Principles and Practice in Pediatric Vascular Trauma: Part 2: Fundamental Vascular Principles, Pediatric Nuance, and Follow-up Strategies.

As of 2020, penetrating injuries became the leading cause of death among children and adolescents ages 1-19 in the United States. For those patients who survive and receive advanced medical care, vascular injuries are a significant cause of morbidity and trigger notable trauma team angst. Moreover, penetrating injuries can lead to life-threatening hemorrhage and/or limb-threatening ischemia if not addressed promptly. Vascular injury management demands timely and unique expertise, particularly for pediatric patients. In part 1 of this review, we discussed the scope and extent of the epidemic of traumatic vascular injuries in pediatric patients, reviewed current evidence and outcomes, discussed various challenges and advantages of a myriad of existing team structures, and outlined potential outcome targets and solutions. However, in order to optimize care for pediatric vascular trauma, we must also understand the fundamental best practice principles, surgical options and approaches, medical management, and recommendations for ongoing, outpatient follow-up. In part 2, we will address the best evidence, combined with expert consensus, regarding strategies for diagnosing, managing, and ongoing follow-up of vascular trauma, with particular focus on the nuances that define the unique approaches to pediatric patients. LEVEL OF EVIDENCE: n/a.

Principles and Practice in Pediatric Vascular Trauma: Part 1: Scope of Problem, Team Structure, Multidisciplinary Dynamics, and Solutions.

As of 2020, penetrating injuries became the leading cause of death among children and adolescents ages 1-19 in the United States. For the patients who initially survive and receive advanced medical care, vascular injuries are a significant cause of morbidity and additionally trigger notable trauma team angst. Moreover, penetrating injuries can lead to life-threatening hemorrhage and/or limb-threatening ischemia if not addressed promptly. Vascular injury management demands timely and unique expertise, particularly for pediatric patients. As the frequency of vascular injuries requiring operative management increases, it becomes clear that an ad hoc approach is not ideal. An integrated team would provide the best approach for rapid hemorrhage control and revascularization, but the structure of vascular response teams at children's hospitals is highly variable. In part 1 of this review, we will evaluate the scope and extent of the epidemic of traumatic vascular injuries in pediatric patients, review current evidence and outcomes, discuss various challenges and advantages of different team structures, and outline potential outcome targets and pediatric vascular trauma response solutions. LEVEL OF EVIDENCE: n/a.

Device updates in pediatric and neonatal ECMO.

Since the early use of extracorporeal life support (ECLS), new innovations and technological advancements have augmented the ability to use this technology in children and neonates. Cannulae have been re-designed to maintain structure and allow for single cannula venovenous (VV) ECLS in smaller patients. Circuit technology, including pumps and tubing, has evolved to permit smaller priming volumes and lower flow rates with fewer thrombotic or hemolytic complications. New oxygenator developments also improve efficiency of gas exchange. This paper serves as an overview of recent device developments in ECLS delivery to pediatric and neonatal patients.

A hydrogen-sulfide derivative of mesalamine reduces the severity of intestinal and lung injury in necrotizing enterocolitis through endothelial nitric oxide synthase.

Necrotizing enterocolitis (NEC) remains a devastating disease that affects preterm infants. Hydrogen sulfide (H2S) donors have been shown to reduce the severity of NEC, but the optimal compound has yet to be identified. We hypothesized that oral H2S-Mesalamine (ATB-429) would improve outcomes in experimental NEC, and its benefits would be dependent on endothelial nitric oxide synthase (eNOS) pathways. NEC was induced in 5-day-old wild-type (WT) and eNOS knockout (eNOSKO) pups by formula feeding and stress. Four groups were studied in both WT and eNOSKO mice: 1) breastfed controls, 2) NEC, 3) NEC + 50 mg/kg mesalamine, and 4) NEC + 130 mg/kg ATB-429. Mesalamine and ATB-429 doses were equimolar. Pups were monitored for sickness scores and perfusion to the gut was measured by Laser Doppler Imaging (LDI). After euthanasia of the pups, intestine and lung were hematoxylin and eosin-stained and scored for injury in a blind fashion. TLR4 expression was quantified by Western blot and IL-6 expression by ELISA. P < 0.05 was significant. Both WT and eNOSKO breastfed controls underwent normal development and demonstrated milder intestinal and pulmonary injury compared with NEC groups. For the WT groups, ATB-429 significantly improved weight gain, reduced clinical sickness score, and improved perfusion compared with the NEC group. In addition, WT ATB-429 pups had a significantly milder intestinal and pulmonary histologic injury when compared with NEC. ATB-429 attenuated the increase in TLR4 and IL-6 expression in the intestine. When the experiment was repeated in eNOSKO pups, ATB-429 offered no benefit in weight gain, sickness scores, perfusion, intestinal injury, pulmonary injury, or decreasing intestinal inflammatory markers. An H2S derivative of mesalamine improves outcomes in experimental NEC. Protective effects appear to be mediated through eNOS. Further research is warranted to explore whether ATB-429 may be an effective oral therapy to combat NEC.

The assessment of microbiome changes and fecal volatile organic compounds during experimental necrotizing enterocolitis.

INTRODUCTION: Necrotizing enterocolitis (NEC) remains a devastating disease that affects the gastrointestinal tract of the preterm infant. Volatile organic compounds (VOCs) have emerged as a non-invasive biomarker in many diseases. We hypothesized that fecal VOC profiles would be significantly different between control and NEC pups in a NEC mouse model. METHODS: Experimental NEC was induced in five-day-old mice. Breastfed and formula-fed control groups were also studied. After four days, pups were euthanized and intestines were H&E stained and blindly scored. Stool microbiome analysis was performed via 16S rRNA sequencing. VOC analysis was assessed by the CyranoseⓇ 320 eNose device and p<0.05 was significant. RESULTS: NEC pups had severe intestinal injury when compared to controls. Microbiome analysis showed that both control groups had significantly higher microbial diversity and relative abundance of Lactobacillus than NEC, and lower relative abundance of Escherichia. Fecal VOC profile for NEC pups was significantly different from controls. CONCLUSIONS: Experimental NEC was associated with intestinal dysbiosis. Fecal VOC analysis by the CyranoseⓇ 320 eNose device can discriminate NEC pups from both breastfed and formula-fed controls. Further research is warranted to establish whether fecal VOCs can be used as a biomarker or predictive algorithm to diagnose NEC.

Operative Traumatic Aortic Injuries at an Urban Pediatric Hospital.

PURPOSE: Limited data are available describing the long-term results of pediatric patients undergoing aortic repair secondary to trauma. Therefore, this descriptive investigation was completed to abrogate this deficit. METHODS: A retrospective review of an urban level 1 pediatric trauma database maintained at a high-volume dedicated children's hospital between 2008-2018 was completed to capture all cases of severe traumatic aortic injury and associated demographics, mechanisms, injury severity, treatment, and clinical outcomes. RESULTS: In the prespecified interval, 2189 children (age <18 years) presented to our facility as a level 1 trauma activation. Of these cases, a total of 10 patients (.5%) had a demonstrable thoracic or abdominal aortic injury. The mean age of our study cohort was 10.4 ± 5.7 years. The mechanism of injury consisted of 8 participants involved in motor vehicle accidents, 1 pedestrian struck by a vehicle, and 1 struck by a falling boulder. Injuries were identified via CT angiogram (n = 9) or autopsy (n = 1) and consisted of 6 thoracic aortas and 4 abdominal aortas. The mean trauma injury severity score was 37.6 ± 19.9. Seven of the patients underwent open surgical intervention, 1 underwent endovascular intervention, 1 was treated with medical management, and 1 patient expired in the trauma bay before surgery could be performed. Aortic pathologies observed were 6 transections, 2 dissections, and 2 occlusions. Five of the ten patients underwent nonaortic surgical procedures. To determine operative outcomes, we excluded the 2 patients who did not receive aortic intervention. In the 8 remaining patients, the mean hospital length of stay was 12.8 ± 4.8 days with 6.8 ± 4.1 days in the intensive care unit. All 9 participants who survived the initial trauma evaluation were discharged from the hospital. Mean follow-up was 38.3 ± 43.0 months; during which, we observed no additional aortic-related morbidity, mortality, and reinterventions. The only stent-graft deployed remained in stable position without evidence of endoleak or migration by duplex. CONCLUSION: Traumatic aortic injury is exceedingly rare in children and primarily of blunt etiology. Of the patients who survive the scene, operative repair seems to be associated with excellent perioperative and long-term survival.

Human Mesenchymal Stem Cell Hydrogen Sulfide Production Critically Impacts the Release of Other Paracrine Mediators After Injury.

BACKGROUND: The use of mesenchymal stem cells (MSCs) for treatment during ischemia is novel. Hydrogen sulfide (H2S) is an important paracrine mediator that is released from MSCs to facilitate angiogenesis and vasodilation. Three enzymes, cystathionine-beta-synthase (CBS), cystathionine-gamma-lyase (CSE), and 3-mercaptopyruvate-sulfurtransferase (MPST), are mainly responsible for H2S production. However, it is unclear how these enzymes impact the production of other critical growth factors and chemokines. We hypothesized that the enzymes responsible for H2S production in human MSCs would also critically regulate other growth factors and chemokines. MATERIALS AND METHODS: Human MSCs were transfected with CBS, MPST, CSE, or negative control small interfering RNA. Knockdown of enzymes was confirmed by polymerase chain reaction. Cells were plated in 12-well plates at 100,000 cells per well and stimulated with tumor necrosis factor-α (TNF-α; 50 ng/mL), lipopolysaccharide (LPS; 200 ng/mL), or 5% hypoxia for 24 h. Supernatants were collected, and cytokines measured by multiplex beaded assay. Data were compared with the Mann-Whitney U-test, and P < 0.05 was significant. RESULTS: TNF-α, LPS, and hypoxia effectively stimulated MSCs. Granulocyte colony-stimulating factor (GCSF), epidermal growth factor, fibroblast growth factor, granulocyte/monocyte colony-stimulating factor (GMCSF), vascular endothelial growth factor, and interferon gamma-inducible protein 10 were all significantly elevated when CSE was knocked down during TNF-α stimulation (P < 0.05). Knockdown of MPST during LPS stimulation more readily increased GCSF and epidermal growth factor but decreased GMCSF (P < 0.05). CBS knockdown decreased production of GCSF, fibroblast growth factor, GMCSF, and vascular endothelial growth factor (P < 0.05) after hypoxia. CONCLUSIONS: The enzymes that produce H2S in MSCs are also responsible for the production of other stem cell paracrine mediators under stressful stimuli. Therefore, reprogramming MSCs to endogenously produce more H2S as a therapeutic intervention could also critically impact other paracrine mediators, which may alter the desired beneficial effects.

Practice patterns in imaging guidance for ECMO cannulation: A survey of the American Pediatric Surgical Association.

BACKGROUND: Surgeon-specific variations in pediatric extracorporeal membrane oxygenation (ECMO) cannulation technique are not well characterized. Advances in technology have led to changing techniques with no formal consensus statement for reference. METHODS: A survey was e-mailed to 1301 members of the American Pediatric Surgical Association (APSA). Categorical data was compared with Chi-squared and Kendall's tau-ß tests, and multiple column comparisons were performed with the Bonferroni correction. RESULTS: Response rate was 19%, with 248 pediatric general surgeons responding to the survey. 89.4% of respondents stated that cannulation was typically performed in the ICU. Venoarterial (VA) ECMO cannulation was more often performed open (88.6%) than venovenous (VV) ECMO (42.2%). Surgeons cannulate for VA ECMO and VV ECMO without imaging guidance 44% and 21.5% of the time, respectively. There was no difference in estimated rate of cannula repositioning by cannulation strategy. For venous and arterial cannulation in VA ECMO, surgeons were more likely to use the femoral as opposed to the neck when children were older than 13 years and weighed more than 35 kg regardless of the presence or absence of preexisting femoral arterial or venous access. CONCLUSION: Practice patterns for ECMO cannulation are variable among pediatric surgeons. Standardization could reduce the occurrence of unsafe practices and potentially decrease complications and improve patient outcomes. LEVEL OF EVIDENCE: Level IV.

Sildenafil as a Rescue Agent Following Intestinal Ischemia and Reperfusion Injury.

BACKGROUND: Acute mesenteric ischemia carries a significant morbidity. Measures to improve blood flow parameters to the intestine may ameliorate the disease. Sildenafil, a phosphodiesterase 5 inhibitor, increases cyclic guanosine monophosphate and has been shown to prevent the effects of ischemia when given before injury. However, its effects as a rescue agent have not been established. We therefore hypothesized that sildenafil, when given as a rescue agent for intestinal ischemia, would improve mesenteric perfusion, limit intestinal epithelial injury, and decrease intestinal leukocyte chemoattractants. METHODS: Eight to 12 wk-old-male C57BL/6J mice underwent laparotomy and temporary occlusion of the superior mesenteric artery for 60 min. Following ischemia, reperfusion was permitted, and before closing the abdomen, sildenafil was injected intraperitoneally in a variety of concentrations. After 24 h, reperfusion was reassessed. Animals were euthanized and intestines evaluated for histologic injury and leukocyte chemoattractants. RESULTS: Postischemic administration of sildenafil did not improve mesenteric perfusion following intestinal ischemia and reperfusion injury. However, sildenafil did improve histologic injury scores in dose ranges of 0.01 to 10 mg/kg. No difference was noted in histological injury with 100 mg/kg dose, and all members of the 1000 mg/kg group died within 24 h of injury. Epithelial protection was not facilitated by the leukocyte chemoattractants Regulated on Activation, Normal T Cell Expressed, and Secreted, macrophage inflammatory protein 1 alpha, monocyte chemoattractant protein, neutrophil activating protein, or granulocyte colony stimulating factor. CONCLUSIONS: Administration of sildenafil following intestinal ischemia may limit intestinal mucosal injury but does not appear to alter mesenteric perfusion or leukocyte chemoattractant influx. TYPE: Basic science. LEVEL OF EVIDENCE: N/A.

Extended hypoxia-mediated H2 S production provides for long-term oxygen sensing.

AIM: Numerous studies have shown that H2 S serves as an acute oxygen sensor in a variety of cells. We hypothesize that H2 S also serves in extended oxygen sensing. METHODS: Here, we compare the effects of extended exposure (24-48 hours) to varying O2 tensions on H2 S and polysulphide metabolism in human embryonic kidney (HEK 293), human adenocarcinomic alveolar basal epithelial (A549), human colon cancer (HTC116), bovine pulmonary artery smooth muscle, human umbilical-derived mesenchymal stromal (stem) cells and porcine tracheal epithelium (PTE) using sulphur-specific fluorophores and fluorometry or confocal microscopy. RESULTS: All cells continuously produced H2 S in 21% O2 and H2 S production was increased at lower O2 tensions. Decreasing O2 from 21% to 10%, 5% and 1% O2 progressively increased H2 S production in HEK293 cells and this was partially inhibited by a combination of inhibitors of H2 S biosynthesis, aminooxyacetate, propargyl glycine and compound 3. Mitochondria appeared to be the source of much of this increase in HEK 293 cells. H2 S production in all other cells and PTE increased when O2 was lowered from 21% to 5% except for HTC116 cells where 1% O2 was necessary to increase H2 S, presumably reflecting the hypoxic environment in vivo. Polysulphides (H2 Sn , where n = 2-7), the key signalling metabolite of H2 S also appeared to increase in many cells although this was often masked by high endogenous polysulphide concentrations. CONCLUSION: These results show that cellular H2 S is increased during extended hypoxia and they suggest this is a continuously active O2 -sensing mechanism in a variety of cells.

Stem Cell Therapy and Hydrogen Sulfide: Conventional or Nonconventional Mechanisms of Action?

PURPOSE: Hydrogen sulfide (H2S) has many beneficial biological properties, including the ability to promote vasodilation. It has been shown to be released from stem cells and increased by hypoxia. Therefore, H2S may be an important paracrine factor in stem cell-mediated intestinal protection. We hypothesized that H2S created through conventional pathways would be a critical component of stem cell-mediated intestinal protection after ischemic injury. METHODS: Human bone marrow-derived mesenchymal stem cells (BMSCs) were transfected with negative control siRNA (Scramble), or with siRNA to CBS, MPST, or CTH. Knockdown was confirmed with PCR and H2S gas assessed with AzMC fluorophore. Eight-week-old male mice then underwent intestinal ischemia for 60 min, after which time, perfusion was restored. BMSCs from each of the above groups were then placed into the mouse abdominal cavity before final closure. After 24 h, mice were reanesthetized and mesenteric perfusion was assessed by Laser Doppler Imaging (LDI). Animals were then sacrificed and intestines excised, placed in formalin, paraffin embedded, and stained with H & E. Intestines were then scored with a common mucosal injury grading scale. RESULTS: PCR confirmed knockdown of conventional H2S-producing enzymes (CBS, MPST, CTH). H2S gas was decreased in MPST and CTH-transfected cells in normoxic conditions, but was not decreased compared with Scramble in any of the transfected groups in hypoxic conditions. BMSCs promoted increased mesenteric perfusion at 24 h postischemia compared with vehicle. Transfected stem cells provided equivalent protection. Histologic injury was improved with BMSCs compared with vehicle. CBS, MPST, and CTH knockdown cell lines did not have any worse histological injury compared with Scramble. CONCLUSIONS: Knocking down conventional H2S-producing enzymes only impacted gas production in normoxic conditions. When cells were transfected in hypoxic conditions, as would be expected in the ischemic intestines, H2S gas was not depressed. These data, along with unchanged perfusion and histological injury parameters with conventional enzyme knockdown, would indicate that alternative H2S production pathways may be initiated during hypoxic and/or ischemic events.

Pediatric earlobe keloids: Outcomes and patterns of recurrence.

PURPOSE: Keloids occur as a result of abnormal wound healing and as many as 70% of keloids and hypertrophic scars affect the pediatric population. Earlobe keloids, similar to lesions elsewhere in the body, remain a challenging problem given the high rates of recurrence and lack of consensus regarding treatment strategy. This study aims to evaluate the outcomes and patterns of recurrences following treatment of earlobe keloids in a large cohort of pediatric patients to facilitate identification of the optimal treatment strategy. METHODS: All pediatric patients who underwent surgical therapy for earlobe keloids over a 10-year period (2004-2015) were identified and demographic, clinical and outcomes data were collected. A follow-up phone survey was administered to assess rates of long-term recurrence and overall satisfaction with the treatment strategy. Data analysis was performed using Student's t-test and Fisher's exact as appropriate. RESULTS: A total of 94 patients with 135 keloids were identified. Mean age was 14 years with slight preponderance of females (52%) and a majority (75%) of the patients were African American (AA). Mean keloid size was 2.4 cm (0.25-11 cm) with ear piercing being the most common inciting etiology. Excision with steroid injection (59%) was the most frequent treatment approach followed by excision alone (25%). During a median follow up of 2 years, keloid recurrence occurred in 27 (28.7%) patients, 19 (70.4%) underwent additional therapy with 10 (52.6%) re-recurrences noted. Median time to recurrence was 23 months, with a slightly higher recurrence rate in AA patients (32%; p = 0.26) and in those age < 10 years (50%; p = 0.11). CONCLUSION: This represents the largest series of earlobe keloids treatment in children. Our data suggest that recurrence rates are unaffected by the age at excision and race of the patient. Moreover, adjuncts to excisional therapy such as steroid injection, compression therapy and radiation also did not appear to influence recurrence. Given the pattern of recurrences studies with longer term follow-up are needed to assess the efficacy of treatment strategies. TYPE OF STUDY: Case series. LEVEL OF EVIDENCE: IV.

Procedural Complexity of TransCarotid Artery Revascularization Is Not Increased in Irradiated and Reoperative Necks.

BACKGROUND: TransCarotid Revascularization (TCAR) with dynamic flow reversal using the ENROUTE Neuroprotection System (ENPS) is a Food and Drug Administration-approved alternative carotid revascularization modality. The purpose of this investigation was to determine whether TCAR in a hostile (fibrotic) surgical field increases procedural complexity and postoperative complications. METHODS: Perioperative variables for all institutional TCARs performed between December 2015 and April 2019 were prospectively captured. Procedures performed as part of the ongoing ROADSTER-2 registry were excluded. Univariate analysis, consisting of Student's T and Fisher's exact testing, comparing virgin and hostile neck TCAR, was performed at an alpha of 0.05. RESULTS: During the study period, 149 total procedures (n = 30, hostile ipsilateral necks) qualified for inclusion. Both hostile and virgin neck groups were comparable with respect to preoperative comorbidities and medication profiles. The ipsilateral hostile neck cohort consisted of ten patients who underwent previous ipsilateral neck radiation and 23 who were status after neck dissection (3 had both). Intraoperatively, there were no differences with respect to estimated blood loss (47.2 vs. 44.8 mL, P = 0.81), operative time (69.5 vs. 74.5 min, P = 0.38), reverse flow time (12.4 vs. 10.4 min, P = 0.34), radiation exposure (217.7 vs. 226.2 mGy, P = 0.88), fluoroscopy time (5.4 vs. 5.0 min, P = 0.65), contrast usage (23.5 vs. 25.0 mL, P = 0.55), and ability to achieve technical success (96.7% vs. 100%, P = 0.58) between virgin and hostile necks, respectively. Perioperative (30-day) ipsilateral stroke and death rate was 2.5% vs. 0% (P = 1.0) and 2.5% vs. 0% (P = 1.0), respectively, between virgin and hostile necks. We observed one postoperative cranial nerve injury in any of our TCAR patients (hostile neck, P = 0.20). Finally, a total of 3 hematomas (requiring washout) occurred in our (2 in virgin necks and one in a hostile neck) surgical cohort (P = 0.49). CONCLUSIONS: Based on this limited, small series, TCAR in hostile surgical fields is not associated with an increase in case complexity and maintains a similar perioperative risk to virgin field procedures.

Mesenchymal stem cells promote mesenteric vasodilation through hydrogen sulfide and endothelial nitric oxide.

Mesenteric ischemia is a devastating process that can result in intestinal necrosis. Mesenchymal stem cells (MSCs) are becoming a promising treatment modality. We hypothesized that 1) MSCs would promote vasodilation of mesenteric arterioles, 2) hydrogen sulfide (H2S) would be a critical paracrine factor of stem cell-mediated vasodilation, 3) mesenteric vasodilation would be impaired in the absence of endothelial nitric oxide synthase (eNOS) within the host tissue, and 4) MSCs would improve the resistin-to-adiponectin ratio in mesenteric vessels. H2S was measured with a specific fluorophore (7-azido-3-methylcoumarin) in intact MSCs and in cells with the H2S-producing enzyme cystathionine ß synthase (CBS) knocked down with siRNA. Mechanical responses of isolated second- and third-order mesenteric arteries (MAs) from wild-type and eNOS knockout (eNOSKO) mice were monitored with pressure myography, after which the vessels were snap frozen and later analyzed for resistin and adiponectin via multiplex beaded assay. Addition of MSCs to the myograph bath significantly increased vasodilation of norepinephrine-precontracted MAs. Knockdown of CBS in MSCs decreased H2S production by MSCs and also decreased MSC-initiated MA dilation. MSC-initiated vasodilation was further reduced in eNOSKO vessels. The MA resistin-to-adiponectin ratio was higher in eNOSKO vessels compared with wild-type. These results show that MSC treatment promotes dilation of MAs by an H2S-dependent mechanism. Furthermore, functional eNOS within the host mesenteric bed appears to be essential for maximum stem cell therapeutic benefit, which may be attributable, in part, to modifications in the resistin-to-adiponectin ratio.NEW & NOTEWORTHY Stem cells have been shown to improve survival, mesenteric perfusion, and histological injury scores following intestinal ischemia. These benefits may be due to the paracrine release of hydrogen sulfide. In an ex vivo pressure myography model, we observed that mesenteric arterial dilation improved with stem cell treatment. Hydrogen sulfide release from stem cells and endothelial nitric oxide synthase within the vessels were critical components of optimizing stem cell-mediated mesenteric artery dilation.

Renal Autotransplant and Celiac Artery Bypass for Aneurysmal Degeneration Related to Neurofibromatosis Type 1.

We present a case of an 18-year-old female with neurofibromatosis type 1 who presented with abdominal pain and weight loss secondary to chronic mesenteric ischemia due to celiac axis occlusion and was subsequently found to have multiple visceral artery aneurysms. Of clinical significance, 2 aneurysms of the right renal artery were noted at the hilum, with the larger one having a diameter of 2.4 cm. After initial endovascular treatment with stenting of a concurrent pancreaticoduodenal artery pseudoaneurysm, staged aorto-hepatic bypass and right nephrectomy with renal autotransplantation after back table resection of the aneurysmal segments were successfully completed.

Pediatric trauma-related coagulopathy: Balanced resuscitation, goal-directed therapy and viscoelastic assays.

The improved understanding of trauma-induced coagulopathy in adults has led to an evolution in the strategies of damage-control resuscitation. While its impact on the care of pediatric trauma patients is of tremendous interest, the evidence is sparse, and a great deal of research is still needed in this domain. Areas of particular interest include age-related differences in hemostasis and balanced resuscitation, advances in functional coagulation assays and effective adjunctive medications, such as tranexamic acid, for hemorrhage control. This review examines the available pediatric data, reviews applicable adult data, and introduces areas of investigation that will impact pediatric trauma care in the future.

Interleukin-6 Therapy Improves Intestinal Recovery Following Ischemia.

BACKGROUND: Interleukin-6 (IL6) has both proinflammatory and anti-inflammatory pathways, but its effects on intestinal recovery following ischemia are unknown. We hypothesized that administration of IL6 following intestinal ischemia would improve mesenteric perfusion and mucosal injury. METHODS: Adult male C57Bl6J mice were anesthetized, and a laparotomy was performed. Baseline intestinal perfusion was assessed by laser Doppler imaging. Intestinal ischemia was induced for 60 min by temporarily occluding the superior mesenteric artery. After ischemia, treatments were administered intraperitoneally before closure (Vehicle: 250 µL phosphate-buffered-saline, IL6 low dose (20 ng), IL6 medium dose (200 ng), or IL6 high dose (2 µg)). Animals were allowed to recover for 24 h, were reanesthetized, and their mesenteric perfusion was reassessed. Perfusion was expressed as percentage of baseline. Animals were then sacrificed, and the intestines were explanted for histological analysis. Separate frozen samples were homogenized and analyzed by ELISA for vascular endothelial growth factor (VEGF) and interferon gamma-induced protein 10. RESULTS: IL6 increased mesenteric perfusion in low dose groups only, whereas it improved postischemic mucosal injury scores in both low and medium dose groups. No differences in perfusion or histology were seen when high dose IL6 was utilized. Intestinal VEGF was higher in the low dose IL6 group compared to vehicle, whereas IP-10 levels were lower in low and medium dose groups compared to vehicle. No differences were noted compared to vehicle in intestinal VEGF and IP-10 with high dose IL6 therapy. CONCLUSIONS: Lower doses of IL6 may serve as effective therapy to decrease intestinal injury after ischemia. Further studies are needed to elucidate the downstream mechanisms before widespread clinical use.

Characterization, Dynamics, and Mechanism of CXCR4 Antagonists on a Constitutively Active Mutant.

The G protein-coupled receptor (GPCR) CXCR4 is a co-receptor for HIV and is involved in cancers and autoimmune diseases. We characterized five purine or quinazoline core polyamine pharmacophores used for targeting CXCR4 dysregulation in diseases. All were neutral antagonists for wild-type CXCR4 and two were biased antagonists with effects on ß-arrestin-2 only at high concentrations. These compounds displayed various activities for a constitutively active mutant (CAM). We use the IT1t-CXCR4 crystal structure and molecular dynamics (MD) simulations to develop two hypotheses for the activation of the N1193.35A CAM. The N1193.35A mutation facilitates increased coupling of TM helices III and VI. IT1t deactivates the CAM by disrupting the coupling between TM helices III and VI, mediated primarily by residue F872.53. Mutants of F872.53 in N1193.35A CXCR4 precluded constitutive signaling and prevented inverse agonism. This work characterizes CXCR4 ligands and provides a mechanism for N1193.35A constitutive activation.