Eventos adversos associados às doses de fentanil utilizadas nos primeiros dez de vida em neonatos submetidos à correção de gastrosquise / Adverse events associated with doses of fentanyl used in the first ten days of life in neonates undergoing gastroschisis repair

Objetivo: Avaliar a associação entre as doses de fentanil utilizadas nos primeiros dez dias de vida de neonatos submetidos à correção cirúrgica de gastrosquise e as complicações respiratórias e gastrointestinais comumente associadas à essa faixa etária e defeito congênito. Métodos: O presente estudo avaliou de forma retrospectiva a coorte de recém-nascidos portadores de gastrosquise operados no IFF no período de janeiro de 2016 até junho de 2021. Dados demográficos dos neonatos e gestantes, das intervenções cirúrgicas, dos procedimentos anestésicos e dos cuidados perioperatórios em unidade de terapia intensiva neonatal foram coletados de prontuários. Os principais desfechos avaliados foram o tempo de intubação orotraqueal e de ventilação mecânica (IOT/VM), tempo de uso de NPT e data de início de dieta enteral. Foram descritos, tempo para dieta oral plena, tempo de internação em unidade de cuidados intensivos neonatais, diagnóstico de sepse, diagnóstico de apnéia, estridor, pneumonia e taxa de mortalidade. Nos primeiros dez dias de vida dos bebês, as doses de fentanil utilizadas no intraoperatório e periopratório, em bolus ou infusão contínua, foram quantificadas. Assim como, fez-se uma análise descritiva das abordagens cirúrgicas, das técnicas anestésicas e das complicações clínico-cirúrgicas apresentadas durante o período de internação na UTI. Por meio de modelagem estatística, o impacto do aumento das dose de fentanil sobre as complicações respiratórias e gastrointestinais foi avaliado. Resultados: No período do estudo 184 crianças receberam correção cirúrgica do defeito de parede no IFF e a taxa de mortalidade foi de 8,69%. Os dados de 176 neonatos foram coletados e 94% desses pacientes foram indentificadas como gastrosquise simples. Nossa coorte de 144 pacientes foi avaliada e os eventos mais frequentemente relacionados ao uso de maiores doses de fentanil foram aumento do tempo de ventilação mecânica, aumento do tempo total de uso de NPT e retardo para início da dieta enteral. Conclusão: O estudo mostrou piores desfechos respiratórios e gastrointestinais nos pacientes que receberam doses maiores de fentanil.

Objective: To evaluate the association between doses of fentanyl used in the first ten days of life in neonates undergoing surgical correction of gastroschisis and the respiratory and gastrointestinal complications commonly associated with this age group and congenital defect. Methods: This study evaluated retrospectively the cohort of newborns with gastroschisis operated at IFF between January 2016 and June 2021. Demographic data of newborns and pregnant women, surgical interventions, anesthetic procedures and perioperative care in the neonatal intensive care unit were collected from medical records. The main outcomes evaluated were time of orotracheal intubation and time on mechanical ventilation (TI/MV), time of use of PN, time to start enteral nutrition, time to full oral diet, length of stay in the neonatal intensive care unit, sepsis diagnosis, diagnosis of apnea,stridor, pneumonia and mortality rate. In the first ten days of the babies' lives, the doses of fentanyl used in the intraoperative and perioperative, in bolus or continuous infusion, were quantified. As well, a descriptive analysis of surgical approaches, anesthetic techniques and the clinical-surgical complications presented during the ICU stay was made. Through statistical modeling, the impact of increasing fentanyl doses on respiratory and gastrointestinal complications was evaluated. Results: During the study period, 184 children received surgical correction of the wall defect at IFF and the mortality rate was 8.69%. The data from 176 neonates were collected and 94% of these patients were identified as simple gastroschisis. Our cohort of 144 patients was evaluated and the most frequently related events to the use of fentanyl in higher doses were increased time on mechanical ventilation, increased total time of PN use, and delay in starting enteral feeding. Conclusion: The study demontrated worse respiratory and gastrointestinal outcomes in the neonates that received higher doses of fentanyl.

Treatment of bowel in experimental gastroschisis with a nitric oxide donor.

OBJECTIVE: To reduce the harmful effect of bowel exposure to amniotic fluid in gastroschisis, we used the nitric oxide (NO) donor S-nitrosoglutathione (GSNO) in an animal model of gastroschisis and assessed the ideal concentration for treatment of changes in bowel. STUDY DESIGN: Gastroschisis was surgically induced in rat fetuses on day 18.5 of gestation. The fetuses were divided into 5 groups (n = 12 animals/group): control (C), gastroschisis (G), gastroschisis + GSNO 5 µmol/L (GNO1), gastroschisis + GSNO 0.5 µmol/L (GNO2), and gastroschisis + GSNO 0.05 µmol/L (GNO3). On day 21.5 of gestation, fetuses were collected by cesarean delivery. Body and intestinal weight were measured and the bowels were either fixed for histometric and immunohistochemical study or frozen for Western blotting. We analyzed bowel morphometry on histological sections and expression of the NO synthase (NOS) enzymes by Western blotting and immunohistochemistry. Data were analyzed by analysis of variance or Kruskal-Wallis test when appropriate. RESULTS: Morphological and histometric measurements of weight, diameter, and thickness of the layers of the intestinal wall decreased with GSNO treatment, especially in the GNO3 group, when compared with the G group (P < .05). The expression of neuronal NOS, endothelial NOS, and inducible NOS decreased mainly in GNO3 group compared to the G group (P < .05), with no difference compared to C group (P > .05). CONCLUSION: Fetal treatment with 0.05 µmol/L GSNO resulted in significant improvement of bowel morphology in gastroschisis.

Corticosteroid effect upon intestinal and hepatic interleukin profile in a gastroschisis rat model.

PURPOSE: To evaluate the effect of corticosteroids on intestinal and liver interleukin profile in an experimental model of gastroschisis in fetal rats. METHODS: Sprague-Dawley rats at 19.5 days of gestation had its fetuses operated for the creation of gastroschisis. Two groups of fetuses were studied with and without maternal administration of dexamethasone. Each group was composed of fetuses who underwent gastroschisis (G), control fetuses without manipulation (C) and sham fetuses (S). A dosage of the following interleukins was carried out in fetal intestinal and liver tissues: IL-1, IL-6, IL-10, tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ). The differences between the groups and subgroups were tested by ANOVA with Tukey post-test, with significant values of p<0.05. RESULTS: Dexamethasone led to an increase in intestinal and liver IL-6 (p<0.05) and a decrease in intestinal TNF-α (p<0.001) in fetuses with gastroschisis. CONCLUSION: Corticosteroids had an effect on the intestinal interleukin profile and a small effect on the liver interleukin profile due to immunological immaturity of the fetus, and also of fetuses with gastroschisis. The steroid action may not be exclusively anti-inflammatory, but also pro-inflammatory, varying with time of pregnancy.

Corticosteroid effect upon intestinal and hepatic interleukin profile in a gastroschisis rat model / Efeito do corticoesteróide sobre o perfil das interleucinas intestinais e hepáticas no modelo de gastrosquise em ratos

PURPOSE: To evaluate the effect of corticosteroids on intestinal and liver interleukin profile in an experimental model of gastroschisis in fetal rats. METHODS: Sprague-Dawley rats at 19.5 days of gestation had its fetuses operated for the creation of gastroschisis. Two groups of fetuses were studied with and without maternal administration of dexamethasone. Each group was composed of fetuses who underwent gastroschisis (G), control fetuses without manipulation (C) and sham fetuses (S). A dosage of the following interleukins was carried out in fetal intestinal and liver tissues: IL-1, IL-6, IL-10, tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ). The differences between the groups and subgroups were tested by ANOVA with Tukey post-test, with significant values of p<0.05. RESULTS: Dexamethasone led to an increase in intestinal and liver IL-6 (p<0.05) and a decrease in intestinal TNF-α (p<0.001) in fetuses with gastroschisis. CONCLUSION: Corticosteroids had an effect on the intestinal interleukin profile and a small effect on the liver interleukin profile due to immunological immaturity of the fetus, and also of fetuses with gastroschisis. The steroid action may not be exclusively anti-inflammatory, but also pro-inflammatory, varying with time of pregnancy.

OBJETIVO: Avaliar a ação do corticosteroide no perfil de interleucinas intestinais e hepáticas no modelo experimental de gastrosquise em fetos de ratos. MÉTODOS: Ratas Sprague-Dawley com 19,5 dias de gestação tiveram fetos operados para criação de gastrosquise. Dois grupos de fetos foram estudados: com e sem administração materna de dexametasona. Cada grupo foi composto por fetos submetidos a gastrosquise (G), fetos controles sem manipulação (C) e fetos sham (S). Realizou-se a dosagem das seguintes interleucinas no tecido intestinal e hepático fetal: IL-1, IL-6, IL-10, fator de necrose tumoral-alfa (TNF-α) e interferon-gama (IFN-γ). As diferenças entre os grupos e subgrupos foram testadas pelo teste de ANOVA com pós-teste de Tukey, com valores significativos de p<0,05. RESULTADOS: A dexametasona levou a um aumento da IL-6 intestinal e hepática (p<0,05) e a uma diminuição do TNF-α intestinal (p<0,001) em fetos com gastrosquise. CONCLUSÃO: O corticosteróide apresentou efeito sobre o perfil de IL intestinal e pouco na hepática, devido a imaturidade imunológica dos fetos e também dos fetos com gastrosquise a ação do esteróide pode não ser exclusivamente anti-inflamatória, mas também pró inflamatória.

Hydrogel protection: a novel approach to reduce bowel inflammation in experimental gastroschisis.

OBJECTIVE: In gastroschisis there is herniation of the fetal bowel into the amniotic cavity that results in severe intestinal dysfunction. In order to reduce bowel exposure to amniotic fluid we used a hydrogel of N-isopropylacrylamide copolymerized with acrylic acid (P(NIPAAm-co-AAc)) to coat the herniated bowel through the use of a fibrin adhesive (Beriplast). STUDY DESIGN: Gastroschisis was created in fetuses of 31 pregnant Sprague-Dawley rats by evisceration of the bowel through a right paramedian incision in the abdominal wall on day 18.5 of pregnancy. The fetuses were separated in four groups of 12 fetuses: control (C), gastroschisis (G), gastroschisis+fibrin adhesive (GA) and gastroschisis+fibrin adhesive+dry hydrogel (GAH). Animals were harvested at day 21.5 of pregnancy and the hydrogel was removed. Fetuses and bowels were weighed and morphometric analysis was performed. Isoelectric focusing of the amniotic fluid determined its electrical charge. We evaluated the hydrogel swelling ratio (Q) in the amniotic fluid. Histological analysis and scanning electronic microscopy (SEM) of the bowel and hydrogel were performed. Our primary outcome was bowel intactness after hydrogel removal and our secondary outcome was the effectiveness of the hydrogel in protecting the bowel against amniotic fluid and its components. Differences among the groups were tested by the ANOVA and Tukey-Kramer post-test method and the statistical significance accepted was for p values <0.05. RESULTS: The mass of swollen hydrogel was 34 times the mass of dry hydrogel. Isoelectric focusing of the amniotic fluid showed that most of its proteins are negatively charged as the hydrogel. SEM showed that removal of the hydrogel did not damage bowel serosa. Bowel weight, diameter and wall thickness were similar between groups C and GAH but bowel diameter and wall thickness was significantly reduced in C and GAH compared to G and GA (p<0.001). CONCLUSION: The P(NIPAAm-co-AAc) hydrogel does not harm the bowel and provides a safe effective protection with reduction of bowel damage in gastroschisis.

Impact of corticosteroid on intestinal injury in a gastroschisis rat model: morphometric analysis.

BACKGROUND/PURPOSE: The goal in the treatment of gastroschisis is to prevent intestinal injury. Corticosteroids are known by their effects at the inflammatory response and by the improvement on the intestinal maturity. The authors evaluated the effects of maternal corticosteroid administration on the intestines of rats that underwent fetal gastroschisis. METHODS: A Correia-Pinto-modified gastroschisis rat model was used. Two groups were assessed: the control group (group 1) and the dexamethasone group (group 2). Each group was composed of control and sham fetuses, and fetuses with gastroschisis. Fetal body weight, intestinal weight, intestinal length, and protein were assessed. Histologic analysis involved measures of intestinal loop diameter, total intestinal wall, mucosa and submucosa, both circular and longitudinal muscle layers, and serosal thicknesses. Differences between groups and subgroups were tested by the analysis of variance method with a significant P value less than .05. RESULTS: Dexamethasone decreased in all the morphometric data except in the intestinal length. Dexamethasone increased the intestinal protein content in fetuses with gastroschisis, and control and sham fetuses. In both groups, all histologic parameters were increased in fetuses with gastroschisis (P < .0001). CONCLUSIONS: Dexamethasone caused a substantial decrease in intestinal weight in GFs, increased the intestinal protein content, and it may be useful in decreasing the intestinal damage of gastroschisis.