First-attempt success rate of video laryngoscopy in small infants (VISI): a multicentre, randomised controlled trial.

BACKGROUND: Orotracheal intubation of infants using direct laryngoscopy can be challenging. We aimed to investigate whether video laryngoscopy with a standard blade done by anaesthesia clinicians improves the first-attempt success rate of orotracheal intubation and reduces the risk of complications when compared with direct laryngoscopy. We hypothesised that the first-attempt success rate would be higher with video laryngoscopy than with direct laryngoscopy. METHODS: In this multicentre, parallel group, randomised controlled trial, we recruited infants without difficult airways abnormalities requiring orotracheal intubation in operating theatres at four quaternary children's hospitals in the USA and one in Australia. We randomly assigned patients (1:1) to video laryngoscopy or direct laryngoscopy using random permuted blocks of size 2, 4, and 6, and stratified by site and clinician role. Guardians were masked to group assignment. The primary outcome was the proportion of infants with a successful first attempt at orotracheal intubation. Analysis (modified intention-to-treat [mITT] and per-protocol) used a generalised estimating equation model to account for clustering of patients treated by the same clinician and institution, and adjusted for gestational age, American Society of Anesthesiologists physical status, weight, clinician role, and institution. The trial is registered at ClinicalTrials.gov, NCT03396432. FINDINGS: Between June 4, 2018, and Aug 19, 2019, 564 infants were randomly assigned: 282 (50%) to video laryngoscopy and 282 (50%) to direct laryngoscopy. The mean age of infants was 5·5 months (SD 3·3). 274 infants in the video laryngoscopy group and 278 infants in the direct laryngoscopy group were included in the mITT analysis. In the video laryngoscopy group, 254 (93%) infants were successfully intubated on the first attempt compared with 244 (88%) in the direct laryngoscopy group (adjusted absolute risk difference 5·5% [95% CI 0·7 to 10·3]; p=0·024). Severe complications occurred in four (2%) infants in the video laryngoscopy group compared with 15 (5%) in the direct laryngoscopy group (-3·7% [-6·5 to -0·9]; p=0·0087). Fewer oesophageal intubations occurred in the video laryngoscopy group (n=1 [<1%]) compared with in the direct laryngoscopy group (n=7 [3%]; -2·3 [-4·3 to -0·3]; p=0·028). INTERPRETATION: Among anaesthetised infants, using video laryngoscopy with a standard blade improves the first-attempt success rate and reduces complications. FUNDING: Anaesthesia Patient Safety Foundation, Society for Airway Management, and Karl Storz Endoscopy.

Preoperative echocardiographic parameters predict primary graft dysfunction following pediatric lung transplantation.

The importance of preoperative cardiac function in pediatric lung transplantation is unknown. We hypothesized that worse preoperative right ventricular (RV) systolic and worse left ventricular (LV) diastolic function would be associated with a higher risk of primary graft dysfunction grade 3 (PGD 3) between 48 and 72 hours. We performed a single center, retrospective pilot study of children (<18 years) who had echocardiograms <1 year prior to lung transplantation between 2006 and 2019. Conventional and strain echocardiography parameters were measured, and PGD was graded. Area under the receiver operating characteristic (AUROC) curves and logistic regression were performed. Forty-one patients were included; 14 (34%) developed PGD 3 and were more likely to have pulmonary hypertension (PH) as the indication for transplant (P = .005). PGD 3 patients had worse RV global longitudinal strain (P = .01), RV free wall strain (FWS) (P = .003), RV fractional area change (P = .005), E/e' (P = .01) and lateral e' velocity (P = .004) but not tricuspid annular plane systolic excursion (P = .61). RV FWS (AUROC 0.79, 95% CI 0.62-0.95) and lateral e' velocity (AUROC 0.87, 95% CI 0.68-1.00) best discriminated PGD 3 development and showed the strongest association with PGD 3 (RV FWS OR 3.87 [95% CI 1.59-9.43], P = .003; lateral e' velocity OR 0.10 [95% CI 0.01-0.70], P = .02). These associations remained when separately adjusting for age, weight, primary PH diagnosis, ischemic time, and bypass time. In this pilot study, worse preoperative RV systolic and worse LV diastolic function were associated with PGD 3 and may be modifiable recipient risk factors in pediatric lung transplantation.

New or Persistent Right Ventricular Systolic Dysfunction Is Associated With Worse Outcomes in Pediatric Acute Respiratory Distress Syndrome.

OBJECTIVES: The trajectory and importance of right ventricular systolic function and pulmonary hypertension during the course of pediatric acute respiratory distress syndrome are unknown. We hypothesized that new or persistent right ventricular systolic dysfunction and pulmonary hypertension would be associated with worse patient outcomes. DESIGN: Retrospective, single-center cohort study. SETTING: Tertiary care, university-affiliated PICU. PATIENTS: Children who had at least two echocardiograms less than 8 days following pediatric acute respiratory distress syndrome diagnosis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Between July 1, 2012, and April 30, 2018, 74 children met inclusion criteria. The first echocardiogram was performed a median of 0.61 days (interquartile range, 0.36-0.94 d) and the second echocardiogram was performed a median of 2.57 days (interquartile range, 1.67-3.63 d) after pediatric acute respiratory distress syndrome diagnosis. Univariate analyses showed that new or persistent right ventricular systolic dysfunction as defined by global longitudinal strain or free wall strain was associated with a greater number of ICU days in survivors (global longitudinal strain p = 0.04, free wall strain p = 0.04), lower ventilator-free days at 28 days (global longitudinal strain p = 0.03, free wall strain p = 0.01), and higher rate of PICU death (global longitudinal strain p = 0.046, free wall strain p = 0.01). Mixed-effects multivariate modeling showed that right ventricular global longitudinal strain and right ventricular fractional area change stayed relatively constant over the course of the first 8 days in nonsurvivors and that there was a linear improvement in global longitudinal strain (p = 0.037) and fractional area change (p = 0.05) in survivors. Worsening right ventricular dysfunction at the time of repeat echocardiogram as defined by global longitudinal strain and free wall strain were independently associated with decreased probability of extubation (subdistribution hazard ratio, 0.30 [0.14-0.67]; p = 0.003 and subdistribution hazard ratio, 0.47 [0.23-0.98]; p = 0.043, respectively). In univariate and multivariate analyses, pulmonary hypertension had no significant associations with outcomes in his cohort. CONCLUSIONS: New or persistent right ventricular systolic dysfunction over the first week following pediatric acute respiratory distress syndrome onset is associated with worse patient outcomes, including decreased probability of extubation and higher PICU mortality.

Prevalence and Outcomes of Pediatric In-Hospital Cardiac Arrest Associated With Pulmonary Hypertension.

OBJECTIVES: In adult in-hospital cardiac arrest, pulmonary hypertension is associated with worse outcomes, but pulmonary hypertension-associated in-hospital cardiac arrest has not been well studied in children. The objective of this study was to determine the prevalence of pulmonary hypertension among children with in-hospital cardiac arrest and its impact on outcomes. DESIGN: Retrospective single-center cohort study. SETTING: PICU of a quaternary care, academic children's hospital. PATIENTS: Children (<18 yr old) receiving greater than or equal to 1 minute of cardiopulmonary resuscitation (cardiopulmonary resuscitation) for an index in-hospital cardiac arrest with an echocardiogram in the 48 hours preceding in-hospital cardiac arrest, excluding those with cyanotic congenital heart disease. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 284 in-hospital cardiac arrest subjects, 57 (20%) had evaluable echocardiograms, which were analyzed by a cardiologist blinded to patient characteristics. Pulmonary hypertension was present in 20 of 57 (35%); nine of 20 (45%) had no prior pulmonary hypertension history. Children with pulmonary hypertension had worse right ventricular systolic function, measured by fractional area change (p = 0.005) and right ventricular global longitudinal strain (p = 0.046); more right ventricular dilation (p = 0.010); and better left ventricular systolic function (p = 0.001). Children with pulmonary hypertension were more likely to have abnormal baseline functional status and a history of chronic lung disease or acyanotic congenital heart disease and less likely to have sepsis or acute kidney injury. Children with pulmonary hypertension were more likely to have an initial rhythm of pulseless electrical activity or asystole and were more frequently treated with inhaled nitric oxide (80% vs 32%; p < 0.001) at the time of cardiopulmonary resuscitation. On multivariable analysis, pulmonary hypertension was not associated with event survival (14/20 [70%] vs 24/37 [65%]; adjusted odds ratio, 1.30 [CI95, 0.25-6.69]; p = 0.77) or survival to discharge (8/20 [40%] vs 10/37 [27%]; adjusted odds ratio, 1.17 [CI95, 0.22-6.44]; p = 0.85). CONCLUSIONS: Pulmonary hypertension physiology preceding pediatric in-hospital cardiac arrest may be more common than previously described. Among this cohort with a high frequency of inhaled nitric oxide treatment during cardiopulmonary resuscitation, pulmonary hypertension was not associated with survival outcomes.

Persistent Mitochondrial Dysfunction Linked to Prolonged Organ Dysfunction in Pediatric Sepsis.

OBJECTIVES: Limited data exist about the timing and significance of mitochondrial alterations in children with sepsis. We therefore sought to determine if alterations in mitochondrial respiration and content within circulating peripheral blood mononuclear cells were associated with organ dysfunction in pediatric sepsis. DESIGN: Prospective observational study SETTING:: Single academic PICU. PATIENTS: One-hundred sixty-seven children with sepsis/septic shock and 19 PICU controls without sepsis, infection, or organ dysfunction. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Mitochondrial respiration and content were measured in peripheral blood mononuclear cells on days 1-2, 3-5, and 8-14 after sepsis recognition or once for controls. Severity and duration of organ dysfunction were determined using the Pediatric Logistic Organ Dysfunction score and organ failure-free days through day 28. Day 1-2 maximal uncoupled respiration (9.7 ± 7.7 vs 13.7 ± 4.1 pmol O2/s/10 cells; p = 0.02) and spare respiratory capacity (an index of bioenergetic reserve: 6.2 ± 4.3 vs 9.6 ± 3.1; p = 0.005) were lower in sepsis than controls. Mitochondrial content, measured by mitochondrial DNA/nuclear DNA, was higher in sepsis on day 1-2 than controls (p = 0.04) and increased in sepsis patients who had improving spare respiratory capacity over time (p = 0.005). Mitochondrial respiration and content were not associated with day 1-2 Pediatric Logistic Organ Dysfunction score, but low spare respiratory capacity was associated with higher Pediatric Logistic Organ Dysfunction score on day 3-5. Persistently low spare respiratory capacity was predictive of residual organ dysfunction on day 14 (area under the receiver operating characteristic, 0.72; 95% CI, 0.61-0.84) and trended toward fewer organ failure-free days although day 28 (ß coefficient, -0.64; 95% CI, -1.35 to 0.06; p = 0.08). CONCLUSIONS: Mitochondrial respiration was acutely decreased in peripheral blood mononuclear cells in pediatric sepsis despite an increase in mitochondrial content. Over time, a rise in mitochondrial DNA tracked with improved respiration. Although initial mitochondrial alterations in peripheral blood mononuclear cells were unrelated to organ dysfunction, persistently low respiration was associated with slower recovery from organ dysfunction.

Toward predictive modeling of catheter-based pulmonary valve replacement into native right ventricular outflow tracts.

BACKGROUND: Pulmonary insufficiency is a consequence of transannular patch repair in Tetralogy of Fallot (ToF) leading to late morbidity and mortality. Transcatheter native outflow tract pulmonary valve replacement has become a reality. However, predicting a secure, atraumatic implantation of a catheter-based device remains a significant challenge due to the complex and dynamic nature of the right ventricular outflow tract (RVOT). We sought to quantify the differences in compression and volume for actual implants, and those predicted by pre-implant modeling. METHODS: We used custom software to interactively place virtual transcatheter pulmonary valves (TPVs) into RVOT models created from pre-implant and post Harmony valve implant CT scans of 5 ovine surgical models of TOF to quantify and visualize device volume and compression. RESULTS: Virtual device placement visually mimicked actual device placement and allowed for quantification of device volume and radius. On average, simulated proximal and distal device volumes and compression did not vary statistically throughout the cardiac cycle (P = 0.11) but assessment was limited by small sample size. In comparison to actual implants, there was no significant pairwise difference in the proximal third of the device (P > 0.80), but the simulated distal device volume was significantly underestimated relative to actual device implant volume (P = 0.06). CONCLUSIONS: This study demonstrates that pre-implant modeling which assumes a rigid vessel wall may not accurately predict the degree of distal RVOT expansion following actual device placement. We suggest the potential for virtual modeling of TPVR to be a useful adjunct to procedural planning, but further development is needed.

Early Right Ventricular Systolic Dysfunction and Pulmonary Hypertension Are Associated With Worse Outcomes in Pediatric Acute Respiratory Distress Syndrome.

OBJECTIVES: The prevalence and importance of early right ventricular dysfunction and pulmonary hypertension in pediatric acute respiratory distress syndrome are unknown. We aimed to describe the prevalence of right ventricular dysfunction and pulmonary hypertension within 24 hours of pediatric acute respiratory distress syndrome diagnosis and their associations with outcomes. DESIGN: Retrospective, single-center cohort study. SETTING: Tertiary care, university-affiliated PICU. PATIENTS: Children who had echocardiograms performed within 24 hours of pediatric acute respiratory distress syndrome diagnosis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Between July 1, 2012, and June 30, 2016, 103 children met inclusion criteria. Echocardiograms were analyzed using established indices of right ventricular and left ventricular systolic function and for evidence of pulmonary hypertension. Echocardiographic abnormalities were common: 26% had low right ventricular fractional area change, 65% had low tricuspid annular plane systolic excursion, 30% had low left ventricular fractional shortening, and 21% had evidence of pulmonary hypertension. Abnormal right ventricular global longitudinal strain and abnormal right ventricular free wall strain were present in 35% and 40% of patients, respectively. No echocardiographic variables differed between or across pediatric acute respiratory distress syndrome severity. In multivariable analyses, right ventricular global longitudinal strain was independently associated with PICU mortality (odds ratio, 3.57 [1.33-9.60]; p = 0.01), whereas right ventricular global longitudinal strain, right ventricular free wall strain, and the presence of pulmonary hypertension were independently associated with lower probability of extubation (subdistribution hazard ratio, 0.46 [0.26-0.83], p = 0.01; subdistribution hazard ratio, 0.58 [0.35-0.98], p = 0.04; and subdistribution hazard ratio, 0.49 [0.26-0.92], p = 0.03, respectively). CONCLUSIONS: Early ventricular dysfunction and pulmonary hypertension were detectable, prevalent, and independent of lung injury severity in children with pediatric acute respiratory distress syndrome. Right ventricular dysfunction was associated with PICU mortality, whereas right ventricular dysfunction and pulmonary hypertension were associated with lower probability of extubation.

An International, Multicenter, Observational Study of Cerebral Oxygenation during Infant and Neonatal Anesthesia.

BACKGROUND: General anesthesia during infancy is associated with neurocognitive abnormalities. Potential mechanisms include anesthetic neurotoxicity, surgical disease, and cerebral hypoxia-ischemia. This study aimed to determine the incidence of low cerebral oxygenation and associated factors during general anesthesia in infants. METHODS: This multicenter study enrolled 453 infants aged less than 6 months having general anesthesia for 30 min or more. Regional cerebral oxygenation was measured by near-infrared spectroscopy. We defined events (more than 3 min) for low cerebral oxygenation as mild (60 to 69% or 11 to 20% below baseline), moderate (50 to 59% or 21 to 30% below baseline), or severe (less than 50% or more than 30% below baseline); for low mean arterial pressure as mild (36 to 45 mmHg), moderate (26 to 35 mmHg), or severe (less than 25 mmHg); and low pulse oximetry saturation as mild (80 to 89%), moderate (70 to 79%), or severe (less than 70%). RESULTS: The incidences of mild, moderate, and severe low cerebral oxygenation were 43%, 11%, and 2%, respectively; mild, moderate, and severe low mean arterial pressure were 62%, 36%, and 13%, respectively; and mild, moderate, and severe low arterial saturation were 15%, 4%, and 2%, respectively. Severe low oxygen saturation measured by pulse oximetry was associated with mild and moderate cerebral desaturation; American Society of Anesthesiology Physical Status III or IV versus I was associated with moderate cerebral desaturation. Severe low cerebral saturation events were too infrequent to analyze. CONCLUSIONS: Mild and moderate low cerebral saturation occurred frequently, whereas severe low cerebral saturation was uncommon. Low mean arterial pressure was common and not well associated with low cerebral saturation. Unrecognized severe desaturation lasting 3 min or longer in infants seems unlikely to explain the subsequent development of neurocognitive abnormalities.

Comparison of 3D Echocardiogram-Derived 3D Printed Valve Models to Molded Models for Simulated Repair of Pediatric Atrioventricular Valves.

Mastering the technical skills required to perform pediatric cardiac valve surgery is challenging in part due to limited opportunity for practice. Transformation of 3D echocardiographic (echo) images of congenitally abnormal heart valves to realistic physical models could allow patient-specific simulation of surgical valve repair. We compared materials, processes, and costs for 3D printing and molding of patient-specific models for visualization and surgical simulation of congenitally abnormal heart valves. Pediatric atrioventricular valves (mitral, tricuspid, and common atrioventricular valve) were modeled from transthoracic 3D echo images using semi-automated methods implemented as custom modules in 3D Slicer. Valve models were then both 3D printed in soft materials and molded in silicone using 3D printed "negative" molds. Using pre-defined assessment criteria, valve models were evaluated by congenital cardiac surgeons to determine suitability for simulation. Surgeon assessment indicated that the molded valves had superior material properties for the purposes of simulation compared to directly printed valves (p < 0.01). Patient-specific, 3D echo-derived molded valves are a step toward realistic simulation of complex valve repairs but require more time and labor to create than directly printed models. Patient-specific simulation of valve repair in children using such models may be useful for surgical training and simulation of complex congenital cases.

Cerebral Oxygen Saturation in Children With Congenital Heart Disease and Chronic Hypoxemia.

BACKGROUND: Increased hemoglobin (Hb) concentration accompanying hypoxemia is a compensatory response to maintain tissue oxygen delivery. Near infrared spectroscopy (NIRS) is used clinically to detect abnormalities in the balance of cerebral tissue oxygen delivery and consumption, including in children with congenital heart disease (CHD). Although NIRS-measured cerebral tissue O2 saturation (ScO2) correlates with arterial oxygen saturation (SaO2), jugular bulb O2 saturation (SjbO2), and Hb, little data exist on the interplay between these factors and cerebral O2 extraction (COE). This study investigated the associations of ScO2 and ΔSaO2-ScO2 with SaO2 and Hb and verified the normal range of ScO2 in children with CHD. METHODS: Children undergoing cardiac catheterization for CHD were enrolled in a calibration and validation study of the FORE-SIGHT NIRS monitor. Two pairs of simultaneous arterial and jugular bulb samples were drawn for co-oximetry, calculation of a reference ScO2 (REF CX), and estimation of COE. Pearson correlation and linear regression were used to determine relationships between O2 saturation parameters and Hb. Data were also analyzed according to diagnostic group defined as acyanotic (SaO2 ≥ 90%) and cyanotic (SaO2 < 90%). RESULTS: Of 65 children studied, acceptable jugular bulb samples (SjbO2 absolute difference between samples ≤10%) were obtained in 57 (88%). The ΔSaO2-SjbO2, ΔSaO2-ScO2, and ΔSaO2-REF CX were positively correlated with SaO2 and negatively correlated with Hb (all P < .001). Although by diagnostic group ScO2 differed statistically (P = .002), values in the cyanotic patients were within the range considered normal (69% ± 6%). COE estimated by the difference between arterial and jugular bulb O2 content (ΔCaO2-CjbO2, mL O2/100 mL) was not different for cyanotic and acyanotic patients (P = .10), but estimates using ΔSaO2-SjbO2, ΔSaO2-ScO2, or ΔSaO2-ScO2/SaO2 were significantly different between the cyanotic and acyanotic children (P < .001). CONCLUSIONS: Children with adequately compensated chronic hypoxemia appear to have ScO2 values within the normal range. The ΔSaO2-ScO2 is inversely related to Hb, with the implication that in the presence of reduced Hb, particularly if coupled with a decreased cardiac output, the ScO2 can fall to values associated with brain injury in laboratory studies.

Neurotoxicity, general anesthesia in young children, and a survey of current pediatric anesthesia practice at US teaching institutions.

BACKGROUND: Recent articles in both scholarly journals and the lay press about the topic of anesthetic related neurotoxicity have increased the awareness and discussion of this topic with parents and other pediatric medical specialties (i.e., surgeons, radiologists, and pediatricians). AIM: The purpose of the present study was to survey how a subset of pediatric anesthesia departments in the US have responded to the issue of anesthetic related neurotoxicity in terms of clinical practice, training and communication with other medical specialties, and the frequency and timing of discussions with families. METHODS: A survey consisting of 22 questions was sent to PALC (Pediatric Anesthesia Leadership Council) & PAPDA (Pediatric Anesthesia Program Directors Association) via SurveyMonkey. The survey was divided into sections on Anesthesia Faculty/Trainees, Parents and Non-Anesthesia Providers. Responses to the survey were solicited via email to PALC and PAPDA, and then followed up with reminders to individual emails using the mailing lists of both organizations. RESULTS: The results of this survey demonstrate that pediatric anesthesia programs around the US do not have a consistent approach in managing the topic of anesthesia-related neurotoxicity with pediatric anesthesiologists, anesthesiology residents, pediatric anesthesiology fellows and their non-anesthesia medical and surgical colleagues, as well as the discussion of this topic with parents. CONCLUSION: A significant need exists to provide information to other pediatric professionals and parents. A consistent message from all providers that includes what is known, and indeed more importantly what is not known may be a useful approach.

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.

Pharmacokinetics of tranexamic acid in neonates, infants, and children undergoing cardiac surgery with cardiopulmonary bypass.

BACKGROUND: Tranexamic acid (TXA) is one of the most commonly used antifibrinolytic medications in children undergoing repair of congenital heart defects. However, a pharmacokinetics analysis of TXA has never been performed in neonates or young children undergoing complex cardiac surgeries using cardiopulmonary bypass, hypothermia, circulatory arrest, and ultrafiltration. A comprehensive pharmacokinetics study was performed in this patient population. METHODS: Fifty-five patients ranging from 2 days through 4 yr old were categorized into three groups: children less than 2 months old, infants 2 months to 1 yr old, and children greater than 1 yr old and weighing up to 20 kg. TXA was given as a bolus of 100 mg/kg followed by an infusion of 10 mg · kg · h throughout the surgery. A dose of 100 mg/kg was placed in the cardiopulmonary bypass prime. A total of 16 to 18 samples were obtained from all patients throughout surgery. Plasma TXA concentrations were measured by high-performance liquid chromatography and modeled under a nonlinear mixed-effects framework with a two-compartment structural model. RESULTS: Cardiopulmonary bypass had a statistically significant impact on all pharmacokinetic parameters. Age was a better covariate than body weight, affecting both the distribution and the elimination of TXA. However, weight performed well in some cases. Other covariates including body surface area, pump prime volume, ultrafiltrate volume, and body temperature did not improve the model. CONCLUSIONS: This TXA pharmacokinetic analysis is reported for the first time in neonates and young children undergoing complex cardiac surgeries with cardiopulmonary bypass. Dosing recommendations are provided as guidance for maintaining desired target concentrations.

Cardiac-specific VLCAD deficiency induces dilated cardiomyopathy and cold intolerance.

The very long-chain acyl-CoA dehydrogenase (VLCAD) enzyme catalyzes the first step of mitochondrial ß-oxidation. Patients with VLCAD deficiency present with hypoketotic hypoglycemia and cardiomyopathy, which can be exacerbated by fasting and/or cold stress. Global VLCAD knockout mice recapitulate these phenotypes: mice develop cardiomyopathy, and cold exposure leads to rapid hypothermia and death. However, the contribution of different tissues to development of these phenotypes has not been studied. We generated cardiac-specific VLCAD-deficient (cVLCAD(-/-)) mice by Cre-mediated ablation of the VLCAD in cardiomyocytes. By 6 mo of age, cVLCAD(-/-) mice demonstrated increased end-diastolic and end-systolic left ventricular dimensions and decreased fractional shortening. Surprisingly, selective VLCAD gene ablation in cardiomyocytes was sufficient to evoke severe cold intolerance in mice who rapidly developed severe hypothermia, bradycardia, and markedly depressed cardiac function in response to fasting and cold exposure (+5°C). We conclude that cardiac-specific VLCAD deficiency is sufficient to induce cold intolerance and cardiomyopathy and is associated with reduced ATP production. These results provide strong evidence that fatty acid oxidation in myocardium is essential for maintaining normal cardiac function under these stress conditions.

Pressure-overload hypertrophy of the developing heart reveals activation of divergent gene and protein pathways in the left and right ventricular myocardium.

Right ventricular (RV) and left ventricular (LV) myocardium differ in their pathophysiological response to pressure-overload hypertrophy. In this report we use microarray and proteomic analyses to identify pathways modulated by LV-aortic banding (AOB) and RV-pulmonary artery banding (PAB) in the immature heart. Newborn New Zealand White rabbits underwent banding of the descending thoracic aorta [LV-AOB; n = 6]. RV-PAB was achieved by banding the pulmonary artery (n = 6). Controls (n = 6 each) were sham-manipulated. After 4 (LV-AOB) and 6 (RV-PAB) wk recovery, the hearts were removed and matched RNA and proteins samples were isolated for microarray and proteomic analysis. Microarray and proteomic data demonstrate that in LV-AOB there is increased transcript expression levels for oxidative phosphorylation, mitochondria energy pathways, actin, ILK, hypoxia, calcium, and protein kinase-A signaling and increased protein expression levels of proteins for cellular macromolecular complex assembly and oxidative phosphorylation. In RV-PAB there is also an increased transcript expression levels for cardiac oxidative phosphorylation but increased protein expression levels for structural constituents of muscle, cardiac muscle tissue development, and calcium handling. These results identify divergent transcript and protein expression profiles in LV-AOB and RV-PAB and provide new insight into the biological basis of ventricular specific hypertrophy. The identification of these pathways should allow for the development of specific therapeutic interventions for targeted treatment and amelioration of LV-AOB and RV-PAB to ameliorate morbidity and mortality.

Vitamin D status in neonates undergoing cardiac operations: relationship to cardiopulmonary bypass and association with outcomes.

OBJECTIVES: To determine the incidence of vitamin D deficiency in neonates with congenital heart disease and whether differences exist by race. In addition, we determined the effect of cardiopulmonary bypass on vitamin D levels and explored associations between 25-hydroxyvitamin D [25(OH)D] levels and postoperative outcomes. STUDY DESIGN: We performed a secondary analysis of a prospective randomized controlled trial in 70 neonates undergoing cardiac surgery. The neonates' 25(OH)D levels were measured in the operating room before skin incision (baseline), at the cessation of cardiopulmonary bypass, and at 24 hours postoperatively. Associations between these levels and clinical outcomes were explored. Vitamin D deficiency was defined as a 25(OH)D level <20 ng/mL. RESULTS: Vitamin D deficiency was present in 84% (59/70); concentrations in African Americans (n = 20) were significantly lower than those of Caucasian/other race/ethnicity (n = 50) (10.2 ± 4.2 vs 16.0 ± 5.6 ng/mL, P < .0001). The 24-hour postoperative 25(OH)D levels were not different from baseline and correlated with a reduced postoperative inotropic requirement (r = -0.316, P = .008). CONCLUSIONS: Vitamin D deficiency is prevalent in neonates with congenital cardiac defects, and lower postoperative 25(OH)D levels are associated with the need for increased inotropic support in neonates undergoing cardiac operations. These findings support that vitamin D deficiency may play a role in myocardial injury and postoperative recovery and warrants further investigation.

Transcriptome and metabolome after porcine hemodynamic-directed CPR compared with standard CPR and sham controls.

Objective: The effect of cardiac arrest (CA) on cerebral transcriptomics and metabolomics is unknown. We previously demonstrated hemodynamic-directed CPR (HD-CPR) improves survival with favorable neurologic outcomes versus standard CPR (Std-CPR). We hypothesized HD-CPR would preserve the cerebral transcriptome and metabolome compared to Std-CPR. Design: Randomized pre-clinical animal trial. Setting: Large animal resuscitation laboratory at an academic children's hospital. Subjects: Four-week-old female piglets (8-11 kg). Interventions: Pigs (1-month-old), three groups: 1) HD-CPR (compression depth to systolic BP 90 mmHg, vasopressors to coronary perfusion pressure 20 mmHg); 2) Std-CPR and 3) shams (no CPR). HD-CPR and Std-CPR underwent asphyxia, induced ventricular fibrillation, 10-20 min of CPR and post-resuscitation care. Primary outcomes at 24 h in cerebral cortex: 1) transcriptomic analysis (n = 4 per treatment arm, n = 8 sham) of 1727 genes using differential gene expression and 2) metabolomic analysis (n = 5 per group) of 27 metabolites using one-way ANOVA, post-hoc Tukey HSD. Measurements and main results: 65 genes were differentially expressed between HD-CPR and Std-CPR and 72 genes between Std-CPR and sham, but only five differed between HD-CPR and sham. Std-CPR increased the concentration of five AA compared to HD-CPR and sham, including the branched chain amino acids (BCAA), but zero metabolites differed between HD-CPR and sham. Conclusions: In cerebral cortex 24 h post CA, Std-CPR resulted in a different transcriptome and metabolome compared with either HD-CPR or sham. HD-CPR preserves the transcriptome and metabolome, and is neuroprotective. Global molecular analyses may be a novel method to assess efficacy of clinical interventions and identify therapeutic targets. Institutional protocol number: IAC 16-001023.

Influence of Immune Cell Subtypes on Mitochondrial Measurements in Peripheral Blood Mononuclear Cells From Children with Sepsis.

INTRODUCTION: Peripheral blood mononuclear cells (PBMCs) are commonly used to compare mitochondrial function in patients with versus without sepsis, but how these measurements in this mixed cell population vary by composition of immune cell subtypes is not known, especially in children. We determined the effect of changing immune cell composition on PBMC mitochondrial respiration and content in children with and without sepsis. METHODS: PBMC mitochondrial respiration and citrate synthase (CS) activity, a marker of mitochondrial content, were measured in 167 children with sepsis at three timepoints (day 1-2, 3-5, and 8-14) and once in 19 nonseptic controls. The proportion of lymphocytes and monocytes and T, B, and NK cells was measured using flow cytometry. More specific CD4+ and CD8+ T cell subsets were measured from 13 sepsis patients and 6 controls. Spearman's correlation and simple and mixed effects linear regression were used to determine the association of PBMC mitochondrial measures with proportion of immune cell subtypes. RESULTS: PBMC mitochondrial respiration and CS activity were correlated with proportion of monocytes, lymphocytes, T B, and NK cells in controls, but not in sepsis patients. PBMC mitochondrial respiration was correlated with CD4+ and CD8+ T cell subsets in both groups. After controlling for differences in immune cell composition between groups using linear regression models, PBMC respiration and CS activity remained lower in sepsis patients than controls. CONCLUSIONS: Mitochondrial measurements from PBMCs varied with changes in immune cell composition in children with and without sepsis. However, differences in PBMC mitochondrial measurements between sepsis patients and controls were at least partially attributable to the effects of sepsis rather than solely an epiphenomena of variable immune cell composition.

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·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 µg·ml(-1)) and plasmin-induced platelet activation (16 µg·ml(-1)) throughout the infusion. CONCLUSIONS: TXA is effective in reducing perioperative blood loss and transfusion requirement in children undergoing craniosynostosis reconstruction surgery.

Obstruction-induced pulmonary vascular remodeling.

Pulmonary obstruction occurs in many common forms of congenital heart disease. In this study, pulmonary artery (PA) banding is used as a model for pulmonary stenosis. Significant remodeling of the vascular bed occurs as a result of a prolonged narrowing of the PAs, and here we quantify the biophysical and molecular changes proximal and distal to the obstruction. Main and branch PAs are harvested from banded and sham rabbits and their mechanical properties are assessed using a biaxial tensile tester. Measurements defined as initial and stiff slopes are taken, assuming a linear region at the start and end of the J-shaped stress-strain curves, along with a transitional knee point. Collagen, elastin assays, Movat's pentachrome staining, and Doppler protocols are used to quantify biochemical, structural, and physiological differences. The banded main PAs have significantly greater initial slopes while banded branch PAs have lower initial slopes; however, this change in mechanical behavior cannot be explained by the assay results as the elastin content in both main and branch PAs is not significantly different. The stiff slopes of the banded main PAs are higher, which is attributed to the significantly greater amounts of insoluble collagen. Shifting of the knee points reveals a decreased toe region in the main PAs but an opposite trend in the branch PAs. The histology results show a loss of integrity of the media, increase in ground substance, and dispersion of collagen in the banded tissue samples. This indicates other structural changes could have led to the mechanical differences in banded and normal tissue.