**1. Introduction**

242 Front Lines of Thoracic Surgery

[47] Radonic T, de Witte P, Baars MJ, Zwinderman AH, Mulder BJ, Groenink M;

2010;12:11:3.

COMPARE study group. Losartan therapy in adults with Marfan syndrome: study protocol of the multi-center randomized controlled COMPARE trial. Trials.

> Cardiothoracic surgeons are faced with the challenge of protecting the brain during the sensitive time of interruption of normal cerebral blood flow. The brain is an exceptionally complex organ with a functional anatomy that is difficult both to understand and assess. Experimental and clinical studies have shown that the mechanism of neural injury is multifactorial. As such, discussions regarding the best surgical strategies for neuroprotection during circulatory arrest are formidable, at best. Although we are armed with excellent experimental and clinical studies that demonstrate the deleterious effects of prolonged exposure to cardiopulmonary bypass (CPB) on brain function and structure, the various neuroprotective strategies, particularly that of deep hypothermic circulatory arrest (DHCA) remain an issue of debate. This is related in part to the gap between the basic science understanding of brain injury caused by these events and the clinical application of various neuroprotective strategies and their subsequent clinical outcomes. The goal here is to address the current understanding of the mechanisms underlying brain injury after HCA and relevant strategies of neural protection, supported by primary experimental data from our laboratory.

#### **2. Hypothermic ciruclatory arrest**

The use of therapeutic hypothermia dates back to the ancient Egyptians, Greeks, and Romans. In modern times, the use of therapeutic hypothermia progressed from observation case reports to animal studies to clinical use in children and then adults. Initially there were observational reports of therapeutic use of hypothermia in patients with severe cerebral trauma, followed by experimental studies in dogs that suggested a therapeutic role for hypothermia for cerebral protection during cardiac surgery. Later, profound hypothermia (12° C, nasopharyngeal) with circulatory arrest (up to 1 hour) was used in children undergoing surgical repair of the tetralogy of Fallot. (Apostolakis & Shuhaiber, 2007)

The use of deep hypothermic cardiopulmonary arrest (DHCA, 14-18°C) was first applied as a method for cerebral protection during the prosthetic replacement of the aortic arch.(Griepp et al, 1997) Later, the use of a DHCA was extended into other major vascular

Neurologic Injury Following Hypothermic Circulatory Arrest 245

To increase the tolerance to ischemia, the use of potentially neuroprotective drugs is an appealing concept, especially since the circulatory arrest interval is well defined and allows a preischemic treatment. Therefore, it is evident that the use of these pharmaceuticals is more promising in HCA patients than for the postischemic treatment of patients after embolic strokes. Studies in a chronic porcine model showed that nontoxic drugs are available that have neuroprotective effects, making them potential candidates for clinical use. Additionally, combining drug treatment with selective perfusion techniques, to support adequate delivery of the agent into the target organ, seems to be a promising concept. Among the various neuroprotective pharmacologic agents are barbiturates, which are believed be protective in focal ischemia by reducing CMRO2, CBF, free fatty acids, free radical and cerebral edema. Steroids decrease proinflammatory responses, while betablockers decrease the inflammatory response. Mannitol reduces cerebral edema, scavenges free radicals and protects the kidneys by lowering renal vascular resistance. Furosemide blocks renal reabsorption of sodium, and insulin controls hyperglycemia, which in turn prevents intracellular acidosis. Lidocaine is a selective blocker of Na+ channels in neuronal membranes and thus, reduces CMRO2. Dexmedetomidine inhibits ischemia-induce norepinephrine release and is protective for both focal and global ischemia. Acadesine

Neurophysiological monitoring during thoracic aortic surgery using HCA became increasingly popular in the last decade. Besides its value during an ongoing operation, the collection of data in combination with outcome analysis might help to improve or change surgical strategies. Continuous recording of electroencephalograms (EEGs) as well as SSEPs is now routine in most neurosurgical units. The use of neuromonitoring in cardiothoracic surgery is in part hampered by the fact that hypothermia has an impact on the sensitivity of neurophysiological measures, so they cannot be used during deep hypothermia. On the other hand, some surgeons have found this an asset, and use disappearance of the EEG to determine the optimal level of hypothermia before they stop the extracorporeal circulation. Therefore, the value of the EEG as an isolated method for ascertaining whether cerebral protection is adequate is questionable. Furthermore, nonsynaptic metabolic activity may persist even when the EEG is isoelectric. On the other hand, the EEG may provide valuable information for those groups which are using relative high blood temperatures during SCP. Furthermore, EEG seems to be a good tool for detecting electrophysiological recovery in the early postoperative period. Monitoring of SSEPs is generally easier than EEG since electric noise does not play such a substantial role. It is generally less influenced by anesthetic drugs, and it remains detectable as long as cortical activity can be encountered. From clinical experience, SSEPs seem especially valuable during surgery on the descending or thoracoabdominal aorta (which is not subject of the present synopsis) but muscle evoked

potentials (MEPs) may be even more sensitive for detection of spinal cord injury.

Hypothermia alters the results of analysis of arterial blood gases by increasing the solubility of CO2 and O2 in plasma. The increase in CO2 solubility decreases the concentration of the insoluble portion and, thus, the partial pressure. However, the total content of CO2 in the

**3.2 Drug interventions** 

appears to mitigate the effects of reperfusion injury.

**3.4 Acid-base management during hypothermia** 

**3.3 Intraoperative neuromonitoring** 

surgeries such as the repair of thoracoabdominal aortic lesions, clipping of giant and complex cerebral aneurysms, and resection of renal carcinoma with tumor thrombus extending into the inferior vena cava or atrium.

Deep hypothermic circulatory arrest (DHCA or HCA) provides 2 clinical benefits. The circulatory arrest component provides a bloodless surgical field without the need for the use of intrusive clamps and cannulae. The deep hypothermic component significantly decreases brain metabolism and oxygen requirements and thus permits a longer period of interrupted blood perfusion to the brain. The cerebral metabolic rate is related exponentially to brain (core body) temperature, with the cerebral metabolic rate decreasing by about 50% for each 6°C drop in brain temperature. Since the first experimental studies, the use of DHCA has become the standard technique for the surgical repair of certain congenital and acquired cardiovascular lesions. The outcome after these operations improved considerably over the past two decades and surgery requiring HCA can usually be performed with an acceptable risk for the patient. However, it is likely that these improvements are more a consequence of an increasing expertise with this type of surgery, rather than the influence of one particular organ protection method employed. Despite this fact, there is still room for improvement, since prolonged periods of HCA are still associated with significant morbidity and mortality. As the brain is the organ most sensitive to ischemic damage, it is considered to be the limiting factor for the duration of HCA. Nevertheless, despite its protective effects, HCA can be detrimental for other organ systems.

The basic established techniques and perfusion strategies during aortic arch replacement number three: hypothermic circulatory arrest (HCA), antegrade cerebral perfusion (ACP), and retrograde cerebral perfusion (RCP). During the past decade and after several experimental studies, RCP lost its previous place in the armamentarium of brain protection, giving it up to ACP as a major method of brain perfusion during HCA. HCA should be applied at a temperature of ≈20°C with long-lasting cooling and rewarming and should not exceed by itself the time of 20–25 min. RCP does not seem to prolong safe brain-ischemia time beyond 30 min, but it appears to enhance cerebral hypothermia by its massive concentration inside the brain vein sinuses. HCA combined with ACP, however, could prolong safe brain-ischemia time up to 80 min. Cold ACP at 10°–13°C should be initially applied through the right subclavian or axillary artery and continued bihemispherically through the left common carotid artery at first and later the anastomosed graft, with a mean perfusion pressure of 40–70 mm Hg. The safety of temporary perfusion is being confirmed by the meticulous monitoring of brain perfusion through internal jugular bulb O2 saturation, electroencephalogram, and transcranial comparative Doppler velocity of the middle cerebral arteries (Kouchoukos et al, 2003).

#### **3. Methods of end-organ protection during DHCA**

#### **3.1 Hypothermia**

Hypothermia acts by reducing the metabolic rate of the brain and improving the balance between energy supply and demand. Hypothermia reduces cerebral blood flow (CBF) in a linear manner, but the decrease in cerebral metabolic rate of oxygen (CMRO2) is not exactly linear. On average, the reduction in CMRO2 is about 7%/1°C. Between 37°C and 22°C, CMRO2 is reduced by about 5%/1°C, and then the reduction accelerates when CMRO2 reaches 20% at 20°C and 17% at 18°C, at which point about 60% of patients achieve electrical silence on electroencephalography (EEG).

#### **3.2 Drug interventions**

244 Front Lines of Thoracic Surgery

surgeries such as the repair of thoracoabdominal aortic lesions, clipping of giant and complex cerebral aneurysms, and resection of renal carcinoma with tumor thrombus

Deep hypothermic circulatory arrest (DHCA or HCA) provides 2 clinical benefits. The circulatory arrest component provides a bloodless surgical field without the need for the use of intrusive clamps and cannulae. The deep hypothermic component significantly decreases brain metabolism and oxygen requirements and thus permits a longer period of interrupted blood perfusion to the brain. The cerebral metabolic rate is related exponentially to brain (core body) temperature, with the cerebral metabolic rate decreasing by about 50% for each 6°C drop in brain temperature. Since the first experimental studies, the use of DHCA has become the standard technique for the surgical repair of certain congenital and acquired cardiovascular lesions. The outcome after these operations improved considerably over the past two decades and surgery requiring HCA can usually be performed with an acceptable risk for the patient. However, it is likely that these improvements are more a consequence of an increasing expertise with this type of surgery, rather than the influence of one particular organ protection method employed. Despite this fact, there is still room for improvement, since prolonged periods of HCA are still associated with significant morbidity and mortality. As the brain is the organ most sensitive to ischemic damage, it is considered to be the limiting factor for the duration of HCA. Nevertheless, despite its protective effects, HCA

The basic established techniques and perfusion strategies during aortic arch replacement number three: hypothermic circulatory arrest (HCA), antegrade cerebral perfusion (ACP), and retrograde cerebral perfusion (RCP). During the past decade and after several experimental studies, RCP lost its previous place in the armamentarium of brain protection, giving it up to ACP as a major method of brain perfusion during HCA. HCA should be applied at a temperature of ≈20°C with long-lasting cooling and rewarming and should not exceed by itself the time of 20–25 min. RCP does not seem to prolong safe brain-ischemia time beyond 30 min, but it appears to enhance cerebral hypothermia by its massive concentration inside the brain vein sinuses. HCA combined with ACP, however, could prolong safe brain-ischemia time up to 80 min. Cold ACP at 10°–13°C should be initially applied through the right subclavian or axillary artery and continued bihemispherically through the left common carotid artery at first and later the anastomosed graft, with a mean perfusion pressure of 40–70 mm Hg. The safety of temporary perfusion is being confirmed by the meticulous monitoring of brain perfusion through internal jugular bulb O2 saturation, electroencephalogram, and transcranial comparative Doppler velocity of the middle cerebral

Hypothermia acts by reducing the metabolic rate of the brain and improving the balance between energy supply and demand. Hypothermia reduces cerebral blood flow (CBF) in a linear manner, but the decrease in cerebral metabolic rate of oxygen (CMRO2) is not exactly linear. On average, the reduction in CMRO2 is about 7%/1°C. Between 37°C and 22°C, CMRO2 is reduced by about 5%/1°C, and then the reduction accelerates when CMRO2 reaches 20% at 20°C and 17% at 18°C, at which point about 60% of patients achieve electrical

extending into the inferior vena cava or atrium.

can be detrimental for other organ systems.

arteries (Kouchoukos et al, 2003).

silence on electroencephalography (EEG).

**3.1 Hypothermia** 

**3. Methods of end-organ protection during DHCA** 

To increase the tolerance to ischemia, the use of potentially neuroprotective drugs is an appealing concept, especially since the circulatory arrest interval is well defined and allows a preischemic treatment. Therefore, it is evident that the use of these pharmaceuticals is more promising in HCA patients than for the postischemic treatment of patients after embolic strokes. Studies in a chronic porcine model showed that nontoxic drugs are available that have neuroprotective effects, making them potential candidates for clinical use. Additionally, combining drug treatment with selective perfusion techniques, to support adequate delivery of the agent into the target organ, seems to be a promising concept.

Among the various neuroprotective pharmacologic agents are barbiturates, which are believed be protective in focal ischemia by reducing CMRO2, CBF, free fatty acids, free radical and cerebral edema. Steroids decrease proinflammatory responses, while betablockers decrease the inflammatory response. Mannitol reduces cerebral edema, scavenges free radicals and protects the kidneys by lowering renal vascular resistance. Furosemide blocks renal reabsorption of sodium, and insulin controls hyperglycemia, which in turn prevents intracellular acidosis. Lidocaine is a selective blocker of Na+ channels in neuronal membranes and thus, reduces CMRO2. Dexmedetomidine inhibits ischemia-induce norepinephrine release and is protective for both focal and global ischemia. Acadesine appears to mitigate the effects of reperfusion injury.

#### **3.3 Intraoperative neuromonitoring**

Neurophysiological monitoring during thoracic aortic surgery using HCA became increasingly popular in the last decade. Besides its value during an ongoing operation, the collection of data in combination with outcome analysis might help to improve or change surgical strategies. Continuous recording of electroencephalograms (EEGs) as well as SSEPs is now routine in most neurosurgical units. The use of neuromonitoring in cardiothoracic surgery is in part hampered by the fact that hypothermia has an impact on the sensitivity of neurophysiological measures, so they cannot be used during deep hypothermia. On the other hand, some surgeons have found this an asset, and use disappearance of the EEG to determine the optimal level of hypothermia before they stop the extracorporeal circulation. Therefore, the value of the EEG as an isolated method for ascertaining whether cerebral protection is adequate is questionable. Furthermore, nonsynaptic metabolic activity may persist even when the EEG is isoelectric. On the other hand, the EEG may provide valuable information for those groups which are using relative high blood temperatures during SCP. Furthermore, EEG seems to be a good tool for detecting electrophysiological recovery in the early postoperative period. Monitoring of SSEPs is generally easier than EEG since electric noise does not play such a substantial role. It is generally less influenced by anesthetic drugs, and it remains detectable as long as cortical activity can be encountered. From clinical experience, SSEPs seem especially valuable during surgery on the descending or thoracoabdominal aorta (which is not subject of the present synopsis) but muscle evoked potentials (MEPs) may be even more sensitive for detection of spinal cord injury.

#### **3.4 Acid-base management during hypothermia**

Hypothermia alters the results of analysis of arterial blood gases by increasing the solubility of CO2 and O2 in plasma. The increase in CO2 solubility decreases the concentration of the insoluble portion and, thus, the partial pressure. However, the total content of CO2 in the

Neurologic Injury Following Hypothermic Circulatory Arrest 247

clinical expression is typically motor-sensory deficit, aphasia, or cortical blindness (Kunihara et al, 2005; Lipton, 1999). Computed tomography and magnetic resonance imaging are

A focal deficit is usually an embolic phenomenon, whereas a prolonged poor perfusion of the brain may produce necrosis in watershed zones. Age, atherosclerosis, and manipulation of the aorta are risk factors for both. Global cerebral ischemia leads to diffuse neurologic deficit, which may be benign and reversible or more debilitating (seizures, Parkinsonism, and coma). Risk factors include increased duration of circulatory arrest and CPB, diabetes mellitus, and hypertension. Transient neurologic dysfunction appears to be a marker of long-term cerebral injury. Deficits of memory and fine-motor function may persist after hospital discharge. Reductions in CMRO2 and the duration of DHCA reduce the risk of neurologic injury. The length of time on CPB might be a better predictor of postoperative

Aortic procedures requiring hypothermic circulatory arrest have been specifically correlated with increased risk of both stroke and mortality in all patients. This may be accentuated in the elderly, who may have less tolerance for neurological insult. Many physicians think patients >75 years old are too frail and lack the reserve to survive a major cardiothoracic surgery. In particular, there remains some hesitancy in performing procedures with a higher risk of stroke in patients with a higher susceptibility for adverse neurological sequelae. This perceived combination of risk and susceptibility may be a barrier to care for elderly patients requiring hypothermic circulatory arrest to address their aortic pathology. According to Coselli et al. (2008), in a study accessing the safety and efficacy of HCA, there are various major complications associated with HCA. These included death (interoperative, during hospital stay, and within 30 days), stroke, paraplegia, paraparesis, uncontrolled bleeding which required reoperation, renal failure, cardiac complications, and vocal cord paralysis.

Hypothermia is the most efficient measure to prevent or reduce ischemic damage to the central nervous system when blood circulation is reduced. The central nervous system has a high metabolic rate and limited energy stores, which make it extremely vulnerable to ischemia (Elrich et al, 2002). Hypothermia acts by reducing the metabolic rate of the brain and improving the balance between energy supply and demand, and thus lengthens the period of tolerated ischemia. Hypothermia reduces cerebral blood flow (CBF) in a linear manner, but the decrease in cerebral metabolic rate of oxygen (CMRO2) is not exactly linear. On average, the reduction in CMRO2 is about 7%/1°C. Between 37°C and 22°C, CMRO2 is reduced by about 5%/1°C, and then the reduction accelerates when CMRO2 reaches 20% at 20°C and 17% at 18°C, at which point about 60% of patients achieve electrical silence on

Although reduction of cerebral metabolism and swift surgery are the two fundamental measures that can prevent or reduce brain damage during circulatory arrest, there are adjunctive protective measures that can be considered. The basic established techniques and perfusion strategies during aortic arch replacement number three: hypothermic circulatory arrest (HCA), antegrade cerebral perfusion (ACP), and retrograde cerebral perfusion (RCP).

usually able to detect a sharply demarcated area of necrosis in the brain.

death and stroke than the duration of DHCA time (Hagl et al, 2003).

**6. Strategies for brain protection during DHCA** 

electroencephalography (EEG) (McCullough et al, 1999).

**6.2 Techniques and perfusion strategies** 

**6.1 Hypothermia – reduction of metabolism** 

blood remains the same. During hypothermia, if a blood sample is taken and warmed to 37°C in the blood gas analyzer, the CO2 initially dissolved will now contribute to the partial pressure of CO2 (PCO2) and the PCO2 will be within the normal normothermic range. If, on the other hand, the value is estimated at the patient's actual temperature, the PCO2 will be reduced despite similar arterial CO2 content. In addition to its effect on gas solubility, hypothermia decreases the metabolic rate and CO2 production. Maintaining the PCO2 within the normal range in rewarmed 37°C blood is called "alpha-stat." If the PCO2 is corrected to the patient's actual temperature and that value is kept within the normal range, the management is called "pH-stat."
