Ron Solar

Ron Solar (ThermopeutiX, San Diego, USA) and colleagues report in EuroIntervention that the TwinFlo catheter (ThermopeutiX), in pigs, was associated with rapid, selective, deep cerebral hypothermia. They add that the catheter may “offer an improved method for neuroprotection during neurosurgery, cardiac arrest, acute stroke, and other ischaemic insult”. Solar talks to BIBA Briefings about the role of hypothermia in neuroprotection.

Why might hypothermia be an effective method of neuroprotection in patients with acute stroke?
There are many pathways that lead from arterial occlusion to cell death, and most of these pathways are metabolically controlled. In the laboratory, hypothermia has been shown to be the most robust method of neuroprotection to date because it acts on most, if not all of these pathways; as these pathways are metabolically controlled, lowering the temperature slows metabolism.

Presumably, there is a limited time window in which hypothermia can be used in acute stroke patients?
Yes, the sooner the brain can be cooled, the better the outcome. Ideally, cooling should occur before recanalisation as hypothermia has been shown to prevent reperfusion injury. However, many experimental studies have shown significant benefits of therapeutic hypothermia even when initiated later. In our pig studies, cooling commenced three and a half to five hours after occlusion and infarct size was significantly reduced compared with a normothermic control. In a first-in-human series of refractory cardiac arrest “rescue” cases, selective cooling with the TwinFlo catheter was initiated up to 13 hours after the arrest with outstanding outcomes.

Are there any potential risks associated with inducing hypothermia in acute stroke patients?
Almost all other previous attempts to use hypothermia in acute stroke patients incorporated systemic hypothermia techniques. Despite these only inducing mild levels of hypothermia in the patient, a number of adverse events were observed; these included shivering, pneumonia, infection, haemodynamic disturbances, and cardiac dysfunction. A small study employing intra-carotid infusions of iced saline reported concerns of volume overload and haemodilution, which meant that this technique could be only used for a very short time.

However, to date, we have not observed any significant adverse events with our approach of selective cerebral hypothermia either in vivo or in clinical use. Because the current device requires a 14F transfemoral access, the risks of groin haematoma and peripheral limb ischaemia are potentially increased compared with the use of smaller sized catheters.

Prior to your study, what have been the challenges of inducing hypothermia in patients with acute stroke?
The greatest challenge has been the absolute failure of all other attempts to show benefit of hypothermia in the clinical setting of acute ischaemic stroke. However, none of the previous attempts were able to cool the brain to temperatures that data show to be most effective for stroke (≤30 degrees Celsius). The majority of clinical studies employed systemic hypothermia techniques, and due to serious detrimental systemic effects, including cardiac dysfunction (as previously mentioned), patients could not be cooled below 32 degrees Celsius.

How is the TwinFlo catheter designed to overcome these challenges?
TwinFlo incorporates a proprietary design that selectively cools the brain, and does so by isolating the carotid artery and perfusing cold blood directly to the brain. The design provides a closed circuit in which the patient’s arterial blood is removed, cooled with a standard extracorporeal circuit, and then pumped selectively to the brain. The design further incorporates a counter-current flow of the warm and cold blood, respectively, which then insulates the cold blood from the systemic circulation and, thus, prevents the adverse events of systemic hypothermia. Furthermore, since we are actively perfusing blood to the brain in a controlled manner, the technique mitigates potential clinical issues—such as blood pressure variability and decreased cerebral blood flow—that have been shown to play a major role effecting outcome in acute stroke.

What were the main results of your study?
Our in vivo studies demonstrated the ability to selectively cool the brain of large pigs to temperatures as low as 15 degrees Celsius without significantly effecting the systemic temperature. Cooling rates as fast as 2 degrees Celsius per minute were attained. In a randomised porcine stroke study, with blinded analysis, compared with a normothermic control group, selectively cooling the brain to 26 degrees Celsius for only 30–90 minutes resulted in a 10-fold reduction in the stroke volume. Also, there were no differences in any of the systemic parameters between the two groups. The initial clinical use of TwinFlo has been in the settings of neurosurgery and refractory cardiac arrest/shock in patients who had little or no options; although the number of cases has been small to date, the outcomes have been quite impressive.

What further studies are needed?
The next steps are studies in acute ischaemic stroke—an initial phase I study to demonstrate safety and feasibility of selective deep hypothermia in this clinical setting, followed by a pivotal trial that would include patients presenting with large vessel occlusion as well as other aetiologies. The pivotal study will be powered to satisfy regulatory and reimbursement requirements, but will also serve to be hypothesis-generating to address parameters for further optimisation of the technique, including depth (temperature), duration and timing of hypothermia in this clinical setting.

If further studies show the TwinFlo catheter to be safe and effective, which acute stroke patients do you think would benefit the most?
Since we are treating the insult to the brain tissue caused by the event (occlusion, hypoxia, anoxia, oedema, haemorrhage, etc.), we believe that selective cerebral hypothermia has the potential to benefit all acute stroke patients (haemorrhagic as well as ischaemic). In particular, the TwinFlo catheter is best suited—and the only technology currently in sight—to provide selective, rapid, deep and safe cerebral hypothermia.