Venous thromboembolism and bleeding in critically ill patients with severe renal insufficiency receiving dalteparin thromboprophylaxis: prevalence, incidence and risk factors

Background

Critically ill patients with renal insufficiency are predisposed to both deep vein thrombosis (DVT) and bleeding. The objective of the present study was to evaluate the prevalence, incidence and predictors of DVT and the incidence of bleeding in intensive care unit (ICU) patients with estimated creatinine clearance <30 ml/min.

Methods

In a multicenter, open-label, prospective cohort study of critically ill patients with severe acute or chronic renal insufficiency or dialysis receiving subcutaneous dalteparin 5,000 IU once daily, we estimated the prevalence of proximal DVT by screening compression venous ultrasound of the lower limbs within 48 hours of ICU admission. DVT incidence was assessed on twice-weekly ultrasound testing. We estimated the incidence of major and minor bleeding by daily clinical assessments. We used Cox proportional hazards regression to identify independent predictors of both DVT and major bleeding.

Results

Of 156 patients with a mean (standard deviation) creatinine clearance of 18.9 (6.5) ml/min, 18 had DVT or pulmonary embolism within 48 hours of ICU admission, died or were discharged before ultrasound testing – leaving 138 evaluable patients who received at least one dose of dalteparin. The median duration of dalteparin administration was 7 days (interquartile range, 4 to 12 days). DVT developed in seven patients (5.1%; 95% confidence interval, 2.5 to 10.1). The only independent risk factor for DVT was an elevated baseline Acute Physiology and Chronic Health Evaluation II score (hazard ratio for 10-point increase, 2.25; 95% confidence interval, 1.03 to 4.91). Major bleeding developed in 10 patients (7.2%; 95% confidence interval, 4.0 to 12.8), all with trough anti-activated factor X levels ≤ 0.18 IU/ml. Independent risk factors for major bleeding were aspirin use (hazard ratio, 6.30; 95% confidence interval, 1.35 to 29.4) and a high International Normalized Ratio (hazard ratio for 0.5-unit increase, 1.68; 95% confidence interval, 1.07 to 2.66).

Conclusion

In ICU patients with renal insufficiency, the incidence of DVT and major bleeding are considerable but appear related to patient comorbidities rather than to an inadequate or excessive anticoagulant from thromboprophylaxis with dalteparin.

Clinical Trial Registration

Number NCT00138099.     

Comparative studies of humoral factors stimulating granulopoiesis in agar in vitro and in diffusion chambers.

The factor stimulating granulopoiesis in diffusion chambers (DCF) was compared with the CSA in post-EMS in two ways: (1) Mouse bone marrow cells were maintained in suspension cultures, containing DCF or EMS, which were assayed at intervals for colony-forming cells, both in agar in vitro and in diffusion chambers. (2) The enhanced growth seen in chambers incubated in pretreated mice was compared with the CSA of serum and DCF recovered from these animals. The results show that the cells forming granulocytic colonies in agar in vitro and in diffusion chambers are closely related, if not identical, and that different sources of CSA may differ in their ability to maintain precursor cell numbers in suspension culture. The CSA of DCF did not correlate with growth enhancement in diffusion chambers or with the levels of CSA in the serum.     

Women's angiographic vitamin and estrogen trial: design and methods

The Women's Angiographic Vitamin and Estrogen trial was a randomized, double-blind, placebo-controlled study designed to test the efficacy of estrogen replacement and antioxidant vitamins for preventing angiographic progression of coronary artery disease. Postmenopausal women with one or more angiographically documented coronary stenoses of 15-75% at baseline were assigned in a 2 x 2 factorial randomization to active hormone replacement therapy (conjugated estrogens for women who had had a hysterectomy or conjugated estrogens with medroxyprogesterone for women with intact uteri) or placebo and to active vitamins E and C or their placebos. Seven clinical centers, five in the United States and two in Canada, randomized 423 women between July 1997 and July 1999. Quantitative coronary angiography was performed at baseline and repeated after projected mean follow-up of 3 years.     

Factor Structure and Validity of a Revised Pain Anxiety Symptom Scale

The Pain Anxiety Symptoms Scale (PASS) (McCracken et al., 1992) is a frequently used 40-item measure designed to assess fearful appraisals of pain, pain-related cognitive and physiological anxiety, and escape/avoidance behavior. Research has shown the PASS to possess a reasonable validity; however, recent evidence has raised questions regarding the factorial validity of its subscales and indicates that revision and expansion appear warranted. Accordingly, we developed a revised and expanded Pain Anxiety Symptoms Scale (PASS-R). In Study 1, we expanded the item pool and administered the questions to a sample of 69 university students. On the basis of expert opinion and item analysis, we retained a total of 72 items. In Study 2, we subjected the responses of 256 university students to the 72-item PASS-R to a principal-components analysis with oblique rotation. This analysis revealed five lower-order factors (Interference, Approach Behaviours, Catastrophic Thoughts, Monitoring and Prevention, and Physiological Arousal) that loaded together on a single higher-order factor. We created new subscales on the basis of the lower-order factor structure and compared these subscales to a number of other self-report measures of pain, pain behavior, and related psychopathology. The PASS-R subscales demonstrated a good to excellent internal consistency as well as a good construct and criterion validity and contributed unique variance to the prediction of behavioral reactions to recent pain experiences (e.g., visiting a physician). Collectively, these results suggest that the PASS-R is a psychometrically sound self-report measure that allows detailed assessment of anxiety-related cognitions, physiological arousal, and behaviors in response to pain. The paper concludes with a discussion of implications of the studies and future research directions.     

SYNTHESIS OF THE FIRST COMPONENT OF HUMAN COMPLEMENT IN VITRO

Isolated segments of human colon and to a lesser extent ileum were capable of synthesizing hemolytically active C'1. This conclusion was based on the following evidence: After elimination of C'1 from tissue with EDTA, we found that segments of the intestinal tract in short-term organ culture showed a 50–1000-fold increase in C'1 activity. The rate of production of C'1 in human intestine was highly temperature dependent; C'1 production was reversibly inhibited by puromycin and actinomycin D. Furthermore, ¹⁴C-labeled amino acids were incorporated into molecules which behaved like C'1. No significant C'1^hu synthesis was observed in isolated segments of jejunum, stomach, liver, kidney, lung, spleen, lymph node, and thymus.     

Unilateral shivering: a result of lateral medullary infarction

Shivering is mediated via the predominantly uncrossed reticulospinal tract. We report a case of a patient with left lateral medullary tract infarct involving the reticulospinal tract who displayed ipsilateral absence of shivering during a febrile episode. The physiology and anatomy of shivering and the reticulospinal tract is reviewed.     

Poly(ethylene imine)-poly(ethylene glycol) copolymers facilitate efficient delivery of antisense oligonucleotides to nuclei of mature muscle cells of mdx mice

Antisense oligonucleotides (AO) can facilitate dystrophin expression via targeted exon skipping in cultured cells of Duchenne muscular dystrophy (DMD) patients and in the mouse model of DMD (mdx mice). However, the lack of effective means to deliver AO to myonuclei remains the foremost limitation to their usefulness in DMD gene therapy. In this study we show that copolymers of cationic poly(ethylene imine) (PEI) and poly(ethylene glycol) (PEG) facilitated efficient cellular uptake and nuclear delivery of AO in mature skeletal muscle fibers isolated from mdx mice. Confocal analysis of dual fluorescently tagged PEG-PEI-AO polyplexes, 24 hr after transfection, showed that the copolymer and AO were colocalized within punctate membrane- associated structures. Importantly, AO was efficiently translocated into myonuclei, whereas the copolymer was mostly excluded. The morphology of all transfected myofibers was perfectly maintained with no indication of damage or cytotoxicity. Quantitative fluorescence analysis showed that transfection with PEG-PEI-AO resulted in a 6-fold higher uptake of AO into myonuclei compared with transfections of AO alone. Interestingly, transfections with rhodamine-labeled PEG-PEI copolymers yielded an approximately 2- fold higher uptake of AO into myonuclei compared with transfections of unlabeled copolymers. Attempts to further increase AO delivery by addition of insulin-transferrin-selenium (ITS) to the medium showed no further improvement in AO delivery. Dose-response analysis indicated saturation of endocytotic uptake of the polyplex. Overall, we conclude that PEG-PEI copolymers represent high-capacity, nontoxic carriers for efficient delivery of AO to nuclei of mature myofibers.