FXR Deletion Attenuates Intestinal Barrier Dysfunction in Murine Acute Intestinal Inflammation.

Accumulating literature suggests that the Farnesoid-X Receptor (FXR), a nuclear bile acid receptor best known for its role in bile acid homeostasis, is also a potent context-dependent regulator of inflammation. FXR may thus be relevant to several intestinal disease states including inflammatory bowel disease, necrotizing enterocolitis, and sepsis. In this study, we tested the effects of FXR deletion on acute murine intestinal inflammation. We found that FXR knockout (KO) mice were protected from intestinal injury and barrier dysfunction induced by LPS injection, dithizone/Klebsiella, and cecal ligation/puncture models. In the LPS model, RNA sequencing and qPCR analysis showed that this protection correlated with substantial reduction in LPS-induced pro-inflammatory gene expression, including lower tissue levels of Il1a, Il1b, and Tnf. Examining functional effects on the epithelium, we found that LPS-induced tight junctional disruption as assessed by internalization of ZO-1 and occludin was ameliorated in FXR KO animals. Taken together, these data suggest a role for FXR in the intestinal barrier during inflammatory injury.

Children with large primary spontaneous pneumothoraxes may benefit from early operative intervention.

PURPOSE: The initial management of primary spontaneous pneumothoraxes (PSP) in children remains controversial, particularly regarding the timing of operative intervention. This study aimed to identify factors associated with failure of non-operative management of PSP. METHODS: A single-center, retrospective review was performed for patients presenting with PSP. Demographics and clinical predictors were collected. Patients successfully managed non-operatively were compared to failed non-operative management. Fischer exact and Mann-Whitney tests were used as appropriate. RESULTS: Fifty-seven pediatric patients were identified as having PSP. Four patients underwent initial surgical intervention, 60% (n = 34) were successfully managed non-operatively, while 33% (n = 19) failed non-operative management and underwent video-assisted thoracic surgery (VATS). Those who failed were more likely to have PSP > 2 cm on initial X-ray (79% vs. 44%, p = 0.021) and have a persistent air leak for > 48 h (47% vs 6%, p ≤ 0.001). LOS was greater in the failure group (11.5 ± 5.1 vs 3.1 ± 2.5, p ≤ 0.001) as well as higher complication rates (21% vs 0%, p = 0.013). CONCLUSION: Our findings suggest that patients presenting with PSP of > 2 cm or have a persistent air leak for > 48 h despite chest tube management are unlikely to be treated by chest tube alone and may benefit from earlier operative intervention.

Intracranial pressure monitoring associated with increased mortality in pediatric brain injuries.

BACKGROUND: Utilization of ICP monitors for pediatric patients is low and varies between centers. We hypothesized that in more severely injured patients (GCS 3-4), there would be a decreased mortality associated with invasive monitoring devices. METHODS: The pediatric Trauma Quality Improvement Program (TQIP) was queried for patients aged ≤ 16 years meeting criteria for invasive monitors. Our primary outcome was mortality. Patients with ICP monitoring were compared to those without. A logistic regression was used to examine the risk of mortality. RESULTS: Of 3,808 patients, 685 (18.0%) underwent ICP monitoring. ICP monitors were associated with increased risk of mortality (OR 1.82, CI 1.36-2.44, p < 0.001). A secondary analysis including type of invasive ICP monitor and dividing GCS into 3 categories revealed both intraventricular drain (OR 1.89, CI 1.3-2.7, p = 0.001) and intraparenchymal pressure monitor (OR 1.86, CI 1.32-2.6, p < 0.001) to be independently associated with an increased likelihood of mortality regardless of GCS, while intraparenchymal oxygen monitoring was not (OR 0.47, CI 0.11-2.05, p = 0.316). The strongest effect was seen in those patients with a GCS of 5-6. CONCLUSION: ICP monitors are an independent risk factor for mortality, particularly with intraventricular drains and intraparenchymal monitors in patients with a GCS 5-6.

Non-Operative Management is More Cost-Effective than Immediate Operation in Perforated Appendicitis Patients with Seven or More Days of Symptoms.

BACKGROUND: Management of perforated appendicitis in children remains controversial. Nonoperative (NO) and immediate operative (IO) strategies are used with varying outcomes. We hypothesized that IO intervention for patients with perforated appendicitis would be more cost-effective than NO management. METHODS: A retrospective chart review of all patients with appendicitis from 2012 to 2015 was performed. Patients with perforated appendicitis were defined by evidence of perforation on imaging. We excluded patients who presented with sepsis, organ failure, and ventriculoperitoneal shunts. NO management was determined by surgeon preference. Univariate and multivariate analyses were performed. RESULTS: IO was performed on 145 patients with perforated appendicitis, whereas 83 were treated with NO management. Compared to IO patients, NO patients incurred higher overall costs, greater length of stay, more readmissions, complications, peripherally inserted central venous catheter lines, interventional radiology drains, and unplanned clinic and emergency department visits (P < 0.0001 for all). Multivariate analysis adjusting for age, days of symptoms, admission C-reactive protein and white blood cell count revealed that NO management was independently associated with increased costs (OR 1.35, 1.12-1.62, 95% CI). Cost curves demonstrated that total cost for IO surpasses that of NO management when patients present with greater than 6.3 d of symptoms (P = 0.01). CONCLUSIONS: Our data suggest that IO is more cost-effective than NO management for patients with perforated appendicitis who present with less than 6.3 d of symptoms, after which point, NO management is more cost-effective. LEVEL OF EVIDENCE: IV.

Ursodeoxycholic acid protects against intestinal barrier breakdown by promoting enterocyte migration via EGFR- and COX-2-dependent mechanisms.

The intestinal barrier is often disrupted in disease states, and intestinal barrier failure leads to sepsis. Ursodeoxycholic acid (UDCA) is a bile acid that may protect the intestinal barrier. We hypothesized that UDCA would protect the intestinal epithelium in injury models. To test this hypothesis, we utilized an in vitro wound-healing assay and a mouse model of intestinal barrier injury. We found that UDCA stimulates intestinal epithelial cell migration in vitro, and this migration was blocked by inhibition of cyclooxygenase 2 (COX-2), epidermal growth factor receptor (EGFR), or ERK. Furthermore, UDCA stimulated both COX-2 induction and EGFR phosphorylation. In vivo UDCA protected the intestinal barrier from LPS-induced injury as measured by FITC dextran leakage into the serum. Using 5-bromo-2'-deoxyuridine and 5-ethynyl-2'-deoxyuridine injections, we found that UDCA stimulated intestinal epithelial cell migration in these animals. These effects were blocked with either administration of Rofecoxib, a COX-2 inhibitor, or in EGFR-dominant negative Velvet mice, wherein UDCA had no effect on LPS-induced injury. Finally, we found increased COX-2 and phosphorylated ERK levels in LPS animals also treated with UDCA. Taken together, these data suggest that UDCA can stimulate intestinal epithelial cell migration and protect against acute intestinal injury via an EGFR- and COX-2-dependent mechanism. UDCA may be an effective treatment to prevent the early onset of gut-origin sepsis. NEW & NOTEWORTHY In this study, we show that the secondary bile acid ursodeoxycholic acid stimulates intestinal epithelial cell migration after cellular injury and also protects the intestinal barrier in an acute rodent injury model, neither of which has been previously reported. These effects are dependent on epidermal growth factor receptor activation and downstream cyclooxygenase 2 upregulation in the small intestine. This provides a potential treatment for acute, gut-origin sepsis as seen in diseases such as necrotizing enterocolitis.

Retrospective Cohort Comparison of Fall Height in Children in the Greater Los Angeles Area: Targeting Populations for Injury Prevention.

The purpose of this study was to determine whether falls from significant height occur more frequently in young children. We conducted a 10-year (2004-2014), comparative study using a retrospective cohort of 4713 children (< 18 years) from the Los Angeles county trauma database who were evaluated for a fall. Exposure was fall height, dichotomized into < 10 ft/low-risk fall and > 10 ft/high-risk fall. Primary outcome was age of fall. Secondary outcomes were disposition from emergency department, injuries, resource utilization, and mortality. Of all falls, 4481 (95%) were low-risk and 232 (5%) high-risk. High-risk falls were more frequent in children 1-3 years old (58 vs. 30%, p < 0.01), associated with higher frequency of intracranial hemorrhage (19 vs. 10%, p < 0.01), intubation (11 vs. 1%, p < 0.01), and neurosurgical procedure (2 vs. 0.8%, p = 0.04). There was no difference in mortality (0.86 vs. 0.13%, p = 0.06). In Los Angeles County, children 1-3 years old are most likely to suffer high-risk falls, which are associated with serious injury. Integration of fall prevention education into routine anticipatory guidance should be strongly considered for children 1-3 years old.

Screening for blunt cerebrovascular injuries in pediatric trauma patients.

BACKGROUND: Adult imaging for blunt cerebrovascular injuries (BCVI) is based on the Denver and Memphis screening criteria where CT angiogram (CTA) is performed for any one of the criteria being positive. These guidelines have been extrapolated to the pediatric population. We hypothesize that the current adult criteria applied to pediatrics lead to unnecessary CTA in pediatric trauma patients. STUDY DESIGN: At our center, a 9-year retrospective study revealed that strict adherence to the Denver and Memphis criteria would have resulted in 332 unnecessary CTAs out of 2795 trauma patients with only 0.3% positive for BCVI. We also conducted a retrospective chart review of 776,355 pediatric trauma patients in the National Trauma Data Bank (NTDB) from 2007 to 2014. Data collection included children between ages 0 and 18, ICD-9 search for blunt cerebrovascular injury, and ICD-9 codes that applied to both Denver and Memphis criteria. RESULTS: Of 776,355 pediatric trauma activations, 81,294 pediatric patients in the NTDB fit the Denver/Memphis criteria for screening CTA neck or angiography based on ICD-9 codes, while only 2136 patients suffered BCVI. Strict utilization of the Denver/Memphis criteria would have led to a negative CTA in 79,158 (97.4%) patients. Multivariate regression analysis indicates that patients with skull base fracture, cervical spine fractures, cervical spine fracture with cervical cord injury, traumatic jugular venous injury, and cranial nerve injury should be considered part of the screening criteria for BCVI. CONCLUSION: Our study suggests the Denver and Memphis criteria are inadequate screening criteria for CTA looking for BCVI in the pediatric blunt trauma population. New criteria are needed to adequately indicate the need for CT angiography in the pediatric trauma population. LEVEL OF EVIDENCE: IV.

Hospital admission unnecessary for successful uncomplicated radiographic reduction of pediatric intussusception.

PURPOSE: After radiologic reduction, patients with ileocolic intussusception are often admitted. We hypothesize that discharge of stable patients after 4 h of emergency department (ED) observation does not result in an increase of adverse outcomes. METHODS: We retrospectively reviewed pediatric patients with ileocolic intussusception between 2011 and 2016, managed with either 24-h inpatient or 4-h ED observation. Outcomes included length of stay, adverse outcomes, and total hospital charges. RESULTS: Fifty-one patients were managed with ED observation and 79 with inpatient observation. Recurrence rates, time to recurrence, and adverse outcomes were similar in both protocols. Total recurrence rates for ED observation was 15% versus 14% for inpatient observation. ED observation reduced time in the hospital by 26.8 h (4.9 versus 31.7 h). CONCLUSION: Discharging patients following uncomplicated hydrostatic reduction of ileocolic intussusception after a 4-h observation period does not result in an increase in adverse outcomes.

Influence of bronchoscopy on the diagnosis of and outcomes from ventilator-associated pneumonia.

BACKGROUND: Ventilator-associated pneumonia (VAP) is a common healthcare-associated infection affecting as many as 27% of mechanically ventilated patients. Ventilator-associated pneumonia is an important source of morbidity and mortality in the surgical intensive care unit (SICU). The optimal diagnostic method for VAP has remained controversial and the role of therapeutic bronchoscopy in the clearance of pulmonary secretions with VAP, in essence source control, remains unknown. Our unit utilizes bronchoscopy inconsistently for these purposes and we chose to evaluate its effectiveness in our patient population with the hypothesis that bronchoscopic diagnosis and therapy results in lower mortality rates and faster clinical resolution. METHODS: We analyzed retrospectively all patients treated for VAP in a single SICU between September 2003 and December 2011. Patients were divided into groups based upon diagnostic method and receipt of therapeutic bronchoscopy, and were analyzed for differences in time to clinical resolution and mortality. RESULTS: A total of 360 patients were included in the study, including 493 episodes of VAP. The diagnostic bronchoscopy group had statistically higher APACHE II scores (p=0.02) and fewer days in hospital prior to diagnosis (p=0.02) when compared with the non-invasive diagnosis group. Diagnostic bronchoscopy was associated with shorter length of stay and shorter duration of antibiotics whereas receipt of a therapeutic bronchoscopy was associated with the opposite effects by multivariable analysis. CONCLUSION: Our hypothesis was disproved and our findings are similar to those found in recent publications. This study supports no definitive conclusions, but further consideration of the role of bronchoscopy is urged in both the diagnosis and treatment of VAP. In our population, bronchoscopy for diagnostic or therapeutic purposes in VAP was not associated with better outcomes. However, differences in baseline characteristics suggest a randomized trial may be needed to answer more completely this question.