Behavioural and neuropsychological outcomes in children exposed in utero to maternal labour epidural analgesia.

BACKGROUND: Recent studies report conflicting results regarding the relationship between labour epidural analgesia (LEA) in mothers and neurodevelopmental disorders in their offspring. We evaluated behavioural and neuropsychological test scores in children of mothers who used LEA. METHODS: Children enrolled in the Raine Study from Western Australia and delivered vaginally from a singleton pregnancy between 1989 and 1992 were evaluated. Children exposed to LEA were compared with unexposed children. The primary outcome was the parent-reported Child Behaviour Checklist (CBCL) reporting total, internalising, and externalising behavioural problem scores at age 10 yr. Score differences, an increased risk of clinical deficit, and a dose-response based on the duration of LEA exposure were assessed. Secondary outcomes included language, motor function, cognition, and autistic traits. RESULTS: Of 2180 children, 850 (39.0%) were exposed to LEA. After adjustment for covariates, exposed children had minimally increased CBCL total scores (+1.41 points; 95% confidence interval [CI] 0.09 to 2.73; P=0.037), but not internalising (+1.13 points; 95% CI -0.08 to 2.34; P=0.066) or externalising (+1.08 points; 95% CI -0.08 to 2.24; P=0.068) subscale subscores. Increased risk of clinical deficit was not observed for any CBCL score. For secondary outcomes, score differences were inconsistently observed in motor function and cognition. Increased exposure duration was not associated with worse scores in any outcomes. CONCLUSIONS: Although LEA exposure was associated with slightly higher total behavioural scores, there was no difference in subscores, increased risk of clinical deficits, or dose-response relationship. These results argue against LEA exposure being associated with consistent, clinically significant neurodevelopmental deficits in children.

The use of honey in the perioperative care of tonsillectomy patients-A narrative review.

Tonsillectomy is one of the most common surgical procedures in childhood. While generally safe, it often is associated with a difficult early recovery phase with poor oral intake, dehydration, difficult or painful swallowing, postoperative bleeding, infection and/or otalgia. Better pain management and the availability of more child friendly medications are within the top consumer priorities in perioperative medicine, highlighting the importance of alternative pain treatments. This review focuses on the potential role of honey in the postoperative setting, its effects, and mechanisms of action. While the application of honey post-tonsillectomy may offer analgesic and healing benefits, it may also reduce postoperative bleeding. A systematic search was carried out using the search terms honey, tonsillectomy. Filters were applied to human studies and English. No other search terms were used or age filters applied to yield a broader range of results. Seven pediatric, four adult, and two studies of mixed pediatric and adult patients with sample sizes ranging from 8 to 52 patients were included in this review. Effect sizes ranged from small to huge across the studies. While the application of honey post-tonsillectomy may offer analgesic and healing benefits, it may also reduce postoperative bleeding. However, while there are potential benefits based on the chemical composition of honey, the current literature is of variable quality and there is need for high quality clinical trials.

High-flow nasal oxygen for children's airway surgery to reduce hypoxaemic events: a randomised controlled trial.

BACKGROUND: Tubeless upper airway surgery in children is a complex procedure in which surgeons and anaesthetists share the same operating field. These procedures are often interrupted for rescue oxygen therapy. The efficacy of nasal high-flow oxygen to decrease the frequency of rescue interruptions in children undergoing upper airway surgery is unknown. METHODS: In this multicentre randomised trial conducted in five tertiary hospitals in Australia, children aged 0-16 years who required tubeless upper airway surgery were randomised (1:1) by a web-based randomisation tool to either nasal high-flow oxygen delivery or standard oxygen therapy (oxygen flows of up to 6 L/min). Randomisation was stratified by site and age (<1 year, 1-4 years, and 5-16 years). Subsequent tubeless upper airway surgery procedures in the same child could be included if there were more than 2 weeks between the procedures, and repeat surgical procedures meeting this condition were considered to be independent events. The oxygen therapy could not be masked, but the investigators remained blinded until outcome data were locked. The primary outcome was successful anaesthesia without interruption of the surgical procedure for rescue oxygenation. A rescue oxygenation event was defined as an interruption of the surgical procedure to deliver positive pressure ventilation using either bag mask technique, insertion of an endotracheal tube, or laryngeal mask to improve oxygenation. There were ten secondary outcomes, including the proportion of procedures with a hypoxaemic event (SpO2 <90%). Analyses were done on an intention-to-treat (ITT) basis. Safety was assessed in all enrolled participants. This trial is registered in the Australian New Zealand Clinical Trials Registry, ACTRN12618000949280, and is completed. FINDINGS: From Sept 4, 2018, to April 12, 2021, 581 procedures in 487 children were randomly assigned to high-flow oxygen (297 procedures) or standard care (284 procedures); after exclusions, 528 procedures (267 assigned to high-flow oxygen and 261 assigned to standard care) in 483 children (293 male and 190 female) were included in the ITT analysis. The primary outcome of successful anaesthesia without interruption for tubeless airway surgery was achieved in 236 (88%) of 267 procedures on high-flow oxygen and in 229 (88%) of 261 procedures on standard care (adjusted risk ratio [RR] 1·02, 95% CI 0·96-1·08, p=0·82). There were 51 (19%) procedures with a hypoxaemic event in the high-flow oxygen group and 57 (22%) in the standard care group (RR 0·86, 95% CI 0·58-1·24). Of the other prespecified secondary outcomes, none showed a significant difference between groups. Adverse events of epistaxis, laryngospasm, bronchospasm, hypoxaemia, bradycardia, cardiac arrest, hypotension, or death were similar in both study groups. INTERPRETATION: Nasal high-flow oxygen during tubeless upper airway surgery did not reduce the proportion of interruptions of the procedures for rescue oxygenation compared with standard care. There were no differences in adverse events between the intervention groups. These results suggest that both approaches, nasal high-flow or standard oxygen, are suitable alternatives to maintain oxygenation in children undergoing upper airway surgery. FUNDING: Thrasher Research Fund, the Australian and New Zealand College of Anaesthetists, the Society for Paediatric Anaesthesia in New Zealand and Australia.

Effect of different lung recruitment strategies and airway device on oscillatory mechanics in children under general anaesthesia.

BACKGROUND: Atelectasis has been reported in 68 to 100% of children undergoing general anaesthesia, a phenomenon that persists into the recovery period. Children receiving recruitment manoeuvres have less atelectasis and fewer episodes of oxygen desaturation during emergence. The optimal type of recruitment manoeuvre is unclear and may be influenced by the airway device chosen. OBJECTIVE: We aimed to investigate the different effects on lung mechanics as assessed by the forced oscillation technique (FOT) utilising different recruitment strategies: repeated inflations vs. one sustained inflation and different airway devices, a supraglottic airway device vs. a cuffed tracheal tube. DESIGN: Pragmatic enrolment with randomisation to the recruitment strategy. SETTING: We conducted this single-centre trial between February 2020 and March 2022. PARTICIPANTS: Seventy healthy patients (53 boys) aged between 2 and 16 years undergoing general anaesthesia were included. INTERVENTIONS: Forced oscillations (5 Hz) were superimposed on the ventilator waveform using a customised system connected to the anaesthesia machine. Pressure and flow were measured at the inlet of the airway device and used to compute respiratory system resistance and reactance. Measurements were taken before and after recruitment, and again at the end of surgery. MAIN OUTCOME MEASURES: The primary endpoint measured is the change in respiratory reactance. RESULTS: Statistical analysis (linear model with recruitment strategy and airway device as factors) did not show any significant difference in resistance and reactance between before and after recruitment. Baseline reactance was the strongest predictor for a change in reactance after recruitment: prerecruitment Xrs decreased by mean (standard error) of 0.25 (0.068) cmH 2 O s l -1 per  1 cmH 2 O -1  s l -1 increase in baseline Xrs ( P  < 0.001). After correcting for baseline reactance, the change in reactance after recruitment was significantly lower for sustained inflation compared with repeated inflation by mean (standard error) 0.25 (0.101) cmH 2 O ( P  = 0.0166). CONCLUSION: Although there was no significant difference between airway devices, this study demonstrated more effective recruitment via repeated inflations than sustained inflation in anaesthetised children. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12619001434189.

Patient positioning and its impact on perioperative outcomes in children: A narrative review.

Patient positioning interacts with a number of body systems and can impact clinically important perioperative outcomes. In this educational review, we present the available evidence on the impact that patient positioning can have in the pediatric perioperative setting. A literature search was conducted using search terms that focused on pediatric perioperative outcomes prioritized by contemporary research in this area. Several key themes were identified: the effects of positioning on respiratory outcomes, cardiovascular outcomes, enteral function, patient and carer-centered outcomes, and soft issue injuries. We encountered considerable heterogeneity in research in this area. There may be a role for lateral positioning to reduce respiratory adverse outcomes, head elevation for intubation and improved oxygenation, and upright positioning to reduce peri-procedural anxiety.

Airway management in the paediatric difficult intubation registry: a propensity score matched analysis of outcomes over time.

Background: The Paediatric Difficult Intubation Collaborative identified multiple attempts and persistence with direct laryngoscopy as risk factors for complications in children with difficult tracheal intubations and subsequently engaged in initiatives to reduce repeated attempts and persistence with direct laryngoscopy in children. We hypothesised these efforts would lead to fewer attempts, fewer direct laryngoscopy attempts and decrease complications. Methods: Paediatric patients less than 18 years of age with difficult direct laryngoscopy were enrolled in the Paediatric Difficult Intubation Registry. We define patients with difficult direct laryngoscopy as those in whom (1) an attending or consultant obtained a Cormack Lehane Grade 3 or 4 view on direct laryngoscopy, (2) limited mouth opening makes direct laryngoscopy impossible, (3) direct laryngoscopy failed in the preceding 6 months, and (4) direct laryngoscopy was deferred due to perceived risk of harm or poor chance of success. We used a 5:1 propensity score match to compare an early cohort from the initial Paediatric Difficult Intubation Registry analysis (August 6, 2012-January 31, 2015, 785 patients, 13 centres) and a current cohort from the Registry (March 4, 2017-March 31, 2023, 3925 patients, 43 centres). The primary outcome was first attempt success rate between cohorts. Success was defined as confirmed endotracheal intubation and assessed by the treating clinician. Secondary outcomes were eventual success rate, number of attempts at intubation, number of attempts with direct laryngoscopy, the incidence of persistence with direct laryngoscopy, use of supplemental oxygen, all complications, and severe complications. Findings: First-attempt success rate was higher in the current cohort (42% vs 32%, OR 1.5 95% CI 1.3-1.8, p < 0.001). In the current cohort, there were fewer attempts (2.2 current vs 2.7 early, regression coefficient -0.5 95% CI -0.6 to -0.4, p < 0.001), fewer attempts with direct laryngoscopy (0.6 current vs 1.0 early, regression coefficient -0.4 95% CI -0.4 to 0.3, p < 0.001), and reduced persistence with direct laryngoscopy beyond two attempts (7.3% current vs 14.1% early, OR 0.5 95% CI 0.4-0.6, p < 0.001). Overall complication rates were similar between cohorts (19% current vs 20% early). Severe complications decreased to 1.8% in the current cohort from 3.2% in the early cohort (OR 0.55 95% CI 0.35-0.87, p = 0.011). Cardiac arrests decreased to 0.8% in the current cohort from 1.8% in the early cohort. We identified persistence with direct laryngoscopy as a potentially modifiable factor associated with severe complications. Interpretation: In the current cohort, children with difficult tracheal intubations underwent fewer intubation attempts, fewer attempts with direct laryngoscopy, and had a nearly 50% reduction in severe complications. As persistence with direct laryngoscopy continues to be associated with severe complications, efforts to limit direct laryngoscopy and promote rapid transition to advanced techniques may enhance patient safety. Funding: None.

Flexible bronchoscopy insufflated and high-flow nasal oxygen pilot trial (BUFFALO protocol pilot trial).

BACKGROUND: Hypoxaemia occurs in approximately 30% of children during anaesthesia for flexible bronchoscopy. High-flow nasal oxygen (HFNO) can prolong safe apnoea time and be used in children with abnormal airways. During flexible bronchoscopy, there is limited evidence if HFNO confers advantages over current standard practice in avoiding hypoxaemia. The aim is to investigate feasibility of HFNO use during anaesthesia for flexible bronchoscopy to reduce frequency of rescue oxygenation and hypoxaemia. METHODS: BUFFALO is a bi-centre, unmasked, randomised controlled, parallel group, protocol for a pilot trial comparing HFNO techniques to standard practice during anaesthesia. Children (n = 81) aged > 37 weeks to 16 years presenting for elective bronchoscopy who fulfil inclusion but not exclusion criteria will be randomised prior to the procedure to HFNO or standard care oxygenation post induction of anaesthesia. Maintenance of anaesthesia with HFNO requires total venous anaesthesia (TIVA) and with standard, either inhalational or TIVA at discretion of anaesthetist in charge of the patient. Outcomes will include the feasibility of recruitment and adherence to trial procedures, acceptability of the intervention of the protocol and completion rates of data collection methods. DISCUSSION: Findings of this trial will determine feasibility to plan for a larger multicentre randomised clinical trial and support the feasibility of the proposed study procedures. TRIAL REGISTRATION: BUFFALO trial was registered with Australia and New Zealand Clinical Trials Registry (TRN12621001635853) on 29 November 2021 and commenced recruitment in May 2022. https://www.anzctr.org.au/ . The primary manuscript will be submitted for publication in a peer-reviewed journal.

Jelly snakes to reduce early postoperative vomiting in children after adenotonsillectomy: The randomized controlled snakes trial.

BACKGROUND: Despite the use of dual antiemetic agents, postoperative nausea and vomiting (PONV) occurs in an unacceptably large number of patients post-tonsillectomy. There has been increased interest in alternative and non-pharmacological treatments for PONV e.g., chewing gum. We investigated if chewing a large confectionary jelly snake had prophylactic antiemetic effects postoperatively in young children. METHODS: Prospective, open-label randomised controlled trial of 240 patients, 2-16 years. Patients administered a confectionary jelly snake to chew postoperatively were compared with a control group. The primary outcome was the number of episodes of vomiting within 6 h of the operation on an intention-to-treat basis. SECONDARY OUTCOMES: incidence of nausea, vomiting at 6 and 24 h, rescue antiemetic use, acceptability, delayed discharge. RESULTS: 233 patients were randomised to receive the confectionary snake (snake group, 118) or standard care (control group, 115). The number of vomiting episodes in 6 h was similar between groups on an intention-to-treat basis, with 39 episodes across 22 (19%) patients in the control group and 31 across 19 (16%) patients in the snake group (p = 0.666). From post anaesthetic care unit until 24 h there was no difference in doses of antiemetics or delayed discharge due to PONV. A secondary as per protocol analysis did not change this result. CONCLUSIONS: Chewing of confectionery jelly snakes within one hour of waking following adenotonsillectomy with vapour-maintained anaesthesia and two prophylactic antiemetics did not further reduce the incidence of early vomiting. REGISTRATION: prospective registration at the Australia and New Zealand Clinical Trials Registry (ACTRN12618000637246).

Predicting obstructive sleep apnoea and perioperative respiratory adverse events in children: role of upper airway collapsibility measurements.

BACKGROUND: Obstructive sleep apnoea (OSA) and perioperative respiratory adverse events are significant risks for anaesthesia in children undergoing adenotonsillectomy. Upper airway collapse is a crucial feature of OSA that contributes to respiratory adverse events. A measure of upper airway collapsibility to identify undiagnosed OSA can help guide perioperative management. We investigated the utility of pharyngeal closing pressure (PCLOSE) for predicting OSA and respiratory adverse events. METHODS: Children scheduled for elective adenotonsillectomy underwent in-laboratory polysomnography 2-12 weeks before surgery. PCLOSE measurements were obtained while the child was anaesthetised and breathing spontaneously just before surgery. Logistic regression was used to assess the predictive performance of PCLOSE for detecting OSA and perioperative respiratory adverse events after adjusting for potential covariates. RESULTS: In 52 children (age, mean [standard deviation] 5.7 [1.8] yr; 20 [38%] females), airway collapse during PCLOSE was observed in 42 (81%). Of these, 19 of 42 (45%) patients did not have OSA, 15 (36%) had mild OSA, and eight (19%) had moderate-to-severe OSA. All 10 children with no evidence of airway collapse during the PCLOSE measurements did not have OSA. PCLOSE predicted moderate-to-severe OSA (odds ratio [OR] 1.71; 95% confidence interval [CI]: 1.2-2.8; P=0.011). All children with moderate-to-severe OSA could be identified at a PCLOSE threshold of -4.0 cm H2O (100% sensitivity), and most with no or mild OSA were ruled out (64.7% specificity; receiver operating characteristic/area under the curve=0.857). However, there was no significant association between respiratory adverse events and PCLOSE (OR 1.0; 95% CI: 0.8-1.1; P=0.641). CONCLUSIONS: Measurement of PCLOSE after induction of anaesthesia can reliably identify moderate or severe OSA but not perioperative respiratory adverse events in children before adenotonsillectomy. CLINICAL TRIAL REGISTRATION: ANZCTR ACTRN 12617001503314.

Taste-Masked Flucloxacillin Powder Part 1: Optimisation of Fabrication Process Using a Mixture Design Approach.

It is extremely challenging to formulate age-appropriate flucloxacillin medicines for young children, because flucloxacillin sodium (FS) has a lingering, highly bitter taste, dissolves quickly in saliva, and requires multiple daily dosing at relatively large doses for treating skin infections. In this paper, we describe a promising taste-masked flucloxacillin ternary microparticle (FTM) formulation comprising FS, Eudragit EPO (EE), and palmitic acid (PA). To preserve the stability of the thermolabile and readily hydrolysed flucloxacillin, the fabrication process employed a non-aqueous solvent evaporation method at ambient temperature. Optimisation of the fabrication method using a mixture design approach resulted in a robust technique that generated stable and reproducible FTM products. The optimised method utilised only a single solvent evaporation step and minimal amounts of ICH class III solvents. It involved mixing two solution phases-FS dissolved in ethanol:acetone (1:4 v/v), and a combination of EE and PA dissolved in 100% ethanol-to give a ternary FS:EE:PA system in ethanol: acetone (3:1 v/v). Solvent evaporation yielded the FTMs containing an equimolar ratio of FS:EE:PA (1:0.8:0.6 w/w). The fabrication process, after optimisation, demonstrated robustness, reproducibility, and potential scalability.

Taste-Masked Flucloxacillin Powder Part 2: Formulation Optimisation Using the Mixture Design Approach and Storage Stability.

Flucloxacillin is prescribed to treat skin infections but its highly bitter taste is poorly tolerated in children. This work describes the application of the D-optimal mixture experimental design to identify the optimal component ratio of flucloxacillin, Eudragit EPO and palmitic acid to prepare flucloxacillin taste-masked microparticles that would be stable to storage and would inhibit flucloxacillin release in the oral cavity while facilitating the total release of the flucloxacillin load in the lower gastrointestinal tract (GIT). The model predicted ratio was found to be very close to the stoichiometric equimolar component ratio, which supported our hypothesis that the ionic interactions among flucloxacillin, Eudragit EPO and palmitic acid underscore the polyelectrolyte complex formation in the flucloxacillin taste-masked microparticles. The excipient-drug interactions showed protective effects on the microparticle storage stability and minimised flucloxacillin release at 2 min in dissolution medium. These interactions had less influence on flucloxacillin release in the dissolution medium at 60 min. Storage temperature and relative humidity significantly affected the chemical stability of the microparticles. At the preferred storage conditions of ambient temperature under reduced RH of 23%, over 90% of the baseline drug load was retained in the microparticles at 12 months of storage.

Paediatric Medicinal Formulation Development: Utilising Human Taste Panels and Incorporating Their Data into Machine Learning Training.

This review paper explores the role of human taste panels and artificial neural networks (ANNs) in taste-masking paediatric drug formulations. Given the ethical, practical, and regulatory challenges of employing children, young adults (18-40) can serve as suitable substitutes due to the similarity in their taste sensitivity. Taste panellists need not be experts in sensory evaluation so long as a reference product is used during evaluation; however, they should be screened for bitterness taste detection thresholds. For a more robust evaluation during the developmental phase, considerations of a scoring system and the calculation of an acceptance value may be beneficial in determining the likelihood of recommending a formulation for further development. On the technological front, artificial neural networks (ANNs) can be exploited in taste-masking optimisation of medicinal formulations as they can model complex relationships between variables and enable predictions not possible previously to optimise product profiles. Machine learning classifiers may therefore tackle the challenge of predicting the bitterness intensity of paediatric formulations. While advancements have been made, further work is needed to identify effective taste-masking techniques for specific drug molecules. Continuous refinement of machine learning algorithms, using human panellist acceptability scores, can aid in enhancing paediatric formulation development and overcoming taste-masking challenges.

A review of pediatric fasting guidelines and strategies to help children manage preoperative fasting.

Fasting for surgery is a routine step in the preoperative preparation for surgery. There have however been increasing concerns with regard to the high incidence of prolonged fasting in children, and the subsequent psycho-social distress and physiological consequences that this poses. Additionally, the past few years have yielded new research that has shown significant inter-individual variation in gastric emptying regardless of the length of the fast, with some patients still having residual gastric contents even after prolonged fasts. Additionally, multiple large-scale studies have shown no long-term sequalae from clear fluid aspiration, although two deaths from aspiration have been reported within the large Wake Up Safe cohort. This has led to a change in the recommended clear fluid fasting times in multiple international pediatric societies; similarly, many societies continue to recommend traditional fasting times. Multiple fasting strategies exist in the literature, though these have mostly been studied and implemented in the adult population. This review hopes to summarize the recent updates in fasting guidelines, discuss the issues surrounding prolonged fasting, and explore potential tolerance strategies for children.

Early life predictors of obstructive sleep apnoea in young adults: Insights from a longitudinal community cohort (Raine study).

OBJECTIVE: Early-life obstructive sleep apnoea (OSA) predictors are unavailable for young adults. This study identifies early-life factors predisposing young adults to OSA. METHODS: This retrospective study included 923 young adults and their mothers from the Western Australian Pregnancy Raine Study Cohort. OSA at 22 years was determined from in-laboratory polysomnography. Logistic regression was used to identify maternal and neonatal factors associated with OSA in young adulthood. RESULTS: OSA was observed in 20.8% (192) participants. Maternal predictors of OSA included gestational diabetes mellitus (odds ratio (OR) 9.54, 95% confidence interval (CI) 1.7, 58.5, P = 0.011), preterm delivery (OR 3.18, 95%CI 1.1,10.5, P = 0.043), preeclampsia (OR 2.95, 95%CI 1.1,8.0, P = 0.034), premature rupture of membranes (OR 2.46, 95%CI 1.2, 5.2, P = 0.015), age ≥35 years (OR 2.28, 95%CI 1.2,4.4, P = 0.011), overweight and obesity (pregnancy BMI≥25 kg/m2) (OR 2.00, 95%CI 1.2,3.2, P = 0.004), pregnancy-induced hypertension (OR 1.89, 95%CI 1.1,3.2, P = 0.019), and Chinese ethnicity (OR 2.36,95%CI 1.01,5.5, P = 0.047). Neonatal predictors included male child (OR 2.10, 95%CI 1.5,3.0, P < 0.0001), presence of meconium-stained liquor during delivery (OR 1.60, 95%CI 1.0,2.5, P = 0.044) and admission to special care nursery (OR 1.51 95%CI 1.0,2.2, P = 0.040). Higher birth lengths reduced OSA odds by 7% for each centimetre (OR 0.93, 95%CI 0.87, 0.99, P = 0.033). CONCLUSIONS: A range of maternal and neonatal factors predict OSA in young adults, including those related to poor maternal metabolic health, high-risk pregnancy and stressful perinatal events. This information could assist in the early identification and management of at-risk individuals and indicates that better maternal health may reduce the likelihood of young adults developing OSA.

Perioperative management of infant inguinal hernia surgery; a review of the recent literature.

Inguinal hernia surgery is one of the most common electively performed surgeries in infants. The common nature of inguinal hernia combined with the high-risk population involving a predominance of preterm infants makes this a particular area of interest for those concerned with their perioperative care. Despite a large volume of literature in the area of infant inguinal hernia surgery, there remains much debate amongst anesthetists, surgeons and neonatologists regarding the optimal perioperative management of these patients. The questions asked by clinicians include; when should the surgery occur, how should the surgery be performed (open or laparoscopic), how should the anesthesia be conducted, including regional versus general anesthesia and airway devices used, and what impact does anesthesia choice have on the developing brain? There is a paucity of evidence in the literature on the concerns, priorities or goals of the parents or caregivers but clearly their opinions do and should matter. In this article we review the current clinical surgical and anesthesia practice and evidence for infants undergoing inguinal hernia surgery to help clinicians answer these questions.