Two-stage vs mixed-effect approach to pharmacodynamic modeling of propofol in children using state entropy

Objectives: To compare the population pharmacodynamic (PD) models of propofol in children derived using two‐stage and mixed‐effect modeling approaches. Methods: Fifty‐two ASA 1 and 2 children aged 6–15 years presenting for gastrointestinal endoscopy were administered a loading dose of 4 mg·kg^?1 of propofol intravenously at an infusion rate determined by a randomization schedule. Using the plasma concentration predicted by the Paedfusor pharmacokinetic (PK) model, the propofol effect on state entropy (SE) was modeled using the two‐stage and the mixed‐effect modeling approaches, and the final population PD models were compared with each other in terms of their prediction performance, using median percentage and absolute percentage errors as well as mean absolute weighted error as metrics. The effects of age and body weight as prospective covariates were examined. Results: The final population models were comparable with each other; the two‐stage and the mixed‐effect approaches resulted in a k_e0 of 2.38 and 2.66 min^?1, γ of 5.29 and 5.68, and EC₅₀ of 4.73 and 4.84 μg·ml^?1, respectively. The bootstrap estimates of the PD parameters were mean (sd ) k_e0 = 2.38 (0.10), γ = 5.30 (0.30), and EC₅₀ = 4.73 (0.14). The PD parameters did not exhibit dependence on age and body weight. The parameters reported in this study in children were different from their adult counterparts reported in previous studies. Conclusions: Models derived using different mathematical approaches produced consistent model parameters. By virtue of its relative computational efficiency, the two‐stage approach can serve as an attractive alternative to the mixed‐effect approach in situations where data are not sparse.     

Evidence of hysteresis in propofol pharmacodynamics

It is commonly assumed that loss of responsiveness and recovery of responsiveness occur at similar concentrations of propofol. However, the ‘conscious’ and ‘anaesthetised’ conditions produced by general anaesthetics may behave as two bistable states. We hypothesised that loss of responsiveness and recovery of responsiveness occur at different propofol concentrations. Propofol was administered to 19 healthy volunteers by effect‐site target‐controlled infusion using increasing and decreasing stable concentration steps of 7 min. Propofol serum concentrations were measured from venous blood samples at the end of each 7‐min step. A long step of 14 min was performed at loss of responsiveness. At this step, propofol concentrations were measured at 7 and 14 min. Propofol concentrations measured at loss of responsiveness and recovery of responsiveness were 2.6 (1.2–4.7) μg.ml^?1 and 1.6 (0.6–3.3) μg.ml^?1, respectively (p < 0.001). Propofol plasma concentration and the corresponding bispectral index values measured at minute 7 and minute 14 of the long step performed at loss of responsiveness were 2.6 (1.2–4.7) vs. 2.6 (1.3–4.3) at recovery of responsiveness, (p = 0.96) and 61.2 (49.0–77.0) vs. 58.4 (45.0–74.0), (p = 0.058), respectively. Loss of responsiveness and recovery of responsiveness appear to occur at different propofol concentrations. However, it is possible that, if equilibration was not achieved between plasma and effect‐sites at the end of each 7‐min step, the higher concentrations found at loss of responsiveness compared with those observed during recovery of responsiveness could be explained by a possible bias in estimations of the effect‐site concentrations of propofol by the Schnider model, rather than neural inertia.     

熵指数和Narcotrend用于靶控输注异丙酚麻醉深度的比较

全身麻醉过程中,因脑电信号能够反映患者镇静水平和麻醉药物浓度,已被广泛用于监测麻醉深度和预测意识变化。熵指数和Narcotrend是两类性质不同的新型脑电信号监测指标。熵指数通过采集不同频率的脑电和额肌电信号形成2个数值-反应熵(response entropy;RE)和状态熵(stateentrop     

Prolonged propofol infusion for mechanically ventilated children

We retrospectively analysed 30‐day mortality and duration of intubation for 8016 children ventilated for three or more days, sedated with midazolam (n = 7716) or propofol (n = 300). We matched the propensity scores of 263 pairs of children. The propensity‐matched 30‐day mortality (95% CI) was similar: 17/263 (6.5%) with midazolam vs. 24/263 (9.1%) with propofol, p = 0.26. Weaning from mechanical ventilation of children sedated with midazolam was slower than weaning of children sedated with propofol, subhazard ratio (95% CI) 1.43 (1.18–1.73), p < 0.001.     

Absence of explicit and implicit memory in unconscious patients using a TCI of propofol

BACKGROUND: Episodes of implicit memory have been described during propofol anaesthesia. It remains unclear whether implicit memory is caused by short periods of awareness or occurs in an unconscious subject. METHODS: Sixty patients were randomized in an experimental group (EG), a control group (CG) and a reference group (RG). Loss of consciousness (LOC) was obtained by progressive stepwise increases of propofol using a target-controlled infusion device (Diprifusor, Alaris Medical Systems, San Diego, CA). A tape containing 20 words was played to the patients in the CG before the start of anaesthesia and to the patients in the EG at a constant calculated concentration of propofol associated with LOC. The tape was not played to the patients in the RG. Three memory tests were performed postoperatively. RESULTS: Explicit and implicit memories were evidenced in the CG but not in the EG. CONCLUSION: In our group of young ASA I/II patients, in the absence of any noxious stimulus, no implicit or explicit memory was found when the calculated concentration of propofol using a Diprifusor was maintained at the level associated with LOC.     

Influence of formulation on propofol pharmacokinetics and pharmacodynamics in anesthetized patients

BACKGROUND: In anesthesia with propofol, variability persists besides sophisticated effect targeting. Drug formulation may be another factor. We have analyzed, retrospectively, the pharmacokinetics (PK) and pharmacodynamics (PD) in monitored surgery patients anesthetized with one each of five formulations of propofol. METHODS: Propofol 1% ('form' 1: Diprivan(Zeneca Limited, Macclesfield, UK), 2: Recofol(Schering Espana, Madrid, Spain), 3: Ivofol(Juste, Madrid, Spain), 4: Propofol Abbott (Abbott Laboratories, Madrid, Spain), 5: Fresenius (Fresenius Kabi Espana, Barcelona, Spain)) was administered to 77 ASA I-II patients of age [mean (range) 44 (18-65) years]. Induction of anesthesia was with varying propofol doses up to endpoints of either 60 on the Bispectral Index system (BIS) in group I (n = 48, model development) or standard clinical signs in group II (n = 29, validation). Maintenance was with three 10-min infusions of 10, 8 and 6 mg kg(-1) h(-1). Three blood samples were obtained from each subject, immediately after induction, and at 15 and 30 min on maintenance, with BIS and hemodynamic variables recorded at these times also. Total and free blood concentrations (Cb) of propofol were determined with HPLC. Pharmacokinetic and PD models with link equilibration rate ke0, were studied with a mixed-effects procedure (NONMEM). RESULTS: The induction dose (group I) showed large interindividual variability [mean (range) 163 (90-290 mg)] that correlated significantly with age, basal systolic blood pressure and formulation. The PK of propofol (basic model) was described by a one-compartment model with (typical value [interindividual coefficient of variation percent (CV%)]) CL=2.30 l min(-1) (27%) and V=8.40 l (80%). Weight (WT) and formulation, within NONMEM, were found to be significant covariates for CL and V, reducing their CV% to 25% and 74%, respectively. The final PK/PD model, which includes formulation, showed a 50% reduction in the CV% for both the ke0 and the residual error. This PK/PD model was validated in group II with 33% precision and no bias. CONCLUSION: The PK and PD are not equal for all formulations, which contributes to an increase in variability of the observed effect.     

Haemodynamic effects of propofol in children

The haemodynamic effects of induction of anaesthesia with propofol in children were studied. Two hundred and sixteen children (ASA 1) were randomly allocated to receive one of six different doses of propofol, from 1.6 mg/kg to 2.6 mg/kg, in 0.2 mg/kg increments. Noninvasive measurement of blood pressure showed that mean arterial pressure was reduced by approximately 15% after 1 minute, and by 30% after 5 minutes. The reduction in pulse rate over a 5-minute period was approximately 17%. These changes were similar in each group, regardless of the dose administered. The propofol was mixed with lignocaine, 0.5 mg/ml, and the incidence of pain on injection into a vein on the dorsum of the hand was 24%. We conclude that, within the dose range of our study, the haemodynamic disturbance after induction of anaesthesia with propofol in children is not dose related.     

Dosage scheme for propofol in children under 3 years of age

BACKGROUND: Propofol is a well-known drug for adults for total intravenous anaesthesia. Since 1999, the use of propofol has been approved for children less than 3 years of age. However, a suitable dosage scheme for these age groups was not available. The purpose of this study was to describe our clinical experience with the use of a new dosage scheme for propofol in patients under 3 years of age, based on experimental data and known pharmacological principles in children. METHODS: A pilot study of 50 patients undergoing TIVA was performed to adapt the existing adult dosage scheme to the requirements of the younger population. Total number and time of administration of boluses and time to awakening were registered and used as criteria to adjust the dosage scheme. The subsequent dosage scheme was then evaluated in 2271 children undergoing anaesthesia for various procedures. Usual anaesthetic parameters were measured to monitor the safety of the patient: ECG, O2 saturation, respiratory frequency and blood pressure. Most of the patients were mechanically ventilated; only 15% were breathing spontaneously. RESULTS: Overall, few side effects were recorded [bradycardia (12%), blood pressure fall (8%), desaturation (1%)], which were easily countered by routine measures. CONCLUSIONS: This dosage scheme provides safe and smooth anaesthesia in children less than 3 years of age and is therefore a useful tool for a TIVA technique in small children.     

Recovery from propofol anaesthesia supplemented with remifentanil

We have examined the effects on recovery end-points of supplementationof a propofol-based anaesthetic with remifentanil. After inductionof anaesthesia with propofol and remifentanil 1.0 µg kg^–1,15 patients each were randomly allocated to target plasma propofolconcentrations of 2, 3, 4 or 5 µg ml^–1for maintenance of anaesthesia. Remifentanil was administeredby infusion for supplementation in doses required for maintenanceof adequate anaesthesia. All patients received 50% nitrous oxidein oxygen and ventilation was controlled. The total amount ofdrugs used and times to different recovery end-points were recorded.Cognitive function was also assessed using a Mini-Mental Statequestionnaire. The median dose of remifentanil for maintenanceof adequate anaesthesia (excluding the initial bolus dose) inthe four groups was 0.21, 0.15, 0.11 and 0.13 µg kg^–1 min^–1respectively (P=0.0026). The median times to eye opening andorientation were shortest in the 2 µg ml^–1group [6.0 and 6.5 min, 8.5 and 10.8 min, 13.4 and15.8 min, and 14.2 and 19.5 min respectively in thepropofol 2, 3, 4, and 5 µg ml^–1 groups respectively(P<0.001)]. The times to discharge from the recovery wardand the Mini-Mental State scores were not significantly different. Br J Anaesth 2001; 86: 361–5     

Addition of ketamine to propofol for initiation of procedural anesthesia in children reduces propofol consumption and preserves hemodynamic stability

Background: There is no ideal anesthesia protocol to perform short invasive procedures in pediatric oncology. The combination of propofol and ketamine may offer advantages over propofol alone.
Methods: In a prospective, randomized, double-blind study, we analyzed 63 consecutive procedures performed in 47 oncology children. All patients received 1 μg/kg fentanyl, followed by propofol 1 mg/kg in group P ( n =33) or propofol 0.5 mg/kg and ketamine 0.5 mg/kg in group PK ( n =30) for the initiation of anesthesia. The need for supplementation with propofol and/or fentanyl to maintain an adequate level of anesthesia was recorded. The hemodynamic and respiratory profile, recovery time and the occurrence of side effects were compared.
Results: Significantly more children required propofol (100% vs. 83.3%) and fentanyl (75.5% vs. 43.3%) rescue doses, and developed hypotension (63.6% vs. 23.4%) and bradycardia (48.5 vs. 23.4%) in group P compared with group PK, with a comparable incidence of respiratory adverse events and recovery times. However, 40% of children in group PK were agitated following recovery compared with 6% in group P.
Conclusions: The combination of propofol and ketamine for invasive procedures in pediatric oncology resulted in reduced propofol and fentanyl consumption and preserved hemodynamic stability, but more children in the combination group recovered with agitation.     

Extravasation of propofol is associated with tissue necrosis in small children

Propofol is widely used for induction of anesthesia and many reports document extravasation and even intra-arterial injections without clinical sequelae. We report a case of tissue necrosis after subcutaneous injection of propofol in a 31-day-old infant.     

Cerebrovascular carbon dioxide reactivity in children anaesthetized with propofol

BACKGROUND: Propofol, by virtue of its favourable pharmacokinetic profile, is suitable for maintenance of anaesthesia by continuous infusion during neurosurgical procedures in adults. It is gaining popularity for use in paediatric patients. To determine the effects of propofol on carbon dioxide cerebrovascular reactivity in children, middle cerebral artery blood flow velocity was measured at different levels of endtidal (PECO2) by transcranial Doppler sonography. METHODS: Ten ASA I or II children, aged 1-6 years undergoing elective urological surgery were enrolled. Anaesthesia comprized propofol aimed at producing an estimated steady-state serum concentration of 3 microg x ml-1 and a caudal epidural block. PECO2 was adjusted randomly in an increasing or decreasing fashion between 3.3, 5.2 and 7.2 kPa (25, 40 and 55 mmHg) with an exogenous source of CO2 while maintaining ventilation parameters constant. RESULTS: Cerebral blood flow velocity increased as PECO2 increased from 3.3 to 5.2 kPa (25-40 mmHg) (P < 0.001) and from 5.2 to 7.2 kPa (40-55 mmHg) (P < 0.001). Mean heart rate and blood pressure did not change significantly. CONCLUSIONS: This study demonstrates that cerebrovascular CO2 reactivity is maintained over PECO2 values of 3.3, 5.2 and 7.2 kPa (25, 40 and 55 mmHg) in healthy children anaesthetized with propofol.     

Quality of recovery in children: sevoflurane versus propofol

BACKGROUND: Sevoflurane, with its low pungency and low blood and tissue solubility, is an attractive anaesthetic in paediatric outpatient surgery. Propofol-anaesthesia is recognised for its rapid and clear-headed emergence. This study was designed to compare emergence and recovery characteristics of sevoflurane and propofol anaesthesia for tonsillectomy in children. METHODS: Children aged 3-10 years, undergoing elective tonsillectomy, were randomly assigned to receive propofol (n=25, induction with 3 mg x kg(-1), maintenance with 100-250 microg x kg(-1) min(-1)) or sevoflurane anaesthesia (n=25, induction 7 vol.%, maintenance 2-3 vol.%). Tracheal intubation was performed with alfentanil 20 microg x kg(-1) and atracurium 0.5 mg x kg(-1). Ventilation was controlled to maintain normocapnia and all patients received N2O/O2 (60:40 vol.%) for induction and maintenance of anaesthesia. At the end of surgery infiltration of the operative sites with bupivacaine 2 mg x kg(-1) was provided for postoperative analgesia. Emergence, recovery, discharge times, and incidence of side effects were compared between the two groups. RESULTS: Time to extubation (14 vs 15 min), time to response to simple verbal command (21 vs 21 min) and time to discharge from the recovery room (45 vs 50 min) were similar in the sevoflurane and propofol groups, respectively. There was a significantly greater incidence of postoperative agitation in the sevoflurane group (46%) compared with the propofol group (9%) (P=0.008). This did not, however, delay discharge from the recovery room. The incidence of nausea and vomiting was not significantly different (8% vs 0%; P=0.49). CONCLUSION: In children, recovery from anaesthesia with sevoflurane results in a higher incidence of agitation compared with propofol.     

Remifentanil and propofol for sedation in children and young adolescents undergoing diagnostic flexible bronchoscopy

Flexible fibreoptic bronchoscopy (FOB) has become a useful diagnostic and therapeutic procedure in children. We investigated 26 patients (3-14 years) for FOB using a new sedation strategy. All patients received oral premedication and inhalation of topical anaesthetic. Sedation for bronchoscopy was achieved with a continuous infusion of remifentanil and intermittent boluses of propofol. Propofol injection was repeated if sedation was inadequate. Sedation could be successfully performed in all children without adverse effects. Endtidal CO2 concentration and arterial oxygen saturation remained stable throughout the study. All children were awake 5+/-1.3 min after stopping remifentanil infusion. Sedation with remifentanil/propofol is a new sedation strategy for diagnostic flexible paediatric bronchoscopy in children with spontaneous ventilation.