Neil Ernst

Effects of Critical Illness and Organ Failure on Therapeutic Argatroban Dosage Requirements in Patients with Suspected or Confirmed Heparin-Induced Thrombocytopenia

BACKGROUND Critically ill patients often require therapeutic argatroban dosages lower than those recommended in package labeling. The magnitude of dosage alteration in relation to severity of organ failure is unknown. OBJECTIVE To compare therapeutic argatroban dosages between critically ill and noncritically ill patients with confirmed or suspected heparin-induced thrombocytopenia and investigate the relationship between total Sequential Organ Failure Assessment (SOFA) score and therapeutic argatroban dosage. METHODS This retrospective cohort study was conducted at an urban academic medical center. Adults without Child-Pugh class C hepatic dysfunction who received argatroban for more than 24 hours over a 3-year period were included. Therapeutic argatroban dosage was that resulting in 2 consecutive activated partial thromboplastin time (aPTT) values 1.5–3 times the patient-specific baseline obtained at least 4 hours apart. Initial argatroban dosages were at the discretion of the managing service. RESULTS Fifty-three patients (critically ill, n = 34; noncritically ill, n = 19) were included. Critically ill patients had higher median [interquartile range] Acute Physiology and Chronic Health Evaluation (APACHE II) (17 [12–21] vs 10 [3.25–17.75]; p = 0.007) and SOFA (11 [7–13] vs 2 [0–2.75]; p < 0.001) scores. Critically ill patients required lower mean ± SD therapeutic argatroban dosage (0.6 ± 0.5 vs 1.4 ± 0.9 µg/kg/min; p < 0.001). There was no significant difference in time to therapeutic aPTT or proportion of aPTTs within therapeutic range. Argatroban dosage was inversely related to SOFA score tertiles (<6: 1.34 ± 0.82 µg/kg/min; 6–9: 0.93 ± 0.54; ≥10: 0.40 ± 0.27; p < 0.001). Total SOFA score at the time of argatroban initiation was independently associated with an argatroban dosage less than 0.75 µg/kg/min (OR 1.5, 95% CI 1.2 to 1.8; p < 0.001). Adverse events were similar between groups. CONCLUSIONS Critically ill patients with single or multiple organ failure require lower therapeutic argatroban dosages compared with noncritically ill patients. Because of an inverse relationship with SOFA score, initial argatroban dosage in critically ill patients should be based on the presence and magnitude of organ failure.

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.

Prevention of perioperative venous thromboembolism.

Venous thromboembolism (VTE) is the most common preventable cause of morbidity and mortality in postoperative patients. Overall, VTE is the second-most-common medical complication, third-mostcommon reason for excess healthcare resource utilization, including prolonged hospital stay, and third-most-common cause of mortality in postoperative patients. Moreover, pulmonary embolism (PE) has been identified as the most common preventable cause of death in hospitalized patients. As supported by exhaustive reviews and evidence-based guidelines, as well as advocacy by United States and international healthcare policy groups, prevention of postoperative VTE is imperative to patient safety and necessary to decrease postoperative morbidity and mortality. Effective prevention also may limit the societal medical resource burden associated with VTE. Despite

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.

995: METHADONE VERSUS SCHEDULED OPIOID THERAPY IN TIME TO CONTINUOUS INFUSION ANALGESIA DISCONTINUATION

Critical Care Medicine • Volume 46 • Number 1 (Supplement) www.ccmjournal.org Learning Objectives: Patients in the intensive care unit (ICU) routinely experience pain. Scheduled opioids may be employed to facilitate weaning of continuous infusion (CI) analgesia in mechanically ventilated (MV) patients to avoid withdrawal. However, an optimum strategy has not been identified. Methadone may be an optimal choice as it possesses a long duration of action and has the ability to be administered intravenously and enterally. Methods: This single center, retrospective, cohort study included adult ICU patients on MV for 48 hours that received CI analgesia plus concomitant methadone or scheduled, enteral immediate release opioids (IRO). The primary outcome was comparison of time to CI analgesia discontinuation. Secondary outcomes included comparison of initial, 96-hour, and final methadone or IRO dose in oral morphine equivalents (OME) at CI analgesia discontinuation and prolonged QTc interval incidence at 96 hours. Logistic regression analyses were performed to determine independent predictors of methadone response. Results: Seventy-four patients were included in the analysis. Time to CI analgesia discontinuation was similar between the two treatment groups (methadone, 69 hours vs IRO, 57.5 hours; p = 0.527). CI analgesia dose at study drug initiation and maximum dose were similar between the two groups. The methadone group received statistically more daily OME at all time points analyzed (initiation, 90 vs 60 mg, p = 0.009; 96 hours, 90 vs 45 mg, p < 0.001; CI analgesia discontinuation, 90 vs 30 mg, p < 0.001). No difference in prolonged QTc interval at 96 hours was observed (methadone, 445 vs IRO, 460 ms; p = 0.110). Patients that received methadone were significantly more likely to discharged with a long-acting opioid prescription (51.4 vs 2.7%, p < 0.001). No independent predictors for methadone response were identified. Conclusions: Methadone was not associated with a quicker time to CI analgesia discontinuation when compared to scheduled IRO. Patients that received methadone were more likely to be discharged with a prescription for a long-acting opioid and received significantly more opioid analgesia until CI analgesia was discontinued.

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.

581: CLINICAL IMPACT OF HYPERCHLOREMIA SECONDARY TO HYPERTONIC SODIUM CHLORIDE ADMINISTRATION

Learning Objectives: Itravenous (IV) hypertonic sodium chloride (HTS) has multiple clinical indications. Isotonic sodium chloride and subsequent hyperchloremia have been associated with acute kidney injury (AKI), prolonged hospital length of stay (LOS), and increased mortality. These associations have not been evaluated with HTS use. The primary objective of this study is to compare the incidence of AKI among peak serum chloride concentrations in patients receiving HTS. Methods: This single-center, retrospective, observational study analyzed adult patients admitted >72 hr and reveiving ≥15 grams of sodium chloride via IV HTS. Patients were divided into tertiles based on peak serum chloride: tertile 1 (T1) ≤108 mmol/L; tertile 2 (T2) 109–116 mmol/L; tertile 3 (T3) ≥117 mmol/L. AKI and in-hospital mortality rates were compared among tertiles. Multivariate logistic regression was performed to identify factors associated with AKI development or mortality. Results: 136 patients were included (T1, 43 [32%]; T2, 52 [38%]; T3, 41 [30%]). Baseline characteristics were similar among tertiles with the exception of T1 including fewer traumatic admissions (19 v 52 v 42%;p=0.003) and more hyponatremia diagnoses (14 v 4 v 0%;p=0.018). Increase in serum chloride from baseline was different among tertiles (6 v 9 v 16%;p<0.001). Rate of AKI increased with peak serum chloride (2 v 10 v 22%;p=0.015). Multivariate logistic regression identified that peak serum chloride independently predicted AKI development (OR 7.1, 95% CI 1–50;p=0.049). Hospital (13 v 16 v 13;p=0.053) and ICU (8 v 11 v 11;p=0.124) LOS (days) were similar among groups. Mortality rate increased with peak serum chloride (5 v 14 v 32%;p=0.003). No factors were identified as independent predictors of mortality. Conclusions: After adjusting for concurrent nephrotoxins and other confounding variables, increasing magnitude of serum chloride was associated with AKI among patients who received HTS. Prospective, multicenter studies are needed to confirm this relationship.

970: Continuous Renal Replacement Therapy and Flow Rate Influence on Cefepime Pharmacokinetics

performed, and if an adverse drug event (ADE) had been averted. Averted ADEs were further categorized by severity level of the potential error. The intervening bedside pharmacist reviewed and classified the interventions recorded during the study. A second pharmacist not involved in data collection reviewed all of the interventions. Results: A total of 148 interventions were included in the study from the before-group pharmacists and a total of 238 interventions were included from the after-group (p <0.001). More bedside activities were performed by pharmacists in the after-group (51%) than the before-group (29%), p <0.001. There were more averted ADEs during the after-study (82%) than the before-study (63%), p <0.001. There was not a difference in the severity level of the averted ADEs between the 2 groups. Conclusions: More interventions were performed by the bedside pharmacists than the satellite-based pharmacists. More ADEs were averted with the presence of a bedside pharmacist, however there was not a difference in the severity levels of the averted ADEs.