Dual Neurostimulant Therapy May Optimize Acute Neurorecovery for Severe Traumatic Brain Injuries.

BACKGROUND: Neurostimulants (NS) can be used to treat patients with a traumatic brain injury (TBI) with altered levels of consciousness. We sought to determine if amantadine alone (monotherapy) versus amantadine + methylphenidate (dual therapy) would correlate with better neurorecovery (NR) among acutely hospitalized patients with a severe TBI. METHODS: We performed a retrospective review of adult patients admitted to our level I trauma center from 2016-2019 with a severe TBI. NR was calculated by dividing the difference between admission and discharge Glasgow Coma Scale (GCS) scores by 12. Resulting ratios were used to divide the cohort into two groups: excellent NR (1) and non-excellent NR (<1). RESULTS: A total of 76 patients comprised the cohort; 19.7% (n = 15) had excellent NR. The excellent NR group had a larger proportion of patients receiving dual therapy compared to the non-excellent group (86.7% versus 59%, P = 0.04). In monotherapy (n = 27), amantadine was initiated 13 (8-20) d following injury and treatment lasted 7 (2-16) d. In dual therapy (n = 49), amantadine was initiated 12 (6-19) d following injury and continued for 9 (4-25.5) d. Methylphenidate was initiated 15 (7-20.5) d following injury and continued for 5 (2-13.5) d. After adjusting for confounders, dual versus monotherapy predicted excellent NR (OR 5.4, 95% CI 1.2 - 38.9, P = 0.03). CONCLUSIONS: During the acute hospitalization for a severe TBI, dual NS therapy compared to monotherapy is associated with an increased likelihood of excellent NR. Larger prospective trials are warranted to validate these findings.

Enhanced Renal Clearance in Patients With Hemorrhagic Stroke.

OBJECTIVES: To evaluate enhanced renal clearance over time in patients with aneurysmal subarachnoid hemorrhage or intracerebral hemorrhage via measured creatinine clearance and to compare measured creatinine clearance to creatinine clearance calculated by the Cockcroft-Gault equation and estimated glomerular filtration rate calculated by the Modification of Diet in Renal Diseases equation. DESIGN: Prospective, observational study. SETTING: Neurosciences ICU in a tertiary care academic medical center. PATIENTS: Study participants had an admission diagnosis of aneurysmal subarachnoid hemorrhage or intracerebral hemorrhage, an expected neurosciences ICU length of stay greater than 48 hours, no evidence of renal dysfunction (admission serum creatinine < 1.5 mg/dL), and no history of chronic kidney disease. INTERVENTIONS: Eight-hour urine collections to measure creatinine clearance were collected daily as the primary method of measuring renal function. Creatinine clearance was also calculated using the Cockcroft-Gault equation and estimated glomerular filtration rate was calculated using the Modification of Diet in Renal Disease equation. Enhanced renal clearance was defined as a measured creatinine clearance greater than the calculated creatinine clearance via Cockcroft-Gault and estimated glomerular filtration rate via Modification of Diet in Renal Disease. Augmented renal clearance was defined by a measured creatinine clearance greater than or equal to 130 mL/min/1.73 m. Relevant demographic, clinical, and outcome data were recorded. MEASUREMENTS AND MAIN RESULTS: Fifty aneurysmal subarachnoid hemorrhage patients and 30 intracerebral hemorrhage patients were enrolled, contributing 590 individual measurements. Patients with aneurysmal subarachnoid hemorrhage had a higher mean measured creatinine clearance compared with the mean calculated creatinine clearance based on the Cockcroft-Gault equation (147.9 ± 50.2 vs 109.1 ± 32.7 mL/min/1.73 m; p < 0.0001) and higher mean measured creatinine clearance compared with the mean calculated estimated glomerular filtration rate based on the Modification of Diet in Renal Disease equation (147.9 ± 50.2 vs 126.0 ± 41.9 mL/min/1.73 m; p = 0.04). Ninety-four percent of participants with aneurysmal subarachnoid hemorrhage experienced augmented renal clearance on at least 1 day. In patients with intracerebral hemorrhage, there was a higher mean measured creatinine clearance over the study period compared with the mean calculated creatinine clearance (119.5 ± 57.2 vs 77.8 ± 27.6 mL/min/1.73 m; p < 0.0001) and higher mean measured creatinine clearance compared with the mean calculated estimated glomerular filtration rate based on the Modification of Diet in Renal Disease equation (119.5 ± 57.2 vs 93.0.0 ± 32.8 mL/min/1.73 m; p = 0.02). Fifty percent of participants with intracerebral hemorrhage experienced augmented renal clearance on at least 1 day. CONCLUSIONS: A substantial group of patients with aneurysmal subarachnoid hemorrhage or intracerebral hemorrhage experienced enhanced renal clearance, which may be otherwise unknown to clinicians. Enhanced renal clearance may lead to increased renal solute elimination over what is expected, resulting in subtherapeutic renally eliminated drug concentrations. This may result in underexposure to critical medications, leading to treatment failure and other medical complications.

Vancomycin Pharmacokinetic Parameters in Patients with Hemorrhagic Stroke.

BACKGROUND: Infections are a common medical complication in hemorrhagic stroke patients, with vancomycin commonly used as empiric therapy. The purpose of this study was to evaluate the pharmacokinetic parameters of vancomycin in hemorrhagic stroke patients. METHODS: This was a retrospective study of adult patients with aneurysmal subarachnoid hemorrhage (aSAH) or intracerebral hemorrhage (ICH) admitted between May 2010 and February 2015 who received vancomycin. Predicted pharmacokinetic parameters based on population data were compared with calculated pharmacokinetic parameters based on serum trough concentrations. RESULTS: Eighty aSAH patients and 66 ICH patients met inclusion criteria. In the aSAH group, the mean dosing regimen was 17.6 ± 4 mg/kg every 12 (8-12) h. The mean measured trough concentration was lower than the predicted trough concentration (9.9 ± 4.1 vs. 19 ± 8.7 µg/mL; p < 0.001). The mean calculated elimination rate constant was higher than the predicted value (0.135 ± 0.04 vs. 0.092 ± 0.03 h(-1); p < 0.001), and the mean calculated half-life was lower than predicted (5.7 ± 1.8 vs. 8.3 ± 2.9 h; p < 0.001). In the ICH group, the mean dosing regimen was 15.9 ± 4.3 mg/kg every 12 (8-12) h. Similarly, the mean measured trough concentration was lower than the predicted trough concentration (10.7 ± 4.6 vs. 17.5 ± 8.5 µg/mL; p < 0.001). The mean calculated elimination rate constant was higher than the predicted value (0.106 ± 0.03 vs. 0.079 ± 0.02 h(-1); p < 0.001), and the mean calculated half-life was lower than predicted (7.2 ± 2.3 vs. 9.6 ± 3.2 h; p < 0.001). CONCLUSIONS: Patients with hemorrhagic stroke exhibited pharmacokinetic alterations favoring increased elimination of vancomycin when compared to predicted pharmacokinetic parameters based on population data. This may result in underexposure to vancomycin, leading to treatment failure and other medical complications.

Implementation of the flipped residency research model to enhance residency research training.

PURPOSE: The attainment of fundamental research skills to create and disseminate new knowledge is imperative for the advancement of pharmacy practice. Research training is an important component of postgraduate residency training; however, the traditional model of performing residency research has several limitations that have hindered the ability of residents to complete high-quality research projects. Therefore, our institution developed and implemented the flipped residency research model with the 2013-2014 pharmacy practice residency class. SUMMARY: The flipped residency research model modifies the research timeline to better align research activities with residents' abilities at specific time points during the year. In the 4 years following implementation of the flipped residency research model, our institution found improvements in a number of areas pertaining to the research process compared with an evaluation of the 7 years prior to implementation. A decrease in the number of reviews required from institutional review boards was observed, resulting in improved institutional review board efficiency. The flipped residency research model also addressed limitations surrounding manuscript development and submission, as demonstrated by an improved publication rate. Additionally, residents who participated in the flipped residency research model self-reported increased comfort with research-related abilities associated with study design, implementation, manuscript development and submission, and biostatistics. CONCLUSION: The modified research timeline of the flipped residency research model better aligns research activities with resident experiences and abilities. This realignment has translated to demonstrable impact in the success of residency projects and dissemination of results. Research is needed to investigate the impact of the flipped residency research model on longer term scholarly success.

Prolonged anticoagulation after discontinuation of argatroban and warfarin therapy in an obese patient with heparin-induced thrombocytopenia.

A 32-year-old, morbidly obese African-American woman developed bilateral pulmonary emboli 12 days after undergoing Roux-en-Y gastric bypass surgery. Three days later, after receiving heparin and warfarin, she developed heparin-induced thrombocytopenia type II (HIT-II). An argatroban 1.5-microg/kg/minute infusion was administered for approximately 2.5 days. The patient also received four doses of warfarin, totaling 37.5 mg. The argatroban infusion was discontinued early on hospital day 6, at which time the patient's international normalized ratio (INR) was 4.36 and activated partial thromboplastin time (aPTT) 85.9 seconds. Her INR and aPTT values continued to rise after the argatroban was discontinued and peaked 3 days later at 5.28 and 123.6 seconds, respectively. At this time her platelet count had improved from 139 x 10(3)/mm(3) to 543 x 10(3)/mm(3). No additional warfarin was administered before discharge. On hospital day 11, the patient was discharged home with an INR of 4.12 and an aPTT of 67.1 seconds. Her aPTT and INR values remained elevated for 19 days after receiving her last dose of warfarin and for 20 days after argatroban discontinuation. She experienced no bleeding complications from these supratherapeutic coagulation parameters. She resumed treatment with warfarin as an outpatient and completed a 6-month course of anticoagulation without further incident. Clinicians should be aware that coagulation parameters may remain elevated longer than expected after argatroban discontinuation in certain patients taking concomitant warfarin. Patients with liver dysfunction and obesity appear most likely to be affected.

The Role of Statin Therapy in Hemorrhagic Stroke.

The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are the most widely utilized class of cholesterol-lowering agents, carrying multiple indications for both primary and secondary cardiovascular risk reduction. Concern was raised by previously published post hoc analyses and observational studies that noted an increased risk of hemorrhagic stroke in patients receiving a statin. Subsequent studies have demonstrated conflicting results regarding the role of statin therapy on hemorrhagic stroke risk and patient outcomes. New evidence suggests that statins taken prior to or continued during admission for intracerebral hemorrhage (ICH) may be associated with positive outcomes. Evidence also suggests deleterious outcomes resulting from the abrupt discontinuation of statins upon hospital admission for multiple disease states including ICH. Conflicting data also exist for the use of statins following aneurysmal subarachnoid hemorrhage (aSAH). Recent evidence suggests statins started during admission for aSAH confer no additional benefit in reducing delayed ischemic neurologic deficits despite initial positive results. Larger scale evaluation of the role of statin therapy following hemorrhagic stroke is warranted. The available literature is reviewed to provide guidance for therapeutic decision making.

The practice of venous thromboembolism prophylaxis in the major trauma patient.

BACKGROUND: The incidence of venous thromboembolism (VTE) without prophylaxis is as high as 80% after major trauma. Initiation of prophylaxis is often delayed because of concerns of injury-associated bleeding. As the effect of delays in the initiation of prophylaxis on VTE rates is unknown, we set out to evaluate the relationship between late initiation of prophylaxis and VTE. METHODS: Data were derived from a multicenter prospective cohort study evaluating clinical outcomes in adults with hemorrhagic shock after injury. Analyses were limited to patients with an Intensive Care Unit length of stay >or=7 days. The rate of VTE was estimated as a function of the time to initiation of pharmacologic prophylaxis. A multivariate stepwise logistic regression model was used to evaluate factors associated with late initiation. RESULTS: There were 315 subjects who met inclusion criteria; 34 patients (11%) experienced a VTE within the first 28 days. Prophylaxis was initiated within 48 hours of injury in 25% of patients, and another one-quarter had no prophylaxis for at least 7 days after injury. Early prophylaxis was associated with a 5% risk of VTE, whereas delay beyond 4 days was associated with three times that risk (risk ratio, 3.0, 95% CI [1.4-6.5]). Factors associated with late (>4 days) initiation of prophylaxis included severe head injury, absence of comorbidities, and massive transfusion, whereas the presence of a severe lower extremity fracture was associated with early prophylaxis. CONCLUSIONS: Clinicians are reticent to begin timely VTE prophylaxis in critically injured patients. Patients are without VTE prophylaxis for half of all days within the first week of admission and this delay in the initiation of prophylaxis is associated with a threefold greater risk of VTE. The relative risks and benefits of early VTE prophylaxis need to be defined to better direct practice in this high-risk population.