nogrЭкспериментальная и клиническая гастроэнтерологияExperimental and Clinical Gastroenterology1682-8658«Global Media Technologies»10.31146/1682-8658-ecg-219-11-81-101nogr-2604Research ArticleЭКСПЕРИМЕНТАЛЬНАЯ ГАСТРОЭНТЕРОЛОГИЯEXPERIMENTAL GASTROENTEROLOGYБиохимические маркеры и предикторы развития некротизирующего энтероколита у новорожденных с дуктус-зависимыми врожденными пороками сердца, перенесших кардиохирургическое лечение: когортное исследованиеBiomarkers and predictors of postoperative necrotizing enterocolitis in neonates with duct-dependent congenital heart defects undergoing cardiac surgery: a cohort studyhttps://orcid.org/0000-0001-6939-6961КаплинаА. В.KaplinaA. V.kaplinashi@gmail.comhttps://orcid.org/0000-0002-0141-6986КаюмоваЕ. Е.KayumovaE. E.noemail@neicon.ruВасильеваЕ. Ю.Vasil'evaE. Yu.noemail@neicon.ruhttps://orcid.org/0000-0001-7336-4102ВасичкинаЕ. С.VasichkinaE. S.noemail@neicon.ruhttps://orcid.org/0000-0001-9948-7303ПервунинаТ. М.PervuninaT. M.noemail@neicon.ruШемякинаО. О.ShemyakinaO. O.noemail@neicon.ruГурьяноваН. А.GuryanovaN. A.noemail@neicon.ruКиселеваН. С.KiselevaN. S.noemail@neicon.ruhttps://orcid.org/0000-0003-2387-4344СкоробогатоваЮ. В.SkorobogatovaYu. V.noemail@neicon.ruПелевинаЕ. В.PelevinaE. V.noemail@neicon.ruЕфимоваЕ. В.EfimovaE. V.noemail@neicon.ruНовикЭ. В.NovikE. V.noemail@neicon.ruВалееваО. Н.ValeevaO. N.noemail@neicon.ruМалородоваА. Н.MalorodovaA. N.noemail@neicon.ruhttps://orcid.org/0000-0002-0479-0850ПетроваН. А.PetrovaN. A.noemail@neicon.ruФедеральное государственное бюджетное учреждение «Национальный медицинский исследовательский центр имени В.А. Алмазова» Министерства здравоохранения Российской ФедерацииРоссияAlmazov National Medical Research CentreRussian Federation20232603202401181101Copyright © Каплина А.В., Каюмова Е.Е., Васильева Е.Ю., Васичкина Е.С., Первунина Т.М., Шемякина О.О., Гурьянова Н.А., Киселева Н.С., Скоробогатова Ю.В., Пелевина Е.В., Ефимова Е.В., Новик Э.В., Валеева О.Н., Малородова А.Н., Петрова Н.А., 20242024Каплина А.В., Каюмова Е.Е., Васильева Е.Ю., Васичкина Е.С., Первунина Т.М., Шемякина О.О., Гурьянова Н.А., Киселева Н.С., Скоробогатова Ю.В., Пелевина Е.В., Ефимова Е.В., Новик Э.В., Валеева О.Н., Малородова А.Н., Петрова Н.А.Kaplina A.V., Kayumova E.E., Vasil'eva E.Y., Vasichkina E.S., Pervunina T.M., Shemyakina O.O., Guryanova N.A., Kiseleva N.S., Skorobogatova Y.V., Pelevina E.V., Efimova E.V., Novik E.V., Valeeva O.N., Malorodova A.N., Petrova N.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.nogr.org/jour/article/view/2604

Развитие некротизирующего энтероколита (НЭК) у новорожденных с дуктус-зависимыми врожденными пороками сердца (ВПС), перенесших кардиохирургическое лечение, сопровождается высокой летальностью. Анализ предикторов НЭК у новорожденных с дуктус-зависимыми ВПС необходим для понимания патогенеза НЭК, разработки подходов к профилактике и достижения более благоприятных исходов кардиохирургического лечения. Цель исследования: разработка модели прогнозирования развития НЭК у новорожденных после кардиохирургического лечения дуктус-зависимых ВПС. Материалы и методы. Выполнено прогностическое когортное исследование, включавшее доношенных новорожденных с дуктус-зависимыми ВПС, которым выполнено кардиохирургическое лечение в ФГБУ «НМИЦ им. В.А. Алмазова» с января 2021 г. по сентябрь 2023 г. Исходом являлось развитие / отсутствие развития НЭК IB-III стадии в послеоперационном периоде. Проведен иммуноферментный анализ уровней биохимических маркеров НЭК (кишечный белок, связывающий жирные кислоты (i-FABP, нг/мл), клаудин-3 (CLDN3, нг/мл), кальпротектин (CALPR, нг/мл), ишемией модифицированный альбумин (IMA, нг/мл), сосудистый эндотелиальный фактор роста А (VEGF A, пг/мл)) перед коррекцией ВПС и в 1 сутки (через 12-14 часов) после операции. Оценивались клинические характеристики, показатели С-реактивного белка, клинического анализа крови, данные ультразвукового исследования органов брюшной полости (УЗИ ОБП), фракция выброса левого желудочка / единственного желудочка сердца (ЕЖ/ЕЖС) (%, по Тейхольцу) в дооперационном и раннем послеоперационном периодах, параметры операции, P(v-a)CO2/C(a-v)O2 при поступлении из операционной, вазоактивный инотропный индекс (ВИИ) и уровень лактата артериальной крови в первые 24 ч после операции. Ассоциация между предикторами и развитием НЭК после кардиохирургического лечения оценивалась при помощи логистического регрессионного анализа. Внутренняя проверка модели проводилась при помощи 10-кратной перекрестной проверки. Результаты. В период наблюдения оперативное лечение дуктус-зависимых ВПС перенесли 187 новорожденных, из них у 32 детей развился НЭК IB-III стадий в послеоперационном периоде (17,1%), оперативное лечение НЭК потребовалось двум детям (6,3%). После соблюдения критериев невключения и исключения сформирована основная группа (30 детей, у которых развился НЭК IB-III стадий в послеоперационном периоде, из них НЭК III стадии у 1 ребенка) и группа сравнения (40 детей без НЭК). При однофакторном анализе предикторами НЭК являлись задержка внутриутробного развития (ЗВУР), искусственное вскармливание до операции, большие уровни IMA до и в 1 сутки после операции, проведение процедур до коррекции ВПС (процедура Рашкинда / вальвулопластика / стентирование), более низкая фракция выброса ЛЖ / ЕЖС в раннем послеоперационном периоде, больший максимальный уровень ВИИ в первые 24 часа после операции, а также больший уровень индекса резистивности кровотока в верхней брыжеечной артерии (IR ВБА) и утолщение кишечной стенки в 1 сутки после операции. Независимые дооперационные предикторы НЭК (AUC модели 0,885, специфичность 0,867): задержка внутриутробного развития (ЗВУР) (ОШ 32,2 (1,4-730,3), p=0,029), искусственное вскармливание (ОШ 12,6 (2,6-60,2), p=0,002), более высокие уровни IMA (ОШ 1,03 (1,01-1,04), p=0,004), низкие уровни CLDN3 (ОШ 0,5 (0,3-0,9), p=0,013). Независимые послеоперационные предикторы НЭК: уровни IMA (ОШ 1,02 (1,01-1,03), p=0,030), P(v-a)CO2/C(a-v)O2 (ОШ 2,3 (1,2-4,4), p=0,008), также IR ВБА>0,93 (ОШ 7,2 (1,6-32,4), p=0,011) и утолщение кишечной стенки в 1 сутки после операции (ОШ 4,9 (1,3-19,2), p=0,021), специфичность модели повышало добавление VEGF A в качестве предиктора (отрицательно ассоциировался с развитием НЭК), но предиктор не являлся значимым. С учетом трансформации данных модели: AUC=0,862, специфичность 0,800. Модель с учетом дооперационных (ЗВУР, искусственное вскармливание) и послеоперационных предикторов (IMA, P(v-a)CO2/C(a-v)O2, IR>0.93 в ВБА, утолщение кишечной стенки) имела высокую прогностическую ценность (AUC=0,921, специфичность 0,83). Заключение. Выявленные независимые предикторы косвенно свидетельствуют о синергичном влиянии искусственного вскармливания, ЗВУР и гипоксии на повышение риска развития НЭК в послеоперационном периоде у доношенных новорожденных с дуктус-зависимыми ВПС. Питание грудным молоком / смешанное вскармливание в дооперационном периоде может способствовать снижению риска НЭК в послеоперационном периоде. Низкие уровни CLDN3 до операции ассоциировались с развитием НЭК, однако трактовка результата неоднозначна.

The development of necrotizing enterocolitis (NEC) in neonates with duct-dependent congenital heart defects (CHD) who underwent cardiac surgery is accompanied by high mortality. Analysis of predictors is necessary for understanding the pathophysiology of NEC and development of approaches for prevention to achieve favorable outcomes of cardiac surgery. The purpose of the study was to develop a prognostic model for predicting the development of NEC after cardiac surgery in neonates with duct-dependent CHD. Methods. A prognostic cohort study was performed that included full-term neonates with duct-dependent CHD who underwent cardiac surgery at the Almazov National Medical Research Center from January 2021 to September 2023. The outcome was the development/absence of stage IB-III NEC in the postoperative period. Biomarkers of NEC (intestinal fatty acid binding protein (i-FABP, ng/ml), claudin-3 (CLDN3, ng/ml), calprotectin (CALPR, ng/ml), ischemia modified albumin (IMA, ng/ml), vascular endothelial growth factor A (VEGF A, pg/ml)) were measured by ELISA in the blood serum before cardiac surgery and 12-14 hours after surgery. We also analyzed clinical characteristics of neonates, C-reactive protein levels, complete blood count, abdominal ultrasound, ejection fraction (EF, Teicholtz) in the preoperative and postoperative periods, surgical parameters, P(v-a)CO2/C(a-v)O2 upon arrival from the operating room, vasoactive inotropic score (VIS) and arterial blood lactate levels in the first 24 hours after surgery. The association between predictors and the development of NEC after cardiac surgery was assessed using univariate and multivariate logistic regression analysis. Internal validation of the model was performed using 10-fold cross-validation. Results. During the observation period, 187 neonates underwent surgical treatment of duct-dependent CHD, of which 32 children developed stage IB-III NEC in the postoperative period (17.1%), two neonates required surgical treatment of NEC (6.3%). After meeting the non-inclusion and exclusion criteria, two groups of patients were formed: a main group (30 neonates who developed stages IB-III NEC in the postoperative period, of which stage III NEC was in one neonate) and a comparison group (40 neonates without NEC). Groups were comparable by types of CHD. Predictors associated with NEC (univariate analysis): intrauterine growth retardation (IUGR), formula feeding before surgery, high levels of IMA before on the first postoperative day (POD), procedures performed before surgery (Rashkind procedure/valvuloplasty/stenting), lower EF in in the early postoperative period, a higher maximum level of VIS in the first 24 hours after surgery, as well as a higher level of IR in the superior mesenteric artery (SMA) and thickening of the intestinal wall on the first postoperative day (POD) Independent preoperative predictors of NEC (AUC of model 0.885, specificity 0.867): IUGR (OR 32.2 (1.4-730.3), p=0.029), formula feeding (OR 12.6 (2.6-60.2), p=0.002), IMA level before surgery (OR 1.03 (1.01-1.04), p=0.004), CLDN3 level before surgery (OR 0.5 (0.3-0.9), p=0.013). Independent early postoperative predictors of NEC: IMA level on 12-14 hour after surgery (OR 1.02 (1.01-1.03), p=0.030), P(v-a)CO2/C(a-v)O2 immediately after surgery (OR 2.3 (1.2-4.4), p=0.008), IR>0.93 in SMA (OR 7.2 (1.6-32.4), p=0.011) and thickness of intestinal wall by ultrasound on POD 1 (OR 4.9 (1.3-19.2), p=0.021). Adding of VEGF A level (12-14 hour after surgery, negatively associated with NEC) to the model increased the specificity, but the predictor was not significant. AUC of postoperative model 0.862, specificity 0.800. The final model included preoperative (IUGR, formula feeding) and postoperative predictors (IMA, P(v-a)CO2/C(a-v)O2, IR of SMA>0.93, intestinal wall thickness), AUC=0.921, specificity 0.83. Conclusion. The identified predictors indirectly indicate the role of hypoxia in the pathophysiology of NEC in term neonates with duct-dependent CHD. Breast milk feeding/mixed feeding in the preoperative period may help reduce the risk of NEC in the postoperative period. Low levels of CLDN3 before surgery were associated with the development of NEC, but the interpretation of the result is controversial.

некротизирующий энтероколитврожденные пороки сердцаP(v-a)CO2/C(a-v)O2кишечный белоксвязывающий жирные кислоты (i-FABP)клаудин-3 (CLDN3)кальпротектин (CALPR)ишемией модифицированный альбумин (IMA)сосудистый эндотелиальный фактор роста А (VEGF A)necrotizing enterocolitiscongenital heart defectsP(v-a)CO2/C(a-v)O2intestinal fatty acid binding protein (i-FABP)claudin-3 (CLDN 3)calprotectinischemia modified albumin (IMA)vascular endothelial growth factor A (VEGF A)ReferencesWu W., He J., Shao X. Incidence and mortality trend of congenital heart disease at the global, regional, and national level, 1990-2017. Medicine (Baltimore). 2020;99(23):e20593. doi:10.1097/MD.0000000000020593Wu W., He J., Shao X. Incidence and mortality trend of congenital heart disease at the global, regional, and national level, 1990-2017. Medicine (Baltimore). 2020;99(23):e20593. doi:10.1097/MD.0000000000020593Bokerija E.L. Perinatal cardiology: the present and the future. Part I: congenital heart disease. 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The authors declare that there are no conflicts of interest present.