Risk of thromboembolic events after protocolized warfarin reversal with 3-factor PCC and factor VIIa.

Bleeding events and life-threatening hemorrhage are the most feared complications of warfarin therapy. Prompt anticoagulant reversal aimed at replacement of vitamin K-dependent clotting factors is essential to promote hemostasis. A retrospective cohort study of warfarin-treated patients experiencing a life-threatening hemorrhage treated with an institution-specific warfarin reversal protocol (postimplementation group) and those who received the prior standard of care (preimplementation group) was performed. The reversal protocol included vitamin K, 3-factor prothrombin complex concentrate, and recombinant factor VIIa. Demographic and clinical information, anticoagulant reversal information, and all adverse events attributed to warfarin reversal were recorded. A total of 227 patients were included in final analysis, 109 in the preimplementation group and 118 in the postimplementation group. Baseline patient characteristics were similar in both groups, with the exception of higher average Sequential Organ Failure Assessment scores in the postimplementation group (P = .0005). The most common indication for anticoagulation reversal was intraparenchymal hemorrhage. Prereversal international normalized ratios (INRs) were similar in both groups. Attainment of INR normalization to less than 1.4 was higher, and rebound INR was lower in the postimplementation group (P < .0001; P = .0013). Thromboembolic complications were significantly higher in the postimplementation group (P = .003). Elevated baseline Sequential Organ Failure Assessment score and mechanical valve as an indication for anticoagulation were independently associated with thrombotic complications (P = .005). A warfarin reversal protocol consisting of 3-factor prothrombin complex concentrate, recombinant factor VIIa, and vitamin K more consistently normalized INR values to less than 1.4 as compared to the prior standard of care in a diverse patient population. This success came at the cost of a 2-fold increase in risk of thromboembolic complications.

Antimicrobial prophylaxis during Hirudo medicinalis therapy: a multicenter study.

BACKGROUND: Medicinal leeches (Hirudo medicinalis) are indicated for salvage of tissue flaps, grafts, or replants when venous congestion threatens tissue viability. The purpose of this study was to evaluate the efficacy of prophylactic antimicrobial agents in patients who received medicinal leech therapy. MATERIALS AND METHODS: A multicenter retrospective cohort study of all adult patients between January 1, 2010, and February 28, 2013, who received medicinal leech therapy was conducted. RESULTS: Antimicrobial prophylaxis was documented in 54 (91.5%) of the included patients, ciprofloxacin, trimethoprim-sulfamethoxazole, piperacillin-tazobactam, and ceftriaxone in 33 (61.1%), 18 (33.3%), 2 (3.7%), and 2 (3.7%) patients, respectively. Surgical site infection (SSI) was found in seven (11.9%) patients, all of whom received antimicrobial prophylaxis. Aeromonas spp. was isolated in four infections, and all isolates were resistant to the chosen prophylactic agent. The SSI incidence was similar between antimicrobial prophylaxis agents. CONCLUSION: Trimethoprim-sulfamethoxazole and ciprofloxacin appear equally effective at preventing leech-associated infections.

Utility of ampicillin-sulbactam for empiric treatment of ventilator-associated pneumonia in a trauma population.

BACKGROUND: Ampicillin-sulbactam is guideline-recommended treatment for early-onset ventilator-associated pneumonia (VAP). However, intensive care unit clinicians are encountering increasing resistance to ampicillin-sulbactam. We sought to analyze the time period for early-onset VAP in our trauma population by using daily evaluation of resistance to ampicillin-sulbactam. METHODS: A retrospective cohort study was completed on all mechanically ventilated trauma patients admitted to a rural level-1 trauma center from January 2003 to December 2008 who were diagnosed with VAP. Daily bacterial resistance to ampicillin-sulbactam > 15% was defined as the threshold for early empiric antibiotic failure for the first episode of VAP. A univariate analysis of risk factors for multi-drug resistant pathogens (MDRPs) and comorbidities was completed to assess for predisposing factors for ampicillin-sulbactam resistance. RESULTS: One hundred sixty-three pathogens were identified in 121 trauma patients diagnosed with VAP. Of these isolates, 71% were gram-negative, 28% were gram-positive, and 1% was fungal. Methicillin-susceptible Staphylococcus aureus (23.9%), H aemophilus influenzae (20.9%), and Pseudomonas aeruginosa (11.7%) were the most common infecting organisms. Daily ampicillin-sulbactam resistance was 40%, 26%, 32%, 43%, 50%, and 60% on days 3 to 7 and ≥ 8 days, respectively. Only the presence of MDRP risk factors (89% vs. 65%, p < 0.01) and hospital LOS (36.8 [22.8-49.0] vs. 25.7 days [19.0-32.5], p < 0.01) was different between ampicillin- sulbactam resistant and ampicillin-sulbactam susceptible VAP groups. On univariate analysis, hospital length of stay >4 days and antibiotic use within 90 days were associated with ampicillin-sulbactam resistant VAP (p < 0.01). CONCLUSIONS: Ampicillin-sulbactam is not an effective empiric therapy for early-onset VAP in our rural trauma population. The utility of ampicillin-sulbactam should be reviewed at other institutions to assess for appropriate empiricism.

Management of prehospital antiplatelet and anticoagulant therapy in traumatic head injury: a review.

Trauma and emergency department clinicians encounter a growing number of patients admitted with traumatic head injury on prehospital antithrombotic therapies. These patients appear to be at increased risk of developing life-threatening intracranial hemorrhage. It is imperative that trauma clinicians understand the mechanism and duration of commonly prescribed outpatient antithrombotics in order to appropriately assess and treat patients who develop intracranial hemorrhage. This review summarizes current literature on the morbidity and mortality associated with premorbid non-steroidal anti-inflammatory drugs, aspirin, clopidogrel, warfarin, and heparinoids in the setting of traumatic head injury, and also examines the current strategies for reversal of these therapies.

A Retrospective Study of Early vs Delayed Home Dose Basal Insulin in the Acute Management of Diabetic Ketoacidosis.

BACKGROUND: Insulin via continuous intravenous infusion (ICII) is a standard of care for treating patients with diabetic ketoacidosis (DKA). Once DKA is resolved, ICII is transitioned to subcutaneous therapy. However, recent guidelines recommend continuation of home dose subcutaneous basal insulin (HDBI) in patients with DKA. The objective of this study was to evaluate outcomes in patients who received early vs delayed HDBI. METHODS: This is a retrospective cohort study of patients ≥16 years old admitted to the medical intensive care unit between 1 July 2012 and 30 June 2015 with a primary diagnosis of DKA who received ICII and HDBI. Patients were stratified into early or delayed groups if they received HDBI before or after resolution of DKA, respectively. The primary outcome was incidence of transitional failure, defined as resumption of ICII or recurrence of DKA after initial ICII discontinuation. RESULTS: A total of 106 admissions were included for analysis; 33 (31.1%) received early HDBI. The incidence of transitional failure was similar between the early and delayed groups (OR, 0.60; 95% CI, 0.26 to 1.44; P = 0.72). In the early group, ICII duration was shorter at 13.8 hours [interquartile range (IQR), 10.1 to 16.5] vs 17.1 hours (IQR, 12.6 to 21.1; P = 0.04), with a trend toward lower rates of hypoglycemia (OR, 0.41; 95% CI, 0.16 to 1.05; P = 0.058). CONCLUSION: There was no significant difference in incidence of transitional failure between early and delayed HDBI. Early HDBI was associated with a shorter duration of ICII and a trend toward less hypoglycemia. A prospective analysis is needed to confirm these findings.

Community-acquired methicillin-resistant Staphylococcus aureus pneumonia.

Community-acquired methicillin-resistant Staphylococcus aureus is increasingly recognized as an important pathogen causing skin and soft tissue infections. We report a case of severe necrotizing pneumonia caused by community-acquired methicillin-resistant S. aureus in a peripartum woman. This case illustrates that community-acquired methicillin-resistant S. aureus must be considered as a potential pathogen in severe community-acquired pneumonia.

Surgical Site Infections in Patients With Type 3 Open Fractures: Comparing Antibiotic Prophylaxis With Cefazolin Plus Gentamicin Versus Piperacillin/Tazobactam.

OBJECTIVES: The purpose of this study was to compare rates of surgical site infection (SSI) in patients with type 3 open fractures who had received cefazolin plus gentamicin versus piperacillin/tazobactam for antibiotic prophylaxis. DESIGN: Retrospective cohort study. SETTING: Level 1 trauma center. PATIENTS: Seven hundred sixty-six patients admitted between January 1, 2004, and December 31, 2012, with open fractures were identified using the National Trauma Data Bank by searching International Classification of Diseases, Ninth Revision (ICD-9) codes. Electronic medical record review revealed 134 patients with type 3 open fractures, of which 72 were included in the final analysis. INTERVENTION: Administration of cefazolin plus gentamicin or piperacillin/tazobactam for type 3 open fracture antibiotic prophylaxis. MAIN OUTCOME MEASUREMENTS: SSI, nonunion, death, and rehospitalization rates at 1 year. RESULTS: Surgical site infection at 1 year occurred in 12 of 37 patients (32.4%) in the cefazolin plus gentamicin group and 11 of 35 patients (31.4%) in the piperacillin/tazobactam group (P = 1.000). Nonunion, death, and rehospitalization rates at 1 year were similar between the 2 groups. Although there was no statistically significant difference in SSI at 30 days between groups, the rate was higher in the cefazolin plus gentamicin group (21.6% vs. 11.4%; P = 0.246). CONCLUSIONS: At our institution, use of piperacillin/tazobactam as compared with cefazolin plus gentamicin for antibiotic prophylaxis in patients with type 3 open fractures showed similar rates of SSI, nonunion, mortality, and rehospitalization at 1 year after injury. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

A Retrospective Study on the Protective Effects of Topical Vancomycin in Patients Undergoing Multilevel Spinal Fusion.

BACKGROUND: Topical vancomycin may be an effective intervention to decrease the risk of postoperative surgical site infections (SSIs). The primary objective of this study was to evaluate the impact of topical vancomycin with intravenous (IV) cefazolin compared with IV cefazolin alone on the incidence of SSI in instrumented multilevel spinal fusion (MLSF) surgery. METHODS: This was a retrospective cohort study of patients 18 years and older who underwent instrumented MLSF surgery between January 1, 2010, and July 31, 2014. Patients who underwent anterior cervical diskectomy and fusion, had spine surgery within 3 months prior to index case, received antibiotics other than IV cefazolin prior to surgery, or had preoperative length of stay longer than 5 days were excluded. SSIs were identified using Centers for Disease Control and Prevention National Healthcare Safety Network definitions. Summary statistics were computed. Variables found to be associated with increased risk of SSI through univariate analysis were included in a multivariate analysis. RESULTS: Among 326 patients, 29 (8.9%) developed an SSI. Univariate analysis showed a trend toward decreased SSI incidence in the cohort receiving topical vancomycin with IV cefazolin compared with IV cefazolin alone, although this was not statistically significant ([6/116] 5.2% vs [23/210] 11.0%, p = 0.08). Topical vancomycin was associated with a protective effect against SSI in the multivariate analysis (odds ratio [OR] 0.26, p = 0.02). Significant risk factors for the development of SSI included female sex (OR 3.3, p = 0.01), increasing invasiveness score (p < 0.01), and diabetes mellitus (OR 5.1, p < 0.01). CONCLUSION: Topical vancomycin administered in addition to IV cefazolin was associated with a decreased risk of SSI in high-risk MLSF patients. Female patients and those with diabetes mellitus were at higher risk of developing postsurgical infection. Further prospective studies are needed to confirm these results and to define the most clinically effective dose of topical vancomycin in this patient population.

Pharmacist input into statewide treatment protocols for emergency medical services.

PURPOSE: A pharmacist's role in helping Vermont health officials standardize pharmacotherapy-related protocols used by emergency medical services (EMS) personnel across the state is described. SUMMARY: Pharmacists with expertise in emergency medicine (EM) or critical care are ideally positioned to provide guidance on optimizing and standardizing medication-use aspects of state and local EMS protocols. In 2012, the medical director of the EMS division of the Vermont Department of Health requested that an EM pharmacist at a Burlington academic medical center review draft EMS protocols designed to replace the existing patchwork of local protocols with statewide standards of care; among the 92 draft protocols reviewed, 62 pertained to medication use. The pharmacist provided a wide range of suggestions on 33 protocols, including (1) evidence-based recommendations on use of vasopressor agents for septic shock, (2) recommendations to optimize medication ordering and preparation in the prehospital setting, (3) recommendations on prehospital management of pediatric shock and appropriate use of chemical restraints, and (4) recommendations to promote use of smart infusion pumps by EMS personnel. All of the pharmacist's suggestions were incorporated into the final protocols, which took effect in March 2014. The protocols have helped standardize care for patients receiving EMS services throughout Vermont while reducing the potential for medication errors. CONCLUSION: An EM pharmacist participated in the review and development of statewide EMS treatment protocols that focused on choice of medication therapy, dosage, administration, and identification and minimization of potential risks of medication errors.

Compliance with the Eastern Association for the Surgery of Trauma guidelines for prophylactic antibiotics after open extremity fracture.

CONTEXT: Prophylactic antibiotics, paired with wound care and surgical intervention, is considered the standard of care for patients with open fracture. Guidelines from the Eastern Association for the Surgery of Trauma (EAST) recommend specific prophylactic antimicrobial therapy based on the type of open fracture. AIMS: We quantified adherence to EAST guideline recommendations and documented the incidence of infection in patients with open fracture. SETTINGS AND DESIGN: A retrospective, observational study of all patients with open fracture admitted to our facility from January 2004 to December 2008 was conducted. MATERIALS AND METHODS: Patients were divided into compliant and noncompliant groups according to the EAST guideline recommendations. Compliance was defined as an appropriate spectrum of therapy for guideline suggested duration. We assessed for surgical and non-surgical site infections, and morbidity outcomes. STATISTICAL ANALYSIS: Nominal data were explored using summary measures. Continuous variables were compared using the Student t-test or the Mann-Whitney U-test. Dichotomous data were compared using χ(2) statistic or Fisher's exact test. RESULTS: The final analysis included 214 patients. Prophylactic antibiotics were guideline compliant in 28.5% of patients, and ranged from 10.0% in type 3b fractures to 52.7% in type 1 fractures. The most common reason for non-compliance was the use of guideline recommended coverage that exceeded the suggested duration (71.2%). Patients who received non-compliant therapy required prolonged hospital lengths of stay (6 vs. 3 days, P = 0.0001). The overall incidence of infection was similar regardless of guideline compliance (17.0% vs. 11.5%, P = 0.313). CONCLUSIONS: Prophylactic antibiotics for open fracture frequently exceeded guideline recommendations in duration and spectrum of coverage, especially in more severe fracture types. Non-compliance with EAST recommendations was associated with increased in-hospital morbidity.

Hemopericardium in a patient treated with dabigatran etexilate.

Dabigatran etexilate is a new oral anticoagulant used for the prevention of systemic thromboembolism in patients with atrial fibrillation. Acute bleeding episodes are known to occur with dabigatran etexilate therapy; however, only a few case reports in the literature describe such events. We describe a 70-year-old man treated with dabigatran etexilate for newly diagnosed, nonvalvular atrial fibrillation who developed a large hemopericardium that appeared to be temporally related to dabigatran etexilate administration. One month after starting the drug, an incidental finding of a small pericardial effusion was found on echocardiography. One month later, the patient came to his pulmonologist's office complaining of shortness of breath; a large pericardial effusion was found on a noncontrast computed tomographic scan, and the patient was admitted to the hospital. Laboratory monitoring of his coagulation status was limited due to the lack of assays available to directly monitor the therapeutic effects of dabigatran. The internal laboratory was able to perform a dilute thrombin time (DTT) test as part of a quality improvement project aiming to validate an assay for monitoring patients receiving dabigatran therapy. A DTT was therefore performed in conjunction with routine coagulation assays to evaluate the patient's coagulation status. After pericardiocentesis, the patient recovered without incident and was discharged without anticoagulant therapy. Although the Naranjo adverse reaction probability scale only indicated a possible relationship (score of 1) between the patient's development of hemopericardium and dabigatran etexilate therapy, investigation into the patient's clinical course, comorbidities, and laboratory results led us to conclude that dabigatran etexilate was responsible for the hemopericardium. To our knowledge, this report is the first to describe a case of potentially life-threatening pericardial bleeding that was temporally related to starting dabigatran etexilate therapy. Although we found that the DTT was a viable method of monitoring coagulation status in a patient receiving dabigatran etexilate therapy, the assay lacks approval by the United States Food and Drug Administration, which limits its clinical utility and widespread use at this time. Clinicians should be aware of the potential for life-threatening bleeding with use of this agent and the difficulty associated with monitoring and reversing this therapy in the setting of acute bleeding.

Anticoagulation management around percutaneous bedside procedures: is adjustment required?

BACKGROUND: Percutaneous endoscopic gastrostomy (PEG) and percutaneous dilatational tracheostomy (PDT) are frequently performed bedside in the intensive care unit. Critically ill patients frequently require anticoagulant (AC) and antiplatelet (AP) therapies for myriad indications. There are no societal guidelines proffering strategies to manage AC/AP therapies periprocedurally for bedside PEG or PDT. The aim of this study is to evaluate the management of AC/AP therapies around PEG/PDT, assess periprocedural bleeding complications, and identify risk factors associated with bleeding. METHODS: A retrospective, observational study of all adult patients admitted from October 2004 to December 2009 receiving a bedside PEG or PDT was conducted. Patients were identified by procedure codes via an in-hospital database. A medical record review was performed for each included patient. RESULTS: Four hundred fifteen patients were included, with 187 PEGs and 352 PDTs being performed. Prophylactic anticoagulation was held for approximately one dose before and two doses or less after the procedure. There was wide variation in patterns of holding therapy in patients receiving anticoagulation via continuous infusion. There were 19 recorded minor bleeding events, 1 (0.5%) with PEG and 18 (5.1%) with PDT, with no hemorrhagic events. No association was found between international normalized ratio, prothrombin time, or activated partial thromboplastin time values and bleed risk (p = 0.853, 0.689, and 0.440, respectively). Platelet count was significantly lower in patients with a bleeding event (p = 0.006). CONCLUSIONS: We found that while practice patterns were quite consistent in regard to the management of prophylactic anticoagulation, it varied widely in patients receiving therapeutic anticoagulation. It seems that prophylactic anticoagulation use did not affect bleed risk with PEG/PDT.

Adaptive trial design: its growing role in clinical research and implications for pharmacists.

PURPOSE: Current trends and recent developments in use of adaptive trial design methodology for pharmaceutical research, as well as barriers to wider acceptance and implications for pharmacists, are discussed. SUMMARY: Traditional clinical drug trials typically take many months or years to complete. In contrast, trials incorporating adaptive design elements allow researchers to make midstudy adjustments so that trial objectives are addressed more efficiently. Properly designed adaptive trials can enable researchers to conclude trials of unsuccessful treatments earlier or bring effective drugs to market sooner, improving patient safety and yielding substantial time and cost savings. Challenges and concerns with adaptive trial methodology include inadequate knowledge of adaptive design techniques among health care professionals and increased potential for bias or misinterpretation of trial results stemming from earlier access to data. Over the past decade, U.S. and European regulatory bodies have issued a number of documents to better define acceptable practices for designing, conducting, and reporting the results of adaptive trials, including updated Food and Drug Administration guidance released in 2010. Pharmacists need to stay current with developments in the field to properly assess and interpret trial results. CONCLUSION: Adaptive trial design is an emerging study methodology that allows for design modifications during a study, with the objective of implementing trial data as early as possible for the benefit of patients and the drug development process.

Sedation, analgesia, and delirium in the critically ill patient.

Most critically ill patients receive a myriad of psychoactive medications during their hospital stay. An understanding of the pharmacology of the more commonly used sedative and analgesic therapies enables the clinician to aptly utilize these medications and limit toxicity. A key to the appropriate provision of sedative and analgesic pharmacotherapy is a thorough patient assessment, use of validated monitoring tools, and defined therapeutic goals. Limiting these therapies while optimizing patient comfort has been shown to reduce the duration of mechanical ventilation and reduce intensive care unit (ICU) and hospital length of stay and should be the aim of the multidisciplinary medical team. This review is intended to provide the reader with a fundamental understanding of how to facilitate comfort of the mechanically ventilated critically ill adult patients and how to minimize medication-related toxicities.

Phentolamine continuous infusion in a patient with pheochromocytoma.

PURPOSE: Use of continuous phentolamine infusion therapy for management of serious cardiovascular complications during adrenalectomy for pheochromocytoma is reported. SUMMARY: In preparation for surgical resection of a pheochromocytoma, a 38-year-old woman received outpatient oral therapy with the α-adrenergic-receptor blocker phenoxybenzamine for 25 days with the goal of reducing cardiovascular risks associated with catecholamine surge during surgery. Due to inappropriate dosage adjustment, however, outpatient phenoxybenzamine therapy did not achieve adequate α-adrenergic-receptor blockade; during the laparoscopic resection procedure, the woman developed severe hypertension, leading to cardiac arrest and discontinuation of the operation. After resuscitative measures, the patient was admitted to the surgical intensive care unit for mechanical ventilation, medical management (including intermittent bolus injections of phentolamine and a continuous i.v. infusion of esmolol for control of blood pressure and heart rate), and hemodynamic monitoring; despite those measures, cardiovascular instability persisted during the immediate postoperative period. The day after the abortive surgery attempt, a continuous infusion of phentolamine mesylate (1 mg/hr, adjusted hourly to achieve the blood pressure target) was initiated. Four days after initiation of continuous phentolamine infusion, the patient was deemed to be hemodynamically stable, and the surgery was successfully performed. CONCLUSION: A continuous infusion of phentolamine was used in a patient with pheochromocytoma to control perioperative hypertensive episodes during surgical adrenalectomy.