David P. Reardon

Evaluation of Warfarin Reversal with 4-Factor Prothrombin Complex Concentrate Compared to 3-Factor Prothrombin Complex Concentrate at a Tertiary Academic Medical Center.

BACKGROUND The U.S. Food and Drug Administration recently approved a four-factor prothrombin complex concentrate (4-PCC) for warfarin reversal. The literature supporting its use over three-factor prothrombin complex concentrate (3-PCC) is limited. OBJECTIVE Our objective was to retrospectively compare the efficacy of 3-PCC to 4-PCC in reversing warfarin in patients who were actively bleeding. METHODS We conducted a single-center, retrospective cohort analysis of adult patients who received 3-PCC or 4-PCC for international normalized ratio (INR) reversal. Our study excluded patients not actively bleeding and not on warfarin. The main outcome was the percentage of patients who achieved warfarin reversal defined as INR ≤ 1.3 at first INR check post factor administration. We recorded baseline data including PCC dose, location of bleed, pre- and posttreatment INR, and time to INR reversal. RESULTS We included a total of 53 patients. Intracranial hemorrhage was the most common site of bleeding (26 [74.3%] in 3-PCC vs. 12 [66.7%] in 4-PCC). The mean dose of 3-PCC was 25.5 units/kg, compared to 27.9 units/kg of 4-PCC. The mean baseline INR was 2.3 in the 3-PCC group and 3 in the 4-PCC group (p = 0.03), and the first posttreatment INRs were 1.4 and 1.2, respectively (p < 0.01). Warfarin reversal was achieved in 15 (42.9%) patients who received 3-PCC and 15 (83.3%) patients who received 4-PCC (p < 0.01). Faster time to INR reversal was noted in the 4-PCC group vs. the 3-PCC group (3.7 vs. 5 h, p = 0.48). CONCLUSION A higher percentage of patients achieved warfarin reversal with 4-PCC compared to 3-PCC treatment. A prospective randomized control trial is necessary to confirm our results.

Early vasopressin reduces incidence of new onset arrhythmias

PURPOSE The objective of this study was to determine the effect of early vs late vasopressin therapy on catecholamine dose and duration. MATERIALS AND METHODS We conducted a single-center, retrospective chart review of adult patients admitted to the medical intensive care unit between January 2010 and December 2011 with septic shock requiring catecholamine and vasopressin therapy. Patients were included in the early group if vasopressin was initiated within 6 hours and the late group if vasopressin was initiated between 6 and 48 hours of catecholamine(s). RESULTS Duration of catecholamine and vasopressin therapy was similar between the 35 patients in the early group and the 36 in the late group. Vasopressin therapy was associated with a decrease in catecholamine requirements in both groups. Early vasopressin was associated with fewer new onset arrhythmias (37.1% vs 62.9%, P<.001). There was no difference in mortality, hospital, or intensive care unit length of stay between the early and late group vasopressin groups (88.6% vs 88.9%, P=1; 14 vs 10 days, P=.48; 9 vs 7 days, P=.71, respectively). CONCLUSIONS Early initiation of vasopressin therapy in adult critically ill patients with septic shock was associated with no difference in total catecholamine requirements but decreased incidence of new onset arrhythmias.

Pathophysiology, assessment, and management of pain in critically ill adults.

PURPOSE The pathophysiology of pain in critically ill patients, the role of pain assessment in optimal pain management, and pharmacologic and nonpharmacologic strategies for pain prevention and treatment are reviewed. SUMMARY There are many short- and long-term consequences of inadequately treated pain, including hyperglycemia, insulin resistance, an increased risk of infection, decreased patient comfort and satisfaction, and the development of chronic pain. Clinicians should have an understanding of the basic physiology of pain and the patient populations that are affected. Pain should be assessed using validated pain scales that are appropriate for the patients communication status. Opioids are the cornerstone of pain treatment. The use of opioids, administered via bolus dosing or continuous infusion, should be guided by patient-specific goals of care in order to avoid adverse events. A multimodal approach to pain management, including the use of regional analgesia, may improve patient outcomes and decrease opioid-related adverse events, though there are limited relevant data in adult critically ill patient populations. Nonpharmacologic strategies have been shown to be effective adjuncts to pharmacologic regimens that can improve patient-reported pain intensity and reduce analgesic requirements. Analgesic regimens need to take into account patient-specific factors and be closely monitored for safety and efficacy. CONCLUSION Acute pain management in the critically ill is a largely underassessed and undertreated area of critical care. Opioids are the cornerstone of treatment, though a multimodal approach may improve patient outcomes and decrease opioid-related adverse events.

Evaluation of sedatives, analgesics, and neuromuscular blocking agents in adults receiving extracorporeal membrane oxygenation

Purpose: The objective of this study was to evaluate the use of sedative, analgesic, and neuromuscular blocking agents (NMBAs) in patients undergoing extracorporeal membrane oxygenation (ECMO) support. Materials and methods: This was a 2‐year, prospective, observational study of adult intensive care unit patients on ECMO support for more than 48 hours. Results: We analyzed 32 patients, including 15 receiving VA (venoarterial) ECMO and 17 VV (venovenous) ECMO. The median daily dose of benzodiazepines (midazolam equivalents) was 24 mg, and the median daily dose of opioids (fentanyl equivalents) was 3875 &mgr;g. There was a moderate negative correlation between the day of ECMO and the median daily benzodiazepine dose (r = −0.5515) and a very weak negative correlation for the median daily opioid dose (r = −0.0053). On average, patients were sedated to Richmond Agitation Sedation Scale scores between 0 and −1. Continuous infusions of opioids, benzodiazepines, propofol, dexmedetomidine, and NMBAs were administered on 404 (85.1%), 199 (41.9%), 95 (20%), 32 (6.7%), and 60 (12.6%) ECMO days, respectively. Patients in the VA arm received a continuous infusion opioid (96.4% vs 81.6% days; P < .001) and benzodiazepine (58.2% vs 37.0% days; P < .001) more frequently. Conclusions: Patients received relatively low doses of sedatives and analgesics while at a light level of sedation on average. Patients rarely required neuromuscular blockade.

Implementation of a Hemostatic and Antithrombotic Stewardship program

Hemostatic and antithrombotic (HAT) agents are high risk, high cost products. They require close monitoring and dose titration to adequately treat or prevent thrombosis while avoiding bleeding events. Incorporating the principles of inpatient anticoagulation management service into a stewardship program not only improves outcomes and decreases cost, but also improves transitions of care, exposes gaps in therapy management, and leads to the development of institution specific protocols and guidelines. We implemented a HAT Stewardship to provide real time clinical surveillance and management of these agents in an effort to optimize appropriate use, decrease serious adverse events, and minimize costs. The stewardship is staffed daily by an interdisciplinary team comprised of a pharmacist, hematology attending, and medical director. The stewardship focuses on (1) management of heparin-induced thrombocytopenia (HIT), (2) management of patients with Hemophilia A/B with inhibitors and acquired Factor VIII deficiency due to inhibitors, (3) oversight of anticoagulation in patients on extracorporeal membrane oxygenation and (4) assistance with anticoagulation management for patients with mechanical cardiac assist devices. Through implementation of this service, we have been able to demonstrate improved patient care and a positive economic impact exceeding the cost of this program by almost sixfold. Other centers should consider instituting a HAT Stewardship to maximize patient outcomes and minimize adverse events.

Aminocaproic acid for the management of bleeding in patients on extracorporeal membrane oxygenation: Four adult case reports and a review of the literature.

BACKGROUND Extracorporeal membrane oxygenation (ECMO) is associated with a significant risk of bleeding and thrombosis. Despite high rates of bleeding and bleeding-related mortality in patients on ECMO, there is little evidence available to guide clinicians in the management of ECMO-associated bleeding. METHODS We report the use of aminocaproic acid in four patients with bleeding on ECMO and a review of the literature. RESULTS High D-dimer levels and low fibrinogen levels suggested that an antifibrinolytic agent may be effective as an adjunct to control bleeding. After aminocaproic acid administration, bleeding was controlled in each patient as evidenced by clinical and laboratory parameters. One patient suffered a cardiac arrest and care was withdrawn. CONCLUSIONS In patients on ECMO with evidence of fibrinolysis, aminocaproic acid may be an effective option to control bleeding and to stabilize clot formation.

Implementation of a Prolonged Infusion Guideline for Time-Dependent Antimicrobial Agents at a Tertiary Academic Medical Center.

Administration of time-dependent beta-lactam antibiotic as a prolonged infusion may maximize the pharmacodynamic target of time above the minimum inhibitory concentration. We describe the implementation of a prolonged infusion at a tertiary academic medical center, and a 1-year compliance analysis with the guideline. After performing a thorough literature search, a guideline was developed by members of the Department of Infectious Diseases and Department of Pharmacy. Approval and endorsement of the guideline was obtained by the Antimicrobial Subcommittee and Pharmacy and Therapeutics Committee. Physical champions were instrumental in the implementation of the guideline institution-wide. We then performed a 1-year retrospective analysis of guideline compliance from January 1, 2011 to December 31, 2011. Noncompliant administrations were obtained from smart infusion pumps. The total number of doses administered was taken from pharmacy information resources. In total, nearly 85,000 time-dependent doses were administered. Compliance with the prolonged infusion guideline was 89%. Rates of compliance did not significantly differ between medications (P = 0.555). Obtaining support from key stakeholders in collateral services and institutional leadership was vital for the success of this guideline. Compliance with the guideline 1 year after implementation was high. Implementation of a prolonged infusion guideline is feasible with institutional support and motivation.

Sedation Variability Increases Incidence of Delirium in Adult Medical Intensive Care Unit Patients at a Tertiary Academic Medical Center.

Background: Variability in sedation may increase the incidence of delirium and mortality, as well as increased intensive care unit (ICU) and hospital lengths of stay (LOS), despite mean Richmond Agitation Sedation Scale (RASS) scores at goal. Coefficient of variation (CV) can be used to represent variability with a higher ratio indicating increased variability. Study Question: Do patients with an increased variability in sedation, as evaluated by CV in RASS, have an increased incidence of delirium? Methods: We conducted a retrospective chart review of adult medical ICU patients requiring mechanical ventilation (MV) for ≥24 hours between January and April 2013. Patients were excluded if intubated at an outside hospital, neuromuscularly blocked, suffering from anoxic brain injury, or had a goal RASS of −4 or −5. Outcomes assessed included the presence of delirium, as evaluated by the Confusion Assessment Method, RASS, CV in RASS, duration of MV, ICU, and hospital LOS, and survival. Results: Of 45 included patients, 32 experienced delirium during their ICU admission and 13 did not. The groups were similar at baseline. There was no difference in mean RASS when comparing the delirium and nondelirium groups (−1.6 ± 1.3 vs. −1.8 ± 0.8, respectively; P = 0.61). Patients with delirium had a greater CV in RASS (0.3 ± 0.135 vs. 0.2 ± 0.105; P = 0.02), a longer MV duration [4 (2–8) vs. 3 (2–3) days; P = 0.045], and a trend toward increased ICU LOS [8 (5–12.25) vs. 4 (3–8) days; P = 0.096], but no difference in hospital LOS [13 (10–25) vs. 18 (9–39) days; P = 0.83] and survival (71.9% vs. 69.2%; P = 1.0). Conclusion: Medical ICU patients with delirium had a higher CV in RASS compared with patients without delirium, suggesting that greater variability in sedation may increase the incidence of delirium. Patients with delirium also had a greater duration of MV and a trend toward longer ICU LOS.

Prothrombin Complex Concentrate (4PCC): A Review of its Use in Reversal of Vitamin K Antagonists

Bleeding continues to be a major adverse drug event associated with warfarin anticoagulation. The cornerstone of warfarin-related bleeding management involves repletion of affected plasma coagulation factor levels. Prothrombin complex concentrate (human) is a 4-factor prothrombin complex concentrate that contains vitamin K-dependent coagulation factors II, VII, IX, and X and anticoagulant proteins C and S. It recently received Food and Drug Administration approval for warfarin reversal for patients with major bleeding or requiring urgent surgery or other invasive procedures. Its role in reversing target-specific oral anticoagulants appears to be limited to the Factor Xa inhibitors as an emergent intervention.

Pharmacy leaders of tomorrow shaping practice today

In March of 2010, I scrambled in the ASHP Residency Matching Program to become the inaugural trainee in the combined postgraduate year (PGY) 1 and 2 health-system pharmacy administration residency at Hennepin County Medical Center in Minneapolis, while David successfully matched for a PGY1 pharmacy