Comparison of the analgesic effects of intrabursal oxycodone and bupivacaine after acromioplasty.

STUDY OBJECTIVES: To compare the peripheral analgesic effect of oxycodone, an opioid agonist, to the effect of bupivacaine infiltration and parenteral oxycodone administration in conjunction with shoulder surgery. DESIGN: Prospective, randomized, double-blind study. SETTING: University teaching hospital. PATIENTS: 42 ASA physical status I and II patients scheduled for shoulder surgery with general anesthesia. INTERVENTIONS: Patients were randomized to three study groups: at the end of the surgery patients received either 10 ml of 0.5% bupivacaine (group BIB) or 5 mg of oxycodone in 10 ml of saline (group OIB) in the subacromial bursa; or 5 mg of oxycodone intramuscularly (group OIM). Postoperative analgesia was provided by patient-controlled analgesia (PCA). MEASUREMENTS AND MAIN RESULTS: The fentanyl requirements were recorded for the 24-hour postoperative period and the total perioperative period. Postoperative pain was assessed by visual analog scale for pain (VASP). Plasma oxycodone concentrations were measured in groups OIB and OIM. The total perioperative fentanyl consumption was significantly lower in groups BIB (0.97 +/- 0.09 mg) and OIB (1.23 +/- 0.12 mg) than in group OIM (1.61 +/- 0.12 mg) (p = 0.01 and 0.048, respectively). Groups BIB and OIB were similar (p = 0.34). The absorption of oxycodone was significantly lower after subacromial than after intramuscular administration. CONCLUSION: Intrabursal oxycodone and intrabursal bupivacaine reduced perioperative analgesic requirements similarly. Intrabursal oxycodone may offer an effective, simple, and safe method for postoperative analgesia after shoulder surgery.

The effect of clonidine or midazolam premedication on perioperative responses during ketamine anesthesia.

UNLABELLED: The use of ketamine as a sole anesthetic induces marked central sympathetic stimulation, causing increased heart rate, blood pressure (BP), and oxygen consumption (VO2). Both alpha 2-agonists and benzodiazepines have been used to attenuate these potentially harmful ketamine-induced responses. This double-blind, randomized, placebo-controlled study was designed to compare the perioperative metabolic, hemodynamic, and sympathoadrenal responses to IM clonidine (2 micrograms/kg) and midazolam (70 micrograms/kg) premedication during ketamine anesthesia. VO2 was measured continuously using indirect calorimetry in 30 ASA physical status I patients. The patients received ketamine, mivacurium, and fentanyl for the induction of anesthesia. Anesthesia was maintained using a ketamine infusion and fentanyl boluses i.v. Preoperatively, both VO2 and BP decreased significantly after the administration clonidine and midazolam compared with placebo (P < 0.01). Intraoperatively, VO2 was higher in the midazolam group than in the placebo and clonidine groups (P < 0.05). Postoperatively, there were no significant differences in BP and VO2, although they stayed at lower level in the clonidine group during the whole postoperative period. Clonidine decreased pre- and postoperative plasma catecholamine concentrations (P < 0.05). Our results indicate that a midazolam-ketamine combination may induce potentially harmful metabolic stimulation, whereas the sympatholytic effects of clonidine on ketamine-anesthetized patients may be beneficial, as perioperative VO2 was decreased. IMPLICATIONS: Ketamine causes sympathetic stimulation with an ensuing increase in oxygen consumption. Anticipating that clonidine might attenuate this response, we measured oxygen consumption in patients undergoing surgery during ketamine anesthesia. Patients treated with a clonidine-ketamine combination had lower intra- and postoperative oxygen consumption than those treated with a midazolam-ketamine combination.

Effect of clonidine and dexmedetomidine premedication on perioperative oxygen consumption and haemodynamic state.

Premedication has been shown to affect both oxygen consumption and metabolic rate. We have compared the perioperative metabolic and haemodynamic effects of two alpha 2-agonists, clonidine and the more selective dexmedetomidine, in 30 ASA I patients undergoing plastic surgical procedures under general anaesthesia. Patients were premedicated with clonidine 4 micrograms kg-1 (n = 10), dexmedetomidine 2.5 micrograms kg-1 (n = 10) or saline (n = 10) i.m. The doses of clonidine and dexmedetomidine were intended to be equipotent. The maximum decrease in preoperative oxygen consumption was 8% and decreases in systolic and diastolic arterial pressures were 11% from baseline after clonidine and dexmedetomidine. During operation, the maximum reduction in heart rate was 18% in the clonidine and dexmedetomidine groups compared with the placebo group. After operation, the maximum decrease in systolic arterial pressure was 11%, diastolic arterial pressure 15% and oxygen consumption 17% in the clonidine and dexmedetomidine groups compared with placebo. In summary, both clonidine 4 micrograms kg-1 and dexmedetomidine 2.5 micrograms kg-1 decreased perioperative oxygen consumption effectively, with a similar haemodynamic profile.

The sedative and sympatholytic effects of oral tizanidine in healthy volunteers.

Tizanidine, an imidazoline derivative with alpha 2-receptor-mediated central muscle relaxant activity, is in widespread clinical use for the treatment of spasticity. To evaluate its possible role in anesthesia we assessed the sedative and sympatholytic effects of orally administered tizanidine in a double-blind, placebo-controlled, randomized, cross-over study in six healthy male volunteers. Three different doses of tizanidine (4, 8, and 12 mg) were tested and compared to clonidine 150 micrograms. The sedative and sympatholytic effects of tizanidine 12 mg were comparable in magnitude to those of clonidine 150 micrograms, but the effects of clonidine were longer lasting. Similarly, the observed decreases in arterial blood pressure (diastolic, 13% and 19%; systolic, 10% and 8% for tizanidine and clonidine, respectively) and salivation were comparable in magnitude but of shorter duration after tizanidine 12 mg than after clonidine. Clonidine and tizanidine 12 mg had also similar effects on the secretion of growth hormone. Our results indicate that the effects of a single 12-mg oral dose of tizanidine resemble those of 150 micrograms oral clonidine, but are of shorter duration. Tizanidine may thus be a useful alternative to clonidine as an orally active, short-acting alpha 2-adrenoceptor agonist in the perioperative period.

Anticholinergic drugs: effects on oxygen consumption and energy expenditure.

Premedication has been shown to affect both oxygen consumption (VO2) and energy expenditure (EE). The metabolic responses to anticholinergic drugs have not been studied. In this study the effects of anticholinergic drugs on VO2 and EE (calculated from the measured rates of VO2 and carbon dioxide production [VCO2]: EE [kcal/d] = 3.581 x VO2 [L/d] + 1.448 x VCO2 [L/d] - 32.4) were measured in six healthy female volunteers. They were given intramuscular atropine (15 micrograms/kg), glycopyrrolate (8 micrograms/kg), scopolamine (8 micrograms/kg), and placebo in a random double-blind cross-over design. The consecutive sessions were at least 1 wk apart for each subject. VO2 and EE were measured using an indirect calorimetry (Deltatrac). Cardiovascular responses were assessed using standard noninvasive monitoring. Plasma drug concentrations were analyzed using a sensitive modification of radioreceptor assay. Subjective responses were measured with visual analog scale (VAS). Atropine and glycopyrrolate induced a significant increase in heart rate with a simultaneous decrease in pressure rate quotient (PRQ), while scopolamine caused a significant decrease in heart rate with a simultaneous increase in PRQ. Scopolamine significantly decreased both VO2 and EE, whereas glycopyrrolate increased VO2. Atropine had no significant effect on metabolic variables. Only scopolamine induced sedation in this study. In conclusion, atropine, glycopyrrolate, and scopolamine differ not only in their cardiovascular and central nervous system effects, but also in their effects on metabolism.

Clinical and metabolic responses to different kinds of premedication in ASA III patients.

Clinical and metabolic responses to atropine plus pethidine and to scopolamine plus morphine premedication were studied in 45 ASA physical status III patients undergoing gynaecological procedures. Atropine 0.5 mg plus pethidine 50 mg intramuscularly (Group 1), scopolamine 0.24 mg plus morphine 8 mg (Group 2), or intramuscular placebo (Group 3) premedication were given in random, double-blind fashion. Scopolamine-morphine premedication caused a significant decrease in energy expenditure (EE) and oxygen consumption (VO2) (from 1229 +/- 193 to 1184 +/- 221 kcal/24 h, P = 0.004 and from 105 +/- 11 to 102 +/- 12 ml/min/m2, P = 0.006, respectively) simultaneously with a decrease in rate-pressure product (RPP) (P = 0.0001) and an increase in pressure-rate quotient (PRQ) (P = 0.034). Atropine-pethidine premedication induced a decrease in RPP but not in EE or VO2. In the placebo group both RPP and VO2 first increased and then slowly returned to the levels measured prior to premedication. The RPP was significantly lower in Group 2 than in Groups 1 and 3 at both 30 and 60 min. The degrees of subjective tiredness and anxiolysis were significantly greater in Groups 1 and 2 (showing good sedative and anxiolytic effect) than in Group 3. These results show that in ASA III patients, atropine-pethidine premedication does not decrease the sympathoadrenal reaction to the degree its anxiolytic and sedative effect would suggest. This may indicate neuroendocrine stress induced by atropine-pethidine.

Premedication for outpatient cataract surgery: a comparative study of intramuscular alfentanil, midazolam and placebo.

The effects of i.m. alfentanil and midazolam on anxiety, sedation, hemodynamics, oxygen saturation and intraocular pressure were studied in 90 patients scheduled for outpatient cataract surgery with regional anesthesia. The study was randomized, double-blind, placebo-controlled, and performed on outpatients with ASA physical status I-III and mean age 67.7 +/- 11.7 years. Alfentanil (12.5 micrograms/kg) administered into the deltoid muscle had a marked anxiolytic and short sedative effect, and was associated with stable hemodynamics. Midazolam (20 micrograms/kg) administered similarly had a more prolonged anxiolytic and sedative effect, which impaired co-operation in some patients during surgery. The regional blockade was associated with a significant reduction of oxygen saturation (SpO2), regardless of the premedication used (P less than 0.05). A slight reduction of intraocular pressure (IOP) was found after premedication, but the change was not statistically significant. We conclude that i.m. alfentanil is well tolerated, and its anxiolytic and short sedative effects make it especially suitable as premedication for day-case cataract surgery.

Clinical interactions with alpha-2-adrenergic agonists in anesthetic practice.

With the continued use of alpha-2-adrenergic agonists in anesthetic practice, careful attention should be given to the potential for drug interactions. Based on a review of the basic and applied pharmacology of this class of compound, we have made recommendations for the safe and efficacious use of alpha-2-adrenergic agonists in the clinical setting.

Clinical and metabolic responses to different types of premedication.

Clinical and metabolic responses to three types of premedication were studied in ASA physical status I patients given any one of the following: (a) 0.5 mg of atropine and 50 mg of meperidine given intramuscularly plus an oral placebo tablet (n = 14), (b) 10 mg of oral diazepam and an intramuscular placebo (2 mL NaCl, concentration = 0.9) (n = 14), or (c) oral and intramuscular placebo (n = 14). Based both on subjective estimates (tiredness, fear, anxiety, dryness of mouth) and, especially, on metabolic responses (energy expenditure, oxygen consumption), oral diazepam appears to be superior to the combination of an opiate (meperidine) plus an anticholinergic (atropine). Atropine plus meperidine significantly increased energy expenditure above predicted values (2061 +/- 365 vs 1714 +/- 361 kcal/24 h, P = 0.004), calculated using the Harris-Benedict equation, based on sex, weight, height, and age, as well as increased oxygen consumption above levels seen with diazepam premedication (160 +/- 29 vs 137 +/- 17 mL.min-1. m-2). These findings indicate an iatrogenic stress factor induced by premedication with atropine plus meperidine.

Dexmedetomidine premedication for minor gynecologic surgery.

The effects of four different doses (0.167, 0.33, 0.67, and 1.0 microgram/kg) of dexmedetomidine, a novel alpha 2-adrenoceptor agonist, on anesthetic requirements, hemodynamics, and plasma catecholamine levels were investigated in a single-blind fashion in 20 healthy (ASA physical status I) women scheduled for uterine dilatation and curettage. The drug was administered intravenously 15 min before anesthesia induction with thiopental. Nitrous oxide/oxygen (70%/30%) was used for maintenance. Dexmedetomidine was well tolerated, and no serious drug-related subjective side effects or adverse events were observed. The most prominent subjective effects were tiredness and decreased salivation. The total amount of thiopental needed to perform uterine dilatation and curettage was decreased dose-dependently from 400 +/- 166 mg (mean +/- SD) after 0.167 microgram/kg of dexmedetomidine to 180 +/- 65 mg after 1.0 micrograms/kg of dexmedetomidine (P = 0.028). Blood pressure, heart rate, and plasma norepinephrine levels were reduced after dexmedetomidine. The optimal dose of dexmedetomidine for single-dose intravenous premedication studies in minor surgery appears to be in the range of 0.33-0.67 micrograms/kg.

Propofol, the newest induction agent of anesthesia.

Propofol is a rapidly acting intravenous anesthetic agent which has many advantageous kinetic properties explaining its usefulness by bolus dose for induction of anesthesia or for administration by continuous intravenous infusion. It is rapidly distributed in the body with a half-life of only around 2 min and has an efficient hepatic and extrahepatic clearance (total body clearance may exceed liver blood flow). Premedication has little effect on the already good induction characteristics of propofol. The incidence of cardiorespiratory depression appears to be higher than that of other induction agents, but, on the other hand, the absence of tachycardiac response prevents the increase in cardiac oxygen demands. In patients with cardiac disease, especially after high or repeated doses, propofol may be more depressant to the cardiovascular system than thiopentone resulting in imbalance of regional myocardial oxygen demand and supply. Recovery from propofol is rapid and clear-headed with almost no hangover effect. This makes it very suitable for out-patient anesthesia and for cardioversion. However, even with the new emulsion formulation of the drug, pain on injection is still a problem. With regard to a longer lasting combination anesthesia propofol remains an alternative to older induction agents. When given as a continuous intravenous infusion for total intravenous anesthesia or for sedation in intensive care unit propofol has shown little accumulation. Its clinical effects are predictable, consistent and recovery is rapid, independent of the dose given. Propofol has proved to be a useful induction agent regardless of the age of patients, but in the elderly there appears to exist a marked sensitivity to it. Up to now there is no evidence that propofol in emulsion drug form can produce allergic or anaphylactoid reaction more often than other induction agents in use and no severe hematological nor visceral toxicity have been reported. In the present situation, when althesin is not marketed any more due to a high frequency of anaphylactoid reactions and etomidate will have a limited use in clinical practice because of its blocking effect on adrenocortical function, propofol offers an important alternative anesthetic agent to thiopentone.

Oral isosorbide-5-mononitrate: pharmacokinetics and clinical efficacy.

Isosorbide-5-mononitrate is a longer acting active metabolite than the parent drug, isosorbide dinitrate (ISDN), with a half-life of around 4 hours. In coronary heart disease, myocardial infarction and in heart failure it causes a typical nitrate action on the central hemodynamics, but due to a complete systemic availability with high and predictable systemic drug levels, a drug action with a lower interindividual variability than with ISDN is to be expected. There is a close correlation between serum level and effect. The antianginal exercise tolerance increasing and unwanted effects as well as the development of tolerance to the drug action are comparable with those of ISDN. This naturally long-acting metabolite in ISDN works usually with a standard dosage of 20 mg twice daily.

Labetalol in the treatment of angina pectoris.

The present review shows that labetalol has many advantageous properties in the treatment of patients suffering from angina pectoris with or without hypertension. These patients respond with vasoconstriction to a variety of internal and external influences. The selective alpha 1-blocking component in addition to the non-selective beta-blockade of labetalol attenuates the increased coronary vascular resistance and improves coronary haemodynamics especially under stress in a manner which should be favourable in myocardial ischaemia. In addition, the alpha 1-blocking component may prevent different kinds of arrhythmias generated by alpha-adrenoceptor stimulation. Labetalol has no effect on renal blood flow, glomerular filtration rate, plasma electrolyte concentrations, glucose tolerance, lipoprotein cholesterol ratio, renin-angiotensin-aldosterone system, uric acid levels, or on platelet aggregation. Intravenously administrated labetalol has proved to be effective in patients with acute myocardial infarction, especially if associated with hypertension. In order to avoid postural hypotension, oral treatment should be started with a low dose of 100 mg twice daily. The usual dosage in patients without hypertension is 200 mg twice daily, but in patients with hypertension doses up to 1200 mg or even more have been used. In low doses up to 400 mg daily, the unwanted effects are few and often self-limited. High doses can cause side effects related to both beta- and alpha-blocking properties of labetalol. As an antianginal agent labetalol has proved to be at least as effective as selective or non-selective beta-blockers.

Simultaneous determination of bupivacaine and its two metabolites, desbutyl- and 4'-hydroxybupivacaine, in human serum and urine.

A sensitive and selective high-performance liquid chromatographic (HPLC) method for the determination of bupivacaine and its two metabolites, desbutyl- and 4'-hydroxybupivacaine, in human serum and urine is described. Bupivacaine, both metabolites and the internal standard, etidocaine, are extracted with diethyl ether and then back-extracted into an acidic aqueous phase. After subsequent extraction into diethyl ether, evaporation and reconstitution in the mobile phase, bupivacaine and the metabolites are determined by HPLC using a reversed-phase C8 column with tetrahydrofuran-potassium phosphate buffer (8:92, v/v, pH 2.4) as the mobile phase. The sensitivity of the method is 10 micrograms/l for bupivacaine and both metabolites and the extraction efficiencies are 95, 54 and 92% for bupivacaine and desbutyl- and 4'-hydroxybupivacaine, respectively. The reproducibility of the method is good, the coefficients of variation varying between 1.8 and 7.4% in the concentration range 0.10-2.00 mg/l. The procedure was applied to human serum and urine samples from two elderly women who had been operated on under epidural analgesia (plain bupivacaine, 1.5 mg/kg) because of uterine prolapse.

Pharmacokinetics and clinical effects of scopolamine in caesarean section patients.

A new method (ELISA) was used to evaluate the pharmacokinetics of scopolamine following intravenous (0.005 mg/kg), intramuscular (0.01 mg/kg), and oropharyngeal (0.035 mg/kg) administration of the drug to pregnant patients anaesthetized for caesarean section. After intravenous (N = 4) the drug fast disappeared from the circulation with a half-life of about 5 min., and the serum levels generally were measurable up to 3 hours, mean elimination half-life was 1.85 hours. A fast absorption was found after intramuscular injection, tmax = 10 min. (N = 4), and the drug had a clinically significant oropharyngeal absorption as well, tmax was around 1 hour (N = 6). The intramuscular and oropharyngeal, but not the intravenous, administrations produced a marked postoperative sedative and amnesic effects. All three administration ways caused a significant antisecretory action.

Current status of labetalol, the first alpha- and beta-blocking agent.

Labetalol is a unique antihypertensive agent which is a competitive peripheral antagonist at both alpha- and beta-adrenoceptor sites. Clinically, it possesses about one fourth of the beta-adrenoceptor blocking activity of propranolol and one half of the alpha-adrenoceptor blocking activity of phentolamine with a beta- to alpha-blocking ratio of approximately 7:1. Nowadays, the clinical profile of labetalol is clearly defined. Perorally, it has often been used in the treatment of mild, moderate and severe hypertension and intravenously in the management of hypertensive emergencies. It offers many advantages over beta-blockers with no prominent side-effects. Hemodynamically, labetalol reduces blood pressure, heart rate and, first of all, peripheral resistance with almost no change in resting cardiac output or stroke volume. Labetalol appears to be useful particularly in patients whose blood pressure is not adequately controlled by beta-blockers alone or combined with a diuretic, but sometimes at the expense of postural hypotensive side-effects. It has proved to be safe in patients with coronary artery disease or after acute myocardial infarction and in pregnant patients, but in phaechromocytoma further clinical experience is needed. In induced hypotension during anesthesia and surgery no invasive blood pressure measurements are needed. The most frequent adverse effects include fatigue, postural hypotension, headache and gastrointestinal complaints. On the whole, labetalol expands the armamentarium of the practising physician in the treatment of hypertension of different origin.

Midazolam: the first water-soluble benzodiazepine. Pharmacology, pharmacokinetics and efficacy in insomnia and anesthesia.

Midazolam is a 1,4-benzodiazepine derivative with a unique chemical structure: depending on environmental pH, the drug can produce highly water-soluble salts (pH less than 4) or exist in lipophilic diazepine ring-closed form (pH greater than 4). This characteristic contributes to rapid onset of action and to good local tolerance after parenteral administration. After both oral and parenteral administration, midazolam has a fast absorption rate and is rapidly excreted, with a half-life of only about 2 hours. A reasonably good correlation has been found between plasma levels and clinical effects, indicating a fast but brief response. As a hypnotic, midazolam is mainly indicated in insomniac patients with difficulties in falling asleep or having a pathologic sleep pattern during the first half of the night. No marked hangover effects are present the next morning. In anesthesiology, midazolam appears to be a useful, short-acting, sedative-anxiolytic and amnesic premedicant after both oral and parenteral administration. In minor surgery, however, the slow, unpredictable onset and variable duration of action, as compared with thiopental, may inhibit its routine use as an induction agent, especially in young patients, without heavy premedication. In major surgery, midazolam is an alternative to thiopental for induction of anesthesia in spite of its slow, variable induction time. Its advantages include good cardiovascular stability, transient and mild respiratory depression, low frequency of venous irritation, production of anterograde amnesia and short duration of action in comparison with other benzodiazepines.

Use of benzodiazepines during pregnancy, labour and lactation, with particular reference to pharmacokinetic considerations.

Knowledge of the pharmacokinetic properties of the benzodiazepines is playing an increasingly important role in their use during pregnancy, labour and lactation. All of the benzodiazepine derivatives are lipophilic, undissociated agents which readily penetrate membranes. Thus, they exhibit rapid placental transfer with significant fetal uptake of the drug. In the first trimester of pregnancy there is seldom a clear indication for the use of benzodiazepines. In late pregnancy and at parturition there may be more clear indications for their use. During delivery, the lowest effective dose should be used, since after high doses the so-called 'floppy infant syndrome' may occur, and the slow elimination of these agents by the newborn should be considered. Oxazepam, lorazepam, nitrazepam and, especially, flunitrazepam, appear to penetrate the human placenta more slowly than diazepam, but the clinical significance of this phenomenon remains uncertain. All of these derivatives appear in human milk, but only high clinical doses might be expected to exert a possible effect on the nursing newborn.

A comparative clinical study of dioxonium and pancuronium as muscle relaxants in small children.

Dioxonium (30, 40, and 60 microgram/kg i.v.), a new depolarizing agent, weas compared with pancuronium (0.05 and 0.1 mg/kg i.v.) as a muscle relaxant in combination anesthesia during general surgical operations in small children. Generally, the conditions during intubation, maintenance of anesthesia, and in the recovery room were comparable after both drugs. There were no differences in the cardiovascular responses either. However, a wider intra- and interindividual variation in the drug response was observed after dioxonium, especially after repeated administrations.

Serum growth hormone, serum immunoreactive insulin and blood glucose response to oral and intravenous diazepam in man.

The effect of diazepam on blood glucose, serum immunoreactive insulin (IRI), and growth hormone (GH) were studied in 10 volunteers who received diazepam in oral doses of 5 and 10 mg, and intravenously 10 mg. They also received placebo and saline treatment. There was a dose-dependent rise in GH after diazepam administration, and the rise was related to the peak plasma level of the drug. A highly significant correlation between the concentrations of serum GH and plasma diazepam was found. During the i.v. and oral administration of 10 mg of diazepam, the peak GH levels, reached in 30 and 60 minutes (19.6+/-2.9 and 15.2+/-3.2ng/ml, respectively), were significantly higher than those during saline and placebo periods (4.3+/-0.8 and 5.9+/-1.1 ng/ml, respectively). There was a tendency to a rise of blood glucose levels, but no significant changes of serum IRI.