterial blood samples were collected at 1, 2, 3, 5, 10, 20, 40, and 60 min post-bolus, at the end of surgery, and at 1, 3, 5, 30, 60, and 120 min after stopping the infusion. Model performance was visually inspected with measured/predicted plots. Median performance error (MDPE) and the median absolute performance error (MDAPE) were calculated to measure bias and accuracy of each model. RESULTS: Performance of the eight models tested differed markedly during the different stages of propofol administration. Most models underestimated propofol concentration 1 min after the bolus dose, suggesting an overestimation of the initial volume of distribution. Six of the eight models tested were within the accepted limits of performance (MDPE<20% and MDAPE<30%). The model derived by Short and colleagues performed best. CONCLUSIONS: Our results suggest that six of the eight models tested perform well in young children. Since most models overestimate the initial volume of distribution, the use for TCI might result in the administration of larger bolus doses than necessary.

Influence of obesity on propofol pharmacokinetics: derivation of a pharmacokinetic model.

BACKGROUND: The objective of this study was to develop a pharmacokinetic (PK) model to characterize the influence of obesity on propofol PK parameters. METHODS: Nineteen obese ASA II patients undergoing bariatric surgery were studied. Patients received propofol 2 mg kg(-1) bolus dose followed by a 5-20-40-120 min, 10-8-6-5 mg kg(-1) h(-1) infusion. Arterial blood samples were withdrawn at 1, 3, 5 min after induction, every 10-20 min during propofol infusion, and every 10-30 min for 2 h after stopping the propofol infusion. Arterial samples were processed by high-performance liquid chromatography. Time-concentration data profiles from this study were pooled with data from two other propofol PK studies available at http://www.opentci.org. Population PK modelling was performed using non-linear mixed effects model. RESULTS: The study involved 19 obese adults who contributed 163 observations. The pooled analysis involved 51 patients (weight 93 sd 24 kg, range 44-160 kg; age 46 sd 16 yr, range 25-81 yr; BMI 33 sd 9 kg m(-2), range 16-52 kg m(-2)). A three-compartment model was used to investigate propofol PK. An allometric size model using total body weight (TBW) was superior to all other models investigated (linear TBW, free fat mass, lean body weight, normal fat mass) for all clearance parameters. Variability in V2 and Q2 was reduced by a function showing a decrease in both parameters with age. CONCLUSIONS: We have derived a population PK model using obese and non-obese data to characterize propofol PK over a wide range of body weights. An allometric model using TBW as the size descriptor of volumes and clearances was superior to other size descriptors to characterize propofol PK in obese patients.