Adherence to Swedish guidelines for pain treatment in relation to pediatric tonsil surgery: A survey of the multidisciplinary team.

BACKGROUND: Pain management in children after tonsil surgery is essential, and optimal pain treatment has been discussed for many years. Data from the National Tonsil Register in Sweden (NTRS) and a national mapping have demonstrated the need for national pain treatment guidelines for pediatric tonsil surgery. As a result, Swedish national guidelines, together with updated patient information on the website tonsilloperation.se, were developed and implemented in 2013. OBJECTIVES: The objective of this study was to evaluate the professionals' opinions of and adherence to pain treatment guidelines for pediatric tonsil surgery patients in a two-year follow-up. METHOD: This descriptive cross-sectional study was based on data from an inter-professional questionnaire, which was validated by an expert group using a content validity index (S-CVI 0.93). The questionnaire was sent to all Swedish ear, nose and throat (ENT) departments (n = 49) that the NTRS identified as performing tonsil surgery on children younger than 18 years of age. In each clinic, we asked for responses from staff in each of the following professions: ENT physicians, anesthesia physicians, registered nurse anesthetists, and registered nurses in the ENT departments. RESULTS: Respondents from 48 ENT departments participated, and 139/163 (85%) completed questionnaires were returned. The guidelines were reported as being clear, ensuring patient safety and providing optimal pharmacological treatment. Treatment was given according to the guidelines: Half of the departments gave pre- or intraoperative treatment with clonidine, betamethasone and high-dose paracetamol (acetaminophen). A multimodal pain approach (paracetamol and COX-inhibitors) after hospital discharge was prescribed by all departments after tonsillectomy and, extensively, after tonsillotomy. One-third of the departments prescribed paracetamol with a higher normal dose for the first three postoperative days. Half of the departments prescribed rescue analgesics, clonidine or opioids after tonsillectomy. None of the departments prescribed codeine or tramadol, drugs that are discouraged in the guidelines. The majority of the departments used the website tonsilloperation.se to provide information to the patients and their caregivers. CONCLUSION: The respondents' opinions of and the ENT departments adherence to the Swedish national guidelines were considered to be good. The national implementation process in Sweden has impacted the manner in which ENT departments treat pain after tonsil surgery.

Pharmacokinetics after a single dose of naloxone administered as a nasal spray in healthy volunteers.

BACKGROUND: There is increasing interest in the use of intranasal naloxone to reverse adverse opioid effects during management of procedural pain in children and in adults after overdose. There are limited data on the pharmacokinetics of intranasal naloxone so in this study we aimed to detail the pharmacokinetic profile of the commercially marketed injectable solution of naloxone 0.4 mg/ml when administered as an intranasal spray. METHODS: Twenty healthy volunteers received naloxone as an intranasal spray at a dose of 10 µg/kg. Venous blood sampling was carried out for 90 min after administration to determine the time profile of the plasma concentrations of using tandem mass spectrometry. Pharmacokinetic parameters were calculated using a one-compartment model. RESULTS: Median time to maximum naloxone concentration (Tmax) was 14.5 (95% CI: 9.0-16.5) min, mean maximum naloxone concentration (Cmax) was 1.09 ± 0.56 ng/ml and mean AUC0-90 min was 37.1 ± 15.0 ng*min/ml. Elimination half-life estimated from the median concentration data was 28.2 min. CONCLUSION: Our results show a faster uptake of intranasal naloxone to maximum concentration compared with previous studies although with a marked variation in maximum concentration. The findings are consistent with our clinical experience of the time profile for reversing the effects of sufentanil sedation in children.

Swedish guidelines for the treatment of pain in tonsil surgery in pediatric patients up to 18 years.

BACKGROUND: Surgery of the tonsils often causes severe pain lasting for many days as been shown by data from the National Tonsil Surgery Register in Sweden. Tonsillotomy is associated with fewer readmissions due to bleeding, number of days requiring analgesics and health care contacts due to pain compared to tonsillectomy. The register data demonstrate the necessity of better-evidenced based pain treatment guidelines for tonsil-surgery. OBJECTIVES: To develop evidenced based pain treatment guidelines for tonsil-surgery in Sweden. METHODS: The evidence based guidelines were designed by an updated literature review and from the clinical expertise in the pediatric pain field, which thereafter were reviewed by ENT-doctors and anesthetists from each ENT-clinic in Sweden. RESULTS: A multimodal pain treatment approach is advocated, including premedication and administration during anesthesia, with paracetamol (acetaminophen), clonidine and betamethasone. If not given as a premedication the combination can be administered intravenously in the initial phase of anesthesia. At the end of surgery, if no bleeding problems, cox-inhibitors can be given. After discharge from hospital, the recommendations for pain relief are paracetamol combined with cox-inhibitors (ibuprofen, diclofenac) and if needed oral clonidine in favor of opioids. When pain intensity decreases, discontinue the analgesic treatment in the following order: opioid, clonidine, paracetamol and at last ibuprofen. The need for analgesic treatment after tonsillectomy is usually 5-8 days, after tonsillotomy only 3-5 days. Parents are recommended to contact the hospital if the child has difficulties in drinking or eating adequately and/or suffers from pain despite taking the recommended medication regularly. CONCLUSIONS: Swedish guidelines for tonsil-surgery provide practical evidence-based pain treatment recommendations.

Pharmacokinetics after a single intravenous dose of the opioid ketobemidone in neonates.

BACKGROUND: Ketobemidone is often used as an alternative to morphine in children in the Scandinavian countries. In an earlier study, we have examined the pharmacokinetic properties in children in different age groups but have not focused on neonates. The aim of this clinical trial was to explore the pharmacokinetics of ketobemidone in neonates. METHODS: Fifteen full-term neonates (eight females) from 37 gestational weeks at birth and scheduled for elective surgery were included in the trial. Their median age was 3 days (range 1-18 days). Ketobemidone hydrochloride was administered as a single intravenous bolus dose, and ketobemidone concentrations were measured by liquid chromatography-mass spectrometry over 10 h. Pharmacokinetic parameters were calculated with standard compartmental methods. RESULTS: The median (range) values for ketobemidone clearance, apparent volume of distribution, volume of central compartment, distribution half-life and elimination half-life were 0.46 (0.23-0.84) l/h/kg, 4.64 (3.50-7.31) l/kg, 1.71 (0.16-3.47) l/kg, 2.85 (1.04-10.78) min and 7.26 (3.5-11.3) h. CONCLUSION: Compared with our previous study in children older than 1 year of age, the elimination of ketobemidone appeared to be slower in full-term neonates. Despite a low pharmacokinetic variability of ketobemidone as observed in the present neonatal patient population, we recommend individualizing the dose of ketobemidone based on observations of analgesic efficacy.

Pharmacokinetics after an intravenous single dose of the opioid ketobemidone in children.

BACKGROUND: Ketobemidone is often used as an alternative to morphine in children in the Scandinavian countries. The aim of this clinical trial was to explore the pharmacokinetics of ketobemidone in children because these properties have not been reported previously. METHODS: Thirty children, newborn to 10 years, scheduled for elective surgery were included in the trial. Ketobemidone hydrochloride was administered as a single intravenous bolus dose and ketobemidone and norketobemidone concentrations were measured by LC-MS over 8 h. Pharmacokinetic parameters were determined using compartmental methods. RESULTS: Six children were excluded from pharmacokinetic analysis because of incomplete blood sampling. The values of ketobemidone clearance (l/h/kg) given as median (range) were 0.84 (0.29-3.0) in Group A (0-90 days), 0.89 (0.55-1.35) in Group B (1-2.5 years) and 0.74 (0.50-0.99) in Group C (7-10 years). The corresponding values for apparent volume of distribution (l/kg) were 4.4 (3.7-6.9) (Group A), 2.6 (2.0-5.6) (Group B) and 3.9 (2.7-5.0 (Group C), and for elimination half-life (h) 3.0 (1.4-8.9) (Group A), 2.0 (1.2-4.7) (Group B) and 3.7 (2.4-6.9) (Group C), respectively. In the two neonates the elimination half-life was almost 9 h. The metabolite norketobemidone did not reach levels above the limit of quantification (0.07 ng/ml) in any of the patients. CONCLUSION: The pharmacokinetic parameters of ketobemidone in children older than 1 month appear to be similar to those in adults. Because of the large interindividual variability of the pharmacokinetics in neonates, further studies especially in this age group are warranted.

Comparison of the analgesic efficacy of ketobemidone and morphine for management of postoperative pain in children: a randomized, controlled study.

BACKGROUND: Ketobemidone has been used as an analgesic for postoperative pain in children, but to our knowledge the effect and occurrence of adverse effects of ketobemidone compared to morphine is not known. The aim was to determine if the analgesic potency and the occurrence of adverse effects of ketobemidone differ from morphine when administered to children, as measured by patient-controlled analgesia consumption (PCA) for postoperative pain. METHODS: Sixty healthy children, aged 6 to 16 years, scheduled for elective surgery were randomized to receive either ketobemidone (Ke) 1 mg ml(-1) or morphine (Mo) 1 mg ml(-1) for postoperative pain through PCA. Drug consumption (microg kg(-1) h(-1)), the number of PCA doses, pain intensity, and adverse effects were recorded at regular intervals. RESULTS: Data on total drug consumption were based on 26 children in the Ke group and 28 in the Mo group. A non-statistically significant difference for total mean consumption of ketobemidone (18.6 microg kg(-1)h(-1)) and morphine (23.2 microg kg(-1)h(-1)) was obtained. The mean dose ratio (Mo/Ke) was 0.80 and the median was 0.94. Children's characteristics, loading dose, PCA doses, VAS scores, and adverse effects showed no significant differences between the groups. CONCLUSION: The analgesic potency and adverse effects of ketobemidone are similar to morphine when used for postoperative pain management in children.

Retrospective evaluation of continuous epidural infusion for postoperative pain in children.

BACKGROUND: The safety and efficacy of postoperative epidural analgesia (EDA) in children are not well documented in larger series of patients given routine postoperative care. The aims of this study were to evaluate the efficacy of pain relief, determine the incidence and type of complications during the entire period of epidural pain treatment in children, and assess the factors affecting efficacy METHODS: Children treated postoperatively with an EDA infusion during the period 18 September 1994 to 1 January 1999 were studied. Data regarding the age, gender, efficacy of analgesia, duration of epidural infusion, types of side-effects and complications, reasons for discontinuation, and types and duration of surgery were collected daily by the Acute Pain Treatment Service. The sensory dermatomal level of the surgical incision site was included retrospectively. RESULTS: Five hundred and eighteen epidural infusions were given to 476 children. Pain relief was rated as 'good' at 76% of visits. There were no major complications or sequelae. Thirty-seven per cent of the epidural infusions were prematurely discontinued, and 21% were discontinued because of unsatisfactory analgesia. Factors related to a higher percentage of unsatisfactory function were surgical incision site located above the umbilicus, gastroenterologic surgery, protracted surgery and age. Age and duration of surgery were significantly related to unsatisfactory function. CONCLUSION: This study shows that continuous epidural infusion for postoperative pain was satisfactory in most cases, and that no major side-effects or complications occurred in children nursed on regular wards. The early recognition of unsatisfactory function of an EDA is important for a child's well being.

Effects of intrathecal galanin on nociceptive responses in rats with mononeuropathy.

The present study was performed on rats with experimental mononeuropathy induced by left common sciatic nerve loose ligation. Unilateral sciatic nerve loose ligation induced decreases of the hindpaw withdrawal latency to the hot-plate test, cold-plate test and the Randall Selitto test. Sciatic nerve loose ligation induced hyperesponsiveness to touch at room temperature also. Intrathecal administration of either 3 or 6 nmol of galanin, but not 1 nmol, induced significant bilateral increases in hindpaw withdrawal latencies to the hot-plate test, cold-plate test and the Randall Selitto tests in rats with left mononeuropathy. The results indicate that galanin may play important roles in transmission of presumed nociceptive information in the spinal cord of mononeuropathic rats.

Effects of calcitonin gene-related peptide-(8-37) on withdrawal responses in rats with inflammation.

The present study was performed to explore the effect of subcutaneous injection of carrageenan into the rat plantar region on hindpaw edema formation and the latency of hindpaw withdrawal to presumed nociceptive stimulation. Subcutaneous injection of carrageenan into the left hindpaw induced a significant increase in the volume of the left hindpaw, leaving the right side unaffected. In addition, we found a bilateral decrease in hindpaw withdrawal latency to heat and mechanical, but not to cold stimulation. The decreased bilateral hindpaw withdrawal latency to heat stimulation lasted for 14 days after carrageenan injection. The decreased bilateral hindpaw withdrawal latency to mechanical stimulation lasted for 2 days after the injection, then reversed and increased from day 3 to 14. Intrathecal injection of either 10 nmol of calcitonin gene-related peptide 8-37 or 26.6 nmol of morphine induced significant bilateral increases in hindpaw withdrawal latency, which were more pronounced with the morphine. The results show that experimentally induced unilateral hindpaw inflammation induces a bilateral decrease in hindpaw withdrawal latencies to presumed nociceptive stimulation while the sensory systems for heat and mechanical stimulation were differently affected after carrageenan injection.

Rectal administration of morphine in children. Pharmacokinetic evaluation after a single-dose.

BACKGROUND: There is limited knowledge about the pharmacokinetics of morphine and its metabolites after rectal administration in children. In this study the pharmacokinetics of two different rectal formulations of morphine were examined and compared with intravenous morphine. METHODS: Children undergoing elective surgery received rectal morphine 0.2 mg/kg before start of surgery. Ten children (mean age 14 months) received morphine rectally in a hydrogel formulation and another 10 children (mean age 16 months) received morphine rectally in a parenteral formulation. For comparison, 6 children (mean age 21 months) were given the same dose intravenously. The plasma concentrations of morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) were measured by HPLC over 6 h after drug administration. RESULTS: The mean rectal bioavailability of morphine was 35% (range 18-59) after hydrogel administration and 27% (range 6-93) after the solution. Mean values of Cmax were 76 nmol/l (25-129) and 56 nmol/1 (15-140), respectively. The results showed that morphine gel had a significantly higher bioavailability (P < 0.02) than the solution. The ratios of plasma (M3G + M6G) to morphine were higher after rectal administration (mean 7.5-8.7) than after i.v. injection (mean 5.3), indicating the presence of first-pass metabolism using the rectal route. CONCLUSIONS: The rectal morphine hydrogel has pharmacokinetic properties which makes it a useful formulation for premedication and pain alleviation in paediatric patients.

Growth hormone improves muscle protein metabolism and whole body nitrogen economy in man during a hyponitrogenous diet.

Healthy male volunteers (n = 12) were given a normocaloric hyponitrogenous diet for a conditioning period of 7 days. Thereafter they were blindly randomized to receive daily injections of methionyl recombinant human growth hormone (met-hGH) 0.06 IU/kg or saline during a second week of hyponitrogenous nutrition. The met-hGH group showed a lower urinary urea excretion and a lower serum concentration of urea as compared with the control group. In skeletal muscle, the polyribosome concentration, indicative of muscle protein synthesis, as well as the concentrations of glutamine, alanine, aspartate, serine, and threonine, decreased in the control group, whereas no such changes were seen in the met-hGH-treated group. Since provision of met-hGH prevented protein catabolism in muscle and improved whole body nitrogen economy, investigations of the possible beneficial effects of met-hGH to prevent skeletal muscle vast after surgical trauma are advocated.

Interaction of diazepam and naloxone on acupuncture induced pain relief.

We have studied if 2 Hz electroacupuncture alleviates chronic nociceptive pain and if so whether the alleviation was related to the release of endogenous opioids. Thirty-two patients suffering from osteoarthritis were subjected to electroacupuncture, with or without pretreatment with naloxone or diazepam. The effect of the different experimental procedures was assessed using scales for the intensity (sensory component) and unpleasantness (affective component) of pain. Electroacupuncture induced a significant alleviation of pain. This alleviation was more significant on the affective scales (p less than 0.01) than on the sensory scales (p less than 0.05). After pretreatment with diazepam or naloxone, the subsequent pain alleviating effect was reduced. These data indicate that acupuncture induced analgesia may partly be mediated through endogenous opioids which are affected by pretreatment with diazepam or naloxone.

Acupuncture and sensory thresholds.

The effect of acupuncture on sensory thresholds was studied in 6 healthy subjects. The modes of acupuncture studied were: 1. manual stimulation, 2. electrical stimulation at 2 Hz, 3. electrical stimulation at 80 Hz. Superfiscial-acupuncture was used as placebo. Insertions of needles or application of electrodes were bilateral, at St 7 (intrasegmental) or Li 4 (extrasegmental). The study showed that manual or electro-acupuncture were effective when used intrasegmentally, raising pain threshold values 1.1 to 1.4 times that prior to stimulation. The pain threshold elevation obtained was not significantly related to plasma levels of beta-endorphin, ACTH or prolactin. Other sensory thresholds, thermal, vibrotactile and electrotactile were unaffected by such conditioned stimulation. Superfiscial-acupuncture had no significant effect on the sensory thresholds tested.