Gregory A. Fleming

Impaired growth hormone secretion in the adult population: relation to age and adiposity.

Growth hormone (GH) release was studied in adults of normal stature, ages 21-86 yr. The subjects were 85-115% of ideal body weight, between the 5th and 95th percentiles in height, and free of active or progressive disease. 9 to 12 individuals in each decade from thirds to ninth were evaluated. The following criteria of GH status were measured: serum GH concentration, analyzed by radioimmunoassay at half-hour intervals for 4 h after onset of sleep, and at 1-h intervals from 8 a.m. to 4 p.m. in 52 subjects; daily retention of N, P, and K in response to 0.168 U human (h)GH/kg body wt3/4/day in 18 subjects; and plasma somatomedin C (SmC) level before and during exogenous hGH treatment in 18 subjects. All 10 individuals, 20-29 yr old, released substantial amounts of endogenous GH during both day and night (average peak serum GH obtained during day and night was 7.3 and 20.3 ng/ml, respectively); average plasma SmC was 1.43 U/ml (95% tolerance limits, 0.64-2.22 U/ml). There was no significant effect of exogenous hGH on elemental balances or on plasma SmC. In contrast, 6 of 12 individuals 60-79 yr old showed the following evidences of impaired GH release; peak waking and sleeping serum GH less than 4 ng/ml; plasma SmC less than 0.38 U/ml; a significant retention in N, P, and K; and a significant rise in plasma SmC, in response to exogenous hGH. Plasma SmC, serum GH during sleep, serum GH during the day, retentions of N, P, and K in response to exogenous hGH, and rise in plasma SmC in response to hGH were all intercorrelated (P less than 0.05). Plasma SmC less than 0.38 U/ml corresponded to peak nocturnal serum GH less than 4 ng/ml. The prevalence of plasma SmC less than 0.38 U/ml increased progressively from age 20 to 90: third decade, 0%; fourth, 11%; fifth, 20%; sixth, 22%; seventh, 42%; eight, 55%; and ninth, 55%. Within each decade, plasma SmC was inversely related to adiposity.

Hypocitraturia in Patients with Gastrointestinal Malabsorption

We measured serum and urinary citrate, oxalate, calcium, and magnesium in 22 normal subjects and in 16 patients with malabsorption. The patients had subnormal levels of serum citrate and magnesium during fasting, subnormal 24-hour levels of urinary citrate, magnesium, and calcium, and excessive levels of urinary oxalate. Daily citrate excretion averaged only 15 per cent of normal. The hypocitraturia in the patients resulted from a subnormal filtered load of citrate and abnormally high net tubular reabsorption of the anion. An oral citrate supplement raised both the serum concentration and the filtered load of citrate to normal fasting values, but net tubular reabsorption remained abnormally high and urinary excretion abnormally low. Intramuscular magnesium sulfate, which corrected the hypomagnesemia and hypomagnesuria, had no effect on serum citrate or its filtered load. Nevertheless the injection restored net tubular reabsorption of citrate to normal and partially improved the hypocitraturia. Full correction of the hypocitraturia was achieved by combined treatment with oral citrate and intramuscular magnesium sulfate. Hypocitraturia may contribute to the formation of oxalate stones in these patients, and therefore our treatment may help to prevent this complication.

Type II hyperprolinaemia in a pedigree of Irish travellers (nomads).

We describe a study of 312 subjects in 71 families near related to a proband with type II hyperprolinaemia. The subjects were Irish travellers (nomads) among whom consanguineous marriage and high fertility are common. Thirteen additional cases of type II hyperprolinaemia were discovered; all were offspring of consanguineous unions. A further 50 subjects were found to have mild hyperprolinaemia. We found a strong association between type II hyperprolinaemia and seizures during childhood but no significant association with mental handicap. Most adults with type II hyperprolinaemia enjoyed normal health and there was no evidence that maternal hyperprolinaemia compromised fetal development. The documented association between type II hyperprolinaemia and seizures may be related to the neuromodulatory or reducing-oxidising effects of proline and pyrroline-5-carboxylate, respectively, that has been shown in vitro. Alternatively, another genetic defect closely linked to the type II hyperprolinaemia allele could be the explanation.

Milrinone Use Is Associated With Postoperative Atrial Fibrillation After Cardiac Surgery

Background— Postoperative atrial fibrillation (AF), a frequent complication after cardiac surgery, causes morbidity and prolongs hospitalization. Inotropic drugs are commonly used perioperatively to support ventricular function. This study tested the hypothesis that the use of inotropic drugs is associated with postoperative AF. Methods and Results— We evaluated perioperative risk factors in 232 patients who underwent elective cardiac surgery. All patients were in sinus rhythm at surgery. Sixty-seven patients (28.9%) developed AF a mean of 2.9±2.1 days after surgery. Patients who developed AF stayed in the hospital longer (P<0.001) and were more likely to die (P=0.02). Milrinone use was associated with an increased risk of postoperative AF (58.2% versus 26.1% in nonusers; P<0.001). Older age (63.4±10.7 versus 56.7±12.3 years; P<0.001), hypertension (P=0.04), lower preoperative ejection fraction (P=0.03), mitral valve surgery (P=0.02), right ventricular dysfunction (P=0.03), and higher mean pulmonary artery pressure (27.1±9.3 versus 21.8±7.5 mm Hg; P=0.001) also were associated with postoperative AF. In multivariable logistic regression, age (P<0.001), ejection fraction (P=0.02), and milrinone use (odds ratio, 4.86; 95% confidence interval, 2.31 to 10.25; P<0.001) independently predicted postoperative AF. When only data from patients with pulmonary artery catheters were analyzed and pulmonary artery pressure was included in the model, age, milrinone use (odds ratio, 4.45; 95% confidence interval, 2.01 to 9.84; P<0.001), and higher pulmonary artery pressure (P=0.02) were associated with an increased risk of postoperative AF. Adding other potential confounders or stratifying analysis by mitral valve surgery did not change the association of milrinone use with postoperative AF. Conclusion— Milrinone use is an independent risk factor for postoperative AF after elective cardiac surgery.

Intervention for Recoarctation in the Single Ventricle Reconstruction Trial Incidence, Risk, and Outcomes

Background— Recoarctation after the Norwood procedure increases risk for mortality. The Single Ventricle Reconstruction (SVR) trial randomized subjects with a single right ventricle undergoing a Norwood procedure to a modified Blalock-Taussig shunt or a right ventricle–pulmonary artery shunt. We sought to determine the incidence of recoarctation, risk factors, and outcomes in the SVR trial. Methods and Results— Recoarctation was defined by intervention, either catheter based or surgical. Univariate analysis and multivariable Cox proportional hazard models were performed with adjustment for center. Of the 549 SVR subjects, 97 (18%) underwent 131 interventions (92 balloon aortoplasty, 39 surgical) for recoarctation at a median age of 4.9 months (range, 1.1–10.5 months). Intervention typically occurred at pre–stage II catheterization (n=71, 54%) or at stage II surgery (n=38, 29%). In multivariable analysis, recoarctation was associated with the shunt type in place at the end of the Norwood procedure (hazard ratio, 2.0 for right ventricle–pulmonary artery shunt versus modified Blalock-Taussig shunt; P=0.02), and Norwood discharge peak echo-Doppler arch gradient (hazard ratio, 1.07 per 1 mm Hg; P<0.01). Subjects with recoarctation demonstrated comorbidities at pre–stage II evaluation, including higher pulmonary arterial pressures (15.4±3.0 versus 14.5±3.5 mm Hg; P=0.05), higher pulmonary vascular resistance (2.6±1.6 versus 2.0±1.0 Wood units·m2; P=0.04), and increased echocardiographic volumes (end-diastolic volume, 126±39 versus 112±33 mL/BSA1.3, where BSA is body surface area; P=0.02). There was no difference in 12-month postrandomization transplantation-free survival between those with and without recoarctation (P=0.14). Conclusions— Recoarctation is common after Norwood and contributes to pre–stage II comorbidities. Although with intervention there is no associated increase in 1-year transplantation/mortality, further evaluation is warranted to evaluate the effects of associated morbidities. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00115934.

Coarctation of the aorta: Management from infancy to adulthood.

Coarctation of the aorta is a relatively common form of congenital heart disease, with an estimated incidence of approximately 3 cases per 10000 births. Coarctation is a heterogeneous lesion which may present across all age ranges, with varying clinical symptoms, in isolation, or in association with other cardiac defects. The first surgical repair of aortic coarctation was described in 1944, and since that time, several other surgical techniques have been developed and modified. Additionally, transcatheter balloon angioplasty and endovascular stent placement offer less invasive approaches for the treatment of coarctation of the aorta for some patients. While overall morbidity and mortality rates are low for patients undergoing intervention for coarctation, both surgical and transcatheter interventions are not free from adverse outcomes. Therefore, patients must be followed closely over their lifetime for complications such as recoarctation, aortic aneurysm, persistent hypertension, and changes in any associated cardiac defects. Considerable effort has been expended investigating the utility and outcomes of various treatment approaches for aortic coarctation, which are heavily influenced by a patients anatomy, size, age, and clinical course. Here we review indications for intervention, describe and compare surgical and transcatheter techniques for management of coarctation, and explore the associated outcomes in both children and adults.

CRISP: Catheterization RISk score for pediatrics: A Report from the Congenital Cardiac Interventional Study Consortium (CCISC)

We sought to develop a scoring system that predicts the risk of serious adverse events (SAEs) for individual pediatric patients undergoing cardiac catheterization procedures.

Percutaneous interventions in high‐risk patients following mustard repair of transposition of the great arteries

To assess safety, efficacy, and intermediate term outcomes of percutaneous interventions in Mustard patients.

Teachers' perceptions concerning the relative values of personal and clinical characteristics and their influence on the assignment of students' clinical grades

Summary. Twenty senior teachers were asked to rank, in order of influence, the seven clinical and five personal characteristics used to grade third‐year medicine clerks. Seventeen perceived themselves to be more influenced by clinical characteristics when assigning grades. Independently, the actual ratings completed over a 3‐year period by these same teachers were analysed to measure the congruency between their perceived and actual grading behaviour. When actually rating students only nine raters were more influenced by clinical characteristics and just one half of the teachers displayed a congruency between their perceived and actual rating behaviour. The implications of these findings are discussed.

Sildenafil Exposure and Hemodynamic Effect after Fontan Surgery

Objective: Determine sildenafil exposure and hemodynamic effect in children after Fontan single-ventricle surgery. Design: Prospective dose-escalation trial. Setting: Single-center pediatric catheterization laboratory. Patients: Nine children post Fontan single-ventricle surgical palliation and undergoing elective cardiac catheterization: median (range) age and weight, 5.2 years (2.5–9.4 yr) and 16.3 kg (9.5–28.1 kg). Five children (55%) were boys, and six of nine (67%) had a systemic right ventricle. Interventions: Catheterization and echocardiography performed before and immediately after single-dose IV sildenafil (0.25, 0.35, or 0.45 mg/kg over 20 min). Measurements and Main Results: Peak sildenafil and desmethyl sildenafil concentration, change in hemodynamic variables measured by cardiac catheterization and echocardiography. Maximum sildenafil concentrations ranged from 124 to 646 ng/mL and were above the in vitro threshold needed for 77% phosphodiesterase type-5 inhibition in eight of nine children and 90% inhibition in seven of seven children with doses more than or equal to 0.35 mg/kg. Sildenafil improved stroke volume (+22%, p = 0.05) and cardiac output (+10%, p = 0.01) with no significant change in heart rate in eight of nine children. Sildenafil also lowered systemic (–16%, p = 0.01) and pulmonary vascular resistance index in all nine children (median baseline pulmonary vascular resistance index 2.4 [range, 1.3–3.7]; decreased to 1.9 [0.8–2.7] Wood Units × m2; p = 0.01) with no dose-response effect. Pulmonary arterial pressures decreased (–10%, p = 0.02) and pulmonary blood flow increased (9%, p = 0.02). There was no change in myocardial performance index and no adverse events. Conclusions: After Fontan surgery, sildenafil infusion acutely improves cardiopulmonary hemodynamics, increasing cardiac index. For the range of doses studied, exposure was within the acute safety range reported in adult subjects.