Intravenous or Oral Acetazolamide for Treatment of Diuretic-Induced Alkalosis in Patients With Heart Failure.

BACKGROUND: Acetazolamide has been used for diuretic-induced metabolic alkalosis, but the preferred dose, route, and frequency of administration remain unknown. OBJECTIVE: The purpose of this study was to characterize dosing strategies and determine the effectiveness of intravenous (IV) and oral (PO) acetazolamide for patients with heart failure (HF) with diuretic-induced metabolic alkalosis. METHODS: This was a multicenter, retrospective cohort study comparing the use of IV versus PO acetazolamide in patients with HF receiving at least 120 mg of furosemide for the treatment of metabolic alkalosis (serum bicarbonate CO2 ≥32). The primary outcome was the change in CO2 on the first basic metabolic panel (BMP) within 24 hours of the first dose of acetazolamide. Secondary outcomes included laboratory outcomes, such as change in bicarbonate, chloride, and incidence of hyponatremia and hypokalemia. This study was approved by the local institutional review board. RESULTS: IV acetazolamide was given in 35 patients and PO acetazolamide was given in 35 patients. Patients in both groups were given a median of 500 mg of acetazolamide in the first 24 hours. For the primary outcome, there was a significant decrease in CO2 on the first BMP within 24 hours after patients received the IV acetazolamide (-2 [interquartile range, IQR: -2, 0] vs 0 [IQR: -3, 1], P = 0.047). There were no differences in secondary outcomes. CONCLUSION AND RELEVANCE: IV acetazolamide resulted in significantly decreased bicarbonate within 24 hours of administration. IV acetazolamide may be preferred to treat diuretic-induced metabolic alkalosis in patients with HF.

First-Line Therapies for VTE Treatment and Secondary Prophylaxis in Patients With Cancer: A New Direction.

OBJECTIVE: To review evidence behind anticoagulants in cancer-associated venous thromboembolism (VTE) with a focus on low-molecular-weight heparins (LMWH) and the role of direct oral anticoagulants (DOACs). DATA SOURCES: PubMed was searched using terms "venous thromboembolism," "cancer," and "anticoagulation." This search was restricted to clinical trials, meta-analyses, and subgroup analyses. Additional references were identified from reviewing literature citations. STUDY SELECTION: English-language prospective and retrospective studies assessing the efficacy and safety of LMWH and DOACs in patients with cancer. DATA ANALYSIS: Several trials were analyzed that compared anticoagulation therapies for prevention of recurrent VTE in patients with cancer. Many studies comparing LMWH and vitamin K antagonists (VKAs) found nonsignificant differences between therapies. A single study demonstrated that LMWHs are superior to VKAs. This evidence supporting LMWH for long-term VTE treatment in patients with cancer is based on comparison to VKA, but results are limited by methodological issues, and the benefit of LMWH may be driven by poor control. Subanalyses of DOAC trials suggest these are equally or more effective as VKA in cancer, but this conclusion is underpowered. CONCLUSION: DOACs have the potential to bypass many challenges with traditional therapy. After analyzing the evidence available, we conclude that after careful consideration of risks and benefits, use of DOACs for VTE treatment are a reasonable option in patients with cancer.

Association of admission vs. nadir serum albumin concentration with short-term treatment outcomes in patients with acute heart failure.

Objectives Hypoalbuminemia occurs in 25% to 76% of patients hospitalized for acute heart failure (HF) and is associated with increased mortality. Hypoalbuminemia may predispose patients to intravascular volume depletion, hypotension, and acute worsening of renal function; however, its association with treatment outcomes during hospitalization is unknown. Methods This retrospective cohort study involved 414 adult patients hospitalized for HF requiring intravenous diuretics. Temporal changes in serum albumin and the association of hypoalbuminemia with urine output, renal function changes, blood pressure, use of intravenous vasoactive drugs, and short-term outcomes were assessed. Results Serum albumin decreased in most patients (72%) during hospitalization. Hypoalbuminemia was present in 29% and 50% of patients based on the mean admission and nadir serum albumin level, respectively. Hypoalbuminemia as assessed by the nadir albumin level was associated with an increased risk of acute worsening of renal function. A nadir albumin level of <3.0 g/dL remained significantly associated in the multivariate analyses. Conclusions Serum albumin commonly decreases during hospitalization for acute HF. Hypoalbuminemia assessed using the nadir level during hospitalization, not the admission level, was associated with an increased risk of acute worsening of renal function. The timing of serum albumin measurement may influence its utility as a biomarker.

Comparison of Intravenous Palivizumab and Standard of Care for Treatment of Respiratory Syncytial Virus Infection in Mechanically Ventilated Pediatric Patients.

OBJECTIVES: Evidence suggests palivizumab may be beneficial for respiratory syncytial virus (RSV) infection in pediatric patients, although it is only approved by the US Food and Drug Administration for RSV prophylaxis. The objective of this study is to compare outcomes among pediatric patients with RSV infection who received intravenous palivizumab and standard of care versus standard of care alone. METHODS: This is a retrospective, single-center cohort study conducted between November 2003 and October 2013. Pediatric patients with active RSV infection treated with intravenous (IV) palivizumab after initiation of mechanical ventilation were matched 1:1 to a control selected from ventilated patients who received standard of care. The primary end point evaluated the duration of mechanical ventilation between groups. Secondary end points included hospital length of stay, intensive care unit length of stay, duration of respiratory support over baseline, time to RSV microbiologic cure, duration of antibiotic therapy, and in-hospital mortality. RESULTS: A total of 22 patients with a median age of 3 months were included in the study. Patients in the treatment group received a median of 2 doses of IV palivizumab, with a mean dose of 14.2 mg/kg. All patients received bronchodilators and corticosteroids, with the exception of 1 patient in the control group, and only 1 treatment group patient received IV ribavirin. Duration of mechanical ventilation was longer in the treatment group (18.9 ± 9.5 vs. 14.3 ± 9.3 days; p = 0.26). No statistically significant differences were observed between groups for any of the secondary end points. CONCLUSIONS: Pediatric patients who received IV palivizumab in addition to standard of care for treatment of RSV infection following initiation of mechanical ventilation experienced similar outcomes to those who received standard of care alone. Further studies are necessary to evaluate the potential benefit of IV palivizumab in addition to current standard of care.

Thromboelastography Does Not Detect Preinjury Antiplatelet Therapy in Acute Trauma Patients.

Thromboelastography (TEG) with platelet mapping has been proposed as an assay to detect the presence of antiplatelet agents (APA), yet no study has evaluated TEG markers of platelet dysfunction in acute trauma patients stratified by the use of preinjury APA. We hypothesized that patients on preinjury APA would demonstrate prolonged TEG markers of platelet dysfunction compared with those not on preinjury APA. This retrospective review evaluated all trauma patients admitted to a Level I trauma center from February 2011 to April 2013 who received a TEG within the first 24 hours of admission. Patients were classified as receiving preinjury APA or no APA if their documented medications included either aspirin or adenosine diphosphate (ADP) antagonists, including clopidogrel, prasugrel, and ticagrelor. A total of 129 patients were included (APA, n = 35; no APA n = 94) in the study. The time from admission to the first TEG was similar (APA 175 ± 289 minutes versus no APA 216 ± 321 minutes, P = 0.5). There was no significant difference in TEG markers of platelet dysfunction, including per cent ADP inhibition (APA 61.7 ± 25.8% versus no APA 62.3 ± 28.8%; P = 0.91) or per cent arachidonic acid inhibition (APA 58.2 ± 31% versus no APA 53.8 ± 34%; P = 0.54). Both groups had similar proportion of severe platelet dysfunction, defined as ADP inhibition greater than 70 per cent (APA 40% versus no APA 40%; P = 0.8) and arachidonic acid inhibition greater than 70 per cent (APA 40% versus no APA 39%; P = 0.89). In conclusion, platelet dysfunction after major trauma is common. Therefore, TEG alone should not be used to evaluate for the presence of APA due to apparent lack of specificity.

Bleeding risk with systemic thrombolytic therapy for pulmonary embolism: scope of the problem.

Acute pulmonary embolism represents a major complication of venous thromboembolism that is associated with high morbidity and mortality. Guidelines recommend the rapid initiation of anticoagulation and consideration of thrombolytic therapy in select patients, including those with hypotension or at high risk of developing hypotension. Evaluation for thrombolytic therapy should only be considered after assessment of contraindications and risk for major bleeding. The objective of this perspective article is to evaluate the bleeding risk associated with systemic thrombolytic therapy in the management of acute pulmonary embolism and discuss strategies to minimize this risk. Risk stratification of acute pulmonary embolism will be discussed to identify patient populations that warrant specific consideration of risk for major bleeding with thrombolytic therapy. In addition, the incidence, patient-specific risk factors, and pharmacologic characteristics, including concurrent anticoagulation and thrombolytic therapy, will be evaluated in the context of risk for major hemorrhage. Finally, supporting evidence for strategies to minimize risk of hemorrhage, including evaluation of contraindications, weight adjusted dosing, infusion strategy and catheter-directed thrombolytic administration will be evaluated. Despite published guidelines and review articles, select aspects to thrombolytic therapy for the management of pulmonary embolism remain controversial and under recognized, including risk of major hemorrhage. When making decisions about the role of thrombolytic therapy in pulmonary embolism, clinicians must be knowledgeable about the associated risks of thrombolytic therapy and individually evaluate patient risk factors prior to determining appropriate candidacy for thrombolytic therapy. For patients considered to be at high risk of major bleeding, strategies to minimize risk should be considered, including weight-adjusted doses and catheter directed therapy. Additional research is needed specific to the acute pulmonary embolism setting to validate risk factors and strategies to minimize major hemorrhage.

Length of Stay Comparison between Rivaroxaban and Warfarin in the Treatment of Pulmonary Embolism: Results from a Real-World Observational Cohort Study.

Background. Trials have shown that novel oral anticoagulants may decrease length of stay versus warfarin. A comparison of length of stay in the treatment of pulmonary embolism (PE) has not been performed outside post hoc analysis of a large clinical trial. Objective. To evaluate if rivaroxaban decreases length of stay compared to warfarin plus enoxaparin in the treatment of PE. Methods. This was a multicenter, retrospective, observational cohort study. Patients were identified based on discharge diagnosis of PE and were excluded if they received anticoagulants prior to admission and had additional indications for anticoagulation or reduced creatinine clearance. The primary endpoint was length of stay. Secondary endpoints included time from initial dose of oral anticoagulant to discharge and length of stay comparison between subgroups. Results. Inclusion criterion was met by 158 patients (82 warfarin, 76 rivaroxaban). The median length of stay was 4.5 days (interquartile range [IQR], 2.7, 5.9) in the warfarin group and 1.8 days (IQR, 1.2, 3.7) in the rivaroxaban group (P < 0.001). Time interval from first dose of oral anticoagulant to discharge was shorter with rivaroxaban (P < 0.001). Conclusions. Patients given rivaroxaban had decreased length of stay versus those given warfarin plus enoxaparin for the treatment of PE.

Management of dabigatran-associated intracerebral and intraventricular hemorrhage: a case report.

BACKGROUND: Dabigatran is an oral, reversibly bound, direct thrombin inhibitor currently approved in the United States for prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. In the phase III trial leading to approval of the agent, the incidence of life-threatening bleeding was 1.80%/year in the dabigatran 150 mg twice daily arm. Because there is no direct antidote or reversal agent for this drug, the need to manage life-threatening hemorrhages with procoagulant products will arise. OBJECTIVE: To describe a case of dabigatran-associated intracerebral and intraventricular hemorrhage and subsequent management with activated prothrombin complex concentrate. CASE REPORT: An 85-year-old man currently taking dabigatran 150 mg twice daily presented to the Emergency Department for incoordination, expressive aphasia, and weakness. A computed tomography image of his head demonstrated an intracranial hemorrhage. The last dose of dabigatran was approximately 14 h prior to arrival, and conventional coagulation assays (thrombin time and activated partial thromboplastin time) confirmed the presence of dabigatran in the patient's serum. The patient received 27.5 units/kg of activated prothrombin complex concentrate (FEIBA®; Baxter Healthcare Corporation, Deerfield, IL) after an initial intravenous fluid bolus. His activated partial thromboplastin time was not completely normalized by the use of FEIBA; however, the patient's neurological examination slightly improved and remained stable throughout his hospital course despite some intraventricular expansion of the hematoma. After discharge to physical rehabilitation, the patient developed an ischemic cerebrovascular accident and was discharged home on hospice. CONCLUSION: Due to lack of an available antidote, activated prothrombin complex concentrate was utilized as a nonspecific procoagulant to stabilize an intracerebral hemorrhage in a patient on dabigatran.

Analysis of antithrombotic therapy after cardioembolic stroke due to atrial fibrillation or flutter.

BACKGROUND: Guidelines recommend that all patients with atrial fibrillation and a history of ischemic stroke should receive an anticoagulant. Prior analyses show that warfarin is underutilized in most populations. OBJECTIVE: To examine the use of antithrombotic and anticoagulant therapy in patients with atrial fibrillation or flutter during the index hospitalization for acute, ischemic stroke. METHODS: Retrospective electronic medical record review of 200 patients treated at a tertiary care hospital with a primary ICD-9 code for ischemic stroke and a secondary ICD-9 code for atrial fibrillation or flutter. Exclusion criteria were active bleeding, pregnancy, age less than 18, pre-existing warfarin allergy, or dabigatran use. RESULTS: Fifty-two percent of patients received at least one dose of warfarin during the index hospitalization. There was no relationship between CHADS2 score and likelihood of receiving warfarin (P > .05). There was no significant difference in adverse event rate in patients receiving warfarin compared to those receiving aspirin (3.8% vs 9.1%; P = .14), but the rate of hemorrhagic transformation was lower in patients receiving warfarin (1% vs 7%; P = .03). The composite of hemorrhagic stroke or hemorrhagic transformation was significantly lower in patients receiving bridging therapy (0% vs 11%; P = .03). Sixteen patients were readmitted for stroke within 3 months of discharge. Ten were readmitted for ischemic stroke, 3 for hemorrhagic stroke or hemorrhagic transformation, and 3 for systemic bleeding. Ten patients (62.5%) were receiving warfarin at readmission, but only one of these patients had a therapeutic INR. CONCLUSIONS: Warfarin was underutilized as secondary stroke prophylaxis in these high-risk patients. Bridging therapy appeared to be safe and was not associated with an increase in adverse events.

Thiazide diuretics as chronic antihypertensive therapy in patients with severe renal disease--is there a role in the absence of diuresis?

OBJECTIVE: To determine whether thiazides have a chronic antihypertensive effect, in the absence of diuresis, in patients with severe renal disease (creatinine clearance <30 mL/min) or in those receiving dialysis. DATA SOURCES: A search was performed in PubMed, CENTRAL, and International Pharmaceutical Abstracts, using MeSH terms and/or key words. MeSH terms included kidney failure, chronic and exploded terms hydrochlorothiazide, renal dialysis, and thiazides. Key words included thiazide*, hydrochlorothiazide, chlorothiazide, chlorthalidone, indapamide, metolazone, methyclothiazide, bendroflumethiazide, hemodialysis, dialysis, kidney failure, renal failure, renal insufficiency, hypertension, vasodilation, vascular, and diuretics. STUDY SELECTION AND DATA EXTRACTION: All relevant English-language publications were evaluated. Studies evaluating the efficacy of thiazides in renal insufficiency or dialysis were limited to those that included blood pressure measurements. Studies were included only if treatment duration was at least 4 weeks to evaluate chronic antihypertensive effects. DATA SYNTHESIS: Thiazide diuretics are associated with a chronic reduction in peripheral vascular resistance secondary to a purported vasodilatory effect. However, few clinical studies have evaluated the chronic antihypertensive efficacy of thiazide and thiazide-like diuretics in patients with severe renal disease or those on dialysis. Agents studied include hydrochlorothiazide, chlorothiazide, indapamide, and metolazone, with results varying by drug and patient population. Hydrochlorothiazide 25-200 mg daily, chlorothiazide 500 mg twice daily, and indapamide 2.5 mg daily provided long-term blood pressure reduction in patients with severe renal disease who were not on dialysis. In studies involving patients on dialysis, hydrochlorothiazide 50 mg daily and metolazone 5 mg daily did not affect blood pressure; however, 1 study suggested that indapamide 2.5 mg daily may confer an antihypertensive effect. All studies were small (≤12 subjects) and had methodological limitations. CONCLUSIONS: Thiazide diuretics may decrease peripheral vascular resistance independent of natriuresis. However, because current clinical data are inconclusive as to the efficacy of these agents at chronically lowering blood pressure in patients with severe renal disease or in those on dialysis, thiazide diuretics cannot be routinely recommended for this indication.

Statins in sepsis.

Sepsis is a common intensive care unit event occurring in approximately 750 000 patients annually, with a case mortality rate approaching 50%. Sepsis is characterized by a chaotic and excessive release of inflammatory cytokines and procoagulants including tumor necrosis factor, interleukin (IL)-1, IL-6, IL-8, platelet-activating factor, and tissue factor. Efforts to inhibit individual cytokines in order to modify poor outcomes have been generally disappointing, suggesting the need to target multiple inflammatory mediators to obtain clinical benefit. Statins lower lipids by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which in turn inhibits the rate-limiting step in cholesterol biosynthesis. In addition to lowering total cholesterol, statins have pleiotropic effects on inflammation and immunity. Instead of impacting a single entity in the sepsis syndrome, statins may have positive effects on multiple inflammatory, immunomodulating, and coagulation targets involved in the development of infection and sepsis. There have been a number of institutional- and population-based studies that have evaluated the impact of statins in patients with infection and sepsis. Most of these studies, but not all, have demonstrated a number of positive outcomes in patients with statins, including reduction in mortality. Based on these data, statins are a promising therapy in the management of patients with sepsis and warrant larger and more rigorous clinical trials.