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OBJECTIVES: Postconcussion symptoms (PCS) are a common complication of mild traumatic brain injury (TBI). Currently, there is no validated clinically available method to reliably predict at the time of injury who will subsequently develop PCS. The purpose of this study was to determine if PCS following mild TBI can be predicted during the initial presentation to an emergency department (ED) using a novel robotic-assisted assessment of neurologic function. METHODS: All patients presenting to an urban ED with a chief complaint of head injury within the preceding 24 hours were screened for inclusion from March 2013 to April 2014. The enrollment criteria were as follows: 1) age of 18 years or greater, 2) ability and willingness to provide written informed consent, 3) blunt head trauma and clinical diagnosis of isolated mild TBI by the treating physician, and 4) blood alcohol level of <100 mg/dL. Eligible mild TBI patients were enrolled and their neuromotor function was assessed in the ED using a battery of five tests that cover a range of proprioceptive, visuomotor, visuospatial, and executive function performance metrics. At 3 weeks postinjury, participants were contacted via telephone to complete the Rivermead Post-Concussion Symptoms Questionnaire to assess the presence of significant PCS. RESULTS: A total of 66 mild TBI patients were enrolled in the study with 42 of them completing both the ED assessment and the follow-up; 40 patients were included in the analyses. The area under the receiver operating characteristic curve (AUC) for the entire test battery was 0.72 (95% confidence interval [CI] = 0.54 to 0.90). The AUC for tests that primarily measure visuomotor and proprioceptive performance were 0.80 (95% CI = 0.65 to 0.95) and 0.71 (95% CI = 0.53 to 0.89), respectively. CONCLUSIONS: The robotic-assisted test battery has the ability to discriminate between subjects who developed PCS and those who did not. Additionally, poor visuomotor and proprioceptive performance were most strongly associated with subsequent PCS.

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BACKGROUND: Incidence of methicillin-resistant Staphylococcus aureus (MRSA) is increasing in complicated skin and skin structure infection (cSSSI) presenting to emergency departments (EDs). Treatment is heterogeneous and can require inpatient admission to an observation unit (OU). Vancomycin is commonly used in the OU for treatment, but increasing MRSA resistance to vancomycin suggests the need for alternatives. Daptomycin is an alternative but it is not known how it compares with vancomycin. OBJECTIVE: This study tested the hypothesis that daptomycin is noninferior to vancomycin for the treatment of cSSSI in an OU, using a relative risk (RR) of 1.3 as the noninferiority limit. METHODS: Subjects admitted to an ED-based OU with a diagnosis of cSSSI were eligible. Consenting subjects were randomized 1:1 to intravenous (i.v.) vancomycin at 15 mg/kg dosing every 12 h or i.v. daptomycin at 4 mg/kg once. Subjects were followed until they met objective criteria for discharge home or hospital admission. Discharged patients were prescribed 10-14 days of oral cephalexin and trimethoprim-sulfamethoxazole, or clindamycin if allergic to either of these medications. The primary endpoint was meeting objective discharge criteria with no change in antibiotic therapy or return to the ED for the same cellulitis within 30 days of OU discharge. RESULTS: There were 100 patients enrolled. RR for satisfying the endpoint was 1.07 (95% confidence interval 0.58-1.98) for daptomycin compared with vancomycin. Hospital admission rates were 36% and 32% for daptomycin and vancomycin treatment, respectively. CONCLUSION: Daptomycin was not inferior to vancomycin in the treatment of cSSSI in an OU.

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UNLABELLED: The objective of this paper is to demonstrate the effective deployment of a robotic assessment tool for the evaluation of mild traumatic brain injury (mTBI) patients in a busy, resource-constrained, urban emergency department (ED). METHODS: Functional integration of new robotic technology for research in the ED presented several obstacles that required a multidisciplinary approach, including participation from electrical and computer engineers, emergency medicine clinicians, and clinical operations staff of the hospital. Our team addressed many challenges in deployment of this advanced technology including: 1) adapting the investigational device for the unique clinical environment; 2) acquisition and maintenance of appropriate testing space for point-of-care assessment; and 3) dedicated technical support and upkeep of the device. Upon successful placement of the robotic device in the ED, the clinical study required screening of all patients presenting to the ED with complaints of head injury. Eligible patients were enrolled and tested using a robot-assisted test battery. Three weeks after the injury, patients were contacted to complete follow-up assessments. RESULTS: Adapting the existing technology to meet anticipated physical constraints of the ED was performed by engineering a mobile platform. Due to the large footprint of the device, it was frequently moved before ultimately being fully integrated into the ED. Over 14 months, 1423 patients were screened. Twenty-eight patients could not be enrolled because the device was unavailable due to operations limitations. Technical problems with the device resulted in failure to include 20 patients. A total of 66 mTBI patients were enrolled and 42 of them completed both robot-assisted testing and follow-up assessment. Successful completion of screening and enrollment demonstrated that the challenges associated with integration of investigational devices into the ED can be effectively addressed through a collaborative patient-oriented research model. CONCLUSION: Effective deployment and use of new robotic technology for research in an urban academic ED required significant planning, coordination, and collaboration with key personnel from multiple disciplines. Clinical Impact: A pilot clinical study on mTBI patients using the robotic device provided useful data without disrupting the ED workflow. Integration of this technology into the ED serves as an important step toward pursing active clinical research in an acute care setting.

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Plasmin, a direct fibrinolytic, shows a significantly superior hemostatic safety profile compared to recombinant tissue plasminogen activator (rtPA), the only FDA-approved thrombolytic for the treatment of acute ischemic stroke. The improved safety of plasmin is attributed to the rapid inhibition of free plasmin by endogenous plasmin inhibitors present in very high concentrations (1 µM). However, this rapid inhibition prevents the intravenous (IV) administration of plasmin. In emergency situations, catheter-based local administration is not practical. There is a need for an alternative technique for IV administration of plasmin. A possible solution is the encapsulation of plasmin in echogenic liposomes (ELIP) for protection from inhibitors until ultrasound (US)-triggered release at the clot site. ELIP are bilayer phospholipid vesicles with encapsulated gas microbubbles. US induces oscillation and collapse of the gas bubbles, which facilitates ELIP rupture and delivery of the encapsulated contents. Plasmin-loaded ELIP (PELIP) were manufactured and characterized for size, gas and drug encapsulations, and in vitro thrombolytic efficacy using a human whole blood clot model. Clots were exposed to PELIP with and without exposure to US (center frequency 120 kHz, pulse repetition frequency 1667 Hz, peak-to-peak pressure of 0.35 MPa, 50 % duty cycle). Thrombolytic efficacy was calculated by measuring the change in clot width over a 30-min treatment period using an edge detection MATLAB program. The mean clot lysis obtained with PELIP in the presence of US exposure was 31 % higher than that obtained without US exposure and 15 % higher than that obtained with rtPA treatment (p < 0.05).The enhanced clot lysis is attributed to the US-mediated release of plasmin from the liposomes.

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Post-Concussion Syndrome (PCS) is a common sequelae of mild Traumatic Brain Injury (mTBI). Currently, there is no reliable test to determine which patients will develop PCS following an mTBI. As a result, clinicians are challenged to identify patients at high risk for subsequent PCS. Hence, there is a need to develop an objective test that can guide clinical risk stratification and predict the likelihood of PCS at the initial point of care in an Emergency Department (ED). This paper presents the results of robotic-assisted neurologic testing completed on mTBI patients in the ED and its ability to predict PCS at 3 weeks post-injury. Preliminary results show that abnormal proprioception, as measured using robotic testing is associated with higher risk of developing PCS following mTBI. In this pilot study, proprioceptive measures obtained through robotic testing had a 77% specificity (95CI: 46%-94%) and a 64% sensitivity (95CI: 41%-82%).

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OBJECTIVES: Recombinant tissue plasminogen activator (rt-PA) is a lytic medication widely used in the emergency department to treat acute thrombotic disorders such as ischemic stroke and myocardial infarction. It is known in the clinical use of this drug that it can be less effective in approximately 25% of individuals receiving such treatment. However, there are no data on the variation of lytic efficacy of rt-PA in decreasing individuals' clot size over time. In this study, in vitro lytic efficacy was determined by measuring the decrease in clot diameter after 30 minutes of drug exposure. The authors sought to explore whether there are individuals who do not respond to this lytic therapy and to estimate the rate of nonresponse. METHODS: Human whole blood clots were made from blood drawn from 22 adult volunteers. The only exclusion criterion was the use of aspirin within 72 hours of the blood draw. Blood clots were allowed to spontaneously form at room temperature and were then incubated at 37°C for 3 hours to ensure complete clot retraction. Sample clots from the same individuals were then exposed to human fresh-frozen plasma (hFFP) control or rt-PA in hFFP (rt-PA) at a concentration of 3.15 µg/mL. All clots were exposed at 37°C for 30 minutes, and clot diameter was measured as a function of time, using a microscopic imaging technique. The fractional clot loss (FCL), which is the percentage decrease in clot diameter at 30 minutes, was used as a measure of lytic efficacy. RESULTS: Means with standard deviation (SD) FCL values were 8.6% (±3.0%) for control and 20.6% (±9.3%) for rt-PA-treated clots. The mean (±SD) difference in FCL values was 12.0% (±8.8%) and was significant (p < 0.05, paired t-test). Five of the 22 subjects (23%) were "rt-PA nonresponders," in that their FCL (rt-PA) values fell within that of the FCL control values. CONCLUSIONS: Overall, rt-PA does not produce clot lysis in vitro in clots from a substantial minority of the population, likely due to individual variations in clot composition and structure.

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High-dose hydroxymethylglutaryl coenzyme. A reductase inhibitor (statin) administration reduces neuronal injury and improves outcomes in experimental models of acute ischemic stroke, and has been shown to be safe in a phase 1 dose-escalation study using lovastatin at doses higher than currently approved for daily use. Statins also affect the hemostatic system by upregulating t-PA expression and decreasing plasminogen activator inhibitor (PAI-1) expression, platelet adhesion and thrombus formation in animal models. Since a thrombolytic agent, recombinant tissue plasminogen activator (rt-PA), is currently the only FDA-approved therapy for use in ischemic stroke patients, it is important to ascertain whether high statin doses impact the efficacy of rt-PA. The main goal of this study was to evaluate the effect of a high dose of lovastatin and its active form, lovastatin hydroxy acid, on rt-PA thrombolysis in an in vitro model. Percentage clot lysis was measured in the presence and absence of rt-PA in three different treatment groups: lovastatin, lovastatin hydroxy acid, and ethanol. The effect of ethanol on clot lysis was studied since ethanol was used to disperse the highly hydrophobic lovastatin. The decrease in clot width over time was measured using microscopic imaging of an in vitro human whole blood clot model; an approximately 400 µm diameter clot was formed on suture silk, suspended in human fresh frozen plasma (hFFP) and exposed to treatment. In the absence of rt-PA, clot lysis did not show statistically significant differences in the percentage clot lysis between different treatment groups (p=0.103). In the presence of rt-PA, clot lysis was greater than in the absence of rt-PA for all groups, but there were no statistically significant differences between treatment groups (p=0.385). In this in vitro study, high doses of lovastatin neither impaired nor enhanced the lytic efficacy of rt-PA.

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The potential for hypothermia as a neuroprotectant during stroke has led to its increase in clinical use. At the same time, combination pharmaceutical therapies for ischemic stroke using recombinant tissue plasminogen activator (rt-PA), and GP IIb-IIIa inhibitors, such as Eptifibatide (Epf ), are under study. However, there is little data on how the reactions triggered by these agents are impacted by temperature. Here, clot lysis during exposure to the combination of rt-PA and Epf is measured in an in vitro human clot model at hypothermic temperatures. The hypothesis is that lytic efficacy of rt-PA and Epf decreases with decreasing temperature. Whole blood clots from 31 volunteers were exposed to rt-PA (0.5 µg/mL) and Epf (0.63 µg/mL) in human fresh-frozen plasma (rt-PA+Epf ), rt-PA alone in plasma (rt-PA Alone), or to plasma alone (Control), at temperatures from 30°C to 37°C, for 30 minutes. Clot lysis was measured using a microscopic imaging technique; the mean fractional clot loss (FCL) at 30 minutes was used to determine lytic efficacy. Temperature had a significant impact on FCL in clots exposed to rt-PA+Epf, with the FCL being lower at 30°C to 36°C than at 37°C. The FCL remained significantly higher for rt-PA+Epf­treated clots than Controls regardless of temperature, with the exception of measurements made at 30°C when no significant differences in the FCL were observed between groups. The use of hypothermia as a neuroprotectant may negatively impact the therapeutic benefit of thrombolytic agents.

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Incidence of intra-cranial hemorrhage linked to treatment of ischemic stroke with recombinant tissue plasminogen activator (rt-PA) has led to interest in adjuvant therapies such as ultrasound (US) or plasminogen, to enhance rt-PA efficacy and improve patient safety. High-frequency US (∼MHz) such as 2-MHz transcranial Doppler (TCD) has demonstrated increased recanalization in situ. Low-frequency US (∼kHz) enhanced thrombolysis (UET) has demonstrated higher lytic capabilities but has been associated with incidence of intracerebral hemorrhage in some clinical trials. In vitro studies using plasminogen have shown enhancement of lysis. This study compared rt-PA-induced lysis using adjuvant therapies, with 120-kHz or 2-MHz pulsed US, or plasminogen, in an in vitro human whole blood clot model. Blood was drawn from 30 subjects after local institutional approval. Clots were exposed to rt-PA at concentrations of 0 to 3.15 µg/ml. Clots were exposed to rt-PA alone (rt-PA) or in combination with plasminogen (Plg), 120-kHz US (120-kHz), or 2-MHz US (2-MHz). Thrombolytic efficacy was determined by assessing the percent fractional clot loss (FCL) at 30 minutes using microscopic imaging. There was no enhancement of lysis for combination therapy with [rt-PA]=0 µg/ml. Adding rt- PA increased lysis for all groups. As [rt-PA] increased, lysis tended to increase for 120-kHz and Plg (FCL: from 50% to 70%, 120-kHz; 65% to 83%, Plg) but not for 2-MHz (58% to 52%). Lytic efficacy in combination therapy depends on rt- PA concentration and the adjuvant therapy type. For non-zero rt-PA concentrations, all combination therapies produced more lysis than rt-PA alone.

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INTRODUCTION: Recombinant tissue plasminogen activator (rt-PA) is the only FDA approved lytic therapy for acute ischemic stroke. However, there can be complications such as intra-cerebral hemorrhage. This has led to interest in adjuncts such as GP IIb-IIIa inhibitors. However, there is little data on combined therapies. Here, we measure clot lysis for rt-PA and eptifibatide in an in vitro human clot model, and determine the drug concentrations maximizing lysis. A pharmacokinetic model is used to compare drug concentrations expected in clinical trials with those used here. The hypothesis is that there is a range of rt-PA and eptifibatide concentrations that maximize in vitro clot lysis. MATERIALS AND METHODS: Whole blood clots were made from blood obtained from 28 volunteers, after appropriate institutional approval. Sample clots were exposed to rt-PA and eptifibatide in human fresh-frozen plasma; rt-PA concentrations were 0, 0.5, 1, and 3.15 µg/ml, and eptifibatide concentrations were 0, 0.63, 1.05, 1.26 and 2.31 µg/ml. All exposures were for 30 minutes at 37 C. Clot width was measured using a microscopic imaging technique and mean fractional clot loss (FCL) at 30 minutes was used to determine lytic efficacy. On average, 28 clots (range: 6-148) from 6 subjects (3-24) were used in each group. RESULTS AND CONCLUSIONS: FCL for control clots was 14% (95% Confidence Interval: 13-15%). FCL was 58% (55-61%) for clots exposed to both drugs at all concentrations, except those at an rt-PA concentration of 3.15 µg/ml, and eptifibatide concentrations of 1.26 µg/ml (Epf) or 2.31 µg/ml. Here, FCL was 43% (36-51) and 35% (32-38) respectively. FCL is maximized at moderate rt-PA and eptifibatide concentration; these values may approximate the average concentrations used in some rt-PA and eptifibatide treatments.

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BACKGROUND: Recombinant tissue plasminogen activator (tPA) is a thrombolytic widely used clinically in the treatment of acute thrombotic disease such as ischemic stroke, myocardial infarction, and deep venous thrombosis. This has led to much interest in tPA based lytic therapies leading to laboratory based in-vitro and in-vivo investigations using this drug. However, tPA reconstituted in solution exhibits full activity for only 6-8 hours, according to the manufacturer. Therefore, methods to store reconstituted tPA for long durations while maintaining activity would be of assistance to laboratories using this enzyme. FINDINGS: In this work, the enzymatic activity of tPA stored at -80 C over time was measured, using an ELISA technique that measured the amount of active tPA bound to plasminogen activator inhibitor 1 (PAI-1) in a given sample. Sample of tPA solution mixed to a concentration of 1 (mg/ml) were stored in cryogenic vials at -80 C for up to 7 years. For a given sample, aliquots were assayed for tPA activity, and compared with a tPA standard to determine relative enzymatic activity. Results are reported as means with standard errors, and 12 measurements were performed for each sample age. CONCLUSION: There was no decrease in tPA activity for samples stored up to 7 years. Such cryogenic storage is a viable method for the preservation of tPA solution for laboratory investigations of tPA-based lytic therapies.

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BACKGROUND AND PURPOSE: Currently, the only FDA-approved therapy for acute ischemic stroke is the administration of recombinant tissue plasminogen activator (tPA). Echogenic liposomes (ELIP), phospholipid vesicles filled with gas and fluid, can be manufactured to incorporate tPA. Also, transcranial ultrasound-enhanced thrombolysis can increase the recanalization rate in stroke patients. However, there is little data on lytic efficacy of combining ultrasound, echogenic liposomes, and tPA treatment. In this study, we measure the effects of pulsed 120-kHz ultrasound on the lytic efficacy of tPA and tPA-incorporating ELIP (t-ELIP) in an in-vitro human clot model. It is hypothesized that t-ELIP exhibits similar lytic efficacy to that of rt-PA. METHODS: Blood was drawn from 22 subjects after IRB approval. Clots were made in 20-microL pipettes, and placed in a water tank for microscopic visualization during ultrasound and drug treatment. Clots were exposed to combinations of [tPA]=3.15 microg/ml, [t-ELIP]=3.15 microg/ml, and 120-kHz ultrasound for 30 minutes at 37 degrees C in human plasma. At least 12 clots were used for each treatment. Clot lysis over time was imaged and clot diameter was measured over time, using previously developed imaging analysis algorithms. The fractional clot loss (FCL), which is the decrease in mean clot width at the end of lytic treatment, was used as a measure of lytic efficacy for the various treatment regimens. RESULTS: The fractional clot loss FCL was 31% (95% CI: 26-37%) and 71% (56-86%) for clots exposed to tPA alone or tPA with 120 kHz ultrasound. Similarly, FCL was 48% (31-64%) and 89% (76-100%) for clots exposed to t-ELIP without or with ultrasound. CONCLUSIONS: The lytic efficacy of tPA containing echogenic liposomes is comparable to that of tPA alone. The addition of 120 kHz ultrasound significantly enhanced lytic treatment efficacy for both tPA and t-ELIP. Liposomes loaded with tPA may be a useful adjunct in lytic treatment with tPA.

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INTRODUCTION: Fibrinolytics such as recombinant tissue plasminogen activator (rt-PA) are used to treat thrombotic disease such as acute myocardial infarction (AMI) and ischemic stroke. Interest in increasing efficacy and reducing side effects has led to the study of adjuncts such as GP IIb-IIIa inhibitors and ultrasound (US) enhanced thrombolysis. Currently, GP IIb-IIIa inhibitor and fibrinolytic treatment are often used in AMI, and are under investigation for stroke treatment. However, little is known of the efficacy of combined GP IIb-IIIa inhibitor, fibrinolytic and ultrasound treatment. We measure the lytic efficacy of rt-PA, eptifibatide (Epf) and 120 kHz ultrasound treatment in an in-vitro human clot model. MATERIALS AND METHODS: Blood was drawn from 15 subjects after IRB approval. Clots were made in 20 microL pipettes, and placed in a water tank for microscopic visualization during lytic treatment. Clots were exposed to control, rt-PA (rt-PA), eptifibatide (Epf), or rt-PA+eptifibatide (rt-PA + Epf), with (+US) or without (-US) ultrasound for 30 minutes at 37 degrees C in human plasma. Clot lysis was measured over time, using a microscopic imaging technique. The fractional clot loss (FCL) and initial lytic rate (LR) were used to quantify lytic efficacy. RESULTS AND CONCLUSIONS: LR values for (- US) treated clots were 0.8+/-0.1(control), 1.8+/-0.3 (Epf), 1.5+/-0.2 (rt-PA), and 1.3+/-0.4 (rt-PA + Epf) (% clot width/minute) respectively. In comparison, the (+ US) group exhibited LR values of 1.6+/-0.2 (control), 4.3+/-0.4 (Epf), 6.3+/-0.4 (rt-PA), and 4.6+/-0.6 (rt-PA + Epf). For (- US) treated clots, FCL was 6.0+/-0.8 (control), 9.2+/-2.5 (Epf), 15.6+/-1.7 (rt-PA), and 28.0+/-2.2% (rt-PA + Epf) respectively. FCL for (+ US) clots was 13.5+/-2.4 (control), 20.7+/-6.4 (Epf), 44.4+/-3.6 (rt-PA) and 30.3+/-3.6% (rt-PA + Epf) respectively. Although the addition of eptifibatide enhances the in-vitro lytic efficacy of rt-PA in the absence of ultrasound, the efficacy of ultrasound and rt-PA is greater than that of combined ultrasound, rt-PA and eptifibatide exposure.

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It has been known for some time that the application of ultrasound can enhance the efficacy of thrombolytic medications such as recombinant tissue plasminogen activator (rt-PA). Potential clinical applications of this ultrasound-enhanced thrombolysis (UET) include the treatment of myocardial infarction, acute ischemic stroke, deep venous thrombosis and other thrombotic disorders. It may be possible to reduce the dose of rt-PA while maintaining lytic efficacy; however there is little data on the rt-PA concentration dependence of UET. In this work, the rt-PA concentration dependence of clot lysis resulting from 120 kHz UET exposure was measured in an in vitro human clot model. Clots were exposed to rt-PA for 30 min, with (UET treated) or without 120 kHz ultrasound (rt-PA treated) at 37 degrees C, and the clot width measured as a function of time. The rt-PA concentration ranged from 0-10 microg/mL. The initial lytic rate for the UET-treated group was greater than that of the rt-PA group at almost all rt-PA concentrations, and exhibited a maximum over concentration values of 1-3 microg/mL.

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UNLABELLED: Results of previous studies suggest that pacing strength stimuli can capture activation during ventricular arrhythmia locally near pacing sites. The existence of spatio-temporal distribution of excitable gap during arrhythmia suggests that multiple and timed stimuli delivered over a region may permit capture over larger areas. OBJECTIVE OF THE STUDY: Our objective in this study was to evaluate the efficacy of using spatially distributed pacing (DP) to capture activation during ventricular arrhythmia. METHODS: Data were obtained from rabbit hearts which were placed against a lattice of parallel wires through which biphasic pacing stimuli were delivered. Electrical activity was recorded optically. Pacing stimuli were delivered in sequence through the parallel wires starting with the wire closest to the apex and ending with one closest to the base. Inter-stimulus delay was based on conduction velocity. Time-frequency analysis of optical signals was used to determine variability in activation. A decrease in standard deviation of dominant frequencies of activation from a grid of locations that spanned the captured area and a concurrence with paced frequency were used as an index of capture. RESULTS: Results from five animals showed that the average standard deviation decreased from 0.81 Hz during arrhythmia to 0.66 Hz during DP at pacing cycle length of 125 ms (p = 0.03) reflecting decreased spatio-temporal variability in activation during DP. Results of time-frequency analysis during these pacing trials showed agreement between activation and paced frequencies. CONCLUSIONS: These results show that spatially distributed and timed stimulation can be used to modify and capture activation during ventricular arrhythmia.

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Combined ultrasound and tissue plasminogen activator (rt-PA) therapy, or ultrasound enhanced thrombolysis (UET), has been shown to improve recanalization in patients with acute ischemic stroke. We measured the effect of ultrasound duty cycle on the lytic efficacy of 120 kHz UET in an in vitro human clot model. The hypothesis was that an increase in duty cycle increases rt-PA lytic efficacy. Human whole blood clots were exposed to 120-kHz ultrasound and rt-PA for 30 min in human plasma. The duty cycle ranged from 0% to 80%, where 0% represents sham exposure. Clot lytic rate was measured by recording the clot width over time. The clot width after 30 min exposure to rt-PA and ultrasound decreases with increasing duty cycle. The initial lytic rate increased linearly with duty cycle.

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INTRODUCTION: A heart in fibrillation can be entrained by long-lasting alternating current (AC) stimuli, leading to defibrillation. To investigate the role entrainment plays in defibrillation, computer simulations of AC cardioversion in a three-dimensional slice of the canine heart were performed. METHODS AND RESULTS: A bidomain finite element model of a 1-mm thick slice across the ventricles of a canine heart was used to simulate termination of transmural reentry with AC shocks. Cardioversion defibrillation thresholds (DFTs) were determined for 200-msec (L) AC shocks at varying frequencies. At the DFT, the entire tissue is entrained by the AC shock. DFT decreases as the frequency of the long-lasting AC shock increases. We hypothesize that this decrease is due to the short period of the high-frequency AC waveform, leaving strong virtual electrode polarization (VEP) after the shock ends. To test this hypothesis, the end-shock VEP were compared for different frequencies, demonstrating stronger polarization as frequency increased. To examine whether entrainment by the long-lasting AC shock contributes to the VEP at the end of the shock, additional simulations were conducted using single-period (Z) AC waveforms. Z waveform DFTs were higher than L waveform DFTs; the Z waveform VEP was weaker than the L waveform VEP at the same frequency. This indicates that entrainment contributes to the development of stronger VEP and, thus, to lower DFT at high frequencies. CONCLUSION: This study offers for the first time a mechanistic insight into cardioversion with long-lasting AC shocks.

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