A randomised controlled trial of a novel tramadol chewable tablet: pharmacokinetics and tolerability in children.

Tramadol is a bitter atypical opioid analgesic drug and is prescribed to treat postoperative pain in children. However, in many countries there is no licensed paediatric tramadol formulation available. We have formulated a novel chewable chocolate-based drug delivery system for the administration of tramadol to children. This pilot, single-centre, open-label, randomised clinical study assessed the taste tolerability and comparative population pharmacokinetics of the novel tramadol chewable tablet against a compounded tramadol hydrochloride oral liquid, at a dose of 1 mg.kg-1 . A 5-point facial hedonic scale was used by the children, parents and nurses to assess tolerability. One hundred and forty-one children aged 3-16 years were given tramadol 30 min before general anaesthesia. Blood samples were taken following the induction of anaesthesia and for up to 5 h following tramadol administration. Tramadol and its active metabolite O-desmethyltramadol were analysed using reversed-phase high-performance liquid chromatography. A population pharmacokinetic model was built using non-linear mixed effects modelling. The relative bioavailability for the tablet was 1.25 times higher (95%CI 1.16-1.35) than for tramadol hydrochloride oral liquid, while the absorption rate constant for the tablet was significantly lower (1.97 h-1 vs. 3.34 h-1 , p < 0.001). Larger inter-individual variability in absorption rates were observed with the liquid tramadol. The tramadol chewable tablet was more acceptable in taste to children when assessed by the children, parents and nurses (all p < 0.001). We conclude that the novel tramadol chewable tablet has favourable acceptability and more reliable relative bioavailability in children compared with tramadol hydrochloride oral liquid.

Paraspinal desmoid fibromatosis after lumbar epidural analgesia.

A 14-year-old girl with cerebral palsy presented for bilateral lower limb surgery for spasticity. A lumbar epidural catheter was sited under general anaesthesia on the third attempt and used intra-operatively with good effect. A local anaesthetic infusion was used for postoperative analgesia but was noted to be leaking under the dressing with a patchy, unilateral block. The catheter was therefore removed on the second postoperative day. Following discharge, the patient progressively developed new back and leg pain for which she was re-admitted seven weeks later. This was investigated and initially thought to be myositis of the erector spinae muscles on magnetic resonance imaging. When the patient failed to respond to treatment, a muscle biopsy demonstrated desmoid fibromatosis. Trauma may cause or accelerate the development of desmoid fibromatosis, which has also been theorised to arise from scar tissue in previously injured areas. We hypothesise that challenging epidural placement or the leakage of the local anaesthetic agent into the surrounding muscular tissue, inducing local myonecrosis, could have been the triggering or accelerating event in tumour development. This may be the first reported case of extra-abdominal desmoid fibromatosis in association with epidural placement.

Propofol use in children with allergies to egg, peanut, soybean or other legumes.

Propofol is the most commonly administered intravenous agent for anaesthesia in children. However, there are concerns that the emulsified preparation may not be safe in children with an allergy to egg, peanut, soybean or other legumes. We conducted a retrospective study of children with immunologically confirmed egg, peanut, soybean or legume allergy and who underwent general anaesthesia at Princess Margaret Hospital for Children between 2005 and 2015. We extracted details regarding allergy diagnosis, each anaesthetic administered and any adverse events or signs of an allergic reaction in the peri-operative period. A convenience sample of patients without any known food allergies was identified from our prospective anaesthesia research database and acted as a control group. We identified 304 food-allergic children and 649 procedures where propofol was administered. Of these, 201 (66%) had an egg allergy, 226 (74%) had a peanut allergy, 28 (9%) had a soybean allergy and 12 (4%) had a legume allergy. These were compared with 892 allergy-free patients who were exposed to propofol. In 10 (3%) allergy patients and 124 (14%) allergy-free patients, criteria for a possible allergic reaction were met. In nine of the food-allergic children and in all the controls valid non-allergic explanations for the clinical symptoms were found. One likely mild allergic reaction was experienced by a child with a previous history of intralipid allergy. We conclude that genuine serious allergic reaction to propofol is rare and is not reliably predicted by a history of food allergy.

A novel, palatable paediatric oral formulation of midazolam: pharmacokinetics, tolerability, efficacy and safety.

Midazolam is one of many bitter drugs where provision of a suitable oral paediatric formulation, particularly in the pre-anaesthetic setting, remains a challenge. To overcome this problem, a novel chocolate-based tablet formulation has been developed with positive pre-clinical results. To further investigate the potential of this formulation, 150 children aged 3-16 years who were prescribed midazolam as a premedication were randomly assigned to receive 0.5 mg.kg-1 either as the novel formulation or an intravenous solution given orally, which is the current standard at our institution. Tolerability was assessed by each child, parent and nurse using a 5-point facial hedonic scale and efficacy was determined as the time to onset of sedation. Blood samples for midazolam and 1-hydroxymidazolam levels were analysed using high-performance liquid chromatography. Population pharmacokinetics were evaluated using non-linear mixed effects modelling. The novel formulation had significantly improved tolerability scores from children, parents and nurses (all p < 0.001). Time to effect was not different between the groups (p = 0.140). The pharmacokinetics of midazolam and 1-hydroxymidazolam were able to be modelled simultaneously. The novel formulation was subject to a higher estimated first-pass metabolism compared with the intravenous solution (8.6% vs. 5.0%) and a significantly lower relative bioavailability of 82.1% (p = 0.013), with no other significant differences. Exposure relative to dose was in the range previously reported for midazolam syrup. We conclude that the novel chocolate-based formulation of midazolam provides improved tolerability while remaining efficacious with suitable pharmacokinetics when used as a premedicant for children.

Cuffed vs. uncuffed tracheal tubes in children: a randomised controlled trial comparing leak, tidal volume and complications.

Cuffed tracheal tubes are increasingly used in paediatric anaesthetic practice. This study compared tidal volume and leakage around cuffed and uncuffed tracheal tubes in children who required standardised mechanical ventilation of their lungs in the operating theatre. Children (0-16 years) undergoing elective surgery requiring tracheal intubation were randomly assigned to receive either a cuffed or an uncuffed tracheal tube. Assessments were made at five different time-points: during volume-controlled ventilation 6 ml.kg-1 , PEEP 5 cmH2 O and during pressure-controlled ventilation 10 cmH2 O / PEEP 5 cmH2 O. The pressure-controlled ventilation measurement time-points were: just before a standardised recruitment manoeuvre; just after recruitment manoeuvre; 10 min; and 30 min after the recruitment manoeuvre. Problems and complications were recorded. During volume-controlled ventilation, leakage was significantly less with cuffed tracheal tubes than with uncuffed tracheal tubes; in ml.kg-1 , median (IQR [range]) 0.20 (0.13-0.39 [0.04-0.60]) vs. 0.82 (0.58-1.38 [0.24-4.85]), respectively, p < 0.001. With pressure-controlled ventilation, leakage was less with cuffed tracheal tubes and stayed unchanged over a 30-min period, whereas with uncuffed tracheal tubes, leakage was higher and increased further over the 30-min period. Tidal volumes were higher in the cuffed group and increased over time, but in the uncuffed group were lower and decreased over time. Both groups showed an increase in tidal volumes following recruitment manoeuvres. There were more short-term complications with uncuffed tracheal tubes, but no major complications were recorded in either group at long-term follow-up. With standardised ventilator settings, cuffed tracheal tubes produced better ventilation characteristics compared with uncuffed tracheal tubes during general anaesthesia for routine elective surgery.

Premedication with salbutamol prior to surgery does not decrease the risk of perioperative respiratory adverse events in school-aged children.

BACKGROUND: Perioperative respiratory adverse events (PRAE) remain the leading cause of morbidity and mortality in the paediatric population. This double-blinded randomized control trial investigated whether inhaled salbutamol premedication decreased the occurrence of PRAE in children identified as being at high risk of PRAE. METHODS: Children with at least two parentally reported risk factors for PRAE undergoing elective surgery were eligible for recruitment. They were randomized to receive either salbutamol (200 µg) or placebo prior to their surgery and PRAE (bronchospasm, laryngospasm, airway obstruction, desaturation, coughing and stridor) were recorded. RESULTS: Out of 470 children (6-16 yr, 277 males, 59%) recruited, 462 were available for an intention-to-treat analysis. Thirty-two (14%) and 27 (12%) children from the placebo and salbutamol groups experienced PRAE. This difference was not significant [odds ratio (OR): 0.83, 95% confidence interval (CI): 0.48-1.44, P : 0.51]. Oxygen desaturation [14/232 (6%) vs 14/230 (6%), OR: 1.01, 95% CI: 0.47-2.17, P : 0.98] and severe coughing [12/232 (5%) vs 10/230 (4%), OR: 0.83, 95% CI: 0.35-1.97, P : 0.68] were the most common PRAE, but did not significantly differ between the groups. The occurrence of PRAE was slightly lower in children with respiratory symptoms who received salbutamol compared with placebo [16/134 (12%) vs 21/142 (15%), OR: 0.93, 95% CI: 0.38-2.26, P : 0.87], but was not significantly different. CONCLUSIONS: Premedication with salbutamol to children aged between 6 and 16 years and at high risk of PRAE prior to their surgery did not reduce their risk of PRAE. TRIAL REGISTRATION NUMBER: ACTRN12612000626864 ( www.anzctr.org.au ).

Surgical pleth index: prediction of postoperative pain in children?

BACKGROUND: Surgical Pleth Index (SPI) is a non-invasive, dimensionless score (0-100) aimed to allow an estimate of intraoperative nociception. Thus, it may be a useful tool to guide intraoperative analgesia. However, no optimum SPI target range for the use in children has yet been defined. It was the aim of this study to define a clinically appropriate SPI target to predict moderate-severe postoperative pain in children. METHODS: After ethics approval 105 children (2-16 yr) undergoing elective sevoflurane/opioid-based anaesthesia were included. SPI was recorded directly before the end of surgery and compared with acute postoperative pain (age appropriately assessed on different pain scales in the age groups two to three yr, four to eight yr and nine to16 yr) in the postoperative acute care unit (PACU). RESULTS: Data of 93 children were analysed. A significant negative correlation was found between age and SPI (r=-0.43; P=0.03). The SPI cut-off value with the highest sensitivity (76%) and specificity (62%) in all children combined was 40. The negative predictive value for SPI ≤ 40 to predict the absence of moderate-severe pain in PACU was 87.5%. The commonly used SPI cut-off (50) published in all related studies had neither any clinically relevant sensitivity nor specificity to predict the presence or absence of acute pain in PACU. CONCLUSIONS: The results suggest that a lower (≤ 40) than previously published (50) target for SPI may be more appropriate in studies investigating SPI guided anaesthesia in children, if the avoidance of moderate-severe postoperative pain is the main goal. CLINICAL TRIAL REGISTRATION: ACTRN12616001139460.

Peripheral neuropathy masquerading as an epidural complication.

BACKGROUND: Epidural anaesthesia generally provides safe postoperative pain control, but does carry a small risk of nerve damage. CASE DESCRIPTION: A 30-year-old woman with long standing rheumatoid arthritis underwent a primary total knee replacement under general anaesthetic. Postoperatively, a continuous epidural infusion was used for pain relief. On discontinuation of the epidural, she was confirmed to have a foot drop. Her subsequent investigation and management for neuropathic pain was coordinated by the acute pain service. Magnetic resonance imaging excluded a central lesion. Nerve conduction studies 6 weeks later confirmed peripheral nerve lesions. The patient's neurological deficit was not due to her epidural, but rather her intraoperative tourniquet. DISCUSSION: The episode raises a number of discussion points for our pain service around the use of epidurals for knee replacement surgery, the management of nerve injury and the ease at which the epidural can be blamed for coincident injuries. International evidence would suggest that neurological complications following knee replacement are more likely to be related to surgery can epidural analgesia.

Caesarean section in a parturient with a spinal cord stimulator.

A 35-year-old G2P1 parturient at 32 weeks of gestation with an implanted spinal cord stimulator was admitted for urgent caesarean section. Spinal anaesthesia was performed below the spinal cord stimulator leads at the L4-5 level, and a healthy female infant was delivered. A basic description of the technology and resulting implications for the parturient are discussed.

Long-term assessment of renal function following nephrectomy for stage I renal carcinoma.

OBJECTIVE: To evaluate the impact of nephrectomy on renal function in people who are potential candidates for nephron sparing surgery, i.e. partial nephrectomy. PATIENTS AND METHODS: A retrospective analysis was carried out of 109 patients (35 women, 74 men) who had undergone a nephrectomy for stage I renal carcinoma at the University of Michigan between 1960 and 1979. All patients had a functioning contralateral kidney and had undergone at least one post-operative serum creatinine evaluation. Statistical analysis was by Pearson's correlation coefficient. RESULTS: One individual developed a transitional cell carcinoma in the remaining renal pelvis and was treated with nephroureterectomy. No other patient progressed to dialysis. Five patients had post-operative serum creatinine levels from 221 to 354 mumol/l, one of whom had undergone both a nephrectomy and a partial nephrectomy for bilateral renal tumours. The remaining four had renal disease including diabetes, hypertension, pyelonephritis and renal artery stenosis. There was a strong association between pre-operative and post-operative serum creatinine values. CONCLUSION: Patients with low stage renal tumours and a normal contralateral kidney are at low risk of progression to renal failure.