Architecture of the protein-conducting channel associated with the translating 80S ribosome.

In vitro assembled yeast ribosome-nascent chain complexes (RNCs) containing a signal sequence in the nascent chain were immunopurified and reconstituted with the purified protein-conducting channel (PCC) of yeast endoplasmic reticulum, the Sec61 complex. A cryo-EM reconstruction of the RNC-Sec61 complex at 15.4 A resolution shows a tRNA in the P site. Distinct rRNA elements and proteins of the large ribosomal subunit form four connections with the PCC across a gap of about 10-20 A. Binding of the PCC influences the position of the highly dynamic rRNA expansion segment 27. The RNC-bound Sec61 complex has a compact appearance and was estimated to be a trimer. We propose a binary model of cotranslational translocation entailing only two basic functional states of the translating ribosome-channel complex.

Remifentanil and fentanyl during anaesthesia for major abdominal and gynaecological surgery. An open, comparative study of safety and efficacy.

BACKGROUND: and objective This open, multicentre study compared the efficacy and safety of remifentanil with fentanyl during balanced anaesthesia with 0.8% isoflurane (end-tidal concentration) for major abdominal and gynaecological surgery, and the efficacy and safety of remifentanil for pain management in the immediate postoperative period. METHODS: Two-hundred and eighty-six patients were randomized to receive remifentanil 1 microg kg(-1) followed by 0.2 microg kg(-1) min-1 (n=98), remifentanil 2 microg kg(-1) followed by 0.4 microg kg(-1) min(-1) (n=91) or fentanyl 3 microg kg(-1) (n=97) at induction. Thereafter, the study opioids and isoflurane were titrated to effect during the operation. RESULTS: Compared with fentanyl, remifentanil 2 microg kg(-1) followed by 0.4 microg kg(-1) min(-1) reduced the incidence of response to tracheal intubation (30% vs. 13%, P < 0.01), skin incision (33% vs. 4%, P < 0.001) and skin closure (11% vs. 3%, P < 0.05), respectively. Patients receiving remifentanil 1 microg kg(-1) followed by 0.2 microg kg(-1) min(-1) had fewer responses to skin incision than the fentanyl group (12% vs. 33%, P < 0.001), but the incidences of response to tracheal intubation and skin closure were similar. Significantly fewer patients in both remifentanil groups had > or = 1 responses to surgical stress intraoperatively compared with fentanyl (68% and 48% vs. 87%, P < 0.003). The mean isoflurane concentrations required were less in both remifentanil groups compared with the fentanyl group (0.1%, P=0.05). In remifentanil-treated patients, continuation of the infusion at 0.1 microg kg(-1) min(-1) with titration increments of +/- 0.025 microg kg(-1) min(-1) was effective for the management of immediate postoperative pain prior to transfer to morphine analgesia. However, a high proportion of patients experienced at least moderate pain whilst the titration took place. CONCLUSIONS: Anaesthesia combining isoflurane with a continuous infusion of remifentanil was significantly more effective than fentanyl at blunting responses to surgical stimuli. Significantly fewer patients responded to tracheal intubation with remifentanil at 0.4 microg kg(-1) min(-1), supporting the use of a higher initial infusion rate before intubation. Both remifentanil and fentanyl were well-tolerated, with reported adverse events typical of mu-opioid agonists.

[Meperidine (pethidine) outdated as analgesic in acute pancreatitis]. / Pethidine achterhaald als pijnstiller bij acute pancreatitis.

The most important symptom in acute pancreatitis is pain. This pain often is so severe that treatment is started with opioid analgesics. In daily practice meperidine is often the analgesic of first choice because it is supposed to cause less spasm of the M. sphincter ampullae hepatopancreaticae (sphincter of Oddi). Drawbacks of the use of meperidine compared with other opiods are myoclonias, tremors and convulsions due to accumulation of the metabolite norpethidine, and hypotension, tachycardia and erythema due to release of more histamine from mast cells. From literature study it appeared that all opioids have a spasmogenic effect on the sphincter of Oddi, that there are no good arguments to assume that this effect is less when meperidine is used, and that there is no good evidence that this spasmogenic effect of opioid analgesics influences the course of acute pancreatitis in an unfavourable way. Since the profile of effects and side effects of meperidine is unfavourable, we prefer the use of opioids with a larger therapeutic width.

Oral dolasetron mesylate for prevention of postoperative nausea and vomiting: a multicenter, double-blind, placebo-controlled study. The Oral Dolasetron PONV Prevention Study Group.

STUDY OBJECTIVE: To examine the safety and effectiveness of a range of single oral doses of dolasetron mesylate for the prevention of postoperative nausea and vomiting. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: 32 hospitals. PATIENTS: 789 female ASA physical status I, II, and III patients, ages 18 to 60 years, weighing between 45 and 100 kg, scheduled for major gynecologic surgery (including abdominal hysterectomy, gynecologic laparotomy, or vaginal hysterectomy) with general anesthesia. INTERVENTIONS: 25, 50, 100, or 200 mg oral doses of dolasetron mesylate or placebo were administered 1 to 2 hours before induction of anesthesia. Efficacy was assessed for 24 hours postrecovery by measuring complete response (no emetic episodes, no rescue medication), total response (complete response with no nausea), time to first emetic episode or rescue, and patient visual analog scale evaluations of nausea severity and satisfaction with antiemetic therapy. MEASUREMENTS AND MAIN RESULTS: Complete response rates for the 50, 100, and 200 mg dose groups were statistically greater than placebo (p < or = 0.018). Likewise, total response rates were statistically greater in the 50, 100, and 200 mg dose groups than in the placebo group (p = 0.012). Percentage of patients with no nausea and patient satisfaction scores were significantly higher for each dolasetron dose group than placebo (p < or = 0.047 and p < or = 0.004, respectively). Efficacy peaked at the 50 mg dose. The incidence of adverse events was similar in the placebo (30.1%) and dolasetron groups (29.4%). Headache was the most frequent treatment-related adverse event, with 2% to 5% incidence across groups. Incidence of adverse events did not increase with increasing dolasetron doses. Dose-related decreases in blood pressure at acute time points were not clinically significant. CONCLUSION: Single oral doses of dolasetron, administered 1 to 2 hours before induction of anesthesia, are safe and effective for preventing postoperative nausea and vomiting in this patient sample. Maximal antiemetic response was seen with the 50 mg oral dolasetron dose.

Sufentanil pharmacokinetics in young adult and elderly surgical patients.

Sufentanil 3 microgram kg-1 was administered as an intravenous (i.v.) bolus to 12 elderly patients, aged 65-87 years and 12 young adults, 17-43 years of age, all ASA class I-II, scheduled for orthopaedic surgery. Plasma sufentanil concentrations were measured by a specific radioimmunoassay. Plasma concentration time-curves for the young adult and the elderly groups were superimposible. Pharmacokinetic parameters were calculated from the derived compartmental models. Elimination half-lives, clearance and total volumes of distribution were calculated with non-compartment methods. The major pharmacokinetic parameters, elimination half-life, clearance and volume of distribution did not differ between both groups. The age-related differences in the action of sufentanil cannot be explained by its pharmacokinetic properties.

A single i.v. dose of ondansetron 8 mg prior to induction of anaesthesia reduces postoperative nausea and vomiting in gynaecological patients.

The effect of a single intravenous dose of ondansetron in preventing postoperative nausea and emesis (retching and vomiting) (PONV) was investigated in a randomized, double-blind, placebo-controlled, multicentre, international study. Women of ASA class I-III, requiring gynaecological laparotomy, vaginal hysterectomy, or major vaginal surgery were selected for study. Two hundred and thirty-five received placebo, 231 received 1 mg ondansetron, 228 received 8 mg ondansetron and 229 received 16 mg ondansetron, as an infusion over five minutes before the induction of anaesthesia. A standardized balanced anaesthetic technique was employed. This consisted of premedication with either diazepam or temazepam, thiopentone induction, maintenance with nitrous oxide in oxygen supplemented with enflurane or isoflurane, intraoperative analgesia with fentanyl, neuromuscular blockade with any choice of agent and reversal with neostigmine and atropine. Postoperative analgesia was achieved with morphine, and prochlorperazine or metoclopramide were given if a rescue antiemetic was required. A greater percentage of patients in the 8 mg and 16 mg ondansetron groups experienced no postoperative emesis (44% and 39% respectively) than in the placebo and 1 mg ondansetron groups (29% and 28% respectively) for the first 24 hr postoperative period (8 mg vs placebo and 1 mg: P < or = 0.001; 16 mg vs placebo: P < 0.05; 16 mg vs 1 mg: P < 0.05). Similarly, the percentage of patients who did not experience postoperative nausea were 20%, 26%, 31% and 28% for the placebo, 1 mg, 8 mg and 16 mg ondansetron treatment groups, respectively (8 mg and 16 mg vs placebo P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Oral ondansetron in the prevention of postoperative nausea and vomiting.

The effect of three times daily oral ondansetron in preventing postoperative nausea and vomiting was investigated in two randomized, double-blind, placebo-controlled, multi-centre studies. The first study compared ondansetron 1, 8 and 16 mg to placebo, and the second study compared 8 mg ondansetron to placebo. Both studies included ASA Class I-III female patients about to undergo major abdominal gynaecological surgery or vaginal hysterectomy. In the first study, the 8 and 16 mg ondansetron groups had a significantly lower incidence of nausea and vomiting in the 0-24 h period following recovery from anaesthesia than the placebo group. Ondansetron 8 mg three times daily was also significantly better than placebo in the second study. Side-effects mainly consisted of constipation, headache, and asymptomatic elevation of liver enzymes. The incidence of side-effects was similar in ondansetron- and placebo-treated patients. There appeared to be no clinically important benefit of the 16 mg three times daily ondansetron regimen over the 8 mg three times daily dose, therefore 8 mg three times daily is recommended as the optimal oral dose in the prevention of postoperative nausea and vomiting.

Comparison of intravenous and intranasal sufentanil absorption and sedation.

The absorption and sedation following an intranasal dose of sufentanil were evaluated and compared with those of the same dose given intravenously. Sixteen adult patients scheduled for elective surgery were randomly allocated to receive as premedication 15 micrograms sufentanil either intravenously or intranasally. Before administration and at fixed time intervals thereafter, the degree of sedation was assessed, vital signs were recorded and venous blood samples were taken for the determination of sufentanil plasma concentrations. Peroperative sedation of rapid onset and limited duration was seen in both groups. However, the onset of sedation was more rapid after intravenous injection. At 10 min, all patients in the IV group were sedated versus only two in the intranasal group (P less than 0.01). No significant intergroup differences in sedation were seen at 20 to 60 min. This clinical effect is in agreement with the measured plasma levels, which were significantly lower after intranasal application at 5 and 10 min, being 36 and 56 per cent of those after IV dosing, respectively. From 30 min, plasma concentrations were virtually identical for the two routes of administration. The AUC0-120 min after intranasal dosing was 78 per cent of that after intravenous injection. Intranasal dosing induced no clinically significant changes in vital signs, whereas after IV sufentanil, a clinically significant decrease in PaO2 was seen at 5 min. The results of this study show that sufentanil, when administered intranasally, is rapidly and effectively absorbed from the human nasal mucosa, so that this route may be an attractive alternative for a premedicant, avoiding the discomfort of an intravenous or intramuscular injection.

[A sufentanil dosage study in general surgery]. / Sufentanil-Dosierungsstudie bei allgemeinen chirurgischen Eingriffen.

Sufentanil is widely used for cardiac surgery in initial doses up to 15 micrograms/kg. It was expected that for general surgery much smaller doses would be appropriate. The aim of the study, therefore, was to find a dosage scheme for sufentanil that could be used in general surgery for operations lasting 1 h. METHODS. In 62 patients (Table 1), anesthesia was induced with 15 micrograms sufentanil and 0.2 mg/kg etomidate. According to a random group allocation, a bolus injection of sufentanil was administered 1 min before incision, so that the patients received 0.5, 1.0 or 1.5 micrograms/kg along with the initial dose. During maintenance anesthesia, repeat doses of 10 micrograms sufentanil were injected as required (rise in blood pressure and/or heart rate by more than 20%, or other stress signs i.e., sweating, movement). Intubation was facilitated by means of atracurium 0.5 mg/kg. Increments of 5-10 mg were given when needed. RESULTS. In the group of patients who had received 1.0 micrograms/kg, both the number requiring repeat doses, and the total number of repeat doses were significantly lower than in the 0.5 microgram/kg group. A further increase to 1.5 micrograms/kg did not prove to have any advantage and it led to a drop in blood pressure, that was more pronounced and of longer duration than in the other groups. CONCLUSION. A dose of 1.0 micrograms/kg, therefore, appeared to be the optimum initial dose in general surgery for operations lasting at least 1 h.

Recovery from fixed-dose midazolam-induced anaesthesia and antagonism with flumazenil for outpatient arthroscopy.

This study evaluated recovery after a fixed dose of midazolam as induction agent and the influence of flumazenil on recovery parameters in patients undergoing day-case surgery (arthroscopy of the knee). In 40 unpremedicated patients, anaesthesia was induced with midazolam 0.2 mg/kg, vecuronium bromide 0.1 mg/kg intravenously and 3 vol.% isoflurane in oxygen prior to intubation. Anaesthesia was maintained with nitrous oxide 66% in oxygen and 0.9 vol.% isoflurane. Ten minutes after the end of anaesthesia 20 patients received 0.2 mg flumazenil intravenously, followed by increments of 0.1 mg at 60 s intervals until eye opening. Recovery was assessed by the time to eye-opening, to answering five set questions correctly, and to recovering ocular balance (Maddox Wing test), and by comparing pre- and postoperative performance in a pencil and paper test (the p-deletion test). With the exception of ocular balance, all parameters showed a quicker improvement without side-effects in the flumazenil group. After 4 h all patients were fit for discharge. One month after the procedure, all patients were satisfied with the anaesthesia. Full recovery took on average 1.5 days (range between 0 h-10 days). Whilst the technique employing a fixed dose of midazolam as induction agent gives satisfactory intraoperative anaesthesia for day-case arthroscopy, further improvement can be made with the use of flumazenil which hastens recovery.

Recovery from propofol infusion as the main agent for outpatient arthroscopy. A comparison with isoflurane.

Propofol by continuous intravenous infusion has been compared with isoflurane as the main anaesthetic agent for outpatient arthroscopy of the knee. In 40 unpremedicated patients, anaesthesia was induced with propofol 2 mg/kg and vecuronium bromide 0.1 mg/kg and maintained after tracheal intubation with nitrous oxide 66% in oxygen. One group received 3% isoflurane prior to intubation and 0.9% during maintenance, while the other received a continuous intravenous infusion of propofol at a rate of 10 mg/kg/hour. Recovery was assessed by the time to opening eyes, to be able to answer five questions correctly, to recovery of ocular balance (Maddox Wing test) and by comparing pre- and postoperative performance in a paper and pencil test (the p-deletion test). After 3 hours all the patients were fit for discharge. Recovery tests showed no differences between the groups. All patients were satisfied with the anaesthesia. Full recovery took on average 1.5 days (range between 1 hour and 14 days) in both groups. Patients' opinion 1 month after the procedure should be included in every study concerning recovery. Anaesthesia by continuous propofol infusion results in quick recovery comparable with that following isoflurane anaesthesia.

Effect of etomidate on cortisol biosynthesis: site of action after induction of anaesthesia.

To determine the site of inhibition of etomidate on cortisol biosynthesis, plasma cortisol, aldosterone, 17 alpha-hydroxyprogesterone, 11-deoxycortisol and ACTH levels were measured in healthy women before and after the administration of a single dose of either 0.20 mg kg-1 etomidate (mean value, n = 10) or 3.15 mg kg-1 thiopental (n = 9) for induction of anaesthesia in a randomized trial. Etomidate produced a smaller increase in plasma cortisol and had a later onset of action than thiopental. Plasma ACTH levels, however, rose higher in the etomidate-induced patients to reach peak levels 6 h after drug administration. In the same group, plasma aldosterone remained below the control levels but still within the normal range, whereas it rose about 2-fold in the thiopental group. Plasma levels of 17 alpha-hydroxyprogesterone and 11 beta-deoxycortisol were hardly modified after thiopental but increased significantly and remained high for 6 h after etomidate injection. This marked rise in precursors together with a blunted and delayed cortisol response to high ACTH levels, and slightly lowered plasma aldosterone concentration indicates a blockage of 11 beta-hydroxylation in adrenal cortisol synthesis after induction of anaesthesia with etomidate.

Alfentanil used in the aged: a clinical comparison with its use in young patients.

The clinical effects of an i.v. bolus dose of 50 micrograms kg-1 alfentanil were studied during surgical anaesthesia in 10 elderly patients and compared with those of the same dosage in nine young adults. Plasma samples, to determine alfentanil concentrations, were taken at regular intervals during the first hour following injection. Cardiovascular changes were minor. A transient fall in systolic blood pressure shortly after the alfentanil administration was seen in both groups but was more pronounced in the elderly patients. The quality of initial intra-operative analgesia was good in all patients. The duration of action of 50 micrograms kg-1 alfentanil, as judged by the occurrence of signs of insufficient analgesia, was longer in the elderly patients (mean: 36 min) than in young patients (mean: 22 min). The alfentanil plasma levels extrapolated for these time points were similar. Hence, the difference in duration of action must be due to the slower elimination from the body in the elderly patient, rather than an increased sensitivity. On these grounds, age should be one of the criteria for selecting the appropriate dose of alfentanil.

Alfentanil analgesia for surgical procedures of medium and long duration.

The clinical potential of alfentanil, a short acting narcotic analgesic as a supplement to only nitrous oxide/oxygen was evaluated in 141 patients having surgery of medium and long duration. Following induction of anesthesia with thiopentone alfentanil 1 mg was injected just prior to intubation. Anesthesia was maintained with a mixture of nitrous oxide/oxygen, (2:1) with analgesia achieved by a loading dose of alfentanil 0.1 mg/kg slowly given over 5 to 10 minute period prior to surgery. Additional increments (10-15 micrograms/kg) were given when the expected length of the operation was more than 30 minutes. The course of anesthesia was rated good in 96.4% of the patients. Cardiovascular stability was a feature in almost all patients. Stress responses due to severe surgical stimuli were almost immediately abolished by the administration of small increments of alfentanil (0.5-1 mg). Recovery was extremely rapid and without side-effects. Reversal of respiratory depression was rarely needed.

[Continuous alfentanil infusion in surgical interventions of intermediate and long duration]. / Alfentanil-Dauerinfusion für chirurgische Eingriffe mittlerer und längerer Dauer.

Alfentanil, a new short-acting narcotic analgesic, was studied as a continuous infusion for surgical procedures of medium and long duration in 80 patients. Anaesthesia was induced with thiopentone immediately followed by 1 mg of alfentanil to attenuate the stress response to intubation. Alfentanil 100 micrograms/kg was then slowly given as a loading dose before surgery started and anaesthesia maintained by a continuous infusion at a rate of 0.5-1 micrograms/kg/min. Patients were ventilated with a 66% nitrous oxide in oxygen. The course of anaesthesia was good in 76 of the patients, while 27 needed small increments of alfentanil on top of the infusion. Cardiovascular stability was a feature in almost all patients. Recovery was extremely rapid and without complications. Naloxone to reverse respiratory depression was only used twice.

Total intravenous anesthesia with etomidate, alfentanil and droperidol.

Forty-six women admitted for gynecologic surgery, were given alfentanil 1 mg, droperidol 2.5 mg and etomidate 0.3 mg/kg body weight intravenously for induction. Anesthesia was maintained using etomidate infused at a rate of 0.1 mg/kg/min for 5 minutes and at 0.01 mg/kg/min afterwards. Analgesia was achieved with a bolus injection of alfentanil prior to surgery, supplemented with additional injections of alfentanil as needed. Controlled ventilation was done with a mixture of air/oxygen. Anesthesia was uneventful in all but two patients. Blood pressure and heart rate remained stable during the entire operative period. Recovery from anesthesia was smooth, although the combination with etomidate and droperidol appears to prolong the recovery time.

Double-blind comparison of the postoperative respiratory depressant effects of alfentanil and fentanyl.

Alfentanil was compared with fentanyl in a double blind study of 90 female patients undergoing laparoscopic sterilizations. The analgesic was combined with droperidol and etomidate for induction and with etomidate, nitrous oxide and occasional increments of succinylcholine for maintenance of anesthesia. Twenty-four percent of the patients required reversal of postoperative respiratory depression after fentanyl compared with 7% after alfentanil (p = 0.042). When the last dose of analgesic had been given more than 10 minutes before the end of the operation, none of the alfentanil patients required reversal of respiratory depression while under the same circumstances 26% of the fentanyl patients required naloxone (p = 0.005). Awakening was delayed in all patients, exceeding a mean time of 20 minutes in both groups. However, 84% of patients were alert on awakening after alfentanil compared with 62% of patients after fentanyl (p = 0.032). Duration and quality of postoperative analgesia were similar in both groups. Cardio-vascular stability was satisfactory in all patients and side effects were minor and infrequent.