Four-factor prothrombin complex concentrate reverses apixaban-associated bleeding in a rabbit model of acute hemorrhage.

BACKGROUND: Apixaban is a direct factor Xa inhibitor approved for the treatment and prevention of thromboembolic disease. There is a lack of data regarding its reversal in cases of acute bleeding or prior to emergency surgery that needs addressing. OBJECTIVES: This study assessed whether a four-factor prothrombin complex concentrate (4F-PCC; Beriplex(®) /Kcentra(®) , CSL Behring) can effectively reverse apixaban-associated bleeding in an in vivo rabbit model and evaluated the correlations between in vivo hemostasis and in vitro coagulation parameters. METHODS: For dose-finding purposes, anesthetized rabbits were treated with a single intravenous dose of apixaban (800-1600 µg kg(-1) ) and, following a standardized kidney incision, volume of blood loss and time to hemostasis were measured. In a subsequent study phase, anesthetized rabbits were treated with apixaban 1200 µg kg(-1) followed by 4F-PCC (6.25-100 IU kg(-1) ), and the effects on the same bleeding parameters were assessed. In parallel, coagulation parameters were monitored. RESULTS: Dose-dependent increases in time to hemostasis and total blood loss were observed post apixaban administration. Preincision treatment with 4F-PCC resulted in a statistically significant reversal in bleeding time (all doses) and volume (doses ≥ 12.5 IU kg(-1) ). Of the coagulation parameters measured, thrombin generation initiated using the RD reagent (phospholipids only) was the most sensitive to in vivo measures of 4F-PCC's hemostatic efficacy, although some correlations were also observed for prothrombin time and whole blood clotting time. CONCLUSIONS: In this rabbit model of acute hemorrhage, 4F-PCC showed potential for reversing the bleeding effects of apixaban. Clinical data in apixaban-treated patients are needed to confirm these results.

Phase III trial of bortezomib, cyclophosphamide and dexamethasone (VCD) versus bortezomib, doxorubicin and dexamethasone (PAd) in newly diagnosed myeloma.

We aimed at demonstrating non-inferiority of bortezomib/cyclophosphamide/dexamethasone (VCD) compared to bortezomib/doxorubicin/dexamethasone (PAd) induction therapy with respect to very good partial response rates or better (⩾VGPR) in 504 newly diagnosed, transplant-eligible multiple myeloma patients. VCD was found to be non-inferior to PAd with respect to ⩾VGPR rates (37.0 versus 34.3%, P=0.001). The rates of progressive disease (PD) were 0.4% (VCD) versus 4.8% (PAd; P=0.003). In the PAd arm, 11 of 12 patients with PD had either renal impairment (creatinine ⩾2 mg/dl) at diagnosis or the cytogenetic abnormality gain 1q21, whereas no PD was observed in these subgroups in the VCD arm. Leukocytopenia/neutropenia (⩾3°) occurred more frequently in the VCD arm (35.2% versus 11.3%, P<0.001). Neuropathy rates (⩾2°) were higher in the PAd group (14.9 versus 8.4%, P=0.03). Serious adverse events, both overall and those related to thromboembolic events, were higher in the PAd group (32.7 versus 24.0%, P=0.04 and 2.8 versus 0.4%, P=0.04). Stem cell collection was not impeded by VCD. VCD is as effective as PAd in terms of achieving ⩾VGPR rates with fewer PD and has a favorable toxicity profile. Therefore, VCD is preferable to PAd as induction therapy.

Exercise does not change high-density lipoprotein cholesterol in women after ten weeks of training.

Effects of a 10 wk, three times per wk individualized bicycle ergometer training program were investigated in 16 healthy sedentary women 19-29 yr-old who were not taking oral contraceptives or other medications. Twelve women were in an interval type program, 6 in a continuous program, all performing 30 min exercise per session at 70% maximum heart rate reserve. Conditioning responses did not differ between the training regimens. Training produced increases in maximum oxygen uptake and physical work capacity. Percent body fat determined by underwater weighing was significantly reduced as was resting heart rate, after the training program. Maximum heart rate was unchanged. Despite changes in "fitness" variables, post-training values of high density lipoprotein cholesterol and triglycerides did not differ from pretraining. High-density lipoprotein cholesterol was significantly reduced at 2 and 5 wk of training and returned to control levels at 10 wk. Exercise conditioning leading to improved physical fitness in healthy women may not be associated with increments in high density lipoprotein cholesterol levels.

Correlations between ejection times measured from the carotid pulse contour and the impedance cardiogram.

Systolic time interval (STI) analysis is a commonly employed noninvasive technique for evaluating myocardial function. It requires simultaneous recording of an electrocardiogram, phonocardiogram, and the carotid pulse contour, from which left ventricular ejection time is measured. The carotid pulse contour may be difficult to record when there is subject movement, such as with exercise or other stresses utilized in aerospace medical research. Impedance cardiography is a relatively new noninvasive technique for measuring stroke volume. It also provides a measure of systolic ejection time without the necessity of recording a carotid pulse contour. The purpose of this study was to determine the correlation between left ventricular ejection time (LVET) determined from conventional STI analysis and systolic ejection time (T) obtained with impedance cardiography. The electrocardiogram, phonocardiogram, carotid pulse contour, and impedance cardiogram were monitored simultaneously in 17 male subjects 39-63 years of age (6 normotensive, 7 with established hypertension, and 4 with labile hypertension). Subjects were monitored at seated rest and during submaximal and maximal cycle ergometer exercise. Beat-by-beat analysis revealed high intrasubject correlations between LVET and T for each subject during all three activity levels. Correlations between LVET and T for the combined group of 17 subjects were: rest r = 0.990, submaximal exercise r = 0.976, maximal exercise r = 0.986; p less than 0.01. These results indicate impedance cardiography can be used in the determination of STIs for the evaluation of ventricular function, as well as for the noninvasive determination of stroke volume and cardiac output.

Influence of respiration on stroke volume determined by impedance cardiography.

The conventional method of calculating stroke volume (SV) with impedance has been to measure changes in thoracic impedance for only those beats of the impedance cardiogram (IC) which cross on a specific baseline. This severely limits the number of usable beats since respiration produces oscillation of the IC around this baseline. This study investigated the influence of respiration on SV calculated independent of the baseline in seven women, 20-44 years old, in each of three postures: seated, supine, and standing. SV was determined in three continuous respiratory cycles from the following beats: 1. all; 2. all inspiratory (I); 3. I on baseline; 4. all expiratory (E); 5. E on baseline; 6. all end-E; 7. end-E on baseline (conventional). The absolute values for SV, heart rate (HR), and cardiac output (Q) were posture dependent. SVs did not differ among the respiratory phases in the standing and seated postures; in the supine posture, the smallest SV occurred at end-E on baseline. HR varied with respiration in both the standing and seated postures but not in the supine posture. Despite significant changes in HR in the seated and standing postures, Qs did not differ among the respiratory phases. Supine Qs were significantly smaller during end-E due primarily to a small SV. Consequently, when reporting Q values for supine subjects, it is important to designate the respiratory phase and baseline criteria. Our results indicate that SVs calculated independent of the baseline in general agree with the more conventional method of calculation. Therefore, we recommend the calculation of SV independent of the baseline. The reliability of the data will be increased by increasing the number of observations and SVs can be determined under circumstances where it is difficult to obtain end-E beats on the baseline.

Transthoracic impedance: differences between men and women with implications for impedance cardiography.

Impedance cardiography (IC) is a reliable noninvasive technique for monitoring stroke volume (SV) and cardiac output. Transthoracic impedance (Zo) is one variable in the equation used for the calculation of SV. Thoracic impedance reflects the resistivity offered by tissues and air and the length and cross-sectional area of the thoracic volume. The purpose of this study was to evaluate possible differences in Zo between men and women. Measurements (Mean +/- S.D.) of Zo in 29 men (age 25.6 +/- 4.6 yr) and 35 women (24.2 +/- 6.0 yr) in the seated posture revealed Zo values were significantly (p less than 0.05) greater for the women (31.5 +/- 3.3 ohm) than the men (23.5 +/- 1.84 ohm). The observed differences in Zo cannot be attributed to thoracic length; distances between the monitoring electrodes were similar for the men (25.1 cm) and the women (25.7 cm). We hypothesize that the greater Zo observed for women is due to a smaller thoracic cross-sectional area and greater resistivity resulting primarily from relatively more fat tissue, smaller heart size, and lesser central blood volume as compared with men.

Reversal of dabigatran anticoagulation by prothrombin complex concentrate (Beriplex P/N) in a rabbit model.

BACKGROUND: One limitation of the direct thrombin inhibitor dabigatran is the lack of specific antidotes that allow acute bleeding events to be managed or urgent interventional procedures performed. Prothrombin complex concentrates (PCCs) have served as a standard treatment for the reversal of coumarin anticoagulation. OBJECTIVES: This study was designed to determine in an animal model whether a PCC (Beriplex P/N) can effectively reverse the effects of dabigatran. An additional objective was to evaluate markers of dabigatran-associated bleeding diathesis. METHODS: Anesthetized rabbits were treated with 0.4 mg kg(-1) dabigatran followed by PCC doses of 20, 35 or 50 IU kg(-1) or placebo. After a standardized kidney incision, volume of blood loss and time to hemostasis were determined. RESULTS: From an initial mean of 29 mL, blood loss progressively declined by 5.44 mL with a 95% confidence interval (CI) of 2.21-8.67 mL per 10 IU kg(-1) increment in PCC dose (P = 0.002). At a PCC dose of 50 IU kg(-1) blood loss was fully normalized. Increasing PCC doses shortened the median time to hemostasis from 20.0 to 5.7 min (P < 0.001). The rate of hemostasis was nearly trebled with each 10 IU kg(-1) increment in PCC dose (rate ratio, 2.89; CI, 1.64-5.09). CONCLUSIONS: In this animal study, PCC showed potential as an agent for reversing the effects of dabigatran. Further investigation is warranted.

Health risk appraisal: process, problems, and prospects for nursing practice and research.

A number of methodological concerns and certain dimensions relevant to future development are generated in the above research: 1. The issue of test reactivity is especially critical in health risk appraisal instruments, since more advanced tools are designed to stimulate the recipient to take actions that might alter post-test results. Therefore, research studies using health risk appraisals need to control for the interaction effects of testing. Since health risk appraisals are reactive, the interaction of test effects with other experimental treatment (e.g. counseling) cannot be handled by use of non-reactive measures, as methodologists frequently suggest. 2. A second major threat to validity is the issue of experimental mortality. The clients who complete the health risk appraisal instrument are usually assumed to be self-motivated. Where engaged in large scale trials, however, their participation may be coerced at the outset but not enforced throughout the course of the study. Because of this some studies have a high proportion of dropouts. 3. Where this has not been the case, a third threat to validity, selectivity, is often a paramount concern, inasmuch as the populations who have subscribed to the instrument under their own motivation may be already pre-selected as very low risk individuals. In light of the paucity of controlled studies using health risk appraisals, it is difficult to draw conclusions regarding the state of the art. In summary, some general dimensions of the activity surround the development and use of health risk appraisals are: 1. The health risk appraisal appears to be more effective in motivating change with older rather than younger individuals. 2. Individuals given a health risk assessment within a supportive educational process do better than individuals exposed only to the results of a health risk appraisal. 3. Individuals given only a health risk appraisal and results without supportive education do better than individuals given no health risk appraisal. 4. Research participants and users of the instrument are, in almost every study, a self-selected group and appear to be healthier than the general population. One might question whether they are the more motivated population.

Trauma of discovery: women's narratives of being informed they are HIV-infected.

The purposes of this research report are to describe women's subjective experiences of being informed of a positive HIV antibody test and, from their point of view, to explain the meaning and impact of discovering that one is HIV-infected. In this qualitative narrative study, a racially diverse, low-income sample of 38 HIV-infected women shared their stories of HIV discovery during in-depth interviews. Findings of a multi-staged narrative analysis suggest that, for women like those in this study, the discovery of HIV seropositivity is a traumatic event, carrying with it elements that are common to other types of trauma: perceived threat to one's life and perceived responsibility for the deaths of others. Overarching personal meanings, or metaphors, framed these women's experiences of the trauma of HIV discovery. HIV discovery was an epiphany for 10% of the sample, a confirmation for 37%, and a calamity for 53%. Among their calamitous reactions were shock, fear, anguish, and suicidality. The impact of learning that they were HIV-infected often took its toll in unrelenting misery, escalated drug use, transmission risks, and destabilization of relationships, income, and shelter. Extensive excerpts from participants' interviews illustrate analytic findings. Implications for counselling and follow-up at diagnosis and early in the course of HIV illness are elaborated.

Cudahy high school survey and focus groups: assessment of the needs of a teen population. A community-campus collaboration.

Collaboration between local public health agencies and university schools of nursing can be advantageous to both parties. Students need opportunities to learn aggregate-based care; health officers need community partnerships that expand their potential to accomplish core functions. This article offers a case study to illustrate a collaborative relationship. A high school survey and a plan for teen services were the focus of the joint endeavor. With guidance from faculty, students offered labor and expertise; the agency offered a real world laboratory for learning.

Cefotaxime toxicity studies: a review of preclinical studies and some clinical reports.

Toxicologic studies indicate that cefotaxime is well tolerated by animals. It is difficult to demonstrate acute toxicity. Subacute and chronic effects include local reactions at the site of injection, some hematologic changes with enlargement of the spleen, cecal enlargement in rats and mice, and slight changes in kidney tubules. Special studies indicate that the potential for nephrotoxicity in animals is minimal, and limited clinical reports show no nephrotoxicity in humans. In animals cefotaxime is well tolerated when combined with furosemide, gentamicin, lidocaine, or probenecid. Intrathecal or suboccipital injections of cefotaxime produce convulsions. At concentrations studied cefotaxime was not mutagenic, and no effects on fertility or teratology were observed in animals.

Beyond community assessment into the real world of learning aggregate practice.

One certainty for nursing, and therefore for nursing education, is that nurses of the 21st century will be called upon to deliver aggregate-based care. Faculty, seeking ways to prepare students for this challenge, often use community assessment as a strategy to help develop skills required to implement care at the aggregate level. In this unique program, community projects completed during an undergraduate community and family health nursing course are expanded in scope to include community diagnosis, planning, intervention, and outcome evaluation. Projects offer immediate benefit to the agency and may continue for several semesters, involving students in various phases of the nursing process.

Central hemodynamics during progressive upper- and lower-body exercise and recovery.

The purpose of this study was to compare stroke volume (SV) and myocardial contractility responses during and immediately after upper- and lower-body exercise. Nine men (mean 28 yr, 78 kg) completed progressive intensity discontinuous tests on both an arm crank and cycle ergometer. Exercise for each power output (PO) was 7 min with 20-min rest periods interspersed. Impedance cardiography was used to measure cardiac output (Q), SV, and contractility on a beat-by-beat basis during exercise and a 15-s recovery period. Q increased linearly, and total peripheral resistance decreased exponentially with increasing PO levels. During recovery from exercise, the Q and heart rate (HR) values decreased immediately at all PO levels. When the exercise VO2 exceeded 1.0 1 X min-1, SV fell significantly during recovery for both exercise modes. In general, the recovery myocardial contractility indices remained similar to exercise values. It was concluded that immediately after low intensities of exercise, Q decreases because of a fall in HR. After moderate- and high-intensity exercise, Q decreases because of a fall in both HR and SV.