Sequential design methods for binary response variables exist for determination of the concentration or dose associated with the 50% point along the dose-response curve; the up-and-down method of ...Dixon and Mood is now commonly used in anesthesia research. There have been important developments in statistical methods that (1) allow the design of experiments for the measurement of the response at any point (quantile) along the dose-response curve, (2) demonstrate the risk of certain statistical methods commonly used in literature reports, (3) allow the estimation of the concentration or dose-the target dose-associated with the chosen quantile without the assumption of the symmetry of the tolerance distribution, and (4) set bounds on the probability of response at this target dose. This article details these developments, briefly surveys current use of the up-and-down method in anesthesia research, reanalyzes published reports using the up-and-down method for the study of the epidural relief of pain during labor, and discusses appropriate inferences from up-and-down method studies.
Results of the FUEL Trial Goldberg, David J; Zak, Victor; Goldstein, Bryan H ...
Circulation (New York, N.Y.),
02/2020, Volume:
141, Issue:
8
Journal Article
Peer reviewed
Open access
The Fontan operation creates a total cavopulmonary connection, a circulation in which the importance of pulmonary vascular resistance is magnified. Over time, this circulation leads to deterioration ...of cardiovascular efficiency associated with a decline in exercise performance. Rigorous clinical trials aimed at improving physiology and guiding pharmacotherapy are lacking.
The FUEL trial (Fontan Udenafil Exercise Longitudinal) was a phase III clinical trial conducted at 30 centers. Participants were randomly assigned udenafil, 87.5 mg twice daily, or placebo in a 1:1 ratio. The primary outcome was the between-group difference in change in oxygen consumption at peak exercise. Secondary outcomes included between-group differences in changes in submaximal exercise at the ventilatory anaerobic threshold, the myocardial performance index, the natural log of the reactive hyperemia index, and serum brain-type natriuretic peptide.
Between 2017 and 2019, 30 clinical sites in North America and the Republic of Korea randomly assigned 400 participants with Fontan physiology. The mean age at randomization was 15.5±2 years; 60% of participants were male, and 81% were white. All 400 participants were included in the primary analysis with imputation of the 26-week end point for 21 participants with missing data (11 randomly assigned to udenafil and 10 to placebo). Among randomly assigned participants, peak oxygen consumption increased by 44±245 mL/min (2.8%) in the udenafil group and declined by 3.7±228 mL/min (-0.2%) in the placebo group (
=0.071). Analysis at ventilatory anaerobic threshold demonstrated improvements in the udenafil group versus the placebo group in oxygen consumption (+33±185 3.2% versus -9±193 -0.9% mL/min,
=0.012), ventilatory equivalents of carbon dioxide (-0.8 versus -0.06,
=0.014), and work rate (+3.8 versus +0.34 W,
=0.021). There was no difference in change of myocardial performance index, the natural log of the reactive hyperemia index, or serum brain-type natriuretic peptide level.
In the FUEL trial, treatment with udenafil (87.5 mg twice daily) was not associated with an improvement in oxygen consumption at peak exercise but was associated with improvements in multiple measures of exercise performance at the ventilatory anaerobic threshold.
URL: https://www.clinicaltrials.gov. Unique identifier: NCT02741115.
Background: Lymphangioleiomyomatosis (LAM) is a rare multisystem disorder affecting primarily women of child-bearing age, and characterized
by cystic lung destruction, tumors of the kidney ...(angiomyolipomas AMLs), and involvement of the axial lymphatics (lymphangioleiomyomas).
Patients with LAM experience loss of pulmonary function attributed to the proliferation of abnormal-appearing smooth muscle-like
cells (LAM cells). It is possible to group the LAM population by the presence or absence of extrapulmonary involvement ( eg , AMLs, lymphangioleiomyomas, chylous effusions). Serum vascular endothelial growth factor (VEGF)-D, a lymphangiogenic factor,
is higher in LAM patients than in healthy volunteers and has been proposed as a tool in the differential diagnosis of cystic
lung disease. We assessed serum VEGF-D concentrations in relationship to clinical phenotype in LAM patients.
Methods: Serum VEGF-D levels were quantified by enzyme immunosorbent assay for 111 patients with LAM and 40 healthy volunteers. VEGF-D
levels in patients with pulmonary LAM, with or without extrapulmonary manifestations, were compared to those of healthy volunteers.
Results: Serum VEGF-D levels were greater in patients with LAM compared to those of healthy volunteers (p < 0.001). However, when
patient samples were grouped based on the extent of lymphatic extrapulmonary involvement ( eg , lymphangioleiomyomas and adenopathy), the statistical difference was maintained only for patients with LAM with lymphatic
involvement (p < 0.001), not for those patients whose disease was restricted to the lung. Serum VEGF-D levels are a good biomarker
for lymphatic involvement (area under the curve AUC, 0.845; p < 0.0001), and a fair predictor for LAM disease (AUC, 0.751;
p < 0.0001). Serum levels correlated to CT scan grade (p = 0.033).
Conclusions: Serum VEGF-D concentration is a measure of lymphatic involvement in patients with LAM.
Lymphangioleiomyomatosis (LAM), a disease affecting women and causing cystic lung lesions, and, in some instances, leading to respiratory failure and death, appears to be exacerbated by estrogens. ...Hence, hormonal therapy with progesterone is frequently employed; however, efficacy has not been demonstrated. Our aim was to determine whether progesterone administration slowed the decline in lung function in LAM.
Retrospective study.
National Institutes of Health, Bethesda, MD.
The study population comprised 348 patients with LAM participating in a longitudinal research protocol. Declines in diffusion capacity of the lung for carbon monoxide (Dlco) and FEV1 were measured in 275 patients observed for approximately 4 years. The declines in Dlco and FEV1 of patients treated with progesterone, po (n = 67) or IM (n = 72), were compared with those of untreated patients (n = 136).
Overall yearly rates of decline in Dlco and FEV1 were 2.4 ≤ 0.4% predicted (0.69 ≤ 0.07 mL/min/mm Hg) and 1.7 ≤ 0.4% predicted (75 ≤ 9 mL), respectively (mean ≤ SEM). The most significant predictors of functional decline were initial lung function and age. After adjusting for initial FEV1, age, and duration of disease, patients treated with IM progesterone tended to have lower rates of decline in FEV1 than patients treated po (1.9 ≤ 0.6% predicted vs 3.2 ≤ 0.8% predicted, respectively; p = 0.081). However, there was no significant difference in rates of decline in FEV1 between patients treated with IM progesterone and untreated patients (1.9 ≤ 0.6% predicted vs 0.8 ≤ 0.5% predicted, respectively; p = 0.520), and patients treated with po progesterone and untreated patients (3.2 ≤ 0.8% predicted vs 0.8 ≤ 0.5% predicted, respectively; p = 0.064). After adjusting for initial Dlco, rates of decline in Dlco were significantly higher in patients treated with po progesterone (3.6 ≤ 0.7% predicted, p = 0.002) and IM progesterone (2.8 ≤ 0.5% predicted, p = 0.022) than in untreated patients (1.6 ≤ 0.6% predicted).
Within the limitations of a retrospective study, our data suggest that progesterone therapy does not slow the decline in lung function in LAM.
Angiotensin-converting enzyme inhibitor therapy improves clinical outcome and ventricular function in adults with heart failure. Infants with single-ventricle physiology have poor growth and are at ...risk for abnormalities in ventricular systolic and diastolic function. The ability of angiotensin-converting enzyme inhibitor therapy to preserve ventricular function and improve somatic growth and outcomes in these infants is unknown.
The Pediatric Heart Network conducted a double-blind trial involving 230 infants with single-ventricle physiology randomized to receive enalapril (target dose 0.4 mg . kg(-1) . d(-1)) or placebo who were followed up until 14 months of age. The primary end point was weight-for-age z score at 14 months. The primary analysis was intention to treat. A total of 185 infants completed the study. There were 24 and 21 withdrawals or deaths in the enalapril and placebo groups, respectively (P=0.74). Weight-for-age z score was not different between the enalapril and placebo groups (mean+/-SE -0.62+/-0.13 versus -0.42+/-0.13, P=0.28). There were no significant group differences in height-for-age z score, Ross heart failure class, brain natriuretic peptide concentration, Bayley scores of infant development, or ventricular ejection fraction. The incidence of death or transplantation was 13% and did not differ between groups. Serious adverse events occurred in 88 patients in the enalapril group and 87 in the placebo group.
Administration of enalapril to infants with single-ventricle physiology in the first year of life did not improve somatic growth, ventricular function, or heart failure severity. The results of this randomized trial do not support the routine use of enalapril in this population.
Background Cardiovascular disease, including aortic root dilation, dissection, and rupture, is the leading cause of mortality in patients with Marfan syndrome (MFS). The maximal aortic root diameter ...at the sinuses of Valsalva is considered the best predictor of adverse cardiovascular outcome. Although advances in therapy have improved life expectancy, affected individuals continue to suffer cardiovascular morbidity and mortality. Recent studies in an FBN1 -targeted mouse model of MFS with aortic disease similar to that seen in humans showed that treatment with losartan normalized aortic root growth and aortic wall architecture. Methods The Pediatric Heart Network designed a randomized clinical trial to compare aortic root growth and other short-term cardiovascular outcomes in subjects with MFS receiving atenolol or losartan. Individuals 6 months to 25 years of age with a body surface area–adjusted aortic root z score >3.0 will be eligible for inclusion. The primary aim is to compare the effect of atenolol therapy with that of losartan therapy on the rate of aortic root growth over 3 years. Secondary end points include progression of aortic regurgitation; incidence of aortic dissection, aortic root surgery, and death; progression of mitral regurgitation; left ventricular size and function; echocardiographically derived measures of central aortic stiffness; skeletal and somatic growth; and incidence of adverse drug reactions. Conclusion This randomized trial should make a substantial contribution to the management of individuals with MFS and expand our understanding of the mechanisms responsible for the aortic manifestations of this disorder.
Lymphangioleiomyomatosis (LAM) is a destructive lung disease of women caused by proliferation of neoplastic-like LAM cells, with mutations in the TSC1/2 tumor suppressor genes. Based on case reports, ...levels of cancer antigen 125 (CA-125), an ovarian cancer biomarker, can be elevated in patients with LAM. We hypothesized that elevated serum CA-125 levels seen in some patients with LAM were due to LAM, not other malignancies, and might respond to sirolimus treatment.
Serum CA-125 levels were measured for 241 patients at each visit. Medical records were reviewed for co-morbidities, disease progression, and response to sirolimus treatment. CA-125 expression in LAM cells was determined by using immunohistochemical analysis.
Almost 25% of patients with LAM had at least one elevated serum CA-125 measurement. Higher serum CA-125 levels correlated with lower FEV1, premenopausal status, and pleural effusion in a multivariate model (each P < .001). Serum CA-125 levels decreased following sirolimus treatment (P = .002). CA-125 and α-smooth muscle actin were co-expressed in LAM lung nodules.
Higher serum CA-125 levels were associated with pleural effusions and reduced pulmonary function and were decreased with sirolimus therapy. LAM cells express CA-125. Some elevated serum CA-125 levels may reflect serosal membrane involvement.
The Fontan operation creates a circulation characterized by elevated central venous pressure and low cardiac output. Over time, these characteristics result in a predictable and persistent decline in ...exercise performance that is associated with an increase in morbidity and mortality. A medical therapy that targets the abnormalities of the Fontan circulation might, therefore, be associated with improved outcomes. Udenafil, a phosphodiesterase type 5 inhibitor, has undergone phase I/II testing in adolescents who have had the Fontan operation and has been shown to be safe and well tolerated in the short term. However, there are no data regarding the long-term efficacy of udenafil in this population. The Fontan Udenafil Exercise Longitudinal (FUEL) Trial is a randomized, double-blind, placebo-controlled phase III clinical trial being conducted by the Pediatric Heart Network in collaboration with Mezzion Pharma Co, Ltd. This trial is designed to test the hypothesis that treatment with udenafil will lead to an improvement in exercise capacity in adolescents who have undergone the Fontan operation. A safety extension trial, the FUEL Open-Label Extension Trial (FUEL OLE), offers the opportunity for all FUEL subjects to obtain open-label udenafil for an additional 12 months following completion of FUEL, and evaluates the long-term safety and tolerability of this medication. This manuscript describes the rationale and study design for FUEL and FUEL OLE. Together, these trials provide an opportunity to better understand the role of medical management in the care of those who have undergone the Fontan operation.
Objective The initial palliative procedure for patients born with hypoplastic left heart syndrome and related single right ventricle anomalies, the Norwood procedure, remains among the highest risk ...procedures in congenital heart surgery. The classic Norwood procedure provides pulmonary blood flow with a modified Blalock–Taussig shunt. Improved outcomes have been reported in a few small, nonrandomized studies of a modification of the Norwood procedure that uses a right ventricle–pulmonary artery shunt to provide pulmonary blood flow. Other nonrandomized studies have shown no differences between the two techniques. Methods The Pediatric Heart Network designed a randomized clinical trial to compare outcomes for subjects undergoing a Norwood procedure with either the right ventricle–pulmonary artery or modified Blalock–Taussig shunt. Infants with a diagnosis of single, morphologically right ventricle anomaly who are undergoing a Norwood procedure are eligible for inclusion in this study. The primary outcome is death or cardiac transplant 12 months after random assignment. Secondary outcomes include postoperative morbidity after Norwood and stage II palliation procedures, right ventricular function and pulmonary arterial growth at stage II palliation, and neurodevelopmental outcomes at 14 months old. Incidence of adverse events will also be compared between treatment groups. Conclusion This study will make an important contribution to the care of patients with hypoplastic left heart syndrome and related forms of single, morphologically right ventricle. It also establishes a model with which other operative interventions for patients with congenital cardiovascular malformations can be evaluated in the future.
Lymphangioleiomyomatosis (LAM) is a rare disease, occurring in women, characterized by cystic degeneration of the lungs, abdominal tumors, and proliferation of abnormal smooth muscle cells. Lung ...function abnormalities consist of impairment of the diffusion capacity (DL(CO)) and airflow obstruction. The objective of this study was to correlate the functional impairment with histologic measures of disease severity to identify predictors of disease outcome. Lung function of 143 patients and lung biopsies of 74 of these patients were reviewed for evidence of airway disease and scoring of disease severity. A positive response to bronchodilators was associated with more severe airflow obstruction, a predominantly solid pattern of LAM lesions in the lung biopsy, and greater rate of decline in expiratory flow. Airway inflammation, present in 61% of the lung specimens, was not associated with reversible airway obstruction and did not correlate with the severity of airflow obstruction. DL(CO) correlated best with the LAM histologic score (LHS), a demonstrated predictor of outcome. We conclude that reversible airway obstruction is found in LAM patients with accelerated loss of lung function and a predominantly solid pattern of LAM lesions. Impairment of DL(CO) correlates with LHS, a predictor of survival and time to lung transplantation.
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