Reversal of opioid-induced bladder dysfunction by intravenous naloxone and methylnaltrexone.

Peripheral mechanisms may be involved in opioid actions on the urinary bladder. This double-blind study investigated whether opioid inhibition of bladder function is reversed by methylnaltrexone, a peripheral opioid antagonist. Thirteen healthy male volunteers received an intravenous (i.v.) infusion of remifentanil, 0.15 mcg/kg/min, then a single i.v. dose of study medication (methylnaltrexone 0.3 mg/kg, naloxone 0.01 mg/kg, or saline). Urodynamics were measured with indwelling bladder and rectal catheters, and pupil size was assessed with infrared pupillometry. Remifentanil decreased detrusor pressure in 21/25 sessions and caused complete urinary retention in 18/25. Voiding was possible in 7/7, 5/12, and 0/6 sessions after naloxone, methylnaltrexone, and saline, respectively (P=0.0013). Remifentanil caused marked miosis that was reversed by naloxone, but not methylnaltrexone or placebo (P<0.0001). The pupil data confirm that methylnaltrexone did not reverse central opioid effects. Reversal of urinary retention by methylnaltrexone indicates that peripheral mechanisms may play a role in opioid-induced bladder dysfunction.

Pharmacokinetics and pharmacodynamics of inhaled versus intravenous morphine in healthy volunteers.

BACKGROUND: A new pulmonary drug delivery system produces aerosols from disposable packets of medication. This study compared the pharmacokinetics and pharmacodynamics of morphine delivered by an AERx prototype with intravenous morphine. METHODS: Fifteen healthy volunteers were enrolled. Two subjects were administered four inhalations of 2.2 mg morphine each at 1-min intervals or 4.4 mg over 3 min by intravenous infusion. Thirteen subjects were given twice the above doses, i.e., eight inhalations or 8.8 mg intravenously over 7 min. Arterial blood sampling was performed every minute during administration and at 2, 5, 7, 10, 15, 20, 45, 60, 90, 120, 150, 180, and 240 min after administration. The effect of morphine was assessed by measuring pupil diameter and ventilatory response to a hypercapnic challenge. Pharmacokinetic and pharmacodynamic analyses were performed simultaneously using mixed-effect models. RESULTS: The pharmacokinetic data after intravenous administration were described by a three-exponent decay model preceded by a lag time. The pharmacokinetic model for administration by inhalation consisted of the three-exponent intravenous pharmacokinetic model preceded by a two-exponent absorption model. The authors found that, with administration by inhalation, the total bioavailability was 59%, of which 43% was absorbed almost instantaneously and 57% was absorbed with a half-life of 18 min. The median times to the half-maximal miotic effects of morphine were 10 and 5.5 min after inhalation and intravenous administration, respectively (P < 0.01). The pharmacodynamic parameter ke0 was approximately 0.003 min-1. CONCLUSIONS: The onset and duration of the effects of morphine are similar after intravenous administration or inhalation via this new pulmonary drug delivery system. Morphine bioavailability after such administration is 59% of the dose loaded into the dosage form.

Pediatric evaluation of the bispectral index (BIS) monitor and correlation of BIS with end-tidal sevoflurane concentration in infants and children.

UNLABELLED: The bispectral index (BIS) has been developed in adults and correlates well with clinical hypnotic effects of anesthetics. We investigated whether BIS reflects clinical markers of hypnosis and demonstrates agent dose-responsiveness in infants and children. In an observational arm of this study, BIS values in children undergoing general anesthesia were observed and compared with similar data collected previously in a study of adults. In a second arm of the study, a range of steady-state end-tidal concentrations of sevoflurane was administered and corresponding BIS documented. Data were examined for differences between infants (0-2 yr) and children (2-12 yr). No difference was seen in BIS values in children before induction, during maintenance, and on emergence compared with adult values. There was no difference in BIS between infants and children at similar clinical levels of anesthesia. In children and infants, BIS was inversely proportional to the end-tidal concentration of sevoflurane. The sevoflurane concentration for a BIS = 50 (95% confidence interval) was significantly different: 1. 55% (1.40-1.70) for infants versus 1.25% (1.12-1.37) for children. Although validation with specific behavioral end points was not possible, BIS correlated with clinical indicators of anesthesia in children as it did in adults: as depth of anesthesia increased, BIS diminished. BIS correlated with sevoflurane concentration in infants and children. The concentration-response difference between infants and children was consistent with data showing that minimum alveolar concentration is higher in children less than 1 yr of age. IMPLICATIONS: The use of bispectral index (BIS) during general anesthesia improves the titration of anesthetics in adults. The data from this study suggest that the same equipment and method of electroencephalogram analysis may be applied to infants and children.

The tumescent technique: the effect of high tissue pressure and dilute epinephrine on absorption of lidocaine.

Injection of lidocaine into the subcutaneous tissues by the tumescent technique results in a delayed absorption of the local anesthetic and has allowed clinicians to exceed the maximum recommended dose of lidocaine without reported complications. However, little knowledge exists about the mechanisms that permit such high doses of lidocaine to be used safely with this technique. The presence of low concentration epinephrine and the increased tissue pressure resulting from the tumescent injection have both been implicated as important factors, but neither has been studied in patients whose results were not altered by the variability of the suction procedure. The purpose of this work was to determine the effect of tissue pressure during tumescent injection and presence of low concentration epinephrine on the absorption of lidocaine from subcutaneous tissues in human volunteers. Twenty healthy female human volunteers were randomized into four study groups. After body fat measurements, all subjects received an injection of 7 mg/kg of lidocaine into the subcutaneous tissues of both lateral thighs. The injected solution consisted of 0.1% lidocaine and 12.5 meq/liter sodium bicarbonate in normal saline with or without 1:1,000,000 epinephrine. Tissue pressure was recorded during injection using a specially designed double-barreled needle. The time required for injection was also recorded. Subjects in group 1 received lidocaine with epinephrine injected by a high-pressure technique. Group 2 subjects received lidocaine with epinephrine injected by a low-pressure technique. Group 3 subjects received lidocaine without epinephrine injected under high pressure. Group 4 subjects received lidocaine without epinephrine injected under low pressure. Following injection, sequential blood samples were drawn over a 14-hour period, and plasma lidocaine concentrations were determined by gas chromatography. No suction lipectomy was performed. Maximum tissue pressure during injection was 339 +/- 63 mmHg and 27 +/- 9 mmHg using high- and low-pressure techniques, respectively. Addition of 1:1,000,000 epinephrine, regardless of the pressure of injected fluid, significantly delayed the time to peak plasma concentration by over 7 hours. There was no significant difference in the peak plasma concentration of lidocaine among the four groups. Peak plasma concentrations greater than 1 mcg/ml were seen in 11 subjects. Epinephrine (1:1,000,000) significantly delays the absorption of lidocaine administered by the tumescent technique. High pressure generated in the subcutaneous tissues during injection of the solution does not affect lidocaine absorption. The delay in absorption may allow time for some lidocaine to be removed from the tissues by suction lipectomy. In addition, the slow rise to peak lidocaine concentration in the epinephrine groups may allow the development of systemic tolerance to high lidocaine plasma levels.

A randomized, double-blind, dose-response study of ondansetron in the prevention of postoperative nausea and vomiting.

STUDY OBJECTIVE: To determine the dose-response relationship of ondansetron in preventing postoperative nausea and vomiting (PONV) in women undergoing elective surgery. DESIGN: Prospective, randomized, double-blind study. SETTING: University-affiliated hospital. PATIENTS: 175 women aged 18 to 80 years scheduled for elective surgery. INTERVENTIONS: One of six doses of ondansetron (0.5 mg, 1 mg, 2 mg, 4 mg, 8 mg, 16 mg) or placebo was given prior to the induction of general anesthesia with propofol. Maintenance was with nitrous oxide, isoflurane, opioid, and muscle relaxant. MEASUREMENTS AND MAIN RESULTS: The study period began when the patient emerged from anesthesia. Nausea scores were recorded on a 0 to 10 scale at multiple time points during the 24-hour study period. Patient satisfaction via a visual analog scale (VAS) was determined at 1 and 24 hours after awakening. Rescue medication was given for severe nausea, three emetic episodes within 15 minutes, or if requested by the patient. The primary efficacy variable was the need for rescue antiemetic therapy. The dose-response curve (by logistic regression) of the percentage of patients not rescued versus dose indicated an ED50 of 0.54 mg (95% confidence interval 0.03-1.05 mg). Fewer patients required rescue in the 4 mg dose group compared with lower doses. However, the difference reached significance only in comparison with the 0.5 mg dose group. Survival analysis of the need for rescue, and nausea score versus time curves, also both suggested the superiority of the 4 mg dose compared with lower doses. In addition, there was a highly significant correlation between the lack of need for rescue and satisfaction with anesthesia at 24 hours after emergence. CONCLUSION: The recommended dose of ondansetron for PONV prophylaxis in women remains 4 mg.

Pharmacokinetics and pharmacodynamics of remifentanil in persons with renal failure compared with healthy volunteers.

BACKGROUND: Remifentanil is an opioid analgesic for use in anesthesia. An ester linkage renders it susceptible to rapid metabolism by blood and tissue esterases. Thus it was hypothesized that remifentanil elimination would be independent of renal function. Because its principal metabolite (GR90291) is eliminated renally, it would depend on renal function. This study was designed to evaluate the pharmacokinetics and pharmacodynamics of remifentanil and its metabolite in persons with and without renal failure. METHODS: Two groups of volunteers received two-stage infusions of remifentanil: low dose with 0.0125 microg x kg(-1) x min(-1) for 1 h followed by 0.025 microg x kg(-1) x min(-1) for 3 h; and high dose with 0.025 microg x kg(-1) x min(-1) for 1 h followed by 0.05 microg x kg(-1) x min(-1) for 3 h. Blood samples were collected for analysis of remifentanil and GR90291 concentrations. The pharmacokinetics of remifentanil were fit using a one-compartment pharmacokinetic model. Remifentanil's effect was determined intermittently using minute ventilation during a hypercapnic (7.5% CO2) challenge. RESULTS: Fifteen patients with renal failure and eight control participants were enrolled. The clearance and volume of distribution of remifentanil were not different between those with renal failure and the controls. Patients with renal failure showed a marked reduction in the elimination of GR90291; the half-life of the metabolite increased from 1.5 h in the controls to more than 26 h in patients with renal failure. The steady-state concentration of GR90291 is likely to be more than 25 times higher in persons with renal failure. There were no obvious differences in opioid effects on minute ventilation in the controls and in patients with renal failure. CONCLUSIONS: The pharmacokinetics and pharmacodynamics of remifentanil were not altered in patients with renal disease, but the elimination of its principal metabolite, GR90291, was markedly reduced. Based on simulations, the concentration of GR90291 at the end of a 12-h remifentanil infusion of 2 microg x kg(-1) x min(-1) is not likely to produce significant opioid effects.

Anesthetic drug interaction: an overview.

Modern anesthetic techniques involve combinations of intravenous (i.v.) and inhaled anesthetic drugs that may produce synergistic (supraadditive), additive, or antagonistic interactions. Synergistic interaction is most likely to occur when two or more drugs produce similar effects by different mechanisms. All of the tested combinations of opioids and i.v. sedative-hypnotics have been shown to produce synergistic hypnotic effects, and the majority of these interactions are predictable and useful in daily practice. Opioids, benzodiazepines, lidocaine, and alpha-2 agonists can all reduce the requirements for volatile anesthetics, but only the opioids and the alpha-2 agonists produce this effect at clinically acceptable concentrations. The usefulness of a drug interaction depends on whether it produces greater efficacy or reduced toxicity. Surprisingly, these outcomes have only been specifically measured for a handful of common drug combinations.

Pharmacokinetics and pharmacodynamics of remifentanil in volunteer subjects with severe liver disease.

BACKGROUND: Remifentanil, a new mu-opioid agonist with an extremely short duration of action, is metabolized by circulating and tissue esterases; therefore, its clearance should be relatively unaffected by changes in hepatic or renal function. This study was designed to determine whether severe hepatic disease affects the pharmacokinetics or pharmacodynamics of remifentanil. METHODS: Ten volunteers with chronic, stable, severe hepatic disease and awaiting liver transplantation and ten matched controls were enrolled. Each subject was given a 4-h infusion of remifentanil. The first five pairs received 0.0125 microgram x kg(-1) x min(-1) for 1 h followed by 0.025 microgram x kg(-1) x min(-1) for 3 h; the second five pairs received double these infusion rates. During and after the infusion, arterial blood was obtained for pharmacokinetic analyses, and the ventilatory response to a hypercarbic challenge was assessed. Simultaneous pharmacokinetic and pharmacodynamic analyses were performed. The pharmacokinetics were described using a one-compartment intravenous infusion model, and ventilatory depression was modelled using the inhibitory E(max) model. The pharmacokinetics of the metabolite GR90291 were determined using noncompartmental methods. RESULTS: There were no differences in any of the pharmacokinetic parameters for remifentanil or GR90291 between the two groups. The subjects with liver disease were more sensitive to the ventilatory depressant effects of remifentanil. The EC(50) values (the remifentanil concentrations determined from simultaneous pharmacokinetic/pharmacodynamic analyses to depress carbon dioxide-stimulated minute ventilation by 50%) in the control and hepatic disease groups were 2.52 ng/ml (95% confidence interval 2.07-2.97 ng/ml) and 1.56 ng/ml (95% confidence interval 1.37-1.76 ng/ml), respectively. CONCLUSIONS: The pharmacokinetics of remifentanil and GR90291 are unchanged in persons with severe, chronic liver disease. Such patients may be more sensitive to the ventilatory depressant effects of remifentanil, a finding of uncertain clinical significance, considering the extremely short duration of action of the drug.

Initial clinical experience with remifentanil, a new opioid metabolized by esterases.

Remifentanil is a new, esterase-metabolized opioid for anesthesia. Nonspecific esterases terminate the drug effect, with a context-sensitive half-time which plateaus at 3-4 min. This dose-ranging pilot study was designed to estimate the dose requirement of remifentanil for abolition of the responses to skin incision and intraoperative stimuli, and to determine the speed of recovery. Fifty-one unpremedicated patients took part at two centers. Anesthesia was induced with propofol, 67% nitrous oxide, and vecuronium. Remifentanil was then given (1 microgram/kg, plus an infusion of 0.0125-1.0 micrograms.kg-1.min-1). Responses were defined as: > 15% increase in systolic blood pressure or > 20% increase in heart rate, tearing, sweating, movement, or coughing. Responses to incision or surgery were treated with 0.5 micrograms/kg remifentanil boluses and a 50% increase in infusion rate, which could be done twice. Subsequent responses were treated with propofol or isoflurane. Remifentanil and nitrous oxide administration were terminated after the incision was closed. ED50 for response to skin incision varied between the two study sites (0.020 and 0.087 microgram.kg-1.min-1). ED50 for response to all surgical stimuli was 0.52 microgram.kg-1.min-1. At 0.3 microgram.kg-1.min-1 or more, only 3 of 21 patients required isoflurane. Recovery was not longer in patients receiving larger doses to spontaneous ventilation (2.5-4.6 min), tracheal extubation (4.2-7.0 min), and response to verbal command (3.0-4.6 min). Postoperative pain was reported in most patients (92%) at a median time of 21 min. We conclude that remifentanil was effective and well tolerated as a component of nitrous oxide-opioid-relaxant anesthesia.(ABSTRACT TRUNCATED AT 250 WORDS)

Perioperative drug interactions.

The various classes of IV and inhalation anesthetics all appear to potentiate one another. Many of these interactions are clinically useful in outpatient anesthesia, and many are quite predictable. True synergy is most likely to occur when two drugs produce similar actions by slightly different mechanisms. These principles are particularly well demonstrated by the interactions of hypnotic drugs at the locus ceruleus. It is possible that the reduced anesthetic requirements seen in some disease states may involve similar mechanisms.

Central nervous system symptoms after intravenous lignocaine: dose-response during pregnancy.

There is continuing controversy over what dose of what drug should be used to identify an accidental intravascular or subarachnoid catheter placement in obstetric epidural anaesthesia. The purpose of this randomized, double-blind study was to evaluate the dose-effect relationship for the production of central nervous system (CNS) symptoms by intravenous lignocaine. Sixty first-trimester, pregnant patients divided into groups of 10 received saline or one of five doses of lignocaine (0.39, 0.5, 0.63, 0.79, and 1.0 mg kg-1) i.v. An ED95 of 1.12 mg kg-1 was calculated to produce reliable CNS symptoms when injected intravascularly. Lignocaine is an effective and reliable marker for intravenous injection in pregnant women.

A randomized, double-blind pilot study examining the use of intravenous ondansetron in the prevention of postoperative nausea and vomiting in female inpatients.

STUDY OBJECTIVE: To compare the efficacy and safety profiles of intravenous (IV) ondansetron (two 8 mg doses 8 hours apart) and a placebo when used in the prevention of postoperative nausea and emesis (vomiting or retching). DESIGN: Randomized, double-blind, placebo-controlled, parallel, multicenter pilot study. SETTING: Four university hospitals in the United States. PATIENTS: Two hundred seven women scheduled to undergo inpatient surgical procedures during general anesthesia. INTERVENTIONS: Patients were randomized to receive, in a double-blind fashion, either two 8 mg doses of IV ondansetron or a placebo. The first study drug dose was administered before induction of anesthesia; the second dose was given 8 hours later. Each study drug dose was admixed with normal saline to 20 ml and administered IV over 2 to 5 minutes. Vital signs were monitored immediately before and 1 minute after completion of the study drug infusion. MEASUREMENTS AND MAIN RESULTS: For the 24-hour period following operation, 60% of the patients who received ondansetron and 26% of the patients who received the placebo were emesis-free (p < 0.001). Subanalyses based on patients' previous history of general anesthesia indicated that ondansetron was superior to the placebo in preventing emesis regardless of history [66% vs. 33% in patients who had never had general anesthesia or had had no nausea or emesis following previous anesthesia (p = 0.001) and 50% vs. 17% in patients who had nausea or emesis following previous anesthesia (p = 0.005)]. Ondansetron also was superior to the placebo for the prevention of nausea over the 24-hour study period regardless of anesthesia history. Ondansetron was generally well tolerated. The adverse event, vital sign, and clinical laboratory test profiles were similar to those for the placebo. No patient who received ondansetron had untoward changes in central nervous system function, including sedation. CONCLUSIONS: Prophylactic IV ondansetron appears to be safe and causes a significant reduction in the frequency and severity of postoperative nausea and emesis.

Ondansetron does not affect alfentanil-induced ventilatory depression or sedation.

Ondansetron is a selective 5-hydroxytryptamine type 3 receptor antagonist effective as an antiemetic in patients experiencing post-operative or cancer chemotherapy-induced nausea and vomiting. Currently, no information is available regarding the interaction of ondansetron with opioids, although a serotonin antagonist might be expected to modify some opioid actions. This study was designed to measure the effects of ondansetron on alfentanil-induced ventilatory depression and sedation in healthy male volunteers. Ventilatory drive (measured as the end-tidal CO2 necessary to produce a minute ventilation of 15 l/min) was determined in 29 subjects using a modification of the Read rebreathing technique. Sedation was measured by asking the subjects to complete visual analog scales. Alfentanil was administered as a bolus (5 micrograms/kg) followed by a continuous infusion (0.25-0.75 micrograms.kg-1.min-1) for at least 90 min. Study medication (ondansetron 8 or 16 mg or vehicle placebo) was then administered in a randomized, double-blind manner, and the alfentanil was infused for an additional 15 min. Measurements of ventilatory drive and sedation were made at baseline, during alfentanil infusion, after study medication, and at 30-min intervals after alfentanil was discontinued. Alfentanil produced significant ventilatory depression (P less than 0.001) and sedation (P less than 0.001) in all three groups. Neither placebo nor ondansetron produced further change in the intensity of either alfentanil effect. After discontinuation of the opioid, both ventilatory depression and sedation decreased, and the rate of recovery was not significantly different between groups. The data indicate that alfentanil-induced sedation and ventilatory depression are not significantly affected by the subsequent administration of ondansetron.

Ondansetron is effective in decreasing postoperative nausea and vomiting.

The efficacy of ondansetron, a selective 5-HT3 receptor antagonist, in preventing postoperative nausea and vomiting in surgical patients was studied. Fifty women were randomized in a double-blind manner to receive either two 8 mg doses of intravenous ondansetron or two doses of placebo vehicle: the first given just before general anesthesia induction and the second 8 hours later. During the first 24 postoperative hours, the number of emetic episodes was recorded and the subjects rated their nausea on a scale from 0 to 10. Ondansetron-treated subjects had fewer emetic episodes (p less than 0.001) and lower subjective nausea scores (p less than 0.001). The number of complete responders (no emetic episodes and no rescue therapy) was 1 of 24 (4%) and 15 of 26 (58%) in the placebo and ondansetron groups, respectively (p less than 0.001). Ondansetron is clearly more effective than placebo in the prophylaxis of postoperative nausea and vomiting. The adverse event profile for ondansetron was similar to that of placebo.

Comparison of the sedative effects of butorphanol and midazolam.

Although kappa opioid agonists and certain agonist-antagonists are known to be sedating, this effect has not been well characterized in a drug-naive population. We compared the sedative properties of intravenous butorphanol with those of midazolam or the combination in 126 healthy preoperative patients. Subjects were randomly assigned to receive one of nine treatments in a double-blind fashion: 7.1, 22.5, or 71.4 micrograms/kg butorphanol; 4.3, 13.6, or 42.9 micrograms/kg midazolam; or 3.6 + 2.2, 11.3 + 6.8, or 35.7 + 21.5 micrograms/kg butorphanol and midazolam in combination. Eight visual analogue scales (VAS) were completed by the subject and an observer. The subject then performed two psychomotor tests (the Trieger dot test and the Halstead trail-making test) and was shown two playing cards in order to assess memory. The test drug was administered, and 5 min later the evaluations were repeated and two more cards were shown. On the following day the subjects were asked to recall the names of the playing cards. Butorphanol, midazolam, and their combination produced dose-related changes in VAS scores that were significant and qualitatively similar: subjects became sleepy, less nervous, weak, and less clear-thinking. There was no significant euphoria or dysphoria. The sedative and depressant effects on respiratory rate of the high-dose combination were significantly greater than those predicted by simple additivity: 14 of 14 subjects receiving the high dose of the butorphanol/midazolam combination had lid droop and marked sedation, and 2 of 14 subjects had respiratory rates of less than 4 breaths per min. All three drug treatments caused significant, dose-dependent impairment of psychomotor function.(ABSTRACT TRUNCATED AT 250 WORDS)

Fentanyl and sufentanil anesthesia revisited: how much is enough?

This study was undertaken to determine if fentanyl and sufentanil could produce dose-related suppression of hemodynamic and hormonal responses to surgical stimulation. Eighty patients scheduled for elective CABG were studied in two consecutive protocols: protocol I was a randomized double-blind study of 40 patients who received a single dose of fentanyl (50 or 100 micrograms/kg) or sufentanil (10, 20, or 30 micrograms/kg). Hemodynamic measurements and hormonal concentrations (renin, aldosterone, cortisol, and catecholamines) were determined before and after induction and after intubation and sternotomy. Protocol II was an open randomized study of 40 patients who received sufentanil in one of four doses: 30 micrograms/kg as a single dose, 10 micrograms/kg plus infusion 0.05 microgram.kg-1.min-1, 20 micrograms/kg plus infusion 0.1 microgram.kg-1.min-1, or 40 micrograms/kg plus infusion 0.2 microgram.kg-1.min-1. Hemodynamic measurements and plasma sufentanil and catecholamine concentrations were determined before and after induction and after intubation, sternotomy, and aortic cannulation. Both protocols defined a hemodynamic response as a 15% or more increase in systolic blood pressure (SBP) from control and a hormonal response 50% or more increase over control. During protocol I, 18 patients had a hemodynamic response (average increase in SBP 22.6 +/- 2%) and 35 patients had a total of 59 hormonal responses. During protocol II, 24 patients had a hemodynamic response (average increase in SBP - 31 +/- 3%) and there were 15 catecholamine responses. There were no differences between dose groups in either protocol. It was concluded that in these dose ranges, suppression of hemodynamic or hormonal stress responses is not related to opioid dose.(ABSTRACT TRUNCATED AT 250 WORDS)