Liver fibrosis is characterized by excessive deposition of extracellular matrix in the liver during chronic injury. During early stages of this disease, cells begin to synthesize and secrete profibrotic proteins that stimulate matrix production and inhibit matrix degradation. Although it is clear that these proteins are important for development of fibrosis, what remains unknown is the mechanism by which chronic liver injury stimulates their production. In the present study, the hypothesis was tested that hypoxia-inducible factor-1alpha (HIF-1alpha) is activated in the liver during chronic injury and regulates expression of profibrotic proteins. To investigate this hypothesis, mice were subjected to bile duct ligation (BDL), an animal model of liver fibrosis. HIF-1alpha protein was increased in the livers of mice subjected to BDL by 3 days after surgery. To test the hypothesis that HIF-1alpha is required for the development of fibrosis, control and HIF-1alpha-deficient mice were subjected to BDL. Levels of type I collagen and alpha-smooth muscle actin mRNA and protein were increased in control mice by 14 days after BDL. These levels were significantly reduced in HIF-1alpha-deficient mice. Next, the levels of several profibrotic mediators were measured to elucidate the mechanism by which HIF-1alpha promotes liver fibrosis. Platelet-derived growth factor (PDGF)-A, PDGF-B, and plasminogen activator inhibitor-1 mRNA levels were increased to a greater extent in control mice subjected to BDL compared with HIF-1alpha-deficient mice at 7 and 14 days after BDL. Results from these studies suggest that HIF-1alpha is a critical regulator of profibrotic mediator production during the development of liver fibrosis.

Background/Aims During the development of liver fibrosis, mediators are produced that stimulate cells in the liver to differentiate into myofibroblasts and to produce collagen. Recent studies demonstrated that the transcription factor, hypoxia-inducible factor-1α (HIF-1α), is critical for upregulation of profibrotic mediators, such as platelet-derived growth factor-A (PDGF-A), PDGF-B, and plasminogen activator inhibitor-1 (PAI-1) in the liver during the development of fibrosis. What remains unknown is the cell type-specific regulation of these genes by HIF-1α in liver cell types. Accordingly, the hypothesis was tested that HIF-1α is activated in hypoxic hepatocytes and regulates production of profibrotic mediators by these cells. Methods In this study, hepatocytes were isolated from the livers of control and HIF-1α or HIF-1β-Deficient mice and exposed to hypoxia. Results Exposure of primary mouse hepatocytes to 1% oxygen stimulated nuclear accumulation of HIF-1α and upregulated PAI-1, vascular endothelial cell growth factor, and the vasoactive peptides adrenomedullin-1 (ADM-1) and ADM-2. In contrast, levels of PDGF-A and PDGF-B mRNAs were unaffected in these cells by hypoxia. Exposure of HIF-1α-Deficient hepatocytes to 1% oxygen only partially prevented upregulation of these genes, suggesting that other hypoxia-regulated transcription factors, such as HIF-2α, may also regulate these genes. In support of this, HIF-2α was activated in hypoxic hepatocytes, and exposure of HIF-1β-Deficient hepatocytes to 1% oxygen completely prevented upregulation PAI-1, VEGF, and ADM-1, suggesting that HIF-2α may also contribute to upregulation of these genes in hypoxic hepatocytes. Conclusions Collectively, our results suggest that HIFs may be important regulators of profibrotic and vasoactive mediators by hypoxic hepatocytes.

ObjectivePediatric liver transplantation presents a number of anesthetic challenges, especially in providing adequate perioperative analgesia. In an effort to reduce opioid consumption and improve functional outcomes following pediatric liver transplantation, we have instituted a novel analgesia protocol centered on the provision of continuous regional analgesia with erector spinae plane (ESP) blockade.CasesWe describe preincisional bilateral ESP catheter placement in two pediatric patients undergoing orthotopic liver transplantation. The first case was a 12-year-old boy with maple syrup urine disease undergoing initial transplantation and the second case was an 8-year-old boy who underwent an 11 hours complex redo liver transplant in the setting of glycogen storage disease type 1A requiring initial liver transplant in 2014. The 8-year-old boy presented to the operating suite with acute Budd-Chiari syndrome with comorbid ascites and a large right pleural effusion. In both cases, ESP blockade resulted in good analgesia, markedly reduced intraoperative and postoperative opioid consumption as compared with institutional data and published rates of consumption and was associated with rapid return of bowel function.ConclusionsThese early experiences suggest a role for continuous ESP blockade to improve analgesia and potentially change the paradigm of treatment in this fragile patient population. The technique should be considered in similar interventions. Further study will be undertaken to validate our observation.

Objective To evaluate the clinical effectiveness of bolus dose fentanyl and midazolam to treat episodic intracranial hypertension (ICH) in children with severe traumatic brain injury (TBI). Design Retrospective cohort. Setting Pediatric intensive care unit (PICU) in a university-affiliated children’s hospital Level I trauma center. Patients Thirty-one children aged 0–18 years with severe TBI (Glasgow Coma Scale Score ≤ 8) who received bolus doses of fentanyl and/or midazolam for treatment of episodic ICH. Interventions None. Measurements and Main Results The area under the curve (AUC) from high resolution intracranial pressure (ICP) pressure-time plots was calculated to represent cumulative ICH exposure: AUC for ICP above 20 mmHg (AUC-ICH) was calculated in 15 minute epochs before and after administration of fentanyl and/or midazolam for the treatment of episodic ICH. Our primary outcome measure, the difference between pre- and post-drug administration epochs (ΔAUC-ICH), was calculated for all occurrences. We examined potential covariates including age, injury severity, mechanism and time after injury; time after injury correlated with ΔAUC-ICH. In a mixed effects model, with patient as a random effect, drug/dose combination as a fixed effect, and time after injury as a covariate, ICH rose after administration of fentanyl and/or midazolam (overall aggregate mean ΔAUC-ICH= +17 mmHg*min, 95%CI 0–34 mmHg*min; p=0.04). The mean ΔAUC-ICH increased significantly after administration of high-dose fentanyl (p=0.02), low-dose midazolam (p=0.006) and high-dose fentanyl plus low-dose midazolam (0.007). Secondary analysis using age dependent thresholds showed no significant impact on cerebral perfusion pressure deficit (mean ΔAUC-CPP). Conclusions Bolus dosing of fentanyl and midazolam fails to reduce the ICH burden when administered for episodic ICH. Paradoxically, we observed an overall increase in ICH burden following drug administration, even after accounting for within subject effects and time after injury. Future work is needed to confirm these findings in a prospective study design.

Varicella-related hospitalization and ED visit rates decreased significantly for both white and black children in Hamilton County, Ohio, after the introduction of varicella vaccine, and the racial disparity found before licensure decreased after licensure.

Background: Combined practice in pediatric anesthesiology (PA) and pediatric critical care medicine (PCCM) was historically common but has declined markedly with time. The reasons for this temporal shift are unclear, but existing evidence suggests that length of training is a barrier to contemporary trainees. Among current practitioners, restriction in dual-specialty practice also occurs, for reasons that are unknown at present. We sought to describe the demographics of this population, investigate their perceptions about the field, and consider factors that lead to attrition. METHODS: We conducted a cross-sectional, observational study of physicians in the United States with a combined practice in PA and PCCM. The survey was distributed electronically and anonymously to the distribution list of the Pediatric Anesthesia Leadership Council (PALC) of the Society for Pediatric Anesthesia (SPA), directing the recipients to forward the link to their faculty meeting our inclusion criteria. Attending-level respondents (n = 62) completed an anonymous, 40-question multidomain survey. RESULTS: Forty-seven men and 15 women, with a median age of 51, completed the survey. Major leadership positions are held by 44%, and 55% are externally funded investigators. A minority (26%) have given up one or both specialties, citing time constraints and politics as the dominant reasons. Duration of training was cited as the major barrier to entry by 77%. Increasing age and faculty rank and lack of a comparably trained institutional colleague were associated with attrition from dual-specialty practice. The majority (88%) reported that they would do it all again. CONCLUSIONS: The current cohort of pediatric anesthesiologist–intensivists in the United States is a small but accomplished group of physicians. Efforts to train, recruit, and retain such providers must address systematic barriers to completion of the requisite training and continued practice.

IntroductionLower urinary tract reconstruction in paediatric urology represents a physiologically stressful event that is associated with high complication rates, including readmissions and emergency room visits. Enhanced recovery after surgery (ERAS) protocol is a set of multidisciplinary, perioperative strategies designed to expedite surgical recovery without adversely impacting readmission or reoperation rates. Early paediatric urology data demonstrated ERAS reduced complications in this population.Methods and analysisIn 2016, a working group of paediatric urologists and anaesthesiologists convened to develop an ERAS protocol suitable for patients undergoing lower urinary tract reconstruction and define study process measures, patient-reported outcomes and clinically relevant outcomes in paediatric and adolescent/young adult patients. A multicentre, prospective, propensity-matched, case–control study design was chosen. Each centre will enrol five pilot patients to verify implementation. Subsequent enrolled patients will be propensity matched to historical controls. Eligible patients must be aged 4–25 years and undergoing planned operations (bladder augmentation, continent ileovesicostomy or appendicovesicostomy, or urinary diversion). 64 ERAS patients and 128 controls will be needed to detect a decrease in mean length of stay by 2 days. Pilot phase outcomes include attainment of ≥70% mean protocol adherence per patient and reasons for protocol deviations. Exploratory phase primary outcome is ERAS protocol adherence, with secondary outcomes including length of stay, readmissions, reoperations, emergency room visits, 90-day complications, pain scores, opioid usage and differences in Quality of Recovery 9 scores.Ethics and disseminationThis study has been registered with authors’ respective institution review boards and will be published in peer-reviewed journals. It will provide robust insight into the feasibility of ERAS in paediatric urology, determine patient outcomes and allow for iteration of ERAS implementations as new best practices and evidence for paediatric surgical care arise. We anticipate this study will take 4 years to fully accrue with completed follow-up.Trial registration numberNCT03245242.

The objective of this study was to provide data-driven recommendations for the contents of a wilderness medical kit. Many similar recommendations in the current literature pertain to specialized pursuits or expeditions and are based solely on the opinions of the authors. By studying a relatively homogeneous group of 565 participants in a summer trek program in the New York Adirondack State Park, we were able to analyze 3955 person-days of actual exposure. All incidents were coded by ICD-9 criteria, and actual utilization of first-aid supplies for these incidents was quantified. These supplies were supplemented by items recommended by current practice guidelines for treatment of the observed incidents. The findings were used to generate data-based recommendations for the contents of a first-aid kit which would be adequate to meet the needs of such groups, which probably resemble much of the wilderness use in the United States today.