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.

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.

Predictive ability of propofol effect-site concentrations during fast and slow infusion rates.

BACKGROUND: The performance of propofol effect-site pharmacokinetic models during target-controlled infusion (TCI) might be affected by propofol administration rate. This study compares the predictive ability of three effect-site pharmacokinetic models during fast and slow infusion rates, utilizing the cerebral state index (CSI) as a monitor of consciousness. METHODS: Sixteen healthy volunteers, 21-45 years of age, were randomly assigned to receive either a bolus dose of propofol 1.8 mg/kg at a rate of 1200 ml/h or an infusion of 12 mg/kg/h until 3-5 min after loss of consciousness (LOC). After spontaneous recovery of the CSI, the bolus was administered to patients who had first received the infusion and vice versa. The study was completed after spontaneous recovery of CSI following the second dose scheme. LOC was assessed and recorded when it occurred. Adequacies of model predictions during both administration schemes were assessed by comparing the effect-site concentrations estimated at the time of LOC during the bolus dose and during the infusion scheme. RESULTS: LOC occurred 0.97 +/- 0.29 min after the bolus dose and 6.77 +/- 3.82 min after beginning the infusion scheme (P<0.05). The Ce estimated with Schnider (ke0=0.45/min), Marsh (ke0=1.21/min) and Marsh (ke0=0.26/min) at LOC were 4.40 +/- 1.45, 3.55 +/- 0.64 and 1.28 +/- 0.44 microg/ml during the bolus dose and 2.81 +/- 0.61, 2.50 +/- 0.39 and 1.72 +/- 0.41 microg/ml, during the infusion scheme (P<0.05). The CSI values observed at LOC were 70 +/- 4 during the bolus dose and 71 +/- 2 during the infusion scheme (NS). CONCLUSION: Speed of infusion, within the ranges allowed by TCI pumps, significantly affects the accuracy of Ce predictions. The CSI monitor was shown to be a useful tool to predict LOC in both rapid and slow infusion schemes.

Propofol consumption and recovery times after bispectral index or cerebral state index guidance of anaesthesia.

BACKGROUND: We compared the propofol requirements and recovery times when either the bispectral index (BIS) monitor or the cerebral state monitor (CSM) is used to guide propofol anaesthesia. METHODS: Forty patients undergoing laparoscopic cholecystectomy were studied. All patients were monitored with both monitors and were randomly allocated into two groups according to the monitor used to titrate propofol administration. Propofol was administered to maintain BIS or CSM within 40 and 60. Propofol consumption and clinical markers of recovery were assessed after surgery. RESULTS: In the CSM group, the values of cerebral state index (CSI) and BIS were 47 (5) and 38 (6), respectively (P=0.00054). In the BIS group, the values of CSI and BIS were 47 (5) and 45 (2), respectively (P=0.15). In the BIS group, the total amount of propofol used was lower [109 (20) microg kg(-1) min(-1)] than in the CSM group [130 (27) microg kg(-1) min(-1)] (P=0.018). The time to eye opening was lower in the BIS [7.2 (3.5) min] than in the CSM group [10.7 (6.6)] (P=0.038). There were no differences in fentanyl consumption, or in other clinical markers of recovery. CONCLUSIONS: Compared with BIS, propofol anaesthesia guided with CSI resulted in 20% higher propofol doses. This, however, does not lead to clinically relevant differences in recovery times.

Prospective evaluation of the time to peak effect of propofol to target the effect site in children.

BACKGROUND: The plasma-effect site equilibration rate constant (k(e0)) of propofol has been determined in children with the use of the time to maximum effect (t(peak)), however, it has not been validated. The objective was to measure the t(peak;) of propofol with two depths of anesthesia monitors in children and to evaluate these measurements with a target-controlled infusion (TCI) system. METHODS: Unpremedicated, ASA I children from 3 to 11 years were studied. In Part 1, children were monitored simultaneously with the bispectral index (BIS) and the A-Line ARX-index (AAI) from the Alaris A-Line auditory-evoked potential monitor/2. The t(peak) after a bolus dose of propofol was measured. In Part 2, the t(peak) measured was used to target the effect site with a TCI system. The median (MD) and the absolute median (MDA) difference between the predicted time of peak concentration at the effect site (Ce) and the measured time of peak effect in the index of depth of anesthesia (t(error)) was used to evaluate the performance of the system. RESULTS: The BIS recordings were of a better quality than the AAI. The mean +/- standard deviation t(peak) was 65 +/- 14 s with the BIS (n=25) and 201 +/- 74 s with the AAI (n=10)(P<0.001). Validation was only performed with the BIS monitor in 40 children, yielding an MD t(error) of -9.5 s and an MDA t(error) of 10.0 s. CONCLUSIONS: The small delay between the evolution of Ce of propofol and the observed effect suggests that this can be a useful model to target the effect site in children.

Estimation of the plasma effect-site equilibration rate constant (ke0) of rocuronium by the time of maximum effect: a comparison with non-parametric and parametric approaches.

BACKGROUND: The first order plasma-effect-site equilibration rate constant (k(e0)) links the pharmacokinetics (PK) and pharmacodynamics (PD) of a given drug. For the calculation of the k(e0), one method uses a single point of the response curve corresponding to the time to peak effect of a drug (t(peak)); however, it has not been validated. This study compares the k(e0) calculated with the method of t(peak) and the k(e0) calculated with traditional non-parametric and parametric methods. METHODS: Fifteen adult patients receiving total intravenous anaesthesia (TIVA) were studied. All patients were monitored with an NMT Monitor 221 (GE Healthcare, Helsinki, Finland) to obtain the evoked compound EMG of the adductor pollicis to a train-of-four stimuli at 10 s intervals. During TIVA, rocuronium 0.15 mg kg(-1) was given i.v. as a bolus, and the neuromuscular response was recorded until recovery from block. Using the t(peak) and the complete response curve, k(e0) of rocuronium was calculated with the three methods using the predicted plasma concentrations of rocuronium from a PK model. Values of k(e0) are median (range). RESULTS: The k(e0)s obtained were 0.19 min(-1) (0.09-0.72) with the 't(peak)' method, 0.20 min(-1) (0.14-0.44) with the non-parametric method, and 0.19 min(-1) (0.11-0.38) [typical value (range)] with the parametric method (NS). CONCLUSIONS: If the t(peak) can be adequately estimated from the data, the 't(peak) method' is a valid alternative to traditional methods to calculate the k(e0).

[Anesthesia for electroconvulsive therapy: clinical experience]. / Anestesia en terapia electroconvulsiva. Experiencia clínica.

OBJECTIVE: To assess the utility of propofol and succinylcholine in obtaining optimal convulsions and assuring patient safety during electroconvulsive therapy. PATIENTS AND METHODS: This was a prospective observational study of patients undergoing electroconvulsive therapy under general anesthesia with propofol and succinylcholine. We recorded patient characteristics, doses of propofol and succinylcholine, electroencephalographically-recorded duration of convulsions, and complications. Descriptive statistics were compiled and the data were subjected to analysis of correlations, comparison with the Student t test for independent samples, the Mann-Whitney U test, and analysis of variance. RESULTS: We studied 108 patients, 62% women and 38% men, 80% classified as ASA 1 and 20% as ASA 2. The patients underwent 844 sessions of electroconvulsive therapy; their mean (SD) age was 39.95 (18.09) years. The doses of propofol and succinylcholine were 1.34 (0.32) mgxkg(-1) and 1.35 (0.26) mgxkg(-1), respectively. The mean recorded duration of the first convulsion (29.87 [22.42] seconds) was negatively correlated with age (r = -0.12) and unrelated to propofol dose (r = 0.06) or body weight (r = 0.02). Male and schizophrenic patients had longer-lasting convulsions (P < .01). Cardiovascular complications occurred in 2.4% and psychomotor agitation in 1.4%; there were no respiratory complications, musculoskeletal injuries, nausea, or vomiting. CONCLUSIONS: Electroconvulsive therapy can be safely applied in an operating room or similar space undergeneral anesthesia and with a neuromuscular blockade in order to prevent psychological or musculoskeletal trauma. Propofol did not affect the convulsions at the dosages administered.

[Pharmacodynamics of propofol in children and adults: comparison based on the auditory evoked potentials index]. / Farmacodinamia del propofol en niños y adultos: comparación usando el índice de potenciales evocados auditivos.

INTRODUCTION: The clinically useful concentrations of propofol to provide loss of consciousness in children have not been determined. Therefore, target-controlled infusion systems are used with parameters taken from results for adults. As a result, hypnosis can be inadequate in the pediatric population. We studied the dose-response relationship by comparing the predicted effect-site concentration (Ce) and the level of hypnosis measured by a monitor of depth of anesthesia based on auditory evoked potentials. MATERIAL AND METHODS: After injection of a submaximal bolus dose of propofol, the auditory evoked potential index was measured in 25 children (3-11 years old) and 25 adults (35-48 years old). We calculated the predicted Ce of propofol using the plasma effect-site equilibration rate constant (ke0) for each patient and the pharmacodynamic parameters of propofol for adults from the model of Schnider and for children from the models of Kataria and of the Paedfusor system. The relation of Ce to evoked potentials was analyzed with a sigmoid Emax model in the NONMEM program. RESULTS: The mean (SD) propofol doses in adults and children were 1.6 (0.1) mg x kg(-1) and 2.7 (0.3) mg x kg(-1), respectively. The Ce associated with auditory evoked potentials at 50% of the maximum effect (Ce50) for adults was 6.45 (0.59) microg/mL(-1), which was significantly higher than that estimated by either model for children (Kataria, 2.06 [0.24] microg/mL(-1); Paedfusor, 3.56 [0.22] microg/mL; P<0.001 between adults and children for both models). CONCLUSION: Children seem to be more sensitive to propofol than adults, suggesting that the higher dose requirements described for children would be attributable to pharmacokinetic differences between the 2 populations.

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.

Effect site concentrations of propofol producing hypnosis in children and adults: comparison using the bispectral index.

BACKGROUND: No study has determined the concentration of propofol producing a degree of hypnosis compatible with anaesthesia in children. As a result, concentrations determined in adults are recommended for children. As this can result in an inadequate depth of anaesthesia, we determined the predicted effect site concentration (C(e)) of propofol necessary to obtain a bispectral index (BIS) of 50 in 50% (EC(e50)) of children and adults. METHODS: Twenty adults (aged 33-44 years) and 20 children (aged 3-11 years) undergoing surgery under general anaesthesia were studied. All were monitored with a BIS monitor, and a target controlled infusion of propofol aiming for a constant C(e) value was started. After 10 min, patients were evaluated using a sedation scale, and the last 5 min was used to determine the mean BIS for this C(e) value. The C(e) value of propofol was defined using the up-and-down method of Dixon and Massey. The first patient in each group received C(e)= 6 microg/ml; thereafter, it was modified in 0.5 microg/ml decrements/increments with positive or negative responses, respectively. A positive response was BIS < 50 and a negative response was BIS > or = 50. The EC(e50) value was compared using unpaired Student's t-test. The prediction probability (P(K)) was used to study the association between BIS and the sedation score. RESULTS: The mean EC(e50) (95% confidence interval) values were 3.75 microg/ml (2.97-4.75 microg/ml) in adults and 3.65 microg/ml (3.36-3.96 microg/ml) in children (not significant). All patients with BIS < 50 were unarousable with tactile stimulation. The P(K) value was 0.99 in both groups. CONCLUSIONS: The predicted C(e) value of propofol resulting in BIS = 50 was similar in adults and children aged 3-11 years. The predicted C(e) value of propofol producing hypnosis in adults also seems to be useful in this paediatric population.

Target-controlled infusion of remifentanil or fentanyl during extra-corporeal shock-wave lithotripsy.

BACKGROUND AND OBJECTIVE: Target-controlled infusions (TCIs) of remifentanil and fentanyl in conscious sedation regimes for extra-corporeal shock-wave lithotripsy have not been reported. We estimated the effect site concentrations of remifentanil and fentanyl needed to obtain adequate analgesia in 50% of patients (EC50) and compared both drugs in terms of intra- and post-procedure complications. METHODS: Forty-four adult patients were randomly distributed into two groups: Group R received remifentanil and Group F received fentanyl TCI with initial effect site concentrations of 1.5 and 2 ng mL(-1), respectively. Pain was assessed using a 10-point verbal analogue scale and <3 was considered adequate analgesia. Increments or decrements of 0.5 ng mL(-1) were then introduced for subsequent patients according to Dixon's up and down method. During the rest of the procedure, TCI was adjusted to maintain verbal analogue scale <3. RESULTS: Remifentanil and fentanyl EC50 were 2.8 ng mL(-1) (95% confidence interval (CI): 1.8-3.7 ng mL(-1)) and 2.9 ng mL(-1) (95% CI: 1.7-4.1 ng mL(-1)), respectively (n.s.). At EC50, the probability of having a respiratory rate <10 was 4% (95% CI: 0-57%) for remifentanil and 56% (95% CI: 13-92%) for fentanyl. Hypoxaemia, vomiting and sedation were more frequent in Group F during and after the procedure (P < 0.05). CONCLUSIONS: A similar EC50 but more respiratory depression, sedation and PONV were found with fentanyl TCI than with remifentanil TCI.