The HAVEN study-hydroxychloroquine in ANCA vasculitis evaluation-a multicentre, randomised, double-blind, placebo-controlled trial: study protocol and statistical analysis plan.

BACKGROUND: Patients with non-severe ANCA-associated vasculitis (AAV) are often prescribed immunosuppressive medications that are associated with severe side effects and a reduced quality of life. There is an unmet need for safer effective treatments for these patients. Hydroxychloroquine is being explored due to its effect in similar autoimmune conditions such as systemic lupus erythematosus. METHODS: Double-blind, placebo-controlled multicentre trial recruiting 76 patients across 20 sites. Participants will be randomised 1:1 to hydroxychloroquine or placebo in addition to standard of care immunosuppressive therapies over the course of 52 weeks. A phase II selection design will be used to determine hdroxychloroquine's efficacy, using prednisolone dosage and Birmingham Vasculitis Activity Score as a measure of disease activity. Secondary outcomes will explore other elements of AAV progression, including disease flares and time to remission. DISCUSSION: This trial aims to explore Hydroxychloroquine as a treatment for patients with AAV. If effective, the need for immunosuppressive treatments such as prednisolone could be reduced. Hydroxychloroquine is safer, cheaper and has fewer adverse effects than conventional immunosuppressive treatments. This could improve patient outcomes while saving money for the NHS. TRIAL REGISTRATION: ISRCTN: ISRCTN79334891. Registered 07 June 2021. EudraCT: 2018-001268-40. Registered 13 September 2019. CLINICALTRIALS: gov: NCT04316494. Registered 20 March 2020.

Fluid management knowledge in hospital physicians: 'Greenshoots' of improvement but still a cause for concern.

Fluid management is an essential competency for hospital doctors, but previous studies suggest junior clinicians lack the necessary 'knowledge' and 'prescription skills' to complete this task, resulting in preventable morbidity and mortality. In this study, preregistration (n=146), core (n=66) and specialty (n=133) medical trainees and general medical consultants (n=11) completed a structured questionnaire exploring fluid management training, confidence, serious adverse event experience and a 20-item fluid management 'knowledge' test. Results were compared with those of intensive care consultants (n=20). Most clinicians reported limited training and extensive 'unreported' serious adverse events experience. Knowledge about fluid and electrolyte requirements, fluid composition and chloride toxicity had improved compared to historical reports but overall test scores (median (interquartile range (IQR)): with a maximum score of 20) were low. Foundation year trainees scored 7 (IQR 5-8), core medical trainees scored 9 (IQR 6-10), specialist registrars scored 8 (IQR 6-10) and general medical consultants scored 8 (IQR 6-12) compared with the intensive care consultant score of 16 (IQR 14-16). Although weakly correlated, fluid management 'confidence' appeared higher than 'knowledge' tests would justify. These results suggest that physicians' fluid management knowledge is inadequate, including that of senior colleagues, compounded by poor training and failure to learn from serious adverse events.

Safe pediatric procedural sedation and analgesia by anesthesiologists for elective procedures: A clinical practice statement from the European Society for Paediatric Anaesthesiology.

The growing number of medical procedures performed in children that require cooperation of patients, lack of movement, anxiolysis or/and analgesia triggers the increased need for procedural sedation. This document presents the consensus statement of the European Society for Paediatric Anaesthesiology about the principles connected with the safe management of procedural sedation and analgesia (PSA) by anaesthesiologists for elective procedures in children. It does not aim to provide a legal statement on how and by whom PSA should be performed. The document highlights that any staff taking part in sedation of children must be appropriately trained with the required competencies and must be able to demonstrate regularly that they have maintained their knowledge, skills and clinical experience. The main goal of creating this document was to reflect the opinions of the community of the paediatric anaesthesiologists in Europe regarding how PSA for paediatric patients should be organized to make it safe.

Neurodevelopmental outcome at 5 years of age after general anaesthesia or awake-regional anaesthesia in infancy (GAS): an international, multicentre, randomised, controlled equivalence trial.

BACKGROUND: In laboratory animals, exposure to most general anaesthetics leads to neurotoxicity manifested by neuronal cell death and abnormal behaviour and cognition. Some large human cohort studies have shown an association between general anaesthesia at a young age and subsequent neurodevelopmental deficits, but these studies are prone to bias. Others have found no evidence for an association. We aimed to establish whether general anaesthesia in early infancy affects neurodevelopmental outcomes. METHODS: In this international, assessor-masked, equivalence, randomised, controlled trial conducted at 28 hospitals in Australia, Italy, the USA, the UK, Canada, the Netherlands, and New Zealand, we recruited infants of less than 60 weeks' postmenstrual age who were born at more than 26 weeks' gestation and were undergoing inguinal herniorrhaphy, without previous exposure to general anaesthesia or risk factors for neurological injury. Patients were randomly assigned (1:1) by use of a web-based randomisation service to receive either awake-regional anaesthetic or sevoflurane-based general anaesthetic. Anaesthetists were aware of group allocation, but individuals administering the neurodevelopmental assessments were not. Parents were informed of their infants group allocation upon request, but were told to mask this information from assessors. The primary outcome measure was full-scale intelligence quotient (FSIQ) on the Wechsler Preschool and Primary Scale of Intelligence, third edition (WPPSI-III), at 5 years of age. The primary analysis was done on a per-protocol basis, adjusted for gestational age at birth and country, with multiple imputation used to account for missing data. An intention-to-treat analysis was also done. A difference in means of 5 points was predefined as the clinical equivalence margin. This completed trial is registered with ANZCTR, number ACTRN12606000441516, and ClinicalTrials.gov, number NCT00756600. FINDINGS: Between Feb 9, 2007, and Jan 31, 2013, 4023 infants were screened and 722 were randomly allocated: 363 (50%) to the awake-regional anaesthesia group and 359 (50%) to the general anaesthesia group. There were 74 protocol violations in the awake-regional anaesthesia group and two in the general anaesthesia group. Primary outcome data for the per-protocol analysis were obtained from 205 children in the awake-regional anaesthesia group and 242 in the general anaesthesia group. The median duration of general anaesthesia was 54 min (IQR 41-70). The mean FSIQ score was 99·08 (SD 18·35) in the awake-regional anaesthesia group and 98·97 (19·66) in the general anaesthesia group, with a difference in means (awake-regional anaesthesia minus general anaesthesia) of 0·23 (95% CI -2·59 to 3·06), providing strong evidence of equivalence. The results of the intention-to-treat analysis were similar to those of the per-protocol analysis. INTERPRETATION: Slightly less than 1 h of general anaesthesia in early infancy does not alter neurodevelopmental outcome at age 5 years compared with awake-regional anaesthesia in a predominantly male study population. FUNDING: US National Institutes of Health, US Food and Drug Administration, Thrasher Research Fund, Australian National Health and Medical Research Council, Health Technologies Assessment-National Institute for Health Research (UK), Australian and New Zealand College of Anaesthetists, Murdoch Children's Research Institute, Canadian Institutes of Health Research, Canadian Anesthesiologists Society, Pfizer Canada, Italian Ministry of Health, Fonds NutsOhra, UK Clinical Research Network, Perth Children's Hospital Foundation, the Stan Perron Charitable Trust, and the Callahan Estate.

Enrollment challenges in multicenter, international studies: The example of the GAS trial.

INTRODUCTION: Randomized trials are important for generating high-quality evidence, but are perceived as difficult to perform in the pediatric population. Thus far there has been poor characterization of the barriers to conducting trials involving children, and the variation in these barriers between countries remains undescribed. The General Anesthesia compared to Spinal anesthesia (GAS) trial, conducted in seven countries between 2007 and 2013, provides an opportunity to explore these issues. METHODS: We undertook a descriptive analysis to evaluate the reasons for variation in enrollment between countries in the GAS trial, looking specifically at the number of potential subjects screened, and the subsequent application of four exclusion criteria that were applied in a hierarchical order. RESULTS: A total of 4023 patients were screened by 28 centers in seven countries. Australia and the USA screened the most subjects, accounting for 84% of all potential trial participants. The percentage of subjects eliminated from the screened pool by each exclusion criterion varied between countries. Exclusion due to a predefined condition (H1) eliminated only 5% of potential subjects in Italy and the UK, but 37% in Canada. Exclusions due to a contraindication or a physician's refusal most impacted enrollment in Australia and the USA. The patient being "too large for spinal anesthesia" was the most commonly cited by anesthetists who refused to enroll a patient (64% of anesthetist refusals). The majority of surgeon refusals came from the USA, where surgeons preferred the patient to receive a general anesthetic. The percentage of approached parents refusing to consent ranged from a low of 3% in Italy to a high of 70% in the USA and Netherlands. The most frequently cited reason for parent refusal in all countries was a preference for general anesthesia (median: 43%, range: 32%-67%). However, a sizeable proportion of parents in all countries had a contrasting preference for spinal anesthesia (median: 25%, range: 13%-31%), and 23% of U.S. parents expressed concern about randomization. CONCLUSION: The GAS trial highlights enrollment challenges that can occur when conducting multicenter, international, pediatric studies. Investigators planning future trials should be aware of potential differences in screening processes across countries, and that exclusions by anesthetists and surgeons may vary in reason, in frequency, and by country. Furthermore, investigators should be aware that the U.S. centers encountered particularly high surgeon and parental refusal rates and that U.S. parents were uniquely concerned about randomization. Planning trials that address these difficulties should increase the likelihood of successfully recruiting subjects in pediatric trials.

Prevention of perioperative venous thromboembolism in pediatric patients: Guidelines from the Association of Paediatric Anaesthetists of Great Britain and Ireland (APAGBI).

The Association of Paediatric Anaesthetists of Great Britain and Ireland (APAGBI) Guidelines Working Group on Thromboprophylaxis in Children has reviewed the literature and where possible provided advice on the care of children in the perioperative period. Areas reviewed include the incidence of perioperative venous thromboembolism (VTE), risk factors, evidence for mechanical and chemical prophylaxis, and complications. Safe practice of regional anesthesia with anticoagulant prophylaxis is detailed. In summary, there are few areas of strong evidence. Routine prophylaxis cannot be recommended for young children. Postpubertal adolescents (approximately 13 years and over) are at a slightly increased risk of VTE and should be assessed for prophylaxis and may warrant intervention if other risk factors are present. However, the incidence of VTE is significantly lower than in the adult population. This special interest review presents a summary and discussion of the key recommendations, a decision-making algorithm and a risk assessment chart. For the full guideline, go to www.apagbi.org.uk/publications/apa-guidelines.

Postoperative pain management in children: Guidance from the pain committee of the European Society for Paediatric Anaesthesiology (ESPA Pain Management Ladder Initiative).

The main remit of the European Society for Paediatric Anaesthesiology (ESPA) Pain Committee is to improve the quality of pain management in children. The ESPA Pain Management Ladder is a clinical practice advisory based upon expert consensus to help to ensure a basic standard of perioperative pain management for all children. Further steps are suggested to improve pain management once a basic standard has been achieved. The guidance is grouped by the type of surgical procedure and layered to suggest basic, intermediate, and advanced pain management methods. The committee members are aware that there are marked differences in financial and personal resources in different institutions and countries and also considerable variations in the availability of analgesic drugs across Europe. We recommend that the guidance should be used as a framework to guide best practice.

Surgical practice and outcome in 711 neonates and infants undergoing hernia repair in a large multicenter RCT: Secondary results from the GAS Study.

BACKGROUND: The GAS study is an international RCT to evaluate neurodevelopmental outcome comparing general plus regional anesthesia versus regional anesthesia alone in 722 neonates and infants who had inguinal hernia repair up to 60 weeks of postmenstrual age. This paper comprises a secondary descriptive analysis of hernias, aspects of surgery and outcomes. METHODS: The incidence of unilateral and bilateral hernias, side preponderance, predictive factors for bilateral hernias and surgical approaches were collated. Follow-up outcome data were examined at 2 years. RESULTS: Of 711 eligible patients, there were 679 with hernia data showing that 321 hernias were right-sided, 190 left and 168 bilateral. Male to female ratio was 5:1. Of those with unilateral hernias, 25.8% underwent contralateral exploration and in these cases a patent processus vaginalis was found in 68.9%. Bilateral hernias were more common in younger and female patients. At 2 years there was a recurrence rate of 0.99% and in 2.7% of patients a hernia was evident on the contralateral side (metachrony), and this was unrelated to the anesthesia technique. CONCLUSIONS: Bilateral hernias are associated with lower gestational age at birth and female gender. There was a low incidence of complications and the anesthesia technique did not affect surgical outcome. LEVEL OF EVIDENCE: Level 1 evidence from prospective treatment study.

Incidence of severe critical events in paediatric anaesthesia (APRICOT): a prospective multicentre observational study in 261 hospitals in Europe.

BACKGROUND: Little is known about the incidence of severe critical events in children undergoing general anaesthesia in Europe. We aimed to identify the incidence, nature, and outcome of severe critical events in children undergoing anaesthesia, and the associated potential risk factors. METHODS: The APRICOT study was a prospective observational multicentre cohort study of children from birth to 15 years of age undergoing elective or urgent anaesthesia for diagnostic or surgical procedures. Children were eligible for inclusion during a 2-week period determined prospectively by each centre. There were 261 participating centres across 33 European countries. The primary endpoint was the occurence of perioperative severe critical events requiring immediate intervention. A severe critical event was defined as the occurrence of respiratory, cardiac, allergic, or neurological complications requiring immediate intervention and that led (or could have led) to major disability or death. This study is registered with ClinicalTrials.gov, number NCT01878760. FINDINGS: Between April 1, 2014, and Jan 31, 2015, 31 127 anaesthetic procedures in 30 874 children with a mean age of 6·35 years (SD 4·50) were included. The incidence of perioperative severe critical events was 5·2% (95% CI 5·0-5·5) with an incidence of respiratory critical events of 3·1% (2·9-3·3). Cardiovascular instability occurred in 1·9% (1·7-2·1), with an immediate poor outcome in 5·4% (3·7-7·5) of these cases. The all-cause 30-day in-hospital mortality rate was 10 in 10 000. This was independent of type of anaesthesia. Age (relative risk 0·88, 95% CI 0·86-0·90; p<0·0001), medical history, and physical condition (1·60, 1·40-1·82; p<0·0001) were the major risk factors for a serious critical event. Multivariate analysis revealed evidence for the beneficial effect of years of experience of the most senior anaesthesia team member (0·99, 0·981-0·997; p<0·0048 for respiratory critical events, and 0·98, 0·97-0·99; p=0·0039 for cardiovascular critical events), rather than the type of health institution or providers. INTERPRETATION: This study highlights a relatively high rate of severe critical events during the anaesthesia management of children for surgical or diagnostic procedures in Europe, and a large variability in the practice of paediatric anaesthesia. These findings are substantial enough to warrant attention from national, regional, and specialist societies to target education of anaesthesiologists and their teams and implement strategies for quality improvement in paediatric anaesthesia. FUNDING: European Society of Anaesthesiology.

Neurodevelopmental outcome at 2 years of age after general anaesthesia and awake-regional anaesthesia in infancy (GAS): an international multicentre, randomised controlled trial.

BACKGROUND: Preclinical data suggest that general anaesthetics affect brain development. There is mixed evidence from cohort studies that young children exposed to anaesthesia can have an increased risk of poor neurodevelopmental outcome. We aimed to establish whether general anaesthesia in infancy has any effect on neurodevelopmental outcome. Here we report the secondary outcome of neurodevelopmental outcome at 2 years of age in the General Anaesthesia compared to Spinal anaesthesia (GAS) trial. METHODS: In this international assessor-masked randomised controlled equivalence trial, we recruited infants younger than 60 weeks postmenstrual age, born at greater than 26 weeks' gestation, and who had inguinal herniorrhaphy, from 28 hospitals in Australia, Italy, the USA, the UK, Canada, the Netherlands, and New Zealand. Infants were randomly assigned (1:1) to receive either awake-regional anaesthesia or sevoflurane-based general anaesthesia. Web-based randomisation was done in blocks of two or four and stratified by site and gestational age at birth. Infants were excluded if they had existing risk factors for neurological injury. The primary outcome of the trial will be the Wechsler Preschool and Primary Scale of Intelligence Third Edition (WPPSI-III) Full Scale Intelligence Quotient score at age 5 years. The secondary outcome, reported here, is the composite cognitive score of the Bayley Scales of Infant and Toddler Development III, assessed at 2 years. The analysis was as per protocol adjusted for gestational age at birth. A difference in means of five points (1/3 SD) was predefined as the clinical equivalence margin. This trial is registered with ANZCTR, number ACTRN12606000441516 and ClinicalTrials.gov, number NCT00756600. FINDINGS: Between Feb 9, 2007, and Jan 31, 2013, 363 infants were randomly assigned to receive awake-regional anaesthesia and 359 to general anaesthesia. Outcome data were available for 238 children in the awake-regional group and 294 in the general anaesthesia group. In the as-per-protocol analysis, the cognitive composite score (mean [SD]) was 98.6 (14.2) in the awake-regional group and 98.2 (14.7) in the general anaesthesia group. There was equivalence in mean between groups (awake-regional minus general anaesthesia 0.169, 95% CI -2.30 to 2.64). The median duration of anaesthesia in the general anaesthesia group was 54 min. INTERPRETATION: For this secondary outcome, we found no evidence that just less than 1 h of sevoflurane anaesthesia in infancy increases the risk of adverse neurodevelopmental outcome at 2 years of age compared with awake-regional anaesthesia. FUNDING: Australia National Health and Medical Research Council (NHMRC), Health Technologies Assessment-National Institute for Health Research UK, National Institutes of Health, Food and Drug Administration, Australian and New Zealand College of Anaesthetists, Murdoch Childrens Research Institute, Canadian Institute of Health Research, Canadian Anesthesiologists' Society, Pfizer Canada, Italian Ministry of Heath, Fonds NutsOhra, and UK Clinical Research Network (UKCRN).

Predictors of Failure of Awake Regional Anesthesia for Neonatal Hernia Repair: Data from the General Anesthesia Compared to Spinal Anesthesia Study--Comparing Apnea and Neurodevelopmental Outcomes.

BACKGROUND: Awake regional anesthesia (RA) is a viable alternative to general anesthesia (GA) for infants undergoing lower abdominal surgery. Benefits include lower incidence of postoperative apnea and avoidance of anesthetic agents that may increase neuroapoptosis and worsen neurocognitive outcomes. The General Anesthesia compared to Spinal anesthesia study compares neurodevelopmental outcomes after awake RA or GA in otherwise healthy infants. The aim of the study is to describe success and failure rates of RA and report factors associated with failure. METHODS: This was a nested cohort study within a prospective, randomized, controlled, observer-blind, equivalence trial. Seven hundred twenty-two infants 60 weeks or less postmenstrual age scheduled for herniorrhaphy under anesthesia were randomly assigned to receive RA (spinal, caudal epidural, or combined spinal caudal anesthetic) or GA with sevoflurane. The data of 339 infants, where spinal or combined spinal caudal anesthetic was attempted, were analyzed. Possible predictors of failure were assessed including patient factors, technique, experience of site and anesthetist, and type of local anesthetic. RESULTS: RA was sufficient for the completion of surgery in 83.2% of patients. Spinal anesthesia was successful in 86.9% of cases and combined spinal caudal anesthetic in 76.1%. Thirty-four patients required conversion to GA, and an additional 23 patients (6.8%) required brief sedation. Bloody tap on the first attempt at lumbar puncture was the only risk factor significantly associated with block failure (odds ratio = 2.46). CONCLUSIONS: The failure rate of spinal anesthesia was low. Variability in application of combined spinal caudal anesthetic limited attempts to compare the success of this technique to spinal alone.

Apnea after Awake Regional and General Anesthesia in Infants: The General Anesthesia Compared to Spinal Anesthesia Study--Comparing Apnea and Neurodevelopmental Outcomes, a Randomized Controlled Trial.

BACKGROUND: Postoperative apnea is a complication in young infants. Awake regional anesthesia (RA) may reduce the risk; however, the evidence is weak. The General Anesthesia compared to Spinal anesthesia study is a randomized, controlled trial designed to assess the influence of general anesthesia (GA) on neurodevelopment. A secondary aim is to compare rates of apnea after anesthesia. METHODS: Infants aged 60 weeks or younger, postmenstrual age scheduled for inguinal herniorrhaphy, were randomized to RA or GA. Exclusion criteria included risk factors for adverse neurodevelopmental outcome and infants born less than 26 weeks gestation. The primary outcome of this analysis was any observed apnea up to 12 h postoperatively. Apnea assessment was unblinded. RESULTS: Three hundred sixty-three patients were assigned to RA and 359 to GA. Overall, the incidence of apnea (0 to 12 h) was similar between arms (3% in RA and 4% in GA arms; odds ratio [OR], 0.63; 95% CI, 0.31 to 1.30, P = 0.2133); however, the incidence of early apnea (0 to 30 min) was lower in the RA arm (1 vs. 3%; OR, 0.20; 95% CI, 0.05 to 0.91; P = 0.0367). The incidence of late apnea (30 min to 12 h) was 2% in both RA and GA arms (OR, 1.17; 95% CI, 0.41 to 3.33; P = 0.7688). The strongest predictor of apnea was prematurity (OR, 21.87; 95% CI, 4.38 to 109.24), and 96% of infants with apnea were premature. CONCLUSIONS: RA in infants undergoing inguinal herniorrhaphy reduces apnea in the early postoperative period. Cardiorespiratory monitoring should be used for all ex-premature infants.

Neurosurgical conditions and procedures in infancy are associated with mortality and academic performances in adolescence: a nationwide cohort study.

BACKGROUND: Few human cohort studies on anesthesia-related neurotoxicity and the developing brain have focused on and compared specific surgeries and conditions. These studies cannot disentangle the effects of anesthesia from those of the surgery and underlying conditions. This study aimed at assessing the impact of specific neurosurgical conditions and procedures in infancy on mortality and academic achievements in adolescence. METHODS: A nationwide unselected register-based follow-up study of the Danish birth cohorts 1986-1990 compared academic performances of all children having undergone neurosurgeries as infants with a randomly selected, age-matched 5% sample of the same cohorts. The two groups were compared regarding mortality prior to June 1st, 2006, average test scores at ninth grade, and finally the proportion of children not attaining test scores. RESULTS: The exposure group comprised 228 and the control group 14 698 individuals. Hydrocephalus (n = 130), craniotomy (n = 43), and myelomeningocele/encephalocele children (n = 55) had a higher mortality (18.5.0%, 18.6%, and 7.3%, respectively) vs controls (1.3%; P < 0.00001, P < 0.00001, and P = 0.0052, respectively). Average test scores were significantly lower than controls in hydrocephalus and craniotomy (P = 0.0043 and P = 0.0077) but not myelomeningocele/encephalocele children (P = 0.2785); the proportion of available test scores were significantly lower in all three groups (40.8%, 60.0%, and 67.3%, respectively) vs 86.8% in controls (P < 0.00001, P = 0.000077, and P = 0.000064). CONCLUSION: Neurosurgery in infancy was associated with high mortality and significantly impaired academic achievements in adolescence. When studying anesthesia-related neurotoxicity and the developing brain, focus on specific surgeries/conditions is important. Pooling of major/minor conditions and major/minor surgeries should be avoided.

Children's cognitive recovery after day-case general anesthesia: a randomized trial of propofol or isoflurane for dental procedures.

BACKGROUND: Postoperative cognitive dysfunction (POCD) is well established in adults but has been underinvestigated in children. As day-case procedures are increasingly common, it is important to establish whether children suffer significant POCD. Pediatric POCD has been associated with several intravenous and inhalation anesthetics, but isoflurane has not been studied. As evidence indicates superior recovery after propofol, the study compared POCD after propofol or isoflurane anesthesia. OBJECTIVES: To compare the effects of propofol versus isoflurane upon children's POCD. METHODS: Fifty-eight children aged 5-14 years were randomized to propofol (total intravenous anesthesia) or isoflurane for day-case dental procedures. Reaction time (RT), verbal and visual memory, psychomotor coordination, and attention were assessed preoperatively, prior to discharge and at 24 h. RESULTS: Reaction time and psychomotor control were impaired postoperatively in both groups but recovered at 24 h. Delayed verbal recall was significantly impaired only after propofol. Both groups had significant impairment of visual memory postoperatively and at 24 h, and of recognition memory postoperatively only. CONCLUSIONS: Propofol and isoflurane exert similar adverse effects on RT, psychomotor coordination, and visual memory. Selective impairment of verbal recall by propofol is consistent with adult evidence of the drug's effect on retrieval. The enduring postoperative impairment of memory has implications for instructions to parents and caregivers for the safety and well-being of children in the 24 h after day-case anesthesia with propofol and isoflurane.

Educational outcome in adolescence following pyloric stenosis repair before 3 months of age: a nationwide cohort study.

BACKGROUND: Immature animals exposed to anesthetics display apoptotic neurodegeneration with subsequent long-term cognitive dysfunctions. Young age at anesthetic exposure is believed to be critical, but human studies are scarce. This study investigated the association between exposure to surgery and anesthesia for pyloric stenosis (PS) before 3 months of age and subsequent educational outcome in adolescence. METHODS: This nationwide unselected register-based follow-up study of the Danish birth cohorts 1986-1990 compared the educational outcome of all children having undergone surgery for PS before 3 months of age with a randomly selected, age-matched 5% sample of the same cohort. Primary analysis compared the average test scores at ninth grade adjusting for gender, birth weight, and parental age and education. Secondary analysis compared the proportions not attaining the test scores between the two groups. RESULTS: The exposure group comprised 779 and the control group consisted of 14 665 individuals. Although the exposure group performed lower than the control group (average score 0.17 lower, 95% CI: 0.08-0.25), after adjusting for known confounders, no statistically significant difference (-0.04, 95% CI: -0.09 to 0.08) between the 2 groups could be demonstrated. However, we found an odds ratio (OR) for test score nonattainment-associated PS repair of 1.37 (95% CI: 1.11-1.68). CONCLUSION: Children operated for PS before 3 months of age have educational performance tests similar to the background population at age 15-16 years after adjusting for known confounders. The higher nonattainment rate could suggest that a subgroup of PS children is developmentally disadvantaged.

The pain-free ward: myth or reality.

Over the last 25 years, pediatric care has changed dramatically with increased survival after premature birth, more complex care, better outcomes, and reduced mortality. There is a better understanding of how pain pathways and receptor systems develop and also how to assess pain at different stages of development. The myth that children do not feel pain has been comprehensively dispelled. Safe analgesic dose regimens for neonates, infants, and children have been developed based upon a better understanding of developmental pharmacokinetics and pharmacodynamics. It is a myth that pain in children cannot be prevented or treated safely and effectively because of the risks of adverse effects and addiction. Large-scale prospective audits have clarified the safety profile and risk-benefit balance for different techniques. There is now a substantial evidence base supporting many techniques of postoperative and procedural pain management for all age-groups of children. Guidelines based upon systematic review of this evidence have been published and updated, but the real challenge is in implementation of accurate pain assessment and safe, effective pain management comprehensively to all children whatever the procedure, clinical setting, developmental stage of the child, or comorbidities. In developed countries, these are core topics in the education of all doctors and nurses who care for children, and they are integrated into clinical practice by acute pediatric pain teams for most hospitals. However, it is disappointing that many country's healthcare systems do not give pediatric pain management a priority and in many parts of the world there are no analgesics available. So pain-free healthcare is sadly lacking in many hospitals. My hope is that the current knowledge can be used more effectively to relieve the unnecessary suffering of children in the 21st century.