The effect of a target controlled infusion of propofol on predictability of recovery from anesthesia in children

Background: Emergence following termination of a general anesthetic depends on the effect site concentration (C_e) of the drug declining to an awakening value (C_e‐awake). C_e‐awake has been described in adults, but is unknown in children. Objectives: To determine C_e‐awake in children following a target‐controlled infusion (TCI) of propofol and to assess a C_e‐driven TCI system’s ability to predict times to emergence from anesthesia. Methods: Subjects undergoing elective surgery, aged 3 months to <10 years were recruited into three age‐stratified groups. A target C_e of 3–4 μg·ml^?1 was selected for induction and subsequently titrated to patient response and surgical stimulus. Preoperative acetaminophen, a remifentanil infusion and regional anesthesia were permitted for supplemental analgesia. State Entropy (SE) was monitored from induction to emergence. Emergence was defined as the time of first purposeful spontaneous movement (PSM). Time zero was defined as the end of propofol infusion. Based on a pilot study, a C_e‐awake of 1.9 μg·ml^?1 was chosen as the wake‐up threshold used by the software to predict emergence times. Results: Data was collected for 90 of 104 recruited patients. PSM occurred at a mean (sd ) C_e of 2.0 (0.5) μg·ml^?1 and an SE of 79 (11). There were no differences between age groups. A wide variation in emergence time was observed, with a mean (sd ) of 16.9 (7) min, and a trend to more rapid emergence in older subjects. Conclusion: A predicted C_e‐awake of 2.0 μg·ml^?1 in children aged 3 months to <10 years was identified with the selected model. For expert users of propofol in children, during shorter surgical procedures, TCI predicted emergence times do not offer significant clinical advantages.     

Effects of dexmedetomidine on propofol and remifentanil infusion rates during total intravenous anesthesia for spine surgery in adolescents

Introduction: Total intravenous anesthesia with propofol and a synthetic opioid is a frequently chosen anesthetic technique for posterior spinal fusion. Despite its utility, adverse effects may occur with high or prolonged propofol dosing regimens including delayed awakening. The current study investigated the propofol‐sparing effects of the concomitant administration of the α₂‐adrenergic agonist, dexmedetomidine, during spinal fusion surgery in adolescents. Methods: The surgical database of the department of orthopedic surgery was searched and patients (12–21 years of age) were identified who had undergone spinal fusion for either idiopathic or neuromuscular scoliosis during the past 24 months. Patients were assigned to two groups. Group 1 included patients anesthetized with propofol and remifentanil and group 2 included patients anesthetized with dexmedetomidine, propofol, and remifentanil. In the latter group, dexmedetomidine was administered as a continuous infusion of 0.5 μg·kg^?1·h^?1 started after the induction of anesthesia without a loading dose. Propofol was adjusted to maintain the bispectral index (BIS) number at 40–50 and remifentanil was adjusted to maintain the mean arterial pressure (MAP) at 50–65 mmHg. Labetolol or hydralazine was used if the MAP could not be maintained at 50–65 mmHg with remifentanil up to a maximum dose of 0.6 μg/kg/min. Statistical analysis included a nonpaired t‐test for parametric data (age, weight, remifentanil/propofol infusion requirements, and heart rate/blood pressure values). A nonparametric statistical analysis (Dunn) was used to compare BIS numbers. Parametric data are presented as the mean ± sd while nonparametric data are presented as the median and the 95th percentile confidence intervals. Results: Twelve patients received propofol–remifentanil–dexmedetomidine and 24 received propofol–remifentanil. There were no differences in the demographic data, BIS numbers or hemodynamic parameters between the two groups. There was a reduction in the propofol infusion requirements in patients who also received dexmedetomidine (71 ± 11 μg·kg^?1·min^?1) compared with those receiving only propofol–remifentanil (101 ± 33 μg·kg^?1·min^?1, P = 0.0045). No difference was noted in the remifentanil infusion requirements or the use of supplemental agents (hydralazine and labetolol) to maintain controlled hypotension. Conclusion: The concomitant use of dexmedetomidine in patients undergoing spinal fusion reduces propofol infusion requirements when compared with those patients receiving only propofol and remifentanil.     

Effects of dexmedetomidine on intraoperative motor and somatosensory evoked potential monitoring during spinal surgery in adolescents

Background: Dexmedetomidine may be a useful agent as an adjunct to an opioid–propofol total intravenous anesthesia (TIVA) technique during posterior spinal fusion (PSF) surgery. There are limited data regarding its effects on somatosensory (SSEPs) and motor evoked potentials (MEPs). Methods: The data presented represent a retrospective review of prospectively collected quality assurance data. When the decision was made to incorporate dexmedetomidine into the anesthetic regimen for intraoperative care of patients undergoing PSF, a prospective evaluation of its effects on SSEPs and MEPs was undertaken. SSEPs and MEPs were measured before and after the administration of dexmedetomidine in a cohort of pediatric patients undergoing PSF. Dexmedetomidine (1 μg·kg^?1 over 20 min followed by an infusion of 0.5 μg·kg^?1·h^?1) was administered at the completion of the surgical procedure, but prior to wound closure as an adjunct to TIVA which included propofol and remifentanil, adjusted to maintain a constant depth of anesthesia as measured by a BIS of 45–60. Results: The cohort for the study included nine patients, ranging in age from 12 to 17 years, anesthetized with remifentanil and propofol. In the first patient, dexmedetomidine was administered in conjunction with propofol at 110 μg·kg^?1·min^?1 which resulted in a decrease in the bispectral index from 58 to 31. Although no significant effect was noted on the SSEPs (amplitude or latency) or the MEP duration, there was a decrease in the MEP amplitude. The protocol was modified so that the propofol infusion was incrementally decreased during the dexmedetomidine infusion to achieve the same depth of anesthesia. In the remaining eight patients, the bispectral index was 52 ± 6 at the start of the dexmedetomidine loading dose and 49 ± 4 at its completion (P = NS). There was no statistically significant difference in the MEPs and SSEPs obtained before and at completion of the dexmedetomidine loading dose. Conclusion: Using the above‐mentioned protocol, dexmedetomidine can be used as a component of TIVA during PSF without affecting neurophysiological monitoring.     

Dexmedetomidine hemodynamics in children after cardiac surgery

Background: Dexmedetomidine has opposing effects on the cardiovascular system. Action in the central nervous system produces sympatholysis and a reduction in blood pressure, while peripherally it causes vasoconstriction leading to an increase in blood pressure. The purpose of our study is to define the concentration–response profile for these hemodynamic effects in children after cardiac surgery. Methods: A simultaneous pharmacokinetic–pharmacodynamic analysis of data from 29 children given a single bolus of dexmedetomidine 1–4 mcg·kg^?1 following cardiac surgery was undertaken using mixed effects modeling. There were four dexmedetomidine concentrations available from each patient, and mean arterial blood pressure (MAP) was recorded electronically every 5 min for 5 h after drug administration. A composite Emax model was used to relate mean arterial pressure changes to plasma dexmedetomidine concentration. Results: Children had a mean age of 2.67 years (range 4 days–14 years) and a mean weight of 12.34 (range 3.4–48.4) kg. The peripheral vasopressor effect was directly related to plasma concentration with an Emax_pos of 50.3 (CV 44.50%) mmHg, EC_50pos 1.1 (48.27%) μg·l^?1 and a Hill_pos coefficient of 1.65. The delayed central sympatholytic response was described with an Emax_neg of ?12.30 (CV 37.01%) mmHg, EC_50neg 0.10 (104.40%) μg·l^?1 and a Hill_neg coefficient of 2.35. The equilibration half‐time (T_1/2keo) was 9.66 (165.23%) min. Conclusions: Dexmedetomidine administered as a single bolus dose following cardiac surgery produces a biphasic effect on MAP. A plasma dexmedetomidine concentration of above 1.0 μg·l^?1 was associated with a 20% increase in MAP in this specific cohort. A dosage regimen involving a small bolus dose (0.5 μg·kg^?1) followed by a continuous infusion should be used to avoid initial increases in MAP.     

A randomized trial of propofol consumption and recovery profile with BIS‐guided anesthesia compared to standard practice in children

Aim: To evaluate the impact of bispectral index (BIS) monitoring on the consumption of propofol and recovery from anesthesia compared to the standard clinical practice in children. Background: Titrating propofol administration using BIS reduces its requirement and shortens the recovery from anesthesia in adults. However, there is still mixed evidence for utility of anesthesia depth monitors in reducing anesthesia requirement in children. Methods/Materials: A prospective randomized study was conducted in 50 ASA I children of 2–12 years, randomly assigned into standard practice (SP) or BIS group. After induction with propofol, anesthesia was maintained with 150 μg·kg^?1·min^?1 propofol infusion. The propofol infusion rate was altered by 20 μg·kg^?1·min^?1 to maintain the systolic blood pressure within 20% of the baseline (SP group) or BIS value between 45 and 60 (BIS group). The rate of propofol infusion was reduced by 50% about 15 min before the end of surgery. The amount of propofol used and the times from stopping the propofol infusion to eye opening, extubation, response to commands and attaining Steward score of 6 were recorded. Results: There was no evidence of a difference in the mean propofol consumption in the two groups (BIS 232.6 ± 136.7 mg, SP 250.8 ± 118.2 mg). The intraoperative hemodynamics and BIS values were similar in the two groups. There was no evidence for a difference between groups in the mean times from termination of anesthetic to eye opening, extubation, response to commands and to achieve a Steward Recovery score of 6. Conclusions: Our study showed no benefit of BIS‐guided propofol administration on anesthetic consumption or recovery compared to standard anesthetic practice.     

Predicted effect-site concentration of propofol and sufentanil for gynecological laparoscopic surgery

Background: This study was to estimate the predicted effect‐site concentration of propofol administered by a target‐controlled infusion (TCI) for maintenance of anesthesia based on the bispectral (BIS) index as a measure of hypnosis in laparoscopic surgery. Method: One‐hundred and sixty unpremedicated patients undergoing gynecologic laparoscopy were assigned randomly to receive one of the target effect‐site concentrations of propofol 2.0, 2.5, 3.0, 3.5 and 4.0 μg/ml during TCI with propofol and sufentanil. The dose–response relationship of propofol for the maintenance of adequate anesthesia based on BIS, movement and hemodynamic response was investigated using a fixed effect‐site concentration of sufentanil (0.2 ng/ml). The BIS values, hemodynamic variables, time course during emergence and intraoperative awareness were also assessed. Results: The predicted effect‐site propofol concentrations for adequate anesthesia at the skin incision in 50% (EC₅₀) and 95% (EC₉₅) of patients undergoing gynecologic laparoscopy were 2.2 and 3.7 μg/ml, respectively. The predicted propofol EC₅₀ and EC₉₅ to maintain adequate anesthesia in these patients were 2.6 μg/ml (95% CI 2.3–2.7 μg/ml) and 3.6 μg/ml (95% CI 3.3–4.0 μg/ml), respectively. The BIS values, effect‐site concentration of propofol, hemodynamic data and time course during emergence and post‐operative adverse events were comparable in each group. There were no reports of intraoperative awareness in the post‐anesthetic care unit. Conclusion: Based on the anesthetic depth assessed by the clinical signs and BIS monitoring, the predicted effect‐site propofol concentrations for the maintenance of anesthesia in patients undergoing gynecologic laparoscopy were similar in those administered adequate anesthesia at the skin incision during TCI.     

Geographic differences in the target-controlled infusion estimated concentration of propofol: bispectral index response curves

Purpose

Variability in drug responses could result from both genetic and environmental factors. Thus, drug effect could depend on geographic location, although regional variation is not generally acknowledged as a basis for stratification. There is evidence that the pharmacokinetic set developed in a European population for the target-controlled infusion (TCI) of propofol does not apply in Chinese patients; however, we are not aware of previous studies comparing the estimated concentration-bispectral index (BIS) response of Caucasian patients in Europe with that of Chinese patients in China.

Methods

The Diprifusor^TM TCI pump, incorporating the pharmacokinetic model proposed by Marsh et al., was applied to 30 Caucasian patients in Austria and 30 Chinese patients in China. The estimated plasma concentration (C_p) of propofol for the two groups was set at 1 μg·mL^?1 and increased by 1 μg·mL^?1 every minute to gradually reach 5 μg·mL^?1 after 5 min. The BIS values were fitted against the estimated C_p and the predicted effect-site concentration (C_e) in a sigmoid E_max model.

Results

The sigmoid E_max curves were shifted significantly to the left in the Chinese group compared with the Austrian group. After 5 min, the BIS value in the Chinese group was lower than in the Austrian group (mean ± standard deviation [SD], 47.2 ± 3.6 vs 63.6 ± 5.4, respectively; P = 0.0006). The estimated C_p at loss of consciousness (LOC), predicted C_e at LOC, and time to LOC, were lower in the Chinese group than in the Austrian group (3.3 ± 0.8 μg·mL^?1, 1.6 ± 0.4 μg·mL^?1, 2.8 ± 0.6 min, respectively, vs 4.6 ± 2.8 μg·mL^?1, 2.4 ± 1.5 μg·mL^?1, 3.9 ± 0.5 min, respectively; P < 0.0001).

Conclusion

When propofol is given using the same TCI protocol, Chinese patients in China lost consciousness faster and at a lower estimated plasma concentration than Caucasians in Austria. Larger studies are needed to map geographically appropriate TCI infusion models.     

Intrathecal clonidine decreases propofol sedation requirements during spinal anesthesia in infants

Background: Propofol is a popular agent for providing procedural sedation in pediatric population during lumbar puncture and spinal anesthesia. Adjuvants like clonidine and fentanyl are administered intrathecally to prolong the duration of spinal anesthesia and to provide postoperative analgesia. We studied the propofol requirement after intrathecal administration of clonidine or fentanyl in infants undergoing lower abdominal surgeries. Methods: Sixty‐five ASA I infants undergoing elective lower abdominal surgery under spinal anesthesia were assigned into four groups in this prospective randomized double‐blinded study. Group B received bupivacaine based on body weight (<5 kg = 0.5 mg·kg⁻¹; 5–10 kg = 0.4 mg·kg⁻¹). Group BC received 1 μg·kg⁻¹ of clonidine with bupivacaine, group BF received 1 μg·kg⁻¹ of fentanyl with bupivacaine, and patients in group BCF received 1 μg·kg⁻¹ each of clonidine and fentanyl with bupivacaine. A bolus of 2–3 mg·kg⁻¹ of propofol bolus was administered for lumbar puncture. Sedation was assessed using a six‐point sedation score (0–5) and a five‐point reactivity score (0–4) which was based on a behavioral score. After achieving a sedation and reactivity score of 3–4, the patients were placed lateral in knee chest position and lumbar puncture performed and test drug administered. Further intraoperative sedation was maintained with an infusion of 25–50 μg·kg⁻¹·min⁻¹ of propofol infusion. Results: The mean ± sd infusion requirement of propofol decreased from 35.5 ± 4.5 in group B to 33.4 ± 5.4 μg·kg⁻¹·min⁻¹ in group BF and further decreased to 16.7 ± 6.2 μg·kg⁻¹·min⁻¹ and 14.8 ± 4.9 μg·kg⁻¹·min⁻¹ in group BC and BCF, respectively. There were no statistically significant differences between BC and BCF groups. The mean sedation and reactivity scores were higher in groups BC and BCF when compared to groups B and BF. Conclusion: Our study show that the requirement of propofol sedation reduces with intrathecal adjuvants. The reduction was significant with the addition of clonidine and clonidine–fentanyl combination as opposed to bupivacaine alone or with fentanyl. There was no significant difference in propofol infusion requirement with the use of bupivacaine alone or with fentanyl.     

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.     

Dexmedetomidine disposition in children: a population analysis

Background: There are few data describing dexmedetomidine population pharmacokinetics (PK) in children (0–15 years) despite increasing use. Methods: An open‐label study was undertaken to examine the PK of i.v. dexmedetomidine 1–4 μg·kg^?1 bolus in children after cardiac surgery (n = 45). A population PK analysis of dexmedetomidine time–concentration profiles (148 observations) was undertaken using nonlinear mixed effects modeling. Estimates were standardized to a 70‐kg adult using allometric size models. Results: Children had a mean age of 3.38 years (range 4 days to 14 years) and weight 15.1 kg (range 3.1–58.9 kg). A two‐compartment disposition model with first order elimination was superior to a one‐compartment model. Population parameter estimates (between subject variability) were clearance (CL) 39.2 (CV 30.36%) l·h^?1 per 70 kg, central volume of distribution (V1) 36.9 (69.49%) l per 70 kg, inter‐compartment clearance (Q) 68.2 (37.6%) l·h^?1 per 70 kg and peripheral volume of distribution (V2) 69.9 (48.6%) l per 70 kg. Clearance at birth was 15.55 l·h^?1 per 70 kg and matured with a half‐time of 46.5 weeks to reach 87% adult rate by 1 year of age. Simulation of an infusion of 1 μg·kg^?1 over 10 min followed by an infusion of 0.7 μg·kg^?1·h^?1 for 50 min suggested that children arouse from sedation at a plasma concentration of 0.304 μg·l^?1. Conclusions: Clearance in neonates is approximately one‐third of that described in adults, consistent with immature elimination pathways. Maintenance dosing, which is a function of clearance, should be reduced in neonates and infants when using a target concentration approach.     

Plasma concentrations of bupivacaine in young infants after continuous epidural infusion

This study reports plasma bupivacaine concentration in seven infants who during major abdominal surgery received lumbar epidural or caudal block anaesthesia. Plasma concentrations (CP) were measured postoperatively after six and twelve h of continuous infusion. Postnatal age ranged from one day to seven months. The local anaesthetic block was performed after induction of anaesthesia. Postoperatively bupivacaine 1.25-2.5 mg·ml^?1 without adrenaline was infused at a rate of 0.5 to 0.83 mg·kg^?1·h^?1. After six h of infusion the mean value measured was 1.59 μg·ml^?1 (range 1.2-1.94 μg·ml^?1). After 12 h the mean value measured was 2.06 μg·ml^?1 (range 1.53-2.98 μg·ml^?1). A marked increase in bupivacaine plasma concentration was seen between six and 12 hours of infusion. Bupivacaine plasma concentration never exceeded 4 μg·ml^?1. Adverse effects that possibly were due to a toxic reaction to bupivacaine were seen in three patients. In conclusion, the dose administered in this study appears to be high and cannot be recommended as safe dosage in this age group.;     

The effect of dexmedetomidine during myringotomy and pressure-equalizing tube placement in children

Background: Bilateral myringotomy (BMT) is a commonly performed otolaryngologic procedure in children. Objectives: To examine the effects of intranasal dexmedetomidine, an α₂‐adrenoceptor agonist, on time‐averaged pain scores, pain control, need for rescue analgesia, and agitation scores in children undergoing BMT. Methods: We designed a trial to enroll 160 children randomized to one of four groups: two study groups, dexmedetomidine (1 or 2 μg·kg^?1), or two control groups representing our institutional standards of practice (intranasal fentanyl‐2 μg·kg^?1 or acetaminophen as needed postoperatively). Results: After 101 children were enrolled, patient caregivers observed that some enrollees were excessively sedated and required prolonged postanesthesia care unit (PACU) stay. This observation led to an unplanned interim analysis and early trial termination. After data were collected, severe nonnormality of pain and agitation scores necessitated a switch of the outcome to assess repeated measurements of the proportion of patients with pain, severe pain, and agitation. Demographics, time to emergence, and agitation were similar among all groups. The risk of requiring acetaminophen rescue (P < 0.0001) and proportion of patients having pain (P = 0.016) was significantly higher in one control group (rescue analgesia only) compared with fentanyl or dexmedetomidine groups. Importantly, length of stay in the PACU was significantly longer in dexmedetomidine‐2 μg·kg^?1‐treated compared with dexmedetomidine‐1 μg·kg^?1‐treated, fentanyl‐treated, or the control group, P = 0.0037. Conclusions: In this trial, we were unable to answer the original question as to the role of dexmedetomidine on time‐averaged pain and agitation scores after BMT. However, our findings clearly demonstrate that in children undergoing BMT, at higher doses, dexmedetomidine significantly prolongs length of stay in the PACU.     

Subhypnotic propofol infusion plus dexamethasone is more effective than dexamethasone alone for the prevention of vomiting in children after tonsillectomy

Background: Postoperative vomiting (POV) is a common complication after tonsillectomy. Dexamethasone is known to decrease postsurgical vomiting. In this study, we compared the effects of dexamethasone alone to dexamethasone plus propofol on postoperative vomiting in children undergoing tonsillectomy. Methods: In a randomized double‐blinded study, we evaluated 80 healthy children, aged 4–12 years, who underwent tonsillectomy with or without adenoidectomy. After anesthesia was induced by inhalation of sevoflurane, 0.15 mg·kg^?1 dexamethasone and 2 μg·kg^?1 fentanyl was administered i.v. to all patients. The patients in the dexamethasone plus propofol group received 1 mg·kg^?1 propofol before intubation and continuously after intubation at a rate of 20 μg·kg^?1·min^?1 until the surgery was completed. Data for postoperative vomiting were grouped into the following time periods: 0–4 and 4–24 h. Data were analyzed using a Student’s t‐test and chi‐squared analysis. Results: The percentage of patients exhibiting a complete response (defined as no retching or vomiting for 24 h) increased from 37.5% in the dexamethasone‐alone group to 75% in the dexamethasone plus propofol group (P = 0.001). Twenty‐two patients (55%) in the dexamethasone‐alone and nine patients (22.5%) in the dexamethasone plus propofol groups experienced vomited during 0–4 h (P = 0.003). Eight patients in the dexamethasone‐alone group and three patients in the dexamethasone plus propofol group received ondansetron as a rescue antiemetic during the postoperative period. Conclusion: For children undergoing tonsillectomy, intraoperative subhypnotic propofol infusion combined with dexamethasone treatment provides a better prophylaxis against postoperative vomiting than does dexamethasone alone.     

An evaluation of intrathecal bupivacaine combined with intrathecal or intravenous clonidine in children undergoing orthopedic surgery: a randomized double-blinded study

Background: Propofol is a popular agent for providing intraoperative sedation in pediatric population during lumbar puncture and spinal anesthesia. Adjuvant‐like clonidine is used increasingly in pediatric anesthesia to provide postoperative analgesia with a local anesthetic agent. The aim of this study was to assess the effects of intrathecal and intravenous clonidine on postoperative analgesia/sedation and intraoperative requirements of propofol after intrathecal bupivacaine for orthopedic surgery in children. Methods: Fifty‐nine ASA I and II children aged 6–8 year undergoing orthopedic surgery were randomized to receive intrathecal 0.5% bupivacaine 0.2–0.4 mg·kg^?1 and intravenous 2 ml saline (Group B), intrathecal 0.5% bupivacaine 0.2–0.4 mg·kg^?1 plus 1 μg·kg^?1 clonidine and intravenous 2 ml saline (Group BCit), and 0.5% bupivacaine 0.2–0.4 mg·kg^?1 and intravenous 1 μg·kg^?1 clonidine in 2 ml of saline (Group BCiv). Intraoperative sedation was maintained with 20–50 μg·kg^?1·min^?1 of propofol infusion. The requirements of propofol, time to first rescue analgesia, and postoperative pain or sedation scores were assessed. The duration of motor and sensory blocks and perioperative adverse events were determined. Results: Clonidine significantly prolonged the time to first rescue analgesia and reduced the requirements of propofol sedation whether administered intravenously or intrathecally. The mean Children and Infants Postoperative Pain Scale scores of children were significantly lower in groups BCit and BCiv than in group B. Postoperative sedation scores were higher in groups BCit and BCiv than in group B. Intrathecal clonidine significantly prolonged the time to regression of the sensory block and recovery of motor block. There were no significant differences among the three groups regarding the incidence of perioperative adverse events. Conclusion: Intrathecal or intravenous clonidine similarly provided better postoperative analgesia and sedation and reduced the requirements of propofol. Only intrathecal clonidine prolonged the duration of sensory and motor blocks.     

The inhibitory effect of esmolol on human plasmacholinesterase

Esmolol, a new cardioselective beta adrenergic blocker inhibits plasmacholinesterase activity in vitro. The concentration of esmolol hydrochloride that inhibits by 50 per cent the hydrolysis of 50.0 µnol·L^?1 benzoylcholine hydrochloride by 1:200 diluted, heparinized pooled plasma of six healthy volunteers at 37° C and 240 nm, determined by the ultraviolet spectrophotometric method of Kalow, was 50 µmol·^?1. Esmolol’s primary metabolite, 3-(4-(2-hydroxy-3-(isopropylamino)propoxy)-phenyllpropionic acid, had an l₅ = 190 µnol·L^?1 . The benzoylcholine hydrolysis rates in the plasma of ten patients who received an esmolol infusion of 500 µg·kg^?1. min^?1 for 4 minutes were 58.6 ± 6.2 µmol·hr^?1·ml^?1 (mean ± SE) before and 55.1 ± 6.6 µmol·hr^?1·ml^?1 after the infusion. The benzoylcholine hydrolysis rates in the plasma of ten patients who received an esmolol infusion of 500 µg·kg^?1·min^?1 for two minutes and 200 µg·kg^?1·min^?1 for an additional two minutes were 70.2 ± 8.9µmol·hr^?1·ml^?1 before and 69.1 ± 9.5 µmol·hr^?1. ml^?1 after the infusion. The pre- and post-infusion plasmacholinesterase activities were not significantly different. Since plasmacholinesterase is responsible for the hydrolysis of succinylcholine and that of the ester-type local anaesthetics this lack of in vivo interaction of esmolol with the hydrolysis of these drugs should be further confirmed by experiments with these combinations in man.     

The effect of changes in arterial CO2 tension on plasma lidocaine concentration

The authors studied the effect of changes in arterial carbon dioxide tension on plasma tidocaine concentrations during a constant lidocaine infusion in eight healthy volunteers. With a PaCO₂ of 41.4 ±. 0.9mmHg (mean ± SE), total plasma lidocaine concentrations were 3.97 ± 0.20 μg·ml^-1. There was no significant change associated with hypercarbia (PaCO₂ = 55.7 ± 1.5mmHg, lidocaine = 3.93 ± 0.18 μg±ml^-1)or hypocarbia (PaCO₂ = 19.5 ± 1.4mmHg, lidocaine = 4.29 ± 0.25 μg·ml^-1), despite the known effects of changes in CO₂ tension on hepatic blood flow and lidocaine protein binding. During hypercarbia, plasma lidocaine binding decreases while total plasma lidocaine remains essentially constant; therefore, increased CO₂ tensions could cause toxicity if total lidocaine concentrations were in the high therapeutic range (5 μg·ml^-1). Four subjects experienced transient symptoms of mild lidocaine toxicity during acute increases in carbon dioxide tension.     

The fentanyl concentration required for immobility under propofol anesthesia is reduced by pre-treatment with flurbiprofen axetil

Purpose

We hypothesized that nonsteroidal anti-inflammatory drugs decrease the plasma fentanyl concentration required to produce immobility in 50% of patients in response to skin incision (Cp50_incision) compared with placebo under target-controlled infusion (TCI) propofol anesthesia.

Methods

Sixty-two unpremedicated patients scheduled to undergo gynecologic laparoscopy were randomly assigned to receive placebo (control group) or flurbiprofen axetil 1 mg·kg^?1 (flurbiprofen group) preoperatively. General anesthesia was induced with fentanyl and propofol, and intubation was performed after succinylcholine 1 mg·kg^?1. Propofol was administered via a target-controlled infusion (TCI) system (Diprifusor?) set at an effect-site concentration of 5 μg·mL^?1. Fentanyl was given by a TCI system using the STANPUMP software (Schafer model). The concentration for the first patient was set at 3 ng·mL^?1 and modified in each group according to the up-down method. Skin incision was performed after more than ten minutes equilibration time. Serum fentanyl concentration, bispectral index (BIS), and hemodynamic parameters were measured two minutes before and after skin incision. The Cp50_incision of fentanyl was derived from the mean of the crossovers (i.e., the serum fentanyl concentrations of successive participants who responded and those who did not or vice versa).

Results

Ten and 11 independent crossover pairs were collected in the control and flurbiprofen groups, respectively, representing 42 of 62 enrolled patients. The mean (SD) fentanyl Cp50_incision was less in the flurbiprofen group [0.84 (0.63) ng·mL^?1] than in the control group [1.65 (1.15) ng·mL^?1]; P = 0.007; however, there were no differences in BIS, blood pressure, or heart rate, between groups.

Conclusion

Preoperative flurbiprofen axetil decreased the Cp50_incision of fentanyl by 49% during propofol anesthesia without changing the BIS or hemodynamic variables.     

40 Hz Auditory steady-state response and EEG spectral edge frequency during sufentanil anaesthesia

Purpose

The auditory steady-state evoked response (ASSR) is an evoked potential which provides a sensitive measure of the effects of general anaesthetics on the brain. We used pharmacokinetic-pharmacodynamic (PK-PD) modelling to compare the effects of sufentanil on the amplitude of the ASSR with its effect on spectral edge frequency (SEF) of the electroencephalogram.

Methods

Nine patients scheduled for elective cardiac surgery participated. Midazolam (70 μg·kg^?1 im) was given 60 min before entering the operating room. Anaesthesia was induced with 5 μg·kg^?1 sufentanil at a rate of 0.83 μg·kg^?1·min^?1. The ASSR, SEF and plasma sufentanil concentrations were measured for 30 min ater induction of anaesthesia before surgery. The half-life between the central and effect site compartments (t_1/2K_eo), the 50% inhibitory concentration (IC₅₀) and the slope factor (gamma) were computed.

Results

The amplitude of the ASSR increased during the first three minutes of infusion of sufentanil by up to 40%. This was followed by a rapid decrease between the fourth and fifth minutes to 16% of baseline. The SEF decreased progressively during the first five minutes of infusion to 18% of baseline. Both measures subsequently showed modest recovery. The parameters gamma, IC₅₀ and t_1/2K_eofor ASSR were (mean ±SD) 6,0 ±3.7, 2.1 ±1,2 ng·ml^?1 and 7.3 ±2.4 min. For SEF the values were 5.9 ±5.2, 1.4 ±0.7 ng·ml^?1 (P < 0.05 compared with ASSR) and 6.8 ±2,4 min.

Conclusion

The sensitivity of ASSR to sufentanil is less than that of the SEF.     

Pediatric models for adult target‐controlled infusion pumps

Target‐controlled infusion (TCI) pumps currently do not satisfactorily cater for the pediatric population, particularly for those under 5 years. Growth and development are two major aspects of children not readily apparent in adults, and these two aspects influence clearance (CL) and volume of distribution (V). In simple terms, V determines initial dose, and CL determines infusion rate at steady state. Three major covariates (size, age, and organ function) contribute to parameter variability in children. Size can be standardized for clearance in a 70‐kg person using the allometric ¾ power model. Remifentanil, a drug cleared by hydrolysis, can be modeled in all age groups by simple application of this model using a standardized clearance of 2790 ml·min^?1 for a 70‐kg person. Allometry alone is insufficient to predict clearance in neonates and infants from adult parameters for most drugs used in anesthesia. The addition of a model describing maturation is required. The sigmoid Emax or Hill model has been found useful for describing this maturation process. Propofol maturation has been described with a mature clearance of 1.83 l·min^?1·70kg^?1, a maturation half‐time (TM₅₀) of 44 weeks and a Hill coefficient of 4.9. Organ function also affects clearance, and propofol clearance is reduced in neonates and infants after cardiac surgery. Although pharmacokinetics (PK) in children is receiving increasing attention and is eminently programmable into a TCI device, pharmacodynamic (PD) measures in children remain poorly defined, partly because the depth of anesthesia monitoring are inadequate. Both PK and PD are necessary for safe use of TCI pumps.     

Changes in carbon dioxide tension and oxygen saturation during deep sedation for paediatric cardiac catheterization

The purpose of this observational study was to determine whether hypercarbia or oxygen desaturation occurred during our current regimens of deep sedation or general anaesthesia of infants and children undergoing cardiac catheterization. Data were gathered prospectively from 50 consecutive infants and children aged 4 months to 12 years undergoing cardiac catheterization. Several anaesthetists used the following regimens, which were not randomized: 1) propofol. 1.5–2.0 mg·kg^?1 and fentanyl 1 μg·kg^?1 IV over 2 min for induction, followed by propofol infusion of 100–150 μg·kg^?1·min^?1; 2) fentanyl 2–3 μg·kg^?1 and midazolam 0.1–0.2 mg·kg^?1 IV over 10–15 min; 3) ketamine 8 mg·kg^?1 IM, or 4) same as regimens 1 or 2, plus pancuronium, intubation and controlled ventilation. Regimens 1, 2, and 3 were associated with spontaneous ventilation through the natural airway. End-tidal carbon dioxide tension (Petco₂), Spo₂, and respiratory rate were monitored for 60 min. The three regimens employing spontaneous ventilation through the natural airway were associated with both statistically and clinically significant increases in Petco₂ and decreases in Spo₂. This raises the possibility that acute exacerbation of PAP and PVR may occur in pulmonary hypertensive patients. In contrast, Petco₂ and Spo₂ did not change significantly from baseline in the controlled ventilation group.