Subchronic administration of (R,S)-ketamine induces ketamine ring hydroxylation in Wistar rats.

Subchronic administration of (R,S)-ketamine, (R,S)-Ket, is used in the treatment of neuropathic pain, in particular Complex Regional Pain Syndrome, but the effect of this protocol on the metabolism of (R,S)-Ket is unknown. In this study, daily administration of a low dose of (R,S)-Ket for 14-days to Wistar rats was conducted to determine the impact of sub-chronic dosing on the pharmacokinetics of (R,S)-Ket and its major metabolites. The data indicate that, relative to a single administration of (R,S)-Ket, subchronic administration resulted in increased clearance of (R,S)-Ket and the N-demethylated metabolite norketamine measured as elimination half-life (t1/2) and decreased plasma concentrations of these compounds. Subchronic administration produced a slight decrease in t1/2 and an increase in plasma concentration of the major metabolite, (2S,6S;2R,6R)-hydroxynorketamine, and produced significant increases in the plasma concentrations of the (2S,6R;2R,6S)-hydroxynorketamine and (2S,4R;2R,4S)-hydroxynorketamine metabolites. The metabolism of (R,S)-Ket predominately occurs via two microsomal enzyme-mediated pathways: (R,S)-Ket⇒(R,S)-norketamine⇒(2S,6S;2R,6R)-hydroxynorketamine and (2S,4R;2R,4S)-hydroxynorketamine and the (R,S)-Ket⇒(2S,6R;2R,6S)-hydroxyketamine⇒(2S,6R;2R,6S)-hydroxynorketamine and (2S,6S;2R,6R)-hydroxynorketamine. The results indicate that the activity of both metabolic pathways are increased by subchronic administration of (R,S)-Ket producing new metabolite patterns and potential differences in clinical effects.

Development and validation of a sensitive LC-MS/MS method for the determination of D-serine in human plasma.

A validated LC-MS/MS method was developed for the determination of d -Serine in human plasma. The method was fully validated for use with human plasma samples and was linear from 0.19 nmol/ml to 25 nmol/ml. The coefficient of variation was ≤5% for the high QC standards and ≤8% for the low QC standards in plasma. d -Serine and l -serine were resolved by pre-column derivatization using (R)-1-Boc-2-piperidine carbonyl chloride as the derivatizating agent. The method was used to determine the concentration of d-serine in plasma samples obtained in patients receiving a continuous 5-day intravenous infusion of (R,S)-ketamine. The changes in d-Ser levels varied in the six patients, with circulating d-Ser levels increasing as much as 35% in a patient, while decreasing 20% in a patient. While only preliminary data, the results suggests the potential importance in determining the d-Ser levels in plasma and their potential role in physiological response.

Evaluation of porous networks of poly(2-hydroxyethyl methacrylate) as interfacial drug delivery devices.

Long-term implantable drug delivery devices are desirable to achieve rapid and reliable delivery of bioactive substances to the body. The limitation of most implantable devices is the resulting chronic inflammatory response and fibrous encapsulation of the implant, which prevents effective drug delivery for prolonged periods. One method of overcoming this problem is the addition of an intermediary that could prevent capsule formation. Biocompatible materials with interconnected pore structures greater than 8-10 microm have been shown to support the ingrowth and maintenance of vascularized tissue. In this investigation, we evaluate the efficacy of using porous hydrogel sponges for the tissue interface in an implantable drug delivery device. Porous networks of poly(2-hydroxyethyl methacrylate) (PHEMA) were synthesized using a thermally initiated free-radical solution polymerization. To characterize the microstructure of the PHEMA networks, scanning electron microscopy and mercury porosimetry were used. By altering the solvent fraction in the reaction mixture, PHEMA sponges were synthesized with interconnected pores ranging in size from from 6 to 15 microm with porosities of 55% to 87%. Following the in vitro evaluation, sponges were attached to the distal end of a 20-gauge catheter tubing, and implanted subcutaneously and intraperitoneally. After 5 months implantation, insulin was infused into the devices from external pumps and rapid insulin absorption was observed in conjunction with dramatic lowering of blood glucose levels. From histological evaluation of explanted devices, we observed highly vascularized tissue surrounding the mesenteric implants. These results indicate that it may be possible to use PHEMA sponges for a tissue intermediary for long-term implantable drug delivery devices.

Accuracy of the hemocue portable glucose analyzer in a large nonhomogeneous population.

Several studies have reported inconsistent results between HemoCue (HC) whole blood glucose measurements compared to plasma glucose. We selected a large patient population with diverse pathologies and healthy volunteers to evaluate HC. For this comparison, whole blood glucose concentration was measured using HC and referenced to laboratory plasma glucose. The population (n = 512) included healthy volunteers, diabetics, and patients with heart failure, liver failure, renal failure, renal and liver transplant, and other chronic diseases. Patients were on a wide variety of medications, vitamins, and food supplements. Venous blood samples were collected in tubes containing potassium oxalate and sodium fluoride. Comparison of the results was made using the method of Bland and Altman and ANOVA at three selected glucose ranges. The glucose measurement ([HC + laboratory]/2) ranges were 24-75, 76-129, and 130-404 mg/dL. A positive bias for all three glucose ranges was observed: 38 +/- 17 mg/dL for the high glucose group compared to 24 +/- 9 mg/dL and 22 +/- 10 mg/dL for the middle and low groups, respectively. In the high glucose group 90% of the values were within 10% (R = 0.97) of the laboratory reference values compared to 81% and 55% in the normal and low glucose groups, respectively. HC glucose measurements were generally within two SD from the laboratory plasma reference. HC consistently yielded lower whole blood glucose measurements than plasma with the largest differences seen in the low glucose range (29%). HC measured more consistently at the higher glucose concentrations and was 16% lower than plasma, although the mean absolute error was highest for that range. No significant effects in the bias could be attributed to disease while possible effects from instrument modifications by the manufacturer remain uncertain.

Serum leptin during recovery following maximal incremental and prolonged exercise.

This study investigated the delayed circulating leptin response to maximal and prolonged treadmill exercise. Six healthy untrained males performed three sessions after an overnight fast: control, maximal exercise, and prolonged exercise at 50% of maximal oxygen consumption. Blood samples were collected prior to exercise, at the end of exercise, and at 60, 120, 180, and 240 min following exercise and control sessions. Blood samples were analyzed for serum leptin, insulin, glucose, free fatty acids, and glycerol. Hemoglobin and hematocrit were measured to correct for plasma volume changes. Resting energy expenditure (REE) and body fat (BF) were also assessed. Immediately at the end of maximal and prolonged exercise, and during the 4 hours of recovery, serum leptin levels did not change significantly compared to their respective baseline values. At 240 min of recovery serum leptin decreased 7% and 9% (p>0.05) from the baseline in the maximal and prolonged sessions, respectively. In the control experiment serum leptin decreased 27% from the baseline at 240 min of the recovery (p < 0.05). No significant differences were found in leptin values between the control and exercise sessions. Control serum leptin was positively correlated (p < 0.05) to BF (r = 0.88) and glucose (r=0.96), and negatively correlated to REE (r= -0.81). In conclusion, maximal or prolonged exercise do not appear to have an influence on circulating serum leptin in the delayed (4 hr) post exercise recovery period.

Postoperative epidural analgesia following radical retropubic prostatectomy: outcome assessment.

BACKGROUND AND OBJECTIVES: We retrospectively examined the effects of epidural analgesia on patients undergoing radical retropubic prostatectomy (RRP). METHODS: Patients (203) underwent radical retropubic prostatectomy under either general or epidural anesthesia alone or a combined general epidural technique. Of those, 143 had an epidural catheter placed and underwent radical retropubic prostatectomy under general anesthesia followed by postoperative epidural analgesia (Group E+G). Twenty-eight patients had the operation under epidural anesthesia followed by epidural analgesia in the postoperative period (Group E). Thirty-two patients had general anesthesia for the operation and postoperative systemic analgesia (Group G). RESULTS: There were no significant differences between the groups with respect to age, height, weight, ASA status, or operation time. The length of postoperative hospital stay was significantly longer in the general anesthesia group patients as compared to the other two groups (P < 0.05). Intraoperative blood loss and blood replacement were significantly higher in the general anesthesia group (P < 0.001). There were no significant differences between the groups with respect to return of bowel function postoperatively, or incidence of complications. CONCLUSIONS: Epidural anesthesia and analgesia following radical retropubic prostatectomy have demonstrated a number of beneficial effects. These include decreased blood loss and shorter hospital stay.

Transdermal fentanyl system plus im ketorolac for the treatment of postoperative pain.

PURPOSE: To assess the safety and efficacy of transdermal fentanyl plus im ketorolac vs im ketorolac alone in the treatment of postoperative pain. METHODS: Ninety-two patients scheduled for surgery involving moderate to severe postoperative pain were randomized to one of two groups. Group A (n = 46) received an active fentanyl patch and group P (n = 46) received a placebo patch. Patches remained in place for 24 hr. Each patient received intraoperative ketorolac, 60 mg im. Patients were monitored for 36 hr postoperatively and the groups were analyzed for ketorolac usage, pain scores, vital signs, serum fentanyl concentrations, and adverse events. Intramuscular ketorolac was available on demand. RESULTS: Group A had lower pain scores at 8.12, 16 and 24 hr after patch placement (P < 0.05). Group A had lower heart rates, lower respiratory rates and fewer dropouts due to inadequate pain relief (4.3% vs 21.7% P < 0.05). Group A patients also used less ketorolac than group P patients (P < 0.05). The incidence of pruritus was higher in group A patients (19% vs 2%, P < 0.05), while the incidence of nausea and vomiting was not different between the two groups. Transdermal fentanyl was adequate "stand-alone" analgesia in only 23.8% of group A patients while 93.7% of the remaining group A patients receiving a combination of transdermal fentanyl and ketorolac had adequate pain relief. CONCLUSION: The transdermal fentanyl delivery system plus ketorolac im was more effective in controlling post-operative pain than ketorolac im alone. The two treatment modalities were comparable in safety with no difference in serious adverse events.

Medical waste in the environment: do anesthesia personnel have a role to play?

STUDY OBJECTIVE: To conduct a feasibility study of the mechanics of recycling single-use anesthesia breathing systems and practices of anesthesiologists and nurse-anesthetists in a tri-state region. STUDY DESIGN: Two-part, open, prospective analysis using pre-printed questionnaire and cost/time analysis of labor and materials. SETTING: Questionnaire sent to 413 anesthesiology departments in Pennsylvania, New Jersey, and Delaware, and hospital/recycling facility for evaluation of time and cost. MEASUREMENTS AND MAIN RESULTS: Time to disassemble and sort the breathing circuits, analysis of costs and obtainable income from byproducts of recycling, and standard survey questionnaire concerning demographic characteristics of respondents and individual department/hospital practitioners. Data analysis included analysis of variance and Kruskal-Wallis tests. Pilot analysis: Sorting of circuits to economic component required ten minutes at an average cost of $1.60 Value of scraps obtainable was $3.44, leaving a gross margin of $1.84 for a box of 18 circuits. Benefit analysis: Extended reduction in the regulated medical waste in our operating room of 16,875 lb, saving $4,387.50 per year. With generation of revenue from scrap, the net gain is $5,994.64 per yr. Questionnaire: Majority (83%) of departments polled would participate in recycling implemented by suppliers. Most respondents would not consider (58%) recycling unless mandated by law. CONCLUSION: The program described is cost-effective and environmentally beneficial.

Preoperative glycopyrrolate: oral, intramuscular, or intravenous administration.

STUDY OBJECTIVE: To evaluate the effects of oral, intramuscular (i.m.) and intravenous (i.v. glycopyrrolate on oral and gastric secretions, and to assess how these routes of administration change intubating conditions. DESIGN: Randomized, double-blinded study. SETTING: University hospital operating room. PATIENTS: 37 ASA status I and II general anesthesia patients. INTERVENTIONS: Patients were randomized to receive glycopyrrolate or placebo just before surgery by three routes: oral, i.m., and i.v.. Glycopyrrolate was received once by one route and placebo by the other two routes. A placebo group received three placebos and no glycopyrrolate. MEASUREMENTS AND MAIN RESULTS: Mouth conditions and intubating conditions were qualitatively assessed by the patient and the intubating anesthesiologist. No difference between groups was noted. Oral and gastric volumes were measured and showed significantly less gastric volume for the i.v. group as compared with the other groups. Oral secretions were reduced in both the i.v. and i.m. groups when compared with placebo or glycopyrrolate administered orally. CONCLUSIONS: Preoperative glycopyrrolate is significantly more effective at reducing oral and gastric secretions if administered intravenously immediately before induction.

Sevoflurane versus isoflurane for maintenance of anesthesia: are serum inorganic fluoride ion concentrations of concern?

Sevoflurane administration can result in increased serum inorganic fluoride ion concentrations, which have been associated with inhibition of renal concentrating ability. We measured serum fluoride levels, renal function, and recovery variables as a function of time in ASA grade I-III patients administered general anesthesia with isoflurane or sevoflurane for at least 1 h. Fifty patients were exposed to sevoflurane (< or = 2.4% inspired concentration) or isoflurane (< or = 1.9% inspired concentration) for maintenance of anesthesia as part of a multicenter trial. Blood was collected for determination of serum fluoride ion concentration, electrolytes, blood urea nitrogen, and creatinine at various time points pre- and postoperatively. Mean serum fluoride levels were significantly increased in sevoflurane versus isoflurane groups at all time points; the mean peak serum levels were 28.2 +/- 14 mumol/L at 1 h for sevoflurane and 5.08 +/- 4.35 mumol/L at 12 h for isoflurane. Sevoflurane-mediated increases in serum fluoride levels peaked at 1 h and, in general, decreased rapidly after discontinuation of the anesthesia. Three of 24 patients exposed to sevoflurane had one or more fluoride levels > 50 mumol/L. One of these patients had a serum inorganic fluoride ion level > 50 mumol/L at 12 h after sevoflurane, and an additional patient had fluoride levels > 33 mumol/L for up to 24 h after sevoflurane discontinuation. Those two patients also demonstrated an increase in serum blood urea nitrogen and creatinine at 24 h after sevoflurane administration compared with baseline. The elimination half-life of serum fluoride ion was 21.6 h. The results of this study suggest the possibility of sevoflurane induced nephrotoxicity.

A comparison of four bedside methods of hemoglobin assessment during cardiac surgery.

The purpose of this study was to compare the accuracy of conductivity, adjusted conductivity, photometric, and centrifugation methods of measuring or estimating hemoglobin (Hb) with Coulter measured HB as the reference. These bedside methods were studied in 25 cardiac surgery patients during euvolemia and hemodilution and after salvaged autologous red blood cell transfusion. In vivo patient blood samples were obtained before induction, at the start of cardiopulmonary bypass (CPB), after CPB, and after blood transfusion. In 10 patients, blood was sampled in vitro from units of processed blood. Hb values were determined using conductivity by Stat-Crit, adjusted conductivity by Nova Stat Profile 9, bedside photometry by HemoCue, and centrifugation methods. The calculated bias values of Coulter test method Hb (mean +/- SD) for in vivo patient blood samples (n = 90) were: Stat-Crit = 0.6 +/- 0.8 g/dL; Nova Stat Profile 9 = -0.7 +/- 0.4 g/dL; HemoCue = -0.1 +/- 0.2 g/dL; and centrifuge = 0.1 +/- 0.5 g/dL (P < 0.0001). Hb bias values (g/dL) for in vitro samples (n = 10) obtained from processed blood were Stat-Crit = 5.1 +/- 0.6; Nova Stat Profile 9 = 3.0 +2- 0.6; HemoCue = 0.4 +/- 0.4; and centrifuge = 0.6 +/- 0.3 (P < 0.0001). Hb assessment by different test methods may be significantly affected during hemodilution and after blood transfusion. In vitro conditions exaggerated the inaccuracy of conductivity and adjusted conductivity Hb estimates. The rank order of closest approximation to the Coulter measurement for all in vivo blood samples was provided by bedside photometry, followed by centrifugation, adjusted conductivity, and uncorrected conductivity methods.

The effects of anesthetic technique on the hemodynamic response and recovery profile in coronary revascularization patients.

This study was undertaken to assess the effects of propofol (versus enflurane, fentanyl, and thiopental) on hemodynamic stability and recovery characteristics when used for maintenance of anesthesia during elective coronary artery bypass grafting (CABG) procedures. Ninety premedicated patients scheduled for elective coronary revascularization had anesthesia induced with fentanyl 25 micrograms/kg intravenously (i.v.). When the mean arterial blood pressure (MAP) increased 10% above preoperative baseline values, patients were randomized to receive one of four anesthetic treatments: enflurane, 0.25-2.0%; fentanyl, 10-20 micrograms/kg i.v. bolus doses; propofol, 50-250 micrograms.kg-1.min-1 i.v.; or thiopental, 100-750 micrograms.kg-1.min-1 i.v.. The maintenance anesthesia was titrated to achieve hemodynamic stability (i.e., maintain the MAP within 10% of the baseline values and heart rate [HR] within 20% of the baseline values). After bypass, anesthetic and cardiovascular drugs were titrated to maintain the MAP > 65 mm Hg and the cardiac index (CI) > 2.3 L.min-1.m-2. Recovery was assessed by noting the times at which patients first opened their eyes, responded to verbal communication, correctly responded to specific commands, underwent tracheal extubation, and were discharged from the intensive care unit (ICU). Although less intraoperative hypertension was noted in the propofol-treated patients (19 +/- 11 min vs 38 +/- 26 min, 30 +/- 24 min, and 30 +/- 23 min in the enflurane, fentanyl, and thiopental groups, respectively) (P = 0.04), the incidence of hypotension did not differ significantly among the groups. Vasopressor drugs were required more often during the prebypass period in fentanyl and propofol patients (4/22 and 5/23, respectively) compared to the thiopental group (0/21) (P < 0.05). During CPB, fentanyl-treated patients required vasoconstrictors more often than patients in the other three treatment groups (14/22 vs 6/24, 4/23, and 5/21 in the enflurane, propofol, and thiopental groups, respectively) (P < 0.01). Although fentanyl-treated patients had significantly greater requirements for inotropic support during weaning from CPB than propofol-treated patients (14/22 vs 7/23) (P < 0.038), there were no significant differences among the groups in the postbypass or ICU periods. Propofol-treated patients responded to verbal stimuli (2.1 +/- 1.3h vs 4.0 +/- 3.5h, 4.7 +/- 2.7h, and 5.6 +/- 3.6h in the enflurane, fentanyl, and thiopental groups, respectively) (P = 0.01) and followed commands earlier (propofol 7.3 +/- 5.2h vs enflurane 12.5 +/- 5.7h, fentanyl 13.1 +/- 6.6h, and thiopental 12.8 +/- 6.7 h) (P = 0.01).(ABSTRACT TRUNCATED AT 400 WORDS)

Sedative and ventilatory effects of midazolam infusion: effect of flumazenil reversal.

The purpose of this study was to evaluate the effects of flumazenil (1 mg i.v.) on the ventilatory response of premedicated patients receiving a continuous infusion of midazolam for sedation. After assessing baseline ventilatory function using a modified Read rebreathing method for determining hypercapnic ventilatory drive, 16 healthy outpatients were administered fentanyl, 50 micrograms i.v., and midazolam 2 mg i.v., followed by a variable-rate midazolam infusion, 0.3-0.5 mg.min-1. Upon termination of the midazolam infusion, serum midazolam concentrations were measured and ventilatory function was reassessed. Then, 10 ml either saline or flumazenil (1 mg) were administered according to a randomized, double-blind protocol. Ventilatory function was subsequently measured at 5 min, 30 min and 60 min intervals after study drug. Compared with the baseline value, midazolam infusion reduced tidal volume and increased respiratory rate and alveolar dead space. However, midazolam did not decrease the slope of the CO2-response curve. Flumazenil reduced the degree of midazolam-induced sedation and the decrease in tidal volume (P < 0.05), but not the change in resting respiratory rate. In some patients, the ventilatory response to hypercarbia actually decreased after flumazenil administration compared with the immediate prereversal (sedated) values. It is concluded that midazolam infusion, 0.43 mg.min-1, did not impair CO2-responsiveness. Flumazenil's effect on central ventilatory drive was more variable than its reversal of midazolam-induced sedation.

The effects of ketorolac and fentanyl on postoperative vomiting and analgesic requirements in children undergoing strabismus surgery.

Fifty-four ASA I and II children 1 to 10 yr of age undergoing strabismus surgery were randomized to receive in a double-blind fashion intravenous ketorolac (0.9 mg/kg), fentanyl (1 microgram/kg), or saline placebo (2 mL) during a standardized general anesthetic. Patients received no analgesic or antiemetics intraoperatively except for the study drug. Patients receiving ketorolac or placebo compared to fentanyl had a significantly lower incidence of postoperative vomiting in the day surgery unit (DSU) (P = 0.03) and overall (DSU plus home) (P = 0.005). The severity (number of episodes) of post-operative vomiting was significantly lower in the DSU, at home (first 24 h after hospital discharge), and overall for patients receiving ketorolac or placebo compared to fentanyl (P < 0.01). Postoperative pain scores and frequency of acetaminophen administration did not differ among the study groups, suggesting that the intraoperative use of ketorolac or fentanyl during pediatric strabismus surgery is unnecessary. No patients required fentanyl postoperatively, indicating that rectal acetaminophen administered in the postanesthesia recovery room provides sufficient analgesia for pediatric strabismus surgery. In conclusion, neither ketorolac nor fentanyl was associated with less postoperative vomiting or analgesic requirements compared to saline placebo administered during pediatric strabismus surgery. Fentanyl should be avoided, as it was associated with a significantly greater incidence of postoperative vomiting compared to ketorolac or placebo.

Intraoperative hemodynamic, renin, and catecholamine responses after prophylactic and intraoperative administration of intravenous enalaprilat.

This study was designed to evaluate effects of enalaprilat, an angiotensin-converting enzyme inhibitor, on hemodynamic and hormonal responses during surgery at endotracheal intubation, incision, and limb-tourniquet inflation. Thirty patients undergoing limb procedures with general anesthesia (N2O/narcotic technique) and a pneumatic tourniquet were randomized to receive either preoperative enalaprilat (1.25 mg intravenously [i.v.] 20 min prior to induction) or intraoperative enalaprilat (0.625 mg i.v. at the onset of tourniquet-associated hypertension), with appropriate placebo controls. Arterial blood pressure and heart rate increased significantly in response to intubation in the placebo group. Although there were no significant differences in catecholamine levels, plasma renin activity was significantly increased at postincision in the preoperative-enalaprilat group versus the placebo group. This suggests that activation of the renin-angiotensin system may play a key role in mediation of intraoperative hemodynamic responses to endotracheal intubation. With respect to tourniquet hypertension, preoperative or intraoperative treatment with enalaprilat reduced neither the pressor response to tourniquet inflation nor the amount of enflurane subsequently required to control arterial blood pressure. These findings suggest that this response is mediated by pain pathways, and may be treated more effectively with anesthesia/analgesia.