RESUMO
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.
RESUMO
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.
RESUMO
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.
Assuntos
Oxigenação por Membrana Extracorpórea , Recém-Nascido , Criança , HumanosRESUMO
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.
Assuntos
Enterocolite Necrosante , Sulfeto de Hidrogênio , Doenças do Recém-Nascido , Lesão Pulmonar , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Dissulfetos , Enterocolite Necrosante/tratamento farmacológico , Enterocolite Necrosante/metabolismo , Amarelo de Eosina-(YS)/metabolismo , Amarelo de Eosina-(YS)/farmacologia , Amarelo de Eosina-(YS)/uso terapêutico , Hematoxilina/metabolismo , Hematoxilina/farmacologia , Hematoxilina/uso terapêutico , Humanos , Hidrogênio/metabolismo , Hidrogênio/farmacologia , Hidrogênio/uso terapêutico , Sulfeto de Hidrogênio/metabolismo , Recém-Nascido , Doenças do Recém-Nascido/metabolismo , Recém-Nascido Prematuro , Interleucina-6/metabolismo , Mucosa Intestinal/metabolismo , Mesalamina/metabolismo , Mesalamina/farmacologia , Mesalamina/uso terapêutico , Camundongos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Sulfetos/metabolismo , Receptor 4 Toll-Like/metabolismo , Aumento de PesoRESUMO
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 Cyranoseâ 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 Cyranoseâ 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.
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Enterocolite Necrosante , Microbiota , Compostos Orgânicos Voláteis , Animais , Enterocolite Necrosante/diagnóstico , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Camundongos , RNA Ribossômico 16SRESUMO
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.
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Aorta/lesões , Procedimentos Cirúrgicos Vasculares , Lesões do Sistema Vascular/cirurgia , Adolescente , Criança , Pré-Escolar , Feminino , Hospitais Pediátricos , Humanos , Lactente , Escala de Gravidade do Ferimento , Tempo de Internação/estatística & dados numéricos , Masculino , Estudos RetrospectivosRESUMO
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.
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Sulfeto de Hidrogênio/metabolismo , Células-Tronco Mesenquimais/metabolismo , Comunicação Parácrina/fisiologia , Hipóxia Celular , Células Cultivadas , Quimiocinas/análise , Quimiocinas/metabolismo , Cistationina beta-Sintase/genética , Cistationina beta-Sintase/fisiologia , Cistationina gama-Liase/genética , Cistationina gama-Liase/fisiologia , Técnicas de Silenciamento de Genes , Humanos , Sulfeto de Hidrogênio/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular/análise , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Lipopolissacarídeos/farmacologia , Comunicação Parácrina/efeitos dos fármacos , Sulfurtransferases/genética , Sulfurtransferases/fisiologia , Transfecção , Fator de Necrose Tumoral alfa/farmacologiaAssuntos
Doença de Crohn/cirurgia , Duodenopatias/cirurgia , Fístula Intestinal/cirurgia , Veias Mesentéricas/cirurgia , Pancreaticoduodenectomia , Fístula Vascular/cirurgia , Adulto , Doença de Crohn/complicações , Duodenopatias/etiologia , Emergências , Feminino , Hemorragia Gastrointestinal/etiologia , Hemorragia Gastrointestinal/cirurgia , Humanos , Fístula Intestinal/etiologia , Fístula Vascular/etiologiaRESUMO
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 13â¯years and weighed more than 35â¯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.
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Cateterismo , Oxigenação por Membrana Extracorpórea , Padrões de Prática Médica/estatística & dados numéricos , Cirurgiões/estatística & dados numéricos , Cirurgia Assistida por Computador , Humanos , Cirurgia Assistida por Computador/métodos , Cirurgia Assistida por Computador/estatística & dados numéricos , Inquéritos e QuestionáriosRESUMO
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.
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Mucosa Intestinal/irrigação sanguínea , Isquemia Mesentérica/tratamento farmacológico , Inibidores da Fosfodiesterase 5/administração & dosagem , Traumatismo por Reperfusão/tratamento farmacológico , Citrato de Sildenafila/administração & dosagem , Animais , Modelos Animais de Doenças , Humanos , Injeções Intraperitoneais , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Masculino , Artéria Mesentérica Superior/cirurgia , Isquemia Mesentérica/complicações , Mesentério/irrigação sanguínea , Mesentério/efeitos dos fármacos , Camundongos , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/patologia , Resultado do TratamentoRESUMO
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 14â¯years with slight preponderance of females (52%) and a majority (75%) of the patients were African American (AA). Mean keloid size was 2.4â¯cm (0.25-11â¯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 2â¯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 23â¯months, with a slightly higher recurrence rate in AA patients (32%; pâ¯=â¯0.26) and in those ageâ¯<â¯10â¯years (50%; pâ¯=â¯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.
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Orelha Externa , Queloide , Adolescente , Orelha Externa/patologia , Orelha Externa/cirurgia , Feminino , Humanos , Queloide/epidemiologia , Queloide/patologia , Queloide/cirurgia , Masculino , Recidiva , Resultado do TratamentoRESUMO
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 24âh, 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 24âh 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.
Assuntos
Sulfeto de Hidrogênio/metabolismo , Intestinos/irrigação sanguínea , Isquemia/terapia , Transplante de Células-Tronco Mesenquimais , Animais , Técnicas de Silenciamento de Genes , Humanos , Intestinos/patologia , Isquemia/patologia , Masculino , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/metabolismo , Redes e Vias Metabólicas , Camundongos , Transfecção/métodosRESUMO
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.
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Artérias Carótidas/cirurgia , Doenças das Artérias Carótidas/cirurgia , Esvaziamento Cervical , Pescoço/irrigação sanguínea , Pescoço/cirurgia , Procedimentos Cirúrgicos Vasculares , Idoso , Perda Sanguínea Cirúrgica , Artérias Carótidas/diagnóstico por imagem , Artérias Carótidas/fisiopatologia , Doenças das Artérias Carótidas/diagnóstico por imagem , Doenças das Artérias Carótidas/fisiopatologia , Bases de Dados Factuais , Feminino , Fibrose , Humanos , Masculino , Pessoa de Meia-Idade , Pescoço/patologia , Esvaziamento Cervical/efeitos adversos , Duração da Cirurgia , Complicações Pós-Operatórias/etiologia , Doses de Radiação , Exposição à Radiação , Radioterapia/efeitos adversos , Fluxo Sanguíneo Regional , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Procedimentos Cirúrgicos Vasculares/efeitos adversos , Procedimentos Cirúrgicos Vasculares/instrumentaçãoRESUMO
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.
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Sulfeto de Hidrogênio/metabolismo , Células-Tronco Mesenquimais/fisiologia , Óxido Nítrico Sintase Tipo III/metabolismo , Circulação Esplâncnica/fisiologia , Vasodilatação/fisiologia , Adiponectina/metabolismo , Animais , Arteríolas/fisiologia , Cistationina beta-Sintase/metabolismo , Técnicas de Silenciamento de Genes , Humanos , Técnicas In Vitro , Masculino , Isquemia Mesentérica , Camundongos , Camundongos Endogâmicos C57BL , Resistina/metabolismoRESUMO
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.
Assuntos
Aneurisma/cirurgia , Artéria Celíaca/cirurgia , Procedimentos Endovasculares/métodos , Transplante de Rim/métodos , Isquemia Mesentérica/cirurgia , Oclusão Vascular Mesentérica/cirurgia , Neurofibromatose 1/complicações , Artéria Renal/cirurgia , Enxerto Vascular/métodos , Adolescente , Aneurisma/diagnóstico por imagem , Aneurisma/etiologia , Aneurisma/fisiopatologia , Angiografia Digital , Artéria Celíaca/diagnóstico por imagem , Artéria Celíaca/fisiopatologia , Feminino , Humanos , Isquemia Mesentérica/diagnóstico por imagem , Isquemia Mesentérica/etiologia , Isquemia Mesentérica/fisiopatologia , Oclusão Vascular Mesentérica/diagnóstico por imagem , Oclusão Vascular Mesentérica/etiologia , Oclusão Vascular Mesentérica/fisiopatologia , Neurofibromatose 1/diagnóstico , Artéria Renal/diagnóstico por imagem , Artéria Renal/fisiopatologia , Circulação Renal , Circulação Esplâncnica , Transplante Autólogo , Resultado do TratamentoRESUMO
INTRODUCTION: Umbilical mesenchymal stem cells (USC) have been shown to reduce illness in animal models of necrotizing enterocolitis (NEC), possibly through the paracrine release of hydrogen sulfide (H2S). We hypothesized that animals treated with USCs with inhibited H2S synthesis would exhibit more severe disease. METHODS: NEC was induced in five-day-old mouse pups by formula feeding and hypoxic and hypothermic stress. Experimental groups received intraperitoneal injection of either saline vehicle or 80,000cells/gram of one of the following cell types: USC, USCs with negative-control siRNA, or USCs with targeted siRNA inhibition of the H2S-producing enzymes. Pups were monitored by clinical assessment and after euthanasia, intestine and lung histologic injury were scored. Tissue was homogenized, and concentrations of IL-6, IL-10, and VEGF were determined by ELISA. For statistical analysis, p<0.05 was considered significant. RESULTS: Animals treated with negative-control siRNA USCs were significantly improved compared to vehicle. Clinical sickness scores as well as intestinal and lung histologic injury scores in the targeted siRNA groups were significantly worse when compared to the negative-control siRNA group. IL-6, IL-10, and VEGF had varying patterns of expression in the different groups. CONCLUSION: Inhibition of H2S production in USCs reduces the beneficial effects of these cells during therapy in experimental NEC. LEVEL OF EVIDENCE: Animal studies are typically described as "foundational evidence" without a true level assigned. TYPE OF STUDY: Animal Study.
Assuntos
Enterocolite Necrosante , Sulfeto de Hidrogênio , Células-Tronco Mesenquimais , Substâncias Protetoras , Cordão Umbilical/citologia , Animais , Modelos Animais de Doenças , Enterocolite Necrosante/metabolismo , Enterocolite Necrosante/fisiopatologia , Sulfeto de Hidrogênio/metabolismo , Sulfeto de Hidrogênio/farmacologia , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/fisiologia , Camundongos , Substâncias Protetoras/metabolismo , Substâncias Protetoras/farmacologiaRESUMO
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.
Assuntos
Interleucina-6/administração & dosagem , Mucosa Intestinal/efeitos dos fármacos , Isquemia Mesentérica/tratamento farmacológico , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Modelos Animais de Doenças , Humanos , Injeções Intraperitoneais , Mucosa Intestinal/patologia , Masculino , Artéria Mesentérica Superior/cirurgia , Isquemia Mesentérica/etiologia , Isquemia Mesentérica/patologia , Mesentério/irrigação sanguínea , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Recombinantes/administração & dosagem , Fluxo Sanguíneo Regional/efeitos dos fármacos , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/patologiaRESUMO
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.
Assuntos
Transtornos da Coagulação Sanguínea/terapia , Planejamento de Assistência ao Paciente , Ressuscitação/métodos , Ferimentos e Lesões/complicações , Antifibrinolíticos/uso terapêutico , Transtornos da Coagulação Sanguínea/diagnóstico , Transtornos da Coagulação Sanguínea/etiologia , Testes de Coagulação Sanguínea/métodos , Transfusão de Sangue/métodos , Criança , Humanos , Pediatria , Ácido Tranexâmico/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: Necrotizing enterocolitis (NEC) in premature infants is often a devastating surgical condition with poor outcomes. GYY4137 is a long-acting donor of hydrogen sulfide, a gasotransmitter that is protective against intestinal injury in experimental NEC, likely through protection against injury secondary to ischemia. We hypothesized that administration of GYY4137 would improve mesenteric perfusion, reduce intestinal injury, and reduce inflammatory responses in experimental NEC and ischemia-reperfusion injury, and that these benefits would be mediated through endothelial nitric oxide synthase-dependent pathways. METHODS: NEC was induced in C57BL/6 wild-type (WT) and endothelial nitric oxide synthase (eNOS) knockout (eNOSKO) pups via maternal separation, formula feeding, enteral lipopolysaccharide, and intermittent hypoxic and hypothermic stress. Pups received daily intraperitoneal injections of 50 mg/kg GYY4137 or phosphate buffered saline vehicle. In separate groups, adult male WT and eNOSKO mice underwent superior mesenteric artery occlusion for 60 min. Before abdominal closure, 50 mg/kg GYY4137 or phosphate buffered saline vehicle was administered into the peritoneal cavity. Laser doppler imaging was used to assess mesenteric perfusion of pups at baseline and on postnatal day 9, and the adult mice at baseline and 24 h after ischemic insult. After euthanasia, the terminal ileum of each animal was fixed, paraffin embedded, sectioned, and stained with hematoxylin and eosin. Sections were blindly graded using published injury scores. Intestinal tissue was homogenized and cytokines measured by ELISA. Data were compared using Mann-Whitney U test, and P-values <0.05 were significant. RESULTS: After NEC and ischemia reperfusion (I/R) injury, GYY4137 improved perfusion in WT mice compared to vehicle, but this effect was lost in the eNOSKO animals. Histologic injury followed a similar pattern with reduced intestinal injury in WT mice treated with GYY4137, and no significant improvement in the eNOSKO group. Cytokine expression after GYY4137 administration was altered by the ablation of eNOS in both NEC and I/R injury groups, with significant differences noted in Interleukin 6 and vascular endothelial growth factor. CONCLUSIONS: GYY4137, a long-acting donor of hydrogen sulfide, has potential as a therapeutic compound for NEC. It improves mesenteric perfusion and intestinal injury in experimental NEC and intestinal I/R injury, and these benefits appear to be mediated through eNOS-dependent pathways.