Arja Hiller

A potentially hazardous interaction between erythromycin and midazolam

Interaction between erythromycin and midazolam was investigated in two double‐blind, randomized, crossover studies. In the first study, 12 healthy volunteers were given 500 mg erythromycin three times a day or placebo for 1 week. On the sixth day, the subjects ingested 15 mg midazolam. In the second study, midazolam (0.05 mg/kg) was given intravenously to six of the same subjects, after similar pre‐treatments. Plasma samples were collected, and psychomotor performance was measured. Erythromycin increased the area under the midazolam concentration–time curve after oral intake more than four times (p <0.001) and reduced clearance of intravenously administered midazolam by 54% (p <0.05). In psychomotor tests (e.g., saccadic eye movements), the interaction between erythromycin and orally administered midazolam was statistically significant (p <0.05) from 15 minutes to 6 hours. Metabolism of both erythromycin and midazolam by the same cytochrome P450IIIA isozyme may explain the observed pharmacokinetic interaction. Prescription of midazolam for patients receiving erythromycin should be avoided or the dose of midazolam should be reduced by 50% to 75%.

Tracheal intubation after induction of anesthesia in children with propofol — remifentanil or propofol-rocuronium

Purpose: To compare the intubating conditions after remifentanil-propofol with those after propofol-rocuronium combination with the aim of determining the optimal dose of remifentanil.Methods: In a randomized, double-blind study 80 healthy children aged three to nine years were assigned to one of four groups (n=20): 2 or 4 µg·kg−1 remifentanil (Re2 or Re4); 2 µg·kg−1 remifentanil and 0.2 mg·kg−1 rocuronium (Re2-Ro0.2); 0.4 mg·kg−1 rocuronium (Ro0.4). After atropine, remifentanil was injected over 30 sec followed by 3.5 mg·kg−1 propofol and rocuronium. After 60 sec, laryngoscopy and intubation were attempted. Intubating conditions were assessed as excellent, good or poor based on ease of ventilation, jaw relaxation, position of the vocal cords, and coughing to intubation.Results: In all children intubation was successful. Overall intubating conditions were better (P<0.01), and the frequency of excellent conditions, 85%, was higher (P<0.01) in the Re4 group than in the Ro0.4 group. No child manifested signs of muscular rigidity. In the remifentanil groups, arterial pressure decreased 11–13% and heart rate 6–9% after anesthetic induction, and remained at that level throughout the study.Conclusion: The best intubating conditions were produced by the combination of 4 µg·kg−1 remifentanil and 3.5 mg·kg−1 propofol. It provided excellent or good intubating conditions in all children without causing undue cardiovascular depression.RésuméObjectif: Comparer les conditions d’intubation après l’usage d’une combinaison de rémifentanil-propofol avec celles d’une combinaison de propofol-rocuronium dans le but de déterminer la dose optimale de rémifentanil.Méthode: Lors d’une étude randomisée et à double insu, 80 enfants en bonne santé, de trois à neuf ans, ont été répartis en quatre groupes (n=20) et ont reçu: 2 ou 4 µg·kg−1 de rémifentanil (Ré2 ou Ré4); 2 µg·kg−1 de rémifentanil et 0,2 mg·kg−1 de rocuronium (Ré2-Ro0,2); 0,4 mg·kg−1 de rocuronium. Après l’administration d’atropine, le rémifentanil a été injecté pendant 30 s et a été suivi de 3,5 mg·kg−1 de propofol et de rocuronium. La laryngoscopie et l’intubation ont été tentées après 60 s. Les conditions d’intubation ont été évaluées comme excellentes, bonnes ou pavures selon la facilité de la ventilation, la relaxation de la mâchoire, la position des cordes vocales et la toux pendant l’intubation.Résultats: L’intubation a été réussie chez tous les enfants. Les conditions générales d’intubation ont été meilleures (P<0,01), et la fréquence d’excellentes conditions, 85 %, plus élevée (P<0,01) dans le groupe Ré4 que dans le groupe Ro0,4. Aucun enfant n’a manifesté de signe de rigidité musculaire. Dans les groupes rémifentanil, la tension artérielle a baissé de 11–13% et la fréquence cardiaque de 6–9% après l’induction de l’anesthésie et sont demeurées à ce niveau tout au long de l’étude.Conclusion: Les meilleures conditions d’intubation ont été réalisées avec la combinaison de 4 µg·kg−1 de rémifentanil et de 3,5 mg·kg−1 de propofol. L’intubation a été bonne ou excellente chez tous les enfants sans causer de dépression cardiovasculaire indue.

Propacetamol and diclofenac alone and in combination for analgesia after elective tonsillectomy

Background:  Diclofenac and paracetamol have different mechanisms and sites of action. Therefore, we tested if their combination is more effective for analgesia after tonsillectomy than either drug alone with respect to rescue analgesic consumption and visual analog scale values.

Tracheal intubation after induction of anaesthesia with propofol, alfentanil and lidocaine without neuromuscular blocking drugs in children

In a double‐blind study, intubating conditions and haemodynamic responses were assessed in two age‐groups of 45 ASA I‐II children, with mean ages of 2.4 and 6.3 years, premedicated with oral midazolam and atropine. The children were randomly allocated to one of three groups: aifentanil 20 μg · kg‐1 + lidocaine 1 mg · kg‐1 (AIRO + Lign); alfentanil 20 μg μ kg‐1 (Alf20); or alfentanil 40 μg · kg‐1 (Alf40), followed by propofol 3.5 mg · kg‐1 in the children aged 1–3 years and 3.0 mg · kg‐1 in the older children. Intubating conditions, 40 s after the administration of propofol, were assessed as good, moderate or impossible on the basis of jaw relaxation, ease of insertion of the endotracheal tube and coughing during intubation. In the younger age group the frequencies of good, moderate or impossible intubating conditions were 87, 13 and 0% in the Alf40, 40, 60 and 0% in the Alf20 (P < 0.05 compared to the Alf40 group) and 53, 47 and 0% in the Alf20 + Lign group. In the older age group the corresponding frequencies were 60, 33 and 7% in the Alf20 + Lign, 47, 53 and 0% in the Alf20 and 47, 40 and 13% in the Alf40 group. All the drugs prevented any increase in arterial pressure and heart rate after tracheal intubation. The QTc interval of the EGG was always in the normal range. Clinically important bradycardia did not occur. In conclusion, the best intubating conditions occurred after propofol 3.5 mg · kg‐1 and alfentanil 40 μg · kg‐1 in the younger age group. In the other children good or moderate intubating conditions occurred in 87–100% after all the drugs used in the present study.

The analgesic efficacy of acetaminophen, ketoprofen, or their combination for pediatric surgical patients having soft tissue or orthopedic procedures.

The combined use of acetaminophen and a nonsteroidal antiinflammatory drug has been shown to provide better postoperative analgesia than either drug alone in several adult studies. However, there are no pediatric studies analyzing similar effects when the currently recommended doses of acetaminophen are used. In a double-blind, placebo-controlled design we randomized 120 children, aged 1–9 yr, undergoing orthopedic or soft tissue surgery, into 3 groups to receive either acetaminophen 60 mg/kg rectally and 40 mg/kg orally, ketoprofen 2 mg/kg IV twice, or the combination of the active drugs. The first drug doses were given at anesthetic induction and the second doses 8 h thereafter. During anesthesia all children received sevoflurane and a continuous infusion of remifentanil. Postoperative pain was evaluated by the behavioral objective pain scale (0–9) for 24 h. The rescue medication was morphine 0.05 mg/kg IV. The primary outcome variable was morphine consumption. For statistical analysis, analysis of variance, &khgr;2 test and Kaplan-Meier survival analysis were used. Morphine requirement was less in the combination than in the acetaminophen group both in the postanesthesia care unit (2.5 ± 1.7 versus 3.9 ± 2.1 morphine doses) and during the 24-h postoperative follow-up (4.1 ± 2.5 versus 5.9 ± 2.9 morphine doses) (P < 0.05). No differences existed between the ketoprofen and the acetaminophen groups. The objective pain scale scores were lowest in the combination group both in the postanesthesia care unit and in the postoperative ward (P < 0.05). When children were divided based on their surgery, opioid requirement and pain scores were less in the combination than in the parent drug groups only after orthopedic surgery. The combination of acetaminophen 100 mg/kg and ketoprofen 4 mg/kg in a day provided better analgesia and lower pain scores after orthopedic, but not soft tissue, surgery in children.

Acetaminophen improves analgesia but does not reduce opioid requirement after major spine surgery in children and adolescents.

Study Design. A randomized, placebo-controlled, double-blind study to evaluate the effect of intravenously (IV) administered acetaminophen on postoperative pain in children and adolescents undergoing surgery for idiopathic scoliosis or spondylolisthesis. Objective. To evaluate effectiveness of IV-administered acetaminophen on postoperative analgesia, opioid consumption, and acetaminophen concentrations after major spine surgery in adolescents. Summary of Background Data. Scoliosis surgery is associated with severe postoperative pain, most commonly treated with IV-administered opioids. Nonsteroidal anti-inflammatory drugs (NSAIDs), as adjuvant to opioids, improve analgesia and reduce the need for opioids. However, by inhibiting cyclo-oxygenase enzymes peripherally, NSAIDs may inhibit bone healing. Acetaminophen, a centrally acting analgesic, does not have the adverse effects of NSAIDs and has improved analgesia in children after another orthopedic surgery. Methods. In an institutional review board approved study, 36 American Society of Anesthesiology patient classification I to III patients of 10 to 18 years of age were analyzed. Acetaminophen 30 mg/kg, administered IV or 0.9% NaCl was administered at the end of scoliosis or spondylolisthesis surgery, and thereafter twice at 8-hour intervals. Timed blood samples for acetaminophen determination were taken between 0.25 and 20 hours after the first dose. All patients received standard propofol-remifentanil anesthesia. Pain scores (visual analogue scale [VAS], 0–10), opioid consumption, and adverse effects were recorded. Results. In the surgical ward, 7 (39%) patients in the acetaminophen and 13 (72%) in the placebo group had a VAS pain score 6 or more (P < 0.05). There were fewer hours with VAS score 6 or more in the acetaminophen group compared with the placebo group (8.7% vs. 17.8% of the hours, P < 0.05). There was no difference in oxycodone consumption during the 24-hour follow-up between the 2 groups. Conclusion. IV-administered acetaminophen 90 mg/kg/day, adjuvant to oxycodone, did improve analgesia, but did not diminish oxycodone consumption during 24 hours after major spine surgery in children and adolescents. All acetaminophen concentrations were in nontoxic levels.

The effect of continuous intravenous indomethacin infusion on bleeding time and postoperative pain in patients undergoing emergency surgery of the lower extremities.

Fifty–four orthopaedic patients were given either indomethacin (25–50 mg bolus plus infusion, 5–7.5 mg h‐1) or only lactated Ringer solution intravenously over 20 h in a randomized and double–blind fashion. The study was started at the casualty department as soon as possible after the decision to operate was made. The patients were given a spinal block with bupivacaine, and the evaluation included postoperative analgesia and IVY bleeding times. Indomethacin plasma concentrations were measured and found to be at a therapeutic level throughout the study. The oxycodone dose (mean s.d.) during the postoperative observation was lower in the indomethacin group (17.4 13.7 mg) than in the control group (25.6 15.6 mg) (P = 0.05). Fewer patients in the indomethacin group needed oxycodone more than once during the follow–up period (P < 0.001). The mean IVY bleeding time was prolonged in the indomethacin group after 20 h of infusion (P < 0.05). No abnormal bleeding was observed immediately postoperatively. However, at the end of the infusion there were more patients who bled through their bandages and casts in the indomethacin group (4/28 vs. 1/26).

Optimally fitted tracheal tubes decrease the probability of postextubation adverse events in children undergoing general anesthesia.

Background : The air leak test is recommended for assessing the appropriate size of an uncuffed tracheal tube (TT) in children. Our objectives were to determine whether there is a certain threshold air leak value beyond which a higher risk for adverse events after removal of TT can be predicted and to define other risk factors related to extubation.

Spectral entropy as a measure of hypnosis and hypnotic drug effect of total intravenous anesthesia in children during slow induction and maintenance.

Background: We evaluated whether spectral entropy (SpE) can measure the depth of hypnosis and the hypnotic drug effect in children during total intravenous anesthesia. Methods: Sixty healthy children, aged 3–16 yr, were studied. Anesthesia was induced with an increasing target controlled infusion of propofol, and maintained by a stable remifentanil infusion and variable concentrations of target controlled infusion propofol. Depth of hypnosis was assessed according to the University of Michigan Sedation Scale (UMSS). Estimated plasma (Cp) and pseudo effect site (Ceff) propofol concentrations reflected the hypnotic drug effect. Patients were stratified to three age groups. The correlations between SpE versus UMSS, Cp, and Ceff were analyzed by Prediction Probability (Pk). The pharmacodynamic relationship between SpE and Cp, and the differences of SpE values between the age groups at the corresponding UMSS levels, were studied. Results: Respective mean Pk values for the youngest, middle, and oldest age groups were: 1) during induction: SpE versus UMSS 0.87, 0.87, and 0.93; SpE versus Cp 0.92, 0.95, and 0.97; and SpE versus Ceff 0.88, 0.94, and 0.95; 2) during maintenance: SpE versus Ceff 0.86, 0.75, and 0.81. The pharmacodynamic analysis determined an association between SpE and Cp that followed the Emax model closely. There were significant differences in SpE values between age groups at corresponding UMSS sedation levels. Conclusions: SpE measures the level of hypnosis and hypnotic drug effect in children during total intravenous anesthesia. There is an age dependency associated with SpE. Anesthesia should not be steered solely on the basis of SpE.

The Narcotrend index indicates age-related changes during propofol induction in children.

BACKROUND: The Narcotrend® electr oencephalogram monitor is designed to measure hypnotic state during anesthesia. We performed this study to evaluate the effectiveness and reliability of the Narcotrend monitor in assessing hypnotic state and loss of consciousness (LOC) during propofol anesthesia induction in children. METHODS: Sixty-two children, aged 1–5 (n = 17), 6–12 (n = 23), and 13–16 (n = 21) yr, scheduled for elective surgery were studied. The patients were premedicated with oral midazolam 0.5 mg/kg. After IV access, propofol target controlled infusion (TCI) was started with 0.5 &mgr;g/mL and increased by 0.5 &mgr;g/mL increments every 2 min until the child did not respond to any verbal command or physical stimuli. A manual scheme was used for children weighing <15 kg. Hypnotic state was measured every minute from the start of the propofol infusion using the University of Michigan Sedation Scale (UMSS). LOC was defined as a transition of UMSS scale value 2 to 3. The Narcotrend index (NI) was recorded before the start of induction and during the whole study period. NI values were noted simultaneously, yet independently of the sedation measurements. Prediction probability (PK) was used to assess the correspondence between NI and UMSS. Sensitivity and specificity of NI for differentiating between consciousness and unconsciousness were calculated. NI values at specific UMSS levels were compared between the different age groups and the relationships between TCI propofol concentrations and sedation levels were assessed using correlation analysis. RESULTS: A PK-value of 0.84 (95% CI [0.80–0.88]) of NI was calculated from the data for the detection of LOC. Similarly, a PK value of 0.82 (95% CI [0.78–0.86]) indicated agreement between NI and UMSS values. The average NI values differed between successive UMSS sedation levels 0 and 1 and levels 1 and 2 (P < 0.01). In the youngest age group, the NI discriminated between UMSS levels 2 and 3, in the second age group between levels 1 and 2 and 2 and 3, and in the oldest age group between 0 and 1. Furthermore, the NI values differed significantly between age groups at UMSS levels 1–4 (P < 0.005), with the NI values being higher in younger compared with older children. The average NI value at LOC was 68. For the detection of consciousness, a sensitivity of 0.67 and specificity of 0.79 were achieved. Spearman correlation coefficients indicated higher association between TCI propofol concentrations and UMSS (0.96) than between NI and UMSS (−0.68). CONCLUSIONS: During propofol induction in children, the Narcotrend electroencephalogram monitor was capable of following changes in the sedation level of children to some extent, but also had a relatively high probability (0.18) of incorrectly predicting changes in conscious state. Therefore, the monitor should not solely be used to guide sedation and anesthesia. NI was age-dependent and younger children had higher NI-values than older children at the same level of sedation.