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.

Dolasetron for the prevention of postoperative nausea and vomiting following outpatient surgery with general anaesthesia: a randomized, placebo-controlled study. The Dolasetron PONV Prevention Study Group.

In a multicentre, randomized, double-blind, placebo-controlled dose-ranging study, 1030 patients undergoing outpatient surgery with general anaesthesia received i.v. dolasetron mesylate (12.5, 25, 50, or 100 mg) or placebo. The principal outcome measure was the proportion of patients who were free of emesis or rescue medication for the 24-h period after the study drug was given; the subsidiary outcome measure was survival time without rescue medication. Effects on nausea were quantified using a visual analogue scale. Compared with placebo, a complete response was significantly higher when all four dolasetron doses were combined (49% vs. 58%, P =0.025). In females, dolasetron, 12.5-mg, dolasetron provided maximum clinical benefit (effectiveness compared with adverse events), with no additional benefit in complete response rates or nausea visual analogue scale scores at higher doses. No significant differences were observed in complete response for any dolasetron dose in males compared with placebo. The majority of adverse events reported were mild or moderate. Dolasetron provided well-tolerated, safe, and effective prophylaxis for post-operative nausea and vomiting with maximum effectiveness observed at a dose of 12.5 mg.

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.

Bispectral analysis of the electroencephalogram predicts conscious processing of information during propofol sedation and hypnosis.

BACKGROUND: The bispectral index (BIS) measures changes in the interfrequency coupling of the electroencephalogram (EEG). The purposes of this study were (1) to determine whether BIS correlates with responses to command during sedation and hypnosis induced by propofol or propofol and nitrous oxide, and (2) to compare BIS to targeted and measured concentrations of propofol in predicting participants' responses to commands. METHODS: Twenty volunteers (15 men and 5 women, aged 22-50 yr) were given propofol by computer-controlled infusion, and EEG was recorded for off-line analysis of BIS. Responses to randomly ordered verbal commands or voice plus touch were measured with two categorical scales (CS1 and CS2, respectively). All subjects received a propofol infusion targeted to achieve effect site concentrations of 1, 2, 4, 2, 1, and 0 microg/ml. Ten participants had repeated infusion, whereas 10 others breathed 30% nitrous oxide and oxygen and received a propofol infusion targeted for 0.5, 1, 2, 4, 2, 1, 0.5, and 0 microg/ml. Five minutes after each targeted concentration had been reached, CS1, CS2, and arterial propofol concentration were determined. The area under the receiver operating characteristic curve was used to compare the accuracy of (1) BIS, (2) targeted propofol concentration, (3) measured concentration, and (4) treatment history as predictors of response. RESULTS: Bispectral index was a strong predictor of CS1 and CS2 (P < 0.0001) and significantly more accurate than targeted or measured propofol concentrations (P < 0.0003 and P < 0.003, respectively). It also provided additional predictive power when combined with treatment history (P < 0.02). Nitrous oxide slightly decreased the probability of response at a given value of BIS (P < 0.05), but accuracy was unaffected. CONCLUSIONS: Bispectral index accurately predicts response to verbal commands during sedation and hypnosis with propofol or propofol plus nitrous oxide. Accuracy is maintained in situations likely to be encountered during clinical use: when propofol concentrations are increasing or decreasing and when repeated measurements are made over time.

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.

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)

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)

Acute myocardial infarction symptoms masked by epidural morphine?

This report describes the case of an 80-year-old woman with a long history of chronic, stable angina pectoris who underwent resection of an abdominal aortic aneurysm and placement of an aortobifemoral bypass graft under a combination of epidural and general anesthesia. Epidural morphine was administered postoperatively for pain management. The patient suffered a massive myocardial infarction (MI) in the immediate postoperative period but experienced no chest pain or discomfort similar to her usual anginal symptoms. The use of epidural and spinal opioids in the treatment of anginal pain is reviewed and discussed in terms of the possibility that such epidural opioid therapy may have masked this patient's anginal symptoms.

Azumolene reverses episodes of malignant hyperthermia in susceptible swine.

Azumolene is an analogue of dantrolene with much greater water solubility. Ten swine susceptible to malignant hyperthermia (MH) were triggered into MH episodes via the inhalation of halothane, and azumolene was effective in terminating all of the MH episodes. There was an inverse relationship between the dose of azumolene required to terminate the MH episode and the time it took for the pig to manifest the signs of MH. Azumolene was found to be similar in potency to dantrolene.

Ketamine does not trigger malignant hyperthermia in susceptible swine.

The use of ketamine in individuals susceptible to malignant hyperthermia (MH) is controversial. We describe our experience with ketamine used for induction and/or maintenance of anesthesia in our herd of swine inbred for susceptibility to MH. A total of 76 MH-susceptible swine were given a total of 112 general anesthetics using ketamine as the induction drug. In 34 of these anesthetics, anesthesia was also maintained with ketamine. Signs of MH did not develop in response to ketamine in any of the pigs.

Safety of amide local anesthetics in patients susceptible to malignant hyperthermia.

Earlier reports on malignant hyperthermia warned against the use of local anesthetics in the amide class in persons susceptible to the syndrome. The preponderance of data supports the safety of amide local anesthetics in such patients, and these agents should not be withheld from persons at risk for developing the syndrome.

Metabolic and morphologic effects of the antimicrobial agent nitrofurantoin on human erythrocytes in vitro.

We have reported previously that the antimicrobial nitrofurantoin stimulates superoxide production and methemoglobin formation from HbO2 as an isolated hemeprotein and in hemolysates [M. Dershwitz and R. F. Novak, J. biol. Chem. 257, 75 (1982); M. Dershwitz and R. F. Novak, J. Pharmac. exp. Ther. 222, 430 (1982)]. The production of hydrogen peroxide and methemoglobin by nitrofurantoin has been determined in normal erythrocytes in vitro. Hydrogen peroxide production increased 5-fold during a 20-hr incubation in the presence of 840 microM nitrofurantoin, while methemoglobin content increased to over 20% of the total hemoglobin concentration of the cells. Consequent metabolic and morphologic alterations also occurred. Concomitant with nitrofurantoin-stimulated hydrogen peroxide production were time- and concentration-dependent decreases in cellular levels of GSH and ATP, as well as alterations in red cell morphology. Significant differences in GSH and ATP levels between control and nitrofurantoin-treated erythrocytes occurred after 12 hr and proceeded maximally from 18 to 21 hr. After a 21-hr incubation, 840 microM nitrofurantoin caused the cellular GSH and ATP levels to fall 65 and 75%, respectively, while controls exhibited only 29 and 43% decreases in ATP and GSH levels, respectively. Studies on the concentration dependence of such decreases demonstrated that the EC50 values for depletion of GSH and ATP were similar in blood obtained from an individual donor. The EC50 values varied from approximately 10 microM to 100 microM among the various donors whose blood was studied. Incubation of normal red cells with nitrofurantoin also resulted in an increased conversion of red cells to echinocytes as observed by scanning electron microscopy. These metabolic effects, coupled with increased oxidative stress via hydrogen peroxide generation, lend support to the mechanism for nitrofurantoin-induced hemolysis in erythrocytes compromised by certain enzyme deficiencies which result in low basal levels of GSH or diminished rates of GSH synthesis.

Studies on the mechanism of nitrofurantoin-mediated red cell toxicity.

The mechanism of nitrofurantoin-mediated depletion of red cell reduced glutathione (GSH) was investigated. Nitrofurantoin caused cellular depletion of GSH in vitro under aerobic and oxygen-depleted conditions, an effect which could be partially inhibited by coincubation with the hemeprotein ligand ethyl isocyanide, or completely prevented by coincubation with 2'-AMP, an inhibitor of NADPH-dependent reductase enzymes. Covalent binding of nitrofurantoin to red cell macromolecules appeared to be a minor process and was not substantially inhibited by either ethyl isocyanide or 2'-AMP. Covalent binding was only slightly greater under oxygen-depleted conditions. Nitrofurantoin increased the rate of superoxide formation in red cell lysate, an effect inhibited by ethyl isocyanide but not by 2'-AMP. These data suggest different mechanisms for nitrofurantoin-mediated depletion of GSH under aerobic and oxygen-depleted conditions. In the presence of oxygen, nitrofurantoin causes the release of superoxide from oxyhemoglobin. The superoxide thus formed may deplete GSH via several mechanisms. In the absence of oxygen, nitrofurantoin is reduced to reactive metabolites via reactions which appear to require the participation of both an NADPH-dependent flavoprotein and hemoglobin.

Generation of superoxide via the interaction of nitrofurantoin with oxyhemoglobin.

Nitrofurantoin was found to interact with HbO2 to cause the concomitant formation of methemoglobin and superoxide. The rate of formation of methemoglobin and superoxide was linearly dependent upon the concentration of nitrofurantoin and could be inhibited by superoxide dismutase, catalase, or the prior conversion of HbO2 to ethylioscyanoferrohemoglobin. The ability of nitrofurantoin to interact with HbO2 and cause superoxide formation may represent one mechanism by which it produces red cell toxicity and suggests that generation of superoxide in erythrocytes may occur via a different mechanism than that which occurs in microsomes.