Remimazolam for sedation and anesthesia in children: A scoping review.

BACKGROUND: Remimazolam, a novel intravenous benzodiazepine recently approved by both the European Medicines Agency and the Food and Drug Agency, shows considerable promise in clinical practice. Its pharmacodynamic profile closely resembles that of midazolam, while its pharmacokinetic properties are similar to those of remifentanil. While research in adult populations continues to accumulate, the pace of pediatric studies is not as significant. This scoping review aims to systematically examine published studies, clinical trials, observational research, case reports, and relevant literature to provide a comprehensive understanding of remimazolam in pediatric sedation and anesthesia. By synthesizing the gathered evidence, we aim to identify gaps in the literature, guide future research endeavors, and inform clinical practices. METHODS: The review follows the guidelines outlined by the Preferred Reporting Items for Systematic Review and Meta-Analysis for Scoping Review. A thorough search strategy was implemented across prominent peer-reviewed databases, with focused efforts to identify relevant grey literature. All primary studies involving the use of remimazolam in pediatric populations were included in this review. RESULTS: Eighteen studies were included in this analysis, comprising 2 randomized controlled trials, 4 prospective cohort trials, 12 case reports, and 692 children in total. CONCLUSION: This scoping review highlights the increasing interest in using remimazolam as a sedative or anesthetic for children. Although initial evidence indicates its effectiveness and safety, more research is necessary to fill knowledge gaps, establish standard protocols, and optimize its use in pediatric anesthesia and sedation. Addressing these challenges will enable clinicians to improve the quality of care and outcomes for pediatric patients undergoing sedation and anesthesia.

Remimazolam for sedation and anesthesia in children: Protocol for a scoping review.

BACKGROUND: Remimazolam, a novel intravenous benzodiazepine recently approved by both the European Medicines Agency and the Food and Drug Agency, holds significant promise in clinical practice. Its pharmacodynamic profile closely mirrors that of midazolam, while its pharmacokinetics properties bear resemblance to remifentanil. Research in adult populations continues to accumulate, but the pediatric studies' pace is not significant. This scoping review aims to methodically scrutinize published studies, clinical trials, observational research, case reports, and pertinent literature to offer a comprehensive insight into the existing understanding of remimazolam in pediatric sedation and anesthesia. The synthesis of gathered evidence will discern lacunae in the literature, direct forthcoming investigations, and enlighten clinical practices. METHODS: The review will adhere to the guidelines outlined by the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) for Scoping Review. A meticulous search strategy will be executed across prominent peer-reviewed databases, with concerted efforts to identify relevant gray literature. All primary investigations involving the administration of remimazolam in pediatric populations will be encompassed within the scope of this review. RESULTS: The encompassed studies will be elucidated through a narrative synopsis, complemented by descriptive statistical analyses of quantitative data where deemed applicable. CONCLUSION: The planned scoping review aims to delineate the existing evidence regarding the utilization of remimazolam in pediatric anesthesia and sedation. It will discern areas of knowledge deficiency, provide guidance for future inquiries, and enhance clinical practices within the field.

Remimazolam and serious adverse events: A scoping review.

Remimazolam is anticipated to be an interesting anaesthetic and sedative. It combines the pharmacodynamic properties of midazolam with pharmacokinetic properties similar to remifentanil. However, worrisome case reports of anaphylaxis, delayed emergence and re-sedation have emerged recently and necessitate further investigation.PubMed (including MEDLINE) and EMBASE were searched for all studies reporting serious adverse events where remimazolam was administered for sedation or anaesthesia.Thirty-six case reports and 73 trials were identified, involving a total of 6740 patients who received remimazolam. Hypotension was reported in 911 cases, delayed emergence in 68 cases, anaphylaxis in 10 cases and re-sedation in 8 cases. The incidence of hypotension seems to be lower compared with other anaesthetics, even in high-risk patients.Delayed emergence might be related to the metabolism of remimazolam through carboxylesterase 1 (CES1), a tissue esterase predominant in the liver. There is significant interindividual variation, and it is inhibited by flavonoids, fatty acids and alcohol. Individual benzodiazepine sensitivity has also been reported. A higher BMI, older age and low plasma albumin concentration are risk factors for delayed emergence. Anaphylaxis might be related to a non-IgE-mediated effect of the excipient dextran-40 or a partially IgE-mediated reaction to remimazolam itself. Resedation has been reported after flumazenil reversal and is explained by the specific pharmacokinetic properties of flumazenil and remimazolam. Reversal by flumazenil should be reserved for and used carefully in patients with delayed emergence. VISUAL ABSTRACT: http://links.lww.com/EJA/A864 .

Outcome following anaesthesia in infancy in the Nordic countries: Subgroup analysis of the NECTARINE study.

INTRODUCTION: The neonate and children audit of anaesthesia practice in Europe (NECTARINE) prospective observational study reported an incidence of 35.2% of critical events requiring intervention during 6542 anaesthetics in 5609 infants up to 60 weeks postmenstrual age (PMA) from 165 centres in 31 European countries. METHODS: Sub-analysis of the cohort from the Nordic countries (8% of the entire cohort) was conducted. Secondary aims were to describe the Nordic countries' anaesthetic practices and compare morbidity and mortality with the overall European cohort. RESULTS: Eleven Nordic centres recruited 447 infants (66% males, 37.3% born preterm and 45% had congenital anomalies) undergoing anaesthesia for 530 surgical or non-surgical procedures at 25-60 weeks PMA. Perioperative critical events triggered interventions in 228/530 (43%) cases. Hypotension (12.6%) or hypoxaemia (11.7%) were more common in younger patients and those with co-morbidities. Hypo/hypercapnia occurred in 1.5%/4.7% of cases. More than two attempts for intubation were required in 13 (2.9%) infants (max three attempts). Distribution of ASA-Physical Status Scores was similar to the total European cohort (40% was ASA > 2). A total of 236/530 (44.5%) patients were admitted to the postoperative intensive care unit. Thirty-day morbidity (complications in 87/447 = 19.5%) and mortality (8/447, 1.8%) did not differ from the overall European cohort. Hospital re-admissions were significant up to 90 days (98/447 = 21.9%). CONCLUSIONS: In Nordic countries, anaesthesia in young infant children is resource-demanding, and perioperative critical events and co-morbidities are common. Thirty-day morbidity and mortality data in the Nordic countries did not differ from the overall European cohort.

Children's rights - the basis of quality in pediatric anesthesia.

PURPOSE OF REVIEW: In 1989, the United Nations passed the 'Convention on the Rights of the Child' (UNCRC) and, among others claimed the highest attainable standard of health for children and consequently the highest level of safety and quality in paediatric anaesthesia. SAFETOTS (Safe Anesthesia For Every Tot, www.safetots.org ), an initiative of international active paediatric anaesthetists, has derived 10 rights, the '10 R' of children undergoing anaesthesia care, which are critical for the well being of the child. RECENT FINDINGS: The current situation in paediatric anaesthesia care in Europe does not always meet the requirements demanded by the UNCRC. Anaesthesia-related complications in children are still persistent. Anaesthesiologists are frequently asked to provide care for newborns, infants and small children without having sufficient child-specific expertise, resulting in an increased morbidity and mortality. SUMMARY: This article will explain these statutes of children's rights and their implications for everyday paediatric anaesthesia. Furthermore, it will also express the institutional and political changes that are needed to guarantee children their right to enjoy the highest attainable standard of health.

Neonates undergoing pyloric stenosis repair are at increased risk of difficult airway management: secondary analysis of the NEonate and Children audiT of Anaesthesia pRactice IN Europe.

BACKGROUND: Hypertrophic pyloric stenosis in otherwise healthy neonates frequently requires urgent surgical procedure but anaesthesia care may result in respiratory complications, such as hypoxaemia, pulmonary aspiration of gastric contents, and postoperative apnoea. The primary aim was to study whether or not the incidence of difficult airway management and of hypoxaemia in neonates undergoing pyloric stenosis repair was higher than that in neonates undergoing other surgeries. METHODS: Data on neonates and infants undergoing anaesthesia and surgery for pyloric stenosis were extracted from the NEonate and Children audiT of Anesthesia pRactice In Europe (NECTARINE) database, for secondary analysis. RESULTS: We identified 310 infants who had anaesthesia for surgery for pyloric stenosis. Difficult airway management (more than two attempts at laryngoscopy) was higher in children with pyloric stenosis when compared with the entire NECTARINE cohort (7.9% [95% confidence interval {CI}, 5.22-11.53] vs 4.4% [95% CI, 1.99-6.58]; relative risk [RR]=1.81 [95% CI, 1.21-2.69]; P=0.004), whereas transient hypoxaemia with oxygen saturation <90% was comparable between the two cohorts. Postoperative complications occurred in 16 children (5.6%) within the 30-day follow-up. No mortality was reported at 30 and 90 days. CONCLUSIONS: Children undergoing surgery for pyloric stenosis had a higher incidence of difficult intubation compared with the entire NECTARINE cohort. CLINICAL TRIAL REGISTRATION: NCT02350348.

Emergence agitation in paediatric day case surgery: A randomised, single-blinded study comparing narcotrend and heart rate variability with standard monitoring.

BACKGROUND: Postoperative emergence agitation remains a significant challenge in paediatric anaesthesia. Although short-lived, it may cause harm to the patient and negative experiences for all. Differentiating agitation, delirium and pain is difficult. Electroencephalography allows precise titration of anaesthetic depth, and heart rate variability monitoring permits immediate intervention regarding nociception and pain. We examined if one of these measures could be used to reduce postoperative agitation in an unselected paediatric day surgical population. OBJECTIVE: The primary outcome was postoperative agitation with a Richmond Agitation-Sedation Scale greater than 0. Secondary outcomes were: length of stay, postoperative nausea and vomiting, fentanyl and propofol consumption, pain scores and use of postoperative analgesics. DESIGN: A randomised, single-blinded study constituting children aged 1 to 6 years, undergoing minor general day surgical procedures. SETTING: Paediatric day surgical department 29th March 2019 to 12th June 2020. PATIENTS: Ninety-eight children (ASA 1 or 2) were enrolled, and 93 children were included in the final analysis. INTERVENTIONS: Children received standard monitoring (n=31), standard monitoring plus either Narcotrend (n=31), or Anaesthesia Nociception Index monitoring (n=31). Sevoflurane or fentanyl was titrated immediately according to monitor thresholds. RESULTS: Kaplan-Meier analysis yielded a statistically significant difference between the groups (P = 0.016) with the lowest agitation levels in the Anaesthesia Nociception Index group, intermediate levels in the control group and the highest agitation levels in the Narcotrend monitored group. Intergroup pairwise comparison however, showed no difference. The Anaesthesia Nocioception Index group received slightly more fentanyl (P = 0.277). The control group patients had the highest pain scores despite receiving more caudal blocks and the Narcotrend group had more sevoflurane adjustments. Other secondary outcomes were comparable. CONCLUSION: Children in the Anaesthesia Nociception Index group were the least agitated with the highest fentanyl doses, without increasing the length of stay in the PACU or postoperative nausea and vomiting. CLINICAL REGISTRATION: The study was registered in REDCap online trial database 1/11/2018 trial registration nr. OP720. https://open.rsyd.dk/OpenProjects/openProject.jsp?openNo=720&lang=da.

[Preoperative risk assessment of patients with congenital heart disease in non-cardiac surgery].

Over the last decades, remarkable advances in survival in patients with congenital heart disease (CHD) have been reported. Currently, 90% of infants born with CHD can expect to reach adulthood. Moderate and severe CHD is associated with increased perioperative mortality. To ensure optimal management of CHD patients undergoing non-cardiac surgery, preoperative risk assessment is pivotal, along with a multidisciplinary approach and collaboration across hospitals. The objective of this review is to provide a simple model to identify CHD patients at risk prior to non-cardiac surgery.

Morbidity and mortality after anaesthesia in early life: results of the European prospective multicentre observational study, neonate and children audit of anaesthesia practice in Europe (NECTARINE).

BACKGROUND: Neonates and infants requiring anaesthesia are at risk of physiological instability and complications, but triggers for peri-anaesthetic interventions and associations with subsequent outcome are unknown. METHODS: This prospective, observational study recruited patients up to 60 weeks' postmenstrual age undergoing anaesthesia for surgical or diagnostic procedures from 165 centres in 31 European countries between March 2016 and January 2017. The primary aim was to identify thresholds of pre-determined physiological variables that triggered a medical intervention. The secondary aims were to evaluate morbidities, mortality at 30 and 90 days, or both, and associations with critical events. RESULTS: Infants (n=5609) born at mean (standard deviation [sd]) 36.2 (4.4) weeks postmenstrual age (35.7% preterm) underwent 6542 procedures within 63 (48) days of birth. Critical event(s) requiring intervention occurred in 35.2% of cases, mainly hypotension (>30% decrease in blood pressure) or reduced oxygenation (SpO2 <85%). Postmenstrual age influenced the incidence and thresholds for intervention. Risk of critical events was increased by prior neonatal medical conditions, congenital anomalies, or both (relative risk [RR]=1.16; 95% confidence interval [CI], 1.04-1.28) and in those requiring preoperative intensive support (RR=1.27; 95% CI, 1.15-1.41). Additional complications occurred in 16.3% of patients by 30 days, and overall 90-day mortality was 3.2% (95% CI, 2.7-3.7%). Co-occurrence of intraoperative hypotension, hypoxaemia, and anaemia was associated with increased risk of morbidity (RR=3.56; 95% CI, 1.64-7.71) and mortality (RR=19.80; 95% CI, 5.87-66.7). CONCLUSIONS: Variability in physiological thresholds that triggered an intervention, and the impact of poor tissue oxygenation on patient's outcome, highlight the need for more standardised perioperative management guidelines for neonates and infants. CLINICAL TRIAL REGISTRATION: NCT02350348.

The Use of Tablet Computers to Reduce Preoperative Anxiety in Children Before Anesthesia: A Randomized Controlled Study.

PURPOSE: Children undergoing surgery and general anesthesia often experience preoperative anxiety (POA) with related negative short-, medium- and long-term consequences. Anxiolytic premedication has negative side effects, and nonpharmacologic interventions are often resource demanding and not always readily available in a busy clinical setting. The use of an age-appropriate game on a tablet computer may reduce POA, postoperative pain, and occurrence of emergence delirium (ED). DESIGN: Children aged 3 to 6 years scheduled to undergo elective minor surgery were randomly assigned to play a game on a tablet computer while in the holding area before anesthesia (n = 30) or prepared as per departmental standard only (n = 30). METHODS: POA, ED, and levels of pain were assessed by the modified Yale Preoperative Anxiety Scale, Pediatric Anesthesia Emergence Delirium, and Face, Legs, Activity, Cry, Consolability scale, respectively. FINDINGS: A total of 60 children were randomized to either the intervention group or the control group. Gender, bodyweight, duration of anesthesia and surgery, and fentanyl dosages were comparable between the two groups. Tablet-gaming children tended to be less anxious than control subjects at the time of anesthesia induction (modified Yale Preoperative Anxiety Scale, 55.7 vs 65.8; 95% confidence interval, -0.63 to 20.8; P = .066). There was no difference in occurrence of ED or pain 20 minutes after arrival in the postanesthesia care unit. CONCLUSIONS: Although not statistically significant, the use of an age-appropriate tablet computer game may reduce the level of anxiety at the anesthetic induction in 3 to 6 years old children undergoing elective day-case surgery. However, the occurrence of ED and levels of pain appeared unaffected. Standardization of nonpharmacologic interventions to reduce perioperative anxiety and pain is required.