Implementation of a Regional Oxygen Saturation Thought Algorithm and Association with Clinical Outcomes in Pediatric Patients Following Cardiac Surgery.

Near infrared spectroscopy is routinely used in the noninvasive monitoring of cerebral and somatic regional oxygen saturation (rSO2) in pediatric patients following surgery for congenital heart disease. We sought to evaluate the association of a bedside rSO2 thought algorithm with clinical outcomes in a cohort of pediatric patients following cardiac surgery. This was a single-center retrospective cohort study of patients admitted following cardiac surgery over a 42-month period. The intervention was the implementation of an rSO2 thought algorithm, the primary goal of which was to supply bedside providers with a thought aide to help identify, and guide response to, changes in rSO2 in post-operative cardiac surgical patients. Surgical cases were stratified into two 18-month periods of observation, pre- and post-intervention allowing for a 6-month washout period during implementation of the thought algorithm. Clinical outcomes were compared between pre- and post-intervention periods. There were 434 surgical cases during the period of study. We observed a 27% relative risk reduction in our standardized mortality rate (0.61 to 0.48, p = 0.01) between the pre- and post-intervention periods. We did not observe differences in other post-operative clinical outcomes such as ventilator free days or post-operative ICU length of stay. Providing frontline clinical staff with education and tools, such as a bedside rSO2 thought algorithm, may aide in the earlier detection of imbalance between oxygen delivery and consumption and may contribute to improved patient outcomes.

Emergency department care of patients with Duchenne muscular dystrophy.

Patients with Duchenne muscular dystrophy are living longer and are increasingly seen in Emergency Departments. Though the most common cause of death remains progressive respiratory failure, increased life expectancies have unmasked the significance of progressive myocardial dysfunction, now associated with nearly 40% of mortalities in the DMD population. Cardiac complications such as arrhythmias and cardiomyopathy are becoming ever more widely recognized. Emergency physicians may encounter DMD patients with untreated, undiagnosed or worsening of known heart disease. This review will initially familiarize the emergency physician with the pathophysiology and lifetime trajectory of care for these patients before describing specific emergency department evaluation and treatment.

Clinical utility of the Prostate Health Index (phi) for biopsy decision management in a large group urology practice setting.

BACKGROUND: Deciding when to biopsy a man with non-suspicious DRE findings and tPSA in the 4-10 ng/ml range can be challenging, because two-thirds of such biopsies are typically found to be benign. The Prostate Health Index (phi) exhibits significantly improved diagnostic accuracy for prostate cancer detection when compared to tPSA and %fPSA, however only one published study to date has investigated its impact on biopsy decisions in clinical practice. METHODS: An IRB approved observational study was conducted at four large urology group practices using a physician reported two-part questionnaire. Physician recommendations were recorded before and after receiving the phi test result. A historical control group was queried from each site's electronic medical records for eligible men who were seen by the same participating urologists prior to the implementation of the phi test in their practice. 506 men receiving a phi test were prospectively enrolled and 683 men were identified for the historical control group (without phi). Biopsy and pathological findings were also recorded for both groups. RESULTS: Men receiving a phi test showed a significant reduction in biopsy procedures performed when compared to the historical control group (36.4% vs. 60.3%, respectively, P < 0.0001). Based on questionnaire responses, the phi score impacted the physician's patient management plan in 73% of cases, including biopsy deferrals when the phi score was low, and decisions to perform biopsies when the phi score indicated an intermediate or high probability of prostate cancer (phi ≥36). CONCLUSIONS: phi testing significantly impacted the physician's biopsy decision for men with tPSA in the 4-10 ng/ml range and non-suspicious DRE findings. Appropriate utilization of phi resulted in a significant reduction in biopsy procedures performed compared to historical patients seen by the same participating urologists who would have met enrollment eligibility but did not receive a phi test.

Impact of volume expansion on the efficacy and pharmacokinetics of liposome bupivacaine.

Liposome bupivacaine is a prolonged-release liposomal formulation of bupivacaine indicated for single-dose infiltration into the surgical site to produce postsurgical analgesia of longer duration than traditional local anesthetics. This review summarizes the available data on how volume expansion may impact the analgesic efficacy of liposome bupivacaine. The Phase II and III clinical studies that involved surgical site administration of liposome bupivacaine at various concentrations in different surgical settings revealed no apparent concentration-efficacy relationship. A single-center, prospective study comparing the efficacy of transversus abdominis plane infiltration with liposome bupivacaine administered in a lower (266 mg/40 mL) vs a higher (266 mg/20 mL) dose concentration in subjects undergoing robotic-assisted laparoscopic prostatectomy also reported similar postsurgical pain intensity scores and opioid usage in both treatment groups. The pharmacokinetic profile of liposome bupivacaine following subcutaneous injections in rats was unaltered by differences in drug concentration, dose, or injection volume within the ranges tested. Volume expansion of liposome bupivacaine to a total volume of 300 mL or less does not appear to impact its clinical efficacy or pharmacokinetic profile, thus allowing flexibility to administer the formulation across a wide range of diluent volumes.

Pediatric cardiomyopathies: causes, epidemiology, clinical course, preventive strategies and therapies.

Pediatric cardiomyopathies, which are rare but serious disorders of the muscles of the heart, affect at least one in every 100,000 children in the USA. Approximately 40% of children with symptomatic cardiomyopathy undergo heart transplantation or die from cardiac complications within 2 years. However, a significant number of children suffering from cardiomyopathy are surviving into adulthood, making it an important chronic illness for both pediatric and adult clinicians to understand. The natural history, risk factors, prevalence and incidence of this pediatric condition were not fully understood before the 1990s. Questions regarding optimal diagnostic, prognostic and treatment methods remain. Children require long-term follow-up into adulthood in order to identify the factors associated with best clinical practice including diagnostic approaches, as well as optimal treatment approaches. In this article, we comprehensively review current research on various presentations of this disease, along with current knowledge about their causes, treatments and clinical outcomes.

Solid tumors following kidney transplantation in children.

Kidney transplant recipients have an increased risk of cancer. Data on non-LPD malignancies (solid tumors) in pediatric renal transplant recipients are limited. We performed a cohort study using the NAPRTCS transplant registry to describe the incidence of non-LPD malignancy compared with the general pediatric population. The observed incidence rate of non-LPD malignancy in the NAPRTCS transplant registry was 72.1 per 100,000 person-years (SIR 6.7; 95% CI, 5.3, 8.5); a 6.7-fold increased risk compared with the general pediatric population (10.7 cases per 100,000 person-years). Non-LPD malignancy was diagnosed in 35 subjects at a median of 726 days post-transplant. The most common type of malignancy was renal cell carcinoma. The increased risk of non-LPD malignancy was seen in all patients regardless of age, gender, race, etiology of end-stage kidney disease, and transplant era. The specific type of immunosuppression was not identified as a risk factor. In this first large-scale study of North American pediatric renal transplant recipients, we observed a 6.7-fold increased risk of non-LPD malignancy compared with the general pediatric population. Further examination of this unique patient population may provide greater insight into the impact of transplant and immunosuppression on malignancy risk.

Associations between fibroblast growth factor 23 and cardiac characteristics in pediatric heart failure.

BACKGROUND: In adults with heart failure, elevated levels of fibroblast growth factor 23 (FGF23) are associated with mortality. Data on FGF23 levels in pediatric heart failure are lacking. PATIENTS AND METHODS: We conducted a cross-sectional study of 17 healthy children (mean age 13 years) and 20 pediatric patients with heart failure (mean age 12 years) who underwent echocardiography and for whom the following measurements were taken: plasma FGF23 and parathyroid hormone (PTH) and serum phosphate, creatinine and N-terminal prohormone brain natriuretic peptide (NT-proBNP). Symptom severity was assessed with the New York Heart Association and the Ross classification systems. RESULTS: Of the 20 patients, 11 had dilated cardiomyopathy, four had congenital heart disease, three had hypertrophic cardiomyopathy, one had a failing heart transplant and one had pulmonary hypertension. Mean phosphate levels in these patients were within the reported reference range for healthy children. Median PTH levels were in the normal range in patients and controls. The median FGF23 level was higher in patients versus controls (110.9 vs. 66.4 RU/ml; P = 0.03) and higher in patients on diuretics versus other patients (222.4 vs. 82.1 RU/ml; P = 0.01). Levels of FGF23 and NT-proBNP were directly correlated (r = 0.47, P = 0.04), and patients with greater physical functional impairment had higher FGF23 levels (142.5 in those with moderate-severe limitation vs. 92.8 RU/ml in those with no limitation; P = 0.05). Among patients with dilated cardiomyopathy, higher FGF23 levels were associated with a greater left ventricular end-diastolic diameter (r = 0.63, P = 0.04). CONCLUSION: FGF23 levels are elevated in children with heart failure and are associated with diuretic use, severity of heart failure and left ventricular dilation.

The clinical impact of humoral immunity in pediatric renal transplantation.

The development of anti-donor humoral responses after transplantation associates with higher risks for acute rejection and 1-year graft survival in adults, but the influence of humoral immunity on transplant outcomes in children is not well understood. Here, we studied the evolution of humoral immunity in low-risk pediatric patients during the first 2 years after renal transplantation. Using data from 130 pediatric renal transplant patients randomized to steroid-free (SF) or steroid-based (SB) immunosuppression in the NIH-SNSO1 trial, we correlated the presence of serum anti-HLA antibodies to donor HLA antigens (donor-specific antibodies) and serum MHC class 1-related chain A (MICA) antibody with both clinical outcomes and histology identified on protocol biopsies at 0, 6, 12, and 24 months. We detected de novo antibodies after transplant in 24% (23% of SF group and 25% of SB group), most often after the first year. Overall, 22% developed anti-HLA antibodies, of which 6% were donor-specific antibodies, and 6% developed anti-MICA antibody. Presence of these antibodies de novo associated with significantly higher risks for acute rejection (P=0.02), chronic graft injury (P=0.02), and decline in graft function (P=0.02). In summary, antibodies to HLA and MICA antigens appear in approximately 25% of unsensitized pediatric patients, placing them at greater risk for acute and chronic rejection with accelerated loss of graft function. Avoiding steroids does not seem to modify this incidence. Whether serial assessments of these antibodies after transplant could guide individual tailoring of immunosuppression requires additional study.

A high school-based voluntary cardiovascular risk screening program: issues of feasibility and correlates of electrocardiographic outcomes.

Risk factors for adult cardiovascular events can be identified from the prenatal period through childhood. We performed a cardiovascular risk-screening program in students from grades 9-12 in 7 high schools in Hillsborough County, FL. We obtained blood pressure (BP) measurements and calculated body mass index (BMI) as risk factors for future cardiovascular events as well as obtained an electrocardiogram (ECG) for the purposes of detecting possible life-threatening arrhythmias. Of ~14,000 students contacted, 600 (4 %) participated in the screening. Of these, 517 (86 %) were diagnosed with normal, 71 (12 %) with borderline, and 12 (1 %) with abnormal ECGs. Although no participant had any cardiac history, two of the abnormal ECGs indicated a cardiac diagnosis associated with the potential for sudden cardiac death. Both systolic and diastolic BP increased as the ECG diagnosis moved from normal (115.6/73.8) through borderline (121.0/75.9) to an abnormal (125.0/80.7) diagnosis (all P ≤ .0016). An increase in BMI was only observed when an ECG diagnosis was abnormal (P = .0180). Boys had a greater prevalence (18.97 %) of borderline or abnormal ECGs compared with girls (6.75 %), whereas no discernible differences were seen in ECG diagnosis between white and nonwhite individuals (15.09 and 12.26 %, respectively). Although participation rates were low, a high school-based cardiovascular risk-screening program including ECG is feasible. Although ECG diagnosis tended to be related to other known cardiovascular risk factors (BP, BMI), the utility of an abnormal ECG in adolescence as a predictor of future cardiovascular risk will require further evaluation in more controlled settings.

Immune profile of pediatric renal transplant recipients following alemtuzumab induction.

The incidence of developing circulating anti-human leukocyte antigen antibodies and the kinetics of T cell depletion and recovery among pediatric renal transplant recipients who receive alemtuzumab induction therapy are unknown. In a collaborative endeavor to minimize maintenance immunosuppression in pediatric renal transplant recipients, we enrolled 35 participants from four centers and treated them with alemtuzumab induction therapy and a steroid-free, calcineurin-inhibitor-withdrawal maintenance regimen. At 3 months after transplant, there was greater depletion of CD4(+) than CD8(+) T cells within the total, naive, memory, and effector memory subsets, although depletion of the central memory subset was similar for CD4(+) and CD8(+) cells. Although CD8(+) T cells recovered faster than CD4(+) subsets overall, they failed to return to pretransplant levels by 24 months after transplant. There was no evidence for greater recovery of either CD4(+) or CD8(+) memory cells than naïve cells. Alemtuzumab relatively spared CD4(+)CD25(+)FoxP3(+) regulatory T cells, resulting in a rise in their numbers relative to total CD4(+) cells and a ratio that remained at least at pretransplant levels throughout the study period. Seven participants (20%) developed anti-human leukocyte antigen antibodies without adversely affecting allograft function or histology on 2-year biopsies. Long-term follow-up is underway to assess the potential benefits of this regimen in children.

Subsets of human CD4(+) regulatory T cells express the peripheral homing receptor CXCR3.

Regulatory T cells (Tregs) migrate into peripheral sites of inflammation such as allografts undergoing rejection, where they serve to suppress the immune response. In this study, we find that ∼30-40% of human CD25(hi) FOXP3(+) CD4(+) Tregs express the peripheral CXC chemokine receptor 3 (CXCR3) and that this subset has potent immunoregulatory properties. Consistently, we observed that proliferative responses as well as IFN-γ production were significantly higher using CXCR3-depleted versus undepleted responders in the mixed lymphocyte reaction, as well as following mitogen-dependent activation of T cells. Using microfluidics, we also found that CXCR3 was functional on CXCR3(pos) Tregs, in as much as chemotaxis and directional persistence towards interferon-γ-inducible protein of 10 kDa (IP-10) was significantly greater for CXCR3(pos) than CXCR3(neg) Tregs. Following activation, CXCR3-expressing CD4(+) Tregs were maintained in vitro in cell culture in the presence of the mammalian target of rapamycin (mTOR) inhibitor rapamycin, and we detected higher numbers of circulating CXCR3(+) FOXP3(+) T cells in adult and pediatric recipients of renal transplants who were treated with mTOR-inhibitor immunosuppressive therapy. Collectively, these results demonstrate that the peripheral homing receptor CXCR3 is expressed on subset(s) of circulating human Tregs and suggest a role for CXCR3 in their recruitment into peripheral sites of inflammation.

Combined en bloc liver-double kidney transplantation in an infant with IVC thrombosis.

We report a case of a pediatric en bloc liver-double kidney transplant in a patient with IVC thrombosis below the renal veins. The patient is an 11-month-old girl diagnosed with congenital nephrotic syndrome at two months of age. Multifocal liver masses were identified on routine ultrasound at eight months of age. Alpha fetoprotein level was 55 319. Biopsy confirmed hepatoblastoma. CT scan confirmed multiple lesions in both lobes, which would require liver transplantation for resection. She was also found to have thrombosis of her infrarenal IVC secondary to multiple central lines. She was listed for combined liver-kidney transplant and began chemotherapy. After four cycles of chemotherapy, she underwent bilateral nephrectomies followed by a combined en bloc liver-double kidney transplant from a size matched donor. In order to provide adequate venous outflow from the kidneys in the absence of a recipient infrarenal IVC, the donor liver and kidneys were procured en bloc with a common arterial inflow via the infrarenal aorta and common outflow via the suprahepatic IVC. Kidney transplantation in the absence of adequate recipient venous drainage may require unusual vascular reconstruction techniques. This case demonstrates a novel approach in patients who may require combined liver-kidney transplantation.

Serial measurements of serum NT-proBNP as markers of left ventricular systolic function and remodeling in children with heart failure.

BACKGROUND: Increasing serum levels of N-terminal pro-hormone brain natriuretic peptide (NT-proBNP) are associated with worsening heart failure (HF) in adults. We determined whether changes in NT-proBNP level are associated with changes in symptoms and left ventricular (LV) systolic function and remodeling in children with HF secondary to dilated cardiomyopathy. METHODS: We retrospectively examined associations between serum NT-proBNP levels and NYHA/Ross functional class, LV systolic and diastolic diameter (LVSD-z and LVDD-z), LV ejection fraction (LVEF), and LV shortening fraction (LVSF-z) using generalized linear mixed models. Fluctuation in functional class of subjects was also modeled using logistic regression and receiver operating characteristic (ROC) curves. RESULTS: In 36 children (14 males), a 10-fold increase in NT-proBNP serum levels was associated (P < .001) with a 9.8% decrease in LVEF, a 3.25-unit drop in LVSF-z, a 1.53-unit increase in LVDD-z, a 2.64-unit increase in LVSD-z, and an increased odds of being in functional class III/IV (OR 85.5; 95% CI, 10.9 to 671.0). An NT-proBNP level greater than 1000 pg/mL identified children constantly or intermittently in functional class III-IV with 95% sensitivity and 80% specificity. The reliability of a single NT-proBNP value was 0.61, but the means for two and three NT-proBNP values were 0.76 and 0.82, respectively. CONCLUSIONS: In children with HF, NT-proBNP is associated with cardiac symptoms and indices of LV systolic dysfunction and remodeling. NT-proBNP >1000 pg/mL identifies highly symptomatic children. Within subject serial measurements of NT-proBNP are needed for a reliable and accurate determination of disease status and/or course.

Treating children with idiopathic dilated cardiomyopathy (from the Pediatric Cardiomyopathy Registry).

In 40% of children with symptomatic idiopathic dilated cardiomyopathy (IDC), medical therapy fails within 2 years of diagnosis. Strong evidence-based therapies are not available for these children, and how evidence-based therapies for adults with IDC should be applied to children is unclear. Using data from the National Heart, Lung, and Blood Institute's Pediatric Cardiomyopathy Registry, we compared practice patterns of initial therapies for children with IDC diagnosed from 1990 to 1995 (n = 350) and from 2000 to 2006 (n = 219). At diagnosis, 73% had symptomatic heart failure (HF), and 7% had > or =1 family member with IDC. Anti-HF medications were most commonly prescribed initially. Anti-HF medication use was similar across the 2 periods (84% and 87%, respectively), as was angiotensin-converting enzyme inhibitor use (66% and 70%, respectively). These medications were used more commonly in children with greater left ventricular dilation and poorer left ventricular fractional shortening and functional class (p <0.001). Beta-blocker use was 4% to 18% over the 2 periods. Treatments for pediatric IDC have changed little over the previous 25 years. Anti-HF medications remain the most common treatment, and they are often given to children with asymptomatic left ventricular dysfunction. Children with asymptomatic left ventricular dysfunction are often not offered angiotensin-converting enzyme inhibitors without echocardiographic evidence of advanced disease. In conclusion, therapeutic clinical trials are strongly indicated because practice variation is substantial and medical outcomes in these children have not improved in the previous several decades.