Implementation of an adapted Sepsis Risk Calculator algorithm to reduce antibiotic usage in the management of early onset neonatal sepsis: a multicentre initiative in Wales, UK.

OBJECTIVE: Assess the impact of introducing a consensus guideline incorporating an adapted Sepsis Risk Calculator (SRC) algorithm, in the management of early onset neonatal sepsis (EONS), on antibiotic usage and patient safety. DESIGN: Multicentre prospective study SETTING: Ten perinatal hospitals in Wales, UK. PATIENTS: All live births ≥34 weeks' gestation over a 12-month period (April 2019-March 2020) compared with infants in the preceding 15-month period (January 2018-March 2019) as a baseline. METHODS: The consensus guideline was introduced in clinical practice on 1 April 2019. It incorporated a modified SRC algorithm, enhanced in-hospital surveillance, ongoing quality assurance, standardised staff training and parent education. The main outcome measure was antibiotic usage/1000 live births, balancing this with analysis of harm from delayed diagnosis and treatment, disease severity and readmissions from true sepsis. Outcome measures were analysed using statistical process control charts. MAIN OUTCOME MEASURES: Proportion of antibiotic use in infants ≥34 weeks' gestation. RESULTS: 4304 (14.3%) of the 30 105 live-born infants received antibiotics in the baseline period compared with 1917 (7.7%) of 24 749 infants in the intervention period (45.5% mean reduction). All 19 infants with culture-positive sepsis in the postimplementation phase were identified and treated appropriately. There were no increases in sepsis-related neonatal unit admissions, disease morbidity and late readmissions. CONCLUSIONS: This multicentre study provides evidence that a judicious adaptation of the SRC incorporating enhanced surveillance can be safely introduced in the National Health Service and is effective in reducing antibiotic use for EONS without increasing morbidity and mortality.

Peripherally acting µ-opioid receptor antagonists for treatment of opioid-induced constipation in children.

BACKGROUND AND OBJECTIVE: Opioid-induced constipation (OIC) is a common and important problem in paediatric palliative care, critical care, and postoperative settings. Treatment for OIC is often ineffective and limited by enteral intake. A new class of drugs called peripherally acting mu-opioid receptor antagonists (PAMORAs) have been shown to be effective treatments of OIC in adults, including the agents methylnaltrexone and naloxegol. Data in children are limited to several small case reports, mostly in the palliative care setting. The goal of this study was to evaluate the effectiveness and safety of methylnaltrexone and naloxegol in hospitalized children, including those with critical illness. METHODS: We conducted a retrospective study of all children admitted to the Stollery Children's Hospital in Edmonton (Canada) who received either methylnaltrexone or naloxegol for OIC. The primary outcome was median time to first bowel movement (BM) after the first dose of PAMORA. RESULTS: A total of 27 patients were included in the study. Kaplan-Meier survival analysis showed the median time to the first BM after the first dose of PAMORA was 15.5 hours. Seventeen (63%) patients had laxation within 24 hours of first dose. No significant adverse events were observed. CONCLUSION: This study is the largest to date to evaluate efficacy and safety of PAMORAs in children. Future studies should be prospective and include larger numbers of patients with critical illness and postoperative OIC as indications for treatment.

"Developing Experimental Design and Analysis Skills in Undergraduates": IUPS Teaching Satellite Meeting, Brazil, August 2017.

This workshop was held at the Teaching Satellite Meeting of the International Union of Physiological Sciences (IUPS), August 5-8, 2017, in Buzios, Rio de Janiero, Brazil. The satellite meeting was attended by physiology educators from across the globe, of whom 34 attended this workshop. The aim of the workshop was to explore how experimental design is taught to students of physiology in different institutions, to consider the aspects that students find challenging, to share good practice, and to think about how experimental design teaching could be improved. Through small-group discussions that were then shared with the whole group, participants were challenged to develop the outline of a research project to investigate a broad topic and then to identify the challenges that students might face if they were given that task. Finally, the group thought about what, in practical terms, could be done to help develop experimental design skills in undergraduates. The outcomes of the discussions are summarized in this report.

Medical assistance in dying: A paediatric perspective.

The Supreme Court decision in Carter v. Canada (2015) has led to changes to the Canadian Criminal Code, such that physician-assisted death is now a legal option for consenting adult patients who have a 'grievous and irremediable medical condition' that causes 'enduring' and 'intolerable' suffering. In June 2016, Bill C-14 was enacted, allowing medical assistance in dying (MAID) for an eligible adult whose death is 'reasonably foreseeable'. An independent report on the status of 'mature minors' (who are currently excluded under federal legislation), with focus on their potential eligibility for MAID, was required by the 2016 Act and is expected to be presented to Parliament by December 2018. Ensuring that newborns, children and youth receive the highest possible standard of care as they are dying is a privilege and a responsibility for physicians and allied professionals. Bringing a thoughtful, respectful and personal approach to every end-of-life situation is an essential and evolving duty of care, and the process should meet each patient's (and family's) unique social, cultural and spiritual needs. This statement describes the current Canadian legal and medical context of MAID and articulates a paediatric perspective that has emerged from-and been informed by-the broad, structured consultation process unfolding in Canada and elsewhere. Although 'mature minors' are the only youth currently mandated for further legislative consideration in Canada, the need to examine requests for and attitudes around MAID for minors of all ages remains compelling for two main reasons: Canadian health care professionals are increasingly being approached by the parents of 'never-competent' infants and children, including those too young to make a reasoned decision, and by youth themselves, to discuss MAID-related issues. Results from a Canadian Paediatric Surveillance Program (CPSP) survey, discussed below, indicate that parents raise such questions with paediatricians more often than do minors.The discussion of MAID policy in Canada has been framed as much by the issue and context of suffering as by considerations of autonomy. While current legislation clearly prohibits MAID for incapable persons at the request of any other person, it is possible that parents may request MAID on behalf of their dying child.

Supporting and communicating with families experiencing a perinatal loss.

Perinatal loss is one of the most devastating events a family can experience. This practice point focuses on circumstances that are likely to involve paediatric health care professionals. Recommendations are provided for compassionate communication, bereavement, sibling care and counselling to support families.

Pediatric palliative care in Canada in 2012: a cross-sectional descriptive study.

BACKGROUND: Pediatric palliative care focuses on comprehensive symptom management and enhancing quality of life for children with life-threatening conditions and their families. Our aim was to describe Canadian programs that provided specialized pediatric palliative care in 2012 and the children who received it and to estimate the proportion of children who might benefit that received specialized care. METHODS: A cross-sectional descriptive design was used. Specialized pediatric palliative care programs were included in the study if they offered multidisciplinary consulting pediatric palliative care services to a wide range of children and served all populations of children with life-threatening illness regardless of diagnosis. Investigators in programs that had taken part in a prior study were invited to participate. New programs that met the inclusion criteria were identified through snowball sampling within pediatric palliative care networks. Program data were obtained via surveys with coinvestigators, and health record reviews were used to obtain information about the children who received care through the programs. RESULTS: All 13 programs identified, including 3 with a free-standing hospice, agreed to take part in the study. Of the 1401 children who received care, 508 (36.2%) were under 1 year of age, and 504 (36.0%) had a congenital illness or condition originating in the perinatal period. Of the 431 children who died in 2012, 105 (24.4%) died in a critical care setting. Programs with a hospice provided care to 517 children (36.9%). Children in this group tended to be older, more often had a neurologic illness and received care for a longer time than those who received care from programs without a hospice. Overall, 18.6% (95% confidence interval 17.1%-20.3%) of deceased children who might have benefitted from specialized pediatric palliative care based on diagnosis received such care, with 110 (25.2%) receiving care for less than 8 days. INTERPRETATION: Program growth and changes in patients' demographic and clinical characteristics indicate improved reach of programs. However, barriers remain that prevent most children with life-threatening conditions from receiving specialized pediatric palliative care services.

Postnatal Diagnosis of a Baby With Multiple Rare Congenital Anomalies Including Syngnathia, Brain Dysmorphism, and Skin Pigmentation.

Syngnathia is a rare congenital disorder of jaw fusion with a paucity of literature from developed countries. We present a case of an infant noted to have multiple anomalies at birth including syngnathia, microcephaly with a variant of brain abnormality between holoprosencephaly and syntelencephaly, optic nerve hypoplasia, ear canal anomalies, hemi-vertebrae, and suspected hypomelanosis of Ito. To our knowledge, this patient with syngnathia and multiple anomalies is the first to be reported, but whether they are a coincidence, a pathogenetic association, or a new syndrome remains unknown. This case is discussed with a brief review of the literature.

Miller-dieker syndrome associated with congenital lobar emphysema.

Miller-Dieker syndrome (MDS) is a rare genetic syndrome associated with lissencephaly, developmental delay, and high mortality. We describe a patient who was diagnosed postnatally with both MDS and congenital lobar emphysema. We believe that this is the first reported case of the two conditions presenting in the same patient.

Children who 'grow up' in hospital: Inpatient stays of six months or longer.

OBJECTIVE: To describe the clinical course of all infants and children hospitalized for six consecutive months (180 days) or longer at a tertiary/quaternary children's hospital in Western Canada. METHODS: A retrospective review of medical records for all eligible patients from January 1, 2007 to December 31, 2012 at Stollery Children's Hospital (Edmonton, Alberta) was performed. RESULTS: A total of 61 patients experienced 64 eligible hospitalizations. The mean length of stay was 326 days, corresponding to a cumulative 20,892 hospital days (57.2 patient-years). Prevalent procedures resulting in long hospitalization were long-term tracheostomy ± ventilation in 32 (52%) patients, need for organ transplantation in 24 (39%) with completed transplantation in 15 (25%), and ventricular-assist devices (VADs) in seven (11%). Sixteen (26%) patients in the study group died, and 16 (26%) were placed in long-term care or out-of-home care at the end of their long hospitalization. Of children displaced from their family home, 14 (88%) were Aboriginal. CONCLUSION: Infants and children who experience very long hospitalizations have complex illnesses, with substantial risk for mortality and a high rate of displacement from their families after discharge. Aboriginal children appear to be particularly vulnerable to displacement and problem solving for this population must be undertaken, involving a variety of stakeholders.

OBJECTIF: Décrire l'évolution clinique de tous les nourrissons et les enfants hospitalisés pendant au moins six mois consécutifs (180 jours) dans un hôpital de soins tertiaires et quaternaires de l'Ouest canadien. MÉTHODOLOGIE: Les chercheurs ont effectué une analyse rétrospective des dossiers médicaux de tous les patients admissibles du Stollery Children's Hospital d'Edmonton, en Alberta, entre le 1er janvier 2007 et le 31 décembre 2012. RÉSULTATS: Au total, 61 patients ont vécu 64 hospitalisations admissibles. Leur séjour hospitalier moyen durait 326 jours, pour un séjour cumulatif de 20 892 jours d'hospitalisation (57,2 années-patient). Les principales interventions ayant suscité ces longues hospitalisations s'établissaient comme suit : trachéostomie ± ventilation à long terme chez 32 patients (52 %), besoin d'une greffe d'organe chez 24 patients (39 %) et greffe complétée chez 15 patients (25 %), et dispositif d'assistance ventriculaire chez sept patients (11 %). Seize patients (26 %) du groupe d'étude sont décédés, et 16 (26 %) ont été placés en soins de longue durée ou en foyer d'accueil à la fin de leur longue hospitalisation. Parmi les enfants déplacés de leur milieu familial, 14 (88 %) étaient Autochtones. CONCLUSION: Les nourrissons et les enfants qui sont hospitalisés très longtemps ont des maladies complexes, qui s'associent à un risque de mortalité important et à un taux élevé de déplacement du milieu familial après le congé. Les enfants autochtones semblent particulièrement vulnérables à de tels déplacements. Il faudra chercher à résoudre ce problème au sein de cette population, avec la participation de divers intervenants.

Attitudes and practices of pediatric oncologists regarding methadone use in the treatment of cancer-related pain: results of a North American Survey.

Methadone is effective in the treatment of cancer-related pain in adults. Pediatric oncologists may be reluctant to use methadone, given the paucity of existing research and a lack of familiarity with its use. This study's purpose was to assess pediatric oncologists' experience, comfort and practice of methadone prescription, and determine interest in and appropriate venues for education on methadone. A 22-item survey was sent by electronic mail to 1912 practicing pediatric oncologists. Six hundred thirty-one pediatric oncologists (33%) responded to the survey. Seventy-two percent of respondents reported they prescribe methadone to <10% of their patients receiving opioids. Physicians practicing ≥10 years (84% vs. 76%, P=0.01), at centers that see ≥100 new patients per year (86% vs. 76%, P=0.003), or who have received prior education on methadone (89% vs. 54%, P<0.001) were more likely to have prescribed methadone. The primary reasons respondents did not utilize methadone included a lack of knowledge of methadone's pharmacodynamics (39%), effectiveness (39%), and/or dosing equivalence (34%). Perceived competence with dose equivalence, belief that methadone is effective, and working in a division where >20 patients per year died were all independently associated with having prescribed methadone to >10% of patients on opioids. Eighty-five percent of respondents would like additional education on methadone. Many pediatric oncologists lack experience and education in the use of methadone. Formal education initiatives should be implemented to enhance pediatric oncologists' comfort and expertise in methadone use.

Octreotide infusion for malignant duodenal obstruction in a 12-year-old girl with metastatic peripheral nerve sheath tumor.

Malignant bowel obstruction is a common complication of some adult malignancies. In childhood cancer, malignant bowel obstruction is relatively rare. Octreotide, an analogue of the hormone somatostatin, has been shown to be an effective treatment for this condition in adults. However, explicit description of its use for this indication in children was not discovered in the pediatric literature by this group of authors. The following report is that of a 12-year-old female who had copious bilious emesis secondary to malignant obstruction of the distal duodenum, which abated after treatment with a continuous intravenous octreotide infusion.

Cell-extracellular matrix versus cell-cell interactions during the development of the cochlear-vestibular ganglion.

Cells destined to become the neurones of the cochlear-vestibular ganglion (CVG) originate within the otic epithelium. Early in development they detach from their neighbors and migrate out of the epithelium, where they coalesce to form the CVG. To accomplish this process, the neuroblasts must modify their interactions with other cells within the epithelium and with proteins in the extracellular matrix to allow for repositioning. The aim of this study was to investigate the roles of the major families of adhesion molecules that mediate cellular interactions with the extracellular matrix, the integrins, and with other cells, the cadherins, in neuroblast segregation from the otic epithelium. The expression of classical cadherins increased in migrating neuroblasts compared with the otic epithelium. Quantitative RT-PCR revealed that this was concomitant with down-regulation of E-cadherin and up-regulation of N-cadherin in the migrating cells. In contrast, the level of ß1 integrin expression by the epithelium was maintained in migrating neuroblasts. However, although multiple integrin ligands were expressed within the otic basement membrane at this stage of development, only fibronectin (FN) supported neuroblast migration along the substrate in vitro. Inhibition of ß1 integrins resulted in significantly reduced linear migration on FN. Importantly, neuroblasts retained the ability to segregate from the epithelium but remained compacted immediately adjacent to the originating tissue, suggesting dominance of cell-cell over cell-matrix interactions. These data suggest that the balance between cell-cell and cell-substratum interactions directs otic neuroblast migration and gangliogenesis.

Paediatric hanging and strangulation injuries: A 10-year retrospective description of clinical factors and outcomes.

OBJECTIVE: To identify early clinical factors that are correlated with death or severe disability in paediatric patients who have sustained an injury by hanging or strangulation. METHODS: A retrospective review of all patient records from January 1, 1997, to September 30, 2007, was conducted. Patient records were identified by International Classification of Diseases and Related Health Problems, Tenth Revision, Canada diagnostic codes for asphyxia, strangulation, hypoxic-ischemic encephalopathy, hanging, hypoxemia, hypoxia or anoxia. RESULTS: A total of 109 records were identified. Of these, 41 met the inclusion criteria for the study. Of 19 (46%) children who were pulse-less and received cardiopulmonary resuscitation, 16 died and the survivors were severely disabled. Of the 22 (54%) children who were found with a pulse, 18 made a full recovery. CONCLUSIONS: Children who are pulseless at discovery for hanging injuries are at high risk of death or severe disability. Early clinical and neurophysiological indicators should be applied systematically to best guide clinicians and parents in their decision making.

Methadone analgesia for children with advanced cancer.

BACKGROUND: Methadone is frequently used in the treatment of adults with advanced cancer. A criticism of relevant research is the use of single or fixed doses, which does not reflect use in clinical practice. Literature about use of methadone in the treatment of pediatric patients is limited to case reports. The objective of this study is to describe methadone use as primary opioid analgesic for advanced pediatric cancer over a 6.5-year period. PROCEDURE: All 17 patients who received methadone as their primary opioid analgesic through the Northern Alberta Children's Cancer Program from January 2000 to June 2007 were included. Children who received combination opioid therapy were excluded. RESULTS: Rotation to methadone was usually by a complete switch from primary opioid. Conversion ratios of morphine equivalent daily dose (MEDD)/methadone daily dose (TMDD) ranged widely from 1:2 in one patient with sudden pain crisis just prior to death, to 60:1 in a patient who had been treated with opioids for months. Methadone was used for a total of 925 patient-days. There were no significant adverse events in any patient, and all but one patient remained on methadone until the time of their death. Clinically, the effectiveness of analgesia clearly improved at time of conversion in 16 patients. CONCLUSION: With close monitoring, methadone therapy can be done safely in pediatric oncology patient populations in both inpatient and outpatient settings. Our experience suggests improvement in analgesia with the use of methadone, with 16 patients remaining on methadone until they died.

Pediatric patients receiving palliative care in Canada: results of a multicenter review.

OBJECTIVES: To describe the patients who received care from the 8 dedicated pediatric palliative care programs in Canada in 2002 and to estimate the number of children who may have benefited but did not receive services from these programs. DESIGN: Retrospective review of medical records combined with a survey of each program. SETTING: Seven pediatric palliative care programs based in tertiary care settings and 1 freestanding children's hospice. PARTICIPANTS: The programs cared for 317 children during 2002, of whom 123 died during that year. An additional 32 children died by the end of 2003. MAIN EXPOSURE: Pediatric palliative care program. RESULTS: Nearly half (48.6%) of the patients were younger than 5 years, and almost half of these were younger than 1 year. Primary diagnoses were disorders of the nervous system (39.1%), malignancies (22.1%), and conditions arising in the perinatal period or congenital anomalies (22.1%). Most of the children (43.9%) died at home, with those centers reporting more comprehensive home care services having the highest percentage of home deaths. From a national perspective, between 5% and 12% of the children who could benefit from palliative care received services from 1 of these programs. CONCLUSIONS: Pediatric palliative care programs in Canada care for a diverse population of patients with a wide range of age and disease conditions. Only a small percentage of children who die, however, receive services from these dedicated programs.

Temporal and spatial regulation of alpha6 integrin expression during the development of the cochlear-vestibular ganglion.

The neurons of the cochlear-vestibular ganglion (CVG) that innervate the sensory hair cells of the inner ear are derived from the otic epithelium early in development. Neuroblasts detach from neighboring cells, migrate into the mesenchyme where they coalesce to form the ganglion complex, then send processes back into the epithelium. Cell migration and neuronal process formation involve changes in cellular interactions with other cells and proteins in the extracellular matrix that are orchestrated by cell surface-expressed adhesion molecules, including the integrins. I studied the expression pattern of the alpha6 integrin subunit during the early development of the CVG using immunohistochemistry and reverse-transcriptase polymerase chain reaction (RT-PCR) in murine tissue sections, otocyst, and ganglion explants. At embryonic day (E)10.5 alpha6 integrin was expressed in the otic epithelium but not in migrating neuroblasts. Importantly, the loss of alpha6 was associated with exit from the epithelium, not neuronal determination, revealing differentiation cues acutely associated with the cellular environment. Markers of glial and neuronal phenotype showed that alpha6-expressing cells present in the CVG at this stage were glia of neural crest origin. By E12.5 alpha6 expression in the ganglion increased alongside the elaboration of neuronal processes. Immunohistochemistry applied to otocyst cultures in the absence of glia revealed that neuronal processes remained alpha6-negative at this developmental stage and confirmed that alpha6 was expressed by closely apposed glia. The spatiotemporal modulation of alpha6 expression suggests changing roles for this integrin during the early development of inner ear innervation.

Developmental changes in cell-extracellular matrix interactions limit proliferation in the mammalian inner ear.

Hair cell losses can produce severe hearing and balance deficits in mammals and nonmammals alike, but nonmammals recover after epithelial supporting cells divide and give rise to replacement hair cells. Here, we describe cellular changes that appear to underlie the permanence of hair cell deficits in mammalian vestibular organs. In sensory epithelia isolated from the utricles of embryonic day 18 (E18) mice, supporting cells readily spread and proliferated, but spreading and proliferation were infrequent in supporting cells from postnatal day 6 (P6) mice. Cellular spreading and proliferation were dependent on alpha6 integrin, which disappeared from lateral cell membranes by P6 and colocalized with beta4 integrin near the basement membrane at both ages. In the many well-spread, proliferating E18 supporting cells, beta4 was localized at cell borders, but it was localized to hemidesmosome-like structures in the columnar, nondividing supporting cells that were prevalent in P6 cultures. We treated cultures with phorbol myristate acetate (PMA) to activate protein kinase C (PKC) in an initial test of the possibility that maturational changes in supporting cell cytoskeletons or their anchorage might restrict the proliferation of these progenitor cells in the developing mammalian inner ear. That treatment triggered the disassembly of the hemidesmosome-like beta4 structures and resulted in significantly increased cellular spreading and S-phase entry in the P6 epithelia. The results suggest that maturational changes in cytoskeletal organization and anchorage restrict proliferation of mammalian supporting cells whose counterparts are the progenitors of replacement hair cells in nonmammals, thereby leaving mammals vulnerable to persistent sensory deficits caused by hair cell loss.