Novel exported fusion enzymes with chorismate mutase and cyclohexadienyl dehydratase activity: Shikimate pathway enzymes teamed up in no man's land.

Chorismate mutase (CM) and cyclohexadienyl dehydratase (CDT) catalyze two subsequent reactions in the intracellular biosynthesis of l-phenylalanine (Phe). Here, we report the discovery of novel and extremely rare bifunctional fusion enzymes, consisting of fused CM and CDT domains, which are exported from the cytoplasm. Such enzymes were found in only nine bacterial species belonging to non-pathogenic γ- or ß-Proteobacteria. In γ-proteobacterial fusion enzymes, the CM domain is N-terminal to the CDT domain, whereas the order is inverted in ß-Proteobacteria. The CM domains share 15% to 20% sequence identity with the AroQγ class CM holotype of Mycobacterium tuberculosis (∗MtCM), and the CDT domains 40% to 60% identity with the exported monofunctional enzyme of Pseudomonas aeruginosa (PheC). In vitro kinetics revealed a Km <7 µM, much lower than for ∗MtCM, whereas kinetic parameters are similar for CDT domains and PheC. There is no feedback inhibition of CM or CDT by the pathway's end product Phe, and no catalytic benefit of the domain fusion compared with engineered single-domain constructs. The fusion enzymes of Aequoribacter fuscus, Janthinobacterium sp. HH01, and Duganella sacchari were crystallized and their structures refined to 1.6, 1.7, and 2.4 Å resolution, respectively. Neither the crystal structures nor the size-exclusion chromatography show evidence for substrate channeling or higher oligomeric structure that could account for the cooperation of CM and CDT active sites. The genetic neighborhood with genes encoding transporter and substrate binding proteins suggests that these exported bifunctional fusion enzymes may participate in signaling systems rather than in the biosynthesis of Phe.

Measuring Physical Function in the PICU: Development and Testing of a Children's Version (Age 2-18 yr) of the Chelsea Critical Care Physical Assessment Tool.

OBJECTIVES: To adapt and develop a reliable and easily administered outcome measure of physical and respiratory function in critically ill children in the PICU. DESIGN: Modified Delphi study to adapt the Chelsea Critical Care Physical Assessment (CPAx) tool for use in children 2-18 years old, with subsequent prospective testing in a single-center cohort. SETTING: Single-center tertiary PICU. SUBJECTS: Delphi process in 27 panelists (including physiotherapists, occupational therapists, and pediatric intensivists from seven countries from January 2018 to March 2018). Cohort study in 54 patients admitted to PICU for greater than 24 hours over a 3-month period (April 2018 to June 2018), with median age 5.5 years (interquartile range [IQR], 3-12.75 yr), 33 of 54 male, and 38 of 54 invasively ventilated. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Three Delphi iterations were required to reach greater than or equal to 80% consensus in all the children's CPAx (cCPAx) items. In the subsequent cohort study, six physiotherapists used the cCPAx tool and scored 54 participants, with a total 106 observations. The median cCPAx tool score was 14.50 (IQR, 3-25) out of a possible total of 50. Inter-rater reliability for 30 randomly selected participants was excellent (intraclass correlation coefficient, 0.998). Completion rate of cCPAx in the 54 patients occurred in 78 of 106 occasions (74%). CONCLUSIONS: The cCPAx tool content that was developed using Delphi methodology provided a feasible and clinically relevant tool for use in assessing physical morbidity in PICU patients 2-18 years old. Overall, the cCPAx scores were low, demonstrating low levels of physical function and high levels of immobility during PICU care.

Neurodevelopmental outcome and quality of life in children admitted to the paediatric intensive care unit: A single-centre Australian cohort study.

BACKGROUND: The development of new morbidities has become increasingly identified in paediatric critical care medicine. To date, there has been limited research of long-term outcomes following paediatric critical illness in Australia. OBJECTIVES: The objective of this study was to quantify neurodevelopmental impairments in children following paediatric intensive care unit (PICU) discharge and their association with health-related quality of life (HRQoL). METHODS: A single-centre ambidirectional cohort study at an Australian hospital. Parents of children admitted to the PICU between 2015 and 2017 were invited to participate. Neurodevelopmental outcome and HRQoL was prospectively evaluated, using the Ages and Stages Questionnaire (<5 years), Strengths and Difficulties Questionnaire (≥5 years), and Pediatric Quality of Life Inventory™, respectively. RESULTS: A total of 230 parents of critically ill children participated. Children were 1.9 years old (median, interquartile range [IQR]: 0.2, 7.5), male (59.6%), and ventilated (49.1%) at PICU admission. The median time to follow-up was 24.4 months (IQR: 16.3, 36.7). Parent respondents were more likely to be female (85.5%), White (88.3%), and partnered (81.1%). The incidence of overall neurodevelopmental impairment was 30% (33% in children aged <5 years; 24% in children aged ≥5 years). The incidence of poor HRQoL was 37.9%. History of developmental delay was independently associated with overall neurodevelopmental impairment (adjusted odds ratio [aOR]: 4.21, 95% confidence interval: 2.05, 8.63) and poor HRQoL (aOR: 7.29, 95% confidence interval: 3.26, 16.27). Two or more PICU admissions (aOR: 4.10, IQR: 1.82, 9.26) was also associated with poor HRQoL. CONCLUSIONS: This is the first contemporary view of PICU long-term outcomes conducted in Australia and significantly informs ongoing research in this area. Approximately one-third of PICU survivors demonstrate neurodevelopmental impairment and reduced quality of life. Multiple domains of post-intensive care syndrome-paediatrics must be considered to have a comprehensive understanding of child outcomes. Assessment of baseline/premorbid functioning is also essential in order to understand the true impact of illness and PICU admission.

Patient blood management in critically ill children undergoing cardiac surgery: A cohort study.

OBJECTIVE: The objective of this study was to audit current patient blood management practice in children throughout cardiac surgery and paediatric intensive care unit (PICU) admission. DESIGN: This was a prospective observational cohort study. SETTING: This was a single-centre study in the cardiac operating room (OR) and PICU in a major tertiary children's hospital in Australia. PATIENTS: Children undergoing corrective cardiac surgery and requiring admission to PICU for postoperative recovery were included in the study. MEASUREMENTS AND MAIN RESULTS: Fifty-six patients and 1779 blood sampling episodes were audited over a 7-month period. The median age was 9 months (interquartile range [IQR] = 1-102), with the majority (n = 30 [54%]) younger than 12 months. The median number of blood sampling episodes per patient per day was 6.6 (IQR = 5.8-8.0) in total, with a median of 5.0 (IQR = 4.0-7.5) episodes in the OR and 5.0 (IQR = 3.4-6.2) episodes per day throughout PICU admission. The most common reason for blood tests across both OR and PICU settings was arterial blood gas analysis (total median = 86%, IQR = 79-96). The overall median blood sampling volume per kg of bodyweight, patient, and day was 0.63 mL (IQR = 0.20-1.14) in total. Median blood loss for each patient was 3.5 mL/kg per patient per day (IQR = 1.7-5.6) with negligible amounts in the OR and a median of 3.6 mL/kg (IQR = 1.7-5.7) in the PICU. The median Cell Saver® transfusion volume was 9.9 mL/kg per patient per day (IQR = 4.0-19.1) in the OR. The overall median volume of other infusion products (albumin 4%, albumin 20%, packed red blood cells) received by each patient was 20.1 mL/kg (IQR = 10.7-36.4) per day. Sampling events and blood loss were positively associated with PICU stay. CONCLUSIONS: Patient blood management practices observed in this study largely conform to National Blood Authority guidelines. Further implementation projects and research are needed to accelerate implementation of known effective blood conservation strategies within paediatric critical care environments.

General practitioner perspectives on a shared-care model for paediatric patients post-intensive care: A cross-sectional survey.

INTRODUCTION: While paediatric critical illness mortality rates in Australia are declining, the growing cohort of paediatric intensive care unit (PICU) survivors means an increasing number of children facing substantial health challenges after their discharge from intensive care. General practitioners (GPs) play a key role in provision of comprehensive health care to children and families and are ideally positioned to provide developmental surveillance and support the care of both the child and family following critical illness. METHODS: An anonymous, cross-sectional survey of 60 GPs, reached via private invitation (19% response) or via social media weblink, was conducted where the GPs were asked about their current confidence and knowledge in managing children post PICU. This included awareness of short- and long-term problems, of paediatric intensive care syndrome in paediatrics (PICS-p), and of educational materials. Lastly, a parent-completed screening questionnaire and shared-care pathway were proposed to GPs for their feedback on perceived benefit and willingness to participate. Data were analysed using frequency distributions and chi-square statistics. RESULTS: Ninety-three percent of GPs had some level of confidence in caring for a child post PICU admission and low confidence in their knowledge of potential short- and long-term complications. Eighty percent of GPs had not heard of PICS-p, and 93% were unaware of educational materials available on this topic. Ninety-five percent of GPs perceived that the proposed patient-screening tool and shared-care pathways would be beneficial, and 70% predicted that they would definitely use educational materials if accessible through GP central repositories. CONCLUSION: To reduce ongoing health problems for children recovering from critical illness, the family GP plays a pivotal role in providing community-level developmental care, particularly in Australia. Increasing GP confidence and knowledge through education is essential, and using a parent-completed screening questionnaire and shared-care pathway to improve care may be beneficial. GPs must also be involved in the implementation stages of future shared-care models.

Neurodevelopmental and health-related quality-of-life outcomes in adolescence after surgery for congenital heart disease in infancy.

AIM: To assess outcomes in adolescence after surgery for congenital heart disease (CHD) in infancy. Domains analysed included cognition and executive function, social and emotional well-being, adaptive behaviour, academic achievement, and health-related quality of life (HRQoL). METHOD: Twenty-one participants (10 males, 11 females) ranged in age from 14 to 17 years (mean 15y 4.8mo, SD 8.4mo). Twenty had biventricular repairs. All were classified as New York Heart Association class I. Measures included: Wechsler Intelligence and Achievement scales; Wide Range Assessment of Memory and Learning, Second Edition; California Verbal Learning Test - Children's Version; Behaviour Rating Inventory of Executive Function; Conners, Third Edition; Adaptive Behavior Assessment System, Second Edition; Behavior Assessment System for Children, Second Edition; Rey-Osterrieth Complex Figure; and Pediatric Quality of Life Inventory. RESULTS: Outcomes were significantly lower (p≤0.01) than population norms for processing speed, mathematical achievement, attention, and visual-spatial ability. Participants reported more frequent learning problems but more positive family relations. HRQoL was significantly lower across most domains by self- and parent-proxy report. INTERPRETATION: Individuals with CHD may experience difficulties across a range of domains. These findings emphasize the importance of comprehensive screening, early intervention, and long-term follow-up, as deficits may extend into young adulthood. WHAT THIS PAPER ADDS: Identified cognitive, learning, and attentional impairments in adolescents after congenital heart disease surgery in infancy. Combined self-report, caregiver report, and laboratory tasks in a comprehensive neurodevelopmental assessment protocol. Health-related quality of life was lower across most domains.

Antithrombin Dosing Guidelines in Children Underestimate Dose Needed for Plasma Level Increase.

OBJECTIVES: Antithrombin is a cofactor in the coagulation cascade with mild anticoagulant activity and facilitates the action of heparin as an anticoagulant. Antithrombin concentrate dosing guidelines vary but most commonly suggest that each unit of antithrombin concentrate per body weight increases the plasma antithrombin level by 1.5% to 2.2% (depending on manufacturer). We aimed to establish a dosing recommendation dependent on age and disease state. DESIGN: A retrospective analysis of all antithrombin concentrate doses over a period of 5 years. We calculated the increase any respective antithrombin concentrate dose achieved, indexed by body weight, and performed a multivariable analysis to establish independent factors associated with the effectiveness of antithrombin concentrate. SETTING: A PICU at a university-affiliated children's hospital. PATIENTS: One hundred fifty-five patients treated in a PICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The effect of 562 doses of antithrombin concentrate on plasma antithrombin levels administered to 155 patients, of which 414 (73.7%) antithrombin concentrate doses administered during extracorporeal life support treatment, were analyzed. For all patients, each unit of antithrombin concentrate/kg increased plasma antithrombin level by 0.86% (SD 0.47%). Plasma antithrombin level increase was influenced by body weight (increase of 0.76% [interquartile range, 0.6-0.92%] for patients < 5 kg; 1.38% [interquartile range, 1.11-2.10%] for > 20 kg), disease state (liver failure having the poorest antithrombin increase) and whether patients were treated with extracorporeal circulatory support (less antithrombin increase on extracorporeal life support). Heparin dose at the time of administration did not influence with amount of change in antithrombin level. CONCLUSIONS: Current antithrombin concentrate dosing guidelines overestimate the effect on plasma antithrombin level in critically ill children. Current recommendations result in under-dosing of antithrombin concentrate administration. Age, disease state, and extracorporeal life support should be taken into consideration when administering antithrombin concentrate.

Congenital Heart Disease Long-term Improvement in Functional hEalth (CHD LIFE): A partnership programme to improve the long-term functional health of children with congenital heart disease in Queensland.

Children who undergo open-heart surgery in the first year of life for congenital heart disease (CHD) are at high-risk for impaired development across multiple domains. International recommendations include systematic periodic developmental surveillance into adolescence and the establishment of long-term follow-up programmes. This article describes the establishment and evolution of the Queensland Paediatric Cardiac Service neurodevelopmental follow-up programme - CHD LIFE (Long-term Improvement in Functional hEalth). Contextualising best practice recommendations to ensure a family-centred and sustainable approach to understand and support the long-term functional health needs of high-risk children with CHD as standard care was needed. We describe the transition from a centralised pilot Programme to the implementation of an integrated statewide approach aimed at delivering consistent high-level standards of care and a platform to evaluate therapeutic interventions.

Bleeding Assessment Scale in Critically Ill Children (BASIC): Physician-Driven Diagnostic Criteria for Bleeding Severity.

OBJECTIVE: Although bleeding frequently occurs in critical illness, no published definition to date describes the severity of bleeding accurately in critically ill children. We sought to develop diagnostic criteria for bleeding severity in critically ill children. DESIGN: Delphi consensus process of multidisciplinary experts in bleeding/hemostasis in critically ill children, followed by prospective cohort study to test internal validity. SETTING: PICU. PATIENTS: Children at risk of bleeding in PICUs. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Twenty-four physicians worldwide (10 on a steering committee and 14 on an expert committee) from disciplines related to bleeding participated in development of a definition for clinically relevant bleeding. A provisional definition was created from 35 descriptors of bleeding. Using a modified online Delphi process and conference calls, the final definition resulted after seven rounds of voting. The Bleeding Assessment Scale in Critically Ill Children definition categorizes bleeding into severe, moderate, and minimal, using organ dysfunction, proportional changes in vital signs, anemia, and quantifiable bleeding. The criteria do not include treatments such as red cell transfusion or surgical interventions performed in response to the bleed. The definition was prospectively applied to 40 critically ill children with 46 distinct bleeding episodes. The kappa statistic between the two observers was 0.74 (95% CI, 0.57-0.91) representing substantial inter-rater reliability. CONCLUSIONS: The Bleeding Assessment Scale in Critically Ill Children definition of clinically relevant bleeding severity is the first physician-driven definition applicable for bleeding in critically ill children derived via international expert consensus. The Bleeding Assessment Scale in Critically Ill Children definition includes clear criteria for bleeding severity in critically ill children. We anticipate that it will facilitate clinical communication among pediatric intensivists pertaining to bleeding and serve in the design of future epidemiologic studies if it is validated with patient outcomes.

Neuromotor performance in infants before and after early open-heart surgery and risk factors for delayed development at 6 months of age.

BACKGROUND: Early identification of infants with CHD at heightened risk of developmental delays can inform surveillance priorities. This study investigated pre-operative and post-operative neuromotor performance in infants undergoing open-heart surgery, and their developmental status at 6 months of age, to identify risk factors and inform care pathways. METHODS: Infants undergoing open-heart surgery before 4 months of age were recruited into a prospective cohort study. Neuromotor performance was assessed pre-operatively and post-operatively using the Test of Infant Motor Performance and Prechtl's Assessment of General Movements. Development was assessed at 6 months of age using the Ages and Stages Questionnaire third edition. Pre-operative and post-operative General Movements performance was compared using McNemar's test and test of infant motor performance z-scores using Wilcoxon's signed rank test. Risk factors for delayed development at 6 months were explored using logistic regression. RESULTS: Sixty infants were included in this study. In the 23 (38%) infants. A total of 60 infants were recruited. In the 23 (38%) infants assessed pre-operatively, there was no significant difference between pre- and post-operative performance on the GMs (p=0.63) or TIMP (p=0.28). At discharge, 15 (26%) infants presented with abnormal GMs, and the median TIMP z-score was -0.93 (IQR: -1.4 to -0.69). At 6 months, 28 (52.8%) infants presented with gross motor delay on the ASQ-3, significantly negatively associated with gestational age (p=0.03), length of hospital stay (p=0.04) and discharge TIMP score (p=0.01). CONCLUSIONS: Post-operative assessment using the GMs and TIMP may be useful to identify infants requiring individualised care and targeted developmental follow-up. Long-term developmental surveillance beyond 6 months of age is recommended.

Adherence to standard medication infusion concentrations and its impact on paediatric intensive care patient outcomes.

AIM: To review compliance with the DERS, and to evaluate the impact on daily fluid balances as a standard outcome in paediatric intensive care. METHOD: A prospective audit of patients admitted to our tertiary level PICU over a 10day period. The audit tool collated information on patient's weight, diagnosis, medication infusions, whether standard concentrations were selected, daily fluid balance, target fluid balance, and renal support including use of diuretics. RESULTS: Seventy-seven (84%) of patients weighed less than 10kg. On average, there were seven medication infusions per patient and 98% of the medication infusions adhered to standard concentrations for medication infusions and DERS. In 2% of medication infusions staff opted not to use the DERS, or selected non-standard concentration, and 2% of patients had no labels on the syringe. 90% of patients had a minimal positive balance of 0.5mL/kg/h, averaged over 24h; 48% of patients received renal support and 16% of patients were 24h post cardiac surgery, where a negative fluid balance was recorded. It is standard practice post cardiac surgery to receive diuretics. Standard concentrations did not have a significant impact on patients' daily fluid balance. CONCLUSIONS: The use of standard concentrations and short infusions in PICU using DERS is feasible & achievable as demonstrated by high compliance, and does not have a negative impact on patient outcome, especially fluid balance.

Coagulation monitoring correlation with heparin dose in pediatric extracorporeal life support.

OBJECTIVES: Extracorporeal Life Support (ECLS) risks thrombotic and hemorrhagic complications. Optimal anti-coagulation monitoring is controversial. We compared coagulation tests evaluating the heparin effect in pediatric ECLS. METHODS: A retrospective study of children (<18yrs) undergoing ECLS over 12 months in a tertiary pediatric intensive care unit (PICU). Variables included anti-Factor Xa activity (anti-Xa), activated partial thromboplastin time (aPTT), activated clotting time (ACT) and thromboelastogram (TEG®6s) parameters: ratio and delta reaction (R) times (the ratio and difference, respectively, between R times in kaolin assays with and without heparinase). Test results were correlated with unfractionated heparin infusion rate (IU/kg/hr) at the time of sampling. Mean test results of each ECLS run were evaluated according to the presence/absence of complications. RESULTS: Thirty-two ECLS runs (31 patients) generated 695 data-points for correlation. PICU mortality was 22% and the thrombotic complication rate was 66%. The proportion of variation in coagulation test results explained by heparin dose was 13.3% for anti-Xa, 11.9% for ratio R time, and 9.9% for delta R time, compared with <1% for ACT and aPTT. Incorporating individual variation, age and antithrombin activity in a model with heparin dose explained less than 50% of the variation in test results. Correlation varied according to age, day of ECLS run and between individuals, with parallel dose-response lines noted between patients. Significantly lower mean anti-Xa was observed in PICU non-survivors and runs with thrombosis. CONCLUSION: Lower anti-Xa was observed in ECLS runs with complications. Although absolute results from anti-Xa and TEG6®s showed the best correlation with heparin dose, a large proportion of variation in results was unexplained by heparin, while dose response was similar between individuals. Population pharmacokinetic/pharmacodynamic modelling is required, as well as prospective trials to delineate the superior means of adjusting heparin therapy to prevent adverse clinical outcomes.

Tetralogy of Fallot and Its Variants.

OBJECTIVES: The objectives of this review are to discuss the anatomy, pathophysiology, surgical repair, and perioperative management strategies for tetralogy of Fallot and its variants. DATA SOURCE: MEDLINE and PubMed. CONCLUSIONS: Significant refinements have been made in the repair strategy for tetralogy of Fallot, based on improved understanding of postrepair physiology. Important considerations for timing and technique of surgery and perioperative management have been presented, and continued evolution is expected. Expanded use of the pulmonary valve reconstruction technique outlined herein, whatever the age of repair, may improve long-term outcome.

Procalcitonin in the Early Course Post Pediatric Cardiac Surgery.

OBJECTIVE: Procalcitonin has emerged as a promising infection marker, but previous reports from small-sized studies suggest nonspecific elevation of procalcitonin after pediatric heart surgery. As procalcitonin is increasingly used as a marker for infection in the PICU, the aim of this study was to identify factors associated with postoperative procalcitonin elevation and to investigate the role of procalcitonin as an early marker of outcome after cardiac surgery. DESIGN: Prospective observational study. SETTING: Single, tertiary referral PICU. PATIENTS: Patients aged 0-16 years following cardiac surgery with or without cardiopulmonary bypass. INTERVENTIONS: Procalcitonin was measured in all patients at admission to PICU, and on postoperative day 1 and 2. Outcome variables included major adverse event, length of stay in PICU, postoperative renal failure requiring temporary dialysis, duration of mechanical ventilation and duration of inotropic support. A major adverse event was defined as cardiac arrest, need for postoperative extracorporeal life support or death within 3 months of cardiac surgery. MEASUREMENTS AND MAIN RESULTS: In 221 included patients who underwent 232 operations, procalcitonin at admission to PICU was significantly associated with mechanical ventilation prior to surgery (p = 0.001), preoperative myocardial dysfunction (p = 0.002), duration of cardiopulmonary bypass (p < 0.001), intraoperative cross-clamp time (p = 0.015), and serum lactate at admission (p < 0.001). Patients suffering a major adverse event and patients with postoperative renal failure had significantly higher procalcitonin levels at admission to PICU (p = 0.04 and 0.01, respectively). Furthermore, procalcitonin levels at admission correlated significantly with the length of stay in the PICU (p = 0.005), time on mechanical ventilation (p = 0.03), and duration of inotropic support (p = 0.02). CONCLUSIONS: Elevated levels of procalcitonin in the early phase after pediatric cardiac surgery are a marker for increased risk for major adverse events and postoperative renal failure and increased postoperative morbidity.

Anticoagulation strategies and difficulties in neonatal and paediatric extracorporeal membrane oxygenation (ECMO).

OBJECTIVE: The aim of this review is to highlight an emerging problem with anticoagulation-related complications in neonatal and paediatric ECMO, to explore for flaws in the currently recommended anticoagulation management responsible for these problems and to discuss possible strategies mitigating further escalation of the issue. DATA SOURCES: Pertinent neonatal and paediatric literature on the topic of interest and international Extracorporeal Life Support Organisation (ELSO) registry data request. CONCLUSIONS: The international ELSO registry data reveals increasing rates of anticoagulation-related complications during neonatal and paediatric ECMO worldwide. The causes are multifactorial and the proposed solution to the problem is to match anticoagulation management to the pathophysiological complexity of haemostasis on ECMO.

Enteroviral myocarditis in neonates.

Enteroviruses are a leading cause of viral infections in children. While most enteroviral infections are mild and self-limiting, severe disease such as a viral sepsis syndrome, myocarditis, hepatitis and meningoencephalitis may occur. We present two cases of neonatal enteroviral myocarditis. Cardiorespiratory failure occurred in both cases, and severe shock refractory to conventional treatment required support with extracorporeal membrane oxygenation (ECMO). One child with coxsackievirus B3 myocarditis failed to recover and died after 3 weeks on ECMO, while one child could be decannulated successfully after 9 days of ECMO and recovered completely subsequently. In conclusion, neonatal myocarditis has a very high mortality, and ECMO should be considered early in neonates with rapid clinical and echocardiographic deterioration despite adequate inotropic support.

Perioperative dexmedetomidine compared to midazolam in children undergoing open-heart surgery: A pilot randomised controlled trial.

Objective: There is a need for evidence on the best sedative agents in children undergoing open heart surgery for congenital heart disease. This study aimed to evaluate the feasibility and safety of dexmedetomidine in this group compared with midazolam. Design: Double blinded, pilot randomized controlled trial. Setting: Cardiac operating theatre and paediatric intensive care unit in Brisbane, Australia. Participants: Infants (≤12 months of age) undergoing their first surgical repair of a congenital heart defect. Interventions: Dexmedetomidine (up to 1.0mcg/kg/hr) versus midazolam (up to 80mcg/kg/hr), commenced in the cardiac operating theatre prior to surgery. Main outcome measures: The primary outcome was the time spent in light sedation (Sedation Behavior Scale [SBS] -1 to +1); Co-primary feasibility outcome was recruitment, retention and protocol adherence. Secondary outcomes were use of supplemental sedatives, ventilator free days, delirium, vasoactive drug support, and adverse events. Neurodevelopment and health-related quality of life (HRQoL) were assessed at 12 months post-surgery. Results: Sixty-six participants were recruited. The number of SBS scores in the light sedation range were greater in the dexmedetomidine group at 24 hours, 48 hours, and overall study duration (0-14 days) versus the midazolam group (24hr: 76/170 [45%] vs 60/178 [34%], aOR 4.14 [95% CI 0.48, 35.92]; 48hr: 154/298 [52%] vs 122/314 [39%], aOR 6.95 [95% CI 0.77, 63.13]; 0-14 days: 597/831 [72%] vs 527/939 [56%], aOR 3.93 [95% CI 0.62, 25.03]). Feasibility was established with no withdrawals or loss to follow-up at 14 days and minimal protocol deviations. There were no differences between the groups relating to clinical, safety, neurodevelopment or HRQoL outcomes. Conclusions: The use of dexmedetomidine was associated with more time spent in light sedation when compared with midazolam. The feasibility of conducting a blinded RCT of midazolam and dexmedetomidine in children undergoing open heart surgery was also established. The findings justify further investigation in a larger trial. Clinical trial registration: ACTRN12615001304527.

Effectiveness-implementation hybrid-2 randomised trial of a collaborative Shared Care Model for Detecting Neurodevelopmental Impairments after Critical Illness in Young Children (DAISY): pilot study protocol.

INTRODUCTION: In Australia, while paediatric intensive care unit (PICU) mortality has dropped to 2.2%, one in three survivors experience long-term neurodevelopmental impairment, limiting their life-course opportunities. Unlike other high-risk paediatric populations, standardised routine neurodevelopmental follow-up of PICU survivors is rare, and there is limited knowledge regarding the best methods. The present study intends to pilot a combined multidisciplinary, online screening platform and general practitioner (GP) shared care neurodevelopmental follow-up model to determine feasibility of a larger, future study. We will also assess the difference between neurodevelopmental vulnerability and parental stress in two intervention groups and the impact of child, parent, sociodemographic and illness/treatment risk factors on child and parent outcomes. METHODS AND ANALYSIS: Single-centre randomised effectiveness-implementation (hybrid-2 design) pilot trial for parents of children aged ≥2 months and <4 years discharged from PICU after critical illness or injury. One intervention group will receive 6 months of collaborative shared care follow-up with GPs (supported by online outcome monitoring), and the other will be offered self-directed screening and education about post-intensive care syndrome and child development. Participants will be followed up at 1, 3 and 6 months post-PICU discharge. The primary outcome is feasibility. Secondary outcomes include neurodevelopmental vulnerability and parental stress. An implementation evaluation will analyse barriers to and facilitators of the intervention. ETHICS AND DISSEMINATION: The study is expected to lead to a full trial, which will provide much-needed guidance about the clinical effectiveness and implementation of follow-up models of care for children after critical illness or injury. The Children's Health Queensland Human Research Ethics Committee approved this study. Dissemination of the outcomes of the study is expected via publication in a peer-reviewed journal, presentation at relevant conferences, and via social media, podcast presentations and open-access medical education resources. REGISTRATION DETAILS: The trial was prospectively registered with the Australian New Zealand Clinical Trials Registry as 'Pilot testing of a collaborative Shared Care Model for Detecting Neurodevelopmental Impairments after Critical Illness in Young Children' (the DAISY Pilot Study). TRIAL REGISTRATION NUMBER: ACTRN12621000799853.