Joan S. Reisch

Prevention of venous thromboembolism in general surgical patients. Results of meta-analysis.

The results of randomized clinical trials evaluating commonly used methods of deep vein thrombosis (DVT) prophylaxis in moderate- and high-risk general surgery patients were pooled to obtain an unbiased estimate of efficacy and risks. Low-dose heparin (LDH), dextran, heparin-dihydroergotamine (HDHE), intermittent pneumatic compression (IPC), and graded elastic stockings significantly reduced the incidence of DVT; aspirin was ineffective. In contrast to other methods, elastic stockings have not been adequately studied to determine their value in reducing DVT in high-risk patients, such as those with malignancy. Only LDH and dextran were studied in numbers of patients sufficient for demonstrating a clear reduction in pulmonary embolism (PE). In comparison studies, LDH was superior to dextran in preventing DVT, but the two agents were equivalent in protecting against PE. Although HDHE was marginally better than LDH in preventing DVT, it appeared to have no advantage in preventing PE--at least in moderate-risk patients. The incidence of major hemorrhage was not increased with any of the prophylactic agents. However, wound hematomas occurred significantly more frequently with LDH, an effect noted in the pooled data from double-blind and open trials. In comparison trials with LDH, both dextran and HDHE had significantly fewer wound hematomas. LDH administered every 8 hours appeared more effective in reducing DVT than LDH administered every 12 hours; the incidence of wound hematomas was equivalent with both regimens.

Correlation of interleukin-1β and cachectin concentrations in cerebrospinal fluid and outcome from bacterial meningitis

Because interleukin-1 beta (IL-1 beta) and cachectin (tumor necrosis factor) are thought to mediate the bodys response to microbial invasion, we measured IL-1 beta and tumor necrosis factor concentrations in paired cerebrospinal fluid (CSF) samples (on admission to the hospital, CSF1; 18 to 30 hours later, CSF2) from 106 infants and children with bacterial meningitis. In CSF1, IL-1 beta was detected in 95% of samples; the mean (+/- 1 SD) concentration was 944 +/- 1293 pg/ml. Patients with CSF1 IL-1 beta concentrations greater than or equal to 500 pg/ml were more likely to have neurologic sequelae (p = 0.001). Tumor necrosis factor was present in 75% of CSF1 samples; the mean concentration was 787 +/- 3358 pg/ml. In CSF2 the mean IL-1 beta concentration was 135 +/- 343 pg/ml, and IL-1 beta concentrations correlated significantly with CSF2 leukocyte count, with glucose, lactate, protein, and tumor necrosis factor concentrations, and with neurologic sequelae. Tumor necrosis factor was detected in CSF2 specimens of 53 of 106 patients, with a mean concentration of 21 +/- 65 pg/ml. Of the 106 patients, 47 received dexamethasone therapy at the time of diagnosis. These patients had significantly lower concentrations of IL-1 beta and higher glucose and lower lactate concentrations in CSF2, and they had a significantly shorter duration of fever compared with the values in patients not treated with steroids (p less than or equal to 0.002). Our data suggest a possible role of IL-1 beta and tumor necrosis factor as mediators of meningeal inflammation in patients with bacterial meningitis, and might explain, in part, the beneficial effect of dexamethasone as adjunctive treatment in this disease.

Proposed cutoff values to define bladder outlet obstruction in women.

OBJECTIVES There is no accepted urodynamic definition of outlet obstruction in women. Currently, the diagnosis is made on the basis of history and radiographic and endoscopic findings. The goal of this study is to design a pressure-flow nomogram (PdetQmax/Qmax) and define cut-off values for obstruction. METHODS Two groups were studied prospectively in an open study: 124 control and 35 clinically obstructed patients. All had a complete history, physical examination, normal neurologic evaluation, cystoscopy, voiding cystography, and urodynamics-with-pressure-flow study. Pressure-flow plot and receiver operator characteristic curves (ROCs) were constructed to determine optimal cut-off values to predict obstruction for peak flow rate (Qmax) and detrusor pressure at maximal flow (PdetQmax). RESULTS The etiology of obstruction was previous anti-incontinence surgery (n = 13), large cystocele (n = 11), urethral stricture (n = 6), and other (n = 5). On the basis of ROC curves, using cut-off values of Qmax of 15 mL/s or less and 12 mL/s or less, sensitivity was 85.7% and 71.4%, and specificity 78.2% and 90.3%, respectively. Using cut-off values of PdetQmax of more than 25 and more than 30 cm H2O, sensitivity was 74.3% and 71.4%, and specificity 79.8% and 88.7%, respectively. Using a combined cut-off value of Qmax of 1 5 mL/s or less and PdetQmax of more than 20 cm H2O, sensitivity was 74.3% and specificity was 91.1%. CONCLUSIONS Based on this prospective, controlled study, preliminary cut-off values were obtained for refining the definition of outlet obstruction in women.

Prognostic indicators in children with IgA nephropathy — Report of the Southwest Pediatric Nephrology Study Group

Investigators in 13 pediatric nephrology centers reviewed clinical and pathological features in 218 children and adolescents with IgA nephropathy (IgAN), with particular emphasis on 80 patients who had follow-up periods of at least 4 years. Potential prognostic markers in the 80 children were compared between 12 (15%) who developed end-stage renal disease (ESRD) versus 68 who did not. The relationship between clinical and pathological features and the subsequent development of ESRD was examined using stepwise linear discriminant analysis in addition to standard univariate analysis. Seven variables were found to be predictive of ESRD: the presence of glomerular sclerotic changes, especially when this was associated with proliferation or sclerosis in 20% or more of the glomeruli, black race; hypertension at biopsy; proteinuria at biopsy; age at presentation; crescents; male sex. Using the resulting discriminant function, development of ESRD could be correctly predicted in 95% of the subjects. We conclude that ESRD is more common in American children with IgAN than was realized previously. Risk factors previously documented in adult studies have been confirmed, especially the presence of glomerular sclerosis, proteinuria, and hypertension.

Slow-Release Sodium Fluoride in the Management of Postmenopausal Osteoporosis: A Randomized, Controlled Trial

Although fluoride can cause osteoblastic proliferation [1, 2] and stimulate new bone formation [3], its use in managing osteoporosis has been associated with frequent and sometimes serious complications, including gastric bleeding and microfractures [3]. Excessive exposure may lead to fluorosis [4], characterized by a formation of abnormal bone that may be poorly mineralized and mechanically defective. Further, in a placebo-controlled randomized trial [3], continuous treatment with plain (nonsustained release) sodium fluoride and calcium carbonate supplementation did not produce a statistically significant decrease in the spinal fracture rate despite a substantial increase in the lumbar vertebral bone mass. We previously reported [5, 6] a nonrandomized trial in which intermittent slow-release sodium fluoride with continuous calcium citrate supplementation stimulated the formation of normally mineralized bone and decreased the spinal fracture rate without serious complications. In 1986, we initiated a randomized trial using slow-release sodium fluoride plus calcium citrate compared with placebo plus calcium citrate in 99 patients with postmenopausal osteoporosis. The trial is ongoing, with an average duration of treatment in the two study groups of 2.44 and 2.14 cycles (14 mo/cycle) and with 15 patients completing the intended 4 cycles of treatment. Although the study is not expected to be completed until August 1996, this interim analysis was done in response to a request for an update at the Fourth International Symposium on Osteoporosis [7]. The trial will be completed in order to determine if the treatment effect is sustained. We believe that the interim analysis will not affect the conduct of the remainder of the trial. Methods Clinical Data Recruited into the trial were 110 fully ambulatory white women with postmenopausal osteoporosis, all of whom were referred for symptomatic osteoporosis by practicing physicians because of an inadequate response to conventional therapy or the unwillingness of physicians to care for them. No other ethnic groups were enrolled, probably because of the rarity of postmenopausal osteoporosis and the nature of the referred patients in the study areas. The entry criteria were as follows: postmenopausal state, radiographic evidence of osteoporosis, and one or more vertebral fractures believed to be nontraumatic. Exclusion criteria were as follows: the presence of conditions causing bone loss such as hyperparathyroidism, adrenocorticosteroid excess, thyrotoxicosis, chronic diarrheal state or malabsorption, renal tubular acidosis, renal impairment (endogenous creatinine clearance less than 0.7 mL/min per kg); previous treatment with diphosphonate, calcitonin, or fluoride; active peptic ulcer disease; and skeletal fractures that could not be quantified for anatomic or technical reasons. Those taking pharmacologic doses of vitamin D preparations were accepted if they had discontinued the drug for at least 6 months. At recruitment, 31 patients were taking estrogen (treatment initiated after osteoporosis was diagnosed). Thirteen patients had documented recurrent spinal fractures while receiving estrogen. The total duration of estrogen therapy represented about a third of their postmenopausal state (mean, 8 years). This treatment, usually consisting of conjugated estrogen, 0.625 mg/d given continuously or intermittently (25 d/mo), and intermittent progesterone (5 mg/d for 10 d/mo), was continued during the trial. Patients receiving estrogen had similar baseline demographic characteristics as patients not receiving estrogen and were considered at increased risk for further fractures. Randomization and Treatment Scheme Participants were randomly assigned to the two treatment groups, stratified according to estrogen treatment (untreated or estrogen-treated). Patients in the treatment group received slow-release sodium fluoride (Slow Fluoride; Mission Pharmacal Company, San Antonio, Texas), 25 mg twice daily given orally before breakfast and at bedtime intermittently in repeated cycles of 14 months (12 months receiving treatment, followed by 2 months off treatment) and calcium citrate (Citracal, Mission Pharmacal Company) as 400 mg of calcium twice daily before breakfast and at bedtime. In the placebo group, medication identical in appearance to Slow Fluoride that was devoid of sodium fluoride was given on the same time schedule along with calcium citrate at the same dose and schedule. Study Protocol Patients were evaluated in an outpatient setting before treatment and at 3, 6, 9, 12, and 14 months of each cycle. At each visit, a careful history was taken for gastrointestinal and musculoskeletal side effects defined as symptoms that newly appeared or increased from baseline without apparent cause and persisted more than a month during treatment or disappeared during withdrawal. Where severe lower-extremity pain lasted more than 2 weeks, the protocol required a bone scan followed by radiographs for detection of microfracture; however, none was required. In addition, systematic multichannel analysis of venous blood, complete peripheral blood count, and 24-hour urinary calcium were determined at each visit; serum parathyroid hormone, reticulocyte count, and 24-hour urinary hydroxyproline were measured before and at 6 and 12 months of each cycle. Serum fluoride was measured before the morning dose of slow-release sodium fluoride at 0, 6, and 12 months of each cycle. Before treatment and at 12 months of each cycle, a lateral spinal radiograph was obtained to detect spinal fractures; moreover, bone mineral content of the L2 to L4 vertebrae, bone density of the distal third of the radius of the nondominant forearm, and bone density of the femoral neck were measured. Quantitation of Spinal Fractures Lateral spinal films taken before treatment and at 12 months of the first cycle were compared in order to determine new and recurrent fractures occurring during the first cycle of treatment. For each vertebra from T3 to L5, landmarks (anterior and posterior corners and midpoints) were recorded using an electrostatic digitizing board (Scriptel Corporation, Columbus, Ohio) with a coefficient of variation of 1.5%. A computer software program developed by one of the authors was used to compute changes in vertebral heights and area, and to calculate the magnification error between the two sets of radiographs. After correction for the magnification error, if any, a decrease in height of more than 20% of anterior, middle, or posterior height, accompanied by a decrease in area of more than 10% in a previously unaffected vertebra, was considered a new fracture [8], or if the decrease was in a previously fractured vertebra, it was considered to be a recurrent fracture. Identical criteria were used to identify new and recurrent fractures occurring during the second cycle (by comparing 26 months with 12 months), during the third cycle (by comparing 40 months with 26 months), and during the fourth cycle (by comparing 54 months with 40 months). Moreover, spinal films taken after the last cycle of follow-up were compared not only with the immediately preceding films but also with earlier radiographs. The same procedure was followed for the identification of new and recurrent fractures. Thus, it was possible to detect fractures occurring during two or more cycles (cumulative fractures) that escaped disclosure by previous cycle-to-cycle analysis. Bone Mass Measurement During the course of this study, two instruments were used to measure the L2 to L4 bone mineral content and the femoral neck bone density. A dual-photon x-ray absorptiometer (1.5 version, Lunar Radiation, Madison, Wisconsin) was used initially. It was replaced by quantitative digital radiography (Hologic, Waltham, Massachusetts) that yielded different absolute values for bone mass. The following procedures were adopted to accommodate problems imposed by the measurement of bone mass by two different densitometers. First, in estimating the extent of spinal bone loss at baseline, a given patients L2 to L4 bone density obtained by either method was compared with the mean value for a normal 30-year-old woman established for the corresponding instrument. Second, in quantifying changes in the L2 to L4 bone mineral content and the femoral neck bone density produced by treatment, results were expressed as a percentage change for each cycle rather than as absolute values. When the same densitometer was used at the beginning and the end of a given cycle, the experimentally derived values were used to calculate the percentage change in bone mineral content or bone density. For a given cycle with the initial bone mass obtained by the Lunar method and the final bone mass measured by the Hologic technique, a correction factor was applied to convert the Lunar-derived value to the latter value. In patients who initially had bone mass determined by the Lunar method, a concurrent analysis by the Hologic instrument was done before converting to the latter technique for subsequent follow-up measurements. Thus, a correction factor could be calculated. The radial shaft bone density was obtained throughout the study by a single-photon absorptiometer (Norland, Ft. Atkinson, Wisconsin) [9]. For follow-up measurements, actual experimentally derived bone densities were used to calculate the percentage change in bone density for each cycle. The coefficient of variation for the L2 to L4 bone mineral content using the Lunar or Hologic method was 1%, whereas that for the femoral neck bone density and the radial shaft bone density was 1% to 2%. Biochemical Analysis The blood screen was done as SMA-20 (Smith-Kline Laboratory, Dallas, Texas). The serum parathyroid hormone level was analyzed by the whole-molecule, immunoradiometric assay (using a kit from Nichols Institute, San Juan Capistrano, California). The serum fluoride level was measured using an ion-specific electrode. The urinary

Correction of hypocitraturia and prevention of stone formation by combined thiazide and potassium citrate therapy in thiazide-unresponsive hypercalciuric nephrolithiasis

Thirteen patients with hypercalciuric calcium nephrolithiasis continued to form calcium stones when treated with thiazide (4.69 +/- 6.62 [mean +/- SD] stones per patient-year to 5.12 +/- 10.87 stones per patient-year), despite adequate hypocalciuric response (a reduction in urinary calcium levels from 303 +/- 119 mg per day to 193 +/- 88 mg per day, p less than 0.01). Because they had hypocitraturia (250 +/- 86 mg per day versus 643 +/- 236 mg per day in normal subjects, p less than 0.001), potassium citrate (10 to 20 meq three times per day) was added to the ongoing treatment program. During combined treatment with thiazide and potassium citrate, urinary pH significantly rose, and normal levels of urinary citrate were restored. Ten patients stopped forming new stones and all 13 had reduced stone formation rate. Thus, potassium citrate supplementation should be considered in patients requiring thiazide therapy for the control of hypercalciuric nephrolithiasis, especially if they have concurrent hypocitraturia or if it develops during thiazide therapy.

Long-term improvement in renal function after short-term strict blood pressure control in hypertensive nephrosclerosis.

Seventy-nine hypertensive nephrosclerosis patients i entered a prospective randomized singleblind study to 1) establish the pattern of decay of renal function in this population and the variability therein and 2) to determine if strict diastolic blood pressure (DBP) control (≤80 mm Hg) is more effective than conventional levels (90–95 mm Hg) in conserving renal function. Because of unexpected significant improvement in renal function in patients from both groups, which changed the perspectives on the course of this disease as described herein, this report is being published before completion of the trial. The selection criteria were 1) serum creatinine concentration of 1.6–7.0 mg/dl, 2) glomerular filtration rate of less than 70 ml/min/1.73 m2, and 3) absence of diseases (other than hypertension) known to destroy renal function. Renal function was assessed by glomerular filtration rate ([l25I]iothalamate clearance) and serum creatinine concentration. Before randomization, DBP was aggressively treated to reduce it to less than 80 mm Hg. Twenty-two subjects (14 in the strict DBP control group and eight in the conventional DBP control group) have been enrolled in the study for 36 months. In contrast to results from previous studies in humans and rats, renal function improved in both patient groups. Thus, irrevocable progression of renal damage after onset of renal failure from high blood pressure does not necessarily occur, and in fact, long-term improvement of renal function resulted from the effects of the study itself. The study design involving the 2–4-month initial period of aggressive DBP control at 80 mm Hg or less followed by control of DBP at less than 90 mm Hg was associated with long-term improvement in renal function.

Study of the MIB-1 Labeling Index as a Predictor of Tumor Progression in Pilocytic Astrocytomas in Children and Adolescents

PURPOSE The pilocytic astrocytoma (PA) is the most common childhood brain tumor. This report examines the MIB-1 labeling index (LI) as a predictor of progression-free survival (PFS) among childhood PAs. PATIENTS AND METHODS Consecutive PAs were examined to determine whether the MIB-1 LI was associated with tumor progression. Other variables evaluated included tumor location, use of adjuvant therapy, extent of resection, and age at diagnosis. RESULTS One hundred forty-one children were identified (mean +/- SD age, 7.6 +/- 4.7 years; range, 0.43 to 18.56 years); 118 children had adequate tissue for MIB-1 immunohistochemistry. The 5-year PFS was 61.25%. By log-rank analysis, an MIB-1 LI of more than 2.0 was associated with shortened PFS (P =.035). Patients with PAs who underwent complete surgical resection, had tumors located in the cerebellum, and were treated with surgery only also had more prolonged PFS (P =.001 for all). Tumors in the optic pathways were associated with a shorter PFS (P =.001). Restricting the evaluation of MIB-1 LI to only incompletely resected tumors revealed an insignificant trend of MIB-1 LI of more than 2.0 having a shortened PFS. Multivariate analysis demonstrated completely resected tumors and tumors located in the cerebellum as less likely to progress (P =.001 and.019, respectively). CONCLUSION Children with PAs with an MIB-1 LI of more than 2.0 have a shortened PFS. PAs that are completely resected and are located in the cerebellum have a prolonged PFS. This initial study suggests that the MIB-1 LI identifies a more aggressive subset of PAs. Further work should focus on elucidating features of pilocytic astocytomas that will identify prospectively children at risk for progression.

The Effect of Acetazolamide on Regional Cerebral Blood Flow in Normal Human Subjects as Measured by Single-photon Emission Computed Tomography

Regional cerebral blood flow (rCBF) was evaluated in 15 normal, healthy volunteer control subjects before and after the administration of 1 g acetazolamide (ACZ) using a rotating four-detector single-photon emission computed tomograph (SPECT). ACZ, a carbonic anhydrase inhibitor, is a cerebral vasodilator. RCBF values in mL/minute/100 g were derived within eight cortical regions of interest (ROI), and from the whole slice as an expression of whole brain blood flow (WBF). ROI/WBF ratios were established for each ROI in each of the 15 subjects for both pre-ACZ and post-ACZ studies. ACZ produced a 30% +/- 17% increase in WBF. Studies were done in random order, with nine subjects undergoing the post-ACZ study first, and six the pre-ACZ, or baseline, study first. Statistical analysis showed no significant difference in any ROI that might be caused by sequence of test procedures. Ratios were then examined to determine whether rCBF elevation was proportionate in all ROI in all subjects. No significant difference was found in any ROI except for the left parietal, for which marginally significant change was identified. Subjects also were examined for possible age and sex differences in ACZ response, and no differences were found.

Protease inhibitor-based therapy is associated with decreased HIV- related health care costs in men treated at a veterans administration hospital

BACKGROUND Protease inhibitor (PI) therapy for HIV infection is associated with decreased rates of opportunistic infections and death. Statistical models predict that decreased complications will be associated with decreased hospitalization costs. A recent report suggested that the decrease in the HIV hospitalization costs were offset by increases in demand for outpatient services. We performed a study of hospital use and HIV-associated health care costs in our center to determine the following: whether PI therapy is associated with decreased inpatient use; whether PI therapy is associated with decreased outpatient use and costs; whether decreased HIV health care costs are associated with increased use of nucleoside analogues. METHODS The Dallas Veteran Affairs Medical Center provides comprehensive inpatient and outpatient HIV care and thus can evaluate the relation between inpatient and outpatient costs. The mean monthly number of hospital days, Infectious Diseases clinic visits, emergency department visits, other outpatient clinic visits, inpatient costs, outpatient costs, and PI costs were determined from January 1, 1995 through July 31, 1997. This time period was then divided into three intervals. Comparisons of PI use and HIV-related health care costs were during the three intervals was performed using analysis of variance (ANOVA). Significant differences between the baseline characteristics were further analyzed through multiple linear regression. RESULTS A decrease in hospital days, and all outpatient visits including emergency visits, and HIV clinic visits was determined. No difference was found in the rate of use of other outpatient services. The per patient costs of HIV care decreased from a monthly average of