Clare Horkan

Predictors of Hemorrhagic Transformation After Intravenous Recombinant Tissue Plasminogen Activator Prognostic Value of the Initial Apparent Diffusion Coefficient and Diffusion-Weighted Lesion Volume

Background and Purpose— Hemorrhagic transformation (HT) is a potentially dangerous complication of thrombolytic therapy. Recent studies suggest that diffusion-weighted MRI (DWI) can help to predict the risk of intracerebral hemorrhage (ICH) after thrombolysis. We sought to examine which pretreatment DWI parameters and clinical data are predictive of ICH after intravenous thrombolysis. Methods— We retrospectively reviewed our prospective stroke database for patients with ischemic stroke treated with intravenous recombinant tissue plasminogen activator (rtPA) within 3 hours from symptom onset who had DWI before treatment and MRI with T2* sequence or CT 24 to 48 hours later to assess for ICH over the past 4 years. We measured the volumes and voxel-by-voxel apparent diffusion coefficient (ADC) values of the initial DWI lesions and retrieved demographic data, risk factors, National Institutes of Health Stroke Scale (NIHSS) scores on admission, and blood tests results. We examined several variables using univariate and multivariate regression analyses to determine predictors of ICH. Results— Twenty-nine patients fulfilled our inclusion criteria; 17 patients (58%) had ICH, and of these 4 (13%) had symptomatic ICH and fatal outcome. On univariate analysis, higher systolic blood pressure, NIHSS score, serum glucose level, volume of initial DWI lesion, and absolute number of voxels with ADC value ≤550×10−6 mm2/s were statistically associated with ICH, and all were subjected to multivariate analysis. However, only the absolute number of voxels, ie, volume of ischemic tissue on DWI, with ADC ≤550×10−6 mm2/s emerged as an independent predictor of ICH. Conclusions— Our findings suggest that volumetric ADC analysis can be used to assess ICH risk after thrombolysis. This may be particularly helpful if rtPA is to be given outside the 3-hour window.

The Stroke Patient Who Woke Up Clinical and Radiological Features, Including Diffusion and Perfusion MRI

Background and Purpose— Time of stroke onset is uncertain for patients who wake from sleep with stroke. Functional imaging techniques may allow estimation of benefit and risk of acute stroke therapy. We compared the clinical and multimodal MRI findings of patients with uncertain stroke onset with those with known onset time. Methods— Patients imaged within 24 hours of ischemic stroke onset between January 1997 and June 2000 were identified from a prospective stroke registry. Clinical and imaging data from patients with known stroke onset (group I) were compared with those who woke with stroke (group II). Results— A total of 364 patients were identified, of whom 100 (27%) woke from sleep with stroke. Group I and group II did not differ in age, gender, National Institutes of Health Stroke Scale, or TOAST (Trial of Org 10172 in Acute Stroke Treatment) diagnoses. Time from stroke onset was shorter in group I (mean 6.0 versus 13.3 hours, P <0.001); time from detection did not differ between groups (6.0 versus 5.9 hours). Within 3 hours, diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI) lesion volumes were similar in both groups; DWI-PWI mismatch was present in 82% of group I and 73% of group II patients. Mean apparent diffusion coefficient of water (ADC) of group I patients was negatively associated with DWI volume (&bgr;=−0.324, P =0.004) and time from stroke onset (&bgr;=−0.238, P =0.031) in multivariate analysis. The mean ADC of group II patients was lower than that of group I patients within 3 hours of stroke detection (mean 556 versus 665 &mgr;m2/s, P <0.01), but individual group II patients had ADC values as high as 742 &mgr;m2/s, in addition to a DWI-PWI mismatch pattern. Conclusions— Onset time is uncertain in over one quarter of acute ischemic stroke patients. Clinical features of these patients do not differ significantly from those with known onset time. Some patients who wake with stroke seem to have favorable imaging characteristics for acute stroke therapy. Further study is needed to determine whether criteria for therapy based on imaging parameters can safely be applied to these patients.

Radiofrequency Ablation: Effect of Pharmacologic Modulation of Hepatic and Renal Blood Flow on Coagulation Diameter in a VX2 Tumor Model

PURPOSE To determine whether pharmacologic agents can be used to modulate blood flow in hepatic and renal tumors sufficiently to alter the extent of radiofrequency (RF)-induced coagulation. MATERIALS AND METHODS VX2 tumors (8-15 mm) were implanted in the liver (n = 25) or kidney (n = 8) of 33 New Zealand White rabbits. RF was applied to tumors for 6 minutes with use of conventional electrodes (125 mA +/- 35; 90 degrees C +/- 2 degrees C tip temperature). In the hepatic model, blood flow was modulated with use of halothane, epinephrine, or arsenic trioxide (2-6 mg/kg). Laser Doppler flowmetry was used to quantify changes in hepatic blood flow. Correlation of blood flow with induced coagulation diameter was performed. RF ablation was then performed in a renal model with and without arsenic trioxide. RESULTS For liver tumors, halothane and arsenic trioxide reduced blood flow to 40.3% +/- 17.8% and 29% +/- 15% of normal, respectively, whereas epinephrine increased blood flow to 207.8% +/- 97.9%. Correlation of blood flow to coagulation diameter was demonstrated (R(2) = 0.40). Coagulation measured 7 mm +/- 1 with epinephrine, 10 mm +/- 1 with normal blood flow, 12 mm +/- 3 with halothane, and 13 mm +/- 3 with arsenic trioxide (P <.04 compared with controls). In the renal model, arsenic trioxide decreased blood flow (44% +/- 16%) and increased coagulation diameter (10.9 mm +/- 1) compared with controls (84% +/- 11% and 7.6 mm +/- 1; P <.01, both comparisons). CONCLUSIONS RF-induced coagulation necrosis in rabbit hepatic and renal tumors is affected by tumor blood flow. Pharmacologic modulation of tumor blood flow may provide a noninvasive way to decrease blood flow during thermally mediated ablation therapy, potentially enabling the creation of larger zones of coagulation necrosis.

Hybrid Radiofrequency and Cryoablation Device: Preliminary Results in an Animal Model

PURPOSE To determine whether the simultaneous application of combined bipolar radiofrequency (RF) ablation and cryoablation in a hybrid system produces larger ablation zones than RF or cryoablation alone. MATERIALS AND METHODS Multiple 15-minute ablations were performed in ex vivo bovine liver (n = 167) with a hybrid applicator system with RF ablation alone (0.3-0.7 A), cryoablation alone (3,500 psi, two freeze/thaw cycles), and combined RF/cryoablation (0.4-0.7 A, 1,000-3,500 psi) with use of a novel applicator consisting of two 2.5-cm active bipolar RF poles located on the same 18-gauge needle separated by two embedded cryoablation nozzles. Resultant coagulation diameters were compared with use of analysis of variance for more than three groups or Student t tests for two groups. Confirmation of the optimal parameters of combination RF/cryoablation was performed by reassessing a range of argon pressure (1,000-3,500 psi) and RF current (0.4-0.7 A) in in vivo porcine liver (n = 36). Arrays of two to four RF/cryoablation applicators were also assessed in ex vivo (n = 54) and in vivo (n = 12) liver. RESULTS In ex vivo liver, simultaneous RF/cryoablation (0.6 A, 3,000 psi) produced 3.6 cm +/- 0.4 of short-axis coagulation. This was significantly larger than that achieved with optimal RF alone or cryoablation alone (1.5 cm +/- 0.3 and 1.6 cm +/- 0.3, respectively; F = 95; P < .01). The coagulation diameter with simultaneous combination RF/cryoablation was related in parabolic fashion to argon pressure and current with a multivariate r(2) of 0.68. For in vivo liver, optimal combination RF/cryoablation achieved 3.3 cm +/- 0.2 of coagulation, which was significantly larger than that achieved with RF alone (1.1 cm +/- 0.1; P < .01) or cryoablation alone (1.1 cm +/- 0.1 and 1.3 cm +/- 0.1; F = 203; P < .01). The greatest contiguous coagulation was achieved with multiple-applicator arrays. For ex vivo liver, short-axis coagulation measured 5.3 cm +/- 0.1, 6.4 cm +/- 0.1, and 7.6 cm +/- 0.1 for two-, three-, and four-applicator arrays, respectively. For in vivo liver, two-, three-, and four-applicator arrays produced 5.1 cm +/- 0.2, 5.8 cm +/- 0.5, and 7.0 cm +/- 0.5 of confluent coagulation, respectively. CONCLUSION Simultaneous combination RF and cryoablation with use of a novel applicator design yielded significantly larger zones of coagulation than either modality alone. The large ablation diameters achieved warrant further investigation of the device.

The association of acute kidney injury in the critically ill and postdischarge outcomes: a cohort study*.

Objective:Hospital readmissions contribute significantly to the cost of inpatient care and are targeted as a marker for quality of care. Little is known about risk factors associated with hospital readmission in survivors of critical illness. We hypothesized that acute kidney injury in patients who survived critical care would be associated with increased risk of 30-day postdischarge hospital readmission, postdischarge mortality, and progression to end-stage renal disease. Design:Two center observational cohort study. Setting:Medical and surgical ICUs at the Brigham and Women’s Hospital and the Massachusetts General Hospital in Boston, Massachusetts. Patients:We studied 62,096 patients, 18 years old and older, who received critical care between 1997 and 2012 and survived hospitalization. Interventions:None Measurements and Main Results:All data was obtained from the Research Patient Data Registry at Partners HealthCare. The exposure of interest was acute kidney injury defined as meeting Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease Risk, Injury or Failure criteria occurring 3 days prior to 7 days after critical care initiation. The primary outcome was hospital readmission in the 30 days following hospital discharge. The secondary outcome was mortality in the 30 days following hospital discharge. Adjusted odds ratios were estimated by multivariable logistic regression models with inclusion of covariate terms thought to plausibly interact with both acute kidney injury and readmission status. Adjustment included age, race (white vs nonwhite), gender, Deyo-Charlson Index, patient type (medical vs surgical) and sepsis. Additionally, long-term progression to End Stage Renal Disease in patients with acute kidney injury was analyzed with a risk-adjusted Cox proportional hazards regression model. The absolute risk of 30-day readmission was 12.3%, 19.0%, 21.2%, and 21.1% in patients with No Acute Kidney Injury, Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease class Risk, Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease class Injury, and Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease class Failure, respectively. In patients who received critical care and survived hospitalization, acute kidney injury was a robust predictor of hospital readmission and post-discharge mortality and remained so following multivariable adjustment. The odds of 30-day post-discharge hospital readmission in patients with Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease class Risk, Injury, or Failure fully adjusted were 1.44 (95% CI, 1.25–1.66), 1.98 (95% CI, 1.66–2.36), and 1.55 (95% CI, 1.26–1.91) respectively, relative to patients without acute kidney injury. Further, the odds of 30-day post-discharge mortality in patients with Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease class Risk, Injury, or Failure fully adjusted per our primary analysis were 1.39 (95% CI, 1.28–1.51), 1.46 (95% CI, 1.30–1.64), and 1.42 (95% CI, 1.26–1.61) respectively, relative to patients without acute kidney injury. The addition of the propensity score to the multivariable model did not change the point estimates significantly. Finally, taking into account age, gender, race, Deyo-Charlson Index, and patient type, we observed a relationship between acute kidney injury and development of end-stage renal disease. Patients with Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease class Risk, Injury, Failure experienced a significantly higher risk of end-stage renal disease during follow-up than patients without acute kidney injury (hazard ratio, 2.03; 95% CI, 1.56–2.65; hazard ratio, 3.99; 95% CI, 3.04–5.23; hazard ratio, 10.40; 95% CI, 8.54–12.69, respectively). Conclusions:Patients who suffer acute kidney injury are among a high-risk group of ICU survivors for adverse outcomes. In patients treated with critical care who survive hospitalization, acute kidney injury is a robust predictor of subsequent unplanned hospital readmission. In critical illness survivors, acute kidney injury is also associated with the odds of 30-day postdischarge mortality and the risk of subsequent end-stage renal disease.

Repetitive TMS temporarily alters brain diffusion

The authors investigated whether repetitive transcranial magnetic stimulation (rTMS) at 1 Hz (12 minutes; 90% of motor threshold) to the primary motor cortex (M1) leads to changes in diffusion-weighted imaging (DWI). After the rTMS train, there was a temporary small restriction in diffusion within the targeted left M1 that disappeared after 5 minutes. These findings provide a physiologic correlate to the reported behavioral consequences of off-line 1-Hz rTMS and reveal the transitory nature of the effects.

RF ablation with adjuvant therapy: comparison of external beam radiation and liposomal doxorubicin on ablation efficacy in an animal tumor model.

Purpose: To determine the critical thermal dosimetry and relative efficacy for RF ablation combined with external beam radiation (XRT) or liposomal doxorubicin (LD), in an animal tumor model. Materials and methods: This study was performed in two phases, in 13–18 mm diameter R3230 tumors subcutaneously implanted into Fischer rats. In phase 1, tumors (n = 30) were randomized into six groups. RF energy (titrated to 70°C tip temperature) was applied for either 2.5 or 5 min (n = 15, each group). For each duration, one of three adjuvant therapies was applied (n = 5, each): no therapy (control), LD (1 mg intravenously, 30 min post-RF), or XRT (20 Gy at 1 Gy min−1, within 2 h post-RF), with sacrifice at 48 h for pathologic analysis. In phase 2, thermal mapping was performed in 20 tumors throughout RF application (70°C; 5 min), at 1.5–7 mm distances from the active electrode tip. Temperature profiles throughout the tumor were constructed and were used to interpolate temperatures over time at the critical ablation margin, to derive maximum threshold temperature, AUC (area under the curve) and CEM43 (cumulative equivalent minutes at 43°C). Ablation sizes and all calculated values were compared within and across experimental groups using MANOVA statistics with pair-wise T-test for individual comparisons. Results: RF/XRT produced the largest coagulation (11.7 ± 1.5 mm at 2.5 min, ≥15 ± 0.7 mm at 5 min), followed by RF/LD, and then RF alone (p < 0.001 for all comparisons). RF/XRT demonstrated temperature threshold decreases from RF alone of 11.7 ± 0.01°C and 12.7 ± 0.38°C at 2.5 and 5 min respectively (with absolute thresholds of 42°C for XRT compared to 52°C for RF alone). RF/LD had decreases of 4.0°C at 2.5 min and 4.4°C at 5 min. Thermal dose requirements (AUC) decreased by 7.79% or 9.28% for RF/LD compared to ≥19.36% or 25.82% for RF/XRT at 2.5 and 5 min (p < 0.001). CEM43 values followed similar patterns (p < 0.001), but with a reduction of 101 and 104 in magnitude for RF/LD and RF/XRT therapies at 5 min, respectively. Conclusions: For a standardized RF dose, the combination of high dose XRT and RF increased ablation size compared to RF and liposomal doxorubicin or RF alone. Increased ablation size is more closely associated with decreased temperature threshold necessary to induce coagulation, rather than the total thermal dose.

Clarithromycin use preceding fulminant hepatic failure.

determined based on the real-time measurement of anti-HBs titer using lumipuls (Fuji Rebio, Tokyo, Japan), which takes only 1 h. The first patient took 2,000 U of HBIG per 4 days for maintaining over 500 U/ml and then 2,000 U/month was given 2 months after LRLT. One year after transplantation, HBIG was stopped and HBV vaccination (4) was administered. A second patient also underwent the same therapy regimen as the first; however, HBIG treatment was stopped in this patient after 5 months so as to be able to maintain anti-HBV titer above 200 U/ml without the administration of HBIG. Real-time measurement of anti-HBs titer might obviate HBIG treatment, which could spare the patient the cost of

Image-guided Percutaneous Chemical and Radiofrequency Tumor Ablation in an Animal Model

7,000 in the 1st operative wk. We also have performed donor-specific transfusion via the portal vein after LRLT (5, 6). In these patients, steroid therapy was withdrawn within 1 month and FK506 rapidly reduced to 1 mg/day, and 0.5 mg/14 days by 4 months after LRLT. The rapid reduction of immunosuppressants might lead to success in the reduction of HBIG and the vaccination of HBV. In conclusion, i.m. HBIG combined with lamivudine or low dose HBIG combined with lamivudine have been demonstrated (7, 8); however, our clinical trial by intraportal donor-specific transfusion and further understanding of the immunological mechanism in LRLT might contribute to the reduction of HBIG and prevent the recurrence of HBV.

Chemical tumor ablation with use of a novel multiple-tine infusion system in a canine sarcoma model.

PURPOSE To determine whether combining acetic acid instillation before radiofrequency (RF) ablation can improve local tissue electrical conductivity, RF energy deposition, intratumoral heating, and tumor necrosis in a large animal model. MATERIALS AND METHODS Multiple hypovascular canine venereal sarcomas were implanted in 11 mildly immunosuppressed dogs (25 mg/kg cyclosporin A twice daily). Tumors were incubated for 8-12 weeks to 4.2 cm +/- 0.6 in diameter. Treatment strategies included 10% and 15% acetic acid diluted in distilled water, 10% and 15% acetic acid diluted in saturated NaCl solution, 50% acetic acid, and 100% ethanol, with 6 mL of each injected alone or in combination with RF ablation (internally cooled, 1-cm tip; 12 minutes). Two additional control groups were studied in which tumors received either RF alone or distilled water injected alone. Comparisons were also made with groups treated with 36% NaCl with and without RF ablation. Resultant coagulation for these ablative strategies, along with local temperatures and RF parameters such as impedance, current, and power, were compared. RESULTS Increasing coagulation was observed with increasing acetic acid concentrations (1.7 cm +/- 0.4, 2.8 cm +/- 0.6, and 3.5 cm +/- 0.3 for 10%, 15%, and 50% acetic acid alone, respectively; P <.01). The combination of RF ablation with acetic acid resulted in greater coagulation than with either therapy alone (P <.05). However, maximum heating and coagulation were observed with 10% acetic acid diluted in NaCl, with which the entire tumor (diameter, 4.5 cm +/- 0.4) was completely ablated in every case. This was equivalent to results for tumors treated with 36% NaCl combined with RF. RF with a 50% acetic acid concentration resulted in coagulation measuring only 3.7 cm +/- 0.3 (P <.01). Significantly greater RF heating (89.7 degrees C +/- 12.3 at 10 mm) was observed when the tumors were pretreated with 10% or 15% acetic acid in saturated NaCl, compared with 67.9 degrees C +/- 13.7 observed when acetic acid was diluted in water (P <.02). RF combined with ethanol produced less coagulation (2.8 cm +/- 0.3) than combinations with acetic acid because rapid and irreversible impedance increases were observed. CONCLUSION Addition of acetic acid injections to RF ablation substantially increases tumor destruction compared with RF or injection therapy alone. However, lower acetic acid concentrations in saturated NaCl produced greater tumor coagulation, suggesting that, in this hypovascular tumor model, alterations in electrical conductivity play a more important role in increasing tumor ablation efficiency than do the additional ablative effects of acetic acid.