Christopher A. Droege

Phosphodiesterase 4 inhibitors for the treatment of chronic obstructive pulmonary disease: a review of current and developing drugs.

Introduction: Phosphodiesterase (PDE) inhibitors modulate lung inflammation and cause bronchodilation by increasing intracellular cyclic adenosine 3’, 5’-monophosphate in airway smooth muscle and inflammatory cells. Roflumilast is the only approved PDE-4 inhibitor (PDE4I) for use in chronic obstructive pulmonary disease (COPD). Its beneficial clinical effects occur preferentially in patients with chronic bronchitis and frequent COPD exacerbations. Use of roflumilast as adjunctive or alternate therapy to other COPD medications reduces exacerbations and modestly improves lung function. Areas covered: This article reviews the current role of PDE4I in COPD treatment emphasizing roflumilast’s clinical efficacy and adverse effects. This article also reviews developing PDE4Is in early clinical trials and in preclinical studies. Expert opinion: After decades of research in drug development, PDE4Is are a welcomed addition to the COPD therapeutic armamentarium. In its current clinical role, the salubrious clinical effects of PDE4I in reducing exacerbations and stabilizing the frequent exacerbator phenotype have to be cautiously balanced with numerous adverse effects. Developing drugs may provide similar or better clinical benefits while minimizing adverse effects by changing the mode of drug delivery to inhaled formulations, combining dual PDE isoenzyme inhibitors (PDE1/4I and PDE3/4I) and by forming hybrid molecules with other bronchodilators (muscarinic receptor antagonist/PDE4I and β2-agonist/PDE4I).

Effect of a dalteparin prophylaxis protocol using anti-factor Xa concentrations on venous thromboembolism in high-risk trauma patients

BACKGROUND Low anti-factor Xa (anti-Xa) concentrations with twice-daily enoxaparin are associated with venous thromboembolism (VTE) in high-risk trauma patients. Concerns have been raised with once-daily dalteparin regarding effectiveness and achievable anti-Xa concentrations. The purpose of this before-and-after study was to evaluate the effectiveness of a VTE prophylaxis protocol using anti-Xa concentrations and associated dalteparin dose adjustment in high-risk trauma patients. METHODS Adult trauma patients receiving VTE chemoprophylaxis and hospitalized for at least 3 days were prospectively followed during two 6-month epochs before (PRE) and after (POST) implementation of anti-Xa monitoring. In both groups, high-risk patients received dalteparin 5,000 U subcutaneously once daily; low-risk patients received subcutaneous unfractionated heparin. High-risk POST patients with anti-Xa less than 0.1 IU/mL 12 hours after initial dalteparin dose received dalteparin every 12 hours. All patients underwent routine VTE ultrasound surveillance of the lower extremities. The primary outcome was incidence of VTE. RESULTS A total of 785 patients (PRE, n = 428; POST, n = 357) were included. Demographics, injury patterns, Injury Severity Score (ISS), red blood cell transfusions, intensive care unit and hospital stays, and mortality did not differ between groups. Overall, POST patients had lower VTE (7.0% vs. 13%, p = 0.009) including acute VTE (6.4% vs. 12%, p = 0.01) and proximal deep vein thromboembolism (2.2% vs. 5.7%, p = 0.019). Between high-risk patients, VTE occurred in 53 (16.3%) PRE compared with 24 (9.0%) POST patients (p = 0.01); there was no difference in VTE between low-risk patients (PRE, 2.0% vs. POST, 1.1%; p = 0.86). Among 190 high-risk POST patients with anti-Xa, 97 (51%) were less than 0.1 IU/mL. Patients with low anti-Xa had higher rates of VTE (14.0% vs. 5.4%, p = 0.05) and deep vein thromboembolism (14.4% vs. 3.2%, p = 0.01). Younger age (odds ratio, 0.97; 95% confidence interval, 0.95–0.99) and greater weight (odds ratio, 1.02; 95% confidence interval, 1.00–1.03) predicted low anti-Xa on multivariate regression. CONCLUSION A VTE prophylaxis protocol using anti-Xa–based dalteparin dosage adjustment in high-risk trauma patients was associated with decreased VTE. Once-daily dalteparin 12-hour anti-Xa concentrations are suboptimal in a majority of patients and associated with VTE. LEVEL OF EVIDENCE Therapeutic study, level IV.

Long acting muscarinic antagonists for the treatment of chronic obstructive pulmonary disease: a review of current and developing drugs

ABSTRACT Introduction: Long acting muscarinic receptor antagonists (LAMA) reverse airflow obstruction by antagonizing para-sympathetic bronchoconstricting effects within the airways. For years, tiotropium, has been the cornerstone LAMA for chronic obstructive pulmonary disease (COPD) management. Recently, new agents, aclidinium bromide, glycopyrronium bromide, and umeclidinium bromide, have been developed and introduced into clinical practice. Areas covered: This article reviews the clinical efficacy and adverse effects of currently available LAMAs in COPD treatment as well as developing LAMAs in early clinical trials and preclinical studies (V0162, TD-4208, CHF 5407, AZD9164, AZD8683, bencycloquidium). In addition, a new class of molecule that combines muscarinic antagonist and β2-adrenergic properties (MABA) is described and current developmental progress discussed (GSK-961081, THRX-200495). Expert opinion: Future key areas for developing drugs for the management of COPD include prolonged duration of action, optimal delivery systems, synergistic combinations with other drugs, maximization of benefits and minimization of adverse effects. The development of new LAMA and MABA molecules provides exciting progress towards simpler and more effective COPD management.

Update on ultra-long-acting β agonists in chronic obstructive pulmonary disease

Introduction: For the last two decades, long-acting β agonists (LABAs) have been a cornerstone in the management of chronic obstructive pulmonary disease (COPD). They relax airway smooth muscle and augment expiratory airflow, which reduces hyperinflation and improves dyspnea, functional capacity and quality of life. In recent years, Indacaterol, a LABA with an ultra-long duration of action (ultra-LABA), which only requires once-daily dosing, was approved by the FDA. The clinical efficacy of indacaterol is comparable, and, in some aspects better, than the currently available LABAs. Areas covered: This article reviews the pharmacological properties, clinical efficacy, safety and potential role of the ultra-LABAs in COPD management. Expert opinion: Ultra-LABAs are effective bronchodilators with a prolonged duration of action. By decreasing dosing frequency, ultra-LABAs potentially may improve respiratory medication adherence, which is associated with better survival and less healthcare utilization. In addition to their salubrious benefits, β agonists may produce untoward effects. Increased mortality and hospitalizations among patients with left ventricular heart failure, who were treated with β agonists, has caused concern about their use in patients with COPD and heart disease. Further experience and testing will determine the optimal role of ultra-LABAs in the management of COPD.

Pharmacologic choices for procedural sedation.

Medications used in intravenous procedural sedation (IVPS) should be understood at a pharmacologic level. In this chapter, the pharmacology of commonly used analgesic and anesthetic agents will be discussed. The mechanisms of action, adverse effects, pharmacologic considerations, and cardiopulmonary effects are described. Conscious sedation, or moderate sedation, is used for procedures that are typically not well tolerated, but that also do not require deep or prolonged sedation. Patients should be kept at a level where they can respond to verbal commands, and should respond purposefully when stimulated. Titration of doses should be done cautiously, and patients should be monitored for effectiveness, adverse effects, altered metabolism, and potential drug interactions. This chapter will provide an overview of the pharmacology of these agents. An understanding of pharmacologic terminology should be understood. Pharmacokinetics focus on 4 primary processes the body has on the current physiological state of the drug. These processes—often referred to as ADME—include absorption, distribution, metabolism, and excretion. The pharmacokinetics of a drug are highly dependent on dosage, route of

Evaluation of Thrombocytopenia in Critically Ill Patients Receiving Continuous Renal Replacement Therapy

Background: Continuous renal replacement therapy (CRRT) may be associated with thrombocytopenia in critically ill patients. A confounding factor is concomitant use of unfractionated heparin (UFH) and suspicion for heparin-induced thrombocytopenia (HIT). Objective: To determine the impact of CRRT on platelet count and development of thrombocytopenia. Methods: Retrospective analyses evaluated the intrapatient change in platelet count following CRRT initiation. Critically ill adult patients who received CRRT for at least 48 hours were included. The primary outcome was intrapatient change in platelet count from CRRT initiation through the first 5 days of therapy. Secondary outcomes included thrombocytopenia incidence, identification of concomitant factors associated with thrombocytopenia, and frequency of HIT. Results: 80 patients were included. Median platelet count at CRRT initiation (D0) was 128000/µL (81500-212500/µL), which was higher than those on subsequent post-CRRT days (D1: 104500/µL [63000-166750/µL]; D2: 88500/µL [53500-136750/µL]; D3: 91000/µL [49000-138000/µL]; D4: 93000/µL [46000-134000/µL]; and D5: 76000/µL [45500-151000/µL]; P < 0.05 for all). Twenty-five (35%) patients had thrombocytopenia on CRRT D0 compared with D2 (56.3%), D3 (58.7%), and D5 (59.1%); P < 0.05 for all. Controlling for potential confounders, Sequential Organ Failure Assessment score at the time of CRRT initiation was the only independent factor associated with thrombocytopenia. One (1.3%) patient had confirmed HIT. Conclusion and Relevance: This study is the first to demonstrate serial decreases in platelet count across multiple days after CRRT initiation. These data may provide additional insight to thrombocytopenia development in critically ill patients receiving heparin while on CRRT that is not associated with HIT.

Impact of Norepinephrine Weight-Based Dosing Compared With Non–Weight-Based Dosing in Achieving Time to Goal Mean Arterial Pressure in Obese Patients With Septic Shock:

Obesity presents a growing challenge in critically ill patients because of variable medication pharmacokinetics and pharmacodynamics. Vasopressors used in the treatment of septic shock, including norepinephrine, are dosed using weight-based (WB) or non–weight-based (NWB) strategies. Retrospective research has evaluated the effect of total body weight and body mass index on vasopressor requirements, consequently finding that obese patients require less total vasopressor per kilogram to obtain clinical end points such as mean arterial pressure. Although this effect is not completely understood, this may suggest that a NWB dosing strategy is preferred over a WB strategy in obese patients to minimize potential for error.