Discontinuation of the bleeding time test without detectable adverse clinical impact.

BACKGROUND: The bleeding time (BT) test predicts a higher bleeding complication rate in populations at risk for inherited or acquired platelet dysfunction, but it is of limited assistance in evaluating individual patients. There are no reports of clinical outcomes after discontinuation of the BT test. METHODS: Interviews with a subset of the physicians who had ordered the BT test before discontinuation of the test were conducted. The total number of platelet-aggregation tests, the mean number of monthly, unmodified platelet units transfused, the incidence of kidney biopsy complications, and the number of doses of 1-deamino-8-D-arginine vasopressin (DDAVP) administered 5 months before and after discontinuation of the BT test were compared. We recorded the rates of bleeding complications in the Major Surgery Risk Pool during the 12 months before and the 5 months after the discontinuation of the BT test. RESULTS: Clinicians reported they did not significantly change their preprocedural work-ups, postpone an invasive procedure, experience an increase in bleeding complications, or increase their use of blood products after discontinuation of the BT test. Platelet-aggregation tests (n = 9, before and after), platelet transfusions (P = 0.958), and DDAVP administration (before = 24; after = 10) did not increase after discontinuation of the BT test. The rate of postprocedural bleeding complications did not increase significantly in either Major Surgery Risk Pool cases (<3final sigma deviation from the mean rate) or in patients undergoing renal biopsies (P = 0.225 for decrease in hematocrit; P = 1.000 for the percentage of patients transfused) after discontinuation of the BT test. CONCLUSIONS: Our study failed to identify a clinically significant, negative impact of discontinuing the BT test.

Colectomy, mucosal proctectomy, and ileal pouch-anal anastomosis. A prospective trial of optimal antibiotic management.

The ideal prophylactic antibiotic regimen has not been established for patients undergoing colectomy, mucosal proctectomy, and endorectal ileoanal anastomosis, a prolonged operation frequently accompanied by abdominal and pelvic contamination and associated with an infection rate up to 20%. The aim of this study was to evaluate, in a prospective, randomized, double-blind fashion, the efficacy of a short perioperative course compared to an extended postoperative course of intravenous antibiotics (cefoxitin) in patients undergoing colectomy with ileoanal anastomosis. Forty patients with ulcerative colitis or familial polyposis coli received a mechanical and oral antibiotic bowel preparation and a standard three-dose perioperative course of intravenous cefoxitin. Patients then were randomized to receive intravenous cefoxitin, 1 g every 6 hours, or placebo for 5 days. No differences in overall postoperative morbidity were observed and neither group developed intra-abdominal, pelvic, or wound infections. It is concluded that a standard three-dose perioperative course of intravenous antibiotics provides adequate prophylaxis in the prevention of infectious complications in patients undergoing colectomy, mucosal proctectomy, and ileoanal anastomosis.

Cefoxitin disposition in colorectal surgery. Implications for the effective use of prophylactic antibiotics.

Failure of antibiotic prophylaxis to prevent infectious complications following colorectal operations is reported to occur in 5 to 10% of all cases. Factors such as the length of surgery and inadequate antibacterial coverage or duration predispose patients to higher rates of infectious complications. The pharmacokinetics of cefoxitin in eight patients undergoing colectomy, mucosal proctectomy, and endorectal ileal pouch-anal anastomosis (IPAA) for chronic ulcerative colitis or familial polyposis coli were examined. Peak plasma concentrations were 40% higher than values reported in healthy volunteers. During the first dose, the plasma half-life of cefoxitin was similar to plasma half-lives reported in healthy volunteers; however, total body clearance was reduced five- to eightfold. These data suggest that the volume of distribution of cefoxitin was also markedly reduced. Fluid replacement during the operation produced lower cefoxitin peak plasma concentrations after the second dose. Cefoxitin clearance increased during the second dose after fluid replacement, but remained below that reported in healthy volunteers. These data suggest that fluid depletion resulting in decreased kidney perfusion contributed to a reduction in drug clearance. The amount of cefoxitin recovered in the urine during the 12-hour study period averaged 53%. Tissue concentrations of cefoxitin in proximal colon, distal colon, rectal mucosa, and rectal muscle tissue ranged from 0.2 to 9.3 mcg/g of tissue. The preoperative fluid status of the patient, the time of drug administration, and the amount of extra-renal drug elimination appear to be important factors, affecting the disposition of parenterally administered prophylactic antibiotics in patients undergoing colorectal operations.

Cyclosporine metabolite disposition after oral administration in pretransplant end-stage renal disease patients.

The results of this study have shown large interpatient variability in the disposition of M17 and M1 following a single oral dose of CsA in pretransplant end-stage renal disease patients. The differences in the distribution of M17 and M1 in WB and P at 37 degrees C has particular relevance in the interpretation of CsA therapeutic drug monitoring by nonspecific assays such as the RIA. Additional studies characterizing the disposition of M17 and M1 in WB and P separated at 37 degrees C following chronic CsA therapy will be needed to further understand the role of these metabolites in therapeutic drug monitoring of CsA. New analytical techniques or refinements in the present techniques will be required to identify and separate coeluting substances that are now being recognized with the present techniques.

Leukocyturia in cyclosporine-treated renal allograft recipients.

Five hundred eighty-seven daily urine specimens were examined from 179 consecutive renal allograft recipients with the use of quantitative cytodiagnostic urinalysis. Specimens were divided between those patients receiving cyclosporine (CyA) and steroid immunotherapy (73 patients) and those receiving standard azathioprine (Aza) and steroid immunotherapy (106 patients). When patients with urinary tract infections were excluded, an increase in leukocyturia was observed in the CyA-treated patients. Ninety-three percent of the CyA-treated patients had at least one specimen with more than 1,000 neutrophils/10 high-power fields (HPFs) versus 62% of the 106 Aza-treated patients. Sixty-four percent of the specimens examined from the CyA-treated group had more than 1,000 neutrophils/10 HPFs compared with only 18% of specimens from Aza-treated patients. It appears that CyA is a cause of sterile leukocyturia in renal allograft recipients. The significance of leukocyturia in CyA nephrotoxicity needs further definition.

Cefmenoxime pharmacokinetics in healthy volunteers and subjects with renal insufficiency and on hemodialysis.

The pharmacokinetics of cefmenoxime were characterized in five healthy volunteers and in 15 subjects with various degrees of renal insufficiency after a single 10-mg/kg, 5-min intravenous infusion. Five of these subjects were studied both on hemodialysis and during an interdialytic period. Plasma, urine and dialysate were assayed for cefmenoxime by a specific high-pressure liquid chromatographic assay. Peak plasma concentrations of cefmenoxime were ca. 94 micrograms/ml after completion of the infusion. The mean plasma and renal clearances in the healthy volunteers were 281 +/- 66 and 228 +/- 52 ml/min, respectively. Plasma clearance declined in patients with renal insufficiency and correlated significantly with creatine clearance. The mean apparent volume of distribution at steady state in the healthy volunteers was 0.23 liters/kg and was not found to be significantly different in subjects with renal insufficiency. The mean cumulative 24-h urinary recovery of cefmenoxime in healthy volunteers was 81% of the administered dose and decreased with reduced renal function. Cefmenoxine dosage should be reduced in proportion to the decline in creatinine clearance. A simple nomogram for dose selection is provided.

Pharmacokinetic disposition of cefonicid in patients with renal failure and receiving hemodialysis.

Cefonicid is a new cephalosporin with a spectrum of activity similar to that of cefamandole. The pharmacokinetic disposition of the drug was examined in patients with various degrees of renal dysfunction and who were receiving hemodialysis. After patients were given a 7.5 mg/kg dose as an iv infusion, multiple blood and urine samples were obtained at frequent intervals, and the samples were analyzed for cefonicid concentration. Five patients receiving hemodialysis received an additional dose before a dialysis period to assess removal of the drug. The half-life of cefonicid increased markedly with declining renal function (approximately 70 hr in anuric patients). Total clearance and renal clearance decreased linearly with decreases in creatinine clearance. Steady-state volume of distribution remained approximately the same (0.11 liter/kg) in all patients. Cefonicid dosage can be reduced in proportion to decreases in creatinine clearance from normal levels. A simple nomogram is provided.

Nafcillin-induced platelet dysfunction and bleeding.

This paper describes two cases of nafcillin-induced platelet dysfunction, with positive rechallenge data for one patient. Nafcillin resulted in abnormal bleeding times in both patients and a clinically apparent bleeding episode in one of the cases. Platelet function tests were performed on one patient during the initial therapy and after rechallenge with nafcillin. Platelet aggregation showed abnormal responses to ADP, collagen, and epinephrine. Platelet count and morphology were normal. Nafcillin should be recognized as another antibiotic which causes platelet function abnormalities and clinical bleeding episodes.

Nitrogen metabolism in the sheep fetus. Observations on the liver and placenta.

Ammonium ions added in large quantity disappear rapidly from the reservoir of the sheep placenta perfused in situ through the umbilical vessels. Ammonium ions are removed from the reservoir of perfused sheep fetal livers of 108-141 days of conceptual age at a rate of at least 1 mumol/min/g liver. The majority appears as urea. There is little or no change in glutamine concentration. Hepatic carbamoylphosphate synthetase I, ornithine transcarbamylase, argininosuccinate synthetase, argininosuccinase and arginase are present, even at 97 days of conceptual age, in adequate amounts to account for the observed urea production. With the exception of arginase, all levels rise with fetal age. The levels in the maternal liver are comparable with those at 106 days of conceptual age. Arginase is high in the younger fetuses, falls progressively with fetal age and is very low in the mother. It is concluded that (a) the perfused placenta is permeable to ammonia and the placenta may be able to clear ammonia from the fetal circulation at a rate comparable with that of fetal liver; (b) the fetal liver converts ammonia to urea at a rate comparable with the urea production of the fetus; (c) there is virtually no glutamine production by the fetal liver; (d) adequate amounts of the enzymes of urea synthesis are present even in the immature fetal liver to account for the total urea production of the fetus, and (e) the anomalously low arginase level in the maternal liver may conserve maternal arginine, and the high levels in the younger fetuses may be related to fetal polyamine production from maternally derived arginine.

Localization of Tamm-Horsfall glycoprotein in the normal rat kidney and the effect of adrenalectomy on its localization in the hamster and rat kidney.

Immunofluorescence and immunoperoxidase techniques were used to study the localization of Tamm-Horsfall glycoprotein in the normal rat kidney. In the fluorescence microscopical preparations, the glycoprotein was observed in the thick ascending limbs of the loops of Henle and distal convoluted tubules and was thus, in general, similar to our earlier observations on the hamster and man. The situation in the maculae densae was, however, somewhat different, for in the rat the majority of them were seen to possess Tamm-Horsfall glycoprotein on the luminal surfaces of their cells and only a small proportion resembled the hamster and man in lacking it. These observations were confirmed by the immuno-electron microscope technique. Furthermore, it was shown that in the thick ascending limbs and distal convoluted tubules, Tamm-Horsfall glycoprotein is associated with the total plasma membrane systems of its cells. Thus it appears that Tamm-Horsfall glycoprotein is confined to that part of the nephron responsible for the process of urine dilution. As this function is, at least in part, regulated by adrenal cortical hormones, the effect of adrenalectomy on the distribution of the glycoprotein was studied. The results obtained showed varying degrees of disappearance of Tamm-Horsfall glycoprotein in the kidneys of adrenalectomized hamsters, initially from the distal convoluted tubules and later from the thick ascending limbs. In the rat, on the other hand, the effect of adrenalectomy on Tamm-Horsfall glycoprotein was much less pronounced, possibly due to the presence of secondary adrenal tissue. The possible physiological significance of these findings is discussed.

Localization of Tamm-Horsfall glycoprotein in the fetal and neonatal hamster kidney as demonstrated by immunofluorescence and immunoelectron microscopical techniques.

Tamm-Horsfall (T-H) glycoprotein was demonstrated in the developing hamster kidney using immunofluorescence and immunoelectron microscopical techniques. The glycoprotein was first observed in the fetal kidneys on the 12th day of gestation and was confined to the luminal surface of the presumed distal tubules of the medulla. It was not until the 14th day of gestation that T-H glycoprotein was also sometimes seen to be associated with the lateral and basal invaginations of the plasma membranes of the now differentiated distal tubules. On the 16th day (1st day post-partum) the glycoprotein was also found in the cortex. Although the general distribution of T-H glycoprotein was at 3-4 days after birth similar to the adult, the full intensity of staining was not attained until after the 21st day. The possible physiological significance of these findings is discussed.