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.

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.

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 ).