Assessment of an Extended Interval Fondaparinux Dosing Regimen for Venous Thromboembolism Prophylaxis in Critically Ill Patients with Severe Renal Dysfunction Using Antifactor Xa Levels.

OBJECTIVE: Pharmacologic options for venous thromboembolism (VTE) prophylaxis are often limited in critically ill patients due to thrombocytopenia and multisystem organ dysfunction. Fondaparinux offers potential advantages in the critically ill; however, it is currently contraindicated in severe renal dysfunction (SRD). We evaluated anti-factor Xa levels in critically ill patients with SRD who were receiving an extended interval dosing regimen of fondaparinux for VTE prophylaxis. METHODS: A prospective, single-arm, interventional study was conducted at two academic hospitals of the Detroit Medical Center. Eligible patients were in the intensive care unit, had an estimated creatinine clearance of less than 30 ml/minute, and had either acute kidney injury or end-stage renal disease; several patients were taking renal replacement therapy. Fondaparinux was administered at an extended interval dosing regimen of 2.5 mg subcutaneously every 48 hours. Fondaparinux peak and trough anti-factor Xa levels were obtained. Lower extremity venous duplex studies were performed at baseline and study completion to assess for deep vein thrombosis (DVT), and patients were monitored for bleeding complications. RESULTS: Thirty-two patients were enrolled. Patients received a median of four doses (interquartile range two to five) of fondaparinux. Fondaparinux peak (n=98) and trough (n=86) anti-factor Xa levels were 0.36 ± 0.18 mg/L and 0.17 ± 0.11 mg/L (mean ± SD), respectively, and were similar to levels reported in patients with normal renal function receiving conventional once-daily dosing. No lower extremity DVTs or suspected VTE events occurred. Two (6%) patients had significant bleeding events. CONCLUSIONS: In critically ill patients with SRD, an extended interval fondaparinux dosing regimen of 2.5 mg every 48 hours for VTE prophylaxis achieved peak and trough anti-factor Xa levels similar to those reported in noncritically ill patients with normal renal function receiving once-daily fondaparinux. This regimen offers an alternative for patients with SRD when heparinoids must be avoided.

Calcium Administration Is Associated with Adverse Outcomes in Critically Ill Patients Receiving Parenteral Nutrition: Results from a Natural Experiment Created by a Calcium Gluconate Shortage.

STUDY OBJECTIVE: Parenteral calcium is frequently administered to critically ill patients. However, animal studies demonstrate that calcium administration during critical illness heightens inflammation and leads to shock, organ dysfunction, and mortality. We sought to evaluate the association between calcium administration and adverse outcomes in critically ill patients receiving parenteral nutrition (PN). DESIGN: Retrospective cohort examined before and during a calcium gluconate shortage. During the shortage, calcium was absent from PN, but calcium supplementation outside of PN was allowed. The shortage resulted in a natural experiment that included a group of patients who did not receive calcium. SETTING: Intensive care units (ICUs) in three teaching hospitals. PATIENTS: A total of 259 adults who received PN in the ICU for 48 hours or longer. MEASUREMENTS AND MAIN RESULTS: Patients were divided into quartiles based on amount of parenteral calcium received; the lowest quartile received no calcium. End points were in-hospital mortality, acute respiratory failure, new-onset shock, and a composite of any one of these end points. For patients not on mechanical ventilation or vasoactive support when PN started, logistic regression revealed that calcium administration was associated with mortality (odds ratio [OR] 2.48, 95% confidence interval [CI] 1.08-5.69), acute respiratory failure (OR 2.43, 95% CI 1.28-4.60), new-onset shock (OR 2.81, 95% CI 1.22-6.44), and the combined end point (OR 2.33, 95% CI 1.31-4.16). The odds of adverse outcomes increased as the calcium dose increased. CONCLUSION: Calcium administration correlated with adverse outcomes in critically ill patients receiving PN. The data suggest that administration of parenteral calcium to critically ill patients may be harmful.

Vascular catheter tip cultures for suspected catheter-related blood stream infection in the intensive care unit: a tradition whose time has passed?

BACKGROUND: Catheter-related blood stream infections (CR-BSIs) are estimated to occur in 80,000 patients in intensive care units (ICUs) each year in the United States. We sought to determine the clinical utility of vascular catheter cultures in critically ill patients with suspected CR-BSI. METHODS: We reviewed retrospectively all positive (≥15 colony forming units/roll) vascular catheter tip cultures (CTCs) documented over a four-year period in the ICUs of two hospitals. A CR-BSI was defined as matching positive blood and catheter cultures. The time interval between catheter removal and blood culture was recorded. RESULTS: A total of 1,391 CTCs were obtained, of which 468 (34%) were positive and 143 (31% of the positive cultures) were associated with a diagnosis of CR-BSI. In 133 of these 143 cases (93%), the positive blood culture was obtained before or within 24 h after catheter removal and dictated antibiotic therapy. In only 10 of 143 cases (7%) did catheter removal and culture significantly (>1 day) precede the positive blood culture. In 55% of the CR-BSI cases, the catheter was removed empirically and close to the time of blood culture (-1.3±19.0 h). In the remaining 45%, the catheter was removed clinically (after a blood culture was positive), and this action was more remote in time (23.6±19.4 h; p<0.001 vs. empiric removal). Total microbiology laboratory costs for the CTCs were $75,300, and 600 microbiology technician hours were required. CONCLUSION: In an ICU patient population, only about one-third of vascular catheter cultures were positive, and only about one-third of the positive CTCs were associated with CR-BSI. Ninety-three percent of all CR-BSIs were identified by bacteremia either before or coinciding with catheter removal, and the results of the blood culture dictated antimicrobial therapy. Because CTCs rarely changed therapy, they may not be appropriate in the management of suspected CR-BSI in the ICU setting.

Successful use of fondaparinux for bridging early after aortic and mitral mechanical heart valve replacement.

OBJECTIVE: To report a case of successful use of fondaparinux for bridging early after aortic and mitral mechanical heart valve replacement (MHVR). CASE SUMMARY: A 71-year-old female underwent aortic and mitral valve replacements with St. Jude medical bileaflet prostheses, as well as DeVega tricuspid annuloplasty and coronary artery bypass graft. Anticoagulation was initially withheld following the procedure because of thrombocytopenia, large amount of chest tube drainage (~1 L/day), and concerns regarding postoperative bleeding. The thrombocytopenia (baseline platelet count 183 x 10(3)/µL; postoperative platelet count 44 × 10(3)/µL) was thought to be a consequence of the cardiopulmonary bypass; there was a low probability of heparin-induced thrombocytopenia. However, the care team preferred to avoid heparin products and initiated fondaparinux 7.5 mg subcutaneously once daily on postoperative day 8 once the patient's platelet count had recovered to >100 x 10(3)/µL. The treatment was bridged to warfarin on postoperative day 13 and the patient was discharged home after receiving 8 days of fondaparinux. Throughout the patient's hospitalization and upon follow-up on postoperative day 31, there were no signs or symptoms of thromboembolic events or bleeding. DISCUSSION: Unfractionated heparin and low-molecular-weight heparins are the standard of care for bridging to warfarin in patients with MHVR. The use of fondaparinux following MHVR has not been studied in randomized controlled trials. In vitro studies support the effectiveness of fondaparinux in preventing thrombus formation on mechanical heart valves. However, the only data available in humans as of December 2011 are 3 case reports. Two of these case reports described the successful use of fondaparinux for anticoagulation in a patient with an aortic valve replacement. In the third case report, the patient had an aortic and mitral valve replacement. Our case report is novel because it describes the use of fondaparinux early after MHVR, which is the most critical time period for effective thromboprophylaxis. CONCLUSIONS: The use of fondaparinux for postoperative bridging in our patient early after combined aortic and mitral MHVR was effective. However, until studies evaluate the efficacy and safety of fondaparinux in patients with MHVR, its use should be considered only when heparin products are contraindicated.

Effects of surgical gloves on postoperative peritoneal adhesions and cytokine expression in a rat model.

BACKGROUND: Postoperative intraperitoneal adhesions are a major cause of morbidity. We studied the effects of synthetic and latex gloves, and their powders, on postoperative adhesions and cytokine expression in a rat model. METHODS: Rats underwent laparotomy and cecal abrasion. Rats were grouped based on the glove type used: synthetic powder-free (SPF), synthetic powdered (SP), latex powder-free (LPF), and latex powdered (LP). Serum cytokine (tumor necrosis factor [TNF], interleukin-1 [IL-1], and IL-6) levels were measured. Animals were killed and peritoneal adhesions were graded. RESULTS: The SPF group had no adhesions. Adhesions were increased similarly in the SP and LPF groups, and further increased in the LP group. Postoperative serum cytokine levels showed a similar pattern of increases. CONCLUSIONS: The presence of latex or powder on surgical gloves promoted increased adhesions. Serum cytokine levels correlated with the degree of adhesion formation. Strategies to use latex-free, powder-free gloves and/or limit cytokine expression may decrease peritoneal adhesions in the clinical setting.

Multiple heparanases are expressed in polymorphonuclear cells.

BACKGROUND: Heparan sulfate proteoglycans are complex cell surface molecules containing polysaccharides called heparan sulfate. Lysosomes, platelet granules, and neutrophils (polymorphonuclear cells) contain heparanases that degrade heparan sulfate. There are at least two groups of heparanases: connective tissue-activating-peptide (CTAP-III) and mammalian heparanase (hpa). The purpose of this study was to quantify the expression of both CTAP-III and hpa in neutrophils and their heparanase activity. MATERIALS AND METHODS: Neutrophils were isolated from whole blood, total RNA collected, and reverse transcriptase--polymerase chain reaction (RT-PCR) performed. Primers were designed for CTAP-III and hpa-1 sequences from GenBank. Neutrophil lysate underwent Western blot analysis (and quantification) with antibodies to the C-terminus of CTAP-III and the 50-kDa subunit of hpa1. Chromatography separated these components of lysate, which were then tested for heparanase activity. RESULTS: Both CTAP-III (281 bp) and hpa-1 (485 bp) messenger RNA (mRNA) were expressed equally by neutrophils with use of quantitative RT-PCR. By Western blot analysis, a CTAP-III-like protein was detected at 80 kDa, and hpa-1 was detected as a 50-kDa protein, with expression not significantly different (P > 0.05). Heparanase activity was significantly different (P < 0.0001) for the 50-kDa hpa-1 protein (1.51 x 10(-6) micromol/min) and the 80-kDa CTAP-III-like protein (0.85 x 10(-6) micromol/min). CONCLUSIONS: Human neutrophils express mRNA and protein for both a CTAP-III-like protein and hpa-1. Although expressed in similar quantity for mRNA and protein, Hpa-1 was more active as heparanase than the CTAP-III-like protein. With more than one class of heparanase in their granules, neutrophils may be able to modify different kinds of heparan sulfate chains.

Endothelium down-regulates Fas, TNF, and TRAIL-induced neutrophil apoptosis.

BACKGROUND: Neutrophil (PMN) apoptosis regulates PMN functional longevity and is integral to the resolution of inflammation. We have recently shown that PMN contact with an endothelial monolayer down-regulates spontaneous PMN apoptosis. We sought to explore endothelial-mediated down-regulation of PMN apoptosis following mediator-induced apoptosis. We tested the three known membrane-initiated, receptor-ligand apoptotic pathways: Fas, tumor necrosis factor-alpha (TNF), and TNF-related apoptosis inducing ligand (TRAIL). METHODS: PMNs were isolated from peripheral venous blood of healthy volunteers. PMNs were co-cultured in the absence and presence of a human coronary artery endothelial cell (HCAEC) monolayer for 4 h. PMNs were then stimulated with the pro-apoptotic agonists (agonistic anti-Fas IgM, TNF, and TRAIL) for one hour, followed by an assessment of apoptosis after 5 h. PMN apoptosis was measured using an acridine orange/ethidium bromide in situ fluorescent microscopy assay. Caspase 3 activity was assessed using a spectrophotometric assay. RESULTS: In addition to spontaneous PMN apoptosis, endothelial co-culture resulted in significant increases in the percentages of normal cells and decreased percentages of apoptotic cells after stimulation with agonistic anti-Fas IgM, TNF and TRAIL. Endothelial co-culture did not alter PMN caspase 3 activity. CONCLUSION: Endothelial-mediated down-regulation of PMN apoptosis is conferred after 4 h of co-culture. In addition to spontaneous apoptosis, endothelial contact down-regulated the three known membrane-initiated PMN apoptotic pathways: Fas, TNF, and TRAIL. These data imply that endothelial-mediated down-regulation of PMN apoptosis may involve defects in each apoptotic pathway or a single defect in a distal transduction or effector event common to all three pathways. Alterations in the activity of caspase 3 did not appear to serve as a mechanism for endothelial-mediated down-regulation of PMN apoptosis.