Effect of Increasing Depth of Propofol Anesthesia on Upper Airway Configuration in Children

Background: The upper airway tends to be obstructed during anesthesia in spontaneously breathing patients. The purpose of the current study was to determine the effect of increasing depth of propofol anesthesia on airway size and configuration in children.

Methods: Magnetic resonance images of the upper airway were obtained in 15 children, aged 2-6 yr. Cross-sectional area, anteroposterior dimension, and transverse dimension were measured at the level of the soft palate, dorsum of the tongue, and tip of the epiglottis. Images were obtained during infusion of propofol at a rate of 50-80 [mu]g [middle dot] kg-1 [middle dot] min-1 and after increasing the depth of anesthesia by administering a bolus dose of propofol and increasing the infusion rate to 240 [mu]g [middle dot] kg-1 [middle dot] min-1.

Results: Overall, the cross-sectional area of the entire pharyngeal airway decreased with increasing depth of anesthesia. The reduction in cross-sectional area was greatest at the level of the epiglottis (24.5 mm2, 95% confidence interval = 16.9-32.2 mm2; P < 0.0001), intermediate at the level of the tongue (19.3 mm2, 95% confidence interval = 9.2-29.3 mm2; P < 0.0001), and least at the level of the soft palate (12.6 mm2, 95% confidence interval = 2.7-22.6 mm2; P < 0.005) in expiration and resulted predominantly from a reduction in anteroposterior dimension. The airway cross-sectional area decreased further in inspiration at the level of the epiglottis. The narrowest portion of the airway resided at the level of the soft palate or epiglottis in the majority of children.     

Effect of propofol anesthesia and continuous positive airway pressure on upper airway size and configuration in infants

BACKGROUND: Infants are prone to obstruction of the upper airway during general anesthesia. Continuous positive airway pressure (CPAP) is often used to prevent or treat anesthesia-induced airway obstruction. The authors studied the interaction of propofol anesthesia and CPAP on airway caliber in infants using magnetic resonance imaging. METHODS: Nine infants undergoing elective magnetic resonance imaging of the brain were studied. Head position was standardized. Spin echo magnetic resonance images of the airway were acquired at the level of the soft palate, base of the tongue, and tip of the epiglottis. Four sets of images were acquired in sequence: (1) during light propofol anesthesia at an infusion rate of 80 microg . kg(-1) . min(-1), (2) after increasing the depth of propofol anesthesia by administering a bolus dose (2.0 mg/kg) and increasing the infusion rate to 240 microg . kg(-1) . min(-1), (3) during continued infusion of 240 microg . kg(-1). min propofol and application of 10 cm H2O CPAP, and (4) after removal of CPAP and continued infusion of 240 microg . kg(-1). min propofol. RESULTS: Increasing depth of propofol anesthesia decreased airway caliber at each anatomical level, predominantly due to anteroposterior narrowing. Application of CPAP completely reversed the propofol-induced decrease in airway caliber, primarily by increasing the transverse dimension. CONCLUSIONS: Airway narrowing with increasing depth of propofol anesthesia results predominantly from a reduction in anteroposterior dimension, whereas CPAP acts primarily to increase the transverse dimension. Although airway caliber during deep propofol anesthesia and application of CPAP was similar to that during light propofol anesthesia, there were significant configurational differences.     

Assessment of Depth of Anesthesia and Postoperative Respiratory Recovery after Remifentanil-versus Alfentanil-based Total Intravenous Anesthesia in Patients Undergoing Ear-Nose-Throat Surgery

Background: The authors investigated whether total intravenous anesthesia (TIVA) with precalculated equipotent infusion schemes for remifentanil and alfentanil would ensure appropriate analgesia and that remifentanil would result in better recovery characteristics.

Methods: Forty consenting patients (classified as American Society of Anesthesiologists physical status I-III) scheduled for microlaryngoscopy were randomized to receive, in a double-blind manner, either remifentanil (loading dose 1 [mu]g/kg; maintenance infusion, 0.25 [mu]g [middle dot] kg-1 [middle dot] min-1) or alfentanil (loading dose, 50 [mu]g/kg; maintenance infusion, 1 [mu]g [middle dot] kg-1 [middle dot] min-1) as the analgesic component of TIVA. They were combined with propofol (loading dose, 2 mg/kg; maintenance infusion, 100 [mu]g [middle dot] kg-1 [middle dot] min-1). To insure an equal state of anesthesia, the opioids were titrated to maintain heart rate and mean arterial pressure within 20% of baseline, and propofol was titrated to keep the bispectral index (BIS) less than 60. Neuromuscular blockade was achieved with succinylcholine. Drug dosages and the times from cessation of anesthesia to extubation, verbal response, recovery of ventilation, and neuropsychological testing, orientation, and discharge readiness were recorded.

Results: Demographics, duration of surgery, and anesthesia were similar between the two groups. Both groups received similar propofol doses. There were no difference in BIS values preoperatively (mean, 96), intraoperatively (mean, 55), and postoperatively (mean, 96). Recovery of BIS and times for verbal response did not differ. At 20, 30, and 40 min after terminating the opioid infusion, the peripheral oxygen saturation and respiratory rate were significantly higher in the remifentanil group compared with the alfentanil group.     

Effects of Propofol and Remifentanil on Phrenic Nerve Activity and Nociceptive Cardiovascular Responses in Rabbits

Background: The effects of propofol, remifentanil, and their combination on phrenic nerve activity (PNA), resting heart rate (HR), mean arterial pressure (MAP), and nociceptive cardiovascular responses were studied in rabbits.

Methods: Basal anesthesia and constant blood gas tensions were maintained with [alpha]-chloralose and mechanical ventilation. PNA, HR, MAP, and maximum changes in HR and MAP ([DELTA]HR, [DELTA]MAP) evoked by electrical nerve stimulation of tibial nerves were recorded. The comparative effects were observed for propofol at infusion rates from 0.05 to 3.2 mg [middle dot] kg-1 [middle dot] min-1 (group I) and remifentanil from 0.0125 to 12.8 [mu]g [middle dot] kg-1 [middle dot] min-1 alone (group II), and during constant infusions of propofol at rates of 0.1 and 0.8 mg [middle dot] kg-1 [middle dot] min-1 (groups III and IV, respectively). Finally, the effect of remifentanil on propofol blood levels was observed (group V).

Results: The infusion rates for 50% depression (ED50) of PNA, [DELTA]HR, and [DELTA]MAP were 0.41, 1.32, and 1.58 mg [middle dot] kg-1 [middle dot] min-1 for propofol, and 0.115, 0.125, and 1.090 [mu]g [middle dot] kg-1 [middle dot] min-1 for remifentanil, respectively. The ratios for the ED50 values of [DELTA]HR and [DELTA]MAP to PNA were 3.2 and 3.9 for propofol, and 1.1 and 9.5 for remifentanil, respectively. Analysis of the expected and observed responses and isobologrms showed that although their combined effects on PNA, resting HR, and MAP, and [DELTA]MAP were synergistic for [DELTA]HR, they were merely additive. Remifentanil had no effect on propofol blood levels.     

Intravenous Magnesium Sulfate Administration Reduces Propofol Infusion Requirements during Maintenance of Propofol-N2O Anesthesia: Part I: Comparing Propofol Requirements According to Hemodynamic Responses: Part II: Comparing Bispectral Index in Control and Magnesium Groups

Background: The authors investigated whether an intravenous administration of magnesium sulfate reduces propofol infusion requirements during maintenance of propofol-N2O anesthesia.

Methods: Part I study: 54 patients undergoing total abdominal hysterectomy were randomly divided into two groups (n = 27 per group). The patients in the control group received 0.9% sodium chloride solution, whereas the patients in the magnesium group received magnesium (50 mg/kg as a bolus, then 8 mg [middle dot] kg-1 [middle dot] h-1). To maintain mean arterial blood pressure (MAP) and heart rate (HR) at baseline value, the propofol infusion rate was changed when the MAP or the HR changed. The amount of propofol infused excluding the bolus dosage was divided by patient's body weight and total infusion time. Part II study: Another 20 patients were randomly divided into two groups (n = 10 per group). When the MAP and HR had been maintained at baseline value and the propofol infusion rate had been maintained at 80 [mu]g [middle dot] kg-1 [middle dot] min-1 (magnesium group) and 160 [mu]g [middle dot] kg-1 [middle dot] min-1 (control group), bispectral index (BIS) values were measured.

Results: Part I: The mean propofol infusion rate in the magnesium group (81.81 +/- 13.09 [mu]g [middle dot] kg-1 [middle dot] min-1) was significantly less than in the control group (167.57 +/- 47.27). Part II: BIS values in the control group (40.70 +/- 3.89) were significantly less than those in the magnesium group (57.80 +/- 7.32).     

Narcotrend Monitoring Allows Faster Emergence and a Reduction of Drug Consumption in Propofol-Remifentanil Anesthesia

Background: The Narcotrend is a new electroencephalographic monitor designed to measure depth of anesthesia, based on a six-letter classification from A (awake) to F (increasing burst suppression) including 14 substages. This study was designed to investigate the impact of Narcotrend monitoring on recovery times and propofol consumption in comparison to Bispectral Index(R) (BIS(R)) monitoring or standard anesthetic practice.

Methods: With institutional review board approval and written informed consent, 120 adult patients scheduled to undergo minor orthopedic surgery were randomized to receive a propofol-remifentanil anesthetic controlled by Narcotrend, by BIS(R), or solely by clinical parameters. Anesthesia was induced with 0.4 [mu]g [middle dot] kg-1 [middle dot] min-1 remifentanil and a propofol target-controlled infusion at 3.5 [mu]g/ml. After intubation, remifentanil was reduced to 0.2 [mu]g [middle dot] kg-1 [middle dot] min-1, whereas the propofol infusion was adjusted according to clinical parameters or to the following target values: during maintenance to D0 (Narcotrend) or 50 (BIS(R)); 15 min before the end of surgery to C1 (Narcotrend) or 60 (BIS(R)). Recovery times were recorded by a blinded investigator, and average normalized propofol consumption was calculated from induction and maintenance doses.

Results: The groups were comparable for demographic data, duration of anesthesia, and mean remifentanil dosages. Compared with standard practice, patients with Narcotrend or BIS(R) monitoring needed significantly less propofol (standard practice, 6.8 +/- 1.2 mg [middle dot] kg-1 [middle dot] h-1vs. Narcotrend, 4.5 +/- 1.1 mg [middle dot] kg-1 [middle dot] h-1 or BIS(R), 4.8 +/- 1.0 mg [middle dot] kg-1 [middle dot] h-1;P < 0.001), opened their eyes earlier (9.3 +/- 5.2 vs. 3.4 +/- 2.2 or 3.5 +/- 2.9 min), and were extubated sooner (9.7 +/- 5.3 vs. 3.7 +/- 2.2 or 4.1 +/- 2.9 min).     

Dose-Response Relationship and Infusion Requirement of Cisatracurium Besylate in Infants and Children during Nitrous Oxide-Narcotic Anesthesia

Background: To determine the effect of age on the dose-response relation and infusion requirement of cisatracurium besylate in pediatric patients, 32 infants (mean age, 0.7 yr; range, 0.3-1.0 yr) and 32 children (mean age, 4.9 yr; range, 3.1-9.6 yr) were studied during thiopentone-nitrous oxide-oxygen-narcotic anesthesia.

Methods: Potency was determined using a single-dose (20, 26, 33, or 40 [mu]g/kg) technique. Neuromuscular block was assessed by monitoring the electromyographic response of the adductor pollicis to supramaximal train-of-four stimulation of the ulnar nerve at 2 Hz.

Results: Least-squares linear regression analysis of the log-probit transformation of dose and maximal response yielded median effective dose (ED50) and 95% effective dose (ED95) values for infants (29 +/- 3 [mu]g/kg and 43 +/- 9 [mu]g/kg, respectively) that were similar to those for children (29 +/- 2 [mu]g/kg and 47 +/- 7 [mu]g/kg, respectively). The mean infusion rate necessary to maintain 90-99% neuromuscular block during the first hour in infants (1.9 +/- 0.4 [mu]g [middle dot] kg-1 [middle dot] min-1; range: 1.3-2.5 [mu]g [middle dot] kg-1 [middle dot] min-1) was similar to that in children (2.0 +/- 0.5 [mu]g [middle dot] kg-1 [middle dot] min-1; range: 1.3-2.9 [mu]g [middle dot] kg-1 [middle dot] min-1).     

Remifentanil Requirements during Sevoflurane Administration to Block Somatic and Cardiovascular Responses to Skin Incision in Children and Adults

Background: The authors found no studies comparing intraoperative requirements of opioids between children and adults, so they determined the infusion rate of remifentanil to block somatic (IR50) and autonomic response (IRBAR50) to skin incision in children and adults.

Methods: Forty-one adults (aged 20-60 yr) and 24 children (aged 2-10 yr) undergoing lower abdominal surgery were studied. In adults, anesthesia induction was with sevoflurane during remifentanil infusion, whereas in children remifentanil administration was started after induction with sevoflurane. After intubation, sevoflurane was administered in 100% O2 and was adjusted to an ET% of 1 MAC-awake corrected for age at least 15 min before surgery. Patients were randomized to receive remifentanil at a rate ranging from 0.05 to 0.35 [mu]g [middle dot] kg-1 [middle dot] min-1 for at least 20 min before surgery. At the beginning of surgery, only the skin incision was performed, and the somatic and autonomic responses were observed. The somatic response was defined as positive with any gross movement of extremity, and the autonomic response was deemed positive with any increase in heart rate or mean arterial pressure equal to or more than 10% of preincision values. Using logistic regression, the IR50 and IRBAR50 were determined in both groups of patients and compared with unpaired Student t test. A P value less than 0.05 was considered significant.

Results: The IR50 +/- SD was 0.10 +/- 0.02 [mu]g [middle dot] kg-1 [middle dot] min-1 in adults and 0.22 +/- 0.03 [mu]g [middle dot] kg-1 [middle dot] min-1 in children (P < 0.001). The IRBAR50 +/- SD was 0.11 +/- 0.02 [mu]g [middle dot] kg-1 [middle dot] min-1 in adults and 0.27 +/- 0.06 [mu]g [middle dot] kg-1 [middle dot] min-1 in children (P < 0.001).     

Effect of Prophylactic Bronchodilator Treatment with Intravenous Colforsin Daropate, a Water-soluble Forskolin Derivative, on Airway Resistance after Tracheal Intubation

Background: After induction of anesthesia, lung resistance increases. The authors hypothesized that prophylactic bronchodilator treatment with intravenous colforsin daropate, a water-soluble forskolin derivative, before tracheal intubation would result in decreased lung resistance and increased lung compliance after tracheal intubation when compared with placebo medication.

Methods: Forty-six adult patients were randomized to placebo or colforsin daropate treatment. Patients in the control group received normal saline; patients in the colforsin group received 0.75 [mu]g [middle dot] kg-1 [middle dot] min-1 colforsin daropate intravenously until the study ended. Thirty minutes after the study began, the authors administered 5 mg/kg thiamylal and 5 [mu]g/kg fentanyl for induction of general anesthesia and 0.3 mg/kg vecuronium for muscle relaxation. A 15-mg [middle dot] kg-1 [middle dot] h-1 continuous infusion of thiamylal followed anesthetic induction. Four, 8, 12, and 16 min after tracheal intubation, mean airway resistance (Rawm), expiratory airway resistance (Rawe), and dynamic lung compliance (Cdyn) were measured.

Results: Patients in the colforsin group had significantly lower Rawm and Rawe and higher Cdyn after intubation than those in the control group. Differences in Rawm, Rawe, and Cdyn between the two groups persisted through the final measurement at 16 min. At 4 min after intubation, smokers had a higher Rawm and a lower Cdyn than nonsmokers in the control group. After treatment by intravenous colforsin daropate, Rawm, Rawe, and Cdyn values were similar for smokers and nonsmokers after tracheal intubation.     

Narcotrend® Does Not Adequately Detect the Transition between Awareness and Unconsciousness in Surgical Patients

Background: The Narcotrend(R) index (MonitorTechnik, Bad Bramstedt, Germany) is a dimensionless number between 0 and 100 that is calculated from the electroencephalogram and inversely correlates with depth of hypnosis. The current study evaluates the capability of the Narcotrend(R) to separate awareness from unconsciousness at the transition between these levels.

Methods: Electroencephalographic recordings of 40 unpremedicated patients undergoing elective surgery were analyzed. Patients were randomly assigned to receive (1) sevoflurane-remifentanil (<= 0.1 [mu]g [middle dot] kg-1 [middle dot] min-1), (2) sevoflurane-remifentanil (>= 0.2 [mu]g [middle dot] kg-1 [middle dot] min-1), (3) propofol-remifentanil (<= 0.1 [mu]g [middle dot] kg-1 [middle dot] min-1), or (4) propofol-remifentanil (>= 0.2 [mu]g [middle dot] kg-1 [middle dot] min-1). Remifentanil and sevoflurane or propofol were given until loss of consciousness. After tracheal intubation, propofol or sevoflurane was stopped until return of consciousness and then restarted to induce loss of consciousness. After surgery, drugs were discontinued. Narcotrend(R) values at loss and return of consciousness were compared with each other, and anesthetic groups were compared. Prediction probability was calculated from values at the last command before and at loss and return of consciousness.

Results: At 105 of 316 analyzed time points, the Narcotrend(R) did not calculate an index, and the closest calculated value was analyzed. No significant differences between loss and return of consciousness were found. In group 1, Narcotrend(R) values were significantly higher than in group 3. Prediction probability was 0.501.     

Remifentanil-induced Postoperative Hyperalgesia and Its Prevention with Small-dose Ketamine

Background: Remifentanil-induced secondary hyperalgesia has been documented experimentally in both animals and healthy human volunteers, but never clinically. This study tested the hypotheses that increased pain sensitivity assessed by periincisional allodynia and hyperalgesia can occur after relatively large-dose intraoperative remifentanil and that small-dose ketamine prevents this hyperalgesia.

Methods: Seventy-five patients undergoing major abdominal surgery were randomly assigned to receive (1) intraoperative remifentanil at 0.05 [mu]g [middle dot]kg-1 [middle dot]min-1 (small-dose remifentanil); (2) intraoperative remifentanil at 0.40 [mu]g [middle dot]kg-1 [middle dot]min-1 (large-dose remifentanil); or (3) intraoperative remifentanil at 0.40 [mu]g [middle dot]kg-1 [middle dot]min-1 and 0.5 mg/kg ketamine just after the induction, followed by an intraoperative infusion of 5 [mu]g [middle dot] kg-1 [middle dot] min-1 until skin closure and then 2 [mu]g [middle dot]kg-1 [middle dot]min-1 for 48 h (large-dose remifentanil-ketamine). Pain scores and morphine consumption were recorded for 48 postoperative hours. Quantitative sensory tests, peak expiratory flow measures, and cognitive tests were performed at 24 and 48 h.

Results: Hyperalgesia to von Frey hair stimulation adjacent to the surgical wound and morphine requirements were larger (P < 0.05) and allodynia to von Frey hair stimulation was greater (P < 0.01) in the large-dose remifentanil group compared with the other two groups, which were comparable. There were no significant differences in pain, pressure pain detection threshold with an algometer, peak flow, cognitive tests, or side effects.     

The Independent Effect of Propofol Anesthesia on Whole Body Protein Metabolism in Humans

Background: The purpose of this study was to examine the effect of general anesthesia with propofol in the absence of surgical stimulation on whole body protein metabolism.

Methods: Six unpremedicated patients were studied. General anesthesia included propofol (120 [micro sign]g [middle dot] kg-1 [middle dot] min (-1)), vecuronium bromide, and oxygen-enriched air. Changes in protein breakdown, protein oxidation, and synthesis were measured by an isotope dilution technique using a constant infusion of the stable isotope tracer L-[1-(13) C]leucine (0.008 mg [middle dot] kg-1 [middle dot] min-1) before and during 100 min of propofol anesthesia. The plasma concentrations of glucose, lactate, non-esterified fatty acids, and cortisol were measured before and during anesthesia.

Results: An isotopic steady state of plasma [1-(13) C] [Greek small letter alpha]-ketoisocaproate (taken to represent the intracellular leucine precursor pool enrichment for protein synthesis) and expired13 C-carbon dioxide were obtained before and during propofol infusion. Whole body protein breakdown decreased during propofol anesthesia by 6% (P < 0.05), whereas protein synthesis and oxidation did not change significantly. Plasma concentration of cortisol decreased after 90 min of propofol anesthesia (P < 0.05). No significant changes of plasma concentrations of glucose, lactate, and non-esterified fatty acids occurred during propofol administration.     

Determination of the Pharmacodynamic Interaction of Propofol and Remifentanil during Esophagogastroduodenoscopy in Children

Background: Propofol is commonly used to anesthetize children undergoing esophagogastroduodenoscopy. Opioids are often used in combination with propofol to provide total intravenous anesthesia. Because both propofol and remifentanil are associated with rapid onset and offset, the combination of these two drugs may be particularly useful for procedures of short duration, including esophagogastroduodenoscopy. The authors previously demonstrated that the median effective concentration (C50) of propofol during esophagogastroduodenoscopy in children is 3.55 [mu]g/ml. The purpose of this study was to describe the pharmacodynamic interaction of remifentanil and propofol when used in combination for esophagogastroduodenoscopy in pediatric patients.

Methods: The authors studied 32 children aged between 3 and 10 yr who were scheduled to undergo esophagogastroduodenoscopy. Propofol was administered via a target-controlled infusion system using the STANPUMP software based on a pediatric pharmacokinetic model. Remifentanil was administered as a constant rate infusion of 25, 50, and 100 ng [middle dot] kg-1 [middle dot] min-1 to each of three study groups, respectively. A sigmoid Emax model was developed to describe the interaction of remifentanil and propofol.

Results: There was a positive interaction between remifentanil and propofol when used in combination. The concentration of propofol alone associated with 50% probability of no response was 3.7 [mu]g/ml (SE, 0.4 [mu]g/ml), and this was decreased to 2.8 [mu]g/ml (SE, 0.1 [mu]g/ml) when used in combination with remifentanil.     

Comparison of Adenosine and Remifentanil Infusions as Adjuvants to Desflurane Anesthesia

Background: Because adenosine has been alleged to produce both anesthetic and analgesic sparing effects, a randomized, double-blinded study was designed to compare the perioperative effects of adenosine and remifentanil when administered as intravenous adjuvants during general anesthesia for major gynecologic procedures.

Methods: Thirty-two women were assigned randomly to one of two drug treatment groups. After premedication with 0.04 mg/kg intravenous midazolam, anesthesia was induced with 2 [micro sign]g/kg intravenous fentanyl, 1.5 mg/kg intravenous propofol, and 0.6 mg/kg intravenous rocuronium, and maintained with desflurane, 2%, and nitrous oxide, 65%, in oxygen. Before skin incision, an infusion of either remifentanil (0.02 [micro sign]g [middle dot] kg-1 [middle dot] min-1) or adenosine (25 [micro sign]g [middle dot] kg-1 [middle dot] min-1) was started and subsequently titrated to maintain systolic blood pressure, heart rate, or both within 10-15% of the preincision values.

Results: Adenosine and remifentanil infusions were effective anesthetic adjuvants during lower abdominal surgery. Use of adenosine (mean +/- SEM, 166 +/- 17 [micro sign]g [middle dot] kg-1 [middle dot] min-1) was associated with a significantly greater decrease in systolic blood pressure and higher heart rate values compared with remifentanil (mean +/- SEM, 0.2 +/- 0.03 [micro sign]g [middle dot] kg-1 [middle dot] min-1). Total postoperative opioid analgesic use was 45% and 27% lower in the adenosine group at 0-2 h and 2-24 h after surgery, respectively.     

High-dose Remifentanil Does Not Impair Cerebrovascular Carbon Dioxide Reactivity in Healthy Male Volunteers

Background: Cerebrovascular carbon dioxide reactivity during high-dose remifentanil infusion was investigated in volunteers by measurement of regional cerebral blood flow (rCBF) and mean CBF velocity (CBFv).

Methods: Ten healthy male volunteers with a laryngeal mask for artificial ventilation received remifentanil at an infusion rate of 2 and 4 [mu]g [middle dot] kg-1 [middle dot] min-1 under normocapnia, hypocapnia, and hypercapnia. Stable xenon-enhanced computed tomography and transcranial Doppler ultrasonography of the left middle cerebral artery were used to assess rCBF and mean CBFv, respectively. If required, blood pressure was maintained within baseline values with intravenous phenylephrine to avoid confounding effects of altered hemodynamics.

Results: Hemodynamic parameters were maintained constant over time. Remifentanil infusion at 2 and 4 [mu]g [middle dot] kg-1 [middle dot] min-1 significantly decreased rCBF and mean CBFv. Both rCBF and mean CBFv increased as the arterial carbon dioxide tension increased from hypocapnia to hypercapnia, indicating that cerebrovascular reactivity remained intact. The average slopes of rCBF reactivity were 0.56 +/- 0.27 and 0.49 +/- 0.28 ml [middle dot] 100 g-1 [middle dot] min-1 [middle dot] mmHg-1 for 2 and 4 [mu]g[middle dot]kg-1[middle dot]min-1 remifentanil, respectively (relative change in percent/mmHg: 1.9 +/- 0.8 and 1.6 +/- 0.5, respectively). The average slopes for mean CBFv reactivity were 1.61 +/- 0.95 and 1.54 +/- 0.83 cm [middle dot] s-1 [middle dot] mmHg-1 for 2 and 4 [mu]g [middle dot] kg-1 [middle dot] min-1 remifentanil, respectively (relative change in percent/mmHg: 1.86 +/- 0.59 and 1.79 +/- 0.59, respectively). Preanesthesia and postanesthesia values of rCBF and mean CBFv did not differ.     

Remifentanil versus Morphine Analgesia and Sedation for Mechanically Ventilated Critically Ill Patients: A Randomized Double Blind Study

Background: The rapid onset and offset of action of remifentanil could make it quickly adjustable to the required level of sedation in critically ill patients. The authors hypothesized that the efficacy of a remifentanil-based regimen was greater than that of a morphine-based regimen.

Methods: Forty intent-to-treat patients were randomly allocated to receive a blinded infusion of either remifentanil 0.15 [mu]g[middle dot]kg-1[middle dot]min-1 or morphine 0.75 [mu]g[middle dot]kg-1[middle dot]min-1. The opioid infusion was titrated, in the first intent, to achieve optimal sedation defined as Sedation Agitation scale of 4. A midazolam open-label infusion was started if additional sedation was required.

Results: The mean percentage hours of optimal sedation was significantly longer in the remifentanil group (78.3 +/- 6.2) than in the morphine group (66.5 +/- 8.5). This was achieved with less frequent infusion rate adjustments (0.34 +/- 0.25 changes/h) than in the morphine group (0.42 +/- 0.22 changes/h). The mean duration of mechanical ventilation and extubation time were significantly longer in the morphine group (18.1 +/- 3.4 h, 73 +/- 7 min) than in the remifentanil group (14.1 +/- 2.8 h, 17 +/- 6 min), respectively. Remifentanil mean infusion rate was 0.13 +/- 0.03 [mu]g[middle dot]kg-1[middle dot]min-1, whereas morphine mean infusion rate was 0.68 +/- 0.28 [mu]g[middle dot]kg-1[middle dot]min-1. More subjects in the morphine group (9 of 20) than in the remifentanil group (6 of 20) required midazolam. The incidence of adverse events was low and comparable across the two treatment groups.     

Impact of Bispectral Index Monitoring on Stress Response and Propofol Consumption in Patients Undergoing Coronary Artery Bypass Surgery

Background: Bispectral Index (BIS)-titrated administration allows a reduction of propofol infusion rates in patients undergoing surgery. Resulting differences in anesthetic depth might affect the stress response to surgery involving neural circuitry not reflected in the electroencephalogram.

Methods: Forty patients scheduled to undergo elective coronary artery bypass grafting receiving a background infusion of remifentanil (0.3 [mu]g [middle dot] kg-1 [middle dot] min-1) were anesthetized with intravenous propofol delivered by target-controlled infusion according to the Marsh pharmacokinetic model under BIS monitoring. In a randomized, prospective design, 20 patients received propofol at a target concentration of 3 [mu]g/ml, whereas in 20 patients propofol was titrated to maintain a BIS value of 40-50. Plasma concentrations of propofol (by means of gas chromatography-mass spectrometry), epinephrine, norepinephrine (by means of high-pressure liquid chromatography), cortisol (by means of radioimmunoassay), and interleukins 6 and 10 (by means of enzyme-linked immunosorbent assay) were measured repeatedly throughout surgery.

Results: BIS monitoring allowed a 30% reduction of propofol infusion rates and a similar decrease in plasma propofol concentrations in the BIS group without affecting the stress response to surgery for the group mean. None of the patients reported awareness during a standardized interview. Interestingly, propofol-remifentanil anesthesia blunted the release of epinephrine and cortisol to bypass surgery completely even when the propofol infusion rate was reduced according to BIS values.     

Pharmacokinetics of Dopamine in Healthy Male Subjects

Background: Dopamine is an agonist of [alpha], [beta], and dopaminergic receptors with varying hemodynamic effects depending on the dose of drug being administered. The purpose of this study was to measure plasma concentrations of dopamine in a homogeneous group of healthy male subjects to develop a pharmacokinetic model for the drug. Our hypothesis was that dopamine concentrations can be predicted from the infusion dose using a population-based pharmacokinetic model.

Methods: Nine healthy male volunteers aged 23 to 45 yr were studied in a clinical research facility within our academic medical center. After placement of venous and arterial catheters, dopamine was infused at 10 [mu]g [middle dot] kg-1 [middle dot] min-1 for 10 min, followed by a 30-min washout period. Subsequently, dopamine was infused at 3 [mu]g [middle dot] kg-1 [middle dot] min-1 for 90 min, followed by another 30-min washout period. Timed arterial blood samples were centrifuged, and the plasma was analyzed by high-performance liquid chromatography. Mixed-effects pharmacokinetic models using NONMEM software (NONMEM Project Group, University of California, San Francisco, CA) were used to determine the optimal compartmental pharmacokinetic model for dopamine.

Results: Plasma concentrations of dopamine varied from 12,300 to 201,500 ng/l after 10 min of dopamine infusion at 10 [mu]g [middle dot] kg-1 [middle dot] min-1. Similarly, steady-state dopamine concentrations varied from 1,880 to 18,300 ng/l in these same subjects receiving 3-[mu]g [middle dot] kg-1 [middle dot] min-1 infusions for 90 min. A two-compartment model adjusted for body weight was the best model based on the Schwartz-Bayesian criterion.     

Patient State Index: Titration of Delivery and Recovery from Propofol, Alfentanil, and Nitrous Oxide Anesthesia

Background: The Patient State Index (PSI) uses derived quantitative electroencephalogram features in a multivariate algorithm that varies as a function of hypnotic state. Data are recorded from two anterior, one midline central, and one midline posterior scalp locations. PSI has been demonstrated to have a significant relation to level of hypnosis during intravenous propofol, inhalation, and nitrous oxide-narcotic anesthesia. This multisite study evaluated the utility of PSI monitoring as an adjunct to standard anesthetic practice for guiding the delivery of propofol and alfentanil to accelerate emergence from anesthesia.

Methods: Three hundred six patients were enrolled in this multicenter prospective randomized clinical study. Using continuous monitoring throughout the period of propofol-alfentanil-nitrous oxide anesthesia delivery, PSI guidance was compared with use of standard practice guidelines (both before [historic controls] and after exposure to the PSA 4000 monitor [Physiometrix, Inc., N. Billerica, MA; standard practice controls]). Anesthesia was always administered with the aim of providing hemodynamic stability, with rapid recovery.

Results: No significant differences were found for demographic variables or for site. The PSI group received significantly less propofol than the standard practice control group (11.9 [mu]g [middle dot] kg-1 [middle dot] min-1;P < 0.01) and historic control group (18.2 [mu]g [middle dot] kg-1 [middle dot] min-1;P < 0.001). Verbal response time, emergence time, extubation time, and eligibility for operating room discharge time were all significantly shorter for the PSI group compared with the historic control (3.3-3.8 min;P < 0.001) and standard practice control (1.4-1.5 min;P < 0.05 or P < 0.01) groups. No significant differences in the number of unwanted somatic events or hemodynamic instability and no incidences of reported awareness were found.     

Pharmacokinetics of Propofol Infusions in Critically Ill Neonates, Infants, and Children in an Intensive Care Unit

Background: Propofol is a commonly used anesthetic induction agent in pediatric anesthesia that, until recently, was used with caution as an intravenous infusion agent for sedation in pediatric intensive care. Few data have described propofol kinetics in critically ill children.

Methods: Twenty-one critically ill ventilated children aged 1 week to 12 yr were sedated with 4-6 mg [middle dot] kg-1 [middle dot] h-1 of 2% propofol for up to 28 h, combined with a constant morphine infusion. Whole blood concentration of propofol was measured at steady state and for 24 h after infusion using high-performance liquid chromatography.

Results: A propofol infusion rate of 4 mg [middle dot] kg-1 [middle dot] h-1 achieved adequate sedation scores in 17 of 20 patients. In 2 patients the dose was reduced because of hypotension, and 1 patient was withdrawn from the study because of a increasing metabolic acidosis. Mixed-effects population models were fitted to the blood propofol concentration data. The pharmacokinetics were best described by a three-compartment model. Weight was a significant covariate for all structural model parameters; Cl, Q2, Q3, V1, and V2 were proportional to weight. Estimates for these parameters were 30.2, 16.0, and 13.3 ml [middle dot] kg-1 [middle dot] min-1 and 0.584 and 1.36 l/kg, respectively. The volume of the remaining peripheral compartment, V3, had a constant component (103 l) plus an additional weight-related component (5.67 l/kg). Values for Cl were reduced (typically by 26%) in children who had undergone cardiac surgery.