Prophylactic anticoagulation with enoxaparin: Is the subcutaneous route appropriate in the critically ill?

BACKGROUND: Subcutaneously administered low-molecular-weight heparins are widely used for prevention of venous thromboembolism. The appropriateness of the subcutaneous route in critically ill patients has never been established. OBJECTIVE: To determine anti-Xa activities in critically ill patients and in noncritically ill patients receiving prophylactic doses of subcutaneous enoxaparin. DESIGN: Prospective, controlled, open-labeled study. SETTING: Tertiary medical-cardiologic-postoperative intensive care unit and a general medical ward at a university hospital. PATIENTS: A total of 16 intensive care unit patients (group 1; age, 61.1 +/- 16 yrs; male/female ratio, 7/9; Acute Physiology and Chronic Health Evaluation II score, 20.9 +/- 7; mechanical ventilation, n = 15; vasopressors, n = 13) and 13 noncritically ill medical patients (group 2; age, 61.7 +/- 9 yrs; male/female ratio, 7/6) were studied. Body mass index (25.7 +/- 5 vs. 24 +/- 6 kg/m2, p = not significant) was comparable and serum creatinine levels (0.83 +/- 0.25 vs. 1.07 +/- 0.3 mg/dL, group 1 vs. 2) were within the normal range in both groups. Patients with impaired renal function, receiving hemofiltration, or requiring therapeutic anticoagulation were not eligible. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Anti-Xa activities were determined at 0, 1, 3, 6, and 12 hrs after a single daily subcutaneous dose of 40 mg enoxaparin on day 1 and at 3 hrs after 40 mg of enoxaparin on days 2-5. Mean anti-Xa levels at 0 to 12 hrs were consistently lower in group 1 compared with group 2 by analysis of variance (p =.001 between groups and over time), as was the area under the curve at 0 to 12 hrs (2.6 +/- 1 vs. 4.2 +/- 1.7 units x mL(-1) x hr(-1), group 1 vs. 2, p =.008). Significant differences in anti-Xa activity were also found on days 2-5 (p =.001). Peak anti-Xa activities at 3 hrs after administration were negatively correlated with the body mass index (r = -.41, p <.03). No correlation was found between the anti-Xa activity at 3 hrs and the dose of norepinephrine (r =.12, p =.7). CONCLUSION: Critically ill patients with normal renal function demonstrated significantly lower anti-Xa levels in response to a single daily dose of subcutaneous enoxaparin when compared with medical patients in the normal ward.

Amiodarone versus diltiazem for rate control in critically ill patients with atrial tachyarrhythmias.

OBJECTIVE: To compare the rate-lowering effect of diltiazem and two amiodarone regimens in critically ill patients with recent-onset atrial tachyarrhythmias. DESIGN: Prospective, randomized, controlled study. SETTING: Medical cardiologic intensive care unit in a university hospital. PATIENTS: Sixty critically ill patients (Acute Physiology and Chronic Health Evaluation [APACHE] III score 70 +/- 30, age 67 +/- 10 yrs). INTERVENTIONS: Patients with atrial fibrillation (n = 57), atrial flutter (n = 2), or atrial tachycardia (n = 1, and a heart rate consistently >120 beats/min over 30 mins were randomly assigned to one of three intravenous treatment regimens. Group 1 received diltiazem in a 25-mg bolus followed by a continuous infusion of 20 mg/hr for 24 hrs, group 2 received amiodarone in a 300-mg bolus, and group 3 received amiodarone in a 300-mg bolus followed by 45 mg/hr for 24 hrs. MEASUREMENTS AND MAIN RESULTS: The primary study end point was a >30% rate reduction within 4 hrs. The secondary study end point was a heart rate <120 beats/min (a patient was considered to have uncontrolled tachycardia if heart rate was >120 beats/min 4 hrs after study drug). The primary study end point was achieved in 14/20 (70%), 11/20 (55%), and 15/20 (75%) of patients in groups 1, 2, and 3, respectively (chi2 = 1.95, p =.38). Uncontrolled tachycardia was more frequently observed in group 2 (0/20, 9/29 [55%], and 1/20 [5%] of patients in groups 1, 2, and 3, respectively; chi2 = 17, p =.00016). In patients achieving tachycardia control, diltiazem showed a significantly better rate reduction (p =.0001 group 1 vs. group 3, p =.0001 over time; p =.0001 group 1 vs. group 2, p =.001 over time) when compared with the amiodarone groups. Premature drug discontinuation due to hypotension was required significantly more often in group 1 (6/20 [30%], 0/20, and 1/20 [5%] for groups 1, 2, and 3, respectively; chi2 = 10, p =.01). CONCLUSION: Sufficient rate control can be achieved in critically ill patients with atrial tachyarrhythmias using either diltiazem or amiodarone. Although diltiazem allowed for significantly better 24-hr heart rate control, this effect was offset by a significantly higher incidence of hypotension requiring discontinuation of the drug. Amiodarone may be an alternative in patients with severe hemodynamic compromise.

Thrombolytic therapy in acute myocardial infarction.

Early reperfusion of thrombotically occluded coronary arteries by thrombolytic therapy has become a routine option in initial therapy of acute myocardial infarction. Many efforts have been made to improve the biological properties of thrombolytic agents in terms of fibrin specificity, plasma half-life and resistance to natural plasma inhibitors, to improve adjuvant therapy and to shorten the 'pain to reperfusion' time. Numerous randomised, multicentre trials have analysed the benefit of the various thrombolytic agents and regimens, which has enabled the creation of a 'current standard of therapy'. This review presents an update on available thrombolytic agents, their biochemical and pharmacological properties and results from clinical trials.

Effects of vitamin E on chronic and acute endothelial dysfunction in smokers.

OBJECTIVES: The aims of this study were to determine whether chronic or acute impairment of flow mediated vasodilation (FMD) in the brachial artery of smokers can be restored or preserved by the antioxidant vitamin E. BACKGROUND: Transient impairment of endothelial function after heavy cigarette smoking and chronic endothelial dysfunction in smokers result at least in part from increased oxidative stress. METHODS: We studied 22 healthy male smokers (mean +/- SD, 23 +/- 9 cigarettes per day) randomly assigned to receive either 600 IU vitamin E per day (n = 11, age 28 +/- 6 years) or placebo (n = 11, age 27 +/- 6 years) for four weeks and 11 age-matched healthy male nonsmokers. Flow mediated vasodilation and endothelium-independent, nitroglycerin-induced dilation were assessed in the brachial artery using high resolution ultrasound (7.5 MHz) at baseline and after therapy. Subjects stopped smoking 2 h before the ultrasound examinations. At the end of the treatment period, a third scan was obtained 20 min after smoking a cigarette (0.6 mg nicotine, 7 mg tar) to estimate transient impairment of FMD. RESULTS: Flow mediated vasodilation at baseline was abnormal in the vitamin E (5.3 +/- 3.8, p < 0.01) and in the placebo group (6.4 +/- 3.5, p < 0.05) compared with nonsmoking controls (11.6 +/- 4.7). Using a two-way repeated measures analysis of variance (ANOVA) to examine the effects of vitamin E on FMD, we found no effect for the grouping factor (p = 0.5834) in the ANOVA over time but a highly significant difference with respect to time (p = 0.0065). The interaction of the time factor and the grouping factor also proved to be significant (p = 0.0318). Flow mediated vasodilation values remained similar after treatment for four weeks in both groups but declined faster after smoking a cigarette in subjects taking placebo compared with those receiving vitamin E (p values from successive differences for the time/group factor: 0.0001/0.0017). The transient attenuation of FMD (calculated as the percent change in FMD) was related to the improvement of the antioxidant status, estimated as percent changes in thiobarbituric acid-reactive substances (r = -0.67, p = 0.0024). Nitroglycerin-induced dilation did not differ between study groups at baseline or after therapy. CONCLUSIONS: These results demonstrate that oral supplementation of vitamin E can attenuate transient impairment of endothelial function after heavy smoking due to an improvement of the oxidative status but cannot restore chronic endothelial dysfunction within four weeks in healthy male smokers.

Protein C inhibitor (PCI).

PCI is a non-specific serpin that inhibits several proteases of the coagulation and fibrinolytic systems as well as plasma- and tissue kallikreins and the sperm protease acrosin. The precise physiological role of PCI has not been defined yet. Heparin stimulates most PCI/protease reactions, but interferes with the tissue kallikrein/PCI-interaction. Thereby heparin not only regulates PCI-activity but also its specificity in systems containing two or more of its target proteases. This effect is not restricted to heparin, but is also seen with other glycosaminoglycans (GAGs) and large, negatively charged molecules. PCI also binds to GAGs present on the surface of epithelial kidney cells, and GAGs isolated from these cells have a similar effect on PCI activity as heparin. Studies analyzing the role of PCI as an acrosin inhibitor revealed that endogenous PCI is immunocytochemically localized to disrupted acrosomal membranes of morphologically abnormal sperms, while intact sperms are negative for PCI-antigen. In a mouse in vitro fertilization model human PCI inhibited sperm/egg binding and decreased the fertilization rate. Northern blotting of human and mouse mRNA using human and mouse PCI-cDNA probes revealed that in the mouse PCI is exclusively synthesized in the genital tract (testis, seminal vesicle, ovary), while in humans PCI is additionally synthesized in many other organs (e.g., liver, pancreas, heart). Therefore PCI might regulate enzymes involved in fertilization (e.g. acrosin) in both species. Other proteases (e.g., tissue kallikrein) are possibly regulated in a species specific manner by different inhibitors.

Binding of urinary protein C inhibitor to cultured human epithelial kidney tumor cells (TCL-598). The role of glycosaminoglycans present on the luminal cell surface.

Binding of urinary protein C inhibitor (PCI) to cultured human epithelial kidney tumor cells (TCL-598) was studied. Binding was dose-dependent, time-dependent, and saturable. Heparin interfered in a dose-dependent way with PCI binding to TCL-598 as did heparan sulfate and to a lesser degree also dermatan sulfate. Pretreatment of TCL-598 with protamine sulfate inhibited subsequent binding of PCI in a dose-dependent manner and > 100 micrograms/ml protamine sulfate reduced binding of PCI to < 10% of the control. Binding of 125I-PCI was specific, and bound 125I-PCI was recovered from the cells by heparin treatment or detached together with intact cells by EDTA treatment, migrated on sodium dodecyl sulfate-polyacrylamide gel electrophoresis with the same mobility (M(r) = 57,000) as unbound 125I-PCI. Furthermore, cell-bound PCI was functionally active as judged from its ability to inhibit the amidolytic activity of urokinase, and its inhibitory activity was stimulated approximately 3-4-fold as compared to fluid-phase PCI. Immunogold electron microscopy revealed that PCI-antigen presented to the cells from the luminal side bound exclusively to that surface in native as well as in prefixed cells. This binding of PCI was abolished in the presence of heparin (50 micrograms/ml) and after pretreatment of the cells either with protamine sulfate (400 micrograms/ml) or with heparinase III (0.5 unit/ml). A slight decrease in PCI binding was seen after pretreatment of the cells with chondroitinase ABC and chondroitinase AC. In contrast, binding of PCI to extracellular matrices of TCL-598 was decreased to approximately 70% after chondroitinase ABC treatment of the extracellular matrices, whereas both heparinase III or chondroitinase AC treatment only reduced matrix-bound PCI to approximately 95%. These data suggest that heparan sulfate-containing proteoglycans are predominantly involved in binding of PCI to the luminal side of TCL-598, while dermatan sulfate-containing proteoglycans, the overall predominant PCI-binding proteoglycans in TCL extracts, are responsible for PCI binding to the extracellular matrix. Heparan sulfate, however, exposed to an environment containing PCI under physiological conditions, might localize PCI and modulate its target enzyme specificity in vivo.

Urinary protein C inhibitor. Glycosaminoclycans synthesized by the epithelial kidney cell line TCL-598 enhance its interaction with urokinase.

Protein C inhibitor (PCI), also known as plasminogen activator inhibitor 3, inhibits a variety of serine proteases by forming sodium dodecyl sulfate-stable 1:1 complexes. In purified systems PCI is only a weak inhibitor of urokinase. Nevertheless, complexes between PCI and urokinase are found in appreciable amounts in native human urine. Since PCI activity is stimulated by heparin and other glycosaminoglycans, we investigated the presence of stimulating glycosaminoglycans on cells lining the urinary tract. We chose the epithelial kidney tumor cell line TCL-598 as a model and isolated metabolically labeled glycosaminoglycans. TCL-598 incorporated [35S] sulfate into high Mr components (Mr greater than 200,000 and approximately 75,000) as judged from sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography of cell extracts; the Mr greater than 200,000 component bound specifically to PCI-Sepharose 4B and was eluted either with heparin (5 mg/ml) or with NaCl (2.0 M). Treatment of this PCI-binding material with chondroitinase ABC, but not with chondritinase AC or heparitinase, abolished binding to PCI-Sepharose, confirming the glycosaminoglycan nature of this material and suggesting the involvement of dermatan sulfate in binding. These glycosaminoglycans eluted from PCI-Sepharose stimulated urokinase inhibition by PCI in a dose-dependent way and enhanced complex formation of 125I-urokinase and PCI as did in control experiments dermatan sulfate from porcine skin and from bovine mucosa. Our results suggest that PCI activity might be regulated also in vivo by the presence or absence of stimulating glycosaminoglycans; dermatan sulfate-containing glycosaminoglycans associated with kidney cells might be responsible for stimulation of the urokinase inhibitory activity of PCI in the urinary tract; the type of glucosaminoclycans might furthermore regulate enzyme specificity of PCI.