Faculty Bibliography

Intracarotid cold saline infusion (ICSI) is potentially much faster than whole-body cooling and more effective than cooling caps in inducing therapeutic brain cooling. One drawback of ICSI is hemodilution and volume loading. We hypothesized that cooling caps could enhance brain cooling with ICSI and minimize hemodilution and volume loading. Six-hour-long simulations were performed in a 3D mathematical brain model. The Pennes bioheat equation was used to propagate brain temperature. Convective heat transfer through jugular venous return and the circle of Willis was simulated. Hemodilution and volume loading were modeled using a two-compartment saline infusion model. A feedback method of local brain temperature control was developed where ICSI flow rate was varied based on the rate of temperature change and the deviation of temperature to a target (32 degrees C) within a voxel in the treated region of brain. The simulations confirmed the inability of cooling caps alone to induce hypothermia. In the ICSI and the combination models (ICSI and cap), the control algorithm guided ICSI to quickly achieve and maintain the target temperature. The combination model had lower ICSI flow rates than the ICSI model resulting in a 55% reduction of infusion volume over a 6h period and higher hematocrit values compared to the ICSI model. Moreover, in the combination model, the ICSI flow rate decreased to zero after 4h, and hypothermia was subsequently maintained solely by the cooling cap. This is the first study supporting a role of cooling caps in therapeutic hypothermia in adults.

BACKGROUND:We aimed to identify the rate of major neurologic improvement (MNI) at 24 h following endovascular recanalization therapy (ERT) for acute ischemic stroke and its association with short-term outcome. METHODS:We retrospectively reviewed consecutive acute ischemic stroke patients presenting to our institution over 4 years and undergoing ERT. Angiograms were independently reviewed. Data on demographics, medical history, initial NIHSS score, 24-hour NIHSS score, site of acute vascular lesion, pre- and posttreatment Thrombolysis in Myocardial Infarction scores, symptomatic intracerebral hemorrhage (within 36 h of intervention that was associated with a 4-point decline in NIHSS score) and discharge disposition were collected. We used logistic regression analysis to identify predictors of MNI (defined as >or=8-point improvement in NIHSS or a score of 0-1 at 24 h) and favorable discharge status (defined as home or acute rehabilitation). RESULTS:Sixty-eight patients were included (median age = 71 years, 60% women, median NIHSS score = 19.5, anterior circulation = 75%). The modes of ERT were pharmacologic only (28%), mechanical only (35%) and multimodal therapy (37%). Thrombolysis in Myocardial Infarction 2 or 3 recanalization was achieved in 64.7% (mechanical only 46%, pharmacologic only 63% and multimodal 84%). The outcomes were: symptomatic intracerebral hemorrhage (11.8%), MNI (26.5%) and favorable discharge (41.2%). Age (OR = 0.93, p = 0.003) and cardioembolic stroke subtype (OR = 6.0, p = 0.018) were independent predictors of MNI. MNI was a strong predictor of favorable discharge status (OR = 46.4, p < 0.001). CONCLUSIONS:Despite initial stroke severity, MNI occurred in over one fourth of the patients and independently and strongly predicted favorable discharge outcome.

BACKGROUND: Limited access to endothelial tissue is a major constraint when investigating the cellular mechanisms of vascular inflammation in patients with cardiovascular and metabolic diseases. We introduce venous endothelial sampling coupled to quantitative analysis of gene transcripts by real-time PCR, as a novel approach to study endothelial gene expression in human subjects. METHODS: Endothelial cells were collected from a superficial forearm vein using five guide wires sequentially inserted through a 20-gauge angiocatheter in seven patients with history of cardiovascular events related to advanced vascular disease and in 17 healthy subjects. Endothelial cells were purified using magnetic beads coated with endothelial specific antibodies. Endothelial mRNA was amplified using RiboAmp HS RNA Amplification kit (Molecular Devices, Sunnyvale, CA). Amplified RNA was analyzed by real-time PCR. RESULTS: Linearity of RNA amplification was validated by real-time PCR using RNA from 1,000 human umbilical endothelial cells (HUVECs) before and after amplification. In human subjects, vascular disease was associated with significant induction of proatherosclerotic genes: early growth response gene product (Egr-1) and monocyte chemoattractant protein-1 (MCP-1). CONCLUSION: Venous endothelial sampling coupled to real-time PCR analysis is a minimally invasive, safe, and reliable technique to monitor vascular inflammation in human subjects. Expression of genes implicated in the atherosclerotic process is increased in the venous endothelium of patients with arterial vascular disease. Venous endothelial sampling and quantitative analysis of gene expression may help develop new vascular-targeted biomarkers to identify and track the impact of disease states and therapeutic interventions in vascular diseases.

A three-dimensional mathematical model was developed to examine the induction of selective brain cooling (SBC) in the human brain by intracarotid cold (2.8 degrees C) saline infusion (ICSI) at 30 ml/min. The Pennes bioheat equation was used to propagate brain temperature. The effect of cooled jugular venous return was investigated, along with the effect of the circle of Willis (CoW) on the intracerebral temperature distribution. The complete CoW, missing A1 variant (mA1), and fetal P1 variant (fP1) were simulated. ICSI induced moderate hypothermia (defined as 32-34 degrees C) in the internal carotid artery (ICA) territory within 5 min. Incorporation of the complete CoW resulted in a similar level of hypothermia in the ICA territory. In addition, the anterior communicating artery and ipsilateral posterior communicating artery distributed cool blood to the contralateral anterior and ipsilateral posterior territories, respectively, imparting mild hypothermia (35 and 35.5 degrees C respectively). The mA1 and fP1 variants allowed for sufficient cooling of the middle cerebral territory (30-32 degrees C). The simulations suggest that ICSI is feasible and may be the fastest method of inducing hypothermia. Moreover, the effect of convective heat transfer via the complete CoW and its variants underlies the important role of CoW anatomy in intracerebral temperature distributions during SBC.

STUDY OBJECTIVE: The aim of this study is to characterize hospital and patient characteristics associated with administration of thrombolysis in acute ischemic stroke patients in the United States. METHODS: This retrospective, observational, cohort study used data from the Nationwide Inpatient Sample, an administrative discharge database. A total of 366,194 hospitalizations admitted through the emergency department with a primary diagnosis of acute ischemic stroke were selected for analysis. The primary outcome considered in this study is whether the patient received thrombolytic therapy on hospital day 0 or 1. RESULTS: Thrombolysis was used in 1.12% (95% confidence interval [CI] 0.95% to 1.32%) of ischemic stroke hospitalizations. Most hospitals (69.5%; 95% CI 68.4% to 70.6%) treating ischemic stroke patients did not use thrombolysis during the study period. For the hospitals that used thrombolysis, the mean annual number of patients treated with thrombolysis per hospital was 3.06 (95% CI 2.68 to 3.44). In the binary logistic regression analysis, hospital characteristics associated with high use of thrombolysis were teaching hospital status and increasing number of stroke patients treated annually. Patient characteristics associated with higher use of thrombolysis were age younger than 55 years, male sex, and low comorbidity as measured by the modified Charlson Index; white race; and private self-pay health insurance. CONCLUSION: Use of thrombolysis for ischemic stroke in the United States from 1999 to 2004 was infrequent and showed significant differences, depending on hospital and patient demographic characteristics.

A three-dimensional mathematical model was developed to examine the transient and steady-state temperature distribution in the human brain during selective brain cooling (SBC) by unilateral intracarotid freezing-cold saline infusion. To determine the combined effect of hemodilution and hypothermia from the cold saline infusion, data from studies investigating the effect of these two parameters on cerebral blood flow (CBF) were pooled, and an analytic expression describing the combined effect of the two factors was derived. The Pennes bioheat equation used the thermal properties of the different cranial layers and the effect of cold saline infusion on CBF to propagate the evolution of brain temperature. A healthy brain and a brain with stroke (ischemic core and penumbra) were modeled. CBF and metabolic rate data were reduced to simulate the core and penumbra. Simulations using different saline flow rates were performed. The results suggested that a flow rate of 30 ml/min is sufficient to induce moderate hypothermia within 10 min in the ipsilateral hemisphere. The brain with stroke cooled to lower temperatures than the healthy brain, mainly because the stroke limited the total intracarotid blood flow. Gray matter cooled twice as fast as white matter. The continuously falling hematocrit was the main time-limiting factor, restricting the SBC to a maximum of 3 h. The study demonstrated that SBC by intracarotid saline infusion is feasible in humans and may be the fastest method of hypothermia induction.

The therapeutic potential of intra-arterial (IA) drug delivery to the brain has received limited attention in the last decade. In the 1980s, efforts to treat brain tumors with IA chemotherapy, the leading application of this technology, yielded modest results. Poor control of tissue drug concentrations and the potential risk of permanent neurologic injury further prevented the wider use of IA drugs. Yet, IA drugs were anecdotally used for treating a wide spectrum of brain diseases. Recent advances in endovascular technology and the increased safety of angiographic procedures now compel us to reevaluate IA drug delivery. This review describes the pharmacologic principles, applications, and pitfalls of IA drug delivery to the brain.

INTRODUCTION/BACKGROUND:Restoration of blood flow following ischemic stroke can be achieved by means of thrombolysis or mechanical recanalization. However, for some patients, reperfusion may exacerbate the injury initially caused by ischemia, producing a so-called "cerebral reperfusion injury". Multiple pathological processes are involved in this injury, including leukocyte infiltration, platelet and complement activation, postischemic hyperperfusion, and breakdown of the blood-brain barrier. METHODS/RESULTS AND CONCLUSIONS/UNASSIGNED:Magnetic resonance imaging (MRI) can provide extensive information on this process of injury, and may have a role in the future in stratifying patients' risk for reperfusion injury following recanalization. Moreover, different MRI modalities can be used to investigate the various mechanisms of reperfusion injury. Antileukocyte antibodies, brain cooling and conditioned blood reperfusion are potential therapeutic strategies for lessening or eliminating reperfusion injury, and interventionalists may play a role in the future in using some of these therapies in combination with thrombolysis or embolectomy. The present review summarizes the mechanisms of reperfusion injury and focuses on the way each of those mechanisms can be evaluated by different MRI modalities. The potential therapeutic strategies are also discussed.

This study describes a theoretical model of brain cooling by intracarotid cold saline infusion which takes into account redistribution of cold perfusate through the circle of Willis (CoW) and cold venous return (VR) from the head. This model is developed in spherical coordinates on a four tissue layer hemispherical geometrical configuration. Temperature evolution is modeled according to the Pennes bioheat transfer equation. Simulations were run over a 1 hour period and 30 ml/min of freezing cold saline with the baseline model (no VR, no CoW), VR model (without CoW), and CoW model (with VR). The VR model demonstrates continuing temperature drop in the treatment region of the brain not observed in the baseline model and its final mean ipsilateral anterior temperature was approximately 31 degrees C. The temperature effect in the CoW model was present but less robust in the ipsilateral anterior region, as final temperature was 32 degrees C. However, cooling was also achieved in contralateral and posterior brain regions. This model continues to demonstrate the feasibility of intracarotid cold saline infusion for ischemic stroke therapy.