ABSTRACT
Importance: Necrotizing enterocolitis (NEC) requiring surgical intervention is the most common reason for surgical procedures in preterm neonates. Opioids are used to manage postoperative pain, with some infants requiring methadone to treat physiologic opioid dependence or wean from nonmethadone opioid treatment during recovery. Objective: To describe postoperative opioid use and methadone treatment for infants with surgically treated NEC and evaluate postoperative outcomes. Design, Setting, and Participants: A cohort study of infants with surgically treated NEC admitted from January 1, 2013, to December 31, 2022, to 48 Children's Hospital Association hospitals contributing data to the Pediatric Health Information System (PHIS) was performed. Infants who received methadone preoperatively, were aged 14 days or less at the time of the operation, had a congenital heart disease-related operation, or died within 90 days of the operation were excluded. Mixed-effects multivariable logistic regression was used to evaluate thresholds for duration of opioid use after the operation associated with methadone treatment and clinical outcomes associated with methadone use were enumerated. Exposure: Postoperative administration of nonmethadone opioids. Main Outcomes and Measures: Methadone use and postoperative length of stay, ventilator days, and total parenteral nutrition (TPN) days. Results: Of the 2037 infants with surgically treated NEC identified, the median birth weight was 920 (IQR, 700.0-1479.5) g; 1204 were male (59.1%), 911 were White (44.7%), and 343 were Hispanic (16.8%). Infants received nonmethadone opioids for a median of 15 (IQR, 6-30) days after the operation and 231 received methadone (11.3%). The median first day of methadone use was postoperative day 18 (IQR, days 9-64) and continued for 28 days (IQR, 14-73). Compared with infants who received nonmethadone opioids for 1 to 5 days, infants receiving 16 to 21 days of opioids were most likely to receive methadone treatment (odds ratio, 11.45; 95% CI, 6.31-20.77). Methadone use was associated with 21.41 (95% CI, 10.81-32.02) more days of postoperative length of stay, 10.80 (95% CI, 3.63-17.98) more ventilator days, and 16.21 (95% CI, 6.34-26.10) more TPN days. Conclusions and Relevance: In this cohort study of infants with surgically treated NEC, prolonged use of nonmethadone opioids after the operation was associated with an increased likelihood of methadone treatment and increased postoperative length of stay, ventilation, and TPN use. Optimizing postoperative pain management for infants requiring an operation may decrease the need for methadone treatment and improve health care use.
Subject(s)
Enterocolitis, Necrotizing , Infant, Newborn, Diseases , Opioid-Related Disorders , Infant, Newborn , Humans , Male , Infant , Child , Female , Analgesics, Opioid/therapeutic use , Methadone/therapeutic use , Cohort Studies , Enterocolitis, Necrotizing/surgery , Pain, Postoperative/drug therapy , Opioid-Related Disorders/drug therapyABSTRACT
BACKGROUND: Gabapentin is increasingly used as an off-label, opioid-sparing pain medication in children. We investigated perioperative gabapentin administration and postoperative opioid use in children who underwent appendectomy for perforated appendicitis. METHODS: A retrospective cohort study of healthy children ages 2-18 years undergoing appendectomy for perforated appendicitis from 2014 to 2019 was performed using the Pediatric Health Information System®. Propensity score matched (PSM) analysis was conducted with 1:1 matching based on patient and hospital characteristics. Multivariable linear regression analysis was used to evaluate an association between gabapentin, postoperative opioid use, and postoperative length of stay. RESULTS: Of 29,467 children with perforated appendicitis who underwent appendectomy, 236 (0.8%) received gabapentin. In 2014, <10 children received gabapentin, but by 2019, 110 children received gabapentin. On univariate analysis of the PSM cohort, children receiving gabapentin had decreased total postoperative opiate use (2.3 SD ± 2.3 versus 3.0 SD ± 2.5 days, p < 0.001). On adjusted analysis, children receiving gabapentin had 0.65 fewer days of postoperative total opioid use (95% CI: -1.09, -0.21) and spent 0.69 fewer days in the hospital after surgery (95% CI: -1.30, -0.08). CONCLUSION: While overall use is infrequent, gabapentin is increasingly administered to children with perforated appendicitis who undergo an appendectomy and is associated with decreased postoperative opioid use and reduced postoperative length of stay. Multimodal pain management strategies incorporating gabapentin may reduce postoperative opioid consumption, but further studies of drug safety are needed for this off-label use in children undergoing surgery. LEVEL OF EVIDENCE: III.
Subject(s)
Analgesics, Opioid , Appendicitis , Humans , Child , Gabapentin/therapeutic use , Analgesics, Opioid/therapeutic use , Appendectomy , Appendicitis/complications , Appendicitis/drug therapy , Appendicitis/surgery , Propensity Score , Retrospective Studies , Length of StayABSTRACT
BACKGROUND AND AIMS: Biliary atresia (BA), a congenital cholestatic liver disease, commonly culminates in end-stage liver disease. We previously demonstrated in BA that Prominin-1 ( Prom1 )-expressing hepatic progenitor cells (HPCs) expand within regions of developing fibrosis, giving rise to cholangiocytes within biliary ductular reactions. Null mutation of Prom1 or ablation of cells expressing Prom1 significantly diminishes fibrogenesis. FN14, the receptor for TNF-like weak inducer of apoptosis (TWEAK), is expressed by HPCs. TWEAK/FN14 signaling promotes fibrosis in multiple organ systems. Therefore, we hypothesized that TWEAK/FN14 signaling mediates Prom1 -expressing HPC proliferation leading to profibrogenic ductular reactions in BA. APPROACH AND RESULTS: The experimental mouse model of BA mediated by perinatal rhesus rotavirus (RRV) infection resulted in increased co-expression of Fn14 in Prom1 -expressing HPCs within regions of ductular reactions. FN14 antagonist L524-0366 decreased ductular reactions, biliary fibrosis and periportal fibroblast activation in RRV injury. L524-0366 inhibition also demonstrated loss of downstream noncanonical NF-kB signaling expression in RRV injury. Murine HPC organoids demonstrated accelerated organoid growth and proliferation when treated with recombinant TWEAK. Increased organoid proliferation with recombinant TWEAK was lost when also treated with L524-0366. Analysis of a large publicly available RNA sequencing database of BA and normal control patients revealed significant increases in expression of PROM1 , FN14 , and genes downstream of TNF signaling and noncanonical NF-κB signaling pathways in BA infants. Infants who failed to achieve bile drainage after hepatoportoenterostomy had higher relative levels of FN14 expression. CONCLUSION: TWEAK/FN14 signaling activation in Prom1 -expressing HPCs contributes to proliferation of profibrogenic ductular reactions in BA.
Subject(s)
Biliary Atresia , Rotavirus Infections , Rotavirus , Animals , Mice , AC133 Antigen/genetics , Biliary Atresia/metabolism , Fibrosis , Rotavirus/metabolism , Stem Cells/metabolism , Transcription Factors , Tumor Necrosis Factors/metabolism , Tumor Necrosis Factors/pharmacologyABSTRACT
BACKGROUND/PURPOSE: "Pan-scanning" pediatric blunt trauma patients leads to exposure to harmful radiation and increased healthcare costs without improving outcomes. We aimed to reduce computed tomography (CT) scans that are not indicated (NI) by imaging guidelines for injured children. METHODS: In July 2017, our Pediatric Trauma Center prospectively implemented validated imaging guidelines to direct CT imaging for trauma activations and consultations for children younger than 16 years old with blunt traumatic injuries. Patients with suspected physical abuse, CT imaging prior to arrival, penetrating mechanism, and instability precluding CT imaging were excluded. We compared CT scanning rates for pre-implementation (01/2016-06/2017) and post-implementation (07/2017-08/2021) time periods. Guideline compliance was evaluated by chart review and sustained through iterative process improvement cycles. RESULTS: During the pre-implementation era, 61 patients underwent 171 CT scans of which 87 (51%) scans were not indicated by guidelines. Post-implementation, 363 patients had 531 scans and only 134 (25%) CTs were not indicated. Total CTs performed declined after initiation of guidelines (2.80 vs 1.46 scans/patient, p<0.0001). Total NI CTs declined (1.41 vs 0.37 NI scans/patient, p<0.0001) reflected in significant reductions in all anatomic regions: head, cervical spine, chest, and abdomen/pelvis. Charges related to NI scans decreased from $1,490.31/patient to $408.21/patient, saving $218,000 in charges. Based on prior utilization, 146 children were spared excessive radiation with no clinically significant missed injuries since guideline implementation. CONCLUSIONS: Quality improvement and implementation science methodologies to enhance compliance with imaging guidelines for children with blunt injuries can significantly reduce unnecessary CT scanning without compromising care. This practice reduces harmful radiation exposure in a sensitive patient population and may save healthcare systems money and resources.
Subject(s)
Tomography, X-Ray Computed , Unnecessary Procedures , Wounds, Nonpenetrating , Child , Humans , Radiation Exposure/prevention & control , Tomography, X-Ray Computed/statistics & numerical data , Trauma Centers , Wounds, Nonpenetrating/diagnostic imaging , Wounds, Nonpenetrating/therapy , Practice Guidelines as TopicABSTRACT
INTRODUCTION: Children with congenital heart disease (CHD) often experience feeding intolerance due to aspiration, inability to tolerate feed volume, or reflux within the first few months of life, requiring a surgically placed gastrostomy tube (GT) for durable enteral access. However, complications such as GT dislodgement, cellulitis, and leakage related to GT use are common. GT-related complications can lead to unscheduled pediatric surgery clinic or emergency room (ER) visits, which can be time consuming for the family and increase overall healthcare costs. We sought to identify factors associated with GT complications within 2 wk after GT surgery and 1-y after discharge home following GT placement in infants with CHD. METHODS: We performed a retrospective cohort study using the Society of Thoracic Surgeons database and electronic medical records from a tertiary children's hospital. We identified infants <1 y old underwent CHD surgery followed by GT surgery between September 2013-August 2018. Demographics, pre-operative feeding regimen, comorbidities, and GT-related utilization were measured. Postoperative GT complications (e.g., GT cellulitis, leakage, dislodgement, obstruction, and granulation tissue) within 2 wk after the GT surgery and an unplanned pediatric surgery clinic or ER visit within 1-y after discharge home were captured. Bivariate comparisons and multivariable logistic regression evaluated factors associated with GT complications and unplanned clinic or ER visits. A Kaplan-Meier failure curve examined the timing of ER/clinic visits. RESULTS: Of 152 infants who underwent CHD then GT surgeries, 66% (N = 101) had postoperative GT complications. Overall, 83 unscheduled clinic visits were identified after discharge, with 37% (N = 31) due to concerns about granulation tissue. Of 137 ER visits, 48% (N = 66) were due to accidental GT dislodgement. Infants who were hospitalized for ≥2 wk after GT surgery had more complications than those discharged home within 2 wk of the GT surgery (40.6% versus 15.7%, P = 0.002). Infants receiving oral nutrition before CHD surgery (38.6% versus 60%, P=<0.001) or with single ventricle defects (19.8% versus 37.3%, P = 0.02) had fewer GT complications. After adjusting for type of cardiac anomaly, infants receiving oral nutrition prior to CHD surgery had a decreased likelihood of GT complications (odds ratio OR 0.46; 95% confidence intervals CI:0.23-0.93). A Kaplan-Meier failure curve demonstrated that 50% of the cohort experienced a complication leading to an unscheduled ER/clinic visit within 6 mo after discharge. CONCLUSIONS: Unplanned visits to the ER or pediatric surgery clinic occur frequently for infants with CHD requiring a surgically placed GT. Oral feedings before cardiac surgery associated with fewer GT complications. Prolonged hospitalization associated with more GT complications. Optimizing outpatient care and family education regarding GT maintenance may reduce unscheduled visits for this high-risk, device-dependent infant population.
Subject(s)
Gastrostomy , Heart Defects, Congenital , Humans , Infant , Infant, Newborn , Child , Gastrostomy/adverse effects , Retrospective Studies , Cellulitis , Intubation, Gastrointestinal/adverse effects , Heart Defects, Congenital/surgery , Heart Defects, Congenital/complications , Postoperative Complications/epidemiology , Postoperative Complications/etiologyABSTRACT
BACKGROUND: Infants with congenital heart disease (CHD) often experience oral feeding intolerance requiring gastrostomy (GT). Complications related to GT use are common. The study aim was to identify factors associated with continued GT use at one-year. METHODS: A retrospective cohort study was performed at a tertiary children's hospital using the Society of Thoracic Surgeons database and patients' electronic medical record. Infants <1-year with CHD who underwent cardiac and GT surgery between January 2014-October 2019 were identified. Patient demographics, preoperative feeding, clinical variables, and GT use at one-year was evaluated. A separate cohort discharged with a nasogastric tube (NGT) was identified for longitudinal comparisons. RESULTS: Of 137 infants who received a GT, 115 (84%) continued using their GT at one-year. Factors associated with continued GT use included lower median percent of goal oral feeding before GT placement (0% IQR 0-6.5 versus 3.7% IQR 0-31), prolonged hospitalization after GT placement (36% versus 14%, P-value = 0.048), and failure to take oral feeds at discharge (69% versus 27%, P-value <0.001). There was no difference in demographics or clinical comorbidities between groups. Clinic/emergency room visits for GT complications were common (72%). Eight infants discharged with a NGT did not require GT placement. CONCLUSIONS: Patients with CHD tolerating minimal oral nutrition before GT placement, prolonged hospitalization after GT, and difficulty with oral feeds at discharge were more likely to use their GT at 1-year. Outpatient NGT feeding is feasible for select infants with CHD. Efforts to optimize care for this complex, device-dependent population are warranted to minimize risks and facilitate family engagement for long-term care.
Subject(s)
Gastrostomy , Heart Defects, Congenital , Child , Gastrostomy/adverse effects , Heart Defects, Congenital/complications , Heart Defects, Congenital/therapy , Humans , Infant , Infant, Newborn , Intubation, Gastrointestinal/adverse effects , Patient Discharge , Retrospective StudiesABSTRACT
PURPOSE: The purpose of this study was to investigate factors impacting transplant-free survival among infants with biliary atresia. METHODS: A multi-institutional, retrospective cohort study was performed at nine tertiary-level children's hospitals in the United States. Infants who underwent Kasai portoenterostomy (KP) from January 2009 to May 2017 were identified. Clinical characteristics included age at time of KP, steroid use, surgical approach, liver pathology, and surgeon experience. Likelihood of transplant-free survival (TFS) was evaluated using logistic regression, adjusting for patient and surgeon-level factors. Secondary outcomes at 1 year included readmission, cholangitis, reoperation, mortality, and biliary clearance. RESULTS: Overall, 223 infants underwent KP, and 91 (40.8%) survived with their native liver. Mean age at surgery was 63.9 days (± 24.7 days). At 1 year, 78.5% experienced readmission, 56.9% developed cholangitis, 3.8% had a surgical revision, and 5 died. Biliary clearance at 3 months was achieved in 76.6%. Controlling for patient and surgeon-level factors, each additional day of age toward operation was associated with a 2% decrease in likelihood of TFS (OR 0.98, 95% CI 0.97-0.99). CONCLUSION: Earlier surgical intervention by Kasai portoenterostomy at tertiary-level centers significantly increases likelihood for TFS. Policy-level interventions to facilitate early screening and surgical referral for infants with biliary atresia are warranted to improve outcomes.
Subject(s)
Biliary Atresia , Liver Transplantation , Biliary Atresia/surgery , Humans , Infant , Portoenterostomy, Hepatic , Retrospective Studies , Treatment OutcomeABSTRACT
BACKGROUND: In 2014, the price of intravenous acetaminophen more than doubled. This study determined whether increased intravenous acetaminophen cost was associated with decreased utilization and increased opioid use for children undergoing appendectomy. METHODS: A multicenter retrospective cohort study using the Pediatric Health Information System database between 2011 and 2017 was performed. Healthy children 2 to 18 years undergoing appendectomy at 46 children's hospitals in the United States were identified. Intravenous acetaminophen use, opioid use, and pharmacy costs were assessed. Multivariable mixed-effects modeling was used to determine the association between postoperative opioid use, intravenous acetaminophen use, and postoperative length-of-stay. RESULTS: Overall, 110,019 children undergoing appendectomy were identified, with 22.5% (N = 24,777) receiving intravenous acetaminophen. Despite the 2014 price increase, intravenous acetaminophen use increased from 3% in 2011 to 40.1% in 2017 (P < .001), but at a significantly reduced rate. After 2014, adjusted median pharmacy charges decreased from $3,326.5 (interquartile range: $1,717.5-$6,710.8) to $3,264.1 (interquartile range: $1,782.8-$5,934.7, P < .001) for children who received intravenous acetaminophen. In 94,745 children staying ≥1 day after surgery, postoperative opioid use decreased from 73.6% in 2011 to 58.6% in 2017 (P < .001). Use of intravenous acetaminophen alone compared to opioids alone after surgery resulted in similar predicted mean postoperative length-of-stay. CONCLUSION: In children undergoing appendectomy, intravenous acetaminophen use continued to rise, but at a slower rate after a price increase. Furthermore, adjusted pharmacy charges were lower for children receiving intravenous acetaminophen, possibly secondary to a concurrent decrease in postoperative opioid use. These findings suggest intravenous acetaminophen may be more broadly used regardless of perceived costs to minimize opioid use after surgery.
Subject(s)
Acetaminophen/economics , Analgesics, Opioid/therapeutic use , Appendectomy/methods , Appendicitis/surgery , Drug Costs , Acetaminophen/administration & dosage , Acetaminophen/therapeutic use , Administration, Intravenous , Adolescent , Appendectomy/economics , Appendicitis/economics , Child , Child, Preschool , Drug Costs/statistics & numerical data , Female , Humans , Male , Pain, Postoperative/drug therapy , Pain, Postoperative/economics , Retrospective Studies , Treatment Outcome , United StatesABSTRACT
Five established clearing protocols were compared with a modified and simplified method to determine an optimal clearing reagent for three-dimensionally visualizing fluorophores in the murine liver, a challenging organ to clear. We report successful clearing of whole liver lobes by modification of an established protocol (UbasM) using only Ub-1, a urea-based amino sugar reagent, in a simpler protocol that requires only a 24-h processing time. With Ub-1 alone, we observed sufficiently preserved liver tissue structure in three dimensions along with excellent preservation of fluorophore emissions from endogenous protein reporters and lipophilic tracer dyes. This streamlined technique can be used for 3D cell lineage tracing and fluoroprobe-based reporter gene expression to compare various experimental conditions.
Subject(s)
Amino Sugars , Fluorescent Dyes , Liver/diagnostic imaging , Urea , Animals , Fluorescence , MiceABSTRACT
Importance: Opioids are frequently prescribed to children and adolescents after surgery. Prescription opioid misuse is associated with high-risk behavior in youth. Evidence-based guidelines for opioid prescribing practices in children are lacking. Objective: To assemble a multidisciplinary team of health care experts and leaders in opioid stewardship, review current literature regarding opioid use and risks unique to pediatric populations, and develop a broad framework for evidence-based opioid prescribing guidelines for children who require surgery. Evidence Review: Reviews of relevant literature were performed including all English-language articles published from January 1, 1988, to February 28, 2019, found via searches of the PubMed (MEDLINE), CINAHL, Embase, and Cochrane databases. Pediatric was defined as children younger than 18 years. Animal and experimental studies, case reports, review articles, and editorials were excluded. Selected articles were graded using tools from the Oxford Centre for Evidence-based Medicine 2011 levels of evidence. The Appraisal of Guidelines for Research & Evaluation (AGREE) II instrument was applied throughout guideline creation. Consensus was determined using a modified Delphi technique. Findings: Overall, 14â¯574 articles were screened for inclusion, with 217 unique articles included for qualitative synthesis. Twenty guideline statements were generated from a 2-day in-person meeting and subsequently reviewed, edited, and endorsed externally by pediatric surgical specialists, the American Pediatric Surgery Association Board of Governors, the American Academy of Pediatrics Section on Surgery Executive Committee, and the American College of Surgeons Board of Regents. Review of the literature and guideline statements underscored 3 primary themes: (1) health care professionals caring for children who require surgery must recognize the risks of opioid misuse associated with prescription opioids, (2) nonopioid analgesic use should be optimized in the perioperative period, and (3) patient and family education regarding perioperative pain management and safe opioid use practices must occur both before and after surgery. Conclusions and Relevance: These are the first opioid-prescribing guidelines to address the unique needs of children who require surgery. Health care professionals caring for children and adolescents in the perioperative period should optimize pain management and minimize risks associated with opioid use by engaging patients and families in opioid stewardship efforts.
Subject(s)
Analgesics, Opioid/administration & dosage , Pain, Postoperative/drug therapy , Patient Selection , Practice Patterns, Physicians' , Adolescent , Age Factors , Attitude of Health Personnel , Humans , Pain, Postoperative/diagnosis , Pain, Postoperative/etiology , Practice Guidelines as TopicABSTRACT
BACKGROUND: The impact of postoperative opioid use on outcomes for children with perforated appendicitis is unknown. METHODS: A retrospective cohort study was performed using the Pediatric Health Information System database from 2005 to 2015. Children 2 to 18 years with perforated appendicitis who underwent an appendectomy were identified. Postoperative day analgesic use was categorized as nonopioid analgesia alone, opioids (with or without nonopioid analgesia), or no analgesics. The impact of postoperative opioid use on postoperative duration of stay and 30-day readmission was evaluated using multivariable mixed-effects regression analysis. RESULTS: Overall, 47,726 children with perforated appendicitis were identified. On postoperative day 1, 17.7% received nonopioid analgesia alone, 77.6% received opioids, and 4.7% received no analgesics. On adjusted analysis, postoperative day 1 opioid use was associated with a 0.75-day (95% confidence interval: 0.54-0.96) increased postoperative duration of stay. Starting opioids after postoperative day 1 was associated with 2.21 days (95% confidence interval: 1.90-2.51) longer postoperative duration of stay. Among children who received opioids on postoperative day 1, continued use of opioids after postoperative day 1 was associated with a 1.88 day (95% confidence interval: 1.77-1.98) longer postoperative duration of stay. Postoperative day 1 opioid use did not significantly affect 30-day readmission. CONCLUSION: Early and continued postoperative opioid use is associated with prolonged postoperative duration of stay in children undergoing appendectomy for perforated appendicitis. Minimizing opioid use, even on postoperative day 2, may result in a decreased postoperative duration of stay.
Subject(s)
Analgesics, Opioid/adverse effects , Appendectomy , Appendicitis/surgery , Length of Stay , Adolescent , Child , Child, Preschool , Female , Humans , Male , Patient Readmission , Retrospective StudiesABSTRACT
Cholestatic liver injury is associated with intrahepatic biliary fibrosis, which can progress to cirrhosis. Resident hepatic progenitor cells (HPCs) expressing Prominin-1 (Prom1 or CD133) become activated and participate in the expansion of cholangiocytes known as the ductular reaction. Previously, we demonstrated that in biliary atresia, Prom1(+) HPCs are present within developing fibrosis and that null mutation of Prom1 significantly abrogates fibrogenesis. Here, we hypothesized that these activated Prom1-expressing HPCs promote fibrogenesis in cholestatic liver injury. Using Prom1CreERT2-nLacZ/+ ;Rosa26Lsl-GFP/+ mice, we traced the fate of Prom1-expressing HPCs in the growth of the neonatal and adult livers and in biliary fibrosis induced by bile duct ligation (BDL). Prom1-expressing cell lineage labeling with Green Fluorescent Protein (GFP) on postnatal day 1 exhibited an expanded population as well as bipotent differentiation potential toward both hepatocytes and cholangiocytes at postnatal day 35. However, in the adult liver, they lost hepatocyte differentiation potential. Upon cholestatic liver injury, adult Prom1-expressing HPCs gave rise to both PROM1(+) and PROM1(-) cholangiocytes contributing to ductular reaction without hepatocyte or myofibroblast differentiation. RNA-sequencing analysis of GFP(+) Prom1-expressing HPC lineage revealed a persistent cholangiocyte phenotype and evidence of Transforming Growth Factor-ß pathway activation. When Prom1-expressing cells were ablated with induced Diphtheria toxin in Prom1CreERT-nLacZ/+ ;Rosa26DTA/+ mice, we observed a decrease in ductular reactions and biliary fibrosis typically present in BDL as well as decreased expression of numerous fibrogenic gene markers. Our data indicate that Prom1-expressing HPCs promote biliary fibrosis associated with activation of myofibroblasts in cholestatic liver injury.
Subject(s)
AC133 Antigen/biosynthesis , Bile Ducts/pathology , Cholestasis/metabolism , Cholestasis/pathology , Hepatocytes/pathology , Liver Diseases/metabolism , Liver Diseases/pathology , Stem Cells/pathology , Stem Cells/parasitology , AC133 Antigen/genetics , AC133 Antigen/metabolism , Animals , Bile Ducts/metabolism , Cholestasis/genetics , Disease Models, Animal , Female , Fibrosis , Gene Knock-In Techniques , Hepatocytes/metabolism , Liver Diseases/genetics , Male , Mice , Mice, Inbred C57BL , Myofibroblasts/metabolism , Myofibroblasts/pathology , Stem Cells/metabolism , Transcription Factors/metabolismABSTRACT
PURPOSE: Pain in the neonate is often challenging to assess but important to control. Physicians often must balance the need for optimal pain control with the need to minimize oversedation and prolonged opioid use. Both inadequate pain control and overuse of opioids can have long-term consequences, including poor developmental outcomes. The aim of this review is to introduce a comprehensive approach to pain management for physicians, nurses, and surgeons caring for critically ill neonates, focusing on nonopioid alternatives to manage procedural pain. FINDINGS: After review, categories of opioid-sparing interventions identified included (1) nonopioid pharmacologic agents, (2) local and regional anesthesia, and (3) nonpharmacologic alternatives. Nonopioid pharmacologic agents identified for neonatal use included acetaminophen, NSAIDs, dexmedetomidine, and gabapentin. Local and regional anesthesia included neuraxial blockade (spinals and epidurals), subcutaneous injections, and topical anesthesia. Nonpharmacologic agents uniquely available in the neonatal setting included skin-to-skin care, facilitated tucking, sucrose, breastfeeding, and nonnutritive sucking. IMPLICATIONS: The use of various pharmacologic and interventional treatments for neonatal pain management allows for the incorporation of opioid-sparing techniques in neonates who are already at risk for poor neurodevelopmental outcomes. A multifactorial approach to pain control is paramount to optimize periprocedural comfort and to minimize the negative sequelae of uncontrolled pain in the neonate.
Subject(s)
Analgesics, Non-Narcotic/therapeutic use , Pain Management/methods , Pain, Procedural/drug therapy , Anesthesia, Local , Humans , Infant, Newborn , Opioid-Related DisordersABSTRACT
In patients with biliary atresia (BA), the extent of intrahepatic biliary fibrosis negatively correlates with successful surgical bypass of the congenital cholangiopathy as well as subsequent transplant-free survival. We recently linked the expansion of a population of prominin-1 (Prom1)-expressing hepatic progenitor cells to biliary fibrogenesis. Herein, we hypothesized that Prom1-expressing progenitor cells play a role in BA-associated fibrosis. Rhesus rotavirus (RRV)-mediated experimental BA was induced in newborn mice homozygous for the transgene Prom1cre-ert2-nlacz , which was knocked in to the Prom1 gene locus, thus creating functional Prom1 knockout (KO) mice, and their wildtype (WT) littermates. Clinical data and tissue samples from BA infants from the Childhood Liver Disease Research Consortium were analyzed. Extrahepatic biliary obliteration was present in both WT and KO mice; there was no difference in serum total bilirubin (TBili) levels. The intrahepatic periportal expansion of the PROM1pos cell population, typically observed in RRV-induced BA, was absent in KO mice. RRV-treated KO mice demonstrated significantly fewer cytokeratin-19 (CK19)-positive ductular reactions (P = 0.0004) and significantly less periportal collagen deposition (P = 0.0001) compared with WT. RRV-treated KO mice expressed significantly less integrin-ß6, which encodes a key biliary-specific subunit of a transforming growth factor (TGF) ß activator (P = 0.0004). Infants with successful biliary drainage (Tbili ≤1.5 mg/dL within 3 months postoperatively), which is highly predictive of increased transplant-free survival, expressed significantly less hepatic PROM1, CK19, and COLLAGEN-1α compared with those with TBili >1.5 (P < 0.05). Conclusion: Prom1 plays an important role in biliary fibrogenesis, in part through integrin-mediated TGF pathway activation.
Subject(s)
AC133 Antigen/genetics , Bile Duct Diseases/genetics , Bile Duct Diseases/pathology , Biliary Atresia/genetics , Rotavirus/pathogenicity , Animals , Animals, Newborn , Biliary Atresia/pathology , Biopsy, Needle , Cells, Cultured , Disease Models, Animal , Fibrosis/pathology , Gene Expression Regulation , Humans , Immunohistochemistry , Mice , Mice, Knockout , Mutation/genetics , Random Allocation , Risk Assessment , Rotavirus Infections/pathology , Sensitivity and Specificity , Transcription Factors/metabolismABSTRACT
Choledochal cysts (CDCs) and biliary atresia (BA) are rare pediatric hepatobiliary anomalies that require surgical intervention due to increased risk of malignancy and liver failure, respectively. The underlying disease and operative procedures place patients at risk for long-term complications, which may continue to affect them into adulthood. Lack of a transitional care model in the health-care system potentiates the challenges they will face following aging out of their pediatric providers' care. We sought to elucidate the long-term complications and challenges patients with CDCs and BA face, review the current literature regarding transitioning care, and propose guidelines aiding adult providers in continued care and surveillance of these patients. A literature review was performed to assess short-term and long-term complications after surgery and the current standards for transitioning care in patients with a history of CDCs and BA. While transitional programs exist for patients with other gastrointestinal diseases, there are few that focus on CDCs or BA. Generally, authors encourage medical record transmission from pediatric to adult providers, ensuring accuracy of information and compliance with treatment plans. Patients with CDCs are at risk for developing biliary malignancies, cholangitis, and anastomotic strictures after resection. Patients with BA develop progressive liver failure, necessitating transplantation. There are no consensus guidelines regarding timing of follow up for these patients. Based on the best available evidence, we propose a schema for long-term surveillance.