Christine Skibinski

Utility of Radioisotopic Filtration Markers in Chronic Renal Issufficiency: Simultaneous Comparison of 125I-Iothalamate, 169Yb-DTPA, 99mTc-DTPA, and Inulin

Assessment of glomerular filtration rate (GFR) with inulin is cumbersome and time-consuming. Radioisotopic filtration markers have been studied as filtration markers because they can be used without continuous intravenous (IV) infusion and because analysis is relatively simple. Although the clearances of 99m Tc-diethylenetriaminepentaacetic acid (DTPA), 169 Yb-DTPA, and 125 1-iothalamate have each been compared with inulin, rarely has the comparability of radioisotopic filtration markers been directly evaluated in the same subject. To this purpose, we determined the renal clearance of inulin administered by continuous infusion and the above radioisotopic filtration markers administered as bolus injections, simultaneously in four subjects with normal renal function and 16 subjects with renal insufficiency. Subjects were studied twice in order to assess within-study and between-study variability. Unlabeled iothalamate was infused during the second half of each study to assess its effect on clearances. We found that renal clearance of 1251-iothalamate and 169Yb-DTPA significantly exceeded clearance of inulin in patients with renal insufficiency, but only by several mL·min -1 ·1.73 m -2 . Overestimation of inulin clearance by radioisotopic filtration markers was found in all normal subjects. No differences between markers were found in the coefficient of variation of clearances either between periods on a given study day (within-day variability) or between the two study days (between-day variability). The true test variability between days did not correlate with within-test variability. We conclude that the renal clearance of 99m Tc-DTPA, 169 Yb-DTPA, or 125 I-iothalamate administered as a single IV or subcutaneous injection can be used to accurately measure GFR in subjects with renal insufficiency; use of the single injection technique may overestimate GFR in normal subjects.

Lipoprotein(a) is an independent risk factor for cardiovascular disease in hemodialysis patients.

BackgroundAlthough serum lipoprotein(a) [Lp(a)J is an independent risk factor for atherosclerosis in the general population and Lp(a) levels are increased in hemodialysis patients, an association of Lp(a) with the risk of clinical events attributed to atherosclerosis has not been established in the chronic hemodialysis patient population. We therefore determined the association between Lp(a) levels and the risk of clinical events of presumed atherosclerotic etiology in a prospective study of an outpatient hemodialysis population. Methods and ResultsLp(a) was measured by radioimmunoassay in a baseline cardiovascular disease risk assessment in a consecutive series of 129 hemodialysis patients. The relation between baseline Lp(a) and clinical events of presumed atherosclerotic etiology was determined during 48 months of follow-up. Hemodialysis patients had a median Lp(a) concentration that was approximately four times as high as the median Lp(a) concentration in normal controls and twice as high as the levels in controls with angiographic evidence of coronary artery disease [median Lp(a), 38.4 versus 16.9 mg/dl; p < 0.001]. Baseline Lp(a) levels were no different in participants with or with no history of a previous clinical event at the time of the baseline examination. However, baseline Lp(a) concentration (p < 0.001) and a history of atherosclerotic clinical events (p = 0.001) were associated with clinical events during the period of follow-up. In contrast, baseline serum total cholesterol, triglyceride, high density lipoprotein cholesterol, low density lipoprotein cholesterol, age, gender, race, or duration of hemodialysis were unrelated to this risk in the prospective study. Stepwise multiple logistic regression analysis demonstrated that serum Lp(a) concentration (p = 0.001) and the presence of a previous clinical event (p = 0.004) were the only independent contributors to the risk of a clinical event during the period of follow-up. ConclusionsLp(a) is an independent risk factor for clinical events attributed to atherosclerotic cardiovascular disease in patients receiving chronic hemodialysis treatment of end-stage renal disease.

Serum Lp(a) level as a predictor of vein graft stenosis after coronary artery bypass surgery in patients.

Although the serum lipoprotein fraction Lp(a) has been associated with coronary artery atherosclerosis, its relationship to narrowing of saphenous vein grafts has not previously been elucidated. We therefore measured serum Lp(a) levels in 167 symptomatic patients undergoing cardiac catheterization who had had coronary artery bypass surgery 0.7 to 14.3 years earlier. Lp(a), total cholesterol, and total triglyceride levels were compared with the degree of saphenous vein graft stenosis to test for any association. Serum Lp(a) levels were significantly associated with the degree of stenosis of saphenous vein grafts (r = .24, p = .002). Mean Lp(a) levels (mg/dl) in the 135 patients with stenosis were almost double (32.0 +/- 32.7, mean +/- SD) those in the 32 patients with no graft stenosis (16.7 +/- 22.6; p = .002). Graft stenosis was not associated with previous myocardial infarction, hypertension, obesity, diabetes, or smoking. Serum cholesterol levels (mg/dl) were slightly higher in the stenosis group (251.3 +/- 69) than in the no-stenosis group (231.8 +/- 48.8), but the difference was of borderline significance (p = .06). A stepwise increase in mean Lp(a) was found in groups of patients with increasing vein graft stenosis. At a serum Lp(a) level of 31.6 mg/dl or above, 92% of the patients demonstrated vein graft stenosis. Thus, patients with elevated Lp(a) levels have an increased risk of developing saphenous vein graft stenosis after coronary bypass surgery.

Intracarotid amobarbital procedure: I. Prediction of decreased modality-specific memory scores after temporal lobectomy.

Summary: To assess predictive value of the intracarotid amobarbital procedure (IAP) for decreased postoperative modality‐specific memory, we studied 37 temporal lobectomy patients with intractable partial epilepsy who were selected for operation independent of preoperative IAP findings. When ipsilateral IAP failure was defined by an absolute method as a retention score <67%, the results were not associated with decreased modality‐specific memory after operation. When ipsilateral IAP failure was defined by a comparative method as a retention score at least 20% lower after ipsilateral than contralateral injection, the results showed greater differences between groups, but differences still did not achieve statistical significance. Four left‐resection patients who failed the ipsilateral IAP had a median postoperative change in the Wechsler Memory Scale‐Revised (WMS‐R) Verbal Memory Index score of ‐14%, whereas 16 left‐resection patients who passed the ipsilateral IAP had a mean postoperative change in the WMS‐R Verbal Memory Index score of ‐7.5% (p = 0.12). These results suggested that the IAP interpreted comparatively may be a helpful adjunctive test in assessment of relative risk for modality‐specific memory dysfunction after temporal lobectomy, but larger series of operated patients are needed to confirm this possibility. In this series, complete amnesia was not noted after ipsilateral injection, even in patients with postoperative modality‐specific memory decline.

Intracarotid Amobarbital Procedure: II. Lateralizing Value in Evaluation for Temporal Lobectomy

Summary: The intracarotid amobarbital procedure (IAP) was assessed for lateralizing value in 37 patients who later had temporal lobectomy for intractable epilepsy. Among patients who failed IAP memory testing on one side (defined as a retention score for test items at least 20% lower on one side than the other), significantly more patients failed the injection contralateral (16 of 20, 80%) than ip‐silateral (4 of 20, 20%) to the side of later resection (p = 0.008). In addition, preoperative EEG evidence of bilateral temporal epileptogenicity was significantly more frequent among patients who failed the ipsilateral IAP injection (2 of 4, 50%) than among patients who passed the ipsilateral IAP injection (2 of 33, 6%) (p = 0.050). Finally, failure of the contralateral IAP injection involved significantly more severe amnesia for test items (median retention score 25%) than did failure of the ipsilateral injection (median retention score 59%) (p = 0.047). Profoundly low retention scores <33% occurred only with contralateral injection. These findings suggest that the IAP has some adjunctive lateralizing value for the epileptogenic hemisphere in patients with temporal lobe epilepsy, especially when the retention score with one injection is profoundly low.

Prevention of Chronic Cerebral Vasospasm in Dogs with Milrinone

OBJECTIVE Delayed cerebral ischemia resulting from vasospasm is a major cause of morbidity and death in patients with aneurysmal subarachnoid hemorrhage. Milrinone, because it inhibits Type IV cyclic adenosine monophosphate-specific phosphodiesterase enzyme in both cardiac and vascular smooth muscle, is a powerful inotrope and vasodilator, but it has little effect on heart rate or blood pressure. Because of these properties, milrinone is an attractive potential therapy after subarachnoid hemorrhage. The purpose of the present study was to investigate the effect of milrinone on chronic experimental cerebral vasospasm. METHODS A double-hemorrhage canine model of vasospasm was used to study the efficacy of milrinone. Angiographic vasospasm and systemic hemodynamics were compared in a treatment group of animals that received a loading dose of milrinone (0.05 mg/kg, intravenously) and then slow-release (0.05 microgram/kg/min) milrinone pellets (n = 10) and a control group that received placebo pellets (n = 9), over an 8-day period after the initial subarachnoid hemorrhage. The hemorrhage was created by injection of 4 ml of autologous, nonheparinized, arterial blood into the cisterna magna on Days 1 and 3. Hemodynamic measurements, including cardiac output determinations, were made on Days 0, 1, 3, 6, and 8 with a pulmonary artery catheter, and angiographic vasospasm was assessed on Day 8 by comparison with baseline angiograms. RESULTS Treatment with milrinone caused no significant changes in systemic hemodynamics. Angiographic vasospasm, however, was significantly reduced in the Day 8 angiograms for the treated group, compared with the control group (98.28 +/- 14.06 and 67.89 +/- 13.06% of original vessel cross-sectional area, respectively; P < 0.001). CONCLUSION Milrinone is effective in preventing chronic cerebral vasospasm in a canine model of experimental chronic cerebral vasospasm. This effect is independent of changes in systemic hemodynamics. Milrinone and related drugs warrant further investigation for the treatment of cerebral vasospasm.

The clinical spectrum of focal cortical dysplasia and epilepsy

Abstract Focal cortical dysplasia is an important pathologic substrate in patients with epilepsy, but its clinical spectrum has not yet been completely defined. We retrospectively studied 30 epilepsy surgery patients with focal abnormalities of neuronal migration as the only histopathologic finding in resected tissue. Patients comprised two clinical groups. Seventeen patients with extratemporal epilepsy had early (median age, 7.0 years) extratemporal resection or hemispherectomy for severe epilepsy (47% of patients with > 10 partial seizures a day) that began in infancy or early childhood (median age, 1.0 year), usually in the setting of mental retardation or developmental delay (59% of patients), and often with magnetic resonance imaging (MRI) evidence of focal neuronal migration abnormality (44% of patients). In contrast, 13 patients with temporal lobe epilepsy were significantly older at age of seizure onset (median, 8.0 years; p = 0.001) and surgery (median, 22.0 years; p = 0.001), with less severe epilepsy (no patients with an average of > 10 seizures a day; p = 0.004), and without mental retardation or MRI evidence of neuronal migration abnormality ( p = 0.001). In both groups, positron emission tomography (PET) was more sensitive than MRI and showed focal hypometabolism in seven patients with normal MRI. Seizure-free outcome tended to be more common after temporal lobectomy (77%) than after extratemporal resection or hemispherectomy (53%). Pathologic abnormalities were more severe in patients with extratemporal epilepsy than in patients with temporal lobe epilepsy. The clinical spectrum of focal cortical dysplasia included not only infants and children with severe extratemporal epilepsy and mental retardation, but also older patients with temporal lobe epilepsy and at least boderline IQ. Preoperative diagnosis may be difficult in cases with less severe pathologic abnormality, but high-resolution MRI and PET can increase the yield.

Vascular stenting in normal and atherosclerotic rabbits. Studies of the intravascular endoprosthesis of titanium-nickel-alloy.

Percutaneous transluminal balloon angioplasty would be more effective if the rate of recurrent stenosis were reduced. To evaluate the prevention of restenosis after percutaneous transluminal angioplasty, intravascular endoprosthetic stents of titanium-nickel-alloy were implanted transluminally in seven normal and 21 atherosclerotic rabbits. In normal rabbits, a 3.5-mm diameter stent was implanted in the aorta and a 2.5-mm diameter stent in the right iliac artery, which were followed with serial angiograms from 6 weeks (n = 7) to 8 months (n = 4). There was a mean stenosis of 13.1% in the 2.5-mm and 13.6% in the 3.5-mm stent. There was no significant narrowing compared with the adjacent control segments of artery; histopathology showed a thin, fibrous neointima with smooth muscle cells. Each atherosclerotic rabbit was balloon dilated at two separate stenotic sites; each site was 2.0 cm in length. The aortic site (with 28.8 +/- 13.8% mean stenosis [+/- SD]) was dilated with a 3.5-mm balloon, and the iliac site (with 36.5 +/- 14.2% stenosis) was dilated with a 2.5-mm balloon. In each site, an intravascular stent of corresponding diameter and 7-mm length was implanted in one half of the dilated segment, assigned randomly, and the other half served as the angioplasty control. Angiographically observed restenosis rates and the corresponding histopathology were similar in the atherosclerotic segments that had angioplasty alone versus the atherosclerotic segments that had angioplasty plus stenting. The mean neointimal thickness in the aortas and iliac arteries, respectively, measured 247 +/- 181 microns (+/- SD) and 218 +/- 77 microns after 6 weeks (n = 8) versus 321 +/- 168 and 308 +/- 189 microns after 20 weeks (n = 5, p = NS). At 20 weeks follow-up, there was 29.1 +/- 29.8% (median, 16.4%) stenosis in the aortic stent versus 38.9 +/- 24.1% (median, 34.0%) stenosis in the percutaneous transluminal angioplasty control segment of aorta (n = 5, p = NS) and 81.4 +/- 25.5% stenosis in the iliac artery stent versus 89.3 +/- 15.3% stenosis in the PTA control segment of the right iliac artery (n = 5, p = NS). Comparing stenotic arterial segments treated with angioplasty alone with angioplasty plus intravascular stenting in the atherosclerotic rabbits showed that there was no significant difference in either the histopathologic changes or the restenosis rates.

A Prospective, Randomized, Blinded, and Placebo-controlled Trial of Intraoperative Intra-arterial Urokinase Infusion During Lower Extremity Revascularization: Regional and Systemic Effects

ObjectiveThis study was designed to evaluate the safety and regional and systemic effects of three doses of urokinase (UK) infused into the distal arterial circulation during routine operative lower extremity revascularization. MethodsOne hundred thirty-four patients were prospectively randomized to receive one of three bolus doses of UK (125,000, 250,000, or 500,000 U) or placebo (saline) infused into the distal circulation before lower extremity bypass for chronic limb ischemia. Regional (femoral vein) and systemic (arm) blood was sampled before drug infusion, prereperfusion, and postreperfusion, and systemic blood samples were obtained 2 hours postreperfusion. Assays evaluated plasma levels of fibrinogen, fibrin(ogen) degradation products (FDP), fibrin breakdown products (D-dimer and fragment B-β 15–42), and plasminogen. Patients were monitored for clinically evident bleeding complications. The Wilcoxon rank-sum test was used to compare different drug doses with the placebo. ResultsIntraoperative bolus UK infusions produced no significant fibrinogen breakdown compared with placebo. There was a dose-related decline in plasminogen levels, which became significant at a dose of 500,000 U of UK (p < 0.001). There were dose-related increases in plasma FDP, which became significant at dose of 250,000 and 500,000 U (p≤0.005), and in plasma D-dimer, which were significant at all UK doses (p < 0.001). The changes in plasma fibrinogen and markers of fibrin breakdown were similar in the regional and systemic circulations. There was no increase in operative blood loss, blood replaced, or wound hematoma formation. There was an unexplained increased mortality in the placebo group (12.1% vs. 2.0%1 p = 0.033). ConclusionsIntraoperative bolus UK infusion is safe, with no significant fibrinogen depletion or increased operative blood loss or wound hematoma formation. Dose-related plasminogen activation resulted in significant breakdown in cross-linked fibrin in the distal circulation. Intraoperative bolus UK infusion may be valuable as an adjunct in patients with chronic occlusive disease who are undergoing revascularization. Detailed randomized studies are indicated to establish clinical efficacy.

Treatment of androgenic disorders with dexamethasone: Dose-response relationship for suppression of dehydroepiandrosterone sulfate

Glucocorticoids are effective in suppressing androgens in many women whose levels of these steroids are elevated. Their use has been controversial because of inconsistent reports about efficacy and concern about safety. We investigated the dose-response relationship for suppression of dehydroepiandrosterone sulfate (DHEAS) with the use of dexamethasone. Thirty women with an initial DHEAS value of greater than or equal to 300 micrograms/dl were studied. All had cystic or inflammatory acne, hirsutism, or androgenic alopecia. Dexamethasone was given as a single bedtime dosage of 0.125, 0.250, or 0.375 mg. Mean dosage required for suppression was 0.256 mg daily. Suppression of the DHEAS level to less than or equal to 200 micrograms/dl was achieved with 0.125 mg in 25% of women, 0.250 mg in an additional 50%, and 0.375 mg in a further 20%. Most patients were taking spironolactone when the study was performed. Effective suppression is attained with dexamethasone doses significantly lower than previously thought. Use of these doses was not associated with a significant incidence of adverse effects.