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Objective: This study aims to describe the administration of propofol in combination with remifentanil for the induction of general anesthesia during cesarean section (CS). Our aim was to evaluate its impact on the drug concentrations of the maternal and neonatal blood at different induction of anesthesia to delivery (I-D) intervals as well as its effect on newborns., Materials and Methods: In this double-blind randomized controlled study, patients undergoing elective CS were administered anesthesia at short (n = 20) or long (n = 20) I-D intervals. Anesthesia was induced with 1 mg/kg propofol and 1 μg/kg remifentanil and maintained by continuous infusion of 3 mg/kg/h propofol and 7 μg/kg/h remifentanil., Results: The mean plasma propofol concentrations at delivery in the maternal arterial (MA) blood and the fetal umbilical arterial (UA) and venous (UV) blood in the short I-D interval group were 1.91, 1.17, and 0.51 μg/mL, respectively, while those in the long I-D interval group were 1.57, 1.07, and 0.61 μg/mL, respectively. The mean plasma remifentanil concentrations at delivery in the MA, UA, and UV in the short I-D interval group were 2.25, 1.43, and 0.65 ng/mL, respectively, and those in the long I-D interval group were 1.96, 1.25, and 0.75 ng/mL, respectively. There were no statistically significant differences in the neonatal Apgar scores and neurological adaptive capacity scores between the two groups., Conclusions: It is safe to administer propofol in combination with remifentanil by continuous infusion after the bolus dose for the induction of anesthesia during cesarean section. Prolonging the I-D interval within a certain limit will not have any significant influence on the fetus., (Copyright © 2017. Published by Elsevier B.V.)

Study Objective: To examine the influence of epidural and intravenous (IV) lidocaine, and height of the epidural sensory block, on the dose of propofol required for induction of general anesthesia., Design: Randomized controlled study., Setting: University hospital., Patients: 66 adult, ASA physical status 1 and 2 patients, aged 25 to 65 years, undergoing elective abdominal surgery., Interventions: Patients were randomized to 4 groups: the epidural saline control group (Group C; L2-L3 puncture, epidural and IV saline), the IV lidocaine group (Group IV; L2-L3 puncture, saline epidural, IV lidocaine 1 mg/kg), the lumbar epidural lidocaine group (Group EL; L2-L3 puncture, 1.5% lidocaine epidural, IV saline), and the thoracic epidural lidocaine group (Group ET; T9-T10 puncture, 1.5%lidocaine epidural, IV saline). Two minutes after the beginning of the infusion of IV lidocaine or saline, propofol anesthesia was initiated., Measurements: Mean arterial blood pressure (MAP), heart rate (HR), and sensory block height were monitored. The induction dose of propofol, its estimated effect-site concentration (Ce), and plasma concentration were measured at various time points. Finally, we recorded the time taken for the bispectral index (BIS) to decrease to 60, the plasma concentration of lidocaine at induction, and the occurrence of adverse events. The induction time (when BIS reached 60) also was recorded., Main Results: The induction propofol dose, Ce, and plasma concentration of propofol when BIS equaled 60 were significantly lower in Group IV, Group EL, and Group ET than Group C. The above parameters in Group ET (T9 - T10 puncture) were significantly less than in Group EL (L2 - L3 puncture). The induction doses of propofol and plasma concentration of propofol and lidocaine were significantly higher in Group IV than in Groups EL or ET., Conclusions: Epidural and IV lidocaine reduce the dose of propofol required to induce general anesthesia. Administration of lidocaine via the epidural route reduces anesthetic requirements more so than the IV route. Propofol requirements were further reduced in patients with higher sensory epidural block., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The aim of this study was to determine the effects of lidocaine (LIDO) and dexmedetomidine (DEX) or their combination (LIDO-DEX), administered by constant-rate infusion (CRI), on the minimum alveolar concentration (MAC) of sevoflurane in dogs. Seven healthy mongrel dogs were used with a 2-week washout interval between treatments in this study. Anesthesia was induced with propofol and maintained with sevoflurane in oxygen, and MAC of sevoflurane was determined after 90 min equilibration period in the dogs (SEV-MACBASAL). Then, sevoflurane MAC was determined again in the dogs after 45 min equilibration period of one of the following treatments: an intravenous loading dose of lidocaine 2 mg/kg followed by 6 mg/kg/hr CRI (SEV-MACLIDO); an intravenous loading dose of dexmedetomidine 2 µg/kg followed by 2 µg/kg/hr CRI (SEV-MACDEX); or their combination (SEV-MACLIDO-DEX). These SEV-MACs were determined in duplicate. Data were analyzed using ANOVA and post hoc Tuckey test when appropriate. The SEV-MACBASAL was 1.82 ± 0.06%, SEV-MACLIDO was 1.38 ± 0.08%, SEV-MACDEX was 1.22 ± 0.10%, and SEV-MACLIDO-DEX was 0.78 ± 0.06%. The CRI administration of lidocaine, dexmedetomidine and their combination produced a significant reduction in the MAC of sevoflurane by 26.1 ± 9.0% (P<0.0001), 43.7 ± 11.8% (P<0.0002) and 54.4 ± 9.8% (P<0.0001), respectively. The MAC reduction was significantly greater after the CRI combination of lidocaine and dexmedetomidine when compared with lidocaine CRI (P<0.0001) or dexmedetomidine CRI treatments (P<0.025).

Study Objective: To determine the effects of a small-dose ketamine-propofol combination used for sedation during spinal anesthesia on tourniquet-induced ischemia-reperfusion injury., Study Design: Prospective randomized study., Setting: Training and research hospital., Patients: 60 adult, ASA physical status 1 and 2 patients, ages 20-60 years, scheduled for elective arthroscopic knee surgery for meniscal and chondral lesions., Interventions: The initial hemodynamic parameters were recorded and blood samples were collected at baseline (T1); then spinal anesthesia was performed. In Group I (n=30), a combination of 0.5 mg/kg/hr of ketamine and 2 mg/kg/hr of propofol was administered; Group II (n=30) received an equivalent volume of saline as an infusion. A pneumatic tourniquet was applied., Measurements: Malondialdehyde (MDA), superoxide dismutase (SOD), and catalase levels were measured one minute before tournique deflation in the ischemic period (T2), then 5 (T3) and 30 (T4) minutes following tourniquet deflation in the reperfusion period., Main Results: No differences were noted between groups in hemodynamic data (P > 0.05) or SOD levels (P > 0.05). In Group I, MDA levels at T2 were lower than in Group II (P < 0.05). In Group I, catalase levels were lower at T2 and T4 than they were in Group II (P < 0.05)., Conclusion: Small-dose ketamine-propofol combination may be useful in reducing tourniquet-induced ischemia-reperfusion injury in arthroscopic knee surgery., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: On the basis of data indicating that volatile anesthetics induce cardioprotection in cardiac surgery, current guidelines recommend volatile anesthetics for maintenance of general anesthesia during noncardiac surgery in hemodynamic stable patients at risk for perioperative myocardial ischemia. The aim of the current study was to compare increased troponin T (TnT) values in patients receiving sevoflurane-based anesthesia or total intravenous anesthesia in elective abdominal aortic surgery., Methods: A prospective, randomized, open, parallel-group trial comparing sevoflurane-based anesthesia (group S) and total intravenous anesthesia (group T) with regard to cardioprotection in 193 patients scheduled for elective abdominal aortic surgery. Increased TnT level on the first postoperative day was the primary endpoint. Secondary endpoints were postoperative complications, nonfatal coronary events and mortality., Results: On the first postoperative day increased TnT values (>13 ng/l) were found in 43 (44%) patients in group S versus 41 (43%) in group T (P = 0.999), with no significant differences in TnT levels between the groups at any time point. Although underpowered, the authors found no differences in postoperative complications, nonfatal coronary events or mortality between the groups., Conclusions: In elective abdominal aortic surgery sevoflurane-based anesthesia did not reduce myocardial injury, evaluated by TnT release, compared with total intravenous anesthesia. These data indicate that potential cardioprotective effects of volatile anesthetics found in cardiac surgery are less obvious in major vascular surgery.

Background: Injectable forms of anesthesia for nonsurgical facial rejuvenation, although efficacious, are uncomfortable for the patient. Preclinical studies have demonstrated that laser pretreatment at low energies enhances absorption of topical lidocaine., Objectives: The authors assess the safety and efficacy of laser-assisted transdermal delivery of topical anesthetic., Method: Ten patients were split into 2 groups (A and B). All patients received 15 g of BLT (20% benzocaine, 6% lidocaine, and 4% tetracaine triple anesthetic cream) for 20 minutes with no occlusion. Then the cream was removed and the first blood draw taken. Group A patients were pretreated with the full ablative laser and group B patients with a fractional ablative laser to the full face. A further 15 g BLT was applied for another 20 minutes. Group A patients then underwent full ablative laser treatment, and group B received fractionated ablative laser treatment. Blood draws were taken at 60, 90, 120, 180, and 240 minutes after the initial topical anesthetic application, and the serum was analyzed for lidocaine and monoethylglycinexylidide (MEGX) levels. Patients were asked to rate the pain felt at intervals during the procedure., Results: No patient required supplemental nerve blocks. Pain scores were equivalent at the end of the first pass for both groups (P = .436). Group A patients had significantly lower pain scores at the start of the second laser treatment (P = .045), but pain scores became equivalent by the end (P = .323). Combined serum lidocaine and MEGX levels were significantly higher in group A patients up to 90 minutes (peak average of 0.61 µg/mL for group A and 0.533 µg/mL for group B; P = .0253), which corresponded to greater initial analgesic effect., Conclusions: Data from this study demonstrate that topical anesthetic for facial rejuvenation can be enhanced with laser pretreatment while maintaining safe blood serum levels. Further studies should examine optimal application amount and time to allow safe multipass facial rejuvenation without the need for invasive nerve blocks.

Background: Over a 5 yr period, we have encountered three patients in whom remifentanil appeared to have no clinical effect during general anaesthesia (GA). We describe seven anaesthetics in these three patients., Methods: We reviewed the literature on this subject. A simple reproducible test to explore this response was designed. This involved a controlled infusion of increasing doses of remifentanil while observing respiratory variables, pain threshold, pupil size, and Glasgow coma scale score. In addition, blood was sampled for genotyping., Results: No description of this impaired response was found in the review of the literature. Two of the patients agreed to participate in the test. In both patients, we found a seemingly normal analgesic response but a lack of respiratory depression and almost no depression of consciousness, even at doses well above the recommended level for clinical use. The genotyping did not explain the results of the test., Conclusions: The potential causes of this effect are discussed. We advise clinicians to be aware of this unusual response to remifentanil. If such a response is suspected, we recommend the use of another opioid. If this is suspected before GA, we propose the use of our test as a diagnostic tool.

Background: Hormonal and metabolic changes following surgery are markers of the stress response to surgery. We compared hemodynamic parameters and stress response markers (glucose, cortisol, and C-reactive protein) in two groups of patients receiving either propofol or isoflurane combined with remifentanil for maintenance of anesthesia., Methods: We randomly assigned 100 women (ASA I-II) scheduled for diagnostic gynecologic laparoscopy to receive either isoflurane (0.8% end-tidal) or propofol (100 mg/kg/min) in addition to remifentanil (0.25 mg/ kg/min). Heart rate and mean arterial pressure were recorded after induction, 30 seconds after intubation, at four time points after incision, and 60 min after surgery. Serum C-reactive protein, cortisol and glucose concentrations were measured before induction, one hour after incision, and one hour after surgery., Results: After induction, heart rate decreased significantly from baseline in both groups, and remained below baseline until the end of surgery. Mean arterial pressure also decreased significantly in both groups. C-reactive protein levels were not significantly different between groups. In the propofol group, cortisol decreased significantly one hour after incision, but increased in the isoflurane group. Glucose increased significantly in both groups, but was significantly lower in the propofol group one hour after the incision and one hour after surgery., Conclusion: An anesthetic regimen combining propofol and remifentanil attenuates two indicators of the stress response more efficiently than a isoflurane - remifentanil combination.

The pharmacokinetics of ketamine and norketamine enantiomers after administration of intravenous (IV) racemic ketamine (R-/S-ketamine; 2.2 mg/kg) or S-ketamine (1.1 mg/kg) to five ponies sedated with IV xylazine (1.1mg/kg) were compared. The time intervals to assume sternal and standing positions were recorded. Arterial blood samples were collected before and 1, 2, 4, 6, 8 and 13 min after ketamine administration. Arterial blood gases were evaluated 5 min after ketamine injection. Plasma concentrations of ketamine and norketamine enantiomers were determined by capillary electrophoresis and were evaluated by non-linear least square regression analysis applying a monocompartmental model. The first-order elimination rate constant was significantly higher and elimination half-life and mean residence time were lower for S-ketamine after S-ketamine compared to R-/S-ketamine administration. The maximum concentration of S-norketamine was higher after S-ketamine administration. Time to standing position was significantly diminished after S-ketamine compared to R-/S-ketamine. Blood gases showed low-degree hypoxaemia and hypercarbia.

Objective: To evaluate the effects of intravenous lidocaine (L) and ketamine (K) alone and their combination (LK) on the minimum alveolar concentration (MAC) of sevoflurane (SEVO) in dogs., Study Design: Prospective randomized, Latin-square experimental study., Animals: Six, healthy, adult Beagles, 2 males, 4 females, weighing 7.8 - 12.8 kg., Methods: Anesthesia was induced with SEVO in oxygen delivered by face mask. The tracheas were intubated and the lungs ventilated to maintain normocapnia. Baseline minimum alveolar concentration of SEVO (MAC(B)) was determined in duplicate for each dog using an electrical stimulus and then the treatment was initiated. Each dog received each of the following treatments, intravenously as a loading dose (LD) followed by a constant rate infusion (CRI): lidocaine (LD 2 mg kg(-1), CRI 50 microg kg(-1)minute(-1)), lidocaine (LD 2 mg kg(-1), CRI 100 microg kg(-1) minute(-1)), lidocaine (LD 2 mg kg(-1), CRI 200 microg kg(-1) minute(-1)), ketamine (LD 3 mg kg(-1), CRI 50 microg kg(-1) minute(-1)), ketamine (LD 3 mgkg(-1), CRI 100 microg kg(-1) minute(-1)), or lidocaine (LD 2 mg kg(-1), CRI 100 microg kg(-1) minute(-1)) + ketamine (LD 3 mg kg(-1), CRI 100 microg kg(-1) minute(-1)) in combination. Post-treatment MAC (MAC(T)) determination started 30 minutes after initiation of treatment., Results: Least squares mean +/- SEM MAC(B) of all groups was 1.9 +/- 0.2%. Lidocaine infusions of 50, 100, and 200 microg kg(-1) minute(-1) significantly reduced MAC(B) by 22.6%, 29.0%, and 39.6%, respectively. Ketamine infusions of 50 and 100 microg kg(-1) minute(-1) significantly reduced MAC(B) by 40.0% and 44.7%, respectively. The combination of K and L significantly reduced MAC(B) by 62.8%., Conclusions and Clinical Relevance: Lidocaine and K, alone and in combination, decrease SEVO MAC in dogs. Their use, at the doses studied, provides a clinically important reduction in the concentration of SEVO during anesthesia in dogs.

Target controlled infusions of propofol use a pharmacokinetic/pharmacodynamic model to calculate an effect site concentration of the drug. We assessed the cardiovascular stability of 10 healthy patients using non-invasive thoracic bioimpedance and their 'depth' of anaesthesia using the Bispectral index after they had been anaesthetised to a constant effect site concentration of propofol (6.5 min from starting). Each patient had no surgical stimulus and received no intravenous fluid during the study period. The patients also received effect site target controlled remifentanil (steady state 2.5 min from starting) and a bolus of vecuronium to facilitate intubation and ventilation. We mathematically calculated when each measured parameter would reach a state of stability (i.e. with 95% certainty). Heart rate levelled off at 20 min, Bispectral index at 32 min, and cardiac index and mean arterial pressure at 47 min after achieving effect site stability, the final levels being, respectively, 21%, 47%, 14% and 28% lower than those at effect site stability. We conclude that cardiovascular parameters continue to change to a clinically significant degree after achieving a constant effect site concentration of propofol via target controlled infusions.

Background: Measurement of the partial pressure of volatile anesthetics in blood is usually done using a "headspace equilibration" method with gas chromatography. However, it is not often performed in clinical studies because of the technical, equipment, and logistic requirements. To improve the accessibility of this measurement, we tested the use of a common infrared clinical gas analyzer, the Datex-Ohmeda Capnomac, for this purpose., Methods: After characterization of the linearity of the device in measuring the volatile anesthetic concentration in the presence of nitrous oxide, carbon dioxide, and water vapor, blood was tonometered with known concentrations of sevoflurane (actual value between 0.5% and 5.0%) in oxygen and oxygen/nitrous oxide mixtures, as well as mixtures of isoflurane and desflurane in oxygen., Results: Mean bias (standard deviation) overall for sevoflurane in oxygen relative to the tonometered reference partial pressure was -4.5 (4.8%) of the actual concentration. This was not altered significantly by measurement in 40% oxygen/60% nitrous oxide. For isoflurane and desflurane it was -3.9 (3.3%) and -4.6 (3.8%), respectively, of the actual concentration., Conclusions: The accuracy and precision of measurement of volatile anesthetic gas partial pressures in blood by a double headspace equilibration technique, using a clinical infrared gas analyzer, were comparable to that achieved by previous studies using gas chromatography.

Objective: To evaluate the effects of i.v. lidocaine (L) and ketamine (K), alone and in combination (LK), on the minimum alveolar concentration (MAC) of isoflurane (ISO) in goats., Study Design: Randomized crossover design., Animals: Eight, adult mixed breed castrated male goats, aged 1-2 years weighing 24-51 kg., Methods: Anesthesia was induced with ISO that was delivered via a mask. The tracheas were intubated and the animals ventilated to maintain an end-tidal carbon dioxide partial pressure between 25 and 30 mmHg (3.3-4 kPa). Baseline MAC (MAC(B)) that prevented purposeful movement in response to clamping a claw was determined in triplicate. After MAC(B) determination, each goat received one of the following treatments, which were administered as a loading (LD) dose followed by a constant rate infusion, IV: L (2.5 mg kg(-1); 100 microg kg(-1) minute(-1)), K (1.5 mg kg(-1); 50 microg kg(-1) minute(-1)), L and K combination or saline, and the MAC (MAC(T)) was re-determined in triplicate. Plasma concentrations of L and K were measured around each MAC point and the values averaged., Results: The least-squares mean MAC(B) for all treatments was 1.13 +/- 0.03%. L, K, and LK reduced (p < 0.05) MAC(B) by 18.3%, 49.6% and 69.4%, respectively. Plasma concentrations for L, K, and LK were 1617 +/- 385, 1535 +/- 251 and 1865 +/- 317/1467 +/- 185 ng mL(-1), respectively. No change (p > 0.05) occurred with saline., Conclusion: Lidocaine and K caused significant decreases in the MAC of ISO. The combination (LK) had an additive effect. However, the plasma L concentrations were less than predicted, as was the MAC reduction with L., Clinical Relevance: The use of L, K and the combination, at the doses studied, will allow a clinically important reduction in the concentration of ISO required to maintain general anesthesia in goats.

Background: The arterial pharmacokinetics of ketamine and norketamine enantiomers after racemic ketamine or S-ketamine i.v. administration were evaluated in seven gelding ponies in a crossover study (2-month interval)., Methods: Anaesthesia was induced with isoflurane in oxygen via a face-mask and then maintained at each pony's individual MAC. Racemic ketamine (2.2 mg kg(-1)) or S-ketamine (1.1 mg kg(-1)) was injected in the right jugular vein. Blood samples were collected from the right carotid artery before and at 1, 2, 4, 8, 16, 32, 64, and 128 min after ketamine administration. Ketamine and norketamine enantiomer plasma concentrations were determined by capillary electrophoresis. Individual R-ketamine and S-ketamine concentration vs time curves were analysed by non-linear least square regression two-compartment model analysis using PCNonlin. Plasma disposition curves for R-norketamine and S-norketamine were described by estimating AUC, C(max), and T(max). Pulse rate (PR), respiratory rate (R(f)), tidal volume (V(T)), minute volume ventilation (V(E)), end-tidal partial pressure of carbon dioxide (PE'(CO(2))), and mean arterial blood pressure (MAP) were also evaluated., Results: The pharmacokinetic parameters of S- and R-ketamine administered in the racemic mixture or S-ketamine administered separately did not differ significantly. Statistically significant higher AUC and C(max) were found for S-norketamine compared with R-norketamine in the racemic group. Overall, R(f), V(E), PE'(CO(2)), and MAP were significantly higher in the racemic group, whereas PR was higher in the S-ketamine group., Conclusions: Norketamine enantiomers showed different pharmacokinetic profiles after single i.v. administration of racemic ketamine in ponies anaesthetised with isoflurane in oxygen (1 MAC). Cardiopulmonary variables require further investigation.

Background: A computer controlled infusion device for S(+) ketamine was used in combination with a Diprifusor device to provide anaesthesia for 20 ASA I or II patients undergoing elective colonoscopy. The aim of the study was to assess the performance of the pharmacokinetic model for S(+) ketamine used in the delivery algorithm of the device., Results: It was observed that during the first 30 min of infusion there was systematic underprediction by the delivery system of the measured levels of S(+) ketamine. New pharmacokinetic constants were derived from the observed data which provided, on pharmacokinetic simulation, improved prediction of the measured values of S(+) ketamine. Prospective application of this modified model for S(+) ketamine in a further nine study patients was performed and the pharmacokinetic performance of the model was reassessed. The data from all 29 patients was subsequently used to calculate the population distribution of S(+) ketamine clearance. The distribution was found to be normal only in the logarithmic domain. In the normal domain the mode of S(+) ketamine clearance was found to be 35.8 ml kg(-1) min(-1) with 5 and 95% confidence limits of, respectively, 11.5 and 111.1 ml kg(-1) min(-1)., Conclusion: It was necessary to modify the original published pharmacokinetic parameters incorporated into the S(+) ketamine delivery system in order to simulate improved PK performance during short procedures (<1 h duration) where propofol was concurrently administered. This improved performance was confirmed in a further prospective study.

Background: The target blood concentrations of propofol and remifentanil, when used in combination, required to blunt the cough response to tracheal intubation, cuff inflation, and tracheal suctioning without neuromuscular blocking agents are not known., Methods: In a randomized prospective study, 81 patients were enrolled to determine which of three target remifentanil blood concentrations was required to blunt coughing during intubation, cuff inflation, and tracheal suctioning. Anaesthesia was achieved with propofol at a steady effect-site concentration of 3.5 microg ml(-1). The target blood remifentanil concentrations were 5, 10, or 15 ng ml(-1). These concentrations were maintained for 12 min before intubation., Results: There was no cough response to intubation in more than 74% of patients and no significant difference in the incidence of coughing with intubation between the three groups. Significant difference in coughing, diminishing with increasing remifentanil target concentration, was observed with cuff inflation (P=0.04) and tracheal suctioning (P=0.007). Bradycardia and hypotension was more frequent with the remifentanil target concentration of 15 ng ml(-1). Tracheal suctioning resulted in more coughing than intubation (P=0.01) or cuff inflation (P=0.004)., Conclusion: Target remifentanil blood concentrations of 5, 10, and 15 ng ml(-1) associated with a 3.5 microg ml(-1) propofol target blood concentration provided good intubating conditions and absence of cough about 75% of the time. Higher target remifentanil concentrations were associated with less coughing during tracheal tube cuff inflation and tracheal suctioning.

Background: The authors compared the effects of epidural anaesthesia with lidocaine 1% and lidocaine 2% on haemodynamic variables, sevoflurane requirements, and stress hormone responses during surgery under combined epidural/general anaesthesia with bispectral index score (BIS) kept within the range 40-50., Methods: Thirty-three patients undergoing lower abdominal surgery were randomly divided into two groups to receive lidocaine 1% or 2% by epidural with sevoflurane general anaesthesia. Sevoflurane was adjusted to achieve a target BIS of 40-50 during maintenance of anaesthesia with nitrous oxide 60% in oxygen. Measurements included the inspired (FI(SEVO)) and the end-tidal sevoflurane concentrations (E'(SEVO)), blood pressure (BP), and heart rate (HR) before surgery and every 5 min during surgery for 2 h. Plasma samples were taken immediately before and during surgery for measurements of catecholamines, cortisol, and lidocaine., Results: During surgery, both groups were similar for HR, BP and BIS, but FI(SEVO) and E'(SEVO) were significantly higher and more variable with lidocaine 1% than with 2%. Intraoperative plasma concentrations of epinephrine and cortisol were found to be higher with lidocaine 1% as compared with 2%., Conclusions: To maintain BIS of 40-50 during combined epidural/general anaesthesia for lower abdominal surgery, sevoflurane concentrations were lower and less variable with lidocaine 2% than with 1%. In addition, the larger concentration of lidocaine suppressed the stress hormone responses better.

Background and Objective: Although percutaneous nephrolithotomy has many advantages over open surgery, some endocrine and haemodynamic responses have been reported. However, the effects of anaesthetic agents on these responses have not previously been reported. This study compared the effects of sevoflurane and total intravenous anaesthesia using propofol and alfentanil on the haemodynamic and hormonal changes during percutaneous nephrolithotomy., Methods: Forty-two ASA I-II patients aged between 15 and 65 yr were studied. Sevoflurane in Group S (21 patients) or TIVA in Group TIVA (21) was used for the maintenance of anaesthesia. Haemodynamic variables and serum concentrations of sodium and potassium were measured before, during and after the procedure. Arterial blood-gas status, plasma renin, aldosterone and adrenocorticotrophic hormone concentrations were measured before and during the procedure., Results: Mean heart rate was lower during percutaneous nephrolithotomy in Group TIVA compared with Group S (P < 0.01). The mean systolic and diastolic arterial pressures were not different in both groups at any stage of measurement (P < 0.05). Plasma renin, aldosterone and adrenocorticotrophic hormone concentrations were increased during percutaneous nephrolithotomy in both groups, but the increase was greater in Group S (P < 0.05)., Conclusions: In the sevoflurane group, the concentrations of renin, aldosterone and adrenocorticotrophic hormone were significantly higher after 15 min of irrigation compared with the total intravenous anaesthesia group. Although the clinical significance of this difference was not clear, these changes should be considered in certain patient groups.

Oraqix, a novel non-injectable anesthetic gel containing lidocaine and prilocaine and a thermosetting agent has been developed to provide localized anesthesia in periodontal pockets during scaling/root planing (SRP). The aim of this open study was to determine the plasma levels of lidocaine and prilocaine following application of 8.5 g Oraqix (5 cartridges) to 11 patients with generalized periodontitis (> or = 49% of tooth pockets > or = 5 mm and > or = 23% of pockets > or = 6 mm). Oraqix was applied to the pockets during periodontal probing and SRP over a 2.6 3.4 h period. Blood samples were collected up to 10 h after the start of application of Oraqix. Peak plasma levels of lidocaine (0.16-0.55 mg/L) and prilocaine (0.05-0.18 mg/L) occurred 2.0-3.7 h and 2.0-3.3 h, respectively, after the start of application of Oraqix. These levels are well below threshold levels for initial signs of central nervous system (CNS) toxicity. In conclusion, application of 8.5 g Oraqix (212.5 mg of lidocaine base and 212.5 mg of prilocaine base) in periodontal pockets was well tolerated and displayed a wide safety margin with respect to plasma levels normally associated with systemic toxicity.

Background: General anaesthesia is a balance between hypnosis and analgesia. We investigated whether an increase in remifentanil blood concentration would reduce the amount of propofol required to maintain a comparable level of anaesthesia in 60 patients undergoing ambulatory surgery., Methods: Patients were allocated randomly to receive remifentanil to a target blood concentration of 2 ng ml(-1) (low), 4 ng ml(-1) (medium), or 8 ng ml(-1) (high), administered by target-controlled infusion (TCI). After equilibration, propofol TCI was commenced in closed-loop control, with auditory evoked potentials (AEPex) as the input signal, aiming for an AEPex of 35. This was to ensure a comparable and unbiased level of anaesthesia in all patients., Results: We found a dose-dependent decrease in propofol requirements with increasing remifentanil concentrations. The mean (95% CI) propofol target blood concentration during adequate anaesthesia was 4.96 (3.85-6.01) micro g ml(-1) in the low, 3.46 (2.96-3.96) micro g ml(-1) in the medium, and 3.01 (2.20-3.38) micro g ml(-1) in the high group. There was no significant difference when recovery end points were achieved between the groups. Cardiovascular changes were moderate, but most pronounced in the high concentration group, with a decrease in heart rate of 21% compared with baseline. The mean calculated effect site propofol concentration at loss of consciousness was 2.08 (1.85-2.32) micro g ml(-1), and at recovery of consciousness was 1.85 (1.68-2.00) micro g ml(-1)., Conclusions: This study confirms a synergistic interaction between remifentanil and propofol during surgery, whereas the contribution of remifentanil in the absence of stimulation seems limited. In addition, our results suggest that the propofol effect site concentration provides a guide to the value at which the patient recovers consciousness.

Background: The predictive performance of the available pharmacokinetic parameter sets for remifentanil, when used for target-controlled infusion (TCI) during total i.v. anaesthesia, has not been determined in a clinical setting. We studied the predictive performance of five parameter sets of remifentanil when used for TCI of remifentanil during propofol anaesthesia in surgical patients., Methods: Remifentanil concentration-time data that had been collected during a previous pharmacodynamic interaction study in 30 female patients (ASA physical status I, aged 20-65 yr) who received a TCI of remifentanil and propofol during lower abdominal surgery were used in this evaluation. The remifentanil concentrations predicted by the five parameter sets were calculated on the basis of the TCI device record of the infusion rate-time profile that had actually been administered to each individual. The individual and pooled bias [median performance error (MDPE)], inaccuracy [median absolute performance error (MDAPE)], divergence and wobble of the remifentanil TCI device were determined from the pooled and intrasubject performance errors., Results: A total of 444 remifentanil blood samples were analysed. Blood propofol and remifentanil concentrations ranged from 0.5 to 11 micro g ml(-1) and 0.1 to 19.6 ng ml(-1) respectively. Pooled MDPE and MDAPE of the remifentanil TCI device were -15 and 20% for the parameter set of Minto and colleagues (Anesthesiology 1997; 86: 10-23), 1 and 21%, -6 and 21%, and -6 and 19% for the three parameter sets described by Egan and colleagues (Anesthesiology 1996; 84: 821-33, Anesthesiology 1993; 79: 881-92, Anesthesiology 1998; 89: 562-73), and -24 and 30% for the parameter set described by Drover and Lemmens (Anesthesiology 1998; 89: 869-77)., Conclusions: Remifentanil can be administered by TCI with acceptable bias and inaccuracy. The three pharmacokinetic parameter sets described by Egan and colleagues resulted in the least bias and best accuracy.

This study sought to determine the predicted Cp50 of propofol required for laryngeal mask airway insertion (Cp50LMA) and to investigate whether nitrous oxide reduces these required concentrations. Using target-controlled infusion and incorporating the standard Diprifusor pharmacokinetic model, 46 unpremedicated patients were randomly assigned to one of two groups. The patients received either 40% oxygen in air (control group: n = 23), or 60% nitrous oxide in oxygen (nitrous oxide group: n = 23). The target concentration for each patient was determined using the up and down method. Following equilibration between the predetermined blood and effect site concentrations, had been established for > 10 min, laryngeal mask airway insertion was attempted without neuromuscular relaxants. The data were analysed using a probit analysis to obtain Cp50LMA levels. The values for Cp50LMA were 3.24 micro g.ml-1 in the control group and 1.93 microg.ml-1 in the nitrous oxide group.

Background: A ketamine-alfentanil combination has been suggested for total i.v. anaesthesia. We determined the pharmacokinetics of ketamine and alfentanil, alone and together, in three groups of adult male rats, to assess any pharmacokinetic interaction., Methods: Group 1 animals were infused with i.v. ketamine for 5 min; in group 2, constant low plasma concentrations of alfentanil were maintained by computer-controlled infusion; in group 3, the treatments were combined. Serial plasma and terminal tissue concentrations were measured by high performance liquid chromatography or gas chromatography-mass spectrometry., Results: In the presence of alfentanil, the mean plasma ketamine concentration-time area under the curve (AUC) value was significantly lower (by 13%, P<0.05), while clearance (CIT) and volume of distribution (Vss) were significantly higher (by 16 and 28%, respectively, both P<0.05). Tissue:plasma distribution coefficients for ketamine in the presence of alfentanil were significantly higher in forebrain (by 128%, P<0.005), hindbrain (by 207%, P<0.01), gut (by 254%, P<0.005), and fat (by 344%, P<0.0001). Mean AUC values for alfentanil did not differ significantly in the presence of ketamine, but alfentanil tissue concentrations were significantly lower in forebrain (by 77%, P<0.0001), hindbrain (by 28%, P<0.01), heart (by 33%, P<0.01), lung (30%, P<0.05), and gut (by 21%, P<0.05). Corresponding tissue:plasma distribution coefficients were significantly lower for forebrain (by 69%, P<0.0001) alone., Conclusions: The finding that the distribution of ketamine into the brain was increased by low plasma concentrations of alfentanil could have important clinical applications for pain management.

Background: Although the lignocaine (lidocaine)-prilocaine cream EMLA has been extensively studied for the relief of acute treatment-related pain from sharp leg ulcer debridement, no data exist on systemic absorption from prolonged application in patients with chronically painful ulcers., Objectives: To study the plasma concentrations of lignocaine and prilocaine resulting from prolonged application of EMLA to leg ulcers., Methods: A single 24-h application of 5-10 g (median 6.75) of EMLA was given to 10 patients with painful leg ulcers measuring 50-100 cm2. Venous blood samples, drawn between 0.5 and 27 h after cream application, were analysed by gas chromatography using a nitrogen-sensitive detector., Results: The peak plasma levels were in the range 185-705 ng mL(-1) and 62-277 ng mL(-1) for lignocaine and prilocaine, respectively, and were observed 2-4 h (in one patient 6-8 h) after application. The peak plasma concentration of lignocaine, but not of prilocaine, increased significantly with increasing dose. The cream was well tolerated by the patients., Conclusions: The results indicate that a 24-h application of 5-10 g EMLA results in peak plasma concentrations of the two local anaesthetics, which combined are less than one-fifth of those associated with toxic reactions. The analgesic efficacy of EMLA for the relief of chronic ulcer pain deserves further study.

Background, Aims: Oraqix, a new non-injection local anesthetic, lidocaine/prilocaine gel 5%, has been developed to provide pain relief in association with periodontal probing and scaling/root planing (SRP). The aim of this open study was to describe the plasma profiles of lidocaine and prilocaine following a single dose of Oraqix to patients with advanced periodontitis., Methods: 10 patients with 18 to 28 teeth with pocket depths of at least 4 mm were included. Oraqix was applied in the pockets around all the teeth in the mouth by means of a blunt applicator. The total dose applied per patient was 0.9 to 3.5 g. Directly thereafter all the pockets were probed and 3 teeth subjected to SRP. The mouth was rinsed out with a glass of water 20-27 min after the application of the gel. Blood samples were collected before and up to 90 min after the start of application of Oraqix., Results: Peak plasma concentrations of lidocaine (99-266 ng/ml) and prilocaine (46-118 ng/ml) occurred 20-40 min after the start of application. These levels were low compared to those reported to cause initial signs of CNS toxicity (5000-6000 ng/ml). Side-effects were few and mild local effects of short duration., Discussion: In conclusion, there is a large safety margin with respect to systemic effects following the application of up to 3.5 g Oraqix in periodontal pockets.

EMLA Cream (EC; Astra, Westborough, MA) has been widely used as a local anesthetic. Limited safety information is available with respect to the application of EC to the oral mucous membranes. The purpose of this pilot study was to evaluate the efficacy and safety of EC when applied to oral mucosa for fiberoptic intubation. Twenty ASA physical status I-IV patients (11 women and 9 men), 28-57 yr old, who were scheduled for awake, fiberoptic, intubation participated in this open-label study. A total of 4 g of EC was used for 5 min until the patient showed no evidence of a gag reflex (this was evaluated clinically by the patient's acceptance of the William's airway and considered the endpoint for assessing adequate topicalization of the oropharynx). The measured peak plasma concentration of lidocaine or prilocaine did not reach toxic levels in any patient. Methemoglobin levels did not exceed normal values (1.5%) in any patient, and there was no relationship between methemoglobin levels and patient weight, amount of EC used, measured peak plasma concentration, or times to measured peak concentrations of prilocaine or lidocaine. We conclude that EC provided satisfactory topical anesthesia allowing for successful oral fiberoptic intubation in all patients and should be considered a safe alternative for anesthetizing the airway of patients requiring awake oral fiberoptic intubation.

We have studied the pharmacokinetics and pharmacodynamics of alfentanil, fentanyl and sufentanil together with propofol in patients undergoing coronary artery bypass graft surgery (CABG). Sixty patients (age 40-73 yr, 56 male) were assigned randomly to receive alfentanil, fentanyl or sufentanil and propofol. Plasma concentrations of these drugs and times for the plasma concentration to decrease by 50% (t50) and 80% (t80) after cessation of the infusion were determined. Times were recorded to awakening and tracheal extubation. Total dose and plasma concentrations of propofol were similar in all groups. Mean total doses of alfentanil, fentanyl and sufentanil were 443, 45 and 4.4 micrograms kg-1, respectively. Time to awakening did not differ significantly. In patients receiving fentanyl, the trachea was extubated on average 2 h later than in those receiving sufentanil and 3 h later than in those receiving alfentanil (P < 0.05). The t80 of fentanyl was longer (P < 0.05) than that of alfentanil or sufentanil, and there was a linear correlation between the t80 of the opioid and the time to tracheal extubation (r = 0.51; P < 0.01). However, the t50 values for these opioids were similar and did not correlate with recovery time. In conclusion, patients undergoing CABG and who were anaesthetized with fentanyl and propofol needed mechanical ventilatory support for a significantly longer time than those receiving alfentanil or sufentanil and propofol. On the basis of the interindividual variation observed, the time to tracheal extubation was most predictable in patients receiving alfentanil and most variable in patients receiving fentanyl, a finding which may be important if the patients are transferred to a step-down unit on the evening of the operation.

Twenty-one patients were studied to compare the success rate of anesthesia induction using target-controlled infusion of propofol with and without fentanyl. All patients were premedicated with atropine 0.5 mg and hydroxyzine 25-50 mg. Five minutes after intravenous administration of fentanyl 2 micrograms.kg-1, patients were given infusions of propofol designed to achieve target blood concentrations of 3 micrograms.kg-1. Loss of verbal contact was regarded as successful induction. The success rate of anesthesia induction within three minutes of achieving the target concentration was 90%. Pain on injection and reduction in blood pressure were infrequent. Selecting a target concentration of 3 micrograms.kg-1 with fentanyl 2 micrograms.kg-1 can be expected to successfully induce anesthesia in the majority of patients without major hemodynamic side effects and pain on injection.

Objective: To evaluate cardiovascular effects of epidurally administered oxymorphone (OXY) and an OXY-bupivacaine combination (O/B) in halothane-anesthetized dogs., Animals: 6 dogs., Procedure: In a randomized crossover design study, dogs were anesthetized with halothane and given OXY, O/B, and saline solution (SAL). Eucapnia and end-tidal halothane concentration of 1.2% were established. Heart rate (HR), systemic and pulmonary arterial pressures, central venous pressure (CVP), and cardiac output were measured at baseline and 5, 15, 30, 45, 60, and 75 minutes after treatment. At 90 minutes, glycopyrrolate was administered IV, and measurements were repeated at 95 minutes. Cardiac index (CI), stroke volume, stroke index, systemic vascular resistance (SVR), and left ventricular work were calculated. End-tidal halothane concentration was decreased to 0.8% from 17 to 45 minutes and to 0.5% from 47 to 95 minutes for OXY and O/B, whereas for SAL, it was maintained at 1.5 and 1.2%, respectively. Samples were obtained at 0, 2, 5, 15, 30, 45, 60, and 95 minutes for measurement of serum opiate concentration and comparison with values after IM administration of OXY., Results: HR decreased, but CVP and SVR increased in response to OXY and O/B. These changes were reversed after IV administration of glycopyrrolate, resulting in significant increase in CI, compared with that in response to SAL. Serum opiate concentration increased markedly and peaked within 15 minutes after OXY and O/B administration but did not differ from values after IM administration., Conclusions: Epidural administration of OXY results in rapid systemic uptake and decreased HR. Glycopyrrolate administration improves HR, resulting in improved CI at equipotent halothane concentrations.

Plasma concentrations of lidocaine and prilocaine were measured following the application of a 5% eutectic mixture of local anesthetics (EMLA) topical anesthetic cream to the oral mucosa of twelve subjects. For each subject, a total of 8 g of EMLA was occluded to 18 cm2 of buccal mucosa for 30 min. Analysis was carried out by high-pressure liquid chromatography, and results showed peak concentrations at 40 min for lidocaine and prilocaine. The maximum concentration measured in any subject was 418 ng/ml for lidocaine and 223 ng/ml for prilocaine, well below known toxic levels. No adverse local effects were observed from a 30-min application of EMLA. A follow-up pilot study assessing the clinical efficacy of EMLA for achieving sufficient analgesia for restorative procedures showed that the cream was successful in 75% of subjects tested.

We have examined the effect of fentanyl on the pharmacokinetics of midazolam in patients undergoing orthopaedic surgery. Thirty patients were allocated randomly to receive fentanyl 200 micrograms and midazolam 0.2 mg kg-1 (fentanyl group, n = 15) or placebo and midazolam 0.2 mg kg-1 (placebo group, n = 15) in a double-blind manner for induction of anaesthesia. Anaesthesia was maintained with nitrous oxide and isoflurane. Systemic clearance of midazolam was decreased by 30% (P = 0.002) and elimination half-time was prolonged by 50% (P = 0.04) in the fentanyl group compared with the placebo group. There were no differences in the distribution half-time or volume of distribution at steady state between the two groups. These findings indicate that elimination of midazolam was inhibited by fentanyl during general anaesthesia.

The purpose of this study was to investigate the effectiveness of a combination of bupivacaine and lidocaine and that of lidocaine alone for local dental anesthesia. First, on different days, healthy volunteers were given 2% lidocaine with 1/80,000 epinephrine or 2% lidocaine with 1/80,000 epinephrine + 0.5% bupivacaine, after which pain was produced with a pulp tester. No difference was found in the time until onset of anesthetic effect between the preparations. However, the duration of anesthetic effect was longer with both lidocaine and bupivacaine than with lidocaine alone. Next, patients undergoing dental surgery were given one of the anesthetic preparations, after which serum concentrations of the anesthetics and epinephrine were measured. The maximal serum concentration of lidocaine was higher and was reached sooner after injection in patients receiving lidocaine alone (1.74 microgram/ml after 5 min) than in patients receiving both anesthetics (0.85 microgram/ml after 3 min). The mean maximal serum concentration of lidocaine was higher in patients receiving lidocaine alone (1.77 +/- 0.03 microgram/ml) than in those receiving both anesthetics (0.99 +/- 0.45 microgram/ml). Furthermore, the mean plasma concentration of epinephrine 1 min after injection was significantly higher in patients receiving lidocaine alone (0.671 ng/ml) than in patients receiving both lidocaine and bupivacaine (0.323 ng/ml). The results of this study suggest that the combination of lidocaine with epinephrine and bupivacaine produces lower systemic levels of the anesthetic and epinephrine and a longer duration of activity than lidocaine with epinephrine alone for local dental anesthesia.

One hour after a bone marrow biopsy and inhalation of Entonox gas (50% nitrous oxide (N2O) and 50% oxygen), a patient had a markedly reduced transfer factor of the lung for carbon monoxide (TL,CO). Three hours after Entonox, the patient had a normal TL,CO. Since carbon monoxide (CO) and N2O have similar spectral wavelengths, it was proposed that residual N2O in the lungs was interfering with the infra-red analysers used to detect CO concentrations. Experiments were performed to verify the "interference" effect and its duration. Five healthy volunteers performed serial triplicate TL,CO measurements over 3 h on two randomized days (Control vs N2O). The first triplicate TL,CO on each day served as a baseline measurement. Following the baseline measurement on the N2O day, each subject inhaled Entonox for 10 min. To serve as a control for the infrared effect, the identical protocol was repeated using a gas chromatography method for TL,CO determination. The infra-red method showed a marked reduction (> 50%) in TL,CO 30 min after N2O inhalation. This reduction did not return to baseline levels for at least 2 h. In comparison, the gas chromatography method showed no significant reduction in TL,CO. In a group of healthy nonsmoking subjects, N2O markedly affected the measurement of the transfer factor of the lungs for carbon monoxide using infra-red analysers. The time course over which the measurement was reduced was at least 2 h for a 10 min inhalation period. The effect was entirely due to a measurement error associated with infra-red technology.

Twenty-five patients undergoing elective cataract day surgery were studied after receiving a dual-injection peribulbar block with a mixture consisting of equal volumes of 2% lignocaine and 0.75% bupivacaine with hyaluronidase. A maximum of 10 ml of solution was used for the initial block; supplementary injections of up to 10 ml were given to five patients. Venous blood was taken prior to the block and then 1, 10, 20, 30, 60 and 90 min after the block. The peak mean concentrations of lignocaine (0.722 microgram.ml-1) and bupivacaine (0.353 microgram.ml-1) were found at 10-20 min after injection when no top-up was given and at 10 min after the top-up injection when required. All measured serum concentrations of lignocaine and bupivacaine were below the accepted toxic levels of the two drugs. However, the highest individual toxicity score after a top-up was 0.915 which was very close to the toxicity threshold (= 1) when a scoring system was used to assess the combined levels.

The time course of arterial plasma lidocaine concentration, following an epidural anaesthesia via the sacrococcygeal or the S4-S5 trans-sacral approach, was studied in nine healthy piglets (7.8 +/- 1.3 weeks). Plasma lidocaine concentrations were measured for up to six hours after administration (5 mg/kg). Peak plasma concentration was 1.83 +/- 0.17 mg/l. Pharmacokinetic parameters determined from an independent compartment model were not different from those observed after an epidural administration of lidocaine via the sacrococcygeal space in children, except for a wide variability in the time taken to reach the maximum concentration (27.3 +/- 7.4 min) and a shorter half-life of elimination (82.8 +/- 7.0 min). The total body clearance of lidocaine was similar in piglets (17.3 +/- 1.6 ml/min/kg) to that in children. The shorter half-life of elimination was therefore attributed to a smaller volume of distribution in piglets (2.0 +/- 0.2 l/kg).