Perioperative Brain Injury in Relation to Early Neurodevelopment Among Children with Severe Congenital Heart Disease: Results from a European Collaboration.

OBJECTIVE: To examine the relationship between perioperative brain injury and neurodevelopment during early childhood in patients with severe congenital heart disease (CHD). STUDY DESIGN: One hundred and seventy children with CHD and born at term who required cardiopulmonary bypass surgery in the first 6 weeks after birth were recruited from 3 European centers and underwent preoperative and postoperative brain MRIs. Uniform description of imaging findings was performed and an overall brain injury score was created, based on the sum of the worst preoperative or postoperative brain injury subscores. Motor and cognitive outcomes were assessed with the Bayley Scales of Infant and Toddler Development Third Edition at 12 to 30 months of age. The relationship between brain injury score and clinical outcome was assessed using multiple linear regression analysis, adjusting for CHD severity, length of hospital stay (LOS), socioeconomic status (SES), and age at follow-up. RESULTS: Neither the overall brain injury score nor any of the brain injury subscores correlated with motor or cognitive outcome. The number of preoperative white matter lesions was significantly associated with gross motor outcome after correction for multiple testing (P = .013, ß = -0.50). SES was independently associated with cognitive outcome (P < .001, ß = 0.26), and LOS with motor outcome (P < .001, ß = -0.35). CONCLUSION: Preoperative white matter lesions appear to be the most predictive MRI marker for adverse early childhood gross motor outcome in this large European cohort of infants with severe CHD. LOS as a marker of disease severity, and SES influence outcome and future intervention trials need to address these risk factors.

Intermittent intravenous paracetamol versus continuous morphine in infants undergoing cardiothoracic surgery: a multi-center randomized controlled trial.

BACKGROUND: To determine whether intermittent intravenous (IV) paracetamol as primary analgesic would significantly reduce morphine consumption in children aged 0-3 years after cardiac surgery with cardiopulmonary bypass. METHODS: Multi-center, randomized, double-blinded, controlled trial in four level-3 Pediatric Intensive Care Units (PICU) in the Netherlands and Belgium. Inclusion period; March 2016-July 2020. Children aged 0-3 years, undergoing cardiac surgery with cardiopulmonary bypass were eligible. Patients were randomized to continuous morphine or intermittent IV paracetamol as primary analgesic after a loading dose of 100 mcg/kg morphine was administered at the end of surgery. Rescue morphine was given if numeric rating scale (NRS) pain scores exceeded predetermined cutoff values. Primary outcome was median weight-adjusted cumulative morphine dose in mcg/kg in the first 48 h postoperative. For the comparison of the primary outcome between groups, the nonparametric Van Elteren test with stratification by center was used. For comparison of the proportion of patients with one or more NRS pain scores of 4 and higher between the two groups, a non-inferiority analysis was performed using a non-inferiority margin of 20%. RESULTS: In total, 828 were screened and finally 208 patients were included; parents of 315 patients did not give consent and 305 were excluded for various reasons. Fourteen of the enrolled 208 children were withdrawn from the study before start of study medication leaving 194 patients for final analysis. One hundred and two patients received intermittent IV paracetamol, 106 received continuous morphine. The median weight-adjusted cumulative morphine consumption in the first 48 h postoperative in the IV paracetamol group was 5 times lower (79%) than that in the morphine group (median, 145.0 (IQR, 115.0-432.5) mcg/kg vs 692.6 (IQR, 532.7-856.1) mcg/kg; P < 0.001). The rescue morphine consumption was similar between the groups (p = 0.38). Non-inferiority of IV paracetamol administration in terms of NRS pain scores was proven; difference in proportion - 3.1% (95% CI - 16.6-10.3%). CONCLUSIONS: In children aged 0-3 years undergoing cardiac surgery, use of intermittent IV paracetamol reduces the median weight-adjusted cumulative morphine consumption in the first 48 h after surgery by 79% with equal pain relief showing equipoise for IV paracetamol as primary analgesic. Trial Registration Clinicaltrials.gov, Identifier: NCT05853263; EudraCT Number: 2015-001835-20.

Neuromonitoring, neuroimaging, and neurodevelopmental follow-up practices in neonatal congenital heart disease: a European survey.

BACKGROUND: Brain injury and neurodevelopmental impairment remain a concern in children with complex congenital heart disease (CHD). A practice guideline on neuromonitoring, neuroimaging, and neurodevelopmental follow-up in CHD patients undergoing cardiopulmonary bypass surgery is lacking. The aim of this survey was to systematically evaluate the current practice in centers across Europe. METHODS: An online-based structured survey was sent to pediatric cardiac surgical centers across Europe between April 2019 and June 2020. Results were summarized by descriptive statistics. RESULTS: Valid responses were received by 25 European centers, of which 23 completed the questionnaire to the last page. Near-infrared spectroscopy was the most commonly used neuromonitoring modality used in 64, 80, and 72% preoperatively, intraoperatively, and postoperatively, respectively. Neuroimaging was most commonly performed by means of cranial ultrasound in 96 and 84% preoperatively and postoperatively, respectively. Magnetic resonance imaging was obtained in 72 and 44% preoperatively and postoperatively, respectively, but was predominantly reserved for clinically symptomatic patients (preoperatively 67%, postoperatively 64%). Neurodevelopmental follow-up was implemented in 40% of centers and planned in 24%. CONCLUSIONS: Heterogeneity in perioperative neuromonitoring and neuroimaging practice in CHD in centers across Europe is large. The need for neurodevelopmental follow-up has been recognized. A clear practice guideline is urgently needed. IMPACT: There is large heterogeneity in neuromonitoring, neuroimaging, and neurodevelopmental follow-up practices among European centers caring for neonates with complex congenital heart disease. This study provides a systematic evaluation of the current neuromonitoring, neuroimaging, and neurodevelopmental follow-up practice in Europe. The results of this survey may serve as the basis for developing a clear practice guideline that could help to early detect and prevent neurological and neurodevelopmental sequelae in neonates with complex congenital heart disease.

Risk Factors for Perioperative Brain Lesions in Infants With Congenital Heart Disease: A European Collaboration.

BACKGROUND: Infants with congenital heart disease are at risk of brain injury and impaired neurodevelopment. The aim was to investigate risk factors for perioperative brain lesions in infants with congenital heart disease. METHODS: Infants with transposition of the great arteries, single ventricle physiology, and left ventricular outflow tract and/or aortic arch obstruction undergoing cardiac surgery <6 weeks after birth from 3 European cohorts (Utrecht, Zurich, and London) were combined. Brain lesions were scored on preoperative (transposition of the great arteries N=104; single ventricle physiology N=35; and left ventricular outflow tract and/or aortic arch obstruction N=41) and postoperative (transposition of the great arteries N=88; single ventricle physiology N=28; and left ventricular outflow tract and/or aortic arch obstruction N=30) magnetic resonance imaging for risk factor analysis of arterial ischemic stroke, cerebral sinus venous thrombosis, and white matter injury. RESULTS: Preoperatively, induced vaginal delivery (odds ratio [OR], 2.23 [95% CI, 1.06-4.70]) was associated with white matter injury and balloon atrial septostomy increased the risk of white matter injury (OR, 2.51 [95% CI, 1.23-5.20]) and arterial ischemic stroke (OR, 4.49 [95% CI, 1.20-21.49]). Postoperatively, younger postnatal age at surgery (OR, 1.18 [95% CI, 1.05-1.33]) and selective cerebral perfusion, particularly at ≤20 °C (OR, 13.46 [95% CI, 3.58-67.10]), were associated with new arterial ischemic stroke. Single ventricle physiology was associated with new white matter injury (OR, 2.88 [95% CI, 1.20-6.95]) and transposition of the great arteries with new cerebral sinus venous thrombosis (OR, 13.47 [95% CI, 2.28-95.66]). Delayed sternal closure (OR, 3.47 [95% CI, 1.08-13.06]) and lower intraoperative temperatures (OR, 1.22 [95% CI, 1.07-1.36]) also increased the risk of new cerebral sinus venous thrombosis. CONCLUSIONS: Delivery planning and surgery timing may be modifiable risk factors that allow personalized treatment to minimize the risk of perioperative brain injury in severe congenital heart disease. Further research is needed to optimize cerebral perfusion techniques for neonatal surgery and to confirm the relationship between cerebral sinus venous thrombosis and perioperative risk factors.

Early motor outcomes in infants with critical congenital heart disease are related to neonatal brain development and brain injury.

AIM: To assess the relationship between neonatal brain development and injury with early motor outcomes in infants with critical congenital heart disease (CCHD). METHOD: Neonatal brain magnetic resonance imaging was performed after open-heart surgery with cardiopulmonary bypass. Cortical grey matter (CGM), unmyelinated white matter, and cerebellar volumes, as well as white matter motor tract fractional anisotropy and mean diffusivity were assessed. White matter injury (WMI) and arterial ischaemic stroke (AIS) with corticospinal tract (CST) involvement were scored. Associations with motor outcomes at 3, 9, and 18 months were corrected for repeated cardiac surgery. RESULTS: Fifty-one infants (31 males, 20 females) were included prospectively. Median age at neonatal surgery and postoperative brain magnetic resonance imaging was 7 days (interquartile range [IQR] 5-11d) and 15 days (IQR 12-21d) respectively. Smaller CGM and cerebellar volumes were associated with lower fine motor scores at 9 months (CGM regression coefficient=0.51, 95% confidence interval [CI]=0.15-0.86; cerebellum regression coefficient=3.08, 95% CI=1.07-5.09) and 18 months (cerebellum regression coefficient=2.08, 95% CI=0.47-5.12). The fractional anisotropy and mean diffusivity of white matter motor tracts were not related with motor scores. WMI was related to lower gross motor scores at 9 months (mean difference -0.8SD, 95% CI=-1.5 to -0.2). AIS with CST involvement increased the risk of gross motor problems and muscle tone abnormalities. Cerebral palsy (n=3) was preceded by severe ischaemic brain injury. INTERPRETATION: Neonatal brain development and injury are associated with fewer favourable early motor outcomes in infants with CCHD.

Brain Injury in Infants with Critical Congenital Heart Disease: Insights from Two Clinical Cohorts with Different Practice Approaches.

OBJECTIVES: To determine prevalence and risk factors for brain injury in infants with critical congenital heart disease (CHD) from 2 sites with different practice approaches who were scanned clinically. STUDY DESIGN: Prospective, longitudinal cohort study (2016-2017) performed at Hospital for Sick Children Toronto (HSC) and Wilhelmina Children's Hospital Utrecht (WKZ), including 124 infants with cardiac surgery ≤60 days (HSC = 77; WKZ = 47). Magnetic resonance imaging was performed per clinical protocol, preoperatively (n = 100) and postoperatively (n = 120). Images were reviewed for multifocal (watershed, white matter injury) and focal ischemic injury (stroke, single white matter lesion). RESULTS: The prevalence of ischemic injury was 69% at HSC and 60% at WKZ (P = .20). Preoperative multifocal injury was associated with low cardiac output syndrome (OR, 4.6), which was equally present at HSC and WKZ (20% vs 28%; P = .38). Compared with WKZ, HSC had a higher prevalence of balloon-atrioseptostomy in transposition of the great arteries (83% vs 53%; P = .01) and more frequent preoperative focal injury (27% vs 6%; P = .06). Postoperatively, 30% of new multifocal injury could be attributed to postoperative low cardiac output syndrome, which was equally present at HSC and WKZ (38% vs 28%; P = .33). Postoperative focal injury was associated with intraoperative selective cerebral perfusion in CHD with arch obstruction at both sites (OR, 2.7). Compared with HSC, WKZ had more arch obstructions (62% vs 35%; P < .01) and a higher prevalence of new focal injury (36% vs 16%; P = .01). CONCLUSIONS: Brain injury is common in clinical cohorts of infants with critical CHD and related to practice approaches. This study confirms that the high prevalence of brain injury in critical CHD is a clinical concern and does not simply reflect the inclusion criteria of published research studies.

Human neonatal thymectomy induces altered B-cell responses and autoreactivity.

An association between T-cell lymphopenia and autoimmunity has long been proposed, but it remains to be elucidated whether T-cell lymphopenia affects B-cell responses to autoantigens. Human neonatal thymectomy (Tx) results in a decrease in T-cell numbers and we used this model to study the development of autoreactivity. Two cohorts of neonatally thymectomized individuals were examined, a cohort of young (1-5 years post-Tx, n = 10-27) and older children (>10 years, n = 26), and compared to healthy age-matched controls. T-cell and B-cell subsets were assessed and autoantibody profiling performed. Early post-Tx, a decrease in T-cell numbers (2.75 × 109 /L vs. 0.71 × 109 /L) and an increased proportion of memory T cells (19.72 vs. 57.43%) were observed. The presence of autoantibodies was correlated with an increased proportion of memory T cells in thymectomized children. No differences were seen in percentages of different B-cell subsets between the groups. The autoantigen microarray showed a skewed autoantibody response after Tx. In the cohort of older individuals, autoantibodies were present in 62% of the thymectomized children, while they were found in only 33% of the healthy controls. Overall, our data suggest that neonatal Tx skews the autoantibody profile. Preferential expansion and preservation of Treg (regulatory T) cell stability and function, may contribute to preventing autoimmune disease development after Tx.

Amplitude-Integrated Electroencephalography for Early Recognition of Brain Injury in Neonates with Critical Congenital Heart Disease.

OBJECTIVE: To study perioperative amplitude-integrated electroencephalography (aEEG) as an early marker for new brain injury in neonates requiring cardiac surgery for critical congenital heart disease (CHD). STUDY DESIGN: This retrospective observational cohort study investigated 76 neonates with critical CHD who underwent neonatal surgery. Perioperative aEEG recordings were evaluated for background pattern (BGP), sleep-wake cycling (SWC), and ictal discharges. Spontaneous activity transient (SAT) rate, inter-SAT interval (ISI), and percentage of time with an amplitude <5 µV were calculated. Routinely obtained preoperative and postoperative magnetic resonance imaging of the brain were reviewed for brain injury (moderate-severe white matter injury, stroke, intraparenchymal hemorrhage, or cerebral sinovenous thrombosis). RESULTS: Preoperatively, none of the neonates showed an abnormal BGP (burst suppression or worse) or ictal discharges. Postoperatively, abnormal BGP was seen in 18 neonates (24%; 95% CI, 14%-33%) and ictal discharges was seen in 13 neonates (17%; 95% CI, 8%-26%). Abnormal BGP and ictal discharges were more frequent in neonates with new postoperative brain injury (P = .08 and .01, respectively). Abnormal brain activity (ie, abnormal BGP or ictal discharges) was the single risk factor associated with new postoperative brain injury in multivariable logistic regression analysis (OR, 4.0; 95% CI, 1.3-12.3; P = .02). Postoperative SAT rate, ISI, or time <5 µV were not associated with new brain injury. CONCLUSION: Abnormal brain activity is an early, bedside marker of new brain injury in neonates undergoing cardiac surgery. Not only ictal discharges, but also abnormal BGP, should be considered a clear sign of underlying brain pathology.

Perioperative neonatal brain injury is associated with worse school-age neurodevelopment in children with critical congenital heart disease.

AIM: To assess the impact of perioperative neonatal brain injury and brain volumes on neurodevelopment throughout school-age children with critical congenital heart disease (CHD). METHOD: Thirty-four survivors of neonatal cardiac surgery (seven females, 27 males) were included. Neonatal preoperative and postoperative cerebral magnetic resonance imaging was performed and neurodevelopment was assessed at 24 months (SD 0.7, n=32, using Bayley Score of Infant and Toddler Development, Child Behavior Checklist) and 6 years (mean age 5y 11mo; SD 0.3, n=30, using Movement Assessment Battery for Children, Wechsler Preschool and Primary Scale of Intelligence, Child Behavior Checklist, Teacher Report Form). Brain injury, brain volumes, and cortical measures were related to outcome with adjustment for maternal educational level. RESULTS: Two-year cognitive score and 6-year Full-scale IQ were poorer in children with neonatal white matter injury (n=21, all p<0.05), with higher teacher-reported attention problems (p=0.03). Five of six children with involvement of the posterior limb of the internal capsule showed motor problems (p=0.03). Children with a below-average Fulll-scale IQ (<85, n=9) showed smaller volumes of basal ganglia thalami (-8%, p=0.03) and brain stem (-7%, p=0.03). INTERPRETATION: Our findings provide evidence of unfavourable outcome in school-age children with critical CHD who acquire perioperative neonatal brain injury. WHAT THIS PAPER ADDS: This paper extends knowledge about neonatal brain injury and long-term outcome in congenital heart disease. Children with white matter injury show lower IQ and more attention problems at school age. Injury of the posterior limb of the internal capsule increases the risk of motor problems. This study provides evidence for worse outcomes in neonates acquiring brain injury around cardiac surgery.

Deaths and end-of-life decisions differed between neonatal and paediatric intensive care units at the same children's hospital.

AIM: We compared neonatal deaths and end-of-life decisions in a neonatal intensive care unit (NICU) and paediatric intensive care unit (PICU) in a Dutch tertiary children's hospital. SUBJECTS: All 235 full-term infants who died within 28 days of life between 2003 and 2013 in the NICU (n = 199) and PICU (n = 36) were retrospectively studied. RESULTS: The median length of stay was three days in the NICU and seven days in the PICU (p = 0.003). The main reasons for NICU stays were asphyxia (52.8%) and congenital malformations (42.2%), and in the PICU, they were congenital malformations (97.2%) and primarily cardiac problems (83.3%, p < 0.001). The median age of death was three days in the NICU and eight days in the PICU (p < 0.001), and mortality despite full intensive care treatment was 4.0% and 25.0%, respectively. Intensive treatment was discontinued because of poor survival chances in 25.1% of NICU and 52.8% of PICU cases (p < 0.001), and care was redirected because of expected poor quality of life in 70.9% and 22.2%, respectively. CONCLUSION: Differences between the age at death and end-of-life decisions were found between full-term infants in the NICU and PICU in the same children's hospital. Underlying disorders and doctors' attitudes may have played a role.

The digestive tract as the origin of systemic inflammation.

Failure of gut homeostasis is an important factor in the pathogenesis and progression of systemic inflammation, which can culminate in multiple organ failure and fatality. Pathogenic events in critically ill patients include mesenteric hypoperfusion, dysregulation of gut motility, and failure of the gut barrier with resultant translocation of luminal substrates. This is followed by the exacerbation of local and systemic immune responses. All these events can contribute to pathogenic crosstalk between the gut, circulating cells, and other organs like the liver, pancreas, and lungs. Here we review recent insights into the identity of the cellular and biochemical players from the gut that have key roles in the pathogenic turn of events in these organ systems that derange the systemic inflammatory homeostasis. In particular, we discuss the dangers from within the gastrointestinal tract, including metabolic products from the liver (bile acids), digestive enzymes produced by the pancreas, and inflammatory components of the mesenteric lymph.

Neurological injury after neonatal cardiac surgery: a randomized, controlled trial of 2 perfusion techniques.

BACKGROUND: Complex neonatal cardiac surgery is associated with cerebral injury. In particular, aortic arch repair, requiring either deep hypothermic circulatory arrest (DHCA) or antegrade cerebral perfusion (ACP), entails a high risk of perioperative injury. It is unknown whether ACP results in less cerebral injury than DHCA. METHODS AND RESULTS: Thirty-seven neonates with an aortic arch obstruction presenting for univentricular or biventricular repair were randomized to either DHCA or ACP. Preoperatively and 1 week after surgery, magnetic resonance imaging was performed in 36 patients (1 patient died during the hospital stay). The presence of new postoperative cerebral injury was scored, and results were entered into a sequential analysis, which allows for immediate data analysis. After the 36th patient, it was clear that there was no difference between DHCA and ACP in terms of new cerebral injury. Preoperatively, 50% of patients had evidence of cerebral injury. Postoperatively, 14 of 18 DHCA patients (78%) had new injury versus 13 of 18 ACP patients (72%) (P=0.66). White matter injury was the most common type of injury in both groups, but central infarctions occurred exclusively after ACP (0 vs. 6/18 [33%]; P=0.02). Early motor and cognitive outcomes at 24 months were assessed and were similar between groups (P=0.28 and P=0.25, respectively). Additional analysis revealed lower postoperative arterial Pco2 as a risk factor for new white matter injury (P=0.04). CONCLUSIONS: In this group of neonates undergoing complex cardiac surgery, we were unable to demonstrate a difference in the incidence of perioperative cerebral injury after ACP compared with DHCA. Both techniques resulted in a high incidence of new white matter injury, with central infarctions occurring exclusively after ACP. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01032876.

The effect of short-term high versus normal protein intake on whole-body protein synthesis and balance in children following cardiac surgery: a randomized double-blind controlled clinical trial.

BACKGROUND: Infants undergoing cardiac surgery are at risk of a negative protein balance, due to increased proteolysis in response to surgery and the cardiopulmonary bypass circuit, and limited intake. The aim of the study was to quantify the effect on protein kinetics of a short-term high-protein (HP) diet in infants following cardiac surgery. METHODS: In a prospective, double-blinded, randomized trial we compared the effects of a HP (5 g · kg(-1) · d(-1)) versus normal protein (NP, 2 g · kg(-1) · d(-1)) enteral diet on protein kinetics in children <24 months, on day 2 following surgical repair of congenital heart disease. Valine kinetics and fractional albumin synthesis rate (FSRalb) were measured with mass spectrometry using [1-(13)C]valine infusion. The Mann-Whitney U test was used to investigate differences between group medians. Additionally, the Hodges-Lehmann procedure was used to create a confidence interval with a point estimate of median differences between groups. RESULTS: Twenty-eight children (median age 9 months, median weight 7 kg) participated in the study, of whom in only 20 subjects isotopic data could be used for final calculations. Due to underpowering of our study, we could not draw conclusions on the primary outcome parameters. We observed valine synthesis rate of 2.73 (range: 0.94 to 3.36) and 2.26 (1.85 to 2.73) µmol · kg(-1) · min(-1) in the HP and NP diet, respectively. The net valine balance was 0.54 (-0.73 to 1.75) and 0.24 (-0.20 to 0.63) µmol · kg(-1) · min(-1) in the HP and NP group. Between groups, there was no difference in FSRalb. We observed increased oxidation and BUN in the HP diet, compared to the NP diet, as a plausible explanation of the metabolic fate of surplus protein. CONCLUSIONS: It is plausible that the surplus protein in the HP group has caused the increase of valine oxidation and ureagenesis, compared to the NP group. Because too few patients had completed the study, we were unable to draw conclusions on the effect of a HP diet on protein synthesis and balance. We present our results as new hypothesis generating data. TRIAL REGISTRATION: Dutch Trial Register NTR2334.

Minimizing the risk of preoperative brain injury in neonates with aortic arch obstruction.

OBJECTIVE: To determine whether prenatal diagnosis lowers the risk of preoperative brain injury by assessing differences in the incidence of preoperative brain injury across centers. STUDY DESIGN: From 2 prospective cohorts of newborns with complex congenital heart disease studied by preoperative cerebral magnetic resonance imaging, one cohort from the University Medical Center Utrecht (UMCU) and a combined cohort from the University of California San Francisco (UCSF) and University of British Columbia (UBC), patients with aortic arch obstruction were selected and their imaging and clinical course reviewed. RESULTS: Birth characteristics were comparable between UMCU (n = 33) and UCSF/UBC (n = 54). Patients had a hypoplastic aortic arch with either coarctation/interruption or hypoplastic left heart syndrome. In subjects with prenatal diagnosis, there was a significant difference in the prevalence of white matter injury (WMI) between centers (11 of 22 [50%] at UMCU vs 4 of 30 [13%] at UCSF/UBC; P < .01). Prenatal diagnosis was protective for WMI at UCSF/UBC (13% prenatal diagnoses vs 50% postnatal diagnoses; P < .01), but not at UMCU (50% vs 46%, respectively; P > .99). Differences in clinical practice between prenatally diagnosed subjects at UMCU vs UCSF/UBC included older age at surgery, less time spent in the intensive care unit, greater use of diuretics, less use of total parenteral nutrition (P < .01), and a greater incidence of infections (P = .01). In patients diagnosed postnatally, the prevalence of WMI was similar in the 2 centers (46% at UMCU vs 50% at UCSF/UBC; P > .99). Stroke prevalence was similar in the 2 centers regardless of prenatal diagnosis (prenatal diagnosis: 4.5% at Utrecht vs 6.7% at UCSF/UBC, P = .75; postnatal diagnosis: 9.1% vs 13%, respectively, P > .99). CONCLUSION: Prenatal diagnosis can be protective for WMI, but this protection may be dependent on specific clinical management practices that differ across centers.

Population Pharmacokinetics and Target Attainment of Allopurinol and Oxypurinol Before, During, and After Cardiac Surgery with Cardiopulmonary Bypass in Neonates with Critical Congenital Heart Disease.

BACKGROUND: The CRUCIAL trial (NCT04217421) is investigating the effect of postnatal and perioperative administration of allopurinol on postoperative brain injury in neonates with critical congenital heart disease (CCHD) undergoing cardiac surgery with cardiopulmonary bypass (CPB) shortly after birth. OBJECTIVE: This study aimed to characterize the pharmacokinetics (PK) of allopurinol and oxypurinol during the preoperative, intraoperative, and postoperative phases in this population, and to evaluate target attainment of the current dosing strategy. METHODS: Nonlinear mixed-effects modeling was used to develop population PK models in 14 neonates from the CRUCIAL trial who received up to five intravenous allopurinol administrations throughout the postnatal and perioperative periods. Target attainment was defined as achieving an allopurinol concentration >2 mg/L in at least two-thirds of the patients during the first 24 h after birth and between the start and 36 h after cardiac surgery with CPB. RESULTS: A two-compartment model for allopurinol was connected to a one-compartment model for oxypurinol with an auto-inhibition effect on the conversion, which best described the PK. In a typical neonate weighing 3.5 kg who underwent cardiac surgery at a postnatal age (PNA) of 5.6 days, the clearance (CL) of allopurinol and oxypurinol at birth was 0.95 L/h (95% confidence interval 0.75-1.2) and 0.21 L/h (0.17-0.27), respectively, which subsequently increased with PNA to 2.97 L/h and 0.41 L/h, respectively, before CPB. During CPB, allopurinol and oxypurinol CL decreased to 1.38 L/h (0.9-1.87) and 0.12 L/h (0.05-0.22), respectively. Post-CPB, allopurinol CL increased to 2.21 L/h (1.74-2.83), while oxypurinol CL dropped to 0.05 L/h (0.01-0.1). Target attainment was 100%, 53.8%, and 100% at 24 h postnatally, 24 h after the start of CPB, and 36 h after the end of cardiac surgery, respectively. The combined concentrations of allopurinol and oxypurinol maintained ≥ 90% inhibition of xanthine oxidase (IC90XO) throughout the postnatal and perioperative period. CONCLUSIONS: The minimal target concentration of allopurinol was not achieved at every predefined time interval in the CRUCIAL trial; however, the dosing strategy used was deemed adequate, since it yielded concentrations well exceeding the IC90XO. The decreased CL of both compounds during CPB suggests influence of the hypothermia, hemofiltration, and the potential sequestration of allopurinol in the circuit. The reduced CL of oxypurinol after CPB is likely attributable to impaired kidney function.

Placental Pathology Contributes to Impaired Volumetric Brain Development in Neonates With Congenital Heart Disease.

BACKGROUND: Neonates with congenital heart disease are at risk for impaired brain development in utero, predisposing children to postnatal brain injury and adverse long-term neurodevelopmental outcomes. Given the vital role of the placenta in fetal growth, we assessed the incidence of placental pathology in fetal congenital heart disease and explored its association with total and regional brain volumes, gyrification, and brain injury after birth. METHODS AND RESULTS: Placentas from 96 term singleton pregnancies with severe fetal congenital heart disease were prospectively analyzed for macroscopic and microscopic pathology. We applied a placental pathology severity score to relate placental abnormalities to neurological outcome. Postnatal, presurgical magnetic resonance imaging was used to analyze brain volumes, gyrification, and brain injuries. Placental analyses revealed the following abnormalities: maternal vascular malperfusion lesions in 46%, nucleated red blood cells in 37%, chronic inflammatory lesions in 35%, delayed maturation in 30%, and placental weight below the 10th percentile in 28%. Severity of placental pathology was negatively correlated with cortical gray matter, deep gray matter, brainstem, cerebellar, and total brain volumes (r=-0.25 to -0.31, all P<0.05). When correcting for postmenstrual age at magnetic resonance imaging in linear regression, this association remained significant for cortical gray matter, cerebellar, and total brain volume (adjusted R2=0.25-0.47, all P<0.05). CONCLUSIONS: Placental pathology occurs frequently in neonates with severe congenital heart disease and may contribute to impaired brain development, indicated by the association between placental pathology severity and reductions in postnatal cortical, cerebellar, and total brain volumes.

Cerebral ischemia initiates an immediate innate immune response in neonates during cardiac surgery.

BACKGROUND: A robust inflammatory response occurs in the hours and days following cerebral ischemia. However, little is known about the immediate innate immune response in the first minutes after an ischemic insult in humans. We utilized the use of circulatory arrest during cardiac surgery to assess this. METHODS: Twelve neonates diagnosed with an aortic arch obstruction underwent cardiac surgery with cardiopulmonary bypass and approximately 30 minutes of deep hypothermic circulatory arrest (DHCA, representing cerebral ischemia). Blood samples were drawn from the vena cava superior immediately after DHCA and at various other time points from preoperatively to 24 hours after surgery. The innate immune response was assessed by neutrophil and monocyte count and phenotype using FACS, and concentrations of cytokines IL-1ß, IL-6, IL-8, IL-10, TNFα, sVCAM-1 and MCP-1 were assessed using multiplex immunoassay. Results were compared to a simultaneously drawn sample from the arterial cannula. Twelve other neonates were randomly allocated to undergo the same procedure but with continuous antegrade cerebral perfusion (ACP). RESULTS: Immediately after cerebral ischemia (DHCA), neutrophil and monocyte counts were higher in venous blood than arterial (P = 0.03 and P = 0.02 respectively). The phenotypes of these cells showed an activated state (both P <0.01). Most striking was the increase in the 'non-classical' monocyte subpopulations (CD16(intermediate); arterial 6.6% vs. venous 14%; CD16+ 13% vs. 22%, both P <0.01). Also, higher IL-6 and lower sVCAM-1 concentrations were found in venous blood (both P = 0.03). In contrast, in the ACP group, all inflammatory parameters remained stable. CONCLUSIONS: In neonates, approximately 30 minutes of cerebral ischemia during deep hypothermia elicits an immediate innate immune response, especially of the monocyte compartment. This phenomenon may hold important clues for the understanding of the inflammatory response to stroke and its potentially detrimental consequences. TRIAL REGISTRATION: ClinicalTrial.gov: NCT01032876.

Long-term restoration of the human T-cell compartment after thymectomy during infancy: a role for thymic regeneration?

Thymectomy during early childhood is generally thought to have serious consequences for the establishment of the T-cell compartment. In the present study, we investigated the composition of the T-cell pool in the first 3 decades after thymectomy during infancy due to cardiac surgery. In the first 5 years after thymectomy, naive and total CD4(+) and CD8(+) T-cell numbers in the blood and T-cell receptor excision circle (TREC) levels in CD4(+) T cells were significantly lower than in healthy age-matched controls. In the first years after thymectomy, plasma IL-7 levels were significantly elevated and peripheral T-cell proliferation levels were increased by ∼ 2-fold. From 5 years after thymectomy onward, naive CD4(+) and CD8(+) T-cell counts and TRECs were within the normal range. Because TREC levels are expected to decline continuously in the absence of thymic output, we investigated whether normalization of the naive T-cell pool could be due to regeneration of thymic tissue. In the majority of individuals who had been thymectomized during infancy, thymic tissue could indeed be identified on magnetic resonance imaging scans. Whereas thymectomy has severe effects on the establishment of the naive T-cell compartment during early childhood, our data suggest that functional regrowth of thymic tissue can limit its effects in subsequent years.

FOXP3+ CD4+ Tregs lose suppressive potential but remain anergic during transient inflammation in human.

Tregs are crucial in controlling inflammation. Although the transcription factor FOXP3 is the most applicable phenotype marker of Tregs, it does not indisputably characterize suppressive function during T-cell activation in vitro. A question that remains is: what is the functionality of FOXP3(+) T cells during inflammation in vivo? We studied FOXP3(+) T cells in a human model of acute inflammation due to cardiac surgery. Twenty-five children who underwent cardiac surgery for correction of a septum defect were included. Following surgery, we observed a transient systemic inflammatory response accompanied by an increased proportion of CD25(bright) T cells with sustained Treg phenotype. During this transient immune activation, both the percentage of CD4(+) FOXP3(+) cells and the level of expression of FOXP3 in the CD4(+) CD25(bright) CD127(low) population increased. While Tregs remained present during systemic inflammation and continued to be anergic, the capacity to suppress effector T cells was reduced. The reduced suppressive state of Tregs could be induced in vitro by plasma obtained during the peak of inflammation after surgery. These data show that inflammation inhibits Treg function through soluble factors present in plasma. These results underscore the functional role of FOXP3(+) Tregs during inflammation in vivo.