Mitchell Daley

Implications of Augmented Renal Clearance on Drug Dosing in Critically Ill Patients: A Focus on Antibiotics.

Augmented renal clearance (ARC) has been reported in approximately 30–65% of patients in the intensive care unit (ICU) despite the presence of a normal serum creatinine concentration. In certain ICU patient populations (e.g., patients with sepsis or trauma), the incidence increases to roughly 50–85%. Risk factors for ARC include the following: age younger than 50–55 years, male sex, higher diastolic blood pressure, fewer comorbidities, and a lower Acute Physiology and Chronic Health Evaluation II (APACHE II) or modified Sequential Organ Failure Assessment (SOFA) score at ICU admission. In addition, patient populations with the highest reported incidence of ARC include those with major trauma, sepsis, traumatic brain injury, subarachnoid hemorrhage, and central nervous system infection. Due to the high incidence of ARC in patients with a normal serum creatinine concentration, clinicians should consider screening ICU patients deemed high risk by using the ARC scoring system or the identification and assessment algorithm provided in this review. In addition, an 8‐hour continuous urine collection should be considered to assess a measured creatinine clearance for evaluating the necessity of medication dosage adjustments. There is a clear association between ARC and subtherapeutic antibiotic concentrations as well as literature suggesting worse clinical outcomes; thus, the risk of underdosing antibiotics in a patient with ARC could increase the risk of treatment failure. This review examines strategies to overcome ARC and summarizes current pharmacokinetic and pharmacodynamic literature in patients with ARC in an effort to provide dosing guidance for this patient population.

Comparison of Clinical Outcomes in Nonintubated Patients with Severe Alcohol Withdrawal Syndrome Treated with Continuous‐Infusion Sedatives: Dexmedetomidine versus Benzodiazepines

To compare efficacy and safety outcomes in nonintubated patients with severe alcohol withdrawal syndrome (AWS) who required a continuous infusion of a benzodiazepine or dexmedetomidine in addition to standard medical therapy for AWS.

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.

Thromboelastogram does not detect pre-injury anticoagulation in acute trauma patients

Purpose: Thromboelastography (TEG) has been recommended to characterize post‐traumatic coagulopathy, yet no study has evaluated the impact of pre‐injury anticoagulation (AC) on TEG variables. We hypothesized patients on pre‐injury AC have a greater incidence of coagulopathy on TEG compared to those without AC. Methods: This retrospective chart review evaluated all trauma patients admitted to an urban, level one trauma center from February 2011 to September 2014 who received a TEG within the first 24 h. Patients were classified as receiving pre‐injury AC or no AC if their documented medications prior to admission included warfarin, dabigatran, or anti‐Xa (aXa) inhibitors (apixaban or rivaroxaban). The presence of coagulopathy on TEG or conventional assays was defined by exceeding local laboratory reference standards. Results: A total of 54 patients were included (AC, n = 27 [warfarin n = 13, dabigatran n = 6, aXa inhibitor n = 8] vs. no AC, n = 27). Baseline characteristics were similar between groups, including age (72 ± 13 years vs. 72 ± 15; p = 0.85), male gender (70% vs. 74%; p = 0.76) and blunt mechanism of injury (100% vs. 100%; p = 1). There was no difference in the number of patients determined to have coagulopathy on TEG (no AC 11% vs. AC 15%; p = 0.99). Conventional tests, including the international normalized ratio (INR) and activated partial thromboplastin time (aPTT), identified coagulopathy in a high proportion of anti‐coagulated patients (no AC 22% vs. AC 85%; p < 0.01). Conclusion: TEG has limited clinical utility to evaluate the presence of pre‐injury AC. Traditional markers of drug induced coagulopathy should guide reversal decisions.

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:

Background: Currently, a lack of standardization exists in norepinephrine dosing units, the first-line vasopressor for septic shock. Timely achievement of goal mean arterial pressure (MAP) is dependent on optimal vasopressor dosing. Objective: To determine if weight-based dosing (WBD) of norepinephrine leads to earlier time to goal MAP compared with non-WBD in obese patients with septic shock. Methods: This was a retrospective, multicenter cohort study. Patients had a body mass index (BMI) ≥30 kg/m2 and received norepinephrine for septic shock with either a non-WBD strategy (between December 2009 and January 2013) or WBD strategy (between January 2013 and December 2015). The primary outcome was time to goal MAP. Secondary outcomes were norepinephrine duration, dose requirements, and development of treatment-related complications. Results: A total of 287 patients were included (WBD 144; non-WBD 143). There was no difference in median time to goal MAP (WBD 58 minutes, interquartile range [IQR] = 16.8-118.5, vs non-WBD 60 minutes, IQR = 17.5-193.5; P = 0.28). However, there was a difference in median cumulative norepinephrine dose (WBD 12.6 mg, IQR = 4.9-45.9, vs non-WBD 10.5 mg, IQR = 3.9-25.6; P = 0.04) and time to norepinephrine discontinuation (WBD 33 hours, IQR = 15-69, vs non-WBD 27 hours, IQR = 12-51; P = 0.03). There was no difference in rates of atrial fibrillation (WBD 15.3% vs non-WBD 23.7%; P = 0.07) or mortality (WBD 23.6% vs non-WBD 23.1%; P = 0.92). Conclusion: WBD of norepinephrine does not achieve time to goal MAP earlier in obese patients with septic shock. However, WBD may lead to higher norepinephrine cumulative dose requirements and prolonged time until norepinephrine discontinuation.

Optimization of intelligent infusion pump technology to minimize vasopressor pump programming errors

ABSTRACT Background: There is a lack of data evaluating the impact of hard limit implementation into intelligent infusion pump technology (IIPT). The purpose of this study was to determine if incorporation of vasopressor upper hard limits (UHL) into IIPT increases efficacy of alerts by preventing pump programming errors. Methods: Retrospective review from five hospitals within a single healthcare network between April 1, 2013 and May 31, 2014. A total of 65,680 vasopressor data entries were evaluated; 19,377 prior to hard limit implementation and 46,303 after hard limit implementation. The primary outcome was the percent of effective alerts. The secondary outcome was the proportional dose increase from the soft limit provided. Results: A reduction in alert rate occurred after incorporation of hard limits to the IIPT drug library (pre-UHL 4.7% vs. post-UHL 4.0%) with a subsequent increase in the number of errors prevented as represented by a higher effective alert rate (pre-UHL 23.0% vs. post-UHL 37.3%; p < 0.001). The proportional dose increase was significantly reduced (pre-UHL 188% ± 380%] vs. post-UHL 95% ± 128%; p < 0.001). Conclusions: Incorporation of UHLs into IIPT in a multi-site health system with varying intensive care unit and emergency department acuity increases alert effectiveness, reduces dosing errors, and reduces the magnitude of dosing errors that reach the patient.

Are first-generation cephalosporins obsolete? A retrospective, non-inferiority, cohort study comparing empirical therapy with cefazolin versus ceftriaxone for acute pyelonephritis in hospitalized patients

OBJECTIVES Literature is lacking regarding the utilization of first-generation cephalosporins for the treatment of acute pyelonephritis. The aim of this study was to determine whether cefazolin is non-inferior to ceftriaxone for the empirical treatment of acute pyelonephritis in hospitalized patients. The primary outcome included a composite of symptomatic resolution plus either defervescence at 72 h or normalization of serum white blood cell count at 72 h (non-inferiority margin 15%). Secondary outcomes included length of stay and 30 day readmission. A subgroup analysis of the composite outcome was also conducted for imaging-confirmed pyelonephritis. METHODS This was a retrospective, non-inferiority, multicentre, cohort study comparing cefazolin versus ceftriaxone for the empirical treatment of acute pyelonephritis in hospitalized patients. RESULTS Overall, 184 patients received one of the two treatments between July 2009 and March 2015. The composite outcome was achieved in 80/92 (87.0%) in the cefazolin group versus 79/92 (85.9%) in the ceftriaxone group (absolute difference 1.1%, 95% CI -11.1% to 8.9%, P = 0.83), meeting the pre-defined criteria for non-inferiority. The composite outcome for patients with imaging-confirmed pyelonephritis was achieved in 46/56 (82.1%) versus 42/50 (84.0%) for the cefazolin group and the ceftriaxone group, respectively (absolute difference 1.9%, 95% CI -12.8% to 16.5%, P = 0.80). Additionally, there were no statistically significant differences in length of stay or 30 day readmission for cystitis or pyelonephritis. CONCLUSIONS Cefazolin was non-inferior to ceftriaxone with regard to clinical response for the treatment of hospitalized patients with acute pyelonephritis in this study. No difference was observed for length of stay or 30 day readmission.

Clinical Utility of Methicillin-Resistant Staphylococcus aureus (MRSA) Nasal Screening for Antimicrobial Stewardship: A Review of Current Literature

Significant clinical and financial consequences are associated with both inadequate and unnecessary exposure to broad‐spectrum antibiotics. As such, antimicrobial stewardship programs seek objective, reliable, and cost‐effective tests to identify patients at highest or lowest risk for drug‐resistant organisms to guide empirical antimicrobial selection. Use of methicillin‐resistant Staphylococcus aureus (MRSA) nasal screening to rule out MRSA in lower respiratory tract infections has led to significant reductions in duration of vancomycin therapy. The clinical utility of MRSA nasal screening in other types of infection remains less clear. This review describes the performance of MRSA nasal screening in predicting MRSA infection, highlights practical considerations for use of MRSA nasal screening, and provides guidance for incorporating MRSA nasal screening into clinical practice. With a high negative predictive value when the prevalence of MRSA is low, MRSA nasal screening is a valuable antimicrobial stewardship tool with potential applications beyond lower respiratory tract infections. In appropriately selected patients, negative MRSA nasal screening can prevent initiation or guide discontinuation of anti‐MRSA therapy. Antimicrobial stewardship programs should develop institutional guidelines to promote proper use of MRSA nasal screening. Pharmacists are well positioned to assist with education, interpretation, and application of MRSA nasal screening results.

Antibiotic and Antifungal Therapy in the ICU

Few diseases challenge the critical care provider as frequent as the prevention or treatment of an infection. Patient outcomes are determined based on the interplay of an anti-infective drug, host, and pathogen. Although a complete discussion of each of these components is outside of the scope of this chapter, general knowledge of antimicrobial pharmacokinetics-pharmacodynamics and associated alterations in critically ill will be reviewed. Specific indications for antimicrobials will be discussed in other sections of this book. The remaining purpose of this chapter is to understand the pharmacologic properties of commonly used antibiotics and antifungals prescribed in the ICU, with an emphasis on mechanism of action, spectrum of activity, clinical pearls, and strategies to optimize therapy organized by drug classes.

564: CHARACTERIZING THE USE OF 4-FACTOR PROTHROMBIN COMPLEX CONCENTRATE

www.ccmjournal.org Critical Care Medicine • Volume 46 • Number 1 (Supplement) Learning Objectives: Off-label medication use is common in critically ill patients in the United States. Kcentra® is a 4-factor prothrombin complex concentrate (4PCC) approved for warfarin reversal in patients with acute major bleeding or need for urgent surgery. As with other procoagulants, non-approved use occurs. However, there is a paucity of data describing the real-life utilization of 4PCC. The aim of this snapshot analysis is to characterize the FDA approved and non-approved uses of 4PCC in 5 medical centers over a specified period of time. Methods: This multi-center retrospective analysis of 4PCC use in critically ill patients occurred from January 1, 2016 through December 31, 2016. All adult ICU patients who received 4PCC at a participating center were eligible for inclusion. Data included: demographics, 4PCC dose, coagulation parameters before and after 4PCC administration, blood product and hemostatic agent administration as well as incidence of thromboembolic events (TEEs). Results: A total of 104 patients from 5 institutions were included. Anticoagulant use prior to 4PCC was present in 80 patients (76.9%), and 63 (78.8%) were warfarin. The type of bleeding includes: intracranial (n = 33), trauma (n = 23), cardiac surgery (n = 12), GI (n = 12), musculoskeletal (n = 2), other (n = 13). The mean 4PCC dose was 30 IU/kg. The median INR prior to and 12–24 hours following 4PCC was 2.2 and 1.5, respectively. Fortyeight patients (46.2%) received off-label 4PCC which included: massive hemorrhage on novel oral anticoagulants (29.2%), cardiac surgery (25%), acute coagulopathy (20.8%), non-cardiac surgery (10.4%), or other (14.6%). Of 92 patients, excellent and good hemostatic efficacy was achieved in 21 and 49 patients, respectively. Of the patients who achieved excellent hemostatic efficacy, 15 received 4PCC on-label and 6 received 4PCC off-label (p < 0.05). There were 11 TEEs. Conclusions: Although the predominant use of 4PCC was on label, many patients received offlabel 4PCC during the index study period. Further study is needed to identify the relative clinical impact, risk and cost associated with real-life utilization of 4PCC.