Impact of an emergency medicine pharmacist on door to needle alteplase time and patient outcomes in acute ischemic stroke.

PURPOSE: Time is a critical metric in the emergency department (ED) for acute ischemic stroke and thrombolytic therapy. National guidelines have emphasized tracking time from stroke onset to treatment and decreasing door to needle (DTN) time [1, 2]. Multidisciplinary teamwork is encouraged but, there is limited evidence demonstrating the value of the pharmacist on the stroke response team. The goal of this study is to compare DTN times in the ED with or without a pharmacist at bedside and examine the impact on subsequent patient outcomes. METHODS: This was a single-center retrospective cohort study. Investigators identified patients who presented to the ED between August 2016 - May 2020 with signs of ischemic stroke and subsequently received intravenous alteplase. Patients were excluded if they refused alteplase or received alteplase off-campus before being transferred. Pharmacist documentation of clinical interventions was used to identify participation on the stroke response team. The primary outcome was median DTN time. Secondary outcomes included severity of deficits measured by the National Institutes of Health Stroke Scale (NIHSS), hospital length of stay (LOS), 90-day Modified Rankin Scale (mRS), incidence of intracranial hemorrhage (ICH), and inpatient all-cause mortality. RESULTS: Of the 164 patients included, 31 had an emergency medicine pharmacist at bedside (EMP group) and 133 did not (No EMP group). The median DTN time was significantly shorter at 35 min EMP [interquartile range (IQR) 29-44] vs 42 min No EMP [IQR 34-55]; p = 0.003. The number of cases achieving a DTN time of 30 min or less was significantly higher when a pharmacist was involved (35.5% vs.16.5%; p = 0.018) as well as the number of patients receiving alteplase within 45 min (80.7% vs. 57.1%; p = 0.015). NIHSS scores at discharge were lower in the EMP group (2 [IQR 0-5] vs. 4 [IQR 0-8.25]; p = 0.049). In patients with magnetic resonance imaging (MRI) confirmed stroke, a difference was not observed in the secondary outcomes. CONCLUSION: Patients with an emergency medicine pharmacist as part of their stroke response team had significantly lower DTN times. A higher proportion of these cases met benchmark DTN times less than 45 min and 30 min. An emergency medicine pharmacist on a stroke response team has the potential to improve patient care.

Validation of an acute ischemic stroke model: does diffusion-weighted imaging lesion volume offer a clinically significant improvement in prediction of outcome?

BACKGROUND AND PURPOSE: Prediction models for ischemic stroke outcome have the potential to contribute prognostic information in the clinical and/or research setting. The importance of diffusion-weighted magnetic resonance imaging (DWI) in the prediction of clinical outcome, however, is unclear. The purpose of this study was to combine acute clinical data and DWI lesion volume for ischemic stroke patients to determine whether DWI improves the prediction of clinical outcome. METHODS: Patients (N=382) with baseline DWI data from the Glycine Antagonist In Neuroprotection and citicoline (010 and 018) trials were used to develop the prediction models by multivariable logistic regression. Data from prospectively collected patients (N=266) from the Acute Stroke Accurate Prediction Study were used to externally validate the model equations. The models predicted either full recovery or nursing home-level disability/death, as defined by the National Institutes of Health Stroke Scale, Barthel Index, or modified Rankin Scale. RESULTS: The full-recovery models with DWI lesion volume had areas under the receiver operating characteristic curves (AUCs) of 0.799 to 0.821, and those without DWI lesion volume had AUCs of 0.758 to 0.798. The nursing home-level disability/death models with DWI had AUCs of 0.832 to 0.882, and those without DWI had AUCs of 0.827 to 0.867. All models had mean absolute errors < or =0.4 for calibration. CONCLUSIONS: All 12 models had excellent discrimination and calibration, with 8 of 12 meeting prespecified performance criteria (AUC > or =0.8, mean absolute error < or =0.4). Although DWI lesion volume significantly increased model explanatory power, the magnitude of increase was not large enough to be clinically important.

Experimental estimates of the constants relating signal change to contrast concentration for cerebral blood volume by T2* MRI.

Estimates of cerebral blood volume (CBV) obtained from dynamic contrast T2(*)-weighted magnetic resonance imaging (MRI) tend to be significantly higher than values obtained by other methods. This may relate to the common assumption that the proportionality constants relating signal change to contrast concentration are equal in tissue and artery. To test this hypothesis and provide estimates for the ratio of those proportionality constants, the authors compared measurements of CBV by both MRI and computed tomography (CT) scans in nine healthy volunteers obtained using identical kinetic paradigms for the two imaging modalities. Both boluses and infusions of contrast were studied. Measurements were made in nine anatomic regions of interest of the cerebral hemispheres bilaterally. Cerebral blood volume values obtained by CT were generally lower than those obtained by MRI, especially in the cerebral cortex. As a result, the calculated values of the ratios of proportionality constants relating signal change to concentration in tissue and artery after bolus injections were significantly less than 1 in cortex (0.69) and white matter (0.76), although not in deep gray matter structures (0.87). Values of the ratios based on infusion measurements were closer to 1. In addition, CBV measurement errors with bolus MRI were significantly larger than those observed with infusion MRI or by CT. The reasons that the constants differ from 1 and for the larger variance of bolus MRI are discussed in terms of the T2* signal mechanisms. These studies help define the magnitude by which CBV is overestimated with typical T2*-weighted perfusion imaging. Infusion measurements of CBV can reduce the variance intrinsic to T2* MRI and lessen the likelihood of type II error.

Effects of carotid or vertebrobasilar stent placement on cerebral perfusion and cognition.

INTRODUCTION: There are no well-established physiologic or neuropsychological criteria for identifying which patients with stenosis of the cervicocerebral vessels are at high risk of stroke or cognitive impairment. Our purpose was to evaluate changes in cognitive performance and cerebral perfusion associated with endovascular stent placement of the cervicocerebral vessels. METHODS: A consecutive series of 20 patients, 31-88 years of age, who underwent 21 stent procedures for arterial stenosis (10 extracranial carotid stents [ECS], four intracranial carotid stents [ICS], and seven extra- or intracranial vertebrobasilar stents [VBS]) was investigated retrospectively. All patients were evaluated with CT or MR perfusion studies both before and after stent placement. Cognitive response after stent placement was evaluated by using an informant questionnaire. RESULTS: In patients with anterior circulation stenoses (ECS and ICS group), 11 of 14 (79%) had a baseline perfusion abnormality and all 11 patients showed improved perfusion after stent placement. Four of seven (57%) patients with posterior circulation stenoses (VBS group) had a baseline perfusion abnormality and two of the four patients showed improved perfusion after stent placement. Degree of stenosis was the strongest predictor of the presence of a baseline perfusion abnormality (P = .03). Fifteen of 19 (79%) of the patients showed improved cognitive scores after stent placement. Among patients with improvement in perfusion after stent placement, 11 of 13 (85%) had improved cognitive scores. Improved perfusion after stent placement was a significant predictor of cognitive improvement (P = .04). Patients who were stented on an elective basis demonstrated greater improvement in cognition as compared with patients stented urgently (P = .01). CONCLUSION: Endovascular stent placement of the cervicocerebral vessels can safely and effectively resolve cerebral perfusion abnormalities. Improvement in perfusion parameters is associated with cognitive improvement. Larger, blinded, prospective studies are needed to confirm these preliminary observations.

Changes in plasma homocyst(e)ine in the acute phase after stroke.

BACKGROUND AND PURPOSE: Elevated plasma homocyst(e)ine [H(e)] concentration has been associated with an increased risk of stroke. Although the literature suggests that H(e) increases from the acute to the convalescent phase after a stroke, it is not known whether H(e) changes within the acute period. METHODS: A prospective, multicenter study was conducted to examine changes in H(e) during the 2 weeks after an incident stroke. Blood samples were collected at days 1, 3, 5, 7, and between 10 and 14 days after the stroke. RESULTS: Seventy-six participants (51 men) were enrolled from 9 sites from February 1997 through June 1998. Mean age was 65.6 years, and subjects had at least two H(e) measurements. The estimated mean H(e) level at baseline was 11.3+/-0.5 micromol/L, which increased consistently to a mean of 12.0+/-0.05, 12.4+/-0.5, 13.3+/-0.5, and 13.7+/-0.7 micromol/L at days 3, 5, 7, and 10 to 14, respectively. The magnitude of the change in H(e) was not affected by age, sex, smoking status, alcohol use, history of hypertension or diabetes, or Rankin Scale Score. CONCLUSIONS: ; These data suggest that the clinical interpretation of H(e) after stroke and the eligibility for clinical trials assessing treatment for elevated H(e) levels require an adjustment in time since stroke to properly interpret the observed H(e) levels.

Calcium compartments in brain.

Excellent progress has been made toward understanding the physiology and pharmacology of specific calcium-related cellular processes of the brain, but few studies have provided an integrated view of brain calcium kinetics. To further the knowledge of the size and binding properties of brain calcium compartments, the authors have conducted a series of experiments in hippocampal brain slices exposed to high and low extracellular calcium. Slices were incubated in buffers containing 0.001 to 4.5 mmol/L calcium for up to 75 minutes. Slice calcium content was analyzed by three methods: exchange equilibrium with 45Ca, synchrotron-radiation-induced x-ray emission, and inductively coupled plasma. Data were analyzed using a model based on a Langmuir isotherm for two independent sites, with additional extracellular and bound compartments. In parallel experiments, altered low calcium had no effect on slice histology and only mild effects on slice adenylates. When combined with prior 45Ca and fluorescent probe binding experiments, these results suggest that there are at least five kinetically distinct calcium compartments: (1) free extracellular (approximately 10%); (2) loosely associated extracellular plasma membrane (approximately 55%); (3) intracellular compartment with moderate avidity (approximately 17%); (4) tightly bound, nonexchangeable intracellular compartment ( approximately 15%); and (5) free cytoplasmic (<0.01%). If only the third compartment is considered a potential calcium buffer, then the buffering ratio is calculated to be approximately 2,700:1, but if the second compartment is also included, then the buffering ratio would be approximately 13,000:1. This may explain the wide range of estimates observed by fluorescent probe studies.

Edema after intracerebral hemorrhage: correlations with coagulation parameters and treatment.

OBJECT: Development of edema is known to contribute to poor outcome after spontaneous intracerebral hemorrhage (ICH). Recent research has identified thrombin as a key mediator in the development of edema in animal models; however, little has been published correlating the coagulation cascade and edema in humans. METHODS: In this retrospective clinical study of 80 patients with spontaneous supratentorial ICH, the authors sought to identify factors associated with edema development and outcome, including lesion imaging parameters, anticoagulant use, international normalized ratio and platelet count on hospital admission, and treatment with mannitol and steroid medications. A multivariate model was used to identify edema volume, use of mannitol, elevated blood glucose, and the presence of intraventricular hemorrhage as predictors of poor outcome at the time patients were discharged from the hospital. The authors developed a quadratic model for predicting edema volume against time by using a random coefficients model, and found that edema peaks between Days 5 and 6 after onset of ICH. The volume of the hemorrhage and the platelet count correlated significantly with edema volume within the first 24 hours post-ICH in the multiple regression analysis (p < 0.0001, r2 = 0.75). Edema growth during the first 5 days post-ICH also correlated with the platelet count, with an increasing platelet count associated with an increasing growth of edema (p = 0.0013). CONCLUSIONS: The authors propose that factors released from activated platelets at the site of hemorrhage, for example vascular endothelial growth factor, may interact with thrombin to increase vascular permeability and contribute to the development of edema.

A stroke scale for emergency triage.

OBJECTIVES: The National Institutes of Health Stroke Scale (NIHSS) is a widely used scale for managing acute ischemic stroke but may be too complicated for health care providers not focused on stroke care. We devised the Emergency Triage Stroke Scale (ETSS) to specifically predict the NIHSS when used by emergency medical service (EMS) providers and triage nurses, who do not have subspecialty training in the neurology of stroke. METHODS: This scale was designed to match the maximum score in each of the 6 domains of the NIHSS, using information from the routine assessments performed by EMS providers. In all, 48 consecutive patients presenting with symptoms of acute ischemic stroke were assessed. Emergency department (ED) residents, ED nurses, and EMS personnel applied the ETSS while ED attendings and stroke team physicians performed the NIHSS. Scores were analyzed using multivariate analysis of variance, linear regression analysis, the Spearman correlation coefficient, the K statistic for reproducibility, and post hoc reviews. RESULTS: There was excellent agreement between residents and nurses using the ETSS and a strong correlation between the NIHSS and the ETSS performed by residents or nurses. EMS providers performed well but tended to overestimate the NIHSS of sicker patients. Domain scores followed the same general pattern. All ETSS raters showed excellent ability to predict candidacy for thrombolytic therapy based on a predicted NIHSS score of 4 to 23. CONCLUSIONS: The ETSS is a simplified prehospital stroke scale that correlates well with the NIHSS. Clearer instructions with a modest increase in education are likely to allow EMS personnel to achieve similar results.

Nonparametric Residue Analysis of Dynamic PET Data With Application to Cerebral FDG Studies in Normals.

Kinetic analysis is used to extract metabolic information from dynamic positron emission tomography (PET) uptake data. The theory of indicator dilutions, developed in the seminal work of Meier and Zierler (1954), provides a probabilistic framework for representation of PET tracer uptake data in terms of a convolution between an arterial input function and a tissue residue. The residue is a scaled survival function associated with tracer residence in the tissue. Nonparametric inference for the residue, a deconvolution problem, provides a novel approach to kinetic analysis-critically one that is not reliant on specific compartmental modeling assumptions. A practical computational technique based on regularized cubic B-spline approximation of the residence time distribution is proposed. Nonparametric residue analysis allows formal statistical evaluation of specific parametric models to be considered. This analysis needs to properly account for the increased flexibility of the nonparametric estimator. The methodology is illustrated using data from a series of cerebral studies with PET and fluorodeoxyglucose (FDG) in normal subjects. Comparisons are made between key functionals of the residue, tracer flux, flow, etc., resulting from a parametric (the standard two-compartment of Phelps et al. 1979) and a nonparametric analysis. Strong statistical evidence against the compartment model is found. Primarily these differences relate to the representation of the early temporal structure of the tracer residence-largely a function of the vascular supply network. There are convincing physiological arguments against the representations implied by the compartmental approach but this is the first time that a rigorous statistical confirmation using PET data has been reported. The compartmental analysis produces suspect values for flow but, notably, the impact on the metabolic flux, though statistically significant, is limited to deviations on the order of 3%-4%. The general advantage of the nonparametric residue analysis is the ability to provide a valid kinetic quantitation in the context of studies where there may be heterogeneity or other uncertainty about the accuracy of a compartmental model approximation of the tissue residue.

Association of diabetes, homocysteine, and HDL with cognition and disability after stroke.

OBJECTIVE: To delineate factors associated with cognitive function following stroke and test the hypothesis that vascular risk factors associated with oxidative stress impair recovery. METHOD: We performed a post hoc analysis of the extensive longitudinal database from the 3,680 subjects (over 35 years old) entered between 1996 and 2003 into the Vitamin Intervention for Stroke Prevention trial using a linear mixed effects model. The primary outcome variables were scores on the Mini-Mental State Examination (MMSE) and modified Rankin Scale (mRS). RESULTS: MMSE and mRS gradually improved during the 2-year follow-up period. Increased age and nonwhite race, recurrent stroke, diabetes mellitus, left hemisphere cortical lesions, and values of high-density lipoprotein and homocysteine were independent predictors of less successful cognitive recovery. A strong interaction between homocysteine and age indicated a threshold effect beginning in the late 50s. No vitamin treatment effects were identified. Similar factors were identified for recovery of disability as assessed by the mRS, although there were qualitative and quantitative differences. CONCLUSIONS: The finding that diabetes, high-density lipoprotein, and homocysteine predict poorer cognitive function and greater disability after stroke is consistent with the hypothesis that metabolic stress plays a significant role in the poststroke period.

Cerebral blood volume measurements by rapid contrast infusion and T2*-weighted echo planar MRI.

Cerebral blood volume (CBV) provides information complementary to that of cerebral blood flow in cerebral ischemia, tumors, and other conditions. We have developed an alternative theory and method for measuring CBV based on dynamic imaging by MRI or CT during a short contrast infusion. This method avoids several limitations of traditional approaches that involve waiting for steady state or measuring the area under the curve (AUC) during bolus contrast injection. Anesthetized dogs were studied by T2*-weighted echo planar imaging during gadolinium-DTPA infusions lasting 30-60 sec. CBV was calculated from the ratio of the signal changes in tissue and artery. Method responsiveness was compared to AUC measurements using the vasodilator acepromazine. The ratio of signal change in tissue to that in artery rapidly approached an asymptotic value even while the amount of contrast in artery continued to increase. Using 30-sec infusions, the mean (+/- SD) of CBV for control animals was 3.6 +/- 0.9 ml blood/100 g tissue in gray matter and 2.3 +/- 0.8 ml blood/100 g tissue in white matter (ratio = 1.6). Acepromazine increased CBV to 5.7 +/- 1.5 ml blood/100 g tissue in gray matter and 3.1 +/- 0.8 ml blood/100 g tissue in white matter (ratio = 2.0). AUC measurements after bolus injection yielded similar values for control animals but failed to demonstrate any change after acepromazine. It is possible to measure CBV using dynamic MRI or CT during 30-60-sec contrast infusions. This method may be more sensitive to changes in CBV than traditional AUC methods.