Pamela M. Choi

The role of growth factors in intestinal regeneration and repair in necrotizing enterocolitis.

Necrotizing enterocolitis (NEC) is a devastating intestinal disease resulting in major neonatal morbidity and mortality. The pathology is poorly understood, and the means of preventing and treating NEC are limited. Several endogenous growth factors have been identified as having important roles in intestinal growth as well as aiding intestinal repair from injury or inflammation. In this review, we will discuss several growth factors as mediators of intestinal regeneration and repair as well as potential therapeutic agents for NEC.

Insulin-like growth factor 2 and its enterocyte receptor are not required for adaptation in response to massive small bowel resection

PURPOSE Enhanced structural features of resection-induced intestinal adaptation have been demonstrated following the administration of multiple different growth factors and peptides. Among these, the insulin-like growth factor (IGF) system has been considered to be significant. In this study, we employ mutant mouse strains to directly test the contribution of IGF2 and its enterocyte receptor (IGF1R) toward the adaptation response to massive small bowel resection (SBR). METHODS IGF2-knockout (IGF2-KO) (n=8) and intestine specific IGF1R-knockout mice (IGF1R-IKO) (n=9) and their wild type (WT) littermates (n=5, n=7, respectively) underwent 50% proximal SBR. At post-operative day 7, structural adaptation was measured as crypt depth and villus height. Rates of enterocyte proliferation and apoptosis were also recorded. RESULTS The successful deletion of IGF2 and IGF1R expression in the enterocytes was confirmed by RT-PCR and Western blot, respectively. Normal adaptation occurred in both IGF2-KO and IGF1R-IKO mice after 50% SBR. Post-operative rates of proliferation and apoptosis in both IGF2-KO and IGF1R-IKO mice were no different than their respective controls. CONCLUSION IGF2 and functional IGF1R signaling in enterocytes are both dispensable for resection-induced adaptation responses. The mechanism for IGF-stimulation of intestinal adaptation may involve other ligands or cellular compartments within the intestine.

Disruption of retinoblastoma protein expression in the intestinal epithelium impairs lipid absorption.

We previously demonstrated increased villus height following genetic deletion, or knockout, of retinoblastoma protein (Rb) in the intestinal epithelium (Rb-IKO). Here we determined the functional consequences of augmented mucosal growth on intestinal fat absorption and following a 50% small bowel resection (SBR). Mice with constitutively disrupted Rb expression in the intestinal epithelium (Rb-IKO) along with their floxed (wild-type, WT) littermates were placed on a high-fat diet (HFD, 42% kcal fat) for 54 wk. Mice were weighed weekly, and fat absorption, indirect calorimetry, and MRI body composition were measured. Rb-IKO mice were also subjected to a 50% SBR, followed by HFD feeding for 33 wk. In separate experiments, we examined intestinal fat absorption in mice with conditional (tamoxifen-inducible) intestinal Rb (inducible Rb-IKO) deletion. Microarray revealed that the transcriptional expression of lipid absorption/transport genes was significantly reduced in constitutive Rb-IKO mice. These mice demonstrated greater mucosal surface area yet manifested paradoxically impaired intestinal long-chain triglyceride absorption and decreased cholesterol absorption. Despite attenuated lipid absorption, there were no differences in metabolic rate, body composition, and weight gain in Rb-IKO and WT mice at baseline and following SBR. We also confirmed fat malabsorption in inducible Rb-IKO mice. We concluded that, despite an expanded mucosal surface area, Rb-IKO mice demonstrate impaired lipid absorption without compensatory alterations in energy homeostasis or body composition. These findings underscore the importance of delineating structural/functional relationships in the gut and suggest a previously unknown role for Rb in the regulation of intestinal lipid absorption.

Firearm injuries in the pediatric population: a tale of one city

BACKGROUND Firearm-related injuries are a significant cause of morbidity and mortality in children. To determine current trends and assess avenues for future interventions, we examined the epidemiology and outcome of pediatric firearm injuries managed at our regions two major pediatric trauma centers. METHODS Following institutional review board approval, we conducted a 5-year retrospective review of all pediatric firearm victims, 16 years or younger, treated at either of the regions two Level 1 pediatric trauma centers, St. Louis Childrens Hospital and Cardinal Glennon Childrens Medical Center. RESULTS There were 398 children treated during a 5-year period (2008–2013) for firearm-related injuries. Of these children, 314 (78.9%) were black. Overall, there were 20 mortalities (5%). Although most (67.6%) patients were between 14 years and 16 years of age, younger victims had a greater morbidity and mortality. The majority of injuries were categorized as assault/intentional (65%) and occurred between 6:00 pm and midnight, outside the curfew hours enforced by the city. Despite a regional decrease in the overall incidence of firearm injuries during the study period, the rate of accidental victims per year remained stable. Most accidental shootings occurred in the home (74.2%) and were self-inflicted (37.9%) or caused by a person known to the victim (40.4%). CONCLUSION Despite a relative decrease in intentional firearm-related injuries, a constant rate of accidental shootings suggest an area for further intervention. LEVEL OF EVIDENCE Prognostic and epidemiologic study, level IV.

The role of enteral fat as a modulator of body composition after small bowel resection

BACKGROUND After massive small bowel resection (SBR), a postoperative diet high in fat is associated with enhanced villus growth. The purpose of this study was to further elucidate the quantity and composition of enteral fat in structural and metabolic changes after SBR. METHODS C57/Bl6 mice underwent a 50% proximal SBR. Mice were then randomized to receive a low-fat diet (12% kcal fat), medium-fat diet (44% kcal fat), or high-fat diet (HFD; 71% kcal fat) ad libitum. In a separate experiment, mice underwent 50% proximal SBR and then were randomized to liquid diets of 42% kcal of fat in which the fat was composed of menhaden oil, milk fat, or olive oil. After 2 weeks, mice underwent body composition analysis and the small intestine was harvested. RESULTS Mice that ingested the greatest amount of enteral fat (HFD) had the greatest percent lean mass. When the effects of the different kinds of enteral fat were analyzed, mice that consumed menhaden oil had the greatest percent lean mass with the greatest overall retention of preoperative weight. CONCLUSION These findings suggest that enteral fat enriched in omega-3 fatty acids may offer clinically relevant metabolic advantages for patients with short gut syndrome.

Acute coagulopathy in pediatric trauma

Purpose of review To summarize our current understanding of the pathophysiology, diagnosis, and management of acute traumatic coagulopathy in children. Recent findings Traumatic coagulopathy is a complex process that leads to global dysfunction of the endogenous coagulation system and results in worse outcomes and increased mortality. Although the cause is multifactorial, it is common in severely injured patients and is driven by significant tissue injury and hypoperfusion. Viscoelastic coagulation tests have been established as a rapid and reliable method to assess traumatic coagulopathy. Additionally, massive transfusion protocols have improved outcomes in adults, but limited studies in pediatrics have not shown any difference in mortality. Summary Prospective studies are needed to determine how to best diagnose and manage acute traumatic coagulopathy in children.

Both epidermal growth factor and insulin-like growth factor receptors are dispensable for structural intestinal adaptation ☆

PURPOSE Intestinal adaptation structurally represents increases in crypt depth and villus height in response to small bowel resection (SBR). Previously, we found that neither epidermal growth factor receptor (EGFR) nor insulin-like growth factor 1 receptor (IGF1R) function was individually required for normal adaptation. In this study, we sought to determine the effect of disrupting both EGFR and IGF1R expression on resection-induced adaptation. METHODS Intestinal-specific EGFR and IGF1R double knockout mice (EGFR/IGF1R-IKO) (n=6) and wild-type (WT) control mice (n=7) underwent 50% proximal SBR. On postoperative day (POD) 7, structural adaptation was scored by measuring crypt depth and villus height. Rates of crypt cell proliferation, apoptosis, and submucosal capillary density were also compared. RESULTS After 50% SBR, normal adaptation occurred in both WT and EGFR/IGF1R-IKO. Rates of proliferation and apoptosis were no different between the two groups. The angiogenic response was less in the EGFR/IGF1R-IKO compared to WT mice. CONCLUSION Disrupted expression of EGFR and IGF1R in the intestinal epithelial cells does not affect resection-induced structural adaptation but attenuates angiogenesis after SBR. These findings suggest that villus growth is driven by receptors and pathways that occur outside the epithelial cell component, while angiogenic responses may be influenced by epithelial-endothelial crosstalk.

Missed injuries and unplanned readmissions in pediatric trauma patients

BACKGROUND We sought to determine the incidence and characteristics of missed injuries and unplanned readmissions at a Level-1 pediatric trauma center. METHODS We conducted a retrospective review of all trauma patients who presented to our ACS-verified Level-1 pediatric trauma center from 2009 to 2014. RESULTS Overall, there were 27 readmissions and 27 missed injuries (0.38%). Patients who were unplanned readmissions had a greater Injury Severity Score (ISS) (8.6 vs 5.2, p=0.03), had longer hospitalizations (4.9 vs 2.5days, p=0.02), and were more likely to have required operative intervention (51.9% vs 32.3%, p=0.04). Similarly, patients identified with missed injuries had a higher ISS (15.2 vs 5.2, p<0.0001), greater length of stay (12.7 vs 2.5days, p<0.0001), and were also more likely to be intubated (25.9% vs 3.6%, p<0.0001) or require critical care (48.1% vs 10.3%, p<0.0001). Seven missed injuries were in patients who were deemed nonaccidental trauma (25.9%) and significantly altered their hospital course while 10 patients (37%) required operative intervention. On multivariate analysis, only ISS was found to be an independent risk factor for readmissions and missed injuries. CONCLUSIONS Missed injuries and unplanned readmissions were rare occurrences among our pediatric patient population. These events, however, did result in longer hospitalizations and additional procedures. Patients with multisystem injuries and compromised physical exam are at higher risk. LEVEL OF EVIDENCE IV.

Management and outcomes of traumatic hemothorax in children

Background: Adult guidelines for the management of traumatic hemothorax are well established; however, there have been no similar studies conducted in the pediatric population. The purpose of our study was to assess the management and outcomes of children with traumatic hemothorax. Materials and Methods: Following Institutional Review Board approval, we conducted a retrospective cross-sectional study of all trauma patients diagnosed with a hemothorax at a Level-1 pediatric trauma center from 2007 to 2012. Results: Forty-six children with hemothorax were identified, 23 from blunt mechanism and 23 from penetrating mechanism. The majority of children injured by penetrating mechanisms were treated with tube thoracostomy while the majority of blunt injury patients were observed (91.3% vs. 30.4% tube thoracostomy, penetrating vs. blunt, P = 0.00002). Among patients suffering from blunt mechanism, children who were managed with chest tubes had a greater volume of hemothorax than those who were observed. All children who were observed underwent serial chest radiographs demonstrating no progression and required no delayed procedures. Children with a hemothorax identified only by computed tomography, after negative plain radiograph, did not require intervention. No child developed a delayed empyema or fibrothorax. Conclusion: The data suggest that a small-volume hemothorax resulting from blunt mechanism may be safely observed without mandatory tube thoracostomy and with overall low complication rates.

A pilot study of viscoelastic monitoring in pediatric trauma: Outcomes and lessons learned

Background: Examine the characteristics and outcomes of pediatric trauma patients at risk for coagulopathy following implementation of viscoelastic monitoring. Materials and Methods: Injured children, aged <18 years, from September 7, 2014, to December 21, 2015, at risk for trauma-induced coagulopathy were identified from a single, level-1 American College of Surgeons verified pediatric trauma center. Patients were grouped by coagulation assessment: no assessment (NA), conventional coagulation testing alone (CCT), and conventional coagulation testing with rapid thromboelastography (rTEG). Coagulation assessment was provider preference with all monitoring options continuously available. Groups were compared and outcomes were evaluated including blood product utilization, Intensive Care Unit (ICU) utilization, duration of mechanical ventilation, and mortality. Results: A total of 155 patients were identified (NA = 78, CCT = 54, and rTEG = 23). There was no difference in age, gender, race, or mechanism. In practice, rTEG patients were more severely injured, more anemic, and received more blood products and crystalloid (P < 0.001). rTEG patients also had increased mortality with fewer ventilator and ICU-free days. Multivariate logistic regression and covariance analysis indicated that while rTEG use was not associated with mortality, it was associated with increased use of blood products, duration of mechanical ventilation, and ICU length of stay. Conclusions: Viscoelastic monitoring was infrequently performed, but utilized in more severely injured patients. Well-designed prospective studies in patients at high risk of coagulopathy are needed to evaluate goal-directed hemostatic resuscitation strategies in children.