Whole-brain characterization of apoptosis after sevoflurane anesthesia reveals neuronal cell death patterns in the mouse neonatal neocortex.

In the last two decades, safety concerns about general anesthesia (GA) arose from studies documenting brain cell death in various pharmacological conditions and animal models. Nowadays, a thorough characterization of sevoflurane-induced apoptosis in the entire neonatal mouse brain would help identify and further focus on underlying mechanisms. We performed whole-brain mapping of sevoflurane-induced apoptosis in post-natal day (P) 7 mice using tissue clearing and immunohistochemistry. We found an anatomically heterogenous increase in cleaved-caspase-3 staining. The use of a novel P7 brain atlas showed that the neocortex was the most affected area, followed by the striatum and the metencephalon. Histological characterization in cortical slices determined that post-mitotic neurons were the most affected cell type and followed inter- and intracortical gradients with maximal apoptosis in the superficial layers of the posterodorsal cortex. The unbiased anatomical mapping used here allowed us to confirm sevoflurane-induced apoptosis in the perinatal period, neocortical involvement, and indicated striatal and metencephalic damage while suggesting moderate hippocampal one. The identification of neocortical gradients is consistent with a maturity-dependent mechanism. Further research could then focus on the interference of sevoflurane with neuronal migration and survival during development.

Hypnosis as an alternative to general anaesthesia for paediatric superficial surgery: a randomised controlled trial.

BACKGROUND: Reducing perioperative anxiety and controlling pain in children are essential to optimise recovery and outcomes for both children and their parents. By acting on sensory and affective modulation of anxiety and pain, hypnosis is widely used in medical care, especially in anaesthesia. This randomised controlled clinical trial was designed to compare general anaesthesia and intraoperative hypnosis support for perioperative management of children undergoing superficial surgery. METHODS: Children aged 7-16 yr scheduled for day-case superficial surgery were included and randomly assigned to one of the following two groups: general anaesthesia group or hypnosis group. The primary outcome was length of hospital stay. Child and parent anxiety, child pain, and the occurrence of postoperative negative behavioural changes were also evaluated. RESULTS: Sixty children of mean age 10.3 (standard deviation: 2.6) yr were enrolled in the study. Hypnosis was successful in all but one case. The median (25th-75th percentile) length of hospital stay was shorter in the hypnosis group (120 [95-145] vs 240.5 [218-275] min; P<0.001). The general anaesthesia group was associated with a greater incidence of high levels of preoperative anxiety in children (30 vs 11%; P=0.001) and parents (55 vs 30%; P=0.05). Pain scores did not differ between groups. No negative postoperative behavioural changes were reported. CONCLUSIONS: In children aged 7-16 yr, hypnosis appears to be feasible and accepted. The quality of the perioperative experience and the rapid recovery support the use of hypnosis as an effective and safe alternative to general anaesthesia for paediatric superficial surgery. CLINICAL TRIAL REGISTRATION: NCT02505880.

Enhanced recovery after surgery (ERAS) for adolescent idiopathic scoliosis: Standardisation of care improves patient outcomes.

INTRODUCTION: Adolescent idiopathic scoliosis (AIS) surgeries are major paediatric procedures requiring multidisciplinary management. Enhanced recovery after surgery (ERAS) programs, with proven benefits in adults, remain poorly developed in paediatrics. The main objective of this Before/After study was to evaluate the impact of an ERAS program implementation for AIS on length of stay (LOS) and postoperative recovery. METHODS: The ERAS protocol included intrathecal morphine, standardised multimodal analgesia and multidisciplinary measures for early recovery. Retrospective data from adolescents operated between 2015 and 2017 ("Before ERAS" group) were compared with data from patients benefiting from the ERAS program ("After ERAS" group). Patients treated for neuromuscular scoliosis were not included. After a descriptive analysis, a propensity score matching defined two comparable populations. The main outcome was the LOS. The time to first solid food intake, first ambulation, first bowel movement and Foley removal were also analysed. RESULTS: During the "Before ERAS" period, 73 underwent PSF for AIS. Thereafter, 65 patients benefited from the ERAS protocol, including 35 for AIS. After propensity score application, 32 patients of the "After ERAS" group were matched with 32 patients of the "Before ERAS" group. The ERAS implementation was associated with 25% reduction in LOS (2.10 ± 1.60 days p < 0.001). All other enhanced recovery criteria were significantly reduced after ERAS implementation. CONCLUSION: These results confirm the expected benefits of ERAS program in AIS with a significant impact on postoperative recovery and LOS. Patient adherence and the involvement of all caregivers are essential to the success of such a program.

A follow-up of pain reported by children undergoing outpatient surgery using a smartphone application: AlgoDARPEF multicenter descriptive prospective study.

ABSTRACT: In pediatric patients, pain remains the most common complaint after surgery. This French multicenter epidemiological study (AlgoDARPEF) aimed to evaluate the use of a smartphone application (App) to assess the duration and severity of pain experienced by children undergoing outpatient surgery. Children younger than 18 years scheduled for an elective outpatient procedure in one of the participating centers were eligible. Parents were invited to provide daily information for 10 days regarding their child's pain and comfort through a smartphone App using the Parents' Postoperative Pain Measure-Short-Form (PPPM-SF). Children older than 6 years could also provide self-assessments of pain using a numerical rating scale (NRS)-11. Data regarding pain medication, preoperative anxiety, postoperative nausea and vomiting, and parent satisfaction were also analyzed. Repeated-measures analyses of variances (ANOVAs) were used to compare the self-assessments and hetero-assessments of pain. Eleven centers participated in the study, and 1573 patients were recruited. Forty-nine percentage of parents (n = 772) actually used the App at least once. In all surgeries, the average pain rating on the PPPM-SF scale did not exceed 3/10 throughout the follow-up period, as well as for 4 main surgical specialties. Age, visceral surgery, and preoperative anxiety ≥ 4/10 were identified as independent risk factors for experiencing at least 1 episode of pain ≥4/10 during the first 48 postoperative hours. Although these findings indicated that postoperative pain management seems to be satisfactory in the families who used the App, some improvements in anxiety management are suggested. This study shows that inviting parents to use a smartphone App to assess and report the quality of postoperative management in pediatric patients provides useful information. A continuous report regarding pain and adverse events over a 10-day postoperative period by a self-reporting or parent's contribution is possible. Future studies should investigate the ability of live data collection using an App to ensure fast, efficient interactions between patients and physicians.

Epidemiology and complications of anaesthesia in the French centres that participated to NECTARINE: A secondary analysis.

INTRODUCTION: Neonatal and infant anaesthesia are associated with a high risk of perioperative complications. The aim of the current study was to describe those risks in France using the French data from the NECTARINE study. MATERIAL AND METHODS: Data from the French centres that participated to the NECTARINE study were analysed. The primary goal of the study was the description of patients' characteristics, procedures and perioperative management and their comparison with the results of the European NECTARINE study. Secondary outcomes were the description of major perioperative complications and death. RESULTS: Overall, 926 procedures collected in 15 centres (all teaching hospitals) were analysed. Comparison between the French and European NECTARINE cohorts found few differences related to patients' characteristics and procedures. The rate of interventions for critical events (respiratory, haemodynamic, and metabolic) was similar between the two cohorts. Near-infrared spectroscopy monitoring was used in 12% of procedures. Nearly none of the thresholds for these interventions met the published standards. By day 30, complications (respiratory, haemodynamic, metabolic, renal, and liver failure) and death were observed in 14.4% [95% CI 11.6-16.4]% and 1.8% [95% CI 1.1-2.9] of cases, respectively. DISCUSSION: Although the health status of the patients in the French cohort was less severe, procedures, management and postoperative complications and mortality rates were similar to the European cohort. However, thresholds for interventions were often inadequate in both cohorts. Efforts should be undertaken to improve the knowledge and use of new monitoring devices in this population.

Bilateral mandibular block improves pain relief and morphine consumption in mandibular osteotomies: a prospective, randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND: The sensory innervation of the lower jaw mainly depends on the third root of the trigeminal nerve, the mandibular nerve (V3). The aim of this single-center, prospective, randomized, double-blind, placebo-controlled study was to evaluate the effectiveness of bilateral V3 block for postoperative analgesia management in mandibular osteotomies. METHODS: 107 patients undergoing mandibular surgery (75 scheduled osteotomies and 32 mandible fractures) were randomized in two groups. A bilateral V3 block was performed in each group, either with ropivacaine 0.75% (block group, n=50) or with a placebo (placebo group, n=57). A postoperative multimodal analgesia was equally provided to both groups. The primary outcome was the cumulative morphine consumption at 24 hours. Secondary outcomes were the occurrence of severe pain and the incidence of postoperative nausea and vomiting (PONV) in the first 24 hours. Data were analyzed on an intention-to-treat basis. RESULTS: The cumulative morphine consumption at 24 hours was significantly lower in the block group (median 8.0 mg (IQR 2.0-21.3) vs 12.0 mg (IQR 8.0-22.0), p=0.03), as well as the incidence of severe pain during the 24 hours of follow-up (4.0% vs 22.8%, p<0.01). The mandibular block had no impact on the incidence of PONV. CONCLUSION: Bilateral V3 block for mandibular osteotomies is an effective opioid-sparing procedure. It provided better postoperative analgesia in the first 24 hours, and it did not affect PONV incidence. TRIAL REGISTRATION NUMBER: NCT02618993.

Facial expressions of pain in daily clinical practice to assess postoperative pain in children: Reliability and validity of the facial action summary score.

BACKGROUND: Behavioural pain scales are recommended to assess postoperative pain for children who are too young to use self-report tools. Their main limitation is underestimation of pain in the days following an intervention. Although relevant, facial expression is not used in daily clinical practice. This prospective study aimed to assess the validity and reliability of the Facial Action Summary Score (FASS), a five-item scale, to assess postoperative pain until hospital discharge in children <7 years. METHODS: Assessments of pain and anxiety of 123 children using FASS and validated scales were used to study the psychometric validity of the FASS in clinical practice. RESULTS: The content validity was previously investigated in a development study. The internal validity of the FASS was high with excellent reliability (intraclass coefficient = 0.94) and a high Cronbach α (0.89). Convergent validity with pain scales (FLACC [Face, Legs, Activity, Cry, Consoling] and FPS-R [Faces Pain Scale - Revised]) was high (r > 0.8). Sensitivity to change was verified by a significant decrease in the score after rescue analgesia. For a threshold of 2/5, the FASS shows excellent specificity (97%) and sensitivity (82%). The low number of false negatives is the main strength of this tool. CONCLUSIONS: This work highlights the interest in using facial expression in daily clinical practice to manage postoperative pain. The FASS is easy to use with excellent psychometric properties and is particularly sensitive to measure pain in the days following surgery. SIGNIFICANCE: The aim of this study was to prove that facial expression of pain can be used in clinical practice to measure postoperative pain in children. The reduced number of false negatives is the main strength of this tool.

Epidemiology of regional anesthesia in children: Lessons learned from the European Multi-Institutional Study APRICOT.

BACKGROUND: Recently, the European prospective observational multicenter cohort study, APRICOT, reported anesthesia techniques and complications in more than 31 000 pediatric procedures. The main objective of this study was to analyze the current practice in regional anesthesia in the 33 countries that participated to APRICOT. METHODS: Data on regional anesthesia techniques were extracted from the database of APRICOT (261 centers across 33 European countries). All children, aged from birth to 16 years old, were eligible for inclusion during a 2-week period. Type of regional anesthesia, whether used awake or with sedation or general anesthesia, techniques of guidance, and the drugs administered were analyzed. RESULTS: Regional anesthesia was used in 4377 pediatric surgical procedures. The large majority was performed under general anesthesia with central blocks and truncal blocks, representing, respectively, 42.6% and 41.8% of performed techniques. Caudal blocks represented 76.9% of all central blocks. The penile and ilioinguinal/iliohypogastric blocks were the most commonly performed truncal blocks. Anesthetists used mainly anatomical landmarks; ultrasound guidance was applied in only 23.8% of cases. A wide variability of practices was observed in terms of regional anesthesia techniques and local anesthetics among the participating European countries. No serious complications were reported. CONCLUSION: These data show a large predominance of central and truncal blocks in APRICOT study. Ultrasound guidance was mainly used for peripheral nerve blocks while central blocks were performed using landmark techniques.

Does programmed intermittent epidural bolus improve childbirth conditions of nulliparous women compared with patient-controlled epidural analgesia?: A multicentre, randomised, controlled, triple-blind study.

BACKGROUND: Epidural analgesia may change the mechanics of childbirth. These changes are related to the concentration of the local anaesthetic used epidurally but probably also to its mode of delivery into the epidural space. OBJECTIVE: To determine whether the administration of programmed intermittent epidural boluses (PIEB) improves the mechanics of second-stage labour compared with patient-controlled epidural analgesia (PCEA) with a background infusion. DESIGN: A randomised, controlled, triple-blind study. SETTING: Multicentre study including four level III maternity units, January 2014 until June 2016. PATIENTS: A total of 298 nulliparous patients in spontaneous labour were randomised to a PIEB or PCEA group. INTERVENTION: After epidural initiation with 15 ml of 0.1% levobupivacaine containing 10 µg of sufentanil, patients received either an hourly bolus of 8 ml (PIEB) or a continuous rate infusion of 8 ml h (PCEA): the drug mixture used was levobupivacaine 0.1% and sufentanil 0.36 µg ml. MAIN OUTCOME MEASURES: The primary outcome was a composite endpoint of objective labour events: a posterior occiput position in the second stage, an occiput position at birth, waiting time at full cervical dilatation before active maternal pushing more than 3 h, maternal active pushing duration more than 40 min, and foetal heart rate alterations. Vaginal instrumental delivery rates, analgesia and motor blockade scores were also recorded. RESULTS: From the 298 patients randomised, data from 249 (124 PIEB, 125 PCEA) were analysed. No difference was found in the primary outcome: 48.0% (PIEB) and 45.5% (PCEA) of patients, P = 0.70. In addition, no difference was observed between the groups for each of the individual events of the composite endpoint, nor in the instrumental vaginal delivery rate, nor in the degree of motor blockade. Despite an equivalent volume of medication in the groups, a significantly higher analgesia score at full dilatation was observed in the PIEB group, odds-ratio = 1.9 (95% confidence interval, 1.0 to 3.5), P = 0.04. CONCLUSION: The mechanics of the second stage did not differ whether PIEB or PCEA was used. Analgesic conditions appeared to be superior with PIEB, especially at full dilation. TRIAL REGISTRATION: NCT01856166.

Description of practices and complications in the French centres that participated to APRICOT: A secondary analysis.

INTRODUCTION: Analysing national patients' profile and organisation of human resources are important for improving the perioperative quality of care. The aim of the current study was to achieve these goals using the French data from the APRICOT study. MATERIAL AND METHODS: Data from the French centres that participated to the APRICOT study were extracted and analysed. The primary goal of the study was to describe patients' characteristics, procedures and perioperative anaesthetic management in France, and compare them to the results of the European APRICOT trial. Secondary outcomes were the description of major perioperative complications and the determination of human resources organisation possibly associated with these perioperative complications. RESULTS: Overall 3535 procedures collected in 20 facilities (17 teaching hospitals, one community hospital and two private institutions) were analysed. Comparison between the French and European APRICOT cohorts found differences related to the more specialised French centres participating to the study. Overall complications (respiratory complications, haemodynamic instability, cardiac arrest, drug errors, and anaphylactic reactions) were observed in 6.4% [95% CI: 5.6; 6.3] of cases. Multivariate analysis identified the anaesthesiologist's experience of<15 years and the absence of an anaesthetic nurse as human factors independently associated with an increased risk for perioperative complications. DISCUSSION: The current study identified some important differences between the French and the whole APRICOT cohort in terms of preoperative evaluation, surgical specialties involved, and monitoring of neuromuscular blockade. It confirms that, in France, the presence of an anaesthetic nurse and an experienced anaesthesiologist prevents anaesthetic complications.

Transversus Abdominal Plane Block in Children: Efficacy and Safety: A Randomized Clinical Study and Pharmacokinetic Profile.

BACKGROUND: The transversus abdominis plane (TAP) block has become a common regional anesthesia technique for pain management in a wide variety of abdominal procedures. Evidence to support any particular local anesthetic regimen as well as pharmacokinetic and systemic toxicity risks of TAP block remain insufficiently studied in children. The aim of this study was to compare the analgesic effects and investigate pharmacokinetic profile of levobupivacaine after ultrasound-guided TAP block using a low volume/high concentration (LVHC) or a high volume/low concentration (HVLC) solution in children. METHODS: This prospective randomized study included children scheduled for day-case inguinal surgery. Children were randomized to receive TAP block using 0.4 mg·kg levobupivacaine as either HVLC (0.2 mL·kg of 0.2% levobupivacaine) or LVHC (0.1 mL·kg of 0.4% levobupivacaine). The primary outcome was the number of children who required opioid rescue analgesia postoperatively. Pharmacokinetic profile study of levobupivacaine was also performed. RESULTS: Seventy patients were equally randomized, and 65 were included in the final analysis. Seventy-one percent of patients did not require any postoperative opioid analgesia. The number of patients who received rescue analgesia was 12 (35%) in the LVHC group and 7 (23%) in the HVLC group (relative risk, 0.64; 95% confidence interval [CI], 0.29-1.42; P = .26). Mean pain scores (FLACC [faces, legs, activity, cry, and consolability]) at postanesthesia care unit discharge did not differ between LVHC and HVLC groups, respectively, 0.39 ± 0.86 and 1 ± 1.71 with mean group difference -0.60 (95% CI, -1.27 to 0.06; P = .08). The pharmacokinetic profile of levobupivacaine was comparable in the 2 groups: the mean total and free levobupivacaine peak concentrations were 379 ± 248 and 3.95 ± 3.16 ng·mL, respectively, occurring 22.5 ± 11 minutes after injection. The highest total and free levobupivacaine concentrations collected, respectively, 1360 and 15.1 ng·mL, remained far below theoretical toxic thresholds. CONCLUSIONS: In children, quality of postoperative pain control provided by TAP block using levobupivacaine 0.4 mg·kg administered as either HVLC or LVHC did not differ and was associated with a very low risk of local anesthetic systemic toxicity.

Revision of expert panel's guidelines on postoperative pain management.

The French Society of Anaesthesia and Intensive Care Medicine (SFAR) published experts' guidelines on the care of postoperative pain. This was an update of the 2008 guidelines. Fourteen experts analysed the literature (PubMed™, Cochrane™) on questions that had not been treated in the previous guidelines, or to modify the guidelines following new data in the published literature. The used method is invariably the GRADE© method, which guarantees a rigorous work. Seventeen recommendations were formalised on the assessment of perioperative pain, and most particularly in non-communicating patients, on opioid and non-opioid analgesics and on anti-hyperalgesic drugs, such as ketamine and gabapentinoids, as well as on local and regional anaesthesia. The concept of vulnerability and therefore the identification of the most fragile patients in terms of analgesics requirements were specified. Because of the absence of sufficient data or new information, no recommendation was made about analgesia monitoring, the procedures for the surveillance of patients in conventional care structures, or perinervous or epidural catheterism.

Management of the child's airway under anaesthesia: The French guidelines.

OBJECTIVE: To provide French guidelines about "Airway management during paediatric anaesthesia". DESIGN: A consensus committee of 17 experts from the French Society of Anaesthesia and Intensive Care Medicine (Société Française d'Anesthésie-Réanimation, SFAR) and the Association of French speaking paediatric anaesthesiologists and intensivists (Association Des Anesthésistes Réanimateurs Pédiatriques d'Expression Francophone, ADARPEF) was convened. The entire process was conducted independently of any industry funding. The authors followed the principles of the Grading of Recommendations Assessment, Development and Evaluation (GRADE®) system to assess the quality of evidence. The potential drawbacks of making strong recommendations in the presence of low-quality evidence were emphasised. Few recommendations were not graded. METHODS: The panel focused on 7 questions: 1) Supraglottic Airway devices 2) Cuffed endotracheal tubes 3) Videolaryngoscopes 4) Neuromuscular blocking agents 5) Rapid sequence induction 6) Airway device removal 7) Airway management in the child with recent or ongoing upper respiratory tract infection. Population, intervention, comparison, and outcomes (PICO) questions were reviewed and updated as needed, and evidence profiles were generated. The analysis of the literature and the redaction of the recommendations were then conducted according to the GRADE® methodology. RESULTS: The SFAR Guideline panel provides 17 statements on "airway management during paediatric anaesthesia". After two rounds of discussion and various amendments, a strong agreement was reached for 100% of the recommendations. Of these recommendations, 6 have a high level of evidence (Grade 1 ± ), 6 have a low level of evidence (Grade 2 ± ) and 5 are experts' opinions. No recommendation could be provided for 3 questions. CONCLUSIONS: Substantial agreement exists among experts regarding many strong recommendations for paediatric airway management.

Peri-operative respiratory adverse events in children with upper respiratory tract infections allowed to proceed with anaesthesia: A French national cohort study.

BACKGROUND: Peri-operative respiratory adverse events (PRAEs) in paediatric patients with upper respiratory tract infections (URTIs) remain inadequately explored in patients allowed to proceed to anaesthesia and surgery. OBJECTIVE: To determine the incidence and risk factors of PRAE in children with URTI allowed to proceed to anaesthesia. DESIGN: Multicentre cohort study performed over 6 months in France. SETTING: Sixteen centres with dedicated paediatric anaesthetists. PATIENTS: Eligible patients were aged from 0 to 18 years with URTI symptoms on admission or a history of such over the preceding 4 weeks. MAIN OUTCOMES: The primary outcome of the study was to determine predictors of PRAE. Secondary outcomes were: predictors of peri-operative arterial desaturation and of the decision to proceed with anaesthesia and surgery in children with URTI. RESULTS: Overall, 621 children were included and 489 (78.7%) anaesthetised. Of those anaesthetised, 165 (33.5%) and 97 (19.8%) experienced PRAE and arterial desaturation, respectively. Factors predictive of PRAE included patient age, tracheal intubation and the absence of midazolam premedication. Factors predictive of peri-operative arterial desaturation included patient age, anaesthetist experience, endoscopic procedures and the presence of other PRAE. Factors predicting proceeding to anaesthesia in the context of URTI included anaesthetist experience, emergency procedures and the absence of severe URTI symptoms. CONCLUSION: The risk of PRAE in patients anaesthetised in the presence of URTI was similar to previous publications - close to 30%. In the light of our findings, first, current rescheduling indications should be questioned, and second, further medical and organisational strategies should be investigated to reduce PRAE in children with URTI. TRIAL REGISTRATION: The study was registered in the European Networks of Centers for Pharmacoepidemiology and Pharmacovigilance (EUPAS16436).