Vancomycin removal during a plasma exchange transfusion.

OBJECTIVE: To report a case of clinically significant removal of vancomycin during a plasma exchange transfusion in a patient with sickle-cell anemia. CASE SUMMARY: A 46-year-old African American woman with sickle-cell disease was admitted on three separate occasions and treated with vancomycin. Vancomycin serum drug concentrations were obtained on all three admissions. During one of the admissions, a plasma exchange transfusion was performed the same day vancomycin concentrations were obtained. The vancomycin serum drug concentrations were considerably lower than predicted, resulting in potentially subtherapeutic vancomycin concentrations. Bayesian pharmacokinetic forecasting was used in interpreting the vancomycin concentrations. DISCUSSION: Searches from MEDLINE (1966-September 2000) and Drugs and Pharmacology (1990-September 2000) were performed to obtain pertinent published literature. CONCLUSIONS: Plasma exchange transfusions may result in clinically significant removal of vancomycin from the plasma. The potential exists of underdosing vancomycin in patients who are receiving frequent plasma exchange transfusions. Further research may be warranted to determine whether these patients may be candidates for more frequent and vigilant monitoring of vancomycin concentrations.

Pharmacoeconomic assessment of HMG-CoA reductase inhibitor therapy: an analysis based on the CURVES study.

We conducted a post hoc pharmacoeconomic analysis of a multicenter, open-label, randomized, parallel-group, 8-week efficacy-safety comparison of five HMG-CoA reductase inhibitors-atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin. The 534 patients requiring cholesterol-lowering therapy took the drugs for 8 weeks with 15 different regimens. Low-density lipoprotein (LDL) was measured after 6 weeks of diet (baseline) and after 8 weeks of treatment with a study drug. At dosages of 10, 20, and 40 mg/day, atorvastatin was associated with significantly greater reductions in LDL than equivalent dosages of the other agents. Cost-effectiveness calculated as the annual acquisition cost/percentage LDL reduction was greatest with atorvastatin 10 mg ($17.96), fluvastatin 40 mg ($19.83), atorvastatin 20 mg ($22.85), and atorvastatin 40 mg ($24.96). All other dosages were above $25.00/year/percentage LDL reduction. Atorvastatin was the most cost-effective HMG-CoA reductase inhibitor. Fluvastatin 40 mg/day also had a favorable cost:effectiveness ratio but lowered LDL only by 23%.

Neutrophils do not mediate blood-brain barrier permeability early after controlled cortical impact in rats.

Controlled cortical impact (CCI) produces blood-brain barrier (BBB) permeability and an acute inflammatory response in injured brain, associated with upregulation of cell adhesion molecules and accumulation of neutrophils. Nevertheless, the role of acute inflammation in the pathogenesis of BBB permeability after traumatic brain injury (TBI) is undefined. The purpose of this study was to examine the time course of acute inflammation and BBB permeability after CCI in rats and to determine the effect of neutrophil depletion on BBB permeability early after CCI. In the first protocol, four groups of rats (n = 4-7/group) were subjected to CCI. Expression of endothelial (E)-selectin on cerebrovascular endothelium, accumulation of neutrophils, and BBB permeability were measured in brain at 1, 4, 8, and 24 hours after injury by immunohistochemistry or spectrophotometric quantification of Evans blue. E-selectin upregulation and neutrophil accumulation in injured brain occurred at later times than maximal BBB permeability. In a second protocol, rats made neutropenic with a murine monoclonal IgM antibody (RP-3) specific for rat neutrophils were subjected to CCI, given Evans blue at 3.5 hours, and sacrificed at 4 hours after injury. Neutrophil depletion did not affect BBB permeability at 4 hours after CCI. We conclude that events other than those mediated by neutrophils initiate BBB permeability early after CCI.

Blood-brain barrier permeability, neutrophil accumulation and vascular adhesion molecule expression after controlled cortical impact in rats: a preliminary study.

UNLABELLED: Previous studies in our laboratory have shown that controlled cortical impact (CCI) produces an acute inflammatory response in rat brain, including neutrophil accumulation and upregulation of cell adhesion molecules. The purpose of this study was to compare the time course of acute inflammation to blood-brain barrier (BBB) breakdown after (CCI) in rats. METHODS: Male Wistar rats (n = 4-7/group) were subjected to CCI (2.5 mm depth, 4 m/s) and injected with Evans-blue dye (2%, 5 ml/kg) at 30 min, 3.5 h, 7.5 h, or 23.5 h after trauma. 30 min after dye injection rats were saline-perfused. BBB permeability was measured by spectrophotometric quantitation of Evans-blue in injured brain. Alternate cryostat sections from the anterior segment of the injured hemisphere were analyzed immunohistochemically for neutrophils (MoAb RP-3 vs rat neutrophils) or E-selectin (MoAb vs E-selectin). Neutrophils and E-selectin-positive blood vessels were quantitated by light microscopy in 100x cortical and hippocampal fields. RESULTS AND CONCLUSIONS: BBB breakdown was maximal early after CCI, whereas maximum E-selectin upregulation (8 h) and neutrophil accumulation (24 h) occurred later. Events other than acute inflammation initiate BBB permeability after CCI. Acute inflammation may contribute to BBB permeability at 4 h to 24 h after CCI.

The effect of brain temperature on acute inflammation after traumatic brain injury in rats.

The effect of varying brain temperature on neutrophil accumulation in brain and the expression of E-selectin and intercellular adhesion molecule-1 (ICAM-1) on cerebrovascular endothelium after controlled cortical impact (CCI) was studied in rats. Sprague Dawley rats were anesthetized and subjected to CCI to the left parietal cortex. Ten minutes after CCI, brain temperature was modulated and maintained at 32 degrees C, 37 degrees C, or 39 degrees C (n = 8 per group) for 4 h. Rats were then decapitated and immunohistochemistry on brain sections was performed using monoclonal antibodies (MoAb) that recognize neutrophils (RP-3), ICAM-1 (TM-8, Athena Neurosciences), or MoAb that react with E-selectin (La-Roche). Each of these markers was quantified in 100 x fields. Neutrophil accumulation was also quantified with myeloperoxidase (MPO) assay. Absolute neutrophil count (ANC) was measured in blood samples before and 1 h and 4 h after CCI. Neutrophil accumulation in injured brain was decreased in rats maintained at 32 degrees C vs 39 degrees C (4-fold difference as assessed by immunohistochemistry, p < 0.05; 8-fold difference as assessed by MPO assay, p < 0.05). Peripheral blood ANC was not affected by temperature. E-selectin was induced on cerebrovascular endothelium after CCI (p < 0.05), but was only decreased modestly at 32 degrees C versus 39 degrees C (p = 0.11). ICAM-1 was not upregulated on cerebrovascular endothelium at this early time following CCI. Neutrophil accumulation is directly dependent on brain temperature during the initial 4 h after CCI. This appears to be mediated by mechanisms other than effects of temperature on E-selectin or ICAM-1 expression or systemic ANC.

Early neuropathologic effects of mild or moderate hypoxemia after controlled cortical impact injury in rats.

Hypoxemia has detrimental effects after traumatic brain injury (TBI) in both experimental models and humans. The purpose of this study was to determine the effect of mild or moderate hypoxemia on early histologic and motor functional outcome after controlled cortical impact (CCI) in rats. Anesthetized rats underwent CCI and were randomized to receive mild (FiO2 = 13%, n = 6), moderate (FiO2 = 11%, n = 9), or no (FiO2 = 33%, n = 6) hypoxemia for 30 min after trauma. Sham-operated rats without hypoxemia (n = 7) were used as controls. Motor function (beam balance latency) was assessed on days 0-5. Rats were killed 7 days after injury and their brains removed for assessment of survival of hippocampal neurons and contusion volume. Terminal deoxynucleotidyl transferase-mediated biotin-dUTP nick end labeling (TUNEL) was performed on brain sections from rats killed at 6, 24, and 72 h after CCI and moderate hypoxemia to assess DNA fragmentation in situ. Mild and moderate hypoxemia augmented motor function deficits after CCI in a dose-dependent manner. Moderate hypoxemia after CCI reduced 7-day survival of CA3 neurons but not CA1 neurons vs. sham (55 [46-86] vs. 99 [95-130], p < 0.05, and 79 [63-86] vs. 101 [81-123], NS, respectively; % uninjured hemisphere, median [range]). The addition of mild or moderate hypoxemia did not increase contusion volume. TUNEL-positive neurons were seen in ipsilateral cortex and dentate gyrus at 6, 24, and 72 h after trauma, and in ipsilateral CA3 hippocampal neurons and thalamus at 24 and 72 h. Moderate hypoxemia augments CA3 neuronal death and early motor functional deficits after CCI. The pattern of DNA fragmentation in selectively vulnerable neurons suggests that apoptosis may play a role in the delayed neuronal death seen after TBI.

The relationship between brain temperature and neutrophil accumulation after traumatic brain injury in rats.

Mild hypothermia reduces secondary damage after traumatic brain injury (TBI) in rodent models; however, the mechanisms involved in this beneficial effect remain unclear. We previously reported that TBI induces the upregulation of adhesion molecules and infiltration of neutrophils (PMN) in brain. Since PMN accumulation may be associated with the development of hyperemia and blood-brain barrier injury, we hypothesized that hypothermia would reduce acute inflammation after TBI in rats. To test this hypothesis, rats were anesthetized and subjected to TBI by controlled cortical impact to left parietal cortex. Brain temperature was controlled at 32 degrees C, 37 degrees C, or 39 degrees C (n = 8 per group) for 4 h after TBI, then rats were sacrificed and brain were harvested. Immunohistochemistries were performed on brain sections using antibodies that recognize the adhesion molecules E-selectin and intercellular adhesion molecule-1 (ICAM-1), and PMN. PMN were also quantified using a myeloperoxidase (MPO) assay. PMN accumulation in injured brain was decreased in rats maintained at 32 degrees C vs 39 degrees C (4-fold by immunohistochemistry and 8-fold by MPO, p < 0.05). E-selectin was induced after TBI, but not attenuated by hypothermia. ICAM-1 was not up-regulated at this early time after TBI. Based on these preliminary data, we conclude that mild hypothermia reduces PMN accumulation in injured brain during the initial 4 h after TBI, without decreasing adhesion molecule expression.

Information management: an HMO essential.

Health maintenance organizations (HMO), with their diverse audiences and complex operations, offer the best proof that management information systems (MIS) are emerging as an essential and marketable business asset. Authors Paul Egerman and Susan Heineman offer many uses for a good MIS and why such a program is essential to an HMO's success.