The Comparative Pharmacodynamics of Remifentanil and Its Metabolite, GR90291, in a Rat Electroencephalographic Model

Background: The purpose of this study was to investigate the in vivo pharmacodynamics and the pharmacodynamic interactions of remifentanil and its major metabolite, GR90291, in a rat electroencephalographic model.

Methods: Remifentanil and GR90291 were administered according to a stepwise infusion scheme. The time course of the electroencephalographic effect (0.5-4.5 Hz) was determined in conjunction with concentrations of the parent drug and the metabolite in blood.

Results: Administration of remifentanil resulted in concentrations of remifentanil and GR90291 in the ranges 0-120 ng/ml and 0-850 ng/ml, respectively. When the metabolite was administered, concentrations of the metabolite in the range 0-220 [micro sign]g/ml and no measurable concentrations of remifentanil were observed. The mean +/- SE values of the pharmacokinetic parameters clearance and volume of distribution at steady state were 920 +/- 110 ml [middle dot] min-1 [middle dot] kg-1 and 1.00 +/- 0.931/kg for remifentanil and 15 +/- 2 ml [middle dot] min-1 [middle dot] kg-1 and 0.56 +/- 0.08 1/kg for GR90291. The relative free concentrations in the brain, as determined on the basis of the cerebrospinal fluid/total blood concentration ratio at steady state, were 25 +/- 5% and 0.30 +/- 0.11% for remifentanil and GR90291, respectively. Concentration-electroencephalographic effect relations were characterized on the basis of the sigmoidal Emax pharmacodynamic model. The mean +/- SE values for the maximal effect (Emax), the concentration at which 50% of the maximal effect is obtained (EC50), and Hill factor for remifentanil were 109 +/- 12 [micro sign]V, 9.4 +/- 0.9 ng/ml, and 2.2 +/- 0.3, respectively (n = 8). For GR90291, the mean +/- SE values for EC50 and the Hill factor were 103,000 +/- 9,000 [micro sign]g/ml and 2.5 +/- 0.4, respectively (n = 6).     

Brain tumors may alter the relationship between bispectral index values and propofol concentrations during induction of anesthesia

STUDY OBJECTIVE: To compare propofol-predicted effect-site concentrations (PropCe) and bispectral index (BIS) of the electroencephalogram during induction of anesthesia in patients with small brain tumors and to analyze BIS and PropCe at loss of consciousness (LOC). DESIGN: Prospective investigation. SETTING: Operating theater of a university hospital. PATIENTS: 26 ASA physical status I and II patients, 13 of whom were scheduled for nontumor spinal surgeries, and the other 13, for brain surgery for small brain tumor removal. INTERVENTIONS: Anesthesia was induced with a propofol 1% constant infusion rate of 200 mL/h until LOC. MEASUREMENTS: BIS, PropCe, heart rate, and mean arterial pressure were analyzed at the beginning of the propofol infusion and every 30 seconds during induction. MAIN RESULTS: The BIS values were significantly higher in patients with brain tumors in the period from 150 to 210 seconds, with PropCe similar to patients without brain tumors. Loss of consciousness occurred 3.6 +/- 0.8 minutes in patients without brain tumors and 3.9 +/- 0.7 minutes in patients with brain tumors. No differences were observed between groups in the time to LOC (3.6 +/- 0.8 in group 1 vs 3.9 +/- 0.7 in group 2) or in BIS at LOC (48.7 +/- 11.4 in group 1 vs 58.6 +/- 21.7 in group 2). CONCLUSIONS: For similar propofol concentrations, patients with small brain tumors show higher BIS values on induction of anesthesia with propofol.     

Desflurane-remifentanil-nitrous oxide anaesthesia for abdominal surgery: optimal concentrations and recovery features

BACKGROUND: Intraoperative combinations of volatile and opioid agents are used to achieve unconsciousness, hypnotic sparing, haemodynamic stability and uneventful recovery. This study describes the influence of different remifentanil concentrations on these variables when combined with desflurane during abdominal surgery. METHODS: Sixty-one healthy adult patients were randomly allocated to one of five predefined remifentanil target concentrations (3, 5, 7, 10 or 15 ng ml(-1)). Anaesthesia was titrated to maintain mean blood pressure (MBP), heart rate (HR) and BIS trade mark within predetermined values by adjusting desflurane delivery. Postoperative analgesia using propacetamol and morphine was initiated 30-45 min before skin closure, and continued using morphine PCA. RESULTS: Desflurane requirements adjusted to both BIS and haemodynamics were not significantly modified by the remifentanil concentration (median Fet(DES) 2.7% before incision, 2.5% intraoperatively, and 2.2% during closure), resulting in a calculated drug consumption of 0.22-0.25 ml min(-1) (with 1.5 l min(-1) fresh gas flow). High remifentanil concentration decreased MBP and HR, and reduced the duration of tachycardia, but increased the duration of hypotension. The optimal balance was obtained with a remifentanil concentration of 5-7 ng ml(-1) for intubation, 3 ng ml(-1) until incision, 10 ng ml(-1) during intra-abdominal surgery and 5-7 ng ml(-1) during closure. Post-operative morphine requirements were not significantly modified by intraoperative remifentanil concentrations (median 30 mg/24 h, range [2-88]). CONCLUSION: Remifentanil target concentrations from 3 to 15 ng ml(-1) had little influence on desflurane requirements or postoperative morphine consumption, but markedly modified intraoperative haemodynamic stability, suggesting that the target concentration should closely follow the successive noxious stimulations.     

Clinical variables related to propofol effect-site concentrations at recovery of consciousness after neurosurgical procedures

Target controlled infusion (TCI) systems and computer data acquisition software are increasingly used in anesthesia. It was hypothesized that the use of such systems might allow retrieval of information useful to anticipate the effect-site concentrations of propofol at which patients would recover from anesthesia. The goal of the study was to identify variables related to propofol effect-site concentrations at recovery of consciousness (ROC). Sixteen patients with a Glasgow of 15, ASA 1 or 2, subjected to neurosurgical procedures, received TIVA with TCI propofol and remifentanil. Data were collected every 5 seconds from Datex AS3 and Aspect A200XP (BIS). Effect-site TCI was used for propofol (initial effect target 5.0 microg/ml) and for remifentanil (initial plasma target 2.5 ng/ml). All clinical events were noted. Variables possibly related to propofol effect-site concentration at ROC were selected. Data are expressed as mean +/- SD. Effect-site propofol concentration at ROC was 1.3 +/- 0.5 microg/ml. A positive correlation was found between propofol effect-site concentration at ROC and: age (49.3 +/- 17 years) (P = 0.003); mean remifentanil dose during surgery (0.11 +/- 0.05 microg/kg/min) (P = 0.003); mean propofol dose during surgery (0.12 +/- 0.03 mg/kg/min) (P = 0.046); and remifentanil effect-site concentration at ROC (2.85 +/- 2.06 ng/ml) (P = 0.002). Propofol effect-site concentrations were not correlated with: weight, height, LBM, duration of anesthesia, minimum BIS at induction (30.4 +/- 6.8), time till minimum BIS (4.7 +/- 2.2 min), mean and median BIS during surgery (38.2 +/- 4.5 and 37.8 +/- 5.3). BIS-related variables were not useful as ROC predictors. Only drug variables and age correlated with propofol effect-site concentrations at ROC.     

Propofol and remifentanil effect-site concentrations estimated by pharmacokinetic simulation and bispectral index monitoring during craniotomy with intraoperative awakening for brain tumor resection

Different anesthetic techniques have been suggested for craniotomy with intraoperative awakening. We describe an asleep-awake-asleep technique with propofol and remifentanil infusions, with pharmacokinetic simulation to predict the effect-site concentrations and to modulate the infusion rates of both drugs, and bispectral index (BIS) monitoring. Five critical moments were defined: first loss of consciousness (LOC1), first recovery of consciousness (ROC1), final of neurologic testing (NT), second loss of consciousness (LOC2), and second recovery of consciousness (ROC2). At LOC1, predicted effect-site concentrations of propofol and remifentanil were, respectively, 3.6+/-1.2 microg/mL and 2.4+/-0.4 etag/mL. At ROC1, predicted effect-site concentrations of propofol and remifentanil were, respectively, 2.1+/-0.3 microg/mL and 1.8+/-0.3 etag/mL. At NT, predicted effect-site concentrations of propofol and remifentanil were, respectively, 0.9+/-0.3 microg/mL and 1.8+/-0.2 etag/mL. At LOC2, predicted effect-site concentrations of propofol and remifentanil were, respectively, 2.1+/-0.2 microg/mL and 2.5+/-0.2 etag/mL. At ROC2, predicted effect-site concentrations of propofol and remifentanil were, respectively, 1.2+/-0.5 microg/mL and 1.4+/-0.2 etag/mL (data are mean+/-SE). A significative correlation was found between BIS and predicted effect-site concentrations of propofol (r=0.547, P<0.001) and remifentanil (r=0.533, P<0.001). Multiple regression analysis between BIS and propofol and remifentanil predicted effect-site concentrations at the different critical steps of the procedure was done and found also significative (r=0.7341, P<0.001).     

Haemodynamics during remifentanil induction by high plasma or effect-site target controlled infusion

BACKGROUND: During total intravenous anaesthesia, the target controlled infusion concentration of remifentanil can be achieved either in limiting maximum plasma concentration (Cp) to the effect site target concentration which corresponds to a plasma TCI technique (pTCI) or as fast as possible to achieve the effect-site target without limiting Cp (eTCI). The aim of this study was to compare the haemodynamic effects of remifentanil pTCI and eTCI during induction of anaesthesia in ASA III patients undergoing cardiac surgery. METHODS: 28 ASA III patients, scheduled for cardiac surgery, were randomized in two groups: Group pTCI received remifentanil to achieve an effect-site target of 15 ng ml(-1) by limiting Cp to 15 ng ml(-1) and group eTCI received remifentanil to achieve an effect-site target of 15 ng ml(-1) without limiting remifentanil Cp. Before induction, all patients received 30 microg kg(-1) of midazolam intravenously and 2 ml kg(-1) of a gelatin solution. Heart rate, invasive arterial pressure and bispectral index were continuously measured. Differences from baseline values were compared between the two groups using a Mann-Whitney U test. Baseline population characteristics were compared using an analysis of variance. RESULTS: There were no significant differences in haemodynamic parameters between the two groups. In the group pTCI final effect-site concentration was reached in 7.3 +/- 1.4 minutes and in the group eTCI in 2.2 +/- 0.2 minutes (p < 0.05). CONCLUSION: In ASA III patients scheduled for elective cardiac surgery, remifentanil eTCI can be preferred to remifentanil pTCI for induction because of its shorter onset with the same haemodynamic stability.     

Adrenaline: relationship between infusion rate, plasma concentration, metabolic and haemodynamic effects in volunteers.

The present study investigated the relationship between supraphysiological plasma concentrations of adrenaline and the resulting haemodynamic and metabolic effects. Adrenaline was administered at five infusion rates (0.01-0.2 micrograms kg-1 min-1) in an escalating sequence to eight volunteers. The arterial plasma concentration of adrenaline increased from 53 +/- 44 to 4349 +/- 818 ng litre-1 during the highest infusion rate. Typical haemodynamic responses, such as increase in blood pressure and heart rate, were seen. The plasma concentrations of glucose and lactate increased from 5.2 +/- 0.4 to 13.7 +/- 1.3 mmol litre-1 and from 0.9 +/- 0.3 to 4.7 +/- 2.6 mmol litre-1, respectively, during the highest infusion rate without a significant increase in insulin concentration. Non-esterified fatty acids increased from 379 +/- 97 to 1114 +/- 331 mumol litre-1 during the 0.06 microgram kg-1 min-1 infusion rate. Adrenaline had no selective haemodynamic effect. If similar metabolic effects occur in patients during treatment with adrenaline or other sympathomimetics, they may further increase breakdown of energy stores in a situation of increased catabolism, and impair utilization of parenteral nutrition.     

Response surface modeling of remifentanil-propofol interaction on cardiorespiratory control and bispectral index

BACKGROUND: Since propofol and remifentanil are frequently combined for monitored anesthesia care, we examined the influence of the separate and combined administration of these agents on cardiorespiratory control and bispectral index in humans. METHODS: The effect of steady-state concentrations of remifentanil and propofol was assessed in 22 healthy male volunteer subjects. For each subject, measurements were obtained from experiments using remifentanil alone, propofol alone, and remifentanil plus propofol (measured arterial blood concentration range: propofol studies, 0-2.6 microg/ml; remifentanil studies, 0-2.0 ng/ml). Respiratory experiments consisted of ventilatory responses to three to eight increases in end-tidal Pco2 (Petco2). Invasive blood pressure, heart rate, and bispectral index were monitored concurrently. The nature of interaction was assessed by response surface modeling using a population approach with NONMEM. Values are population estimate plus or minus standard error. RESULTS: A total of 94 responses were obtained at various drug combinations. When given separately, remifentanil and propofol depressed cardiorespiratory variables in a dose-dependent fashion (resting V(i) : 12.6 +/- 3.3% and 27.7 +/- 3.5% depression at 1 microg/ml propofol and 1 ng/ml remifentanil, respectively; V(i) at fixed Petco of 55 mmHg: 44.3 +/- 3.9% and 57.7 +/- 3.5% depression at 1 microg/ml propofol and 1 ng/ml remifentanil, respectively; blood pressure: 9.9 +/- 1.8% and 3.7 +/- 1.1% depression at 1 microg/ml propofol and 1 ng/ml remifentanil, respectively). When given in combination, their effect on respiration was synergistic (greatest synergy observed for resting V(i)). The effects of both drugs on heart rate and blood pressure were modest, with additive interactions when combined. Over the dose range studied, remifentanil had no effect on bispectral index even when combined with propofol (inert interaction). CONCLUSIONS: These data show dose-dependent effects on respiration at relatively low concentrations of propofol and remifentanil. When combined, their effect on respiration is strikingly synergistic, resulting in severe respiratory depression.     

Haemodynamic changes and vasopressin release are not consistently associated with carbon dioxide pneumoperitoneum in humans

BACKGROUND: Conflicting haemodynamic changes, suggested to be caused by vasopressin release, have been reported during carbon dioxide (CO2) pneumoperitoneum. However, peritoneal stimulations including open surgery cause both a systemic vasopressor response and a vasopressin release, which are suppressed by opiate administration. Also, a decreased venous return of blood to the heart causes vasopressin release. Furthermore, previous haemodynamic assessments of laparoscopic surgery have been conducted using various anaesthetic regimens, which are likely to have caused various haemodynamic effects. We hypothesised that intraoperative haemodynamic and/or humoral changes would not be observed in association with laparoscopic surgery provided that, (a) normovolaemia is continuously maintained using transoesophageal echocardiographic (TEE) assessment, and (b) adequate depth of general anaesthesia is continuously maintained by bispectral index (BIS) monitoring and high plasma Ievel opiate administration. METHODS: Twenty ASA 1 women undergoing laparoscopic surgery received 10 ml. kg-1 lactated Ringer's solution and thereafter were randomly allocated to receive intraoperatively either 8 ng. ml-1 or 4 ng. ml-1 plasma remifentanil concentrations while BIS was maintained at 50+/-5 by isoflurane alteration. The group receiving 4 ng. ml-1 remifentanil was used as control. Expired CO2 was maintained within a 32-38 kPa range throughout the investigation. Complete TEE haemodynamic investigation was performed before pneumoperitoneum (PP) (T1), and during PP horizontal (T2), with a head-up tilt (T3), with a head-down tilt (T4), horizontal (T5), and PP released (T6). Plasma vasopressin, epinephrine and norepinephrine levels were measured at T1, T3, and T6. ANOVA, Student's t-test and Mann-Whitney U-test were used for statistical analysis. RESULTS: Haemodynamic indices and humoral values did not change significantly within and between remifentanil groups throughout the investigation (all P<0.05). CONCLUSION: Continuous adequate depth of anaesthesia and normovolaemia may have prevented both a humoral and a haemodynamic response, initiated in the peritoneum by the contact with CO2 in previous investigations.     

Facilitation of laryngeal mask airway insertion: effects of remifentanil administered before induction with target-controlled propofol infusion

Eighty-six adult day-case patients were recruited into a prospective, randomised study and allocated to one of two groups. Patients received either intravenous remifentanil 0.3 microg.kg(-1) or an equivalent volume of sodium chloride 0.9% followed by induction of anaesthesia with propofol target-controlled infusion until the effect (brain) site calculated concentration was 2 microg.ml(-1). Jaw opening and ease of laryngeal mask insertion were assessed immediately after mask insertion. A higher incidence of failure of induction of anaesthesia was observed in the control group compared with the remifentanil group [15 (35%) vs. 3 (7%); p < 0.01] and addition of remifentanil significantly increased the ease and success of laryngeal mask insertion, with grade 1 (no coughing/gagging) conditions observed in 29 (68%) of the remifentanil group and 21 (49%) of the control group (p < 0.01).The doses of remifentanil and propofol used were not associated with any significant cardiorespiratory instability. In conclusion, when combined with propofol target-controlled infusion, remifentanil 0.3 microg.kg(-1) facilitates laryngeal mask insertion with minimal adverse haemodynamic changes.     

Intraoperative wake-up test and postoperative emergence in patients undergoing spinal surgery: a comparison of intravenous and inhaled anesthetic techniques using short-acting anesthetics

Surgical procedures on the vertebral column may result in spinal cord damage, leading to neurological deficits that demand immediate therapeutical intervention. We designed this study to determine which anesthetic regimen allows a rapid wake-up test during and after surgery to detect neurological deficits. Fifty-four patients were randomly allocated to the following groups: group PR (propofol/remifentanil): target-controlled infusion with propofol (plasma concentration, 2-4 microg/mL) and remifentanil 0.2-0.5 microg . kg(-1) . min(-1); group PS (propofol/sufentanil): propofol (2-4 microg/mL) and repetitive boluses of 0.1-0.2 microg/kg of sufentanil adjusted to patients requirements; and group DR (desflurane/remifentanil): desflurane/air 3.0-4.0 vol% combined with remifentanil 0.2-0.5 microg . kg(-1) . min(-1). Group PS required significantly longer times for the onset of breathing (8.9 +/- 1.6 min), elevation of the head (17.0 +/- 3.8 min), and motion of the feet (17.0 +/- 7.4 min) than group PR (6.9 +/- 2.6 min, 9.3 +/- 2.2 min, and 9.4 +/- 2.4 min, respectively) or group DR (5.4 +/- 0.8 min, 6.1 +/- 1.0 min, and 6.2 +/- 1.0 min, respectively). The anesthetic regimen with desflurane and remifentanil allowed faster awakening during and after surgery that permitted immediate neurological examination after spinal surgery compared with propofol/remifentanil.     

Effects of remifentanil and fentanyl on intraocular pressure during the maintenance and recovery of anaesthesia in patients undergoing non-ophthalmic surgery

BACKGROUND AND OBJECTIVE: To compare the effects of remifentanil and fentanyl on intraocular pressure during the maintenance and recovery of anaesthesia in patients undergoing elective non-ophthalmic surgery. METHODS: Thirty-two patients (ASA I-II) were randomized into two groups to receive either a continuous infusion of remifentanil (0.25-0.5 microg kg(-1) min(-1), n =16, Group R) or an intermittent bolus of fentanyl (2-5 microg kg(-1), n = 16, Group F) during the maintenance of anaesthesia. For the induction of anaesthesia, Group R received remifentanil 1 microg kg(-1) and Group F received fentanyl 2 microg kg(-1); both groups then received propofol 2 mg kg(-1) with vecuronium 0.1 mg kg(-1). Anaesthesia in both groups was maintained with a continuous infusion of propofol 4-8 mg kg(-1) h(-1). Ventilation of the lungs was controlled to a constant end-tidal PCO2 of 4.7-5.4 kPa. Blood pressure, electrocardiography, heart rate and oxygen saturation were monitored throughout anaesthesia. Intraocular pressure was determined before surgery, during the maintenance of anaesthesia, 2 min after emergence and in the recovery room using a Perkins hand-held applanation tonometer by an ophthalmologist blinded to the anaesthetic technique. RESULTS: After induction of anaesthesia, a significant decrease in intraocular pressure in the remifentanil group from 13.6 +/- 2.6 to 7.1 +/- 3.1 mmHg (P < 0.001) and in the fentanyl group from 13.7 +/- 2.2 to 9.7 +/- 3.4 mmHg (P < 0.001) was observed and maintained during anaesthesia. Thirty minutes after the end of anaesthesia, intraocular pressure returned to baseline values in both groups (remifentanil: 13.9 +/- 2.8 mmHg, P = 0.28; fentanyl: 13.6 +/- 2.3 mmHg, P = 0.59). The intraocular pressure and haemodynamic variables did not differ significantly between the two groups (intraocular pressure, P = 0.7327; blood pressure, P = 0.1295; heart rate, P = 0.8601). CONCLUSIONS: Remifentanil maintains intraocular pressure at an equally reduced level compared with fentanyl.     

Response Surface Modeling of Remifentanil-Propofol Interaction on Cardiorespiratory Control and Bispectral Index

Background: Since propofol and remifentanil are frequently combined for monitored anesthesia care, we examined the influence of the separate and combined administration of these agents on cardiorespiratory control and bispectral index in humans.

Methods: The effect of steady-state concentrations of remifentanil and propofol was assessed in 22 healthy male volunteer subjects. For each subject, measurements were obtained from experiments using remifentanil alone, propofol alone, and remifentanil plus propofol (measured arterial blood concentration range: propofol studies, 0-2.6 [mu]g/ml; remifentanil studies, 0-2.0 ng/ml). Respiratory experiments consisted of ventilatory responses to three to eight increases in end-tidal Pco2 (Petco2). Invasive blood pressure, heart rate, and bispectral index were monitored concurrently. The nature of interaction was assessed by response surface modeling using a population approach with NONMEM. Values are population estimate plus or minus standard error.

Results: A total of 94 responses were obtained at various drug combinations. When given separately, remifentanil and propofol depressed cardiorespiratory variables in a dose-dependent fashion (resting [latin capital V with dot above]i: 12.6 +/- 3.3% and 27.7 +/- 3.5% depression at 1 [mu]g/ml propofol and 1 ng/ml remifentanil, respectively; [latin capital V with dot above]i at fixed Petco2 of 55 mmHg: 44.3 +/- 3.9% and 57.7 +/- 3.5% depression at 1 [mu]g/ml propofol and 1 ng/ml remifentanil, respectively; blood pressure: 9.9 +/- 1.8% and 3.7 +/- 1.1% depression at 1 [mu]g/ml propofol and 1 ng/ml remifentanil, respectively). When given in combination, their effect on respiration was synergistic (greatest synergy observed for resting [latin capital V with dot above]i). The effects of both drugs on heart rate and blood pressure were modest, with additive interactions when combined. Over the dose range studied, remifentanil had no effect on bispectral index even when combined with propofol (inert interaction).     

Remifentanil concentration during target-controlled infusion of propofol

After institutional approval and with written informed consent, eight surgical patients were infused intravenously with remifentanil at 250 ngkg lean body mass (LBM)(-1) x min(-1) for 30 min. Cardiovascular and respiratory parameters were recorded and arterial blood samples were taken at regular intervals. In each patient, the same protocol was repeated 40 min later during propofol infused to a target concentration of 3.0 microg x ml(-1). Blood concentrations of remifentanil and propofol were assayed using capillary gas chromatography and high performance liquid chromatography techniques respectively. The number of subjects enrolled was determined by testing the successive areas under the remifentanil time-concentration curve (AUC) for significant difference or non-difference using sequential analysis. The median measured propofol concentration was 3.5 (range: 2.6-4.5) microg x ml(-1) which did not change significantly during the second remifentanil infusion. The median AUC during propofol infusion was greater than control in all subjects, although there was considerable variation of 94.4 (64.3-129.6) versus 64.6 (34.8-126.9) ng x ml(-1) x min; P=0.008, n=8. After 30 min, there was no significant difference in remifentanil concentration during propofol infusion when compared with remifentanil alone of 4.6 (3.2-5.7) versus 3.8 (1.6-4.9) ng x ml(-1); P=0.73, n=8. Co-administration of propofol and remifentanil may result in greater remifentanil concentrations than when remifentanil is infused alone.     

Effects of Two Target-controlled Concentrations (1 and 3 ng/ml) of Remifentanil on MACBAR of Sevoflurane

Background: The aim of this prospective, randomized, double-blind study was to determine the effects of two different target-controlled concentrations of remifentanil (1 and 3 ng/ml) on the sevoflurane requirement for blunting sympathetic responses after surgical incision (MACBAR).

Methods: Seventy-four patients aged 20-50 yr, with American Society of Anesthesiologists physical status I, were anesthetized with propofol, cisatracurium, and sevoflurane with a mixture of 60% nitrous oxide in oxygen. Then, patients were randomly allocated to receive no remifentanil infusion (n = 27) or a target-controlled plasma concentration of 1 ng/ml (n = 27) or 3 ng/ml remifentanil (n = 20). Sympathetic responses to surgical incision (presence or absence of an increase in either heart rate or mean arterial blood pressure of 15% or more above the mean of the values measured during the 2 min before skin incision) were determined after a 20-min period of stable end-tidal sevoflurane and target-controlled remifentanil concentrations. Predetermined end-tidal sevoflurane concentrations and the MACBAR for each group were determined using an up-and-down sequential-allocation technique.

Results: The MACBAR of sevoflurane was higher in the group receiving no remifentanil (2.8% [95% confidence interval: 2.5-3.0%]) as compared with patients of the groups receiving 1 ng/ml (1.1% [0.9-1.3%]; P = 0.012) and 3 ng/ml remifentanil (0.2% [0.1-0.3%]; P = 0.006). When considering a minimum anesthetic concentration (MAC) value in this age population and the contribution of 60% nitrous oxide (0.55 MAC), the combined MACBAR values, expressed as multiples of the MAC, were 1.95 MAC, 1.1 MAC, and 0.68 MAC, in the three groups, respectively.     

Cardiopulmonary bypass does not alter canine enflurane requirements.

This study determined the effect of cardiopulmonary bypass (CPB) on canine enflurane minimum alveolar concentration (MAC). Fourteen dogs were anesthetized with enflurane in N2O and O2, and after tracheal intubation, the N2O was discontinued. Femoral arterial and pulmonary arterial catheters were placed, and MAC was determined with the tail-clamp method. CPB was initiated via the femoral artery-vein route, with additional venous return obtained from an external jugular vein. Partial CPB was used in the first 10 dogs. In 4 dogs, a membrane oxygenator (group 1) was used, and in the next 6 dogs a bubble oxygenator (group 2) was used. In 4 additional dogs (group 3), using bubble oxygenators, total CPB was achieved by occlusion of the pulmonary artery via a left thoracotomy. The CPB circuit was primed with Ringer's lactate, and circuit blood flows were 70-125 ml.kg-1.min-1, with mean arterial pressures maintained at 50-110 mmHg. MAC was determined again after termination of CPB. In 10 dogs, MAC was also measured during CPB. In 5 dogs MAC was measured after administration of protamine. MAC in all 14 dogs did not change (2.2 +/- 0.3 vs. 2.3 +/- 0.3). MAC remained constant in group 1 (2.4 +/- 0.3 vs. 2.3 +/- 0.4), group 2 (2.2 +/- 0.2 vs. 2.3 +/- 0.3), and group 3 (2.2 +/- 0.1 vs. 2.3 +/- 0.1). Similarly, MAC was unchanged during CPB (2.2 +/- 0.2 vs. 2.2 +/- 0.2) and after protamine (2.3 +/- 0.2 vs. 2.2 +/- 0.3). Temperature was 38.3 +/- 1.2 prebypass and 37.9 +/- 0.9 postbypass.(ABSTRACT TRUNCATED AT 250 WORDS)     

Erythropoietin protects against ischaemic acute renal injury.

BACKGROUND: Erythropoietin (EPO) has recently been shown to exert important cytoprotective and anti-apoptotic effects in experimental brain injury and cisplatin-induced nephrotoxicity. The aim of the present study was to determine whether EPO administration is also renoprotective in both in vitro and in vivo models of ischaemic acute renal failure. METHODS: Primary cultures of human proximal tubule cells (PTCs) were exposed to either vehicle or EPO (6.25-400 IU/ml) in the presence of hypoxia (1% O(2)), normoxia (21% O(2)) or hypoxia followed by normoxia for up to 24 h. The end-points evaluated included cell apoptosis (morphology and in situ end labelling [ISEL], viability [lactate dehydrogenase (LDH release)], cell proliferation [proliferating cell nuclear antigen (PCNA)] and DNA synthesis (thymidine incorporation). The effects of EPO pre-treatment (5000 U/kg) on renal morphology and function were also studied in rat models of unilateral and bilateral ischaemia-reperfusion (IR) injury. RESULTS: In the in vitro model, hypoxia (1% O(2)) induced a significant degree of PTC apoptosis, which was substantially reduced by co-incubation with EPO at 24 h (vehicle 2.5+/-0.5% vs 25 IU/ml EPO 1.8+/-0.4% vs 200 IU/ml EPO 0.9+/-0.2%, n = 9, P<0.05). At high concentrations (400 IU/ml), EPO also stimulated thymidine incorporation in cells exposed to hypoxia with or without subsequent normoxia. LDH release was not significantly affected. In the unilateral IR model, EPO pre-treatment significantly attenuated outer medullary thick ascending limb (TAL) apoptosis (EPO 2.2+/-1.0% of cells vs vehicle 6.5+/-2.2%, P<0.05, n = 5) and potentiated mitosis (EPO 1.1+/-0.3% vs vehicle 0.5+/-0.3%, respectively, P<0.05) within 24 h. EPO-treated rats exhibited enhanced PCNA staining within the proximal straight tubule (6.9+/-0.7% vs vehicle 2.4+/-0.5% vs sham 0.3+/-0.2%, P<0.05), proximal convoluted tubule (2.3+/-0.6% vs vehicle 1.1+/-0.3% vs sham 1.2+/-0.3%, P<0.05) and TAL (4.7+/-0.9% vs vehicle 0.6+/-0.3% vs sham 0.3+/-0.2%, P<0.05). The frequency of tubular profiles with luminal cast material was also reduced (32.0+/-1.6 vs vehicle 37.0+/-1.3%, P = 0.05). EPO-treated rats subjected to bilateral IR injury exhibited similar histological improvements to the unilateral IR injury model, as well as significantly lower peak plasma creatinine concentrations than their vehicle-treated controls (0.04+/-0.01 vs 0.21+/-0.08 mmol/l, respectively, P<0.05). EPO had no effect on renal function in sham-operated controls. CONCLUSIONS: The results suggest that, in addition to its well-known erythropoietic effects, EPO inhibits apoptotic cell death, enhances tubular epithelial regeneration and promotes renal functional recovery in hypoxic or ischaemic acute renal injury.     

复合不同靶浓度异丙酚时瑞芬太尼引起神经外科手术病人呼吸抑制的效应室浓度

目的 确定复合不同靶浓度异丙酚时瑞芬太尼引起神经外科手术病人呼吸抑制的效应室浓度.方法 择期拟行神经外科手术的病人80例,年龄18～64岁,体重45～90 kg,随机分为4组(n=20):瑞芬太尼组(R组)、瑞芬太尼复合异丙酚1μg/ml(RP_1组)、瑞芬太尼复合异丙酚1.5 μg/ml(RP_(1.5)组)和瑞芬太尼复合异丙酚2 μg/ml(RP_2组)组.R组、RP_1组、RP_(1.5)组和RP_2组靶控输注异丙酚,血浆靶浓度分别为0、1、1.5、2μg/ml,达到预设的浓度后,靶控输注瑞芬太尼,初始血浆靶浓度为2 μg/ml,随后每3 min增加瑞芬太尼血浆靶浓度2 μg/ml,直至发生呼吸抑制.记录呼吸抑制时瑞芬太尼效应室浓度、瑞芬太尼用量和其他不良反应发生情况.结果 R组、RP1组、RP1.5组和RP_2组呼吸抑制时瑞芬太尼效应室浓度分别为(5.2±2.1)、(3.2±1.0)、(2.9±1.3)和(2.2±1.0)μg/ml.与R组比较,RP_1组、RP_(1.5)组和RP_2组呼吸抑制时瑞芬太尼效应室浓度降低(P<0.01);与RP1组和RP1.5组比较,RP2组呼吸抑制时瑞芬太尼效应室浓度降低(P<0.01);RP1组和RP1.5组呼吸抑制时瑞芬太尼效应室浓度比较差异无统计学意义(P>0.05).结论 神经外科手术病人清醒状态下瑞芬太尼效应室浓度为(5.2±2.1)ng/ml时可发生呼吸抑制;复合血浆靶浓度1、1.5、2 μg/ml异丙酚镇静时,瑞芬太尼引起呼吸抑制的效应室浓度分别降至(3.2±1.0)、(2.9±1.3)和(2.2±1.0)ng/ml.     

Pharmacokinetic-based total intravenous anaesthesia using remifentanil and propofol for surgical myocardial revascularization

BACKGROUND AND OBJECTIVE: We investigated the following aspects of pharmacokinetic-guided total intravenous anaesthesia with remifentanil and propofol in patients undergoing surgical myocardial revascularization: anaesthetic efficacy, haemodynamic effects, impact on extubation of the trachea and analgesia after operation. METHODS: Thirty-two patients undergoing on-pump coronary bypass surgery received intravenous anaesthesia with remifentanil and propofol. Both drugs were dosed and titrated based on computer-assisted pharmacokinetic models to maintain constant plasma concentrations. The propofol target plasma concentration was 1.2 microg mL(-1) throughout the procedure. A remifentanil target plasma concentration of 8 ng mL(-1) was achieved over 2 min for induction. After tracheal intubation, the opioid plasma concentration was reduced to 4 ng mL(-1), and then titrated up to 8 ng mL(-1) during surgery. Postoperative analgesia was managed with remifentanil infusion until 4 h after tracheal extubation, and a continuous infusion of tramadol was started 1 h before the remifentanil was stopped. RESULTS: After induction of anaesthesia, heart rate (-20%) and cardiac index (-6%) decreased significantly. No hypotensive episodes (mean arterial pressure < 60 mmHg) occurred. Intraoperative haemodynamics were stable. Three cases of myocardial ischaemia were detected: two by transoesophageal echocardiography and one with ST-segment monitoring. The duration of postoperative mechanical ventilation of the lungs was 95 +/- 13 min and the time to extubation was 150 +/- 18 min. Postoperative analgesia was satisfactory in all patients. CONCLUSIONS: Pharmacokinetic-based total intravenous anaesthesia with remifentanil and propofol provides adequate anaesthesia during coronary surgery with cardiopulmonary bypass and allows safe early extubation after operation.     

Pharmacokinetics of intrathecal morphine and meperidine in humans

Two groups of surgical patients each comprising six individuals received an intrathecal injection of morphine 0.3 mg or meperidine 10 mg. Cerebrospinal fluid (CSF) and plasma were sampled frequently during a 6-h period and analyzed for morphine or meperidine. Maximum plasma morphine concentrations were found 5-10 min after injection, and averaged 4.5 +/- 1.1 ng.ml-1 (mean +/- SEM). Maximum CSF morphine concentrations were considerably higher than maximum plasma concentrations, 6410 +/- 1290 ng.ml-1. Maximum plasma concentrations of meperidine were also measured 5 or 10 min after injection and were low (36 +/- 9 ng.ml-1) compared with the maximum CSF concentrations (364 +/- 105 micrograms.ml-1). After a rapid initial decline for about 15 min after injection, the CSF concentrations decreased with a half-life of 89.8 +/- 16.1 min for morphine and 68.0 +/- 5.1 min for meperidine during the rest of the study period. The initial volume of distribution in CSF was similar for both drugs, or 22 +/- 8 ml for morphine and 18 +/- 5 ml for meperidine. After 6 h, 1.6 +/- 0.9% of the injected morphine dose and 0.41 +/- 0.09% of the meperidine dose remained in the initial volume of distribution. Large inter-individual differences in morphine and meperidine CSF kinetics existed, which may explain some of the reported individual differences in duration of effects. The disappearance of meperidine from CSF tended to be faster than that of morphine, which may be explained, in part, by the differences in lipid solubilities of the drugs.