Faculty Bibliography

OBJECTIVE: The objective of our study was to identify whether a substantive difference exists between the imaging interpretations of radiologists at outside referring institutions and those of radiologists at a tertiary care children's hospital and whether such reinterpretation affects the clinical management of pediatric patients. MATERIALS AND METHODS: This retrospective chart review examined the diagnostic imaging reports of all pediatric patients referred to a tertiary care freestanding children's hospital over a 17-month period (January 1, 2009-May 31, 2010); 773 examinations met the inclusion criteria. The original and second interpretations were compared. A fellowship-trained pediatric radiologist and neuroradiologist categorized each case using the content of the two radiology reports as agreement versus minor or major disagreement, and the results were analyzed for statistical significance. A cohort of cases in which a final diagnosis could be confirmed was also analyzed to evaluate the accuracy of both interpretations. RESULTS: Disagreements were found in 323 of 773 reports (41.8%): 168 (21.7%) were major and 155 (20.0%), minor. Neurologic studies were most frequently requested for reinterpretation, 427 (55.2%), most commonly in the setting of trauma, 286 (67.0%). Among the 427 neuroimaging studies, major and minor disagreements occurred in 54 (12.6%) and 91 (21.3%) cases, respectively. Major disagreements most frequently observed were about the presence of fracture and hemorrhage. Among 305 body imaging cases, major and minor disagreements occurred in 99 (32.6%) and 57 (18.7%) cases, respectively. The most common setting for nontraumatic body imaging was concern for appendicitis (168/305 [55.1%]); this indication for imaging was responsible for 40.3% of major disagreements in nontraumatic abdominal imaging. Reinterpretation was rarely requested for radiographic studies (41/773 [5.3%]), which had major and minor disagreement rates of 36.6% and 17.1%, respectively. In the cohort of cases analyzed for final diagnosis, the second interpretation was more accurate than the original in 90.2% of cases with a p value of less than 0.0001. CONCLUSION: Our findings suggest that discrepancy rates for second interpretations in studies of pediatric patients transferred to tertiary care pediatric institutions are substantial. Although the original and second interpretations in the majority of cases were in agreement, major discrepancies were prevalent--12.6% and 32.6% of neuroimaging and body studies, respectively--and the second interpretations were significantly correlated with the final diagnosis. These results indicate that interpretations by subspecialty radiologists at a point-of-care facility provide important clinical information about the pediatric patient and should be recognized by payers as integral to optimal care.

OBJECTIVE:This study tested the hypothesis that interruption of the renin-angiotensin system with either an angiotensin-converting enzyme inhibitor or a mineralocorticoid receptor antagonist will decrease the prevalence of atrial fibrillation after cardiac surgery. DESIGN/METHODS:Randomized double-blind placebo-controlled study. SETTING/METHODS:University-affiliated hospitals. PATIENTS/METHODS:Four hundred forty-five adult patients in normal sinus rhythm undergoing elective cardiac surgery. INTERVENTIONS/METHODS:One week to 4 days prior to surgery, patients were randomized to treatment with placebo, ramipril (2.5 mg the first 3 days followed by 5 mg/day, with the dose reduced to 2.5 mg/day on the first postoperative day only), or spironolactone (25 mg/day). MEASUREMENTS/METHODS:The primary endpoint was the occurrence of electrocardiographically confirmed postoperative atrial fibrillation. Secondary endpoints included acute renal failure, hyperkalemia, the prevalence of hypotension, length of hospital stay, stroke, and death. MAIN RESULTS/RESULTS:The prevalence of atrial fibrillation was 27.2% in the placebo group, 27.8% in the ramipril group, and 25.9% in the spironolactone group (p=.95). Patients in the ramipril (0.7%) or spironolactone (0.7%) group were less likely to develop acute renal failure than those randomized to placebo (5.4%, p=.006). Patients in the placebo group tended to be hospitalized longer than those in the ramipril or spironolactone group (6.8±8.2 days vs. 5.7±3.2 days and 5.8±3.4 days, respectively, p=.08 for the comparison of placebo vs. the active treatment groups using log-rank test). Compared with patients in the placebo group, patients in the spironolactone group were extubated sooner after surgery (576.4±761.5 mins vs. 1091.3±3067.3 mins, p=.04). CONCLUSIONS:Neither angiotensin-converting enzyme inhibition nor mineralocorticoid receptor blockade decreased the primary outcome of postoperative atrial fibrillation. Treatment with an angiotensin-converting enzyme inhibitor or mineralocorticoid receptor antagonist was associated with decreased acute renal failure. Spironolactone use was also associated with a shorter duration of mechanical ventilation after surgery.

The effects of angiotensin-converting enzyme (ACE) inhibition and angiotensin II type 1 receptor blockade (ARB) on fibrinolysis and inflammation after cardiopulmonary bypass (CPB) are uncertain. This study tested the hypothesis that ACE inhibition enhances fibrinolysis and inflammation to a greater extent than ARB in patients undergoing CPB. One week to 5 days before surgery, patients were randomized to ramipril 5 mg/day, candesartan 16 mg/day, or placebo. ACE inhibition increased intraoperative bradykinin and tissue-type plasminogen activator (t-PA ) concentrations as compared to AR B. Both ACE inhibition and AR B decreased the need for plasma transfusion relative to placebo, but only ACE inhibition decreased the duration of hospital stay. Neither ACE inhibition nor AR B significantly affected concentrations of plasminogen activator inhibitor-1 (PAI -1), interleukin (IL )-6, IL -8, or IL -10. ACE inhibition enhanced intraoperative fibrinolysis without increasing the likelihood of red-cell transfusion. By contrast, neither ACE inhibition nor ARB affected the inflammatory response. ACE inhibitors and ARBs may be safely continued until the day of surgery.

The sympathetic nervous system regulates thermogenesis and energy homeostasis in humans. When activated it increases energy expenditure, particularly resting energy expenditure. Most human studies used acute infusion of β-blockers as a model to eliminate sympathetic stimulation and to examine the contribution of the sympathetic nervous system to energy metabolism and balance. Clinically, however, it is also important to assess the effect of chronic sympathetic attenuation on energy metabolism. In this context, we hypothesized that resting energy expenditure is decreased in patients with autonomic failure who, by definition, have low sympathetic tone. We measured 24-hour energy expenditure using whole-room indirect calorimeter in 10 adults with chronic autonomic failure (6 women; age, 64.9±9.1 years; body mass index, 25.2±4.4 kg/m(2)) and 15 sedentary healthy controls of similar age and body composition (8 women; age, 63.1±4.0 years; body mass index, 24.4±3.9 kg/m(2)). In 4 patients, we eliminated residual sympathetic activity with the ganglionic blocker trimethaphan. We found that, after adjusting for body composition, resting energy expenditure did not differ between patients with autonomic failure and healthy controls. However, resting energy expenditure significantly decreased when residual sympathetic activity was eliminated. Our findings suggest that sympathetic tonic support of resting energy expenditure is preserved, at least in part, in pathophysiological models of chronic sympathetic attenuation.

BACKGROUND:Studies in multiple organ systems have shown cross-talk between signaling through the bone morphogenetic protein receptor type 2 (BMPR2) and estrogen pathways. In humans, pulmonary arterial hypertension (PAH) has a female predominance, and is associated with decreased BMPR2 expression. The goal of this study was to determine if estrogens suppress BMPR2 expression. METHODS:A variety of techniques were utilized across several model platforms to evaluate the relationship between estrogens and BMPR2 gene expression. We used quantitative RT-PCR, gel mobility shift, and luciferase activity assays in human samples, live mice, and cell culture. RESULTS:BMPR2 expression is reduced in lymphocytes from female patients compared with male patients, and in whole lungs from female mice compared with male mice. There is an evolutionarily conserved estrogen receptor binding site in the BMPR2 promoter, which binds estrogen receptor by gel-shift assay. Increased exogenous estrogen decreases BMPR2 expression in cell culture, particularly when induced to proliferate. Transfection of increasing quantities of estrogen receptor alpha correlates strongly with decreasing expression of BMPR2. CONCLUSIONS:BMPR2 gene expression is reduced in females compared to males in live humans and in mice, likely through direct estrogen receptor alpha binding to the BMPR2 promoter. This reduced BMPR2 expression may contribute to the increased prevalence of PAH in females.

Biomarkers of oxidative stress and inflammation predict cardiovascular events in maintenance hemodialysis patients. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) reduce cardiovascular mortality in the general population, but their benefit in maintenance hemodialysis patients is not fully explored. To test whether ACE inhibitors and ARBs differentially affect markers of oxidative stress, inflammation, and fibrinolysis during hemodialysis, we conducted a randomized, double-blind, placebo-controlled 3×3 crossover study. We randomly assigned 15 participants undergoing hemodialysis to placebo, ramipril (5 mg/d), and valsartan (160 mg/d) for 7 days, with a washout period of 3 weeks in between the treatments. On the morning of the seventh day of drug treatment, participants underwent serial blood sampling during hemodialysis. Neither ramipril nor valsartan affected BP during hemodialysis. Ramipril increased IL-1β concentrations (P=0.02) and decreased IL-10 concentrations (P=0.04) compared with placebo. Valsartan and ramipril both lowered IL-6 levels during dialysis (P<0.01 for each compared with placebo). Valsartan increased F(2)-isoprostane levels, and ramipril suggested a similar trend (P=0.09). Valsartan and ramipril both lowered D-dimer levels (P<0.01 for both), whereas only ramipril seemed to prevent a rise in vWf levels (P=0.04). In summary, during hemodialysis, valsartan induces a greater anti-inflammatory effect compared with ramipril, although ramipril seems to prevent dialysis-induced endothelial dysfunction as measured by levels of vWf. A prospective clinical trial is necessary to determine whether ACE inhibitors and ARBs also differ with respect to their effects on cardiovascular mortality in this population.

PURPOSE: To determine the incidence and clinical and biomarker predictors of perioperative thrombosis in children with single ventricle physiology undergoing staged palliation. METHODS: Nineteen patients were enrolled and 16 completed the study. Serial ultrasounds of the central venous system were performed to evaluate for thrombus. Plasma antithrombin III, thrombin-antithrombin complex, protein C, protein S, tissue factor pathway inhibitor, plasminogen activator inhibitor-1, tissue plasminogen activator antigen, D-dimer, soluble CD40 ligand, and urinary thromboxane were measured serially before and after surgery. Cardiopulmonary bypass time, aortic cross clamp time, blood product administration, inotrope score, chest tube output, cardiac function by echocardiography, intensive care unit and hospital lengths of stay, and central venous catheter days were recorded. RESULTS: The incidence of perioperative thrombus was 31%. Patients who developed a thrombus had poorer preoperative ventricular function (p = 0.03) and longer cardiopulmonary bypass times (p = 0.03) than those who did not develop a thrombus. Preoperative plasma antithrombin III was lower (p = 0.01) and tissue plasminogen activator antigen concentrations were higher (p = 0.02) in patients with a thrombus compared with patients without a thrombus. When measured over time, antithrombin III remained lower (p = 0.002) and tissue plasminogen activator antigen higher (p = 0.005) in those who developed a thrombus compared with those who did not. There were no other statistically significant differences in biomarkers of coagulation between patients with and without thrombosis. CONCLUSION: One-third of patients undergoing palliative surgery for single ventricle physiology develop thrombosis. Decreased ventricular function, low antithrombin III, and increased tissue plasminogen activator may predict those most suitable for randomized clinical trials of anticoagulation.

BACKGROUND:Coronary artery disease (CAD) is the leading killer in the United States. Patients with severe CAD and ischemia have worse prognosis. Therefore expansion of biomarker research, to identify at-risk individuals and explain the complex biology between cardiovascular growth factors and atherosclerosis is needed. Neuregulin-1β (NRG-1β) is a myocardial stress activated growth and survival factor released from endocardial and endothelial cells. NRG-1β is essential for cardiovascular development and a regulator of angiogenesis. We postulated that plasma and serum levels of NRG-1β would vary in relation to CAD severity and the presence of stress-induced ischemia. METHODS:We measured serum and plasma levels of NRG-1β and vascular endothelial growth factor (VEGF) in 60 patients undergoing cardiac catheterization. CAD severity was calculated from angiographic results using a modified Duke jeopardy score. RESULTS:Serum NRG-1β (sNRG-1β), plasma NRG-1β (pNRG-1β), serum VEGF, and plasma VEGF were detectable in the majority of patients. The pNRG-1β levels were approximately two-fold higher than sNRG-1β. Both sNRG-1β and pNRG-1β correlated inversely with CAD severity. pNRG-1β levels were statistically higher in patients with stress-induced ischemia denoted by a positive myocardial perfusion imaging study that correlated with angiographic findings (P=0.02). CONCLUSION/CONCLUSIONS:Both sNRG-1β and pNRG-1β correlated inversely with angiographic severity of CAD. pNRG-1β levels were two-fold higher than serum and were higher in patients with stress-induced ischemia. Therefore we conclude that plasma is the optimal source for the further exploration of the biological significance of NRG-1β as a biomarker of CAD severity and ischemia.

OBJECTIVE: Pediatricians and orthopedists comprise the largest referral basis for knee MR examinations at our institution. In an era of cost optimization, the purpose of this study was to compare differences in pretest probability for an abnormal finding on knee MRI based on referral subspecialty. MATERIALS AND METHODS: A retrospective review of 501 consecutive knee MR examinations of pediatric patients (56% male; mean age, 14 years; age range, 1-18 years) referred by nononcology orthopedic surgeons and 93 consecutive knee MR examinations of patients (47% male; mean age, 14 years; age range, 2-18 years) referred by general pediatricians from 2005 to 2009 were reviewed. Two patient groups based on the MR report were established: patients with entirely normal MRI findings and those who had a clinically significant MRI finding or findings. The latter group included children with any internal derangement, a discoid meniscus, a neoplasm, or evidence of infection or inflammation. RESULTS: The incidence of an entirely normal knee MRI from pediatrician referral and orthopedic referral was 24% (22/93) and 17% (87/501) (p = 0.15), respectively. The respective incidence of selected specific injuries identified from pediatrician and orthopedic referral included any internal derangement, 39.8% and 48.3% (p = 0.13); neoplasm, 2.2% and 1.4% (p = 0.64); and inflammation, 6.5% and 2.0% (p = 0.03). CONCLUSION: Despite differences in subspecialty training, we found no significant differences in the proportion of normal knee MRI examinations and no statistical difference in the proportion of patients with internal derangement. Further investigation is necessary to determine whether these findings translate into overall cost-savings or differences in patient outcome.

To compare the relative effectiveness of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in reducing cardiovascular mortality in chronic hemodialysis patients, we conducted an observational analysis of all patients initiated on ACEI or ARB therapy undergoing chronic hemodialysis at a large dialysis provider. Survival curves with mortality hazard ratios (HRs) were generated using the Kaplan-Meier method and Cox regression. Outcomes were compared using inverse probability of treatment weighting and propensity score matching. Over 6 years, 22,800 patients were newly initiated on an ACEI and 5828 on an ARB after at least 60 days of chronic hemodialysis. After adjustment for baseline cardiovascular risk factors, there was no significant difference in the risk of cardiovascular, all-cause, or cerebrovascular mortality in patients initiated on an ARB compared with an ACEI (HR of 0.96). A third of 28,628 patients, newly started on an ACEI or ARB, went on to another antihypertensive medication in succession. After adjustment for risk factors, 701 patients initiated on combined ACEI and ARB therapy (HR of 1.45) or 6866 patients on ACEI and non-ARB antihypertensive agent (HR of 1.27) were at increased risk of cardiovascular death compared with 1758 patients initiated on an ARB and non-ACEI antihypertensive therapy. Thus, an ARB, in combination with another antihypertensive medication (but not an ACEI), may have a beneficial effect on cardiovascular mortality. As observational studies may be confounded by indication, even when adjusted, randomized clinical trials are needed to confirm these findings.