Selective brain hypothermia

Handbook of Clinical Neurology, Vol. 157 (3rd series) Thermoregulation: From Basic Neuroscience to Clinical Neurology, Part II A.A. Romanovsky, Editor https://doi.org/10.1016/B978-0-444-64074-1.00052-5 Copyright © 2018 Elsevier B.V. All rights reserved

Chapter 52

Selective brain hypothermia JAE H. CHOI* AND JOHN PILE-SPELLMAN Neurological Surgery PC, Lake Success, NY, United States

Abstract Selective brain hypothermia is a powerful concept for neuroprotection that has been successfully investigated in a variety of animal models of global and focal ischemia. Its major advantages over systemic hypothermia include rapid induction of cooling, ability to achieve profound target brain temperatures, organ-selective cooling, and temperature control. Clinical systems and devices are available or are currently under development that utilize conductive (surface-cooling pads, closed-loop catheters), convective (transnasal coolant delivery), or mass and energy transport (cold intra-arterial infusion) methods to achieve and maintain selective brain hypothermia. The “ideal” brain-cooling system that is characterized by rapid cooling to profound hypothermia, its ability to maintain selective cooling over several days, and is noninvasive in nature, remains unrealistic. Instead, systems may be identified by their distinct advantages to meet a specific need in the care of a patient. This involves the consideration of the timing of ischemic injury (preischemic, intraischemic, postischemic), extent of ischemic damage (excitotoxicity, inflammation, necrosis, edema), and type and setting of therapeutic intervention (intensive care, interventional therapy, surgery). The successful translation of these systems into clinical practice will depend on smart engineering, safety and efficacy, and usability in current clinical work flow.

INTRODUCTION In 1954, with the publication of the results from a canine experiment, Parkins and colleagues proposed a solution to a burning clinical problem. Then, surgical procedures that demanded a circulatory arrest for a longer period of time or that would significantly benefit from such an intervention were difficult to perform due to the critical dependence of the brain on blood oxygen. It was already known that lowering body temperature could alleviate ischemic brain damage because of the strong temperaturedependent change of tissue metabolic demand (Bigelow et al., 1950). However, systemic hypothermia, or wholebody hypothermia, was a double-edged sword due to the frequent triggering of myocardial irritability and cardiac arrhythmia, among others. In order to reap the benefit of hypothermia without the side-effects thereof, Parkins and colleagues (1954) investigated a vascular model of nonsystemic selective

brain hypothermia in 21 dogs. This method involved extracorporeal blood circulation and blood cooling in an ice bath, and selective anterograde cerebral reperfusion with cooled autologous blood. With this, extreme selective brain hypothermia could be achieved within a few minutes with minimum brain temperatures between 8 and 18°C and an average temperature differential of 14
3°C between body and brain. First, the investigators found that dogs with very low brain temperatures 12°C suffered neurologic deficits or died. Following, in the more favorable group of 13 dogs with brain temperatures between 12 and 18°C, circulation was temporarily interrupted and cold perfusion performed for up to 40 minutes before circulation was reinstated and rewarming initiated. Of those, four died from unknown or surgery-related causes, one died from a massive bowel infarction, and eight dogs survived without any neurologic deficits. Now, more than 60 years later, therapeutic hypothermia has proven to be a relevant neuroprotective treatment

*Correspondence to: Jae H. Choi, MD, MS, Unruptured Brain Aneurysm Center, Neurological Surgery P.C., 1991 Marcus Avenue, Suite 108, Lake Success NY 11042, United States. Tel: +1-516-442-2250, E-mail: [email protected]

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in various clinical settings (O’Collins et al., 2006; Polderman, 2008), such as in patients with out-of-hospital cardiac arrest (Bernard et al., 2002; Hypothermia After Cardiac Arrest Study Group, 2002) and neonates with hypoxic-ischemic encephalopathy (Eicher et al., 2005; Gluckman et al., 2005; Shankaran et al., 2005), as well as performing hypothermic circulatory arrest in surgery (Warm Heart Investigators, 1994; Regragui et al., 1996; Plourde et al., 1997; Harrington et al., 2004) and combatting cerebral edema (Clifton et al., 1993; Marion et al., 1997; Polderman et al., 2002; Kollmar et al., 2010). However, in other settings, therapeutic systemic hypothermia has been less conclusive as a neuroprotective strategy, in conjunction with status epilepticus (Legriel et al., 2016), traumatic brain injury (Clifton et al., 2011; Sadaka and Veremakis, 2012), aneurysmal subarachnoid hemorrhage (Todd et al., 2005), ischemic stroke (Lyden et al., 2014; van der Worp et al., 2014), or myocardial infarction (Schwartz et al., 2012). The main reasons for this elusiveness of benefit from hypothermia are the inertia and side-effects of body cooling rather than the lack of effect from the pleiotropic mechanisms of action arising from lowering tissue temperature. Selective brain hypothermia, after more than 60 years, still remains an appealing approach (Slotboom et al., 2004; Konstas et al., 2007; Choi et al., 2010; Esposito et al., 2014). In fact, more attention has been directed recently to developing and testing methods to selectively cool the target organ, the brain, without significantly affecting the temperature of the entire system. In this chapter, we will review the various strategies that have been under consideration for selective brain cooling. Furthermore, we hope to shed some light on the physics and physiology of selective brain cooling, the challenges of local brain cooling in humans, the requirements for such selective cooling systems in order to be clinically effective and useful, and avenues for combined use of both local and systemic cooling systems. This is accompanied and illustrated by findings from preclinical and clinical investigations on selective brain cooling in models of and patients with organ ischemia. Current methods of systemic cooling and their impact and drawbacks in clinical settings have been reviewed in Chapters 49 and 51.

STRATEGIES FOR SELECTIVE BRAIN HYPOTHERMIA The concept of selective hypothermia involves targeting and thermally isolating the tissue or organ of interest from the rest of the body. The more selectively and effectively this is done, the better and longer body normothermia or euthermia is maintained (approximately 36.6°C or 98°F).

Forced hypothermia is not a trivial task as the human body is maintained at a tightly regulated euthermic equilibrium point by multiple independent thermoeffector loops (Romanovsky, 2007), as are almost all mammals, with the exception of hibernating animals (Fig. 52.1) (Carey et al., 2003; Drew et al., 2007). Euthermia is a necessary baseline condition of human life that enables all enzymatic activities of conversion of energy and transformation of matter to occur within boundaries that are physiologically meaningful (Lee et al., 2007; Daniel et al., 2010). As such, the body is equipped with natural mechanisms that counter external forces of thermal stress (Fig. 52.1). Apart from thermally insulating features of the skin and fat tissue, shivering and increase in metabolic activity and core organ blood flow are active mechanisms against cold forces (Giaja, 1925; Frank et al., 1997; Doufas and Sessler, 2004). If cold forces are stronger than the body’s arsenal of inherent countermechanisms, hypothermia ensues. Tissue metabolism and blood flow now decrease as a function of temperature (Rosomoff and Holoday, 1954; Mori et al., 1998; Walter et al., 2000). Heart and respiratory rates drop and blood viscosity rises. With increasing duration of hypothermia, however, the risk of systemic complications grows, as well (Doufas and Sessler, 2004; Polderman, 2009). Selective and localized organ cooling promises to improve the processes and clinical parameters involved in the induction and maintenance of cooling. The ideal characteristics of a system for selective brain cooling are summarized in Table 52.1. Like systemic hypothermia concepts, selective braincooling systems on the market or under development can be divided into external and internal systems (Table 52.2). External systems are applied on to the body surface like a helmet, including scalp and neck, or inserted into the nasal cavities. For instance, the cooling pads cover the head like a helmet for heat exchange with the brain through the layers of the cranium. Often combined with the helmet, the cooling collar or neck wrap exchanges heat with blood in the carotid arteries that feed the circle of Willis. In contrast, internal systems are mostly catheterbased, endovascular devices that may involve closedloop and open (infusion) concepts. The main difference between internal systems for systemic hypothermia and selective brain hypothermia is the location of the catheter. It is located in the inferior vena cava for the former, and in the carotid artery for the latter. However, systemic cold infusions can also be connected to a peripheral venous access. The venous or arterial blood is cooled either as it passes the closed-loop heat exchange catheter or through direct mixing with the infused cold fluid. The most effective and at the same time most

SELECTIVE BRAIN HYPOTHERMIA

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Fig. 52.1. Hypothermia in humans and hibernating mammals. The study of hibernating mammals gives insight into their unique endogenous ability to manage extreme hypothermia. The range of body temperature fluctuations of the arctic ground squirrel during months of hibernation is more than 37°C and may reach below the freezing point of water. In comparison, clinical therapeutic hypothermia covers only a fraction of the thermal spectrum involved in the lives of hibernating mammals. The clinical consequences, however, are often severe, as demonstrated in the occurrence of serious adverse events during systemic hypothermia. (Adapted from Drew KL, Buck CL, Barnes BM, et al. (2007) Central nervous system regulation of mammalian hibernation: implications for metabolic suppression and ischemic tolerance. J Neurochem 102: 1713–1726.)

invasive methods are surgical. It is not difficult to imagine how deeply and quickly brain hypothermia can be achieved by total blood exchange with oxygenated cold fluid followed by direct perfusion of the brain with the cold fluid. For additional information about thermoregulation, see Chapters 1 and 9–11. For the distinct mechanisms of forced cooling of the body and spontaneous hypothermia, see Chapter 33.

PERFORMANCE OF SELECTIVE BRAIN HYPOTHERMIA SYSTEMS The concept of selective hypothermia implies brain cooling is more rapid, deeper, and can be performed with tighter control compared with systemic hypothermia. Various analogies from everyday life may be considered, such as air conditioning a single room versus the entire house or steering a small boat versus a freighter ship. The complexity arises from the fact that cooling is performed in a living system with mechanisms that naturally counteract external forces of cooling that may also apply to selective brain hypothermia: 1.

constant blood circulation and 60,000 miles of vessels with a tightly meshed capillary tissue bed (cerebral intercapillary distance is approximately 50 mm) (Cabin, 1992)

2. tissue metabolism that creates energy and heat (cerebral heat production is 66 J/100 mg/min) (Yablonskiy et al., 2000) 3. several anatomic layers making up the cranium, including scalp, extracranial circulation, calvaria, cerebral meninges, and brain circulation 4. several anatomic layers making up the neck, including skin, vasculature, subcutaneous fat, and muscles 5. possible shivering when external force reduces body temperature below the equilibrium point. The anatomic and physiologic characteristics of the head reveal that protective mechanisms are put in place against external thermal forces that include material insulation (factors 3 and 4 above), metabolic heat production (factors 2 and 5 above), and an extensive vascular network that acts as a radiator or heat pipe (factors 1, 3, and 4 above). Conversely, since thermal energy produced in the brain cannot easily dissipate to the outside, global brain heat production from oxygen and glucose metabolism and heat removal via blood perfusion are in equilibrium (Yablonskiy et al., 2000): Final Brain Temperature

Brain Heat Production

Ctissue•T˙ = (DH° – DHb)•rCMRO2

Brain Heat Removal

–

rB•CB•rCBF•(T–Tarterial)

Table 52.1 Essential characteristics of systems for selective brain hypothermia Requirement for selective cooling

Description and rationale for selective cooling

Parameter for selective cooling

Current standard parameters

Current standard cooling procedures Surface cooling pads, intravascular (central vein) closed-loop cooling catheter, extracorporeal blood cooling and recirculation, intravenous cold fluid infusions, ice packs Deep hypothermia in cardiopulmonary bypass, mild to moderate hypothermia in cardiac arrest, neonatal asphyxia and other investigational studies Cooling for the duration of the surgery (hours) or prolonged over several days

Speed of cooling

Because neuronal cell death is timedependent and irreversible, neuroprotection must be delivered to the relevant tissue bed rapidly

5–15 minutes

60–420 minutes for systemic hypothermia

Depth of cooling

Even mild hypothermia (36°C) has been shown to be neuroprotective. However, potency of protection increases with decrease in temperature This depends on the desired mechanism, clinical setting, and overall safety and efficacy as determined in clinical studies. Maximum duration is also determined by the type of procedure performed and device used for hypothermia Thermal equilibrium between brain and body would occur within minutes once selective cooling is halted. Rewarming process may need to be slower to prevent rebound phenomena Cooling is local, may be limited to the site of injury or damage, and is decoupled from the systemic core temperature

25–36°C

25–36°C

Minutes (preischemia, reperfusion) to hours (inflammation, apoptosis) and days (repair, edema)

Hours to days

Minutes (to hours and days)

Hours to days

Rewarming phase is usually very slow and prolonged following long-term systemic hypothermia to avoid rebound phenomena

Tissue volume or organ

Brain cooling via systemic/ whole-body hypothermia

Induction, maintenance, and reversal of selective hypothermia are fully automated with accurate temperature control. Control is based on operator input and integrated multisensor feedback mechanism

Continuous and in real time; quick changes are possible; flexible temperature control within
1.0°C deviation

Brain temperature depends on systemic core temperature; changes are slow

External heat exchange with surface cooling or internal heat exchange with endovascular, endotracheal, intranasal, or esophageal catheters and tubes, or direct mixing with blood with cold fluid infusion For systemic hypothermia: closed-loop catheters with embedded temperature sensor and feedback mechanism; surface cooling and intravenous cold fluid infusion under core temperature monitoring and manual control; extracorporeal heat exchanger during surgery

Duration of cooling

Rewarming

Localized cooling

Control of cooling

Energy expenditure

Setting, logistics, and spatial footprint

Selective cooling system must remove heat from the brain (800 g) and is capable of removing more heat than the brain produces Selective cooling system is noninvasive and may be used on the field or in the emergency setting. If cooling system is invasive, it may be used as an adjunct organ-protective application to the main procedure

Total heat removal > D Brain Heat For ambulatory systems: highly portable, battery-driven, ease of use. For stationary systems: small footprint and highly adapted to operative space to avoid cluttering and crowding

Systemic cooling system must remove heat from the body (70 kg) and removes more heat than the body produces Systemic cooling systems are more stationary and have limited portability. The systems have a large footprint due to the heavy compressor for the chiller and heat exchanger

Safety and efficacy

Any selective cooling procedure must be safe for the patient and should provide additional efficacy beyond standard or supportive therapy alone

Lack of or only minimal systemic complications during cooling, countermechanisms during induction, and rebound during rewarming

Safety and efficacy shown in out-of-hospital cardiac arrest and neonatal asphyxia; investigational in other acute settings involving trauma and ischemia

New indications

Selective brain cooling for prehospital neuroprotection, neuroprotection as an invasive or noninvasive adjunct to standard procedures or as stand-alone procedure, bridging from selective cooling to long-term systemic hypothermia

Safe and effective; mechanismbased; cost

On-site systemic hypothermia mainly; often induced after acute therapy

Total heat removal > D Body Heat Cooling console with chiller, heat exchanger, fluid reservoir, pump, electronics, and display. In addition, the intravascular cooling catheter, cooling pads, or infusion system. Extracorporeal heat exchange system and blood circulation for surgical procedures Frequent complications of long-term systemic cooling include cardiac dys/ arrhythmia, pneumonia, and other infections, hypotension, coagulopathy, hypokalemia, hematocrit increase, and thrombocytopenia; rebound during rewarming Safe and effective; mechanism-based; cost

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Table 52.2 Systems for selective brain hypothermia and comparison with systemic hypothermia concepts Cooling system and type External systems Surface

Endoluminal

Internal systems Closed-loop catheter

Infusion catheter

Extracorporeal systems or open surgery Blood cooling

Open irrigation

Selective brain cooling

Systemic hypothermia

Tend to be less invasive; many physiologic barriers impeding heat exchange with the brain Cooling helmet and collar/neck wrap Cooling pads, ice packs, cold air-ventilated blankets Mechanism: heat exchange with Mechanism: change of body core brain through all layers of the temperature via surface cooling cranium (conduction) (conduction) Endonasal tube (inert coolant Esophageal tube (cold fluid mist, e.g., perfluorohexane, circulated inside closed-loop tube) sprayed into cavity) Mechanism: heat exchange with Mechanism: change of body core temperature via esophageal and forebrain through layers between gastric cooling (conduction) nasal cavity and intracranial space (convection and conduction) Tend to be more invasive; lower number of physiologic barriers for heat exchange with the brain Circulation of cold fluid in catheter; Circulation of cold fluid in catheter; catheter is located in the central catheter is located in the brain vein, e.g., inferior vena cava feeding artery, e.g., carotid artery Mechanism: change of central Mechanism: change of arterial blood venous blood temperature via temperature in the carotid artery cooled closed-loop catheter via cooled closed-loop catheter (conduction) (conduction) Infusion of cold fluid and mixing with Infusion of cold fluid and mixing with venous blood; catheter is located in arterial blood; catheter is located in the peripheral or central vein the brain feeding artery, e.g., carotid Mechanism: change of arterial blood temperature in the carotid artery via direct mixing with cold fluid The most invasive; most effective cooling

Emcools; Natus Medical; Cryothermic Systems; Bard; Zoll

BeneChill; Quickcool; Advanced Cooling Therapy

FocalCool; Acandia; Zoll

Hybernia Medical; Seiratherm; nonproprietary intravenous cold fluid infusion

Mechanism: change of venous blood temperature via direct mixing with cold fluid

Arterial blood is removed from the circulation, cooled externally, and reintroduced into the arterial circulation; may involve artificial circulatory arrest, temporary vascular occlusion, cardiopulmonary bypass, and blood exchange Craniotomy and direct irrigation of brain with cold fluid

where Ctissue is specific heat of the brain, Ṫ is final brain temperature, DH0 is enthalpy per mole of oxygen, DHb is energy required to release oxygen from hemoglobin, rCMRO2 is regional cerebral metabolic rate of oxygen, rB is density of blood, CB is specific heat of blood, rCBF is regional cerebral blood flow, and T – Tarterial is the difference between brain temperature and arterial input temperature. At rest, brain temperature (thalamic temperature measured with magnetic

Manufacturer/ developing company

Medtronic; ThermopeutiX

resonance thermometry) is slightly higher than arterial or body temperature (measured with a rectal probe), approximately 0.3°C. Both cmRO2 and CBF are temperature-dependent and CBF is coupled to cmRO2 over a wide range of temperature, meaning CBF will change with changes in cmRO2 (Konstas et al., 2007; Neimark et al., 2008): q ¼ q0  ab(T37); o ¼ o0  ab(T37)

SELECTIVE BRAIN HYPOTHERMIA where q is final cmRO2, q0 is baseline cmRO2 at 37°C, a and b are regression coefficients, (T – 37) is new brain temperature, o is final CBF, and o0 is baseline CBF. Furthermore, it is evident that heat removal increases with higher CBF and lower arterial input temperature. For additional information about body and brain temperature, see Chapters 29 and 30.

Cooling helmet and neck wrap Cooling helmets and neck/shoulder wraps consist of pouches or pads filled with phase shift material that is capable of storing and releasing large amounts of energy (Emcools). The pads are stored and precooled in a freezer or refrigerator at the material-specific temperature range. If attached to the skin, the pads exchange heat via conduction with the underlying structure, i.e., scalp or neck, and thus modify head or arterial input temperature. Once heat-exchange is completed, the pads must again be cooled or frozen before they can be reused. However, the medical-grade pads are usually single-use components. A different type of head-cooling device, a cap, consists of a flexible tubing coil through which temperature-controlled cold water is circulated with a pump (closed-loop circulation) (Natus Medical). The coil is put in contact with the scalp and thermally insulated from the ambient temperature with additional caps. Cooling caps have been investigated in infants (Gluckman et al., 2005). Gluckman et al. (2005) studied the outcome in 218 full-term neonates with encephalopathy randomized to 72 hours of head cooling versus no cooling. Cooling pad temperatures were held between 8 and 12°C. Target temperature of 34–35°C, as measured with rectal temperature probes, was achieved within 2 hours of head cooling. Overhead heating was used throughout the cooling period, except for the initiation phase of 20–30 minutes, during which rectal temperature fell to 35.5°C. Although primary outcome of death and severe neurodevelopmental disability at 18 months were similar between both groups, among 172 neonates with moderate electroencephalogram changes cooling significantly improved the primary outcome (48% vs. 66%, p ¼ 0.02) and overall severe neuromotor disability (12% vs. 28%, p ¼ 0.03). In 8 neurocritical care patients, Wang et al. (2004) performed head cooling for 48–72 hours and found that there was an average brain temperature reduction (as measured 0.8 cm subcortically) of –1.6°C compared to +0.22°C in the control group (n ¼ 6). During the first hour of cooling, brain temperature dropped by 1.84°C (range 0.9–2.4°C). No significant complications were detected during the cooling procedure. Clinical outcome was not reported.

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The feasibility of selective cooling with a headcooling system was investigated by Poli (unpublished correspondence) in 10 stroke patients with brain temperature probes treated in the neurocritical care unit. A local cooling rate of –0.5°C was found within the first hour. This cooling procedure was found to be safe. However, there was no reporting of clinical outcome results. In contrast, a study by Corbett and Laptook (1998), in which deep brain temperature (thalamus) was monitored with magnetic resonance thermometry during head cooling in healthy volunteers, found no significant brain cooling despite a reduction of the scalp temperature to 10–15°C and cooling over 50 minutes. The temperatures of the double-layer cooling pads were 4°C (inner) and – 20°C (outer), respectively. Interestingly, the lowest scalp temperature (measured with fiberoptic temperature sensors) was achieved within the first 5 minutes, after which scalp temperature continuously increased by 0.14
0.09°C/min.

Transnasal cooling There are two types of transnasal cooling systems. The closed-loop system circulates cold water within the endonasal tubing to exchange heat with the intracranial space through the cribriform plate via conduction (Quickcool). A second type introduces large amounts of coolant mist, a mixture of an inert perfluorocarbon and oxygen, into the nasal cavities that through convection and conduction cools the intracranial space (BeneChill). Among 194 patients with out-of-hospital cardiac arrest transnasal cooling was used on the field for selective brain cooling together with standard rescue procedures in 93 randomly assigned patients (Pre-ROSC IntraNasal Cooling Effectiveness Study; Castren et al., 2010). Upon arrival at the hospital, the tympanic temperature in the treatment group was significantly lower compared to the temperature in the control group, despite similar baseline temperatures (34.2
1.5°C vs. 35.5
0.9°C, p < 0.001), resulting in an average temperature drop of 1.3°C in 26 minutes. In survivors, transnasal cooling was continued until systemic cooling was initiated. Local cooling was initiated within a median time of 23 minutes and over a median duration of 62 minutes among patients in whom return of spontaneous circulation was achieved (median of 2000 mL of coolant was used). Frequency of serious adverse events was similar between both groups (n ¼ 7/93 or 7.5% in cooling group vs. n ¼ 14/101 or 13.9% in control group, p ¼ 0.23), with epistaxis as the only device-related serious event. Overall survival was 15.1% and 12.9% in the cooling group and control group, respectively (not significant). Among patients with cardiopulmonary resuscitation

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initiated within 10 minutes, however, 56.5% survived to discharge compared with 29.4% in the control group ( p ¼ 0.04, relative risk 1.9). Twenty stroke patients neuro-monitored and treated in the neurocritical care unit underwent systemic cooling with intravenous cold infusion or transnasal cooling in a 1:1 randomized fashion (Poli et al., 2014). Intravenous infusion rate was 4 L/hour over 30 minutes (4°C) and transnasal coolant flow rate was 60 L/min over 1 hour. After 30 minutes of intervention, brain temperatures decreased by 1.31
0.4°C in the infusion group versus 0.68
0.3°C in the transnasal group (p < 0.001). Although systemic cold infusion achieved brain cooling faster than the transnasal approach, their effects on systolic arterial pressure, mean arterial pressure, intracranial pressure, and cerebral perfusion pressure, occurring in both groups with distinctive patterns, raise concerns about the safety of both cooling methods. A similar study in critical care stroke patients investigated the feasibility of brain cooling during 1 hour of transnasal cooling at a coolant flow rate of 80 L/min (Abou-Chebl et al., 2011). In 11 patients with brain temperature probes, brain temperature fell by 1.4
0.4°C. However, core temperature also dropped by 1.1
0.6°C. Transient hypertension was the only adverse event in 1 patient in whom transnasal cooling was consequently stopped.

Closed-loop intra-arterial cooling system The closed-loop selective brain hypothermia system is conceptually the intra-arterial equivalent of the endovascular cooling catheters. Placed in the common carotid artery, usually from a femoral artery access, cold fluid is circulated within the catheter (FocalCool; Acandia). The distal part of the catheter serves as the heat exchanger which may incorporate thermal sensors for feedback control. Heat transfer is via conduction with blood in the carotid artery reducing the arterial input temperature. Fluoroscopic guidance is necessary to place the catheter into the target artery. An intra-arterial cooling catheter system was tested in eight adult sheep (Cattaneo et al., 2016). The closed-loop catheter was equipped with four serially arranged balloons through which cold fluid at 6°C was circulated. The catheter was placed in the common carotid artery and cooling was performed over 180 minutes. The temperature of the ipsilateral temporal cortex was reduced by 1°C after a median time of 8.5 minutes (range 3.8–12.5 minutes) and by 3°C after 85.7 minutes (59.8–137.6 minutes). In six sheep a reduction by 4°C was achieved after 142.1 minutes (109.3–180.0 minutes). Cooling of the ipsilateral frontal cortex was slightly delayed. Although brain cooling was achieved more

quickly and to deeper temperatures, systemic cooling occurred and continuously lowered body temperature over the duration of local cooling by more than 3°C. The temperature of the contralateral brain hemisphere was similar to that of the ipsilateral side.

Infusion system Mixing of cold physiologic fluid with arterial blood in the carotid artery allows energy and mass to be carried directly to the brain via the arterial system (Hybernia Medical). The catheter is placed in the internal carotid artery under fluoroscopic guidance. The safety and feasibility of infusion of cold normal saline into the internal carotid artery were investigated with standard endovascular catheters in elective cerebrovascular patients undergoing follow-up cerebral angiograms (Choi et al., 2010). In 9 out of 18 patients, ipsilateral jugular venous bulb temperature measurement was performed. Following a brief infusion of cold saline at 7.4
2.4°C jugular venous bulb temperature decreased by 0.84
0.08°C after 8.2
1.9 minutes. No systemic shivering or serious adverse events occurred. The data were used to run and validate a computer simulation which suggested a temperature drop of 2.1
0.23°C in the ipsilateral anterior circulation territory (Neimark et al., 2013). There was a strong correlation between calculated and measured jugular venous bulb temperatures (R2 ¼ 0.93) suggesting a good fit between the calculated brain temperature and true brain temperature. An endovascular (intra-arterial) cooling catheter system was tested in 13 pigs that underwent a vascular modification to reduce blood flow into the external carotid artery system (Choi et al., 2016). Using the catheter device cold normal saline at 0–4°C was infused into the internalized common carotid artery and infusion flow rate adjusted to achieve and maintain a brain target temperature of 33°C as measured with parenchymal temperature probes. Target temperature was achieved in the ipsilateral frontal brain matter in a median time of 5 minutes (interquartile range 3.7–10.6 minutes). Target temperature was maintained at 32.5
1.6°C and remained selective to the cooled brain hemisphere (vs. contralateral hemispheric temperature and systemic temperature via rectal/esophageal thermal probes) over the cooling duration of 2 hours with the help of heating blankets. Four pigs were excluded due to complications arising from the surgical procedures and carotid hypersensitivity. Hematocrit decreased slightly from 26.1
2.5% at baseline to 24.2
2.8% (p ¼ 0.045). Pathologic examination found no signs of traumatic or ischemic brain damage from the endovascular device or the cooling procedure. A clinical study investigated the safety of cold intraarterial infusion (carotid artery or vertebral artery) in

SELECTIVE BRAIN HYPOTHERMIA acute ischemic stroke patients undergoing endovascular revascularization therapy (Chen et al., 2016). In 26 stroke patients, cold normal saline at 4°C was infused into the ischemic territory through standard infusion catheters before (10 mL/min for 5 minutes) and after thrombectomy (30 mL/min for 10 minutes). Unfortunately, no measures were taken to assess brain or surrogate brain temperature. However, the procedure appeared to be safe in acute ischemic stroke patients. In another study, patients with acute middle cerebral artery occlusion <6 hours from symptom onset were randomly selected to receive pre-reperfusion superselective cold infusion into the ischemic territory (50 mL/min for 10 minutes) with subsequent endovascular revascularization with local urokinase and balloon dilatation, thrombectomy, or stent implantation (Peng et al., 2016). The normothermia control group received reperfusion therapy only. Brain temperature was not measured. Baseline National Institutes of Health Stroke Scale (NIHSS) scores were 17
8 and 16
7 in the normothermia and hypothermia groups, respectively (not significant). Improvement of neurologic deficits was more pronounced in the hypothermia group compared to the normothermia group at 24 hours (final NIHSS 10
7 vs. 12
6), 7 days (9
6 vs.12
6), and 1 month (7
5 vs. 9
3) after treatment ( p < 0.05). Infarct volumes were determined with magnetic resonance imaging at baseline (25
10 vs. 25
9 mm3 for normothermia vs. hypothermia group) and following treatment at 24 hours (26
10 vs. 13
6 mm3) and 7 days (26
11 vs. 12
7 mm3). Infarct volumes were significantly reduced in the hypothermia group (p < 0.05).

EVIDENCE FROM SELECTIVE BRAIN COOLING IN ANIMAL MODELS Therapeutic hypothermia has been shown to have a remarkable effect on global and focal ischemia. Unlike other neuroprotective approaches, hypothermia acts with a diverse array of molecular pathways (pleiotropic mechanism of action) that are ideally suited to address the damage involved in ischemic injury (Fig. 52.2; Dirnagl et al., 2003). Hypothermia: ●

●

● ●

Extracorporeal heat exchange system Adapted from the classic model of brain cooling in animal experiments and cardiopulmonary bypass surgery, warm blood is taken out of the arterial circulation, cooled in an extracorporeal chiller, and then reperfused into the brain circulation via carotid artery access (ThermopeutiX). The carotid artery is occluded proximal to the reperfusion access to avoid mixing with warm blood from the systemic circulation. In a surgical pig model with stroke induced via clip on a middle cerebral artery branch over 3 hours, an extracorporeal heat exchange system was tested (Mattingly et al., 2016). Following the ischemia phase, the clip was removed. Using the extracorporeal circulation, blood from the descending aorta was passed through an extracorporeal chiller, cooled to 25°C, and reperfused distal to the balloon-occluded common carotid artery ipsilateral to the stroked hemisphere for 3 hours. Nasal temperature was used as a surrogate for brain temperature. Data from 25 out of 28 pigs were analyzed

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(n ¼ 12 were selectively cooled). The median time from completed setup of the extracorporeal circulation to the lowest local temperature was 23.7 minutes (interquartile range 23.2–24.3 minutes). After 3 hours of selective cooling, core temperature (rectal/esophageal) was 34.0
1.3°C and the contralateral hemispheric temperature was 31.6
3.7°C. Stroke volume on T2-weighted magnetic resonance imaging was significantly smaller in the hypothermia group ( p ¼ 0.046), but not on pathologic examination.

● ●

reduces extracellular excitatory activity (neurotransmitter and ion homeostasis) (Busto et al., 1989; Nakashima and Todd, 1996; Sick et al., 1999) suppresses disruption of the blood–brain barrier (prevention of reperfusion injury and hemorrhagic transformation) (Kumura et al., 1996; Peters et al., 1998; Huang et al., 1999; Kidwell et al., 2002) attenuates neutrophil infiltration (anti-inflammatory effect) (Toyoda et al., 1996; Ishikawa et al., 1999) decreases cerebral metabolism (reduces oxygen demand and cerebral blood flow) (Rosomoff and Holoday, 1954; Michelfelder, 1991; Mori et al., 1998; Walter et al., 2000) prevents apoptosis (cell death) (Xu et al., 2002; Wang et al., 2005) has endogenous neuroprotective characteristics (ischemic tolerance and hibernation) (Drew et al., 2007; Christian et al., 2008).

Fig. 52.2. Temporal evolution of ischemic injury. (Reproduced from Dirnagl U, Simon RP, Hallenbeck JM (2003) Ischemic tolerance and endogenous neuroprotection. Trends Neurosci 26: 248–254.)

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In animal models of global or focal cerebral ischemia it has been demonstrated that even slight or moderate reductions in body temperature and selective brain cooling (32–35oC) were neuroprotective (Bacalzo and Wolfson, 1969; Sterz et al., 1991; Schwartz et al., 1996; Yamamoto, 1996; Ding et al., 2004). Moreover, pre- and intraischemic hypothermia achieved dramatic neuroprotection by reducing infarction volume by 50–90% (Chen et al., 1992; Goto et al., 1993; Karibe et al., 1994), suggesting a role of hypothermia in preventing neurologic injury when applied prior to or simultaneously with ischemic insult. A meta-analysis of animal models of ischemic stroke (n ¼ 3353 from 101 publications) found an overall reduction of 44% in infarct size in animals treated with hypothermia (van der Worp et al., 2007). Surprisingly, this effect was also observed in animals treated with only mild hypothermia (33–35oC), relatively short duration of cooling (up to 100 minutes), and longer delay until treatment (180–360 minutes). However, best outcome was observed in animals that were cooled <32oC and in which cooling was performed before or during temporary ischemia. The underlying protective mechanisms in selective hypothermia are not different from those found from systemic hypothermia experiments (Table 52.3). Just like the canine model that Parkins et al. (1954) used, the classic model of selective brain cooling in animals has been extremely invasive and surgically extensive. The procedures involve general anesthesia, mechanical ventilation, numerous surgical access sites,

and vascular remodeling and clamping, and often utilize extracorporeal circulation, pumps, chiller, and oxygenator. This is necessary mainly because of the desire to control for as many variables as possible, amplify speed, duration, and control of brain cooling, and expand the variety and amount of data collected from the experiment. Furthermore, cold cerebral perfusion has proven to be a reliable and effective method to induce profound brain hypothermia with excellent control and minimal delay. Despite the complexity of the procedures numerous studies have been successfully conducted using cerebral perfusion concepts in a variety of animal models (rodents, canines, nonhuman primates) of global and focal cerebral ischemia (Table 52.4). The results of these experiments suggest that selective brain hypothermia is feasible and effective in protecting the brain from the damages of ischemia. However, translation of therapeutic hypothermia into clinical practice has been hampered by the fact that it has been difficult to develop systems that are sufficient in speed, depth, and duration of cooling and offer a practicality that is clinically adequate (ease of use and invasiveness). The latter includes a level of clinical safety that has been only met in settings of high natural mortality, such as out-ofhospital cardiac arrest or hypoxic-ischemic encephalopathy in neonates. It is easy to imagine how selective brain-cooling devices that are more effective, but also practical in achieving brain hypothermia, could improve the outcome in patients with brain ischemia or those who are at risk for iatrogenic brain ischemia. Those include

Table 52.3 Impact of selective brain hypothermia on physiology and outcome in animals Brain temperature (time to reach temperature)

Results

Dog

8–18°C (<15 minutes)

● Good survival in 7/8 ● Good survival after 30 minutes of

Schwartz et al. (1996) Walter et al. (2000)

Baboon

Strauch et al. (2004)

Juvenile pig

18.5–24.5°C (26 minutes) 25°C and higher (9 minutes) 20°C (30 minutes)

Ding et al. (2004)

Rat (middle cerebral artery stroke model)

● ● ● ● ● ● ● ●

Reference

Animal species

Parkins et al. (1954)

CBF, cerebral blood flow.

Juvenile pig

33°C (10 minutes) (controlled experiment, three groups)

hypothermic circulatory arrest Good survival in 10/12 CBF # to <50% from baseline CBF # to <40% from baseline Metabolic rate Q10 ¼ 2.8 1/29 died CBF # to <80% Metabolic rate # to <50% from baseline Reduction in infarct volume and neutrophil infiltration in brain-cooling group ● Improved outcome in brain-cooling group

SELECTIVE BRAIN HYPOTHERMIA

849

Table 52.4 Experimental selective brain hypothermia with cerebral perfusion methods

References

Animal

n cooled (controls)

Weight (kg)

Cold fluid

Ohta et al. (1992)

Dogs

17 (5)

8–12

Otha et al. (1996)

Dogs

12 (0)

Not reported

Ding et al. (2002) Luan et al. (2004) Ding et al. (2004) Zhao et al. (2009)

Rats Rats Rats Rats

0.26–0.3 0.26–0.3 0.26–0.3 0.26–0.3

Jiang et al. (2006)

Rhesus monkeys Dogs

10 (29) 8 (15) 8 (15) 28: 1.5–3 hours after ischemia (35) 7 (5)

Ringer’s lactate Ringer’s lactate Saline Saline Saline Saline

6 (0)

13.81 (0.6)

15 (0)

10–15

Furuse et al. (2007) Nishihara et al. (2009)

Dogs

IA access (infusion)

Brain temperature

Ohta et al. (1992)

VA

Needle thermistor

Ohta et al. (1996)

VA

Needle thermistor

Ding et al. (2002) Luan et al. (2004)

MCA via ECA

Needle thermistor

MCA via ECA

Needle thermistor

Ding et al. (2004) Zhao et al. (2009)

MCA via ECA

Needle thermistor

MCA via ECA

Needle thermistor

Jiang et al. (2006)

ICA

Furuse et al. (2007)

CCA

Nishihara et al. (2009)

CCA

Temperature probes (bifrontal) Temperature probes (bifrontal) Temperature probes bilateral frontal

References

6–10

Ringer’s lactate Ringer’s lactate Ringer’s lactate

Infusion temperature (°C)

Infusion volume (duration)

5

2000 mL (60 minutes)

5

3455
695mL (60 minutes)

23 vs. 37 20 vs. 37 20 vs. 37 20

7 mL (3–4 minutes) 6 mL (9 minutes) 6 mL (10 minutes) 6 mL (11 minutes)

4

1800 mL (63 minutes)

6.5

1200 mL (30 minutes)

13

600 mL vs. 1200 mL vs. 2000 mL (30 minutes)

Safety, mortality, efficacy, performance, histology (cooling group) No death; behavior 10 weeks after procedure normal, histology: no brain ischemia No death; behavior 10 weeks after procedure normal, histology: no brain ischemia No death; improved neuroscore; endothelium intact No death; 48 hours postprocedure histology normal No death; motor performance improved in cooling group Mortality not reported; significant benefit of cooling for up to 2.5 hours after ischemia No death; 3 weeks motor function unaltered; histology: no neuronal loss No death; 8 weeks post procedure normal performance; histology: no ischemic lesions N/A

Feasibility of brain cooling To 28°C in 5.4 minutes; to 20°C in 15.5 minutes To 28°C with 87 mL/min in 4.4 minutes To 32–33°C in 3–4 minutes of 23°C infusion To 33.4°C in cortex/33.9°C striatum in 10-minutes local cooling To 33.4°C in cortex/33.9°C striatum in 10 minutes To 32.8–33.2°C in cortex and to 33.2–33.3°C striatum To 15.5°C in 19.8 minutes

R to 33.6°C, L to 34.3°C in 30min

Cool rate: R 1.8°C/30 minutes, L 1.4°C/min, 1.5 mL/min; R 4.7°C/min, L 3.5° C/min, 3 mL/min; R 4.7°C/min, L 3.6°C/min, 5 mL/min

CCA, common carotid artery; ECA, external carotid artery; IA, intra-arterial; ICA, internal carotid artery; L, left; MCA, middle cerebral artery; R, right; VA, vertebral artery.

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not only acute ischemic stroke patients, but also those who undergo catheter-based interventions, such as carotid angioplasty and stenting and percutaneous coronary interventions. For additional information on the mechanisms of hypothermic neuroprotection, see Chapter 51.

SUMMARY AND CONCLUSIONS ●

●

●

●

●

Therapeutic hypothermia is a powerful neuroprotective treatment that works via a pleiotropic mechanism of action. Selective brain cooling is a concept that aims at targeting the cooling process to the organ of interest or organ at risk and limiting hypothermic exposure to the rest of the body. The advantages of selective brain cooling include speed, depth, and control of cooling, targeted tissue cooling, and minimal systemic side-effects. Experiments in animal models of focal ischemia have shown that selective brain cooling is safe and effective in reducing infarct size and improving neurobehavioral outcome. Clinical devices for selective brain cooling may include external (head and neck cooling pads, intranasal devices) or internal applications (endovascular intra-arterial closed-loop catheters or infusion-type catheters). The most invasive method is extracorporeal heat exchange of blood with re-entry into the arterial system during cardiopulmonary bypass. External systems are less invasive, but also less effective in selectively cooling the brain due to the physiologic barriers preventing heat exchange with brain tissue. Novel minimally invasive endovascular intra-arterial systems are under development that internally modify the precerebral arterial input temperature.

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