A multicenter evaluation of total intravenous anesthesia with remifentanil and propofol for elective inpatient surgery.

Remifentanil is a mu-opioid receptor agonist with a context sensitive half-time of 3 min and an elimination half-life < or = 10 min. This study sought to evaluate the efficacy of remifentanil and propofol total intravenous anesthesia (TIVA) in 161 patients undergoing inpatient surgery. Remifentanil 1 microgram/kg was given intravenously (i.v.) followed by one of two randomized infusion rates: small dose (0.5 micrograms.kg-1.min-1) or large dose (1 microgram.kg-1.min-1). Propofol (0.5-1.0 mg/kg i.v. bolus and 75 micrograms.kg-1.min-1 infusion) and vecuronium were also given. Remifentanil infusions were decreased by 50% after tracheal intubation. End points included responses (hypertension, tachycardia, and somatic responses) to tracheal intubation and surgery. More patients in the small-dose than in the large-dose group responded to tracheal intubation with hypertension and/or tachycardia (25% vs 6%; P = 0.003) but there were no other differences between groups in intraoperative responses. Recovery from anesthesia was within 3-7 min in both groups. The most frequent adverse events were hypotension (systolic blood pressure [BP] < 80 mm Hg or mean BP < 60 mm Hg) during anesthesia induction (10% small-dose versus 15% large-dose group; P = not significant [NS]) and hypotension (27% small-dose versus 30% large-dose group; P = NS), and bradycardia (7% small-dose versus 19% large-dose group; P = NS) during maintenance. In conclusion, when combined with propofol 75 micrograms.kg-1.min-1, remifentanil 1 microgram/kg i.v. as a bolus followed by an infusion of 1.0 microgram.kg-1.min-1 effectively controls responses to tracheal intubation. After tracheal intubation, remifentanil 0.25-4.0 micrograms.kg-1.min-1 effectively controlled intraoperative responses while allowing for rapid emergence from anesthesia.

A double-blind, placebo-controlled pilot study examining the effectiveness of intravenous ondansetron in the prevention of postoperative nausea and emesis.

STUDY OBJECTIVE: To compare the efficacy and safety profiles of ondansetron and a placebo when infused immediately prior to anesthesia induction for the prevention of postoperative nausea and emesis (vomiting or retching). DESIGN: Randomized, double-blind, placebo-controlled, parallel, multicenter pilot study. SETTING: Three U.S. ambulatory surgical facilities. PATIENTS: One hundred eighty ASA physical status I and II women scheduled to undergo ambulatory gynecologic surgical procedures while receiving general endotracheal anesthesia. INTERVENTIONS: Ondansetron 8 mg or a placebo (equivalent volume) was given intravenously (IV) prior to anesthesia induction to prevent postoperative nausea and vomiting. MEASUREMENTS AND MAIN RESULTS: For the first 24 hours following emergency from anesthesia, patients were monitored in the postanesthesia care unit by a research observer and at home via telephone contact and diary cards. More patients in the ondansetron group (62%) than in the placebo group (40%) were emesis-free over the 24-hour study period (p = 0.005). Ondansetron also was more efficacious than the placebo over the 24-hour study period when a surgery duration of more than 45 minutes was considered in the analyses. For all patients, regardless of surgery duration, there was a low degree of nausea during the course of the study. In all instances, the degree of nausea was slightly lower for ondansetron-treated patients than for placebo-treated patients; however, in no instances were the differences statistically significant. Ondansetron and placebo had similar safety profiles as established by laboratory test results, vital sign monitoring, and adverse event reporting. CONCLUSION: Ondansetron, infused IV before anesthesia induction, appears to be safe and effective when used in the prevention of postoperative nausea and emesis.

Comparison of ondansetron versus placebo to prevent postoperative nausea and vomiting in women undergoing ambulatory gynecologic surgery.

BACKGROUND: Postoperative nausea and emesis, especially in ambulatory surgical patients, remains a troublesome problem. This study was performed to compare the incidence of nausea and emesis during the 24-h postoperative period in ondansetron-treated patients versus placebo-treated patients. METHODS: Using a randomized prospective double-blind study design, women between the ages of 18 and 70 yr undergoing gynecologic surgical procedures with general opioid anesthesia on an outpatient basis were enrolled. Ondansetron or placebo was administered prior to induction of anesthesia. Patients were stratified according to history of nausea and emesis during previous exposure to general anesthesia and randomized to dose received. RESULTS: Data from the 544 women showed that all doses of intravenous ondansetron tested (1, 4, and 8 mg) were significantly more effective (62%, 76%, and 77%, respectively) than placebo (46%) in reducing the incidence of emesis following surgery until 24 h after recovery room entry. All these doses were more effective than placebo in patients with no prior history of emesis following surgery and the 4- and 8-mg doses were more effective than placebo in patients with a prior history of emesis following surgery. All doses of ondansetron tested were generally well tolerated with adverse events, clinical laboratory tests, and recovery room vital signs similar to those of placebo. Serum aspartate transaminase (AST) was increased in five patients (1 mg, 2 patients; 4 mg, 1 patient; 8 mg, 2 patients). In the three patients in whom subsequent analysis were performed, the serum AST had decreased to preoperative levels. CONCLUSIONS: Ondansetron given intravenously to prevent postoperative nausea and emesis was highly effective in the 4- and 8-mg doses in women having ambulatory gynecologic surgery.

Prophylactic intravenous ondansetron in female outpatients undergoing gynaecological surgery: a multicentre dose-comparison study.

The efficacy and safety of prophylactic intravenous ondansetron in preventing postoperative nausea and vomiting was investigated in a randomized, stratified, double-blind, placebo-controlled, dose-comparison study of 580 ASA physical class I and II female outpatients undergoing gynaecological surgery and receiving general anaesthesia. Patients received either ondansetron 1, 4 or 8 mg, or placebo i.v. immediately prior to a standardized technique for induction and maintenance of anaesthesia. All patients were intubated and received nitrous oxide and a narcotic. All doses of ondansetron were significantly more effective than placebo in preventing emesis over the 24 h postoperative period. Ondansetron significantly decreased nausea and emesis scores over 24 h postoperatively without causing sedation. No changes in laboratory parameters (haematology, blood chemistry, and liver enzymes) or vital signs (heart rate, blood pressure, and respiratory rate) were observed. Headache and dizziness were the most common side-effects; however, their incidence was the same as with placebo. Ondansetron was generally well tolerated, as evidenced by an adverse event, laboratory safety, and vital sign profile similar to placebo. Ondansetron 4 mg was found to be the optimal prophylactic i.v. dose for female outpatients over the entire 24 h postoperative period. Higher doses may offer an added benefit in some patients, such as those with a history of nausea and vomiting following general anaesthesia.

Neuromuscular and cardiovascular effects of pipecuronium.

Pipecuronium bromide (Arduan) is a bisquaternary, steroid-type neuromuscular blocking agent in clinical use in Eastern Europe. Before its introduction into clinical practice in the USA, in the first phase of this study the neuromuscular potency of pipecuronium was determined under "balanced" and enflurance anaesthesia by the cumulative log dose-response method in 30 patients each. In the second phase the intubation and onset times, clinical duration of the first and repeated doses, spontaneous recovery index, reversibility of its residual neuromuscular effect by an anticholinesterase and its effect on heart rate and blood pressure was compared with the same variables observed in patients, anaesthetized with identical techniques but who had received vecuronium or pancuronium. The neuromuscular potency of pipecuronium was greater under enflurane (ED95 = 23.6 +/- 1.1 micrograms.kg-1 (mean +/- SEM)] than under balanced (ED95 = 35.1 +/- 17 micrograms.kg-1) anaesthesia. Pipecuronium was more potent than vecuronium under both balanced (ED95 = 45.8 micrograms.kg-1) and enflurane anaesthesia (ED95 = 27.4 micrograms.kg-1). Following the administration of 2 x ED95 doses there were no clinically significant differences in the intubation or onset times of pipecuronium, vecuronium and pancuronium. Under balanced anaesthesia the clinical duration of 2 x ED95 dose of pipecuronium (110.5 +/- 0.3 min) or pancuronium (115.8 +/- 8.1 min) were similar and about three times longer than that of vecuronium (36.3 +/- 2.1 min). The recovery indices of pipecuronium (44.5 +/- 8.2 min) and pancuronium (41.3 +/- 4.2 min) were also similar and about three times longer than that of vecuronium (14.3 +/- 1.4 min).(ABSTRACT TRUNCATED AT 250 WORDS)

In vitro comparison of the neuromuscular antinicotinic and intestinal antimuscarinic effects of different nondepolarizing muscle relaxants.

The postsynaptic antimuscarinic properties of different nondepolarizing muscle relaxants were compared with their postsynaptic antinicotinic effect. d-Tubocurarine, pipecuronium and vecuronium were the most selective antagonists on postsynaptic nicotinic receptors. Gallamine, diadonium and Duador (RGH-4201) had relatively greater effect on postsynaptic muscarinic receptors. Therefore, much less side effect is expected to occur when pipecuronium, d-tubocurarine or vecuronium are used.

Presynaptic effect of muscle relaxants on the release of 3H-norepinephrine controlled by endogenous acetylcholine in guinea pig atrium.

The influence of nondepolarizing muscle relaxants (MR) on the resting and electrically evoked release of tritiated norepinephrine (3H-NE) was investigated, in the absence and presence of 10(-4) mol/l cocaine, in the in vitro right atrium preparation of guinea pigs (g.p.) preloaded with 3H-NE. In the absence of MR both resting and stimulated 3H and 3H-NE release remained relatively constant throughout the experiment and the ratios of the evoked release of 3H during consecutive stimulation periods (i.e. S2/S1, S3/S2) were close to unity. None of the MR had any effect on resting 3H release. Atropine (3 x 10(-7) mol/l), gallamine (7 x 10(-5) mol/l), and pancuronium (2 x 10(-6) mol/l), but not d-tubocurarine (5 x 10(-6) mol/l) significantly increased stimulated release of 3H-NE. The effect of MR on resting or evoked release of 3H-NE was not influenced by 10(-4) mol/l cocaine. In the presence of atropine gallamine and pancuronium did not affect the release of 3H-NE. This finding indicates that the effect of MR was mediated via presynaptic muscarinic receptors. Muscle relaxants and atropine inhibited these receptors and removed the tonic inhibitory effect of acetylcholine (ACh) released from the parasympathetic nerve endings on the release of NE from the sympathetic nerve. This was substantiated by the finding that in the present of cholinesterase inhibition, when the effect of endogenous ACh was amplified and thereby the cholinergic tone was dominant, the total release of 3H-NE evoked by stimulation was much lower and muscle relaxants and atropine were much more effective to enhance 3H-NE release. Gallamine and pancuronium also increased the force of contraction of the electrically stimulated atria. These findings indicate that the acceleration of the heart rate observed with gallamine and pancuronium in anesthetized man is due to increased release from, and not the inhibition of reuptake of NE by the sympathetic nerve endings of the right atrium.

A simple method for monitoring muscular relaxation during continuous infusion of vecuronium.

There is considerable individual variation in the dose of vecuronium required for the maintenance of surgical relaxation. Therefore to provide uninterrupted relaxation without overdosage it is advisable to regulate the IV infusion of vecuronium on the basis of appropriate monitoring. Monitoring with mechanomyography (MMG) or electromyography requires costly equipment and is too complex for routine clinical use. Visual observation of the adductor pollicis muscle contracting against zero resistance is not suitable for the reliable assessment of the degree of neuromuscular (NM) block. For clinical purposes satisfactory monitoring can be achieved with the simple device (Myoscan) described. The reliability of the Myoscan was tested in 30 patients by simultaneous monitoring of the force of contraction of the adductor pollicis on one side with the Myoscan and on the contralateral side with the MMG. Retrospective analysis of the MMG indicated that the conduct of anaesthesia would have been virtually the same if it would have been based on MMG monitoring.

Modulation of stimulation-evoked release of newly formed acetylcholine from mouse hemidiaphragm preparation.

A radioisotope method has been developed for measuring the stimulation-evoked release of acetylcholine without the use of cholinesterase inhibitors from the mouse hemidiaphragm preparation which had been loaded with 3H-choline. Evidence has been obtained that 3H-choline was taken up by and released from both innervated and non-innervated mouse hemidiaphragm preparations. However, it was released in the form of 3H-acetylcholine in response to electrical field stimulation only from the innervated preparations. Long lasting (51 min) S1 stimulation of the preparations exhausted the radioactive acetylcholine stores to the extent that S2 did not evoke any release of 3H. These data suggest that when the labelled acetylcholine stores become exhausted, the labelled choline, still present in the tissue, cannot be released by electrical stimulation. Tetrodotoxin (1 mumol/l) administration and Ca withdrawal inhibited, 20-100 mumol/l 4-aminopyridine enhanced the release of 3H-acetylcholine in response to electrical stimulation. Activation of the presynaptic muscarinic receptors by the agonist oxotremorine (50 mumol/l) decreased the liberation of 3H-acetylcholine. The muscarinic antagonist atropine (1 mumol/l) abolished the inhibitory effect of oxotremorine and by itself increased the evoked release of the newly formed 3H-acetylcholine. Adenosine (50 mumol/l) reduced the evoked release of radioactivity. Theophylline (30 mumol/l) prevented the inhibitory effect of adenosine and itself enhanced the release. Xylazine (1 mumol/l), an alpha 2-adrenoceptor agonist did not affect the release. It is concluded that the stimulation-evoked release of 3H-acetylcholine from the mouse phrenic nerve hemidiaphragm preparation preloaded with 3H-choline is derived from the motor nerves. The release of acetylcholine is modulated by activation of presynaptic muscarinic and adenosine receptors.

Effect of mono- and diaminopyridines on release of [3H]norepinephrine from isolated guinea-pig atrium.

Neurochemical evidence has been obtained that 4-aminopyridine, 3,4-diaminopyridine and 3,3-dimethyl-1-(4-amino-3-pyridyl)urea HBr (LF-14), concentration-dependently enhanced the stimulation-evoked release of [3H]norepinephrine ([3H]NE) from isolated guinea-pig atrium. The effects of aminopyridines, compounds known to inhibit potassium channels, were Ca0-dependent. High pressure liquid chromatography, combined with radiochemical detection, indicated that the increased stimulated release of radioactivity was due to [3H]NE. Since the aminopyridines studied also enhanced the release of [3H]NE from atrium treated with cocaine, a blocker of uptake1, it seems likely that the increased release of NE caused by the aminopyridines is due to the enhanced release of NE from sympathetic axon terminals and not to the inhibition of reuptake. It is probable that the sympathomimetic cardiac effects (positive inotropic and chronotropic effect) of aminopyridines observed in animal experiments is due to the increased release of NE, caused by these compounds.

Tubocurarine and pancuronium inhibit evoked release of acetylcholine from the mouse hemidiaphragm preparation.

Using a sensitive radioactive method that measures selectively the evoked release of acetylcholine, it was demonstrated that, when stimulating at 50 Hz, tubocurarine or pancuronium 2 X 10(-5) mol litre-1 or hexamethonium 10(-3) mol litre-1 significantly decreased the evoked release of acetylcholine in the mouse in vitro phrenic nerve-hemidiaphragm preparation.

Direct evidence that pancuronium and gallamine enhance the release of norepinephrine from the atrial sympathetic nerve by inhibiting prejunctional muscarinic receptors.

The effect of different non-depolarizing muscle relaxants (gallamine, pancuronium, vecuronium, D-tubocurarine) on [3H]norepinephrine release in response to electrical stimulation was studied in isolated guinea-pig atrium. High pressure liquid chromatography combined with electrochemical and radiochemical detection revealed that the released radioactivity was mainly in the form of [3H]norepinephrine release. Oxotremorine, a pure muscarinic agonist, reduced the release of tritium. Gallamine and pancuronium, like atropine, prevented the inhibitory effect of oxotremorine. D-Tubocurarine and vecuronium had no such effect. These findings indicate that gallamine and pancuronium exert a presynaptic antimuscarinic, atropine-like effect, by inhibiting muscarinic receptors located on the axon terminals of sympathetic neurons thereby enhancing norepinephrine release. It is suggested that this phenomenon might play some role in tachycardia observed during surgical anaesthesia when gallamine or pancuronium have been administered.

Electrochemical determination of histamine derivatized with o-phthalaldehyde and 2-mercaptoethanol.

High-performance liquid chromatography coupled with electrochemical detection was used to determine histamine following precolumn derivatization with o-phthalaldehyde (OPA) and 2-mercaptoethanol. The isoindole derivative which is obtained as reaction product was electrochemically active at a moderate potential (peak potential +0.4 V). Direct oxidation of histamine required a much higher potential (peak potential +1.05 V) and was of no practical use. No electrochemical signal was observed for the reaction product of histamine with OPA. Changing the pH of the mobile phase had little effect on the electrochemical response of the isoindole derivative of histamine, which was well separated from analogous derivatives of methylated histamines, mono- and polyamines and amino acids by isocratic elution from a reversed-phase column. An example of a practical application of the method to the estimation of histamine in rat brain is presented.

Determination of histamine concentrations in plasma by liquid chromatography/electrochemistry.

Histamine was extracted from deproteinized plasma with Amberlite CG 50 weak cation-exchange resin (analytical recovery of [3H]histamine, 60.5%). The eluate was evaporated and histamine in the redissolved sample was condensed with o-phthalaldehyde and 2-mercaptoethanol at pH 11.5. This adduct was separated by liquid chromatography under isocratic conditions and oxidized on a glassy carbon electrode at +0.4 V for electrochemical detection. 3-Methylhistamine was used as internal standard. As little as 0.45 pmol of standard histamine condensate was detected. The histamine concentration in 88 human plasma samples appeared to be normally distributed; its mean value was 7.20 (SD 2.61) nmol/L. Authentic and extracted histamine produced similar hydrodynamic voltammograms, and exogenous and endogenous histamine gave identical chromatographic characteristics with different mobile phases or different chromatographic columns. Standard and extracted histamine had similar degradation rates when samples were incubated with diamine oxidase (EC 1.4.3.6). Analytical recovery of known amounts of histamine added to pooled plasma was 97.7% (SD 22.3%). The inter- and intra-assay CVs for histamine determinations were 9.0% and 8.6%, respectively.

A simple and sensitive method of acetylcholine identification and assay. Bioassay combined with minicolumn gel filtration or high-performance liquid chromatography.

A modified technique of acetylcholine assay on the guinea pig ileum has been combined with either minivolume gel filtration or high-performance liquid chromatography separation of the samples. In addition, labeled acetylcholine (14C-ACh) was eluted with unlabeled acetylcholine or with the samples expected to contain acetylcholine, and their elution profiles were compared by bioassay plus radioassay of eluate fractions. When the elution of both biological activity and label occurred in the same eluates, it was concluded that the substance assayed on guinea pig ileum was acetylcholine. The method was sensitive to 0.5 ng (1.8 pmol) of acetylcholine and its reproducibility was within 5%. It thus represents a substantial improvement in chemical specificity over the previous bioassay method described by Paton and Vizi (1969).

Presynaptic inhibitory effect of Met-enkephalin on [14C] acetylcholine release from the myenteric plexus and its interaction with muscarinic negative feedback inhibition.

The effect of Met-enkephalin on the release of radioactivity (14C) from a myenteric plexus-longitudinal muscle preparation loaded with [14C]choline has been investigated under different conditions, when the muscarinic receptor mediated negative feedback inhibition was operative or when it was completely excluded by atropine. Separation of the [14C]acetylcholine (ACh) and [14C] choline components of the released radioactivity revealed that during 45-min incubation periods about 3.2% of the ACh store became labeled and that during stimulation only the release of [14C]ACh increased above resting level. The fractional release at rest measured in the 5-min collection period was 1.07 +/- 0.09 X 10(-2) in the absence and 1.56 +/- 0.07 X 10(-2) in the presence of physostigmine. Met-enkephalin had no effect on the release of ACh evoked by a 2-Hz stimulation when cholinesterase was inhibited by physostigmine. However, in the presence of atropine or in the absence of cholinesterase inhibition, the release by stimulation was significantly higher and subject to inhibition by Met-enkephalin. The present results indicate that Met-enkephalin is able to reduce ACh release only under those conditions in which the negative feedback modulation is negligible and the release is not yet reduced completely. These findings also suggest that in the myenteric plexus there is no independent population of cholinergic neurons exclusively sensitive to either ACh or to Met-enkephalin; cholinergic varicosities are equipped with at least both types of receptors we studied. When the effect of Met-enkephalin on twitch tension and on the release of radioactivity was studied simultaneously, a positive correlation was found.(ABSTRACT TRUNCATED AT 250 WORDS)

Common bile duct pressure changes after fentanyl, morphine, meperidine, butorphanol, and naloxone.

Five groups of 10 patients received thiamylal, enflurane, nitrous oxide-oxygen anesthesia for elective cholecystectomy. The common bile duct was intubated via the cystic duct with a 16-g plastic catheter, and the control intraductal pressure was measured. Patients then were given equi-analgesic doses of fentanyl, morphine, meperidine, butorphanol, or placebo intravenously, and the common bile duct pressure was recorded for 20 min. Fentanyl, morphine, and meperidine significantly increased pressure in the common duct (P less than 0.001). Butorphanol produced only insignificant changes. Naloxone given 20 min later significantly (P less than 0.001) decreased pressure in patients given fentanyl, morphine, and meperidine. Naloxone given without narcotics caused an increase in pressure that, although statistically significant (P less than 0.03), was clinically insignificant. In five additional patients anesthetized with thiamylal, nitrous oxide-oxygen and intermittent doses of fentanyl, common bile duct pressures were normal.