A fragment based competitive 19F LB-NMR platform for hotspot directed ligand profiling.

Ligand binding hotspots are regions of protein surfaces that form particularly favourable interactions with small molecule pharmacophores. Targeting interactions with these hotspots maximises the efficiency of ligand binding. Existing methods are capable of identifying hotspots but often lack assays to quantify ligand binding and direct elaboration at these sites. Herein, we describe a fragment-based competitive 19F Ligand Based-NMR (LB-NMR) screening platform that enables routine, quantitative ligand profiling focused at ligand-binding hotspots. As a proof of concept, the method was applied to 4'-phosphopantetheine adenylyltransferase (PPAT) from Mycobacterium abscessus (Mabs). X-ray crystallographic characterisation of the hits from a 960-member fragment screen identified three ligand-binding hotspots across the PPAT active site. From the fragment hits a collection of 19F reporter candidates were designed and synthesised. By rigorous prioritisation and use of optimisation workflows, a single 19F reporter molecule was generated for each hotspot. Profiling the binding of a set of structurally characterised ligands by competitive 19F LB-NMR with this suite of 19F reporters recapitulated the binding affinity and site ID assignments made by ITC and X-ray crystallography. This quantitative mapping of ligand binding events at hotspot level resolution establishes the utility of the fragment-based competitive 19F LB-NMR screening platform for hotspot-directed ligand profiling.

Activated 4-Factor Prothrombin Complex Concentrate as a Hemostatic Adjunct for Neonatal Cardiac Surgery: A Propensity Score-Matched Cohort Study.

BACKGROUND: Prothrombin complex concentrates are an emerging "off-label" therapy to augment hemostasis after cardiopulmonary bypass (CPB), but data supporting their use for neonatal cardiac surgery are limited. METHODS: We retrospectively reviewed neonates undergoing open heart surgery with first-time sternotomy between May 2014 and December 2018 from a hospital electronic health record database. Neonates who received activated 4-factor prothrombin complex concentrate (a4FPCC) after CPB were propensity score matched (PSM) to neonates who did not receive a4FPCC (control group). The primary efficacy outcome was total volume (mL/kg) of blood products transfused after CPB, including the first 24 hours on the cardiovascular intensive care unit (CVICU). The primary safety outcome was the incidence of 7- and 30-day postoperative thromboembolism. Secondary outcomes included 24 hours postoperative chest tube output, time to extubation, duration of CVICU stay, duration of hospital stay, 30-day mortality, and incidence of acute kidney injury on postoperative day 3. We used linear regression modeling on PSM data for the primary efficacy outcome. For the primary safety outcome, we tested for differences using McNemar test on PSM data. For secondary outcomes, we used linear regression, Fisher exact test, or survival analyses as appropriate, with false discovery rate-adjusted P values. RESULTS: A total of 165 neonates were included in the final data analysis: 86 in the control group and 79 in the a4FPCC group. After PSM, there were 43 patients in the control group and 43 in the a4FPCC group. We found a statistically significant difference in mean total blood products transfused for the a4FPCC group (47.5 mL/kg) compared with the control group (63.7 mL/kg) for PSM patients (adjusted difference, 15.3; 95% CI, 29.4-1.3; P = .032). We did not find a statistically significant difference in 7- or 30-day thromboembolic rate, postoperative chest tube output, time to extubation, incidence of postoperative acute kidney injury (AKI), or 30-day mortality between the groups. The a4FPCC group had a significantly longer length of intensive care unit stay (32.9 vs 13.3 days; adjusted P = .049) and hospital stay (44.6 vs 24.1 days; adjusted P = .049) compared with the control group. CONCLUSIONS: We found that the use of a4FPCC as a hemostatic adjunct for post-CPB bleeding in neonatal cardiac surgery was associated with a decrease in mean total blood products transfused after CPB without an increased rate of 7- or 30-day postoperative thromboembolism. Our findings suggest that a4FPCCs can be considered as part of a hemostasis pathway for refractory bleeding in neonatal cardiac surgery.

Fibrinogen Concentrate as an Alternative to Cryoprecipitate in a Postcardiopulmonary Transfusion Algorithm in Infants Undergoing Cardiac Surgery: A Prospective Randomized Controlled Trial.

BACKGROUND: Infants undergoing cardiac surgery are at risk for bleeding and massive transfusion due to an immature coagulation system, complex surgeries, and cardiopulmonary bypass (CPB) effects. Hemodilution from CPB promotes an acquired hypofibrinogenemia that results in impaired fibrin formation, inadequate clot formation, and increased bleeding. In North America, the current standard of care to supplement fibrinogen is cryoprecipitate. An alternative option is the off-label use of fibrinogen concentrate (FC; RiaSTAP; CSL Behring, Marburg, Germany), a purified fibrinogen. Because perioperative allogenic transfusions are associated with increased morbidity and mortality, we sought to determine whether FC would be an acceptable alternative to cryoprecipitate in a post-CPB transfusion algorithm in infants undergoing open-heart surgery. METHODS: We randomized 60 infants (<12 months) undergoing nonemergent cardiac surgery with CPB at 2 tertiary care children's hospitals to receive either cryoprecipitate or FC in a post-CPB transfusion algorithm. Infants underwent a stratified randomization based on institution and surgical complexity. The primary outcome was the difference in number of intraoperative allogenic blood product transfusions. Secondary outcomes included 24-hour chest tube output (CTO), mechanical ventilation time, adverse events (AEs), intensive care unit (ICU) length of stay (LOS), hospital LOS, postoperative thrombosis, and death within 30 days of surgery. The primary analysis followed the intent-to-treat (ITT) principle and was performed using linear regression adjusted for institution and complexity of surgery. A per-protocol (PP) analysis was also performed. RESULTS: Between June 2016 and January 2018, we enrolled 60 patients with complete data available for 25 patients who received cryoprecipitate and 29 patients who received FC. Patients in the cryoprecipitate group (median age: 4 months [2-6 months]) received 5.5 (4.0-7.0) allogeneic blood units in the ITT analysis and 6.0 units (5.0-7.0 units) in the PP analysis. Patients in the FC group (median age: 4 months [2-5]) received 4 units (3.0-5.0 units) in the ITT analysis and 4.0 units (3.0-5.0 units) in the PP analysis. In the adjusted ITT analysis, the FC group received 1.79 units (95% confidence interval [CI], 0.64-2.93; P = .003) less than the cryoprecipitate group. In the adjusted PP analysis, the FC group received 2.67 units (95% CI, 1.75-3.59; P < .001) less than the cryoprecipitate group. There were no significant differences in secondary outcomes or AEs. CONCLUSIONS: Our findings suggest that FC may be considered as an alternative to cryoprecipitate for the treatment of hypofibrinogenemia in infants with bleeding after CPB. Although we found no significant differences between secondary outcomes or AEs, further studies are needed to assess safety.

Evolving pediatric epidural practice: An institution's clinical experience over 20 years-A retrospective observational cohort study.

BACKGROUND AND OBJECTIVES: Epidural analgesia is an effective, established perioperative intervention in all age-groups. In children, however, epidural-related data are limited compared to the adult population. The aim of this study was to examine the use of pediatric epidural analgesia in our institution and, thereby, add to the existing data pool. METHODOLOGY: Patients who received epidural analgesia as part of their perioperative management between 1996 and 2016 at Great Ormond Street Hospital, London, UK, were studied to determine how epidural practice has changed over time, associated incidence of serious adverse events, complications, and patient/parent satisfaction. Epidural use and monitoring were in accordance with standard hospital protocols. Data were prospectively collected and entered into a secure database by trained personnel. These data were subsequently extracted for retrospective analysis. RESULTS: A total of 3876 patients were included. The median age was 4.4 years (range 1 day to 20 years), and the median weight was 20.3 kg. Across all age-groups, the lumbar region was the most common site of epidural insertion while urology (42.2%) and general surgery (37.3%) were the specialities for which it was most utilized. Over the study period, the number of epidurals performed declined while the number of surgical procedures performed simultaneously increased. The infusate most commonly used was local anesthetic with preservative-free morphine (71.9%). In 923 (23.2%) patients, systemic opioids were additionally used for analgesic management by means of patient-controlled analgesia or nurse-controlled analgesia. There was one serious adverse event in the form of permanent nerve injury, giving an overall incidence of approximately 1:3800. Other complications included postoperative nausea and vomiting (35.9%), urinary retention (4.4%), and pruritus (31%). Overall global satisfaction with the service was generally high, with 95% providing a rating of "very good" or "good." CONCLUSION: This study evaluated two decades of epidural practice in our institution. Epidural analgesia remains a safe, effective option for postoperative analgesia, but its use has declined over time, and this trend is likely to continue. Rates of serious adverse events and complications were low and comparable to those published in other similar studies. Global satisfaction among patients/parents remains high.

The use of prothrombin complex concentrate as a warfarin reversal agent in pediatric patients undergoing orthotopic heart transplantation.

BACKGROUND: Patients supported with a ventricular assist device are predisposed to severe bleeding at the time of orthotopic heart transplant due to several risk factors including anticoagulation with vitamin K antagonists. Kcentra, a four-factor prothrombin complex concentrate, has been approved by the FDA for warfarin reversal in adults prior to urgent surgery. There is a lack of published data on the preoperative use of four-factor prothrombin complex concentrates in pediatric patients undergoing cardiacsurgery. METHODS: This is a single-center retrospective analysis of pediatric patients with a continuous-flow ventricular assist device who underwent heart transplant, comparing patients who received Kcentra for anticoagulation reversal with a historical patient cohort who did not. Consecutive patients from January 2013 to December 2017 were analyzed. The primary outcome was volume of blood product transfusion prior to cardiopulmonary bypass initiation. Secondary outcomes include blood product transfusion after cardiopulmonary bypass intraoperatively and up to 24 hours postoperatively, chest tube output within 24 hours of surgery, time to extubation, incidence of thromboembolism, and post-transplant length ofstay. RESULTS: From 2013 to 2017, 31 patients with continuous-flow ventricular assist devices underwent heart transplant, with 27 patients included in the analysis. Fifteen patients received Kcentra compared with 12 patients who received fresh-frozen plasma for anticoagulation reversal. Compared with the control group, patients who received Kcentra had less packed red blood cells, fresh-frozen plasma, and platelets transfused prior to cardiopulmonary bypass initiation. The Kcentra group also received less packed red blood cells on bypass and less packed red blood cells after cardiopulmonary bypass termination. There were no differences in chest tube output, time to extubation, intensive care unit length of stay, or overall hospital length of stay. Neither group had thromboembolic complications detected during the first seven postoperative days. CONCLUSION: This small retrospective study indicates that preoperative warfarin reversal with Kcentra reduces blood product exposure in pediatric patients with ventricular assist devices undergoing heart transplant.

Effectiveness of interdisciplinary interventions in paediatric chronic pain management: a systematic review and subset meta-analysis.

BACKGROUND: Paediatric chronic pain is a significant problem that can have devastating impacts on quality of life. Multimodal interdisciplinary interventions are the mainstay of paediatric treatment. The aim of this article is to provide a comprehensive review of the effectiveness of interdisciplinary interventions in the management of paediatric chronic pain. METHODS: Studies were identified via a search of nine databases. The search strategy included concept blocks pertaining to type of pain, study population, and type of intervention. Eligible studies reported the effects of an intervention co-ordinated by two or more healthcare professionals of different disciplines, and recruited a sample aged 22 yr or below with chronic pain. Twenty-eight studies were included, and 21 provided data for inclusion in between- and within-groups meta-analyses. RESULTS: Patients randomised to interdisciplinary interventions reported significantly lower pain intensity 0-1 month post-intervention compared with patients randomised to the control groups. Within-groups analysis of patients receiving interdisciplinary interventions showed significant improvements pre- to post-intervention in pain intensity, functional disability, anxiety, depression, catastrophising, school attendance, school functioning, and pain acceptance. Few differences were found between interventions delivered in inpatient vs outpatient settings. Significant heterogeneity due mainly to differing outcome variables and intervention content was found in most analyses. CONCLUSIONS: Overall, interdisciplinary interventions show promise in providing a range of clinical benefits for children with chronic pain. Methodologically robust randomised controlled trials using standardised outcome measures are needed, however, to guide clinical care.

STAC3 variants cause a congenital myopathy with distinctive dysmorphic features and malignant hyperthermia susceptibility.

SH3 and cysteine-rich domain-containing protein 3 (STAC3) is an essential component of the skeletal muscle excitation-contraction coupling (ECC) machinery, though its role and function are not yet completely understood. Here, we report 18 patients carrying a homozygous p.(Trp284Ser) STAC3 variant in addition to a patient compound heterozygous for the p.(Trp284Ser) and a novel splice site change (c.997-1G > T). Clinical severity ranged from prenatal onset with severe features at birth, to a milder and slowly progressive congenital myopathy phenotype. A malignant hyperthermia (MH)-like reaction had occurred in several patients. The functional analysis demonstrated impaired ECC. In particular, KCl-induced membrane depolarization resulted in significantly reduced sarcoplasmic reticulum Ca2+ release. Co-immunoprecipitation of STAC3 with CaV 1.1 in patients and control muscle samples showed that the protein interaction between STAC3 and CaV 1.1 was not significantly affected by the STAC3 variants. This study demonstrates that STAC3 gene analysis should be included in the diagnostic work up of patients of any ethnicity presenting with congenital myopathy, in particular if a history of MH-like episodes is reported. While the precise pathomechanism remains to be elucidated, our functional characterization of STAC3 variants revealed that defective ECC is not a result of CaV 1.1 sarcolemma mislocalization or impaired STAC3-CaV 1.1 interaction.

Reporting of Perioperative Adverse Events by Pediatric Anesthesiologists at a Tertiary Children's Hospital: Targeted Interventions to Increase the Rate of Reporting.

BACKGROUND: Incident reporting systems (IRSs) are important patient safety tools for identifying risks and opportunities for improvement. A major IRS limitation is underreporting of incidents. Perioperative anesthesia IRSs have been established at multiple pediatric institutions and a national pediatric anesthesia IRS for perioperative serious adverse events (SAEs) is maintained by Wake Up Safe (WUS), a patient safety organization dedicated to pediatric anesthesia quality improvement. A confidential, electronic, perioperative IRS was instituted at our tertiary children's hospital, which is a WUS member. The primary study aim was to increase the rate of incident reporting by anesthesiologists at our institution through a series of interventions. The secondary aim was to characterize our reporting behavior relative to national practice by referencing SAE data from WUS. METHODS: Perioperative adverse events reported over a 71-month period (November 2010 to September 2016) were categorized and the monthly reporting rates determined. Effects of 6 interventions targeted to increase the reporting rate were analyzed using control charts. Intervention 5 involved interviewing pediatric anesthesiologists to ascertain incident reporting barriers and motivators. A key driver diagram was developed and used to guide an improvement initiative. Incidents that fulfilled WUS criteria for SAEs were identified and categorized. SAE reporting rates over a 27-month period for 12 WUS member institutions were determined. RESULTS: 2689 perioperative adverse events were noted in 1980 of 72,384 anesthetics. Mean monthly adverse event case rate was 273 (95% confidence interval, 250-297) per 10,000 anesthetics. A subgroup involving 54,469 cases had 529 SAEs in 440 anesthetics; a mean monthly SAE case rate of 80 (95% confidence interval, 69-91) per 10,000 anesthetics. Cardiac, respiratory, and airway events predominated. Relative to WUS peer members, our institution is a high-reporting outlier. The rate of incident reporting per 10,000 anesthetics was sustainably increased from 149 ± 35 to 387 ± 73 (mean ± SD) after implementing mandatory IRS data entry and Intervention 5 quality improvement initiative. Barriers to reporting included concern for punitive repercussions, feelings of incompetence, poor education about what constitutes an event, lack of feedback, and the perception that reporting had no value. These were addressed by IRS education, cultivation of a culture of safety where reporting is encouraged, reporter feedback, and better inclusion of anesthesiologists in patient safety work. CONCLUSIONS: Electronic mandatory IRS data entry and an initiative to understand and address reporting barriers and motivators were associated with sustained increases in the adverse event reporting rate. These strategies to minimize underreporting enhance IRS value for learning and may be generalizable.

Current use of factor concentrates in pediatric cardiac anesthesia.

Excessive bleeding following pediatric cardiopulmonary bypass is associated with increased morbidity and mortality, both from the effects of hemorrhage and the therapies employed to achieve hemostasis. Neonates and infants are especially at risk because their coagulation systems are immature, surgeries are often complex, and cardiopulmonary bypass technologies are inappropriately matched to patient size and physiology. Consequently, these young children receive substantial amounts of adult-derived blood products to restore adequate hemostasis. Adult and pediatric data demonstrate associations between blood product transfusions and adverse patient outcomes. Thus, efforts to limit bleeding after pediatric cardiopulmonary bypass and minimize allogeneic blood product exposure are warranted. The off-label use of factor concentrates, such as fibrinogen concentrate, recombinant activated factor VII, and prothrombin complex concentrates, is increasing as these hemostatic agents appear to offer several advantages over conventional blood products. However, recognizing that these agents have the potential for both benefit and harm, well-designed studies are needed to enhance our knowledge and to determine the optimal use of these agents. In this review, our primary objective was to examine the evidence regarding the use of factor concentrates to treat bleeding after pediatric CPB and identify where further research is required. PubMed, MEDLINE/OVID, The Cochrane Library and the Cochrane Central Register of Controlled Trials (CENTRAL) were systematically searched to identify existing studies.

Perioperative management of pediatric en-bloc combined heart-liver transplants: a case series review.

BACKGROUND: Combined heart and liver transplantation (CHLT) in the pediatric population involves a complex group of patients, many of whom have palliated congenital heart disease (CHD) involving single ventricle physiology. OBJECTIVE: The purpose of this study was to describe the perioperative management of pediatric patients undergoing CHLT at a single institution and to identify management strategies that may be used to optimize perioperative care. METHODS: We did a retrospective database review of all patients receiving CHLT at a children's hospital between 2006 and 2014. Information collected included preoperative characteristics, intraoperative management, blood transfusions, and postoperative morbidity and mortality. RESULTS: Five pediatric CHLTs were performed over an 8-year period. All patients had a history of complex CHD with multiple sternotomies, three of whom had failing Fontan physiology. Patient age ranged from 7 to 23 years and weight from 29.5 to 68.5 kg. All CHLTs were performed using an en-bloc technique where both the donor heart and liver were implanted together on cardiopulmonary bypass (CPB). The median operating room time was 14.25 h, median CPB time was 3.58 h, and median donor ischemia time was 4.13 h. Patients separated from CPB on dopamine, epinephrine, and milrinone infusions and two required inhaled nitric oxide. All patients received a massive intraoperative blood transfusion post CPB with amounts ranging from one to three times the patient's estimated blood volume. The patient who required the most transfusions was in decompensated heart and liver failure preoperatively. Four of the five patients received an antifibrinolytic agent as well as a procoagulant (prothrombin complex concentrate or recombinant activated Factor VII) to assist with hemostasis. There were no 30-day thromboembolic events detected. Postoperatively the median length of mechanical ventilation, ICU stay and stay to hospital discharge was 4, 8, and 37 days, respectively. All patients are alive and free from allograft rejection at this time. CONCLUSION: Combined heart and liver transplantation in the pediatric population involves a complex group of patients with unique perioperative challenges. Successful management starts with thorough preoperative planning and communication and involves strategies to deal with massive intraoperative hemorrhage and coagulopathy in addition to protecting and supporting the transplanted heart and liver and meticulous surgical technique. An integrated multidisciplinary team approach is the cornerstone for successful outcomes.

The prevalence of pain at home and its consequences in children following two types of short stay surgery: a multicenter observational cohort study.

BACKGROUND: The potential for pain at home in children following day case surgery has long been recognized. Pain has also been associated with behavioral disturbances and sleep disruption in children following surgery and may also impact negatively on recovery, parental and patient satisfaction, family life, healthcare use, and have an economic cost. AIM: To investigate the prevalence of pain at home, and its consequences, in children following two types of short stay surgery across eight pediatric centers in the UK in an observational cohort study. Reporting of the study was done in adherence with STROBE guidelines. METHOD: Two hundred and forty-one children undergoing either Tonsillectomy with or without Adenoidectomy (T's ± A's) or Orchidopexy surgery (either by Open or Laparoscopic) were recruited. Data collection was via three structured telephone interviews [Day (D) 2, 7 and 14] conducted from a clinical research facility. The normal clinical practices of the centers involved in the study were not altered in any way. Outcomes studied were (i) Pain incidence and severity; (ii) Associated consequences-incidence of psychological disturbances, unplanned use of healthcare services, and social/economic cost to families; and (iii) Comparative pain and associated outcomes for two types of surgery (T's ± A's vs Orchidopexy). RESULTS: The incidence of pain following both operative models was high though it differed between the two groups. In the T's ± A's group, the incidence of pain was high throughout the study period (D2 90.1%, D3-7 88.1%, D8-14 61.8%). The Orchidopexy group demonstrated a similar pattern, though with decreased rates (D2 70.4%, D3-7 34.7%, D8-14 17.1%). Both groups showed similar patterns for the rates of behavioral disturbances (T's & A's: D2 76%, D3-7 73%, D8-14 30% and Orchidopexy: D2 37%, D3-7 20%, D8-14 10%). Seventy percent of the families reported unplanned healthcare use with pain the primary reason in 79% of these. CONCLUSIONS: The prevalence of pain at home, and its potential associated consequences, is high following short stay surgery in children in the UK. In both groups, high incidences were seen for longer periods than is commonly perceived. These findings were consistent between the centers involved suggesting that this is a significant national healthcare issue with potential short- and long-term consequences for the child, their family, and health services.

Exploring weak ligand-protein interactions by long-lived NMR states: improved contrast in fragment-based drug screening.

Ligands that have an affinity for protein targets can be screened very effectively by exploiting favorable properties of long-lived states (LLS) in NMR spectroscopy. In this work, we describe the use of LLS for competitive binding experiments to measure accurate dissociation constants of fragments that bind weakly to the ATP binding site of the N-terminal ATPase domain of heat shock protein 90 (Hsp90), a therapeutic target for cancer treatment. The LLS approach allows one to characterize ligands with an exceptionally wide range of affinities, since it can be used for ligand concentrations [L] that are several orders of magnitude smaller than the dissociation constants K(D). This property makes the LLS method particularly attractive for the initial steps of fragment-based drug screening, where small molecular fragments that bind weakly to a target protein must be identified, which is a difficult task for many other biophysical methods.

Fragment-Based Discovery of Allosteric Inhibitors of SH2 Domain-Containing Protein Tyrosine Phosphatase-2 (SHP2).

The ubiquitously expressed protein tyrosine phosphatase SHP2 is required for signaling downstream of receptor tyrosine kinases (RTKs) and plays a role in regulating many cellular processes. Genetic knockdown and pharmacological inhibition of SHP2 suppresses RAS/MAPK signaling and inhibit the proliferation of RTK-driven cancer cell lines. Here, we describe the first reported fragment-to-lead campaign against SHP2, where X-ray crystallography and biophysical techniques were used to identify fragments binding to multiple sites on SHP2. Structure-guided optimization, including several computational methods, led to the discovery of two structurally distinct series of SHP2 inhibitors binding to the previously reported allosteric tunnel binding site (Tunnel Site). One of these series was advanced to a low-nanomolar lead that inhibited tumor growth when dosed orally to mice bearing HCC827 xenografts. Furthermore, a third series of SHP2 inhibitors was discovered binding to a previously unreported site, lying at the interface of the C-terminal SH2 and catalytic domains.

Review of the off-label use of recombinant activated factor VII in pediatric cardiac surgery patients.

In recent years the off-label use of recombinant activated factor VII (rFVIIa) has markedly increased, particularly in pediatric cardiac surgery patients, and practitioners differ widely in their usage of the drug. In 2009, the Congenital Cardiac Anesthesia Society (CCAS) assembled a task force to review the literature on rFVIIa administration to pediatric cardiac surgery patients. The goal of the CCAS Task Force was to assess current practices and make recommendations about rFVIIa therapy to enhance quality of care, improve patient outcomes, reduce costs, and develop future research. In this review we summarized the important topics on current administration of rFVIIa to pediatric cardiac surgery patients including indications for use, efficacy, safety, dosing, and monitoring. All pediatric and pertinent adult literature regarding the administration of rFVIIa to cardiac surgical patients and published since 2000 were selected and studied. Of the 40 pediatric publications reviewed for this report, only 1 was a prospective randomized controlled trial thus making determinations of efficacy difficult. There is no substantive evidence to support the efficacy of rFVIIa as prophylactic or routine therapy during pediatric cardiac surgery. It may prove reasonable as rescue therapy because current observational evidence suggests that potential benefits of rFVIIa for this indication might outweigh the risks. Rescue therapy is appropriate for bleeding that is massive, potentially life-threatening, and refractory to conventional therapy. Nevertheless, extreme caution is advised when considering the administration of rFVIIa to patients who are at risk for thromboembolic complications because rates for clinical and subclinical thrombosis secondary to rFVIIa therapy are unknown at this time. This review is designed to aid practitioners in deciding when and how to administer rFVIIa to pediatric cardiac surgery patients; it is not intended to determine standard-of-care or practice guidelines. There are insufficient data to make evidence-based recommendations. Randomized controlled trials are needed to assess the efficacy of rFVIIa as prophylactic, routine, or rescue therapy and to determine the drug's safety profile particularly with regard to thrombosis. The CCAS rFVIIa Task Force will continue to monitor the literature, gather data, and make updates as more information becomes available.

Case report: airway and concurrent hemodynamic management in a neonate with oculo-auriculo-vertebral (Goldenhar) syndrome, severe cervical scoliosis, interrupted aortic arch, multiple ventricular septal defects, and an unstable cervical spine.

We report the challenging case of a 1-week-old, term, 2.4 kg neonate with Goldenhar syndrome (including microcephaly, left microtia, left facial palsy, dextro-scoliosis of the cervical spine, and cervico-thoracic levoscoliosis), multiple ventricular septal defects, a type B interrupted aortic arch, a large patent ductus arteriosis, and radiographic and clinical signs concerning for an unstable cervical spine. Our anesthesia team was consulted for perioperative management of this patient during her surgical repair. This case report describes the use of the Air-Q size 1 laryngeal airway (LA) to assist fiberoptic intubation in an ASA 4 neonate with cardiac disease, an anticipated difficult airway with the addition of an unstable cervical spine, as well as the anesthetic techniques used to maintain hemodynamic stability while the airway was secured.

Perioperative management of low birth weight infants for open-heart surgery.

Infants of birth weight ≤2500 g are termed low birth weight (LBW). These children often have considerable morbidity from prematurity and intra-uterine growth restriction. Additionally, LBW infants have increased risk for cardiac and noncardiac congenital anomalies and may require surgery. Primary rather than palliative surgical repair of cardiac lesions has been preferred in recent years. However, LBW remains a risk factor for increased mortality and morbidity after open-heart surgery (OHS). There is a paucity of information about the anesthetic challenges presented by LBW infants undergoing OHS. This review summarizes the perioperative issues of relevance to anesthesiologists who manage these high-risk patients. Emphasis is placed on management concerns that are unique to LBW infants. Retrospective data from the authors' institution are provided for those aspects of anesthetic care that lack published studies. Successful outcome often requires substantial hospital resources and collaborative multi-disciplinary effort.

Cardiomyopathy in childhood.

PURPOSE OF REVIEW: Cardiomyopathy is an important cause of heart failure and a major indication for heart transplantation in children. Unfortunately, there is a paucity of literature to guide the anesthesiologist who cares for these high-risk children. This review describes the cardiomyopathy phenotypes that occur in children and the factors that are associated with clinical outcomes and perioperative complications. Anesthesia considerations will be reviewed. RECENT FINDINGS: During the past decade, there has been a dramatic increase in knowledge related to cardiomyopathy. New genotypes and phenotypes are recognized and new therapies have been devised. Multicenter pediatric cardiomyopathy registries are obtaining data essential for enhanced understanding of the disease. SUMMARY: The diverse spectrum and complexity of pediatric cardiomyopathies mandate a thorough appreciation of the cardiac pathophysiology pertinent to an individual child's perioperative management. Important issues include multisystem disease associated with syndromic or genetic disorders, appropriate preoperative patient assessment to adequately characterize patient risk and guide therapy, and intraoperative and postoperative care plans that target optimal outcomes.

Online paediatric chronic pain management: assessing the needs of UK adolescents and parents, using a cross-sectional survey.

BACKGROUND: Adolescent chronic pain is prevalent, and interdisciplinary treatment is recommended. Although it is well known that technology is a key part of adolescents' daily lives, there have not been any online, interdisciplinary interventions developed for adolescents with chronic pain in a UK healthcare context. Little is known about how adolescents currently use online resources to manage chronic pain, or what guidance they seek. METHODS: Ninety-five participants from the community answered this mixed-methods, online survey (adolescent n = 54, parent n = 41), which assessed the needs of UK-based adolescents for a new online chronic pain management resource. RESULTS: Findings indicated that, at the time of the survey, adolescents frequently used social media platforms, such as Instagram, for chronic pain management. Desired techniques for a new interdisciplinary resource for adolescents included 'advice on explaining chronic pain to others' (86.7% of adolescents) and sleep hygiene (82.2% of adolescents), though access to a range of pain management techniques was desired. Qualitative results indicated endorsement of a new programme by adolescents and parents. CONCLUSIONS: Adolescents and parents had a positive outlook towards the development of a UK-specific online resource to help manage chronic pain. Such an intervention should aim to be made accessible via the National Health Service. Adolescent use of social media platforms to seek support for chronic pain requires further exploration in future research.

Optimizing Professional Practice Evaluation to Enable a Nonpunitive Learning Health System Approach to Peer Review.

Healthcare organizations are focused on 2 different and sometimes conflicting tasks; (1) accelerate the improvement of clinical care delivery and (2) collect provider-specific data to determine the competency of providers. We describe creating a process to meet both of these aims while maintaining a culture that fosters improvement and teamwork. METHODS: We created a new process to sequester activities related to learning and improvement from those focused on individual provider performance. We describe this process, including data on the number and type of cases reviewed and survey results of the participant's perception of the new process. RESULTS: In the new model, professional practice evaluation committees evaluate events purely to identify system issues and human factors related to medical decision-making, resulting in actional improvements. There are separate and sequestered processes that evaluate concerns around an individual provider's clinical competence or behavior. During the first 5 years of this process, 207 of 217 activities (99.5%) related to system issues rather than issues concerning individual provider competence or behavior. Participants perceived the new process as focused on identifying system errors (4.3/5), nonpunitive (4.2/5), an improvement (4.0/5), and helped with engagement in our system and contributed to wellness (4.0/5). CONCLUSION: We believe this sequestered approach has enabled us to achieve both the oversight mandates to ensure provider competence while enabling a learning health systems approach to build the cultural aspects of trust and teamwork that are essential to driving continuous improvement in our system of care.