Selective Cerebrospinal Fluid Hypothermia: Bioengineering Development and In Vivo Study of an Intraventricular Cooling Device (V-COOL)

Abstract

Hypothermia is a promising therapeutic strategy for severe vasospasm and other types of non-thrombotic cerebral ischemia, but its clinical application is limited by significant systemic side effects. We aimed to develop an intraventricular device for the controlled cooling of the cerebrospinal fluid, to produce a targeted hypothermia in the affected cerebral hemisphere with a minimal effect on systemic temperature. An intraventricular cooling device (acronym: V-COOL) was developed by in silico modelling, in vitro testing, and in vivo proof-of-concept application in healthy Wistar rats (n = 42). Cerebral cortical temperature, rectal temperature, and intracranial pressure were monitored at increasing flow rate (0.2 to 0.8 mL/min) and duration of application (10 to 60 min). Survival, neurological outcome, and MRI volumetric analysis of the ventricular system were assessed during the first 24 h. The V-COOL prototyping was designed to minimize extra-cranial heat transfer and intra-cranial pressure load. In vivo application of the V-COOL device produced a flow rate-dependent decrease in cerebral cortical temperature, without affecting systemic temperature. The target degree of cerebral cooling (- 3.0 °C) was obtained in 4.48 min at the flow rate of 0.4 mL/min, without significant changes in intracranial pressure. Survival and neurological outcome at 24 h showed no significant difference compared to sham-treated rats. MRI study showed a transient dilation of the ventricular system (+ 38%) in a subset of animals. The V-COOL technology provides an effective, rapid, selective, and safe cerebral cooling to a clinically relevant degree of - 3.0 °C.

Keywords: Cerebral ischemia; Cerebrospinal fluid; Device; Hypothermia; Neuroprotection; Vasospasm.

Fig. 1

In vivo prototyping of the V-COOL device (a). Successful intraventricular access, verified by injection of methylene blue in the inner lumen of the cannula (b). IN inflow line, OUT outflow line, P inline pressure sensor, T temperature sensor

Fig. 2

Thermometric curves related to inflow rates from in silico (a) and in vitro (b) modelling of the V-COOL device

Fig. 3

Representative tracings showing the dynamics of cerebral cortical temperature in a rat during application of the V-COOL device (a). Mean cerebral cortical cooling (n = 42) during V-COOL application at increasing inflow rates (b). Mean systemic cooling (rectal temperature, n = 42) during V-COOL application at increasing inflow rates (c)

Fig. 4

Representative tracings showing intracranial pressure changes in a rat during application of the V-COOL device (a). Mean intracranial pressure (n = 15) during V-COOL application at increasing inflow rates (b)

Fig. 5

Representative brain MRI images (axial view) of a rat before (a) and after 60-min application of V-COOL (b). The site of V-COOL access is highlighted (dotted circles). Mean ventricular volume (n = 5) was calculated before, immediately after 60-min application of V-COOL, and 24 h after V-COOL removal (c)