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 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.

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.

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 .

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.

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.

Apolipoprotein E ε4 and cognitive function after surgery in middle-aged and elderly Danish twins.

BACKGROUND: Transient cognitive impairment is common in adult patients of all ages following anaesthesia and surgery. Apolipoprotein E (APOE) ε4 carriers may have a larger deterioration in short-term cognitive function after major surgery compared with APOE ε4 noncarriers. OBJECTIVES: The aim was to examine the effect of APOE ε4 on the association between exposure to surgery and anaesthesia, and subsequent cognitive functioning. A more pronounced deterioration in cognitive function in APOE ε4 carriers was hypothesised. DESIGN: An observational cross-sectional and a 6 to 10 years longitudinal twin cohort design. SETTING: Survey and register study of 2936 Danish twins aged 45 to 92 years. MAIN OUTCOME MEASURES: Cognitive function was assessed using five age-sensitive cognitive tests. In the cross-sectional study, we compared twins exposed to surgery with a reference group (unexposed). Linear regression models were used adjusting for sex and age and stratified by APOE ε4 carrier status. In the longitudinal cognitive follow-up study 1671 twins participated. Intrapair analyses were also performed using 70 same-sexed twin pairs concordant for APOE ε4 carrier status, but discordant for major surgery. RESULTS: APOE ε4 carriers had lower cognitive scores compared with noncarriers, and this was statistically significant in elderly twins 70+ years of age (mean difference, -0.67; 95% CI, -1.14 to -0.17). There was no significant impact on cognitive function after surgery according to APOE ε4 carrier status in the cross-sectional study. Similarly, there was no APOE ε4 modification in the longitudinal study. Also, in the intrapair analyses no evidence was found of lower cognitive score after major surgery compared with the nonexposed cotwins among APOE ε4 carriers. CONCLUSION: No evidence was found of more pronounced long-term deterioration in cognitive function after surgery among APOE ε4 carriers, but elderly APOE ε4 carriers in general performed worse on the cognitive tests than noncarriers.

Incidence of severe critical events in paediatric anaesthesia in Scandinavia: Secondary analysis of Anaesthesia PRactice In Children Observational Trial (APRICOT).

BACKGROUND: The Anaesthesia PRactice In Children Observational Trial (APRICOT) in 261 European hospitals revealed a 5.2% incidence of severe critical events in the perioperative period and wide variability in practice. METHODS: A sub-analysis of the Scandinavian data was undertaken to investigate differences from the rest of Europe in the incidence and nature of perioperative severe critical events and to attempt to identify areas for quality improvement. FINDINGS: In the Scandinavian cohorts of 1520 paediatric patients out of 31 127 patients, the overall incidence of perioperative severe critical events was lower than the rest of Europe (4.4% (95% CI [3.5-5.6]) vs 5.2% (95% CI [5.0-5.5]); RR 0.57), albeit the incidence varied across countries. There was a lower rate of bronchospasm (0.9%), stridor (1.1%) and cardiovascular instability (0.9%) than the rest of Europe. The proportion of bronchospasm events occurring at induction was 0.13% in Scandinavian cohort which was less than the rest of Europe (1.2%). The proportion of sicker patients where less experienced teams were managing the care was notably lower in Scandinavia than in the rest of Europe (14.4% vs 20.4% of the American Society of Anesthesiologists Physical Status Classification System Score (ASA-PS III and 8.3% vs 12.8% of the ASA-PS IV. Cardiovascular instability was lower in Scandinavia (0.92%) compared to Europe (1.9%). The incidence of drug errors was low in both the overall APRICOT (0.2%) and in Scandinavia (0.3%). There were no deaths. INTERPRETATION: This sub-analysis shows that current Scandinavia paediatric perioperative clinical practice compares favourably with the rest of Europe. The lower incidence of cardiovascular and respiratory complications could be partly attributed to more experienced dedicated paediatric anaesthesia providers managing the higher risk groups of patients in Scandinavia. Whether this cohort of anaesthetized children is truly representative of the entire Scandinavia countries is unknown. Areas for quality improvement include: standardisation of the definition of severe critical events, increased reporting, development of evidence-based protocols for the management of severe critical events, development and rational implementation of paediatric perioperative risk assessment scores, implementation of current best practice in the provision of competent paediatric anaesthesia service in Europe, development of specific training and ensuring maintenance skills in paediatric anaesthesia. Furthermore, based on data from the original Apricot paper children under the age of 3 years and ASA-PS III and IV patients should not be anaesthetised without direct supervision of a specialist in paediatric anaesthesia. Given the sample size of the Scandinavian cohort this conclusion cannot be investigated further.

Outcomes after paediatric anaesthesia: which ones should have the priority?

PURPOSE OF REVIEW: To review the developments within paediatric anaesthesia and describe the various factors that have contributed to the improvements in anaesthesia-related outcomes in children. RECENT FINDINGS: During the years substantial improvements in paediatric anaesthesia-related outcomes has derived from safety advances in equipment, drugs, human factor analysis, professional standardization and organization, subspecialty care and regionalization. However, universally agreed outcome measures are lacking. SUMMARY: Despite a steadily and significant improvement in paediatric anaesthesia-related outcomes over the years further and future improvements are still necessary in areas such as adverse-event reporting and long-term neurocognitive outcomes with much more focus on patient/family-centred outcomes. Clinical experts and stakeholders should meet and agree on a consensus to identify indicators that could act as outcome measures in future large-scale prospective observational studies and clinical trials. Such an approach will foster benchmarking and continuous quality assessment and improvement at individual, institutional, interinstitutional, regional, national and international levels and facilitate larger scale clinical research. Furthermore, it will attain a high public health importance and will facilitate comparisons between healthcare provision models leading to optimization of perioperative care delivery.

Anesthesia and the developing brain: A way forward for laboratory and clinical research.

All commonly used general anesthetics have been shown to cause neurotoxicity in animal models, including nonhuman primates. Opinion, however, remains divided over how cumulative evidence from preclinical and human studies in this field should be interpreted and its translation to current practices in pediatric anesthesia and surgery. A group of international experts in laboratory and clinical sciences recently convened in Genoa, Italy, to evaluate the current state of both laboratory and clinical research and discuss future directions for basic, translational, and clinical studies in this field. This paper describes those discussions and conclusions. A central goal identified was the importance of continuing to pursue laboratory research efforts to better understand the biological pathways underlying anesthesia neurotoxicity. The distinction between basic and translational experimental designs in this field was highlighted, and it was acknowledged that it will be important for future animal research to try to causally link structural changes with long-term cognitive abnormalities. While inherent limitations will continue to affect the ability of even large observational cohorts to determine if anesthesia impacts neurodevelopment or behavioral outcomes, the importance of conducting further large well-designed cohort studies was also emphasized. Adequately powered cohorts could clarify which populations are at increased risk, provide information on environmental and healthcare-related risk modifiers, and guide future interventional trials. If anesthetics cause structural or functional adverse neurological effects in young children, alternative or mitigating strategies need to be considered. While protective or mitigating strategies have been repeatedly studied in animals, there are currently no human data to support alternative anesthetic strategies in clinical practice. Lastly, it was noted that there is still considerable debate over the clinical relevance of anesthesia neurotoxicity, and the need to evaluate the impact of other aspects of perioperative care on neurodevelopment must also be considered.

Long-term neurocognitive outcomes following surgery and anaesthesia in early life.

PURPOSE OF REVIEW: Repeated controversial and alarming statements of the potential dangers of anaesthetic agents on neurological outcomes in children continue to be issued based primarily on preclinical studies. This review assesses the current evidence of laboratory and clinical data and identifies areas of concerns. RECENT FINDINGS: Published animal and laboratory data consistently indicate that prolonged and excessive use of anaesthetic agents can lead to morphological changes and neurocognitive impairment in animals without a clear cut-off age or a superiority of one technique over another. Retrospective human studies and prospective clinical trials indicate that short exposures to anaesthesia and surgery are safe and have no effect on long-term neurological outcomes. Small and consistent continuing improvements in the perioperative period (aggregation of marginal gains) will impact on long-term neurological morbidity in humans. SUMMARY: It is biologically plausible that anaesthetic agents may induce structural changes during mammalian brain development and beyond. However, in the absence of alternatives the impact of the choice of anaesthetic drugs on long-term neurocognitive outcomes is almost certainly to be of limited relevance in humans. The underlying disease processes, surgical intervention, and trauma as well as other known perioperative factors more significantly affect these outcomes.