Alkaline Phosphatase: A Biomarker of Cardiac Function in Pediatric Patients.

Myocardial dysfunction and heart failure are common in pediatric patients with congenital and acquired heart disease. Alkaline phosphatase (AP) has been suggested as a biomarker for myocardial dysfunction after Fontan operation. We hypothesized that pediatric patients with myocardial dysfunction requiring orthotopic heart transplant (OHT) have diminished AP compared to normal. A retrospective review was performed in all patients who underwent OHT at Arkansas Children's Hospital between January 2007 and October 2012. Anatomic diagnoses, therapeutic interventions, and ventricular ejection fraction (EF) were recorded. Z scores for AP levels in the study group were determined by comparing the observed AP levels to age- and gender-matched normative values. T tests were performed to compare the mean AP Z score prior to and after OHT. p values <0.05 were considered statistically significant. During the study period, 124 OHTs were performed. Complete study data were available and analyzed from 71/124 patients (mean age at OHT 3.9 years; 51% female). The mean AP Z score was significantly lower in the study group prior to OHT compared to normal (p < 0.0001). The initiation of ACE inhibitor therapy prior to OHT was associated with a significant increase in AP and the ventricular EF (p < 0.001 for both). Treatment with milrinone was associated with an increase in EF. AP is significantly lower in pediatric patients with myocardial dysfunction prior to OHT compared to normal. AP increases significantly after the initiation of therapies to improve myocardial function. Diminished AP is an indicator of myocardial dysfunction in pediatric patients.

Improved Survival While Waiting and Risk Factors for Death in Pediatric Patients Listed for Cardiac Transplantation.

Our aim is to determine (a) the effect of changes in pre-transplant management and era of listing on survival of children listed for HTx and (b) risk factors for death while waiting. This retrospective study included all children listed between 1/1993 and 12/2009 at our center. Survival was determined using survival analysis and competing outcomes modeling. There were 254 listed patients of whom 144 (57%) had congenital heart disease, 208 (82%) were status 1, 52 used ECMO (20%), and 28 used ventricular assist device support (VAD) (11%) beginning in 2005. Overall mortality while waiting was 17% at 6 months, and 69% underwent transplant. Seven of 95 patients (7%) died waiting after 2004 compared to 36 of 159 (23%) before. ECMO and earlier year of listing were significant risk factors (p < 0.001) for wait-list mortality, whereas mortality was significantly lower (p = 0.002) after availability of VADs. Race, gender, blood type, and congenital diagnosis were not significant risk factors for death. Survival in pediatric patients listed for HTx has improved significantly in the current era at our institution. The availability of pediatric VADs has had a significant impact on survival while waiting in children listed for transplantation.

Heart Transplantation in the Short Term After Chemotherapy.

Anthracycline antibiotics are an effective therapy for a variety of neoplastic diseases. Dilated cardiomyopathy is a known risk of their use. Because of the risk of new or recurrent neoplasm with immunosuppression transplantation is often delayed. Our patient developed early cardiomyopathy with congestive heart failure 3 months after completion of chemotherapy. Given the severity of her cardiac symptoms the decision was made to proceed with heart transplantation in the short term after completion of her chemotherapy. We report the success to 1 year of this decision and discuss the implications of her genetic and oncologic diagnoses in this clinical scenario.

Hemorrhage requiring surgical intervention among children on pulsatile ventricular assist device support.

Bleeding complications are a source of morbidity after Berlin EXCOR VAD implantation yet remain poorly characterized. We evaluated our experience to describe the bleeding complications among pediatric VAD recipients. We hypothesized that those with bleeding requiring exploration had abnormal coagulation profile compared with those without bleeding. The retrospective study included 43 consecutive patients with end-stage heart failure supported on pediatric mechanical cardiac support as a bridge to transplantation. Day-/event-based analysis on factors below associated with (i) bleeding and (ii) bleeding in next 48 h. Cases with bleeding were compared with day-matched patients without bleeding complications. Among 43 subjects bleeding occurred in 47% of cases, which necessitated exploration or chest tube placement. Twenty of 34 interventions for bleeding occurred in the first seven post-operative days. No differences in coagulation parameters or use of antiplatelet agents were noted among those who had bleeding vs. those who did not. Our results indicate that (i) re-bleeding requiring re-exploration was common, (ii) most of the bleeding occurred early post-implantation, (iii) there were no differences in coagulation parameters or the use of antiplatelet agents within 48 h of bleeding compared with those who did not bleed on each successive post-operative day.

A machine-learning method isolating changes in wrist kinematics that identify age-related changes in arm movement.

Normal aging often results in an increase in physiological tremors and slowing of the movement of the hands, which can impair daily activities and quality of life. This study, using lightweight wearable non-invasive sensors, aimed to detect and identify age-related changes in wrist kinematics and response latency. Eighteen young (ages 18-20) and nine older (ages 49-57) adults performed two standard tasks with wearable inertial measurement units on their wrists. Frequency analysis revealed 5 kinematic variables distinguishing older from younger adults in a postural task, with best discrimination occurring in the 9-13 Hz range, agreeing with previously identified frequency range of age-related tremors, and achieving excellent classifier performance (0.86 AUROC score and 89% accuracy). In a second pronation-supination task, analysis of angular velocity in the roll axis identified a 71 ms delay in initiating arm movement in the older adults. This study demonstrates that an analysis of simple kinematic variables sampled at 100 Hz frequency with commercially available sensors is reliable, sensitive, and accurate at detecting age-related increases in physiological tremor and motor slowing. It remains to be seen if such sensitive methods may be accurate in distinguishing physiological tremors from tremors that occur in neurological diseases, such as Parkinson's Disease.

Parvovirus B19 myocarditis causes significant morbidity and mortality in children.

Although parvovirus B19 (PVB19) currently is the most common cause of viral myocarditis, limited pediatric data exist. Whereas other viruses infect cardiomyocytes, PVB19 targets coronary endothelium, leading to myocardial ischemia and dysfunction. A retrospective review investigated patients with polymerase chain reaction (PCR)-verified PVB19 myocarditis at Texas Children's Hospital and Arkansas Children's Hospital (January 2005 to August 2008). The primary end points of the study were transplant-free survival and circulatory collapse (death, mechanical support, or transplantation). For the 19 patients identified (age, 6 months to 15 years), the most common presenting symptoms were respiratory and gastrointestinal. At admission, all the patients demonstrated ventricular dysfunction requiring inotropic support (median ejection fraction, 24 %; median left ventricle end-diastolic diameter [LVEDD] z-score, 4.6). Whereas T-wave abnormalities were common, ST elevation was evident in five patients (two died and three required transplantation). Serum B-type natrietic peptide was elevated in all 12 patients tested (range, 348-8,058 pg/ml), and troponin I was high in 7 of 9 patients (range, 0.04-14.5 ng/ml). Of the 15 patients with circulatory collapse, nine received mechanical support, eight underwent successful transplantation, and five died. Only six patients (32 %) experienced transplant-free survival, and five patients had full recovery of function at discharge. In the transplant-free survival group, ST changes on presenting electrocardiography were less likely (p = 0.03), and the admission LVEDD z-score tended to be lower (3.3 vs 5.6; p = 0.08). In children, PVB19 myocarditis causes significant mortality and morbidity. Although mechanical intervention can support patients in the initial stage of decompensated heart failure, patients with PVB19 myocarditis often demonstrate persistent dysfunction requiring medical therapy and transplantation.

Safety and efficacy of dexmedetomidine in children with heart failure.

This retrospective observational study aimed to evaluate the safety and efficacy of dexmedetomidine (DEX) for children with heart failure. The study was conducted in the cardiovascular intensive care unit (CVICU) of a single, tertiary care, academic children's hospital. A retrospective review of the charts for all children (up to 18 years of age) with signs and symptoms consistent with congestive heart failure who received DEX in our CVICU between April 2006 and April 2011 was performed. The patients were divided into two groups for study purposes: the DEX group of 21 patients, who received a DEX infusion together with other conventional sedation agents, and the control group of 23 patients, who received conventional sedation agents without the use of DEX. To evaluate the safety of DEX, physiologic data were collected including heart rate, mean arterial pressure (MAP), and inotrope score. To assess the efficacy of DEX, the amount and duration of concomitant sedation and analgesic infusions in both the DEX and control groups were examined. The numbers of rescue boluses for each category before the initiation of sedative infusion and during the sedative infusion also were examined. The baseline characteristics of the patients in the two groups were similar. There was no effect of DEX infusion on heart rate, MAP, or inotrope score at the termination of infusion. The daily amount of midazolam administered was significantly less during the last 24 h of DEX infusion in the DEX group than in the control group (p = 0.04). The daily amount of morphine infusion did not differ between the DEX and control groups during any period. The numbers of sedation and analgesic rescue boluses were lower in DEX group throughout the infusion. No other significant side effects were noted. Two patients in the DEX group had a 50 % or greater drop in MAP compared with baseline in the first 3 h after initiation of DEX infusion, whereas one patient had a 50 % or greater drop in heart rate compared with baseline in the first 3 h after initiation of DEX infusion. Administration of DEX for children with heart failure appears to be safe but should be used cautiously. Furthermore, DEX use is associated with a decreased opiate and benzodiazepine requirement for children with heart failure.

NTproBNP as a marker of rejection in pediatric heart transplant recipients.

Acute rejection is a major morbidity in heart transplant recipients; diagnosis is difficult, and rejection must often be treated reactively. Various serum biomarkers have been investigated for non-invasive monitoring of the cardiac allograft. NTproBNP is produced by the ventricular myocardium and may increase with evolving rejection allowing earlier diagnosis. Retrospective review of serum NTproBNP levels in pediatric heart transplant recipients has been carried out to evaluate the association with episodes of acute rejection. Repeated measures logistic regression was used to model associations for variables with first rejection and within an individual for change in NTproBNP and first rejection. Odds ratios for rejection risk given an increase in serum NTproBNP were calculated. Correlation of NTproBNP levels with renal function as estimated by modified Schwartz equation was performed to look for confounding. Higher serum NTproBNP level was associated with increased risk of rejection, but intersubject variability was wide. However, increase in an individual subject's serum level showed increased risk of rejection, greater with greater rise. Serum NTproBNP levels appear not greatly affected by renal function. NTproBNP shows promise in surveillance for pediatric heart transplant recipients. The greatest use appears to be in following trends for an individual instead of using an absolute value.

Solid organ donation in a child after extracorporeal membrane oxygenation, orthotopic heart transplantation, and ventricular assist device support.

Use of high-risk or marginal donors is the most viable short-term means to boost the organ supply and bridge the widening gap between the number of patients on the waiting list for organ transplantation and the insufficient numbers of organ donors. Expansion of the donor pool requires an understanding of the impact on survival likely to result from extending one or more high risk factors. Use of extended donor pool results in shorter waiting list times and limits the morbidity and mortality associated with long-term mechanical support needed to support diseased organs. In this report, we present one such example of expanding donor pool in which a pediatric patient donated a solid organ after two heart transplants and successful use of ECMO and VAD.

Cystatin C and neutrophil gelatinase-associated lipocalin as markers of renal function in pediatric heart transplant recipients.

We hypothesized that use of Schwartz formula underestimates the prevalence of CKD in PHT recipients. This study determined the prevalence and risk factors for CKD in PHT using novel methods-serum cystatin C, CKiD formula, Revised Schwartz formula, s- and u-NGAL. Serum BUN, creatinine, cystatin C and s- and u-NGAL were measured after prospective enrollment. Schwartz formula GFR was compared with novel methods. CKD was defined as CKiD GFR < 90 mL/min/1.73 m(2) . The s- and u-NGAL were compared between those with and without CKD. Potential risk factors for CKD were analyzed. Seventy-nine patients (46 male children or boys), mean age 9.9 ± 5.8 yr formed the study cohort. The prevalence of mild and moderate CKD was 2- to 3-fold higher using novel methods compared to Schwartz formula. u-NGAL and u-NGAL/Cr were significantly higher in patients with CKD. u- and s-NGAL had negative correlation with estimates of GFR. Women were at a higher risk for CKD (odds ratio 8.7) as was longer duration since transplant (p = 0.009). In conclusion, use of novel methods of GFR estimation unmasked 2- to 3-fold increased prevalence of CKD in PHT. Women and those with longer duration since transplant are at higher risk for CKD.

Pediatric Cardiac Critical Care Transport and Palliative Care: A Case Series.

OBJECTIVE: To present our center's experience with terminal extubation in 3 palliative critical care home transports from the Pediatric Cardiac Intensive Unit. DESIGN: All cases were identified from our Cardiovascular intensive care unit ( CVICU). Patients were terminally ill children with no other surgical or medical option who were transported home between 2014 and 2018, for terminal extubation and end-of-life care according to their families' wishes. INTERVENTIONS: The patients were 7, 9 months, and 19 years; and they had very complex and chronic conditions. The families were approached by the CVICU staff during multidisciplinary meetings, where goals of care were established. Parental expectations were clarified, and palliative care team was involved, as well as home hospice was arranged pre transfer. The transfer process was discussed and all the needs were established. All patients had unstable medical conditions, with needs for transport for withdrawal of life support and death at home. Each case needed a highly trained team to support life while in transport. The need of these patients required coordination with home palliative care services, as well as community resources due to difficulty to get in their homes. CONCLUSIONS: Transportation of pediatric cardiac critical care patients for terminal extubation at home is a relatively infrequent practice. It is a feasible alternative for families seeking out of the hospital end-of-life care for their critically ill and technology dependent children. Our single-center experience supports the need for development of formal programs for end-of-life critical care transports.

Anaerobic Fungal Mevalonate Pathway Genomic Biases Lead to Heterologous Toxicity Underpredicted by Codon Adaptation Indices.

Anaerobic fungi are emerging biotechnology platforms with genomes rich in biosynthetic potential. Yet, the heterologous expression of their biosynthetic pathways has had limited success in model hosts like E. coli. We find one reason for this is that the genome composition of anaerobic fungi like P. indianae are extremely AT-biased with a particular preference for rare and semi-rare AT-rich tRNAs in E coli, which are not explicitly predicted by standard codon adaptation indices (CAI). Native P. indianae genes with these extreme biases create drastic growth defects in E. coli (up to 69% reduction in growth), which is not seen in genes from other organisms with similar CAIs. However, codon optimization rescues growth, allowing for gene evaluation. In this manner, we demonstrate that anaerobic fungal homologs such as PI.atoB are more active than S. cerevisiae homologs in a hybrid pathway, increasing the production of mevalonate up to 2.5 g/L (more than two-fold) and reducing waste carbon to acetate by ~90% under the conditions tested. This work demonstrates the bioproduction potential of anaerobic fungal enzyme homologs and how the analysis of codon utilization enables the study of otherwise difficult to express genes that have applications in biocatalysis and natural product discovery.

Bone mineral status in pediatric heart transplant recipients: a retrospective observational study of an "at risk" cohort.

There is a paucity of literature assessing the burden of bone loss in PHT recipients. We sought to describe the bone mineral status in PHT recipients by doing a retrospective medical record review of those who underwent evaluation of BMD when clinically indicated. Data collected included patient demographics, BMD evaluations, serum calcium, phosphorus, alkaline phosphatase, cumulative steroid dose, osseous complications and their management. Of 149 PHT recipients, 26 underwent BMD evaluation. This evaluation was done at a median of 3.4 yrs after PHT. There total serum calcium, phosphorus and alkaline phosphatase were similar at transplant and BMD study. The median BMD Z-scores were: whole body -0.09 (1.5 to -5.13) and lumbar spine -1.1 (1.5 to -5.16). Bone loss (Z-score <-1) was present in 14 (53.8%). Three patients had spinal fractures and/or avascular necrosis of various bones. Treatment included calcitrol and bisphosphonates; and vertebroplasty for spinal fracture. Bone loss was present in a significant proportion of PHT recipients and may be associated with fractures and avascular necrosis. More than half of our "at risk" cohort had bone loss. Careful surveillance of these patients should be performed to prevent morbidity.

Percutaneous coronary intervention using drug-eluting stents in pediatric heart transplant recipients.

PCI has been used for palliation of CAV in adults, but there are limited data available in children. We sought to evaluate our experience with PCIs for CAV in pediatric heart transplant recipients. Retrospective review of the medical records of all four patients who were diagnosed with CAV, including demographic data and catheterization reports was performed. Of the 149 pediatric heart transplant recipients followed at our institution, 10 were identified with CAV. Four of these 10 underwent 12 PCI procedures for CAV. One donor heart had documented coronary artery disease. Two patients had significant risk factors for coronary artery disease including morbid obesity, hyperlipidemia, and systemic hypertension. PCI involved deployment of bare metal stents (n = 2), paclitaxel-eluting stent (n = 6), and sirolimus-eluting stents (n = 4) with procedural success in all and no early or late mortality. One procedure was complicated by coronary dissection that was successfully treated with stent placement. One patient has been re-transplanted while the other three are not candidates for re-transplantation and have remained asymptomatic as palliation with PCI. PCI using coronary stents is a safe and effective palliative measure for CAV in pediatric heart transplant recipients.

Major depression and comorbid substance use disorders.

PURPOSE OF REVIEW: The presentation of major depressive disorder is often complicated by the co-occurrence of substance use disorders, such as alcohol and illicit drug abuse or dependence. The article reviews the recent systematic research on the distinguishing baseline characteristics including demographic characteristics and the influence of family history, and clinical features such as depressive symptomatology and suicidal ideation, and the outcome of treatment for depression in patients with comorbid major depressive disorder and substance use disorders. The review also addresses the possible explanations cited in the literature as to why these two disorders tend to co-occur and the implications of the comorbidity of these illnesses on treatment. RECENT FINDINGS: Nearly one-third of patients with major depressive disorder also have substance use disorders, and the comorbidity yields higher risk of suicide and greater social and personal impairment as well as other psychiatric conditions. Although the treatment of comorbid major depressive disorder and substance use disorders with medication is likely effective, the differential treatment effects based on substance use disorder comorbidity have been understudied. SUMMARY: Emerging results of recent studies comparing the outcome of major depressive disorder patients with comorbid major depressive disorder and substance use disorders suggest that there are fewer differential effects based on comorbidity than previously anticipated by older assumptions from smaller, less methodologically rigorous studies.

Long-term pharmacotherapy for post-traumatic stress disorder.

This article reviews the literature on the long-term pharmacological treatment of post-traumatic stress disorder (PTSD). A PUBMED search was conducted; only studies on the effects of long-term (>14-weeks) pharmacological treatment for PTSD in adults or children were considered. Our search identified three randomised, double-blind, placebo-controlled studies (one each for sertraline, fluoxetine and risperidone), four open-label studies (one each for sertraline, paroxetine, nefazodone and valproate), one retrospective case series (clozapine) and one pooled analysis (sertraline). All studies involved adult populations, with the exception of the study of clozapine. The studies demonstrate that long-term treatment of PTSD with SSRIs effectively maintains the previous treatment response and improvement in quality of life, converts more patients to responder status and accounts for one-third of overall treatment gains. Greater PTSD severity predicts a longer time to response to these drugs. Discontinuation of SSRI treatment after 12 weeks results in a greater risk of relapse and symptom exacerbation compared with extended treatment. In addition to improved PTSD symptoms, extended treatment with paroxetine improves verbal declarative memory and increases hippocampal volume. Long-term treatment of PTSD with atypical antipsychotics (risperidone and clozapine), non-SSRI antidepressants (nefazodone) and antiepileptic drugs (AEDs; valproate) also appears to result in significant improvements in PTSD symptoms. In conclusion, long-term treatment of PTSD with SSRIs improves the psychiatric and clinical outcome of patients with the disorder and prevents relapse and symptom exacerbation. The effect of other agents (atypical antipsychotics, AEDs and other psychotropic medications) requires further controlled study.

Cardiac transplantation at Arkansas Children's Hospital.

Cardiac transplantation in children has evolved over the past 20 years. In 1990 Arkansas Children's Hospital (ACH) developed a Cardiac Transplant Program as part of its tertiary care of patients with congenital and acquired heart disease. The program evolved into a regional pediatric referral program and is now one of the busiest in the United States. "Bridging" to transplant increased the number of patients surviving long enough to receive a donor heart. This article reviews the historical perspective of pediatric cardiac transplant along with the development and current state of the program at Arkansas Children's Hospital.

Aortic complications following pediatric heart transplantation: A case series and review.

Aortic complications occur rarely after pediatric orthotopic heart transplantation, but are typically accompanied by catastrophic events. We describe the three cases of major aortic complications in our experience of 329 pediatric heart transplants. This case series and review highlight the important risk factors for aortic complications after heart transplantation.

Risk factors for prolonged mechanical ventilation for children on ventricular assist device support.

BACKGROUND: Patients with end-stage heart failure possess many attributes that place them at risk for prolonged mechanical ventilation (MV). However, there are only limited data on MV support among children after ventricular assist device (VAD) implantation. We report the duration of MV after VAD placement, indications for respiratory support in the postimplantation period, and associated patient factors. METHODS: This single-center retrospective study included 43 consecutive children (aged <18 years) with end-stage heart failure who were supported with a VAD as a bridge to transplantation from January 2005 to December 2011. Multivariable analysis was performed using the multiple Poisson regression model for the duration of MV. RESULTS: Overall, 33% (n = 14) remained on MV until heart transplant or death. Of those requiring pre-VAD extracorporeal membrane oxygenation (ECMO) support, 63% (n = 12 of 19) remained on MV until heart transplant or death compared with 8% (n = 2 of 24) among those not on ECMO before VAD (p < 0.001). Patients with moderate or severe mitral regurgitation while on VAD support had 1.7-times more MV days compared with those with none or trivial on-VAD mitral regurgitation. In addition, previous support on ECMO, those with moderate or severe tricuspid regurgitation, and those with only left VAD implants had an increased risk of prolonged MV. CONCLUSIONS: Our results suggest that VAD recipients previously supported on ECMO, those with moderate or severe mitral regurgitation, moderate or severe tricuspid regurgitation, and those with only left VAD implants had an increased risk of prolonged MV. Future studies in larger cohorts are necessary to confirm the findings from this single-institutional experience.

Influence of gender on attention deficit hyperactivity disorder in children referred to a psychiatric clinic.

OBJECTIVE: The substantial discrepancy in the male-to-female ratio between clinic-referred (10 to 1) and community (3 to 1) samples of children with attention deficit hyperactivity disorder (ADHD) suggests that gender differences may be operant in the phenotypic expression of ADHD. In this study the authors systematically examined the impact of gender on the clinical features of ADHD in a group of children referred to a clinic. METHOD: The study included 140 boys and 140 girls with ADHD and 120 boys and 122 girls without ADHD as comparison subjects. All subjects were systematically assessed with structured diagnostic interviews and neuropsychological batteries for subtypes of ADHD as well as emotional, school, intellectual, interpersonal, and family functioning. RESULTS: Girls with ADHD were more likely than boys to have the predominantly inattentive type of ADHD, less likely to have a learning disability, and less likely to manifest problems in school or in their spare time. In addition, girls with ADHD were at less risk for comorbid major depression, conduct disorder, and oppositional defiant disorder than boys with ADHD. A statistically significant gender-by-ADHD interaction was identified for comorbid substance use disorders as well. CONCLUSIONS: The lower likelihood for girls to manifest psychiatric, cognitive, and functional impairment than boys could result in gender-based referral bias unfavorable to girls with ADHD.