Pharmacokinetics and oral bioavailability of glycopyrrolate in children.

Based on plasma levels determined with a radioreceptor assay and following a single oral (50 micrograms/kg) and intravenous (5 micrograms/kg) administration of glycopyrrolate in six healthy children operated twice during a several weeks period, a negligible and variable oral bioavailability was found (3.3; 1.3-13.3%) (median;range). No significant changes in heart rate after oral or intravenous administration of the drug could be seen. Oral glycopyrrolate appears to have no place in paediatric premedication.

Awareness with recall during general anesthesia: incidence and risk factors.

UNLABELLED: We studied the associated factors and incidence of awareness during general anesthesia and the nature of subsequent psychiatric disorders. Patients older than 12 yr undergoing surgery under general anesthesia in a secondary care hospital during 1 yr were included in the study. The doses of anesthetics were calculated for the patients with and without awareness. There were 4818 operations under general anesthesia; 2612 (54%) patients were interviewed. Ten (0.4% of those interviewed) patients were found to have undisputed awareness, and there were nine (0.3%) patients with possible awareness. The doses of isoflurane (P < 0.01) and propofol (P < 0.05) were smaller in patients with awareness. Five patients with awareness underwent a psychiatric evaluation. One patient experienced sleep disturbances afterward, but the other four patients did not have any after effects. In conclusion, awareness is a rare complication of general anesthesia associated with small doses of anesthetics. IMPLICATIONS: In an interview of 2612 patients after general anesthesia, 10 (0.4%) patients with awareness and 9 (0.3%) patients with possible awareness were found. A predisposing factor was small doses of the principal anesthetic. In a psychiatric interview, a large proportion of the patients with awareness were found to have suffered from depression in the past.

Developments in the treatment of cancer pain in Finland: the third nation-wide survey.

This survey was designed to investigate the current status of the management of cancer pain in Finland. In 1995 a questionnaire was randomly sent to 5% (n = 546) of Finnish physicians, excluding specialists not expected to treat cancer patients. Two previous surveys, using the same questionnaire, were conducted in 1985 and 1990 by Vainio. The response rate was 53%. Seventy-nine percent of the respondents treated one or less than one cancer patient a week. Sixty-seven percent of them assessed the severity of cancer pain in their patients as being at least moderate. In 10 years, the proportion of physicians suggesting the WHO analgesic ladder principle to their 'typical cancer patient' had increased from 12% to 28%. At the same time, the suggestions of 'analgesic' without definition had decreased from 48% to 6%. Three simulated patient cases were presented. The mean daily dose of opioids suggested for severe terminal cancer pain corresponded to 72 (18-300) mg of intramuscular morphine in 1995, being only 39 (1-77) mg in 1985 for the same simulated patient case. Continuous infusion of opioid was recommended by 59% of the respondents. Non-steroidal anti-inflammatory drugs as the treatment of choice for bone metastases pain in a patient with breast cancer, was recommended by 68% of the respondents. In the case of local severe pain due to recurrent rectal cancer, 63% of the physicians suggested anaesthetic intervention. Insufficient pain relief and lack of experience were the most common difficulties in pain management. Only one-third of the physicians thought that they had enough time and ability to give sufficient psychological support to their patients.

Tropisetron and metoclopramide in the prevention of postoperative nausea and vomiting. A comparative, placebo controlled study in patients undergoing ophthalmic surgery.

One hundred and twenty patients undergoing elective ophthalmic surgery under general anaesthesia were investigated in a randomised, double-blind, parallel group study of postoperative nausea and vomiting. Patients received tropisetron 0.1 mg.kg-1, metoclopramide 0.25 mg.kg-1 or placebo given at the end of anaesthesia. In comparison with placebo, tropisetron significantly reduced the degree of nausea (p < 0.01), whereas metoclopramide reduced both nausea (p < 0.05) and vomiting (p < 0.05). There were no statistically significant differences between the two active agents in their efficacy to postoperative nausea and vomiting. The patients in the placebo group required rescue antiemesis more often in the postanaesthesia care unit. Our results suggest that tropisetron may not be suitable as a routine, primary therapy for the prevention of postoperative nausea and vomiting.

Dexmedetomidine as intramuscular premedication for day-case cataract surgery. A comparative study of dexmedetomidine, midazolam and placebo.

The effects of dexmedetomidine 1.0 microgram.kg-1, midazolam 20 micrograms.kg-1 and saline placebo were assessed in a double-blind, randomised study in 90 patients undergoing day-case cataract surgery under regional anaesthesia. The trial drug was injected into the deltoid muscle 45 min before the peri-ocular block. Dexmedetomidine 1.0 microgram.kg-1 decreased intra-ocular pressure before, during and after surgery. The maximum reduction in mean (SD) intra-ocular pressure occurred in the dexmedetomine group just before discharge from hospital (17.7 (2.8) mmHg to 11.5 (2.9) mmHg) (p < 0.001 compared with midazolam and placebo). In contrast, midazolam did not differ from saline placebo. Dexmedetomidine and midazolam produced a similar sedative effect of short duration. Dexmedetomidine induced a moderate decrease in blood pressure (p < 0.001 compared with placebo) and a slight but statistically significant decrease in heart rate throughout the study period (p < 0.001 compared with placebo). Dexmedetomidine 1.0 microgram.kg-1 intramuscularly, effectively reduced intra-ocular pressure and produced short-acting sedation with marginal cardiovascular effects; it may be a useful premedicant drug for elderly patients undergoing day-case cataract surgery under regional anaesthesia.

Pharmacokinetics of glycopyrrolate in children.

STUDY OBJECTIVE: To investigate the pharmacokinetics of glycopyrrolate in children. DESIGN: Open study with three parallel groups. SETTING: Pediatric surgery department at a university hospital. PATIENTS: 26 healthy ASA physical status I children undergoing minor surgery. INTERVENTIONS: Patients were assigned to 1 of 3 groups: under 1 year of age (Group 1, n = 8), between 1 and 3 years of age (Group 2, n = 7), and over 3 years of age (Group 3, n = 11). Glycopyrrolate 5 micrograms/kg was given as a single intravenous (i.v.) injection before induction of general anesthesia. Blood samples (for determination of drug concentrations in plasma) were collected via venous cannula inserted into the contralateral antecubital vein. MEASUREMENTS AND MAIN RESULTS: ECG was observed continuously, blood pressure was measured with an automatic noninvasive device, and blood samples were taken just before and at 2, 4, 6, 10, 15, 30, 60, 120, 180, 240, 360, and 480 minutes after injection of glycopyrrolate. Glycopyrrolate concentrations in plasma were determined with a radioreceptor assay. The only significant difference in the pharmacokinetic parameters was the shortened elimination half-life in patients between 1 and 3 years of age. Glycopyrrolate 5 micrograms/kg i.v. did not cause any significant alterations in heart rate. CONCLUSIONS: There were no significant changes in the distribution volume or clearance of glycopyrrolate in children of different ages. The shortened elimination half-life in children between 1 and 3 years of age is of minor clinical importance.

Anticholinergic drugs in paediatric anaesthesia. A survey of their present position in Finland 1990.

A survey regarding the present use of anticholinergic drugs in paediatric patients was carried out amongst anesthetists in Finland. Out of a total of 430 questionnaires 229 were returned after two mailings, giving a reply rate of 53%. Fourty-nine percent of the responders used these drugs routinely in premedication in 1990, while 55% were using them in 1985. In various age groups anticholinergic premedication was given most often to patients aged 0-1 year. The procedures in the airway region and eye surgery were the main indications for the preanaesthetic use of anticholinergic drugs while reflex bradycardia was the most frequent indication for administering these drugs during the perioperative period. Atropine and glycopyrrolate were the most popular drugs and the principal route of administration was intravenously, just before induction of anaesthesia. Glycopyrrolate with neostigmine was the most popular combination when the competitive neuromuscular block was reversed. It is concluded that almost half of the Finnish anaesthetists give anticholinergic premedication to children routinely and the position of anticholinergic drugs in paediatric anaesthesia has changed only a little during the last few years.

Regional anaesthesia for cataract surgery: comparison of three techniques.

Two methods of periocular anaesthesia (PI and PII) were compared with the traditional retrobulbar block in a prospective study of 450 patients undergoing elective cataract extraction and intraocular lens implantation. A solution of local anaesthetic containing equal amounts of 2% lignocaine and 0.5% bupivacaine was used in all the groups. Hyaluronidase (75 IU/10 ml of local anaesthetic solution) was added. Three groups of patients were studied, with 150 patients in each group. The retrobulbar injection (group R) was performed with 4 ml of the anaesthetic solution through the lower eyelid inferotemporally and a further 6 ml was injected for seventh cranial nerve block. In the first periocular technique (group PI) the local anaesthetic was injected inferotemporally (5 ml) through the lower lid and superonasally (5 ml) through the upper lid. In the second periocular technique (PII) the injections were performed inferotemporally (5 ml) and into the medial compartment (2 ml) of the orbit at the medial canthus. Satisfactory anaesthesia could be achieved with all of these methods. Additional block because of insufficient akinesia of the muscles was required in 12% (18/150) in group R, in 19% (28/150) in group PI, and in 11% (16/150) in PII. The medial compartment technique (PII) was associated with the highest percentage of total akinesia of the muscles and lowest reblock rate. All three methods produced sufficient analgesia during surgery and there were no differences in the requirements for additional analgesic drugs during surgery. It is concluded that the medial compartment technique represents a good alternative to retrobulbar block.

Pharmacokinetics and effects of i.m. alfentanil as premedication for day-case ophthalmic surgery in elderly patients.

We have studied the pharmacokinetics and effects of i.m. alfentanil as premedication for peribulbar block in 90 patients undergoing elective day-case cataract surgery. We compared alfentanil 12.5 micrograms kg-1 injected into the deltoid (n = 30) or gluteal muscle (n = 30) 15 min before the peribulbar block, and placebo (n = 30). The alfentanil concentrations were significantly greater in the deltoid group during the study and the mean peak concentration occurred more rapidly in this group. Only alfentanil injected into the deltoid muscle reduced pain (assessed with a visual analogue scale (VAS)) associated with the peribulbar block. A mild sedative effect (VAS) was found in both alfentanil groups. We conclude that i.m. alfentanil appears to be a suitable premedicant for short, painful procedures because it has a short duration of action and is not associated with any clinically significant side effects.

Beta 1- and beta 2-antagonist activity of topically applied betaxolol and timolol in the systemic circulation.

The beta 1- and beta 2-antagonist activity of betaxolol and timolol in the systemic circulation was studied ex-vivo after their ocular administration in thirty patients during cataract surgery. The patients received 40 microliters of 0.5% betaxolol or 0.25% timolol into the lower cul-de-sacs of both eyes. Blood samples were collected up to four h after instillation of the doses. Plasma concentrations of betaxolol and timolol were analyzed using a radioreceptor assay. The ex-vivo-beta 1-and beta 2-receptor occupancies corresponding drug plasma levels were calculated using radioligand binding techniques. The extent of beta 1-receptor occupancy of betaxolol in the systemic circulation was less than 20% and its beta 2-receptor occupancy was negligible. The extent of beta 1-receptor occupancy of timolol was about 65% and its beta 2-receptor occupancy about 80%. Because receptor occupancy is the basis of antagonist activity of beta-blocking agents, this study shows that the beta 1-antagonist activity of betaxolol in the systemic circulation is much less than that of timolol, and that its beta 2-antagonist activity is negligible. The study suggests that the reported side effects of betaxolol in patients with obstructive pulmonary diseases are not mediated via its beta 2-receptor blocking properties.

Pharmacokinetics of glycopyrronium in uraemic patients.

We studied the pharmacokinetics of glycopyrronium in 11 uraemic patients undergoing cadaveric renal transplantation and in seven ASA I control patients undergoing general surgery. Glycopyrronium 4 micrograms kg-1 was given i.v. before induction of anaesthesia. Blood and urine samples were collected for up to 24 h for measurement of glycopyrronium concentrations using a radioreceptor assay. Volume of distribution in the elimination phase (V beta) was similar in both groups, the elimination half-life (T1/2 beta) was longer (P < 0.05), area under the plasma concentration-time curve (AUC) larger (P < 0.01) and plasma clearance (CI) smaller (P < 0.01) in the uraemic patients. In 3 h, mean 0.7 (range 0-3)% and 50 (21-82)% of glycopyrronium was excreted in the urine in the uraemic and healthy patients, respectively (P < 0.001). The 24-h renal excretion was 7 (0-25)% in uraemic and 65 (30-99)% in control patients (P < 0.001). We conclude that the elimination of glycopyrronium is severely impaired in uraemic patients.

The effect of betaxolol and timolol on postoperative intraocular pressure.

Postoperative intraocular pressure (IOP) elevation is a well documented phenomenon after cataract surgery. Many pharmacological agents have been used to prevent this complication. We conducted a randomized double-blind, placebo-controlled study to evaluate the effect of topical betaxolol and timolol on postoperative IOP after extracapsular cataract extraction and intraocular lens implantation. One hundred and twenty patients were randomly divided into three groups. At the end of the operation, the patients were given one drop of 0.5% betaxolol, 0.5% timolol or placebo solution into the lower cul-de-sac of the operated eye. IOP was measured preoperatively and five and twenty-four h postoperatively. There was a significant rise in IOP in the placebo and betaxolol groups but not in the timolol group five h postoperatively. IOP was significantly higher in all groups twenty-four h after the operation than preoperatively. Betaxolol did not have any significant effect on the postoperative IOP, but timolol was effective in preventing the early IOP rise. The differences in the antagonist effects of these drugs and the possible role of beta 2-receptors in mediating the aqueous humour flow are discussed.

Intramuscular dexmedetomidine as premedication for general anesthesia. A comparative multicenter study.

BACKGROUND: Dexmedetomidine is a new potent and selective alpha 2-agonist that might prove useful as a preanesthetic agent. METHODS: A randomized, double-blind study design was used in 192 ASA physical status 1 and 2 patients scheduled for elective abdominal hysterectomy, cholecystectomy, or intraocular surgery under general anesthesia. Intramuscular injection of 2.5 micrograms/kg dexmedetomidine administered 60 min before and intravenous saline placebo 2 min before induction of anesthesia (DEXPLA group, n = 64) was compared with a combination of 0.08 mg/kg intramuscular midazolam 60 min and 1.5 micrograms/kg intravenous fentanyl 2 min before induction (MIDFENT group, n = 64), or a combination of intramuscular dexmedetomidine and intravenous fentanyl (DEXFENT group, n = 64). After thiopental induction, anesthesia was maintained with 70% N2O/O2, and fentanyl was administered according to clinical and cardiovascular criteria. Patients undergoing cholecystectomy received additional enflurane. RESULTS: Dexmedetomidine and midazolam induced comparable preoperative sedation and anxiolysis. The DEXFENT combination blunted the increases in blood pressure and heart rate induced by tracheal intubation more efficiently when compared with the DEXPLA and MIDFENT groups, in which approximately 25 mmHg and 15 beats/min greater increases were observed. The intraoperative fentanyl requirements were greater in MIDFENT patients when compared with both dexmedetomidine groups, in which 56% (DEXFENT group) and 31% (DEXPLA group) less fentanyl, respectively, was needed. Intraoperatively, fluids or vasopressors for hypotension and glycopyrrolate for bradycardia were administered more often to patients receiving dexmedetomidine than to those who did not. Postoperatively, there were no differences in oxygen saturation, analgesic, or antiemetic requirements, but dexmedetomidine-induced blood pressure and heart rate reductions were still evident at the end of the 3-h follow-up period. Bradycardia as an adverse event was reported more frequently in dexmedetomidine patients (20% in the DEXPLA and 33% in the DEXFENT groups) than in MIDFENT patients (8%). CONCLUSIONS: The results suggest that pretreatment with a single intramuscular injection of 2.5 micrograms/kg dexmedetomidine is efficacious, but significantly increases the incidence of intraoperative hypotension and bradycardia in ASA physical status 1 or 2 patients.

Dexmedetomidine as intramuscular premedication in outpatient cataract surgery. A placebo-controlled dose-ranging study.

Alpha 2 agonists have been shown to decrease intra-ocular pressure in ophthalmic surgery. We studied the effects of dexmedetomidine, a new alpha 2 agonist, on intra-ocular pressure, haemodynamic parameters, sedation, anxiolysis and dryness of mouth in 35 (ASA physical status 1-3) patients undergoing day-case cataract surgery under peri-ocular anaesthesia. Five different doses of dexmedetomidine (0.25, 0.5, 0.75, 1.0 and 1.5 micrograms.kg-1) were used in this double-blind, randomised and placebo-controlled study. The trial drug was administered into the deltoid muscle 60 min before surgery. The 1.0 micrograms.kg-1 dose of dexmedetomidine produced a 32% reduction of intra-ocular pressure (p = 0.002). This dose induced moderate sedation, but was not associated with significant haemodynamic changes. A significant decrease in heart rate and systolic blood pressure was seen only with the highest dose of dexmedetomidine. Our results suggest that dexmedetomidine 1.0 micrograms.kg-1 produces sedation and a reduction of intra-ocular pressure with minimal haemodynamic side effects when given intramuscularly as premedication before cataract surgery under regional anaesthesia.

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.

Regional anesthesia for cataract surgery: comparison of retrobulbar and peribulbar techniques.

METHODS. The features of retrobulbar and peribulbar blocks were compared prospectively in 300 patients undergoing elective, ambulatory cataract surgery. Both techniques were clinically applicable, but to achieve total akinesia of the eye muscles, an additional injection was needed in 13% of the patients with retrobulbar block and in 35% with periocular block. RESULTS. In younger patients (less than 65 years), the number of injections and the volume of the local anesthetic needed to produce a total akinesia of the eye were significantly higher when compared with the elderly.

Dexmedetomidine reduces intraocular pressure, intubation responses and anaesthetic requirements in patients undergoing ophthalmic surgery.

We studied the effects of a single i.v. dose of dexmedetomidine, a highly selective and specific alpha 2 adrenoceptor agonist, on intraocular pressure (IOP), haemodynamic and sympathoadrenal responses to laryngoscopy and tracheal intubation, and on anaesthetic requirements in ophthalmic surgery. Thirty ASA I-II patients undergoing cataract surgery were allocated randomly to receive either dexmedetomidine 0.6 microgram kg-1 or saline placebo i.v. 10 min before induction of anaesthesia in a double-blind design. After dexmedetomidine there was a 34% (95% confidence interval (CI) 27-43%) reduction in IOP (P less than 0.001) and 62% (CI 57-68%) decrease in plasma noradrenaline concentrations (P less than 0.001). After intubation, maximum heart rate was 18% (CI 3-33%, P = 0.036) and the maximum IOP 27% (CI 11-43%, P = 0.005) less in the dexmedetomidine group compared with the patients treated with placebo. Within 10 min after intubation, maximum systolic and diastolic arterial pressures were also significantly (P = 0.013 and P = 0.020) smaller in the dexmedetomidine group. The induction dose of thiopentone was smaller (23% (CI 20-26%) P = 0.012), and the use of isoflurane or fentanyl supplements during anaesthesia was less frequent in the dexmedetomidine group. The patients premedicated with dexmedetomidine recovered faster from anaesthesia (P = 0.042). These results suggest that dexmedetomidine may be a useful anaesthetic adjunct in ophthalmic surgery.

Oxygenation during local anaesthesia for cataract surgery.

The oxygenation of 48 elderly patients scheduled for cataract surgery under local anaesthesia was studied using pulse oximetry and nasopharyngeal oxygen measurement. After a control period the patients breathed supplemental oxygen 2 l/min and later 4 l/min, via either a face mask or a nasal catheter. The effects of the two oxygen flow levels and oxygen delivery methods on oxygenation were assessed. The lowest oxygen saturation values were seen after retrobulbar block before the patients were transferred to the operating room. The surgical draping did not cause hypoxaemia and the 2 l/min oxygen flow was sufficient to cause hyperoxaemia in all patients. The face mask and nasal catheter appeared to be equally good in oxygenating the patients.

Surgery of acute peptic ulcer haemorrhage.

During the years 1973-1985, 145 patients with acute peptic ulcer haemorrhage were treated surgically at the Department of Surgery, Turku University Central Hospital. The bleeding site was gastric ulcer in 76 patients; 58 of these were treated by gastric resection and 17 by ulcer excision combined with vagotomy and pyloroplasty. Forty-two out of 69 patients with bleeding duodenal ulcer were treated with partial gastrectomy, the remaining with transfixion and vagotomy and pyloroplasty. The rebleeding rate was 2% and reoperation rate 9% among the patients who had a resection. In contrast 19% of the transfixed and 12% of ulcer excision cases rebled. The primary overall mortality was 12%; 44% of the patients with recurrent bleeding died. Because rebleeding was the most important cause of mortality, partial gastrectomy in bleeding gastric as well as duodenal ulcer may be preferable.