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.

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.

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.

Postoperative pain management in children: guidance from the Pain Committee of the European Society for Paediatric Anaesthesiology (ESPA Pain Management Ladder Initiative) Part II.

The ESPA Pain Management Ladder Initiative is a clinical practice advisory based upon expert consensus supported by the current literature to help ensure a basic standard of perioperative pain management for all children. In 2018 the perioperative pain management of six common pediatric surgical procedures was summarised. The current Pain Management Ladder recommendations focus on five more complex pediatric surgical procedures and suggest basic, intermediate, and advanced pain management methods. The aim of this paper is to encourage best possible pain management practice and to support institutions to create their own pain management concepts according to their financial and human resources due to the diversity of clinical settings in Europe. Furthermore, the authors underline that these recommendations are intended for inpatients only.

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.

General anesthesia without intravenous access in children--a survey of current practice among members of the APAGBI and UK regional representatives of the APAGBI and the AAGBI.

BACKGROUND: The establishment of intravenous (IV) access should be considered for all adults and children undergoing general anesthesia. Inhalational induction prior to the establishment of IV access remains a popular technique in pediatric practice, and most practitioners will subsequently obtain IV access at the earliest opportunity. Previous surveys have indicated that some anesthetists may elect to omit IV access for the duration of anesthesia and surgery; however, the extent of this practice is unclear. A survey of pediatric anesthetists (members of the APAGBI and regional representatives of both the APAGBI and the AAGBI) was conducted to determine the prevalence of anesthesia without IV access in children, together with the circumstances in which this would be considered by practitioners. METHOD: A web-based survey was distributed via email to members of the Association of Paediatric Anaesthetists of Great Britain and Ireland (APAGBI) and regional representatives of both the APAGBI and the Association of Anesthetists of Great Britain and Ireland (AAGBI). In total, 1419 invitations to complete the survey were sent. RESULTS: Seven hundred and twenty seven completed surveys were returned, indicating a response rate of 51%. Twenty-eight respondents reported that they did not anesthetize children age <16 years. Of the remaining 699 respondents, 295 (42%) described circumstances where intravenous access was omitted during general anesthesia. The vast majority (84.7%) indicated that this was a rare occurrence. Only 44 (6.3%) respondents indicated they would always or usually undertake procedures under general anesthesia in children without IV access. Respondents suggested that short procedures, including dental extractions and myringotomy, were circumstances in which this practice was acceptable. CONCLUSION: The majority of respondents to this survey reported that they would usually establish IV access in children undergoing general anesthesia except in specific circumstances.

Pharmacokinetic profiles of epidural bupivacaine and ropivacaine following single-shot and continuous epidural use in young infants.

AIMS: The primary aim of this study was to describe the pharmacokinetics of total and unbound bupivacaine and ropivacaine following epidural bolus and infusion in neonates and young infants. Secondary aims were to investigate the influence of alpha-1-acid glycoprotein (AAG) on the concentration-time profiles and to determine the efficacy and adverse event profile of the epidural regimen. METHODS/MATERIALS: Thirty-one infants aged 40-63 weeks of postmenstrual age (PMA) undergoing hernia repair or abdominal surgery received an epidural injection of 1.5 mg · kg(-1) bupivacaine (0.25%) or ropivacaine (0.2%) followed 2 h later by an infusion of 0.2 mg · kg(-1) · h(-1) in those undergoing abdominal surgery. Total and unbound concentrations of bupivacaine and ropivacaine were analyzed using nonmem. Hourly pain scores and adverse effects were recorded. RESULTS: Bupivacaine data were available from 11 infants (five had infusions) and ropivacaine from 13 infants (four had infusions). Alpha-1-acid glycoprotein and total bupivacaine and ropivacaine concentrations accumulated during infusions, but unbound concentrations did not. Maximum unbound concentrations for bupivacaine and ropivacaine were 0.12 mg · l(-1) (bupivacaine) and 0.13 mg · l(-1) (ropivacaine). Typical clearance/bioavailability estimates of total (unbound) bupivacaine were 0.215 (4.65) l · h(-1) · kg(-1) and of total (unbound) ropivacaine were 0.288 (3.31) l · h(-1) · kg(-1). Pain scores requiring pain team referral occurred once with bupivacaine and four times with ropivacaine. No toxicity was observed. CONCLUSIONS: Epidural infusions of 0.2 mg(-1) · kg(-1) · h(-1) bupivacaine or ropivacaine appeared to be well tolerated and efficacious in this population. No accumulation of unbound drug concentrations occurred.

Academic performance in adolescence after inguinal hernia repair in infancy: a nationwide cohort study.

BACKGROUND: Although animal studies have indicated that general anesthetics may result in widespread apoptotic neurodegeneration and neurocognitive impairment in the developing brain, results from human studies are scarce. We investigated the association between exposure to surgery and anesthesia for inguinal hernia repair in infancy and subsequent academic performance. METHODS: Using Danish birth cohorts from 1986-1990, we compared the academic performance of all children who had undergone inguinal hernia repair in infancy to a randomly selected, age-matched 5% population sample. Primary analysis compared average test scores at ninth grade adjusting for sex, birth weight, and paternal and maternal age and education. Secondary analysis compared the proportions of children not attaining test scores between the two groups. RESULTS: From 1986-1990 in Denmark, 2,689 children underwent inguinal hernia repair in infancy. A randomly selected, age-matched 5% population sample consists of 14,575 individuals. Although the exposure group performed worse than the control group (average score 0.26 lower; 95% CI, 0.21-0.31), after adjusting for known confounders, no statistically significant difference (-0.04; 95% CI, -0.09 to 0.01) between the exposure and control groups could be demonstrated. However, the odds ratio for test score nonattainment associated with inguinal hernia repair was 1.18 (95% CI, 1.04-1.35). Excluding from analyses children with other congenital malformations, the difference in mean test scores remained nearly unchanged (0.05; 95% CI, 0.00-0.11). In addition, the increased proportion of test score nonattainment within the exposure group was attenuated (odds ratio = 1.13; 95% CI, 0.98-1.31). CONCLUSION: In the ethnically and socioeconomically homogeneous Danish population, we found no evidence that a single, relatively brief anesthetic exposure in connection with hernia repair in infancy reduced academic performance at age 15 or 16 yr after adjusting for known confounding factors. However, the higher test score nonattainment rate among the hernia group could suggest that a subgroup of these children are developmentally disadvantaged compared with the background population.

Total intravenous anesthesia (TIVA) in pediatric cardiac anesthesia.

Although inhalational anesthesia with moderate- to high-dose opioid analgesia has been the mainstay of pediatric cardiac anesthesia, the availability of new short-acting drugs, new concepts in pharmacokinetic modeling and computer technology, and advances in surgery and perfusion have made total intravenous anesthesia (TIVA) an attractive option. In this article, we review some of the TIVA techniques used in pediatric cardiac anesthesia.

APA national audit of pediatric opioid infusions.

INTRODUCTION: A prospective audit of neonates, infants, and children receiving opioid infusion techniques managed by pediatric acute pain teams from across the United Kingdom and Eire was undertaken over a period of 17 months. The aim was to determine the incidence, nature, and severity of serious clinical incidents (SCIs) associated with the techniques of continuous opioid infusion, patient-controlled analgesia, and nurse-controlled analgesia in patients aged 0-18. METHODS: The audit was funded by the Association of Paediatric Anaesthetists (APA) and performed by the acute pain services of 18 centers throughout the United Kingdom. Data were submitted weekly via a web-based return form designed by the Document Capture Company that documented data on all patients receiving opioid infusions and any SCIs. Eight categories of SCI were identified in advance, and the reported SCIs were graded in terms of severity (Grade 1 (death/permanent harm); Grade 2 (harm but full recovery and resulting in termination of the technique or needing significant intervention); Grade 3 (potential but no actual harm). Data were collected over a period of 17 months (25/06/07-25/11/08) and stored on a secure server for analysis. RESULTS: Forty-six SCIs were reported in 10 726 opioid infusion techniques. One Grade 1 incident (1 : 10,726) of cardiac arrest occurred and was associated with aspiration pneumonitis and the underlying neurological condition, neurocutaneous melanosis. Twenty-eight Grade 2 incidents (1 : 383) were reported of which half were respiratory depression. The seventeen Grade 3 incidents (1 : 631) were all drug errors because of programming or prescribing errors and were all reported by one center. CONCLUSIONS: The overall incidence of 1 : 10,000 of serious harm with opioid infusion techniques in children is comparable to the risks with pediatric epidural infusions and central blocks identified by two recent UK national audits (1,2). Avoidable factors were identified including prescription and pump programming errors, use of concurrent sedatives or opioids by different routes and overgenerous dosing in infants. Early respiratory depression in patients with specific risk factors, such as young age, neurodevelopmental, respiratory, or cardiac comorbidities, who are receiving nurse-controlled analgesia or continuous opioid infusion suggests that closer monitoring for at least 2 h is needed for these cases. As a result of this audit, we can provide parents with better information on relative risks to help the process of informed consent.

Overview of total intravenous anesthesia in children.

Total intravenous anesthesia (TIVA) can be defined as a technique, in which general anesthesia is induced and maintained using purely i.v. agents. TIVA has become more popular and possible in recent times because of the pharmacokinetic (PK) and pharmacodynamic properties of propofol and the availability of short-acting synthetic opioids. Also, new concepts in PK modeling and advances in computer technology have allowed the development of sophisticated delivery systems, which make control of anesthesia given by the i.v. route as straightforward and user friendly as conventional, inhalational techniques. Monitoring of depth of anesthesia is being validated for these techniques, and in the future, measurements of expired propofol may be possible to guide administration. TIVA is being used increasingly in children.

Publication ethics.

The editor of any medical journal has to be aware of the ethical and legal framework within which medical research is conducted. When research and publications relate to children, then particularly high standards are required in the design, conduct, and reporting of research in order to protect the rights of children and their families. Authors have a number of duties and responsibilities that are mirrored by those of editors and publishers. Of particular importance are the principles of transparency and integrity. Authors should be explicit about who carried out the work and who funded the study. They should declare whether the work has been published before and is not being considered for publication elsewhere. The authors must protect the rights of research participants including their anonymity. Editors and publishers have a duty to ensure high editorial standards and efficient and effective peer review systems. They should follow ethical and responsible publication practices and should safeguard the intellectual property of the authors. This review discusses in detail the duties and responsibilities of authors, editors, and publishers in modern medical publishing.

Survey of i.v. paracetamol (acetaminophen) use in neonates and infants under 1 year of age by UK anesthetists.

BACKGROUND: The license for i.v. paracetamol has recently been extended to include term neonates and infants aged 1 year, at a uniform dose across this age range of 7.5 mg.kg(-1), total daily dose 30 mg.kg(-1).day(-1). We were interested to survey current i.v. paracetamol prescribing practices of anesthetists in the UK, in neonates and infants under 1 year of age. METHODS: We conducted an online survey of 94 linkmen of the Association of Pediatric Anesthetists of Great Britain and Ireland Linkmen representing both general and specialist hospitals and 90 members of the British Pediatric Pain Travelling Club representing the pediatric acute pain teams throughout the UK and Ireland. RESULTS: A total of 105/184 (57%) responded to the survey on behalf of 78 regions and 27 pediatric acute pain teams. Over half (54%) of the respondents indicated i.v. paracetamol use in infants under 1 year of age. A wide range of loading and maintenance doses were used. Total daily doses exceeded the license for age 1-12 months in 70% of cases; for the 36 week postconceptional age (PCA)-1 month age range the proportion was 50%. Over 80% of total daily dosing from age 36 weeks PCA to 1 year fell within dosing suggested by pharmacokinetic studies. Close to 40% of respondents who used i.v. paracetamol in infants, also indicated use in preterm age groups. The total daily dose used in preterm neonates was within the range suggested by pharmacokinetic studies, in over 90% of cases in the age range 32-36 weeks PCA, and for 60% in the under 32 weeks PCA age group. CONCLUSIONS: This survey demonstrates i.v. paracetamol dosing in infants in the UK and Ireland is frequently above the licensed dose and outside the licensed age range but is in keeping with doses suggested by pharmacokinetic studies.