Selective brain cooling with a novel catheter reduces infarct growth after recanalization in a canine large vessel occlusion model.

BACKGROUND: Therapeutic hypothermia has shown potential in cardiac intervention for years; however, its adoption into the neurovascular space has been limited. Studies have pointed to slow cooling and limited depth of hypothermia yielding negative outcomes. Here we present an insulated catheter that allows for consistent infusion of chilled saline directly to the brain. Direct delivery of cold saline allows a faster depth of hypothermia, which could have a benefit to the growth of ischemic lesions. METHODS: Ten canines were randomized to either receive selective brain cooling or no additional therapy. Eight animals were successfully enrolled (n = 4 per group). Each animal underwent a temporary middle cerebral artery occlusion (MCAO) for a total of 45 min. Five minutes prior to flow restoration, chilled saline was injected through the ipsilateral internal carotid artery using an insulated catheter to ensure delivery temperature. The treatment continued for 20 min, after which the animal was transferred to an MRI scanner for imaging. RESULTS: Of the 8 animals that were successfully enrolled in the study, 3 were able to survive to the 30-day endpoint with no differences between the cooled and control animals. There was no difference in the initial mean infarct size between the groups; however, animals that did not receive cooling had infarcts continuing to progress more rapidly after the MCAO was removed (13.8% vs 161.3%, p = 0.016, cooled vs control). CONCLUSIONS: Selective hypothermia was able to reduce the post-MCAO infarct progression in a canine model of temporary MCAO.

Focal cooling of brain parenchyma in a transient large vessel occlusion model: proof-of-concept.

INTRODUCTION: The neuroprotective benefit of therapeutic hypothermia (TH) has been demonstrated, but systemic side effects and time required to achieve effective TH in acute ischemic stroke (AIS) care limits clinical use. We investigate rapid and localized cooling using a novel insulated catheter in an ischemia-reperfusion model. METHODS: In phase I (n=4), cold saline was delivered to the canine internal carotid artery via an insulated catheter. Temperature was measured using intracerebral thermocouples. The coolant flow rate was varied to meet a target temperature of 31-32°C in the hemisphere infused. In phase II (n=8), a temporary middle cerebral artery occlusion was created. Five dogs underwent localized TH at the optimal flow rate from phase I, and the remaining animals were untreated controls. Cooling was initiated 5 min before recanalization and continued for an additional 20 min following 45 min of occlusion duration. The outcome was infarct volume and neurological function. RESULTS: Ipsilateral tissue cooling rates were 2.2±2.5°C/min at a flow rate of 20-40 mL/min with an observed minimum of 23.8°C. Tissue cooling was localized to the ipsilateral side of the infusion with little impact on temperatures of the core or contralateral hemisphere of the brain. In phase II, animals tolerated TH with minimal systemic impact. Infarct volume in treated animals was 0.2±0.2 cm3, which was smaller than in sham animals (3.8±1.0 cm3) as well as six untreated historical control animals (4.0±2.8 cm3) (p=0.013). CONCLUSIONS: Proof-of-concept data show that localised brain TH can be quickly and safely achieved through a novel insulated catheter. The small infarct volumes suggest potential benefit for this approach.

Myocardial tissue salvage is correlated with ischemic border region temperature at reperfusion.

OBJECTIVES: Our pilot study investigated the association between region-specific myocardial tissue temperature and tissue salvage using a novel tri-lumen cooling catheter to provide rapid localized cooling directly to the heart in an open-chest porcine model of ischemia-reperfusion. BACKGROUND: Therapeutic hypothermia remains a promising strategy to limit reperfusion injury following myocardial ischemia. METHODS: Large swine underwent 60 min of coronary occlusion followed by 3 hr of reperfusion. Prior to inducing ischemia, six temperature probes were placed directly on the heart, monitoring myocardial temperatures in different locations. Hemodynamic parameters and core temperature were also collected. Approximately 15 min prior to reperfusion, the cooling catheter was inserted via femoral artery and the distal tip advanced proximal to the occluded coronary vessel under fluoroscopic guidance. Autologous blood was pulled from the animal via femoral sheath and delivered through the central lumen of the cooling catheter, delivering at 50 ml/min, 27°C at the distal tip. Cooling was continued for an additional 25 min after reperfusion followed by a 5-min controlled rewarming. Hearts were excised and assessed for infarct size per area at risk. RESULTS: Although cooling catheter performance was consistent throughout the study (38 W), the resulting tissue cooling was not. Our results show a correlation between myocardial tissue salvage and ischemic border region (IBR) temperature at the time of reperfusion (R2 = 0.59, p = 0.027). IBR tissue is the tissue located at the boundary between healthy and ischemic tissues. CONCLUSIONS: Our findings suggest that localized, rapid, short-term myocardial tissue cooling has the potential to limit reperfusion injury in humans.

Infusion warm during selective hypothermia in acute ischemic stroke.

INTRODUCTION: Mechanical thrombectomy (MT) has dramatically improved the prognosis for acute ischemic stroke (AIS) patients. Despite high recanalization rates, up to half of the patients will not present a good neurological outcome after MT. Therapeutic hypothermia is perhaps the most robust neuroprotectant studied preclinically. MATERIALS AND METHODS: We explored various warming effects that can reduce the effectiveness or potency of selective hypothermia during AIS under conditions similar to actual clinical care. Four different selective hypothermia layouts were chosen. Layouts 1 and 2 used a single catheter without and with an insulated IV bag. Layouts 3 and 4 used two catheters arrange coaxially, without and with an insulated IV bag. Independent variables measured were IV bag exit temperature, catheter inlet temperature, and catheter outlet temperature at four different flow rates ranging from 8 to 25 ml/min over an infusion duration of 20 min. RESULTS: Dominant warming occurs along the catheter pathway compared to warming along the infusion line pathway, ranging from 66% to 72%. Coaxial configurations provided an approximate 4°C cooler temperature benefit on delivered infusate over a single catheter. Brain tissue temperature predictions show that the maximum cooling layout, Layout 4 at maximum flow provides a 1°C within 5 min. CONCLUSION: Significant rewarming effects occur along the infusate flow path from IV bag to site of injury in the brain. Previous selective hypothermia clinical work, using flow rates and equipment at conditions similar to our study, likely produced rapid but not deep tissue cooling in the brain (~ 1°C).

Heat transfer analysis of catheters used for localized tissue cooling to attenuate reperfusion injury.

Recent revascularization success for ischemic stroke patients using stentrievers has created a new opportunity for therapeutic hypothermia. By using short term localized tissue cooling interventional catheters can be used to reduce reperfusion injury and improve neurological outcomes. Using experimental testing and a well-established heat exchanger design approach, the ɛ-NTU method, this paper examines the cooling performance of commercially available catheters as function of four practical parameters: (1) infusion flow rate, (2) catheter location in the body, (3) catheter configuration and design, and (4) cooling approach. While saline batch cooling outperformed closed-loop autologous blood cooling at all equivalent flow rates in terms of lower delivered temperatures and cooling capacity, hemodilution, systemic and local, remains a concern. For clinicians and engineers this paper provides insights for the selection, design, and operation of commercially available catheters used for localized tissue cooling.

Development of a novel automated ion channel recording method using "inside-out" whole-cell membranes.

Efforts to develop novel methods for recording from ion channels have been receiving increased attention in recent years. In this study, the authors report a unique "inside-out" whole-cell configuration of patch-clamp recording that has been developed. This method entails adding cells into a standard patch pipette and, with positive pressure, obtaining a gigaseal recording from a cell at the inside tip of the electrode. In this configuration, the cell may be moved through the air, first rupturing part of the cellular membrane and enabling bath access to the intracellular side of the membrane, and then into a series of wells containing differing solutions, enabling robotic control of all the steps in an experiment. The robotic system developed here fully automates the electrophysiological experiments, including gigaseal formation, obtaining whole-cell configuration, data acquisition, and drug application. Proof-of-principle experiments consisting of application of intracellularly acting potassium channel blockers to K+ channel cell lines resulted in a very rapid block, as well as block reversal, of the current. This technique allows compound application directly to the intracellular side of ion channels and enables the dissociation of compound in activities due to cellular barrier limitations. This technique should allow for parallel implementation of recording pipettes and the future development of larger array-based screening methods.

A respiratory gas exchange catheter: in vitro and in vivo tests in large animals.

OBJECTIVES: Acute respiratory failure is associated with a mortality of 40% to 50%, despite advanced ventilator support and extracorporeal membrane oxygenation. A respiratory gas exchange catheter (the Hattler Catheter) has been developed as an oxygenator and carbon dioxide removal device for placement in the vena cava and right atrium in the treatment of acute respiratory failure to improve survival. METHODS: Differing from a previously clinically tested intravenous gas exchange device (ie, IVOX), the Hattler Catheter incorporates a small, pulsating balloon surrounded by hollow fibers. The pulsating balloon redirects blood toward the fibers, enhances red cell contact with the membrane, and significantly improves gas exchange so that smaller catheter devices are still efficient on insertion and can be inserted through the jugular or femoral vein. Devices were tested in mock circulatory loops and in short-term (8 hours) and long-term (4 days) experiments in calves to study the effect of various sized balloons and the anatomic location of the device in the venous system as a function of hemodynamics and gas exchange. RESULTS: In vitro performance in water demonstrates an oxygen delivery (Vo(2)) of 140 +/- 8.9 mL. min(-1). m(-2) and a carbon dioxide removal (Vco(2)) of 240 +/- 6.1 mL. min(-1). m(-2). Acute in vivo experiments demonstrate a maximum carbon dioxide consumption of 378 +/- 11.2 mL. min(-1). m(-2). Devices positioned in the right atrium had an average carbon dioxide exchange of 305 mL. min(-1). m(-2), whereas in the inferior vena cava position carbon dioxide exchange was 255 mL. min(-1). m(-2). Devices have been tested long term in calves, with gas exchange rates maintained over this time interval (carbon dioxide consumption, 265 +/- 35 mL. min(-1). m(-2)). Plasma-free hemoglobin levels at the end of 4 days have been 4.8 +/- 3.2 mg/dL. Hemodynamic measurements, including a decrease in cardiac outputs and increased mean pressure decreases across the device become significant only with the larger balloon (40-mL) devices (P <.05, 40-mL vs 13-mL devices). Autopsies show no end-organ damage. The device linearly increases its carbon dioxide output with progressive hypercapnea, predicting its ability to meet tidal volume reduction in the therapy of respiratory failure. CONCLUSIONS: Progress has been made toward developing an intravenous gas exchange catheter to provide temporary pulmonary support for patients in acute respiratory failure.