Francis X. McGowan

Adult mouse epicardium modulates myocardial injury by secreting paracrine factors

The epicardium makes essential cellular and paracrine contributions to the growth of the fetal myocardium and the formation of the coronary vasculature. However, whether the epicardium has similar roles postnatally in the normal and injured heart remains enigmatic. Here, we have investigated this question using genetic fate-mapping approaches in mice. In uninjured postnatal heart, epicardial cells were quiescent. Myocardial infarction increased epicardial cell proliferation and stimulated formation of epicardium-derived cells (EPDCs), which remained in a thickened layer on the surface of the heart. EPDCs did not adopt cardiomyocyte or coronary EC fates, but rather differentiated into mesenchymal cells expressing fibroblast and smooth muscle cell markers. In vitro and in vivo assays demonstrated that EPDCs secreted paracrine factors that strongly promoted angiogenesis. In a myocardial infarction model, EPDC-conditioned medium reduced infarct size and improved heart function. Our findings indicate that epicardium modulates the cardiac injury response by conditioning the subepicardial environment, potentially offering a new therapeutic strategy for cardiac protection.

Pharmacokinetics of Remifentanil in Anesthetized Pediatric Patients Undergoing Elective Surgery or Diagnostic Procedures

Remifentanil hydrochloride is an ultra-short-acting opioid that undergoes rapid metabolism by tissue and plasma esterases. We aimed to characterize the pharmacokinetics and determine the hemodynamic profile of remifentanil after a single-bolus dose in children aged 0 to 18 yr. Forty-two children undergoing elective surgical procedures received remifentanil 5 &mgr;g/kg infused over 1 min. Patients were divided into age groups as follows: young infants (≤2 mo), older infants (>2 mo to <2 yr), young children (2 to <7 yr), older children (7 to <13 yr), adolescents (13 to <16 yr), and young adults (16 to <18 yr). Arterial blood samples were collected and analyzed by mass spectroscopy to determine remifentanil pharmacokinetic profiles. Hemodynamic measurements for remifentanil’s effect were made after the infusion. Methods of statistical analysis included analysis of variance and linear regression, with significance at P ≤ 0.05. Complete remifentanil pharmacokinetic data were obtained from 34 patients. The volume of distribution was largest in the infants <2 mo (mean, 452 mL/kg) and decreased to means of 223 to 308 mL/kg in the older patients. There was a more rapid clearance in the infants <2 mo of age (90 mL · kg−1 · min−1) and infants 2 mo to 2 yr (92 mL · kg−1 · min−1) than in the other groups (means, 46 to 76 mL · kg−1 · min−1). The half-life was similar in all age groups, with means of 3.4 to 5.7 min. Seven subjects (17%) developed hypotension related to the remifentanil bolus. Remifentanil showed an extremely rapid elimination similar to that in adults. The fast clearance rates observed in neonates and infants, as well as the lack of age-related changes in half-life, are in sharp contrast to the pharmacokinetic profile of other opioids. Remifentanil in a bolus dose of 5 &mgr;g/kg may cause hypotension in anesthetized children.

Transesophageal echocardiographic guidance of transcatheter closure of atrial septal defect

Transcatheter closure of atrial septal defect (ASD) was accomplished in 10 of 11 patients aged 13 months to 46 years (weight range 11 to 77 kg). Transesophageal echocardiography (TEE) was used simultaneously with fluoroscopic imaging in 4 of these patients aged 4.5 to 46 years (weight range 19 to 77 kg). TEE was used to ascertain defect size, position and number of defects and to ascertain appropriate seating of the defect occluder within the atrial defect. In 2 patients TEE-assisted transcatheter ASD closure was accomplished after previous attempts at transcatheter ASD closure, unaided by TEE, had been unsuccessful. The only unsuccessful ASD closure procedure occurred in the smallest patient in the series (an 11-kg 13-month-old), a child who was too small to undergo TEE using our 11-mm diameter endoscopic probe. The concomitant use of TEE with fluoroscopic imaging provides information that is unique and complementary and may improve the efficacy and safety of the transcatheter technique for ASD closure. The recent availability of a 7-mm diameter TEE probe will extend the use of TEE into the infant age group and may decrease the discomfort and potential morbidity of TEE in older patients.

Association Between a Single General Anesthesia Exposure Before Age 36 Months and Neurocognitive Outcomes in Later Childhood.

IMPORTANCE Exposure of young animals to commonly used anesthetics causes neurotoxicity including impaired neurocognitive function and abnormal behavior. The potential neurocognitive and behavioral effects of anesthesia exposure in young children are thus important to understand. OBJECTIVE To examine if a single anesthesia exposure in otherwise healthy young children was associated with impaired neurocognitive development and abnormal behavior in later childhood. DESIGN, SETTING, AND PARTICIPANTS Sibling-matched cohort study conducted between May 2009 and April 2015 at 4 university-based US pediatric tertiary care hospitals. The study cohort included sibling pairs within 36 months in age and currently 8 to 15 years old. The exposed siblings were healthy at surgery/anesthesia. Neurocognitive and behavior outcomes were prospectively assessed with retrospectively documented anesthesia exposure data. EXPOSURES A single exposure to general anesthesia during inguinal hernia surgery in the exposed sibling and no anesthesia exposure in the unexposed sibling, before age 36 months. MAIN OUTCOMES AND MEASURES The primary outcome was global cognitive function (IQ). Secondary outcomes included domain-specific neurocognitive functions and behavior. A detailed neuropsychological battery assessed IQ and domain-specific neurocognitive functions. Parents completed validated, standardized reports of behavior. RESULTS Among the 105 sibling pairs, the exposed siblings (mean age, 17.3 months at surgery/anesthesia; 9.5% female) and the unexposed siblings (44% female) had IQ testing at mean ages of 10.6 and 10.9 years, respectively. All exposed children received inhaled anesthetic agents, and anesthesia duration ranged from 20 to 240 minutes, with a median duration of 80 minutes. Mean IQ scores between exposed siblings (scores: full scale = 111; performance = 108; verbal = 111) and unexposed siblings (scores: full scale = 111; performance = 107; verbal = 111) were not statistically significantly different. Differences in mean IQ scores between sibling pairs were: full scale = -0.2 (95% CI, -2.6 to 2.9); performance = 0.5 (95% CI, -2.7 to 3.7); and verbal = -0.5 (95% CI, -3.2 to 2.2). No statistically significant differences in mean scores were found between sibling pairs in memory/learning, motor/processing speed, visuospatial function, attention, executive function, language, or behavior. CONCLUSIONS AND RELEVANCE Among healthy children with a single anesthesia exposure before age 36 months, compared with healthy siblings with no anesthesia exposure, there were no statistically significant differences in IQ scores in later childhood. Further study of repeated exposure, prolonged exposure, and vulnerable subgroups is needed.

Cardiovascular causes of airway compression

Compression of the paediatric airway is a relatively common and often unrecognized complication of congenital cardiac and aortic arch anomalies. Airway obstruction may be the result of an anomalous relationship between the tracheobronchial tree and vascular structures (producing a vascular ring) or the result of extrinsic compression caused by dilated pulmonary arteries, left atrial enlargement, massive cardiomegaly, or intraluminal bronchial obstruction. A high index of suspicion of mechanical airway compression should be maintained in infants and children with recurrent respiratory difficulties, stridor, wheezing, dysphagia, or apnoea unexplained by other causes. Prompt diagnosis is required to avoid death and minimize airway damage. In addition to plain chest radiography and echocardiography, diagnostic investigations may consist of barium oesophagography, magnetic resonance imaging (MRI), computed tomography, cardiac catheterization and bronchoscopy. The most important recent advance is MRI, which can produce high quality three‐dimensional reconstruction of all anatomic elements allowing for precise anatomic delineation and improved surgical planning. Anaesthetic technique will depend on the type of vascular ring and the presence of any congenital heart disease or intrinsic lesions of the tracheobronchial tree. Vascular rings may be repaired through a conventional posterolateral thoracotomy, or utilizing video‐assisted thoracoscopic surgery (VATS) or robotic endoscopic surgery. Persistent airway obstruction following surgical repair may be due to residual compression, secondary airway wall instability (malacia), or intrinsic lesions of the airway. Simultaneous repair of cardiac defects and vascular tracheobronchial compression carries a higher risk of morbidity and mortality.

Efficacy of Tranexamic Acid in Pediatric Craniosynostosis Surgery: A Double-blind, Placebo-controlled Trial

Background:Extensive blood loss is common in pediatric craniosynostosis reconstruction surgery. Tranexamic acid (TXA) is increasingly used to reduce perioperative blood loss in various settings, but data on its efficacy are limited in children. The purpose of this randomized, double-blind, placebo-controlled, parallel trial was to evaluate the efficacy of TXA in pediatric craniosynostosis correction surgery. The primary and secondary outcome variables were reduction in perioperative blood loss and reduction in blood transfusion, respectively. Methods:Forty-three children, ages 2 months to 6 yr, received either placebo or TXA in a loading dose of 50 mg·kg−1, followed by an infusion of 5 mg·kg−1·h−1 during surgery. TXA plasma concentrations were measured. Results:The TXA group had significantly lower perioperative mean blood loss (65 vs. 119 ml·kg−1, P < 0.001) and lower perioperative mean blood transfusion (33 vs. 56 ml· kg−1, P = 0.006) compared to the placebo group. The mean difference between the TXA and placebo groups for total blood loss was 54 ml·kg−1 (95% CI for the difference, 23–84 ml·kg−1) and for packed erythrocytes transfused was 23 ml·kg−1 (95% CI for the difference, 7–39 ml·kg−1). TXA administration also significantly diminished (by two thirds) the perioperative exposure of patients to transfused blood (median, 1 unit vs. 3 units; P < 0.001). TXA plasma concentrations were maintained above the in vitro thresholds reported for inhibition of fibrinolysis (10 &mgr;g·ml−1) and plasmin-induced platelet activation (16 &mgr;g·ml−1) throughout the infusion. Conclusions:TXA is effective in reducing perioperative blood loss and transfusion requirement in children undergoing craniosynostosis reconstruction surgery.

Blood Transfusion After Pediatric Cardiac Surgery Is Associated With Prolonged Hospital Stay

BACKGROUND Red blood cell transfusion is associated with morbidity and mortality among adults undergoing cardiac surgery. We aimed to evaluate the association of transfusion with morbidity among pediatric cardiac surgical patients. METHODS Patients discharged after cardiac surgery in 2003 were retrospectively reviewed. The red blood cell volume administered during the first 48 postoperative hours was used to classify patients into nonexposure, low exposure (≤15 mL/kg), or high exposure (>15 mL/kg) groups. Cox proportional hazards modeling was used to evaluate the association of red blood cell exposure to length of hospital stay (LOS). RESULTS Of 802 discharges, 371 patients (46.2%) required blood transfusion. Demographic differences between the transfusion exposure groups included age, weight, prematurity, and noncardiac structural abnormalities (all p<0.001). Distribution of Risk Adjusted Classification for Congenital Heart Surgery, version 1 (RACHS-1) categories, intraoperative support times, and postoperative Pediatric Risk of Mortality Score, Version III (PRISM-III) scores varied among the exposure groups (p<0.001). Median duration of mechanical ventilation (34 hours [0 to 493] versus 27 hours [0 to 621] versus 16 hours [0 to 375]), incidence of infection (21 [14%] versus 29 [13%] versus 17 [4%]), and acute kidney injury (25 [17%] versus 29 [13%] versus 34 [8%]) were highest in the high transfusion exposure group when compared with the low or nontransfusion groups (all p<0.001). In a multivariable Cox proportional hazards model, both the low transfusion group (adjusted hazard ratio [HR] 0.80, 95% confidence interval [CI]: 0.66 to 0.97, p=0.02) and high transfusion group (adjusted HR 0.66, 95% CI: 0.53 to 0.82, p<0.001) were associated with increased LOS. In subgroup analyses, both low transfusion (adjusted HR 0.81, 95% CI: 0.65 to 1.00, p=0.05) and high transfusion (adjusted HR 0.65, 95% CI: 0.49 to 0.87, p=0.004) in the biventricular group but not in the single ventricle group was associated with increased LOS. CONCLUSIONS Blood transfusion is associated with prolonged hospitalization of children after cardiac surgery, with biventricular patients at highest risk for increased LOS. Future studies are necessary to explore this association and refine transfusion practices.

Stress response in infants undergoing cardiac surgery: a randomized study of fentanyl bolus, fentanyl infusion, and fentanyl-midazolam infusion.

There have been significant changes in the management of neonates and infants undergoing cardiac surgery in the past decade. We have evaluated in this prospective, randomized, double-blinded study the effect of large-dose fentanyl anesthesia, with or without midazolam, on stress responses and outcome. Forty-five patients < 6 mo of age received bolus fentanyl (Group 1), fentanyl by continuous infusion (Group 2), or fentanyl-midazolam infusion (Group 3). Epinephrine, norepinephrine, cortisol, adrenocortical hormone, glucose, and lactate were measured after the induction (T1), after sternotomy (T2), 15 min after initiating cardiopulmonary bypass (T3), at the end of surgery (T4), and after 24 h in the intensive care unit (T5). Plasma fentanyl concentrations were obtained at all time points except at T5. Within each group epinephrine, norepinephrine, cortisol, glucose and lactate levels were significantly larger at T4 (P values < 0.01), but there were no differences among groups. Within groups, fentanyl levels were significantly larger in Groups 2 and 3 (P < 0.001) at T4, and among groups, the fentanyl level was larger only at T2 in Group 1 compared with Groups 2 and 3 (P <0.006). There were no deaths or postoperative complications, and no significant differences in duration of mechanical ventilation or intensive care unit or hospital stay. Fentanyl dosing strategies, with or without midazolam, do not prevent a hormonal or metabolic stress response in infants undergoing cardiac surgery.

Procoagulant and anticoagulant factor abnormalities following the fontan procedure: increased factor VIII may predispose to thrombosis

OBJECTIVE Using age-matched controls, this study prospectively evaluated coagulation factor abnormalities and hemodynamic variables in children who had undergone the Fontan operation. METHODS Coagulation factors were assayed in 20 children (mean age 6.4 +/- 2.9 years), at a mean 3.7 +/- 2.3 years after the Fontan procedure; 24 healthy children (mean age 6.8 +/- 2.8 years) were assayed as controls. Concentration of factors II, V, VII, VIII, IX, X; ATIII; plasminogen; proteins C and S; fibrinogen; serum albumin; and liver enzymes were measured. Normal reference intervals based on the control patients were determined using 95% confidence limits. Patient demographic, hemodynamic variables, and elapsed time after the Fontan procedure were evaluated as possible predictors of coagulation abnormalities. RESULTS Concentrations of protein C; factors II, V, VII, X; plasminogen; and ATIII were significantly lower in Fontan patients compared with age-matched controls (P <.01); factor VIII was significantly elevated in 6 patients (35%), 2 of whom had a thromboembolic event. A higher superior vena cava pressure was predictive of an elevated factor VIII level (P =.003). No other specific hemodynamic variables were predictive of a procoagulant or anticoagulant abnormality. CONCLUSION Procoagulant and anticoagulant factor levels were significantly lower in patients after the Fontan operation independent of hemodynamic variables peculiar to the Fontan circulation. Increased factor VIII level requires further evaluation as a cause of thrombosis in patients with Fontan physiology and may also indicate a subset of these patients in whom anticoagulation is indicated.

CON : The Toxic Effects of Anesthetics in the Developing Brain: The Clinical Perspective

Sulpicio G. Soriano, MD, FAAP‡ “All models are wrong, some models are useful” This quote by the statistician George E. P. Box seems to have relevance for the current preeminent controversy in pediatric anesthesiology, namely, developmental neuroapoptotic cell death after an anesthetic exposure in the immature brain. Worldwide, general anesthetics and sedatives are used in hundreds of thousands of neonates and infants every year during surgical operations, invasive procedures, and imaging studies. The possibility of anesthesiainduced neuronal cell loss, as suggested by animal models, during an otherwise uneventful procedure has sparked vigorous discussions among anesthesiologists about the safety of anesthesia in human newborns and infants. These concerns were recently addressed at the March 29, 2007, public hearing of the Anesthesia and Life Support Drugs Advisory Committee of the Food and Drug Administration (transcript available at http://www. fda.gov/ohrms/dockets/ac/07/transcripts/2007-4285t1.pdf). Although the exact mechanism of general anesthesia is not entirely understood, alterations of synaptic transmission involving -aminobutyric acid type A (GABAA) and N-methyl-d-aspartate (NMDA) glutamate receptors, to varying degrees, seem to play an important role. Because GABA and NMDA-mediated neuronal activity is essential for normal mammalian brain development, exposure to anesthetics could potentially interfere with brain maturation, learning, and neurocognitive function. Concerns about the effects of general anesthetics on neuronal structure and neurocognitive function were first raised more than two decades ago. In a series of studies, chronic subanesthetic exposure of pregnant rats to halothane led to delayed synaptogenesis and behavioral abnormalities in their pups. More recently, the potential for ketamine to cause increased neuronal cell death was documented in rat pups. However, although ketamine is rarely used for pediatric anesthesia, general anesthetics routinely used in pediatric practice have subsequently also been implicated not only in producing widespread neuronal cell death, but also in leading to long-term cognitive impairment in adult animals exposed to neonatal anesthesia. A 6-h exposure to a combination of isoflurane, nitrous oxide, and midazolam led to widespread apoptotic brain cell death in 7-day-old rats. When animals were examined in adulthood, many tests of behavior and attention remained normal. However, several tests of spatial learning and memory demonstrated impairment in adult animals that were exposed to the anesthetic cocktail as neonates, compared with their unanesthetized littermates. Several groups of investigators have now confirmed the neurotoxic effects of various anesthetics in a variety of in vivo and in vitro developing animal models. From the *Departments of Anesthesia and Pediatrics, Cincinnati Children’s Hospital Medical Center and University of Cincinnati College of Medicine; and †Institute of Pediatric Anesthesia, Cincinnati Children’s Research Foundation, Cincinnati, Ohio; and ‡Department of Anaesthesia, Children’s Hospital Boston and Harvard Medical School, Boston, Massachusetts. Accepted for publication March 5, 2008. Address correspondence and reprint requests to Dr. Andreas Loepke, Department of Anesthesia, Cincinnati Children’s Hospital Medical Center, ML2001, 3333 Burnet Ave., Cincinnati, OH 45229. Address e-mail to Andreas.Loepke@cchmc.org. Copyright