Does Length of Extended Resection Beyond Transition Zone Change Clinical Outcome for Hirschsprung Pull-Through?

INTRODUCTION: A proximal resection margin greater than 5 cm from the intra-operative histologically determined transition zone has been deemed necessary to minimize the risk of transition zone pull-through. This extended resection may require the sacrifice of vascular supply and even further bowel resection. The impact of extended proximal resection margin on post-operative complications and functional outcomes is unclear. METHODS: A retrospective chart review of patients who underwent primary pull-through for Hirschsprung disease at a single institution between January 2008 and December 2022 was performed. An adequate proximal margin was defined by a circumferential normally ganglionated ring and absence of hypertrophic nerves. The extended margin was defined as the total length of proximal colon with normal ganglion cells and without hypertrophic nerves. Fecal incontinence severity was assessed with the Pediatric Fecal Incontinence Severity Score (PFISS). RESULTS: Eighty seven patients met criteria for inclusion. Median age at primary pull-through was 17 days (IQR 10-92 days), 55% (n = 48) of patients had an extended proximal margin (EPM) ≤ 5 cm, and 45% (n = 39) had an EPM > 5 cm. An EPM ≤5 cm was not associated with increased rates of Hirschsprung associated enterocolitis (≤5 cm 43%, >5 cm 39%, P = 0.701), diversion post pull-through (≤5 cm 10%, >5 cm 5%, P = 0.367) or reoperation for transition zone pull-through (≤5 cm 3%, >5 cm 0%, P = 0.112). EPM ≤5 cm had more frequent involuntary daytime bowel movements (P = 0.041) and more frequent voluntary bowel movements (P = 0.035). There were no differences in other measures of fecal incontinence severity. CONCLUSIONS: Shorter proximal extended margins beyond the adequate ganglionated margin do not significantly impact post-operative complication rates and have an unclear effect on fecal incontinence. TYPE OF STUDY: Case Control. LEVEL OF EVIDENCE: Level III.

Operative Findings in Pediatric and Adolescent Patients With Presumed Adnexal Torsion.

INTRODUCTION: Clinical and radiographic findings often lead to diagnostic laparoscopy for presumed adnexal torsion (AT). To better understand the preoperative factors leading to AT, we evaluated the clinical course of patients with ultrasound findings concerning for AT to assess intraoperative AT rates and predictive factors for AT. METHODS: An institutional review board-approved retrospective review in two hospital centers over a period of 5 y was performed for females (4-18 y) with ultrasound (US) findings concerning for AT (n = 225). Preoperative clinical, radiographic, and intraoperative findings were assessed for patients with intraoperative AT versus for those without. RESULTS: The median age of patients was 14 y. Of those who went to the operating room (OR) (n = 113), AT was found in 57%. There was no difference between patients taken to the OR with or without AT regarding demographics or presentation. The presence of nausea/vomiting, tenderness, leukocytosis, lack of blood flow, or a mass/cyst >5 cm were found to be more likely in patients with AT than in those without. An ovarian volume ratio >15 was noted to be predictive of AT. Six patients initially discharged from the emergency department returned and went to the OR, two of which had AT, both with ovarian salvage. CONCLUSIONS: Limited data are available when counseling patients with presumed AT. We found the larger mean ovarian volume and an ovarian volume ratio >15 were predictive of AT. Despite this, 43% of patients taken to the OR did not have AT. This relatively high rate of not finding AT intraoperatively may be justified given the sequelae of missing AT.

Provider education leads to sustained reduction in pediatric opioid prescribing after surgery.

BACKGROUND: The majority of opioid overdose admissions in pediatric patients are associated with prescription opioids. Post-operative prescriptions are an addressable source of opioids in the household. This study aims to assess for sustained reduction in opioid prescribing after implementation of provider-based education at nine centers. METHODS: Opioid prescribing information was collected for pediatric patients undergoing umbilical hernia repair at nine centers between December 2018 and January 2019, one year after the start of an education intervention. This was compared to prescribing patterns in the immediate pre- and post-intervention periods at each of the nine centers. RESULTS: In the current study period, 29/127 (22.8%) patients received opioid prescriptions (median 8 doses) following surgery. There were no medication refills, emergency department returns or readmissions related to the procedure. There was sustained reduction in opioid prescribing compared to pre-intervention (22.8% vs 75.8% of patients, p<0.001, Fig. (1). Five centers showed statistically significant improvement and the other four demonstrated decreased prescribing, though not statistically significant. CONCLUSIONS: Our multicenter study demonstrates sustained reduction in opioid prescribing after pediatric umbilical hernia repair after a provider-based educational intervention. Similar low-fidelity provider education interventions may be beneficial to improve opioid stewardship for a wider variety of pediatric surgical procedures. LEVELS OF EVIDENCE: (treatment study)-level 3.

Targeting the eCIRP/TREM-1 interaction with a small molecule inhibitor improves cardiac dysfunction in neonatal sepsis.

BACKGROUND: Neonatal sepsis and the associated myocardial dysfunction remain a leading cause of infant mortality. Extracellular cold-inducible RNA-binding protein (eCIRP) acts as a ligand of triggering receptor expressed on myeloid cells-1 (TREM-1). M3 is a small CIRP-derived peptide that inhibits the eCIRP/TREM-1 interaction. We hypothesize that the eCIRP/TREM-1 interaction in cardiomyocytes contributes to sepsis-induced cardiac dysfunction in neonatal sepsis, while M3 is cardioprotective. METHODS: Serum was collected from neonates in the Neonatal Intensive Care Unit (NICU). 5-7-day old C57BL/6 mouse pups were used in this study. Primary murine neonatal cardiomyocytes were stimulated with recombinant murine (rm) CIRP with M3. TREM-1 mRNA and supernatant cytokine levels were assayed. Mitochondrial oxidative stress, ROS, and membrane potential were assayed. Neonatal mice were injected with rmCIRP and speckle-tracking echocardiography was conducted to measure cardiac strain. Sepsis was induced by i.p. cecal slurry. Mouse pups were treated with M3 or vehicle. After 16 h, echocardiography was performed followed by euthanasia for tissue analysis. A 7-day survival study was conducted. RESULTS: Serum eCIRP levels were elevated in septic human neonates. rmCIRP stimulation of cardiomyocytes increased TREM-1 gene expression. Stimulation of cardiomyocytes with rmCIRP upregulated TNF-α and IL-6 in the supernatants, while this upregulation was inhibited by M3. Stimulation of cardiomyocytes with rmCIRP resulted in a reduction in mitochondrial membrane potential (MMP) while M3 treatment returned MMP to near baseline. rmCIRP caused mitochondrial calcium overload; this was inhibited by M3. rmCIRP injection impaired longitudinal and radial cardiac strain. Sepsis resulted in cardiac dysfunction with a reduction in cardiac output and left ventricular end diastolic diameter. Both were improved by M3 treatment. Treatment with M3 attenuated serum, cardiac, and pulmonary levels of pro-inflammatory cytokines compared to vehicle-treated septic neonates. M3 dramatically increased sepsis survival. CONCLUSIONS: Inhibition of eCIRP/TREM-1 interaction with M3 is cardioprotective, decreases inflammation, and improves survival in neonatal sepsis. Trial registration Retrospectively registered.

Outcomes of Initial Subtotal Colectomy for Pediatric Inflammatory Bowel Disease.

BACKGROUND: Subtotal colectomy with end ileostomy (STC-I) has been well established in the adult literature as an initial surgical treatment for refractory inflammatory bowel disease (IBD)-related colitis. However, in the pediatric population, the efficacy of this approach has been less well characterized, likely because of concerns regarding the advisability of leaving a diseased rectum in situ. Our aim was to examine the outcomes after STC-I for refractory IBD at our pediatric tertiary care center. METHODS: An institutional review board-approved retrospective review of patients aged 5-21 y who underwent operative treatment with initial STC-I for medically refractory IBD from January 2010 to August 2018. Only complications related to the STC-I were considered; complications subsequent to reconstruction are excluded from analysis. Early complications were defined as occurring within 60 d of STC-I. We performed descriptive statistics using the Fisher exact test and the Student t-test, as appropriate. RESULTS: Over the study period, 37 patients (aged 12.3 ± 4.2 y) underwent STC-I, with 73.0% performed laparoscopically. Patients were predominately male (51.4%) and Caucasian (48.6%). Thirty-one (83.8%) colectomies were performed for ulcerative colitis, two (5.4%) for Crohn disease, and four (10.8%) for indeterminate colitis. Nutritional status improved postcolectomy. Albumin levels of 3.3 ± 0.8 preoperatively increased to 4.3 ± 0.47 postoperatively (P < 0.001). Colonic bleeding was stopped by STC-I with increases in the hematocrit from 30.5 ± 6.8 preoperative to 38.9 ± 4.1 postoperatively (P < 0.001). Average time to discontinuation of IBD-related medications was 4 wk (n = 27). Forty-eight percent required outpatient rectal treatment for proctitis. Patients did well long term, with 67.5% reestablishing intestinal continuity at our institution. Average postoperative length of stay was shorter in the laparoscopic group compared with those undergoing open operations (5.1 ± 2.2 versus 6.9 ± 1.6 d, P = 0.03). Readmission rate at 30 d was 21.1%. Patients experiencing unplanned readmission or unplanned operations were similar between groups (30% versus 33.3%, P = 0.85 and 30% versus 18.5%, P = 0.45, respectively). Overall, 14 (37.8%) patients experienced a complication with many patients experiencing multiple complications. Early complications occurred in nine (24.3%) patients. Late complications also occurred in 24.3% of patients. There were four (10.8%) patients with five admissions for bowel obstruction, two of whom required operative intervention (5.4%). CONCLUSIONS: Use of STC-I as an initial procedure in the treatment of refractory IBD-related colitis in children is a safe and reasonable surgical approach that allows weaning from immunosuppressing mediations and stops colonic bleeding. Implementing a laparoscopic approach to subtotal colectomy provides further benefit by reducing postoperative length of stay.

Extracellular CIRP and TREM-1 axis promotes ICAM-1-Rho-mediated NETosis in sepsis.

Extracellular cold-inducible RNA-binding protein (eCIRP) is a damage-associated molecular pattern (DAMP). Intercellular adhesion molecule-1 (ICAM-1) expressing neutrophils produce excessive amounts of neutrophil extracellular traps (NETs). We reveal that eCIRP generates ICAM-1+ neutrophils through triggering receptor expressed on myeloid cells-1 (TREM-1) and the ICAM-1+ neutrophils involve Rho GTPase to promote NETosis. Treatment of BMDN with rmCIRP increased the frequency of ICAM-1+ BMDN, while rmCIRP-treated TREM-1-/- BMDN or pretreatment of BMDN with TREM-1 inhibitor LP17 significantly decreased the frequency of ICAM-1+ neutrophils. The frequencies of ICAM-1+ neutrophils in blood and lungs were markedly decreased in rmCIRP-injected mice or septic mice treated with LP17. Coculture of ICAM-1-/- neutrophils or wild-type (WT) neutrophils with WT macrophages in the presence of a peptidylarginine deiminase 4 (PAD4) inhibitor reduced TNF-α and IL-6 compared to WT neutrophils treated with rmCIRP. Treatment of ICAM-1-/- neutrophils with rmCIRP resulted in reduced quantities of NETs compared to WT rmCIRP-treated neutrophils. Treatment of BMDN with rmCIRP-induced Rho activation, while blockade of ICAM-1 significantly decreased Rho activation. Inhibition of Rho significantly decreased rmCIRP-induced NET formation in BMDN. TREM-1 plays a critical role in the eCIRP-mediated increase of ICAM-1 expression in neutrophils, leading to the increased NET formation via Rho activation to exaggerate inflammation.

An extracellular cold-inducible RNA-binding protein-derived small peptide targeting triggering receptor expressed on myeloid cells-1 attenuates hemorrhagic shock.

BACKGROUND: Extracellular cold-inducible RNA-binding protein (eCIRP) is a damage-associated molecular pattern, which is released into the circulation after hemorrhagic shock (HS). Recently, we discovered that triggering receptor expressed on myeloid cells-1 (TREM-1) serves as a new receptor of eCIRP to exaggerate inflammation. Here, we hypothesize that by inhibiting the interaction between eCIRP and TREM-1 with the use of a novel short peptide derived from human eCIRP known as M3, we can inhibit the inflammatory response and acute lung injury in HS. METHODS: Hemorrhagic shock was induced using C57BL/6 mice by cannulating both femoral arteries. One femoral artery was used for removal of blood while the other was used for continuous monitoring of mean arterial blood pressure. The mean arterial pressure of 25 mm Hg to 30 mm Hg was maintained for 90 minutes, followed by a resuscitation phase of 30 minutes with 1 mL of normal saline. The treatment group was given 10 mg/kg of M3 during the resuscitation phase. Four hours after resuscitation, serum and lungs were collected and analyzed for various injury and inflammatory markers by using colorimetry, real-time polymerase chain reaction, and enzyme-linked immunosorbent assay. RESULTS: There was an increase in the serum levels of tissue injury markers (alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase) as well as cytokines (TNF-α and IL-6) when comparing the vehicle group versus the sham group. This increase was significantly inhibited in the M3-treated group. The mRNA expression of proinflammatory cytokines TNF-α, IL-6, and IL-1ß and the chemokines MIP-2 and KC in lungs was significantly increased in the vehicle-treated HS mice, while their expression was significantly decreased in M3-treated HS mice. Finally, M3 treatment significantly decreased the lung injury score compared with vehicle-treated HS mice. CONCLUSION: The novel eCIRP-derived TREM-1 antagonist (M3) can be a potential therapeutic adjunct in the management of hemorrhagic shock.

Inhibition of a triggering receptor expressed on myeloid cells-1 (TREM-1) with an extracellular cold-inducible RNA-binding protein (eCIRP)-derived peptide protects mice from intestinal ischemia-reperfusion injury.

BACKGROUND: Intestinal ischemia-reperfusion injury results in morbidity and mortality from both local injury and systemic inflammation and acute lung injury. Extracellular cold-inducible RNA-binding protein is a damage associated molecular pattern that fuels systemic inflammation and potentiates acute lung injury. We recently discovered a triggering receptor expressed on myeloid cells-1 serves as a novel receptor for extracellular cold-inducible RNA-binding protein. We developed a 7-aa peptide, named M3, derived from the cold-inducible RNA-binding protein, which interferes with cold-inducible RNA-binding protein's binding to a triggering receptor expressed on myeloid cells-1. Here, we hypothesized that M3 protects mice against intestinal ischemia-reperfusion injury. METHODS: Intestinal ischemia was induced in C57BL/6 mice via clamping of the superior mesenteric artery for 60 minutes. At reperfusion, mice were treated intraperitoneally with M3 (10 mg/kg body weight) or normal saline vehicle. Mice were killed 4 hours after reperfusion and blood and lungs were collected for various analysis. A 24-hours survival after intestinal ischemia-reperfusion was assessed. RESULTS: Serum levels of organ injury markers aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and lactate were increased with intestinal ischemia-reperfusion, while treatment with M3 significantly decreased their levels. Serum, intestinal, and lung levels of proinflammatory cytokines and chemokines were also increased by intestinal ischemia-reperfusion, and treatment with M3 significantly reduced these values. Intestinal ischemia-reperfusion caused significant histological intestinal and lung injuries, which were mitigated by M3. Treatment with M3 improved the survival from 40% to 80% after intestinal ischemia-reperfusion. CONCLUSION: Inhibition of triggering receptor expressed on myeloid cells-1 by an extracellular cold-inducible RNA-binding protein-derived small peptide (M3) decreased inflammation, reduced lung injury, and improved survival in intestinal ischemia-reperfusion injury. Thus, blocking the extracellular cold-inducible RNA-binding protein-triggering receptor expressed on myeloid cells-1 interaction is a promising therapeutic avenue for mitigating intestinal ischemia-reperfusion injury.

Outpatient follow-up after pediatric surgery reduces emergency department visits and readmission rates.

PURPOSE: The factors affecting outpatient follow-up (OFU) after pediatric surgery have not been well studied. We evaluate factors impacting OFU and the effect of OFU in pediatric surgical patients. METHODS: A retrospective review of all pediatric patients operated on by the Division of Pediatric Surgery from February 1st to September 30th, 2017, and subsequently discharged was performed. RESULTS: 1242 patients were identified. Overall OFU was 69.6%. Language and distance between patient residence and the hospital had no impact on OFU. Inpatient surgical patients followed-up at a higher rate than ambulatory surgical patients (72.7% vs 64.8%, p < 0.01). Out-of-system transfers had the lowest OFU rate at 52.8% (p < 0.001). Insurance type and patient age had a significant impact on OFU rates. Thirty-day ED visit and readmission rates were significantly lower in those patients with OFU than in those without (8.8% vs 12.7%, p = 0.04 and 3.7% to 11.0%, p < 0.001, respectively). OFU was more beneficial in patients with inpatient procedures or longer hospitalization lengths of stay than in the cohort of ambulatory patients. CONCLUSIONS: Socioeconomic status, hospital presentation, and procedural complexity influenced rates of OFU. OFU was associated with significant reductions in 30-day ED visits and readmissions, and this benefit was more pronounced for complex procedures or patients. TYPE OF STUDY: Retrospective review. LEVEL OF EVIDENCE: Level III.

Pediatric Robotic Surgery.

Pediatric robotic-assisted surgery is quickly gaining traction in pediatric surgical disciplines but presents unique challenges as compared to adult robotic surgery. Small abdominal and thoracic cavities limit working space and operative indications differ from the adult population. This article describes the development of pediatric robotic-assisted surgery, discusses technical limitations and benefits, and reviews training considerations particular to robotic surgery. Applications and published outcomes of common procedures in urology, general and thoracic surgery, otolaryngology, and pediatric surgical oncology are described. Finally, costs and the anticipated future direction of pediatric robotic-assisted surgery are discussed.

Extracellular CIRP as an endogenous TREM-1 ligand to fuel inflammation in sepsis.

Extracellular cold-inducible RNA-binding protein (eCIRP) is a recently discovered damage-associated molecular pattern. Understanding the precise mechanism by which it exacerbates inflammation is essential. Here we identified that eCIRP is a new biologically active endogenous ligand of triggering receptor expressed on myeloid cells-1 (TREM-1), fueling inflammation in sepsis. Surface plasmon resonance revealed a strong binding affinity between eCIRP and TREM-1, and fluorescence resonance energy transfer assay confirmed eCIRP's interaction with TREM-1 in macrophages. Targeting TREM-1 by its siRNA or a decoy peptide, LP17, or by using TREM-1-/- mice dramatically reduced eCIRP-induced inflammation. We developed a potentially novel 7-aa peptide derived from human eCIRP, M3, which blocked the interaction of TREM-1 and eCIRP. M3 suppressed inflammation induced by eCIRP or agonist TREM-1 antibody cross-linking in murine macrophages or human peripheral blood monocytes. M3 also inhibited eCIRP-induced systemic inflammation and tissue injury. Treatment with M3 further protected mice from sepsis, improved acute lung injury, and increased survival. Thus, we have discovered a potentially novel TREM-1 ligand and developed a new peptide, M3, to block eCIRP-TREM-1 interaction and improve outcomes in sepsis.

Extracellular CIRP induces macrophage endotoxin tolerance through IL-6R-mediated STAT3 activation.

Extracellular cold-inducible RNA-binding protein (eCIRP) is a damage-associated molecular pattern, whose effect on macrophages is not entirely elucidated. Here we identified that eCIRP promotes macrophage endotoxin tolerance. Septic mice had higher serum levels of eCIRP; this was associated with a reduced ex vivo immune response of their splenocytes to LPS. Pretreatment of macrophages with recombinant murine CIRP (rmCIRP) resulted in a tolerance to LPS stimulation as demonstrated by a reduction of TNF-α production. We found that eCIRP increased phosphorylated STAT3 (p-STAT3) in macrophages. A STAT3 inhibitor, Stattic, rescued macrophages from rmCIRP-induced tolerance by restoring the release of TNF-α in response to LPS stimulation. We discovered strong binding affinity between eCIRP and IL-6 receptor (IL-6R) as revealed by Biacore, fluorescence resonance energy transfer (FRET), and their colocalization in macrophages by immunostaining assays. Blockade of IL-6R with its neutralizing Ab inhibited eCIRP-induced p-STAT3 and restored LPS-stimulated TNF-α release in macrophages. Incubation of macrophages with rmCIRP skewed them toward an M2 phenotype, while treatment with anti-IL-6R Ab prevented rmCIRP-induced M2 polarization. Thus, we have demonstrated that eCIRP activates p-STAT3 via a novel receptor, IL-6R, to promote macrophage endotoxin tolerance. Targeting eCIRP appears to be a new therapeutic option to correct immune tolerance in sepsis.

Provider education decreases opioid prescribing after pediatric umbilical hernia repair.

PURPOSE: To improve opioid stewardship for umbilical hernia repair in children. METHODS: An educational intervention was conducted at 9 centers with 79 surgeons. The intervention highlighted the importance of opioid stewardship, demonstrated practice variation, provided prescribing guidelines, encouraged non-opioid analgesics, and encouraged limiting doses/strength if opioids were prescribed. Three to six months of pre-intervention and 3 months of post-intervention prescribing practices for umbilical hernia repair were compared. RESULTS: A total of 343 patients were identified in the pre-intervention cohort and 346 in the post-intervention cohort. The percent of patients receiving opioids at discharge decreased from 75.8% pre-intervention to 44.6% (p < 0.001) post-intervention. After adjusting for age, sex, umbilicoplasty, and hospital site, the odds ratio for opioid prescribing in the post- versus the pre-intervention period was 0.27 (95% CI = 0.18-0.39, p < 0.001). Among patients receiving opioids, the number of doses prescribed decreased after the intervention (adjusted mean 14.3 to 10.4, p < 0.001). However, the morphine equivalents/kg/dose did not significantly decrease (adjusted mean 0.14 to 0.13, p = 0.20). There were no differences in returns to emergency departments or hospital readmissions between the pre- and post-intervention cohorts. CONCLUSIONS: Opioid stewardship can be improved after pediatric umbilical hernia repair using a low-fidelity educational intervention. TYPE OF STUDY: Retrospective cohort study. LEVEL OF EVIDENCE: Level II.

MFG-E8-derived peptide attenuates inflammation and injury after renal ischemia-reperfusion in mice.

BACKGROUND: Renal ischemia-reperfusion (renal I/R) injury may lead to acute kidney injury (AKI). After renal I/R, proinflammatory mediators cause immune cell infiltration and further injury. Milk fat globule-epidermal growth factor-factor 8 (MFG-E8) is a protein involved in cell-cell and cell-matrix interactions. MSP68 is an MFG-E8-derived peptide that inhibits neutrophil adhesion and migration. Here, we evaluated whether MSP68 attenuates renal I/R injury. MATERIALS AND METHODS: Adult C57BL/6 mice were subjected to bilateral renal ischemia for 30 min followed by reperfusion and intraperitoneal administration of saline (vehicle) or MSP68 (5 mg/kg). Sham animals underwent laparotomy without renal I/R. The blood collected and studied for BUN, creatinine, and LDH by colorimetry. The kidneys were analyzed for IL-6 and TNFα by qPCR, ELISA, histological injury, and apoptosis by TUNEL. RESULTS: At 24 h after surgery, serum levels of BUN, creatinine, and LDH were markedly higher in vehicle-treated renal I/R mice than in sham mice, but significantly lower in MSP68-treated renal I/R mice. Similarly, compared to sham, renal levels of IL-6 mRNA and protein and TNFα protein were markedly higher in vehicle-treated renal I/R mice, but significantly lower in MSP68-treated renal I/R mice. Vehicle-treated renal I/R mice also had severe renal tubular histological injury, which was significantly lower in MSP68-treated renal I/R mice. Additionally, the kidneys of vehicle-treated renal I/R mice had a 93-fold increase in TUNEL-positive cells, which were reduced by 35% in mice treated with MSP68. CONCLUSION: MSP68 has the potential to be developed as novel therapeutic agent for patients with AKI.

DAMPs and NETs in Sepsis.

Sepsis is a deadly inflammatory syndrome caused by an exaggerated immune response to infection. Much has been focused on host response to pathogens mediated through the interaction of pathogen-associated molecular patterns (PAMPs) and pattern recognition receptors (PRRs). PRRs are also activated by host nuclear, mitochondrial, and cytosolic proteins, known as damage-associated molecular patterns (DAMPs) that are released from cells during sepsis. Some well described members of the DAMP family are extracellular cold-inducible RNA-binding protein (eCIRP), high mobility group box 1 (HMGB1), histones, and adenosine triphosphate (ATP). DAMPs are released from the cell through inflammasome activation or passively following cell death. Similarly, neutrophil extracellular traps (NETs) are released from neutrophils during inflammation. NETs are webs of extracellular DNA decorated with histones, myeloperoxidase, and elastase. Although NETs contribute to pathogen clearance, excessive NET formation promotes inflammation and tissue damage in sepsis. Here, we review DAMPs and NETs and their crosstalk in sepsis with respect to their sources, activation, release, and function. A clear grasp of DAMPs, NETs and their interaction is crucial for the understanding of the pathophysiology of sepsis and for the development of novel sepsis therapeutics.

Early Experience with Variant Two-Stage Approach in Surgical Management of Inflammatory Bowel Disease Colitis in the Pediatric Population.

Introduction: Multistaged surgical management of inflammatory bowel disease (IBD), culminating in ileal pouch-anal anastomosis (IPAA), can provide cure for refractory IBD symptoms while maintaining fecal continence. Surgical approaches to IPAA historically included a three-stage approach done by subtotal colectomy (STC) followed by IPAA with diversion. Recently, a variant two-stage approach without diversion at IPAA has become increasingly utilized, yet evidence of the efficacy of this approach is limited. Methods: Retrospective review of patients aged 5-21 years who underwent initial STC, followed by a total proctocolectomy with IPAA +/- diversion for medically refractory IBD from January 2010 to August 2018 (n = 25). Results: Majority of IPAA procedures were done laparoscopically (88.5%). Thirteen patients (52%) underwent two-stage variant IPAA. There were no differences in readmission rates (66.7% versus 53.8%, P = .5) or reoperation rates (50% versus 30.8%, P = .3) between groups. Forty percent of patients experienced a complication after IPAA. Complication rates were similar between two-stage and three-stage IPAA groups (38.5% versus 50%, P = .33). Complications within the two-stage group included anastomotic leak, pouchitis, wound infection, anastomotic stricture, and incarcerated hernia. Complications within the three-stage group included bloody ostomy output, dehydration, anastomotic stricture, small bowel obstruction, and pouch volvulus. Conclusions: Treatment of refractory IBD in children remains challenging, but STC followed by IPAA is an approach that provides symptom relief and preserves continence. Complication rates remained unchanged regardless of whether IPAA was conducted with or without diversion, demonstrating that the two-stage variant approach is a safe and feasible treatment that may reduce subsequent anesthesia exposure and trips to the operating room.

Modified open technique for laparoscopic gastrostomy tube placement results in more leakage post operatively than Seldinger technique.

BACKGROUND: Laparoscopic gastrostomy tube (GT) placement is a common procedure and frequent cause of morbidity. Some surgeons perform a Seldinger technique (ST), while others perform a modified open technique (MOT). We hypothesized that the modified open technique would result in more complications. METHODS: A prospective study of primary GT placed 12/2016-06/2018, ensuring at least 6 months follow up. We assessed any episode of granulation tissue, troublesome leaking, tube dislodgment, and infection requiring antibiotic or drainage. RESULTS: 92 GT were placed, with 56 were placed as modified open (60.9%). 34 children (37.0%) developed granulation tissue, 18 children (19.6%) experienced tube dislodgment, and 6 children (6.5%) developed a site infection, with no difference depending on technique (P = 0.56, 0.29, and 0.76, respectively). Following ST, 2 children developed leakage (5.6%), whereas 15 children (26.8%) had leakage following the MOT (P = 0.01). CONCLUSION: MOT resulted in significantly more leaks. Other complications were similar between groups. Surgeons choosing MOT should be mindful of the size of gastrotomy at time of surgery, as this may result in increased complications.

Safe phlebotomy reduction in stable pediatric liver and spleen injuries.

PURPOSE: Pediatric blunt solid organ injury management based on hemodynamic monitoring rather than grade may safely reduce resource expenditure and improve outcomes. Previously we have reported a retrospectively validated management algorithm for pediatric liver and spleen injuries which monitors hemodynamics without use of routine phlebotomy. We hypothesize that stable blunt pediatric isolated splenic/liver injuries can be managed safely using a protocol reliant on vital signs and not repeat hemoglobin levels. METHODS: A prospective multi-institutional study was performed at three pediatric trauma centers. All pediatric patients from 07/2016-12/2017 diagnosed with liver or splenic injuries were identified. If appropriate for the protocol, only a baseline hemoglobin was obtained unless hemodynamic instability as defined in an age-appropriate fashion was determined by treating physician discretion. Descriptive statistics were conducted. RESULTS: One hundred four patients were identified of which 38 were excluded from the protocol. There was a significant difference in abnormal shock index, pediatric age-adjusted (SIPA) values, hematocrit, and percentage of patients with hemoglobin less than 10 between the excluded and included patients. Of the 66 patients managed on the protocol, four patients had to be removed, two each on day one and day two. Of those four patients, only one required intervention. There were no mortalities. CONCLUSION: A phlebotomy limiting protocol may be a safe option for stable pediatric splenic and liver injuries cared for in a pediatric trauma center with the resources for rapid intervention should the need arise. The differences in groups highlight the importance of utilizing this protocol in the correct patient population. Reduced phlebotomy offers the potential for reduced resource expenditure without any evidence of increased morbidity or mortality. LEVEL OF EVIDENCE: Level IV.

Inconsistency in Opioid Prescribing Practices After Pediatric Ambulatory Hernia Surgery.

INTRODUCTION: Nonmedical opioid use is a major public health problem. There is little standardization in opioid-prescribing practices for pediatric ambulatory surgery, which can result in patients being prescribed large quantities of opioids. We have evaluated the variability in postoperative pain medication given to pediatric patients following routine ambulatory pediatric surgical procedures. METHODS: Following IRB approval, pediatric patients undergoing umbilical hernia repair, inguinal hernia repair, hydrocelectomy, and orchiopexy from 2/1/2017 to 2/1/2018 at our tertiary care children's hospital were retrospectively reviewed. Data collected include operation, surgeon, resident or fellow involvement, utilization of preoperative analgesia, opioid prescription on discharge, and patient follow-up. RESULTS: Of 329 patients identified, opioids were prescribed on discharge to 37.4% of patients (66.3% of umbilical hernia repairs, 20.6% of laparoscopic inguinal hernia repairs, and 33.3% of open inguinal hernia repairs [including hydrocelectomies and orchiopexies]). For each procedure, there was large intrasurgeon and intersurgeon variability in the number of opioid doses prescribed. Opioid prescription ranged from 0 to 33 doses for umbilical hernia repairs, 0 to 24 doses for laparoscopic inguinal repairs, and 0 to 20 doses prescribed for open inguinal repairs, hydrocelectomies, and orchiopexies. Pediatric surgical fellows were less likely to discharge a patient with an opioid prescription than surgical resident prescribers (P < 0.01). In addition, surgical residents were more likely to prescribe more than twelve doses of opioids than pediatric surgical fellows (P < 0.01). Increasing patient age was associated with an increased likelihood of opioid prescription (P < 0.01). There were two phone calls and two clinic visits for pain control issues with equal numbers for those with and without opioid prescriptions. CONCLUSIONS: There is significant variation in opioid-prescribing practices after pediatric surgical procedures; increased awareness may help minimize this variability and reduce overprescribing. Training level has an impact on the frequency and quantity of opioids prescribed.

C23, an oligopeptide derived from cold-inducible RNA-binding protein, suppresses inflammation and reduces lung injury in neonatal sepsis.

INTRODUCTION: Neonatal sepsis remains a leading cause of infant mortality. Cold-inducible RNA binding protein (CIRP) is an inflammatory mediator that induces TNF-α production in macrophages. C23 is a CIRP-derived peptide that blocks CIRP from binding its receptor. We therefore hypothesized that treatment with C23 reduces systemic inflammation and protects the lungs in neonatal sepsis. METHODS: Sepsis was induced in C56BL/6 mouse pups (5-7 days) by intraperitoneal injection of adult cecal slurry (0.525 mg/g body weight, LD100). One hour later pups received retroorbital injection of C23 (8 mg/kg) or vehicle (normal saline). Ten hours after sepsis induction, blood and tissues were collected for analysis. RESULTS: C23 treatment resulted in a 58% and 69% reduction in serum levels of proinflammatory cytokines IL-6 and IL-1ß, respectively, and a 40% and 45% reduction of AST and LDH, as compared to vehicle-treated septic pups. In the lungs, C23 treatment reduced expression of cytokines IL-6 and IL-1ß by 78% and 74%. In addition, the mRNA level of neutrophil chemoattractants KC and MIP-2 was reduced by 84% and 74%, respectively. These results corresponded to a reduction in histologic lung injury score. Vehicle-treated pups scored 0.49 ±â€¯0.19, while C23 treatment reduced scores to 0.29 ±â€¯0.12 (p < 0.05; Max = 1). Apoptosis in the lungs, measured by TUNEL assay, was also decreased by 53% with C23 treatment (p < 0.05). CONCLUSIONS: Inhibition of CIRP with C23 treatment is protective in septic neonatal mice as demonstrated by reduced inflammatory markers systemically and in the lung. Therefore, C23 has promising therapeutic potential in treatment of neonatal sepsis. LEVEL OF EVIDENCE: Level I.