Perioperative extracorporeal membrane oxygenation in pediatric congenital heart disease: Chinese expert consensus.

BACKGROUND: Congenital heart disease (CHD) is one of the main supportive diseases of extracorporeal membrane oxygenation in children. The management of extracorporeal membrane oxygenation (ECMO) for pediatric CHD faces more severe challenges due to the complex anatomical structure of the heart, special pathophysiology, perioperative complications and various concomitant malformations. The survival rate of ECMO for CHD was significantly lower than other classifications of diseases according to the Extracorporeal Life Support Organization database. This expert consensus aims to improve the survival rate and reduce the morbidity of this patient population by standardizing the clinical strategy. METHODS: The editing group of this consensus gathered 11 well-known experts in pediatric cardiac surgery and ECMO field in China to develop clinical recommendations formulated on the basis of existing evidences and expert opinions. RESULTS: The primary concern of ECMO management in the perioperative period of CHD are patient selection, cannulation strategy, pump flow/ventilator parameters/vasoactive drug dosage setting, anticoagulation management, residual lesion screening, fluid and wound management and weaning or transition strategy. Prevention and treatment of complications of bleeding, thromboembolism and brain injury are emphatically discussed here. Special conditions of ECMO management related to the cardiovascular anatomy, haemodynamics and the surgical procedures of common complex CHD should be considered. CONCLUSIONS: The consensus could provide a reference for patient selection, management and risk identification of perioperative ECMO in children with CHD. Video abstract (MP4 104726 kb).

Nanomaterial-involved neural stem cell research: Disease treatment, cell labeling, and growth regulation.

Neural stem cells (NSCs) have been widely investigated for their potential in the treatment of various diseases and transplantation therapy. However, NSC growth regulation, labeling, and its application to disease diagnosis and treatment are outstanding challenges. Recently, nanomaterials have shown promise for various applications including genetic modification, imaging, and controlled drug release. Here we summarize the recent progress in the use of nanomaterials in combination with NSCs for disease treatment and diagnosis, cell labeling, and NSC growth regulation. The toxicity of nanomaterials to NSCs is also discussed.

ECMO as an effective rescue therapeutic for fulminant myocarditis complicated with refractory cardiac arrest.

Fulminant myocarditis (FM) is a life-threatening disease in children. With a rapid, progressive course of deterioration, it causes refractory cardiorespiratory failure even with optimal clinical intervention. We present the case of a 9-year-old girl with FM complicated by cardiogenic shock, malignant arrhythmia, and refractory cardiac arrest. She received effective cardiopulmonary resuscitation, therapeutic hypothermia, and other supportive treatments. However, the patient rapidly worsened into pulseless ventricular tachycardia and refractory cardiac arrest. Therefore, we performed extracorporeal membrane oxygenation (ECMO) to establish spontaneous circulation after the failure of standard resuscitation measures. The girl recovered with intact cardiac and neurocognitive functions after continued ECMO treatment for 221 hours. Therefore, ECMO is an effective rescue therapeutics for FM, especially when complicated with refractory cardiac arrest.

Assessing the impact of total extracorporeal circulation on hemodynamics in an ovine fetal model.

The present study aimed to evaluate the impact of total extracorporeal circulation on hemodynamics and placental function in an ovine fetal model. Mid-term ovine fetuses (n=6) underwent extracorporeal circulation (30 min), cardioplegic arrest (20 min) and monitoring (120 min). The ascending aorta and umbilical cords of the fetuses were occluded during the bypass and an extracorporeal membrane oxygenator was used as the oxygen source. Biventricular intracardiac pressures, echocardiographic data, blood gas levels and placental function variables were recorded, and statistical analysis was performed using the repeated-measure analysis of variance test. The data indicated that fetal heart rate and blood pressure at 30, 60, 90 and 120 min following the bypass were stable relative to pre-arrest baseline (pre-bypass) values (P>0.05). However, end diastolic pressures in the ovine right ventricles post-bypass were significantly increased at 30, 60, 90 and 120 min relative to pre-bypass pressures (P<0.05). The pulsatility index also increased at 30 min post-bypass relative to the pre-bypass score (0.91±0.06 vs. 0.61±0.14; P=0.007). The mean resistivity index at all time points post-bypass was consistent with the pre-bypass score (P>0.05), while the mean Tei index values for the left and right ventricles post-bypass were significantly higher at all time points relative to pre-bypass values (P<0.05). The pre-bypass fetal blood pH, SaO2, base excess and lactate values were maintained during arrest (P>0.05). Fetal hemodynamics and placental function additionally remained stable for up to 2 h upon reperfusion following total extracorporeal circulation and cardioplegic arrest. Collectively these data suggest that the reproducible ovine fetal model may be useful in the evaluation of fetal cardiac surgery.

MicroRNA-34a targets regulator of calcineurin 1 to modulate endothelial inflammation after fetal cardiac bypass in goat placenta.

INTRODUCTION: Placental dysfunction characterized by vascular endothelial inflammation is one of the most notable responses to fetal cardiac bypass. Regulator of calcineurin 1 (RCAN1) is an important regulator of inflammatory responses. MicroRNAs (miRNAs) are essential post-transcriptional modulators of gene expression, and miRNA-34a (miR-34a) was showed to activate vascular endothelial inflammation. We hypothesized that miR-34a may be a key regulator of placental dysfunction after fetal cardiac bypass. METHODS: We evaluated miRNA expression in goat placentas via small RNA sequencing, quantitative real-time polymerase chain reaction (qRT-PCR) and in situ hybridization. Expression of miRNA target genes was determined via bioinformatics analyses and dual luciferase reporter assays. Furthermore, human umbilical vein endothelial cells (HUVECs) were transfected with miR-34a or a control sequence. The RCAN1, nuclear factor of activated T-cells (NFATC1) and nuclear factor kappa-B (NF-κB) levels in HUVECs and placentas were evaluated via Western blot and qRT-PCR. RESULTS: We demonstrated that miR-34a was highly enriched in goat placenta after cardiopulmonary bypass. Moreover, RCAN1 was identified as a novel direct target of miR-34a. Transfection of miR-34a led to decreased RCAN1 expression and increased NFATC1 and NF-κB expression in HUVECs. Conversely, inhibition of miR-34a rescued RCAN1 expression and reduced NFATC1 and NF-κB expression in HUVECs. CONCLUSIONS: We demonstrated a remarkable role of miR-34a as a regulator of NFATC1-associated placental inflammation through direct targeting of RCAN1. MiR-34a could serve as a novel therapeutic target for limiting the progression of placental inflammation after fetal cardiac bypass.

Decrease in inflammatory response does not prevent placental dysfunction after fetal cardiac bypass in goats.

OBJECTIVE: One of the most significant responses to fetal cardiac bypass is severe placental dysfunction characterized by increased vascular resistance. We tested the hypothesis that fetal cardiac bypass triggers the activation of nuclear factor kappa-B (NF-KB), a major regulator of inflammatory response, and that pharmacologic inhibition of NF-KB activation by pyrrolidine dithiocarbamate alleviates fetal cardiac bypass-induced placental dysfunction. METHODS: Fifteen pregnant goats at 120 to 140 days' gestation were equally divided into the control group with a sham procedure of fetal sternotomy and cannulation (CG), the fetal bypass group (FB), and the fetal bypass group with 300 mg pyrrolidine dithiocarbamate before sternotomy (FP). Fetal cardiac bypass was performed for 30 minutes. Umbilical arterial flow rate was measured by ultrasonic flowmeter and placental vascular resistance was calculated. Fetal plasma levels of nitric oxide (NO), endothlin-1 (ET-1), 6-keto-prostaglandin F1α (6-K), thromboxane B(2) (TXB2), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α) were assayed. IL-6 and TNF-α mRNA were analyzed by real-time polymerase chain reaction. NF-KB activation was evaluated by electrophoretic mobility shift assay. RESULTS: Placental vascular resistance significantly increased in the FB and FP groups compared with the CG group. Increases in plasma levels of NO were observed in all 3 groups. Plasma levels of ET-1 rose significantly in the FB and FP groups without noticeable difference between them. Plasma levels of 6-K, TXB(2), IL-6, and TNF-α increased significantly in the FB group compared with the CG and FP groups. The transcription levels of IL-6 and TNF-α mRNA in the placental tissues of the FB group were significantly higher than in the FP and CG groups. The amount of activated NF-KB in the placental tissues of the FB group was also significantly higher than that in the FP and CG groups. CONCLUSIONS: Fetal cardiac bypass-induced inflammatory response possibly mediated by NF-KB caused placental dysfunction. Pharmacologic inhibition of NF-KB activation and decrease in the inflammatory response did not alleviate the placental dysfunction.

A fetal goat model of cardiopulmonary bypass with cardioplegic arrest and hemodynamic assessment.

OBJECTIVE: Increasing evidence shows that some cardiac defects may benefit from fetal interventions, including fetal cardiac surgery. We attempted to develop an in vivo animal model of fetal cardiopulmonary bypass with cardioplegic arrest. METHODS: Operations were performed on 14 pregnant goats. The extracorporeal circulation circuit consisted of a centrifugal pump, silicone tubings with an inner diameter of 6 mm, a roller pump, and a reservoir. The placenta was the sole oxygenator. Cardiopulmonary bypass was maintained at a mean flow rate of 344 ± 68 mL/kg/min, including 30 minutes of cardiac arrest and 15 minutes of reperfusion. Mean arterial blood pressure and heart rate were monitored. Arterial blood samples were analyzed. The pulse index and resistance index of the fetal umbilical artery were monitored. RESULTS: Experiments were completed in 11 cases (79%), with the fetuses weighing 0.65 to 1.8 kg. Fetal mean arterial blood pressure and heart rate remained stable throughout the experiments. A decrease in partial pressure of oxygen with concomitant increase in carbon dioxide partial pressure was noted, but trends were relatively stable. Metabolic acidosis was recognized during and after cardiac bypass. The pulse index and resistance index of the umbilical artery increased significantly after 2 hours off bypass. CONCLUSIONS: We confirmed the technical feasibility of establishing an in vivo model of fetal cardiac bypass with cardioplegic arrest. This fetal goat model provides reproducible data and is suitable to study clinically relevant problems related to fetal cardiopulmonary bypass, myocardial protection, and hemodynamics.

[Anesthetic management during cardiac bypass in fetal lambs].

OBJECTIVE: To summarize the anesthetic management in fetal lamb cardiac bypass. METHODS: Five ewes at 120-140 days of gestation were anesthetized intramuscularly with katamine hydrochloride, intubated and ventilated with a respirator. Anesthesia was maintained with fentanyl and vecuronium. Lactated Ringer's solution and magnesium sulfate were infused to maintain the mean blood pressure (MAP) over 70 mmHg and uterine relaxation. The fetal lambs received anesthesia with fentanyl and vecuronium intramuscularly via the uterine wall. Fetal cardiac bypass was established with pulmonary artery and right atrium cannulation, lasting for 30 min. The hemodynamic and blood gas data of the ewes and fetal lambs were recorded before bypass, at 30 min during bypass, and at 1 and 2 h after cessation of bypass. The pulse index of the umbilical artery (PIua) and the ewe's uterine artery (PIeu) were monitored simultaneously. RESULTS: The MAP and heart rate (HR) of the fetus remained normal during the anesthesia. PIua increased significantly after cessation of bypass (P<0.05). Although the fetal oxygen tension in the axillary artery remained normal, the fetal lambs showed hypercarbia and acidosis after cessation of bypass (P<0.05). The maternal MAP and HR remained normal. The PIeu decreased significantly during bypass (P<0.05) and recovered the normal level after cessation of bypass. The arterial blood gas of the ewes was normal during the experiment. CONCLUSION: Maintaining high hemodynamics in the ewes, application of uterine relaxation and intensive care during anesthesia are crucial in anesthetic management of cardiac bypass in fetal lambs.