The performance of complex aortic arch surgery necessitates

Cerebral Perfusion Deborah K. Harrington, MB, MRCS, Fernanda Fragomeni, and Robert Stuart Bonser, MD, FRCS Department of Cardiac Surgery, Queen Elizabeth Hospital, University Hospital Birmingham NHS Trust, Edgbaston, Birmingham, United Kingdom Aortic arch surgery necessitates interrupted brain perfusion and carries a risk of brain injury. Various brain protective techniques have been advocated to reduce risk including hypothermic arrest and retrograde or selective antegrade perfusion. Knowledge of the pathophysiologic consequences of deep hypothermia, may aid the surgeon in deciding when to initiate circulatory arrest and for how long. Retrograde cerebral perfusion use was advocated to prolong safe arrest durations but may not improve outcomes. Selective antegrade cerebral perfusion appears to have become the preferred method of brain protection. However, the delivery conditions and optimal perfusate constitution require further study. (Ann Thorac Surg 2007;83:S799 804) 2007 by The Society of Thoracic Surgeons The performance of complex aortic arch surgery necessitates interruption of cerebral perfusion. How the brain is protected and perfused during this period is of crucial importance as despite advances in protective techniques, there remains a relatively high incidence of brain injury [1 3]. Normal Cerebral Perfusion The adult human brain weighs approximately 1,500 g, and at normothermia it receives a blood flow at rest in the awake subject of 45 to 60 ml 100 g 1 brain tissue min 1 at a perfusion pressure that generally exceeds 70 mm Hg. Under standard conditions, including normothermic or moderately hypothermic cardiopulmonary bypass (CPB) with assumed steady state cerebral oxygen consumption (CMRO 2 ), cerebral autoregulation occurs, matching cerebral blood flow (CBF) to metabolism and keeping CBF constant throughout a range of perfusion pressures [4, 5]. Physiologic variables, such as temperature, ph, and hematocrit, which may be controlled during CPB have important effects on cerebral perfusion. Effects of Cooling, Acid Base Management, and Hematocrit on Cerebral Perfusion Cooling is widely used as a mainstay of organ protection because it results in a reduction in metabolic activity and extension of the period of ischemic tolerance. As the brain has no oxygen stores, CMRO 2 is a true index of brain metabolic activity. For every 10 C reduction in temperature, CMRO 2 reduces by a factor (the Q 10 )of2to 4 [4]. Cooling to profound hypothermia (15 o Cto18 o C), Presented at Aortic Surgery Symposium X, New York, NY, April 27 28, 2006. Address correspondence to Dr Bonser, Department of Cardiac Surgery, Queen Elizabeth Hospital, University Hospital Birmingham NHS Trust, Edgbaston, Birmingham B15 2TH, United Kingdom; e-mail: robert. bonser@uhb.nhs.uk. results in a reduction in both CBF and CMRO 2. In animal studies, at 18 C, both CBF and CMRO 2 fall to approximately 35% of baseline. The fall in CMRO 2 is exponential with a steep descent towards electrocerebral silence followed by a flattened tail as metabolism to maintain cellular and ionic integrity continues. The fall in CBF is more linear [6 8]. That indicates that cooling leads to uncoupling of flow and metabolism and loss of cerebral autoregulation with development of luxury perfusion. This perfusion could be beneficial, enhancing the rate and uniformity of brain cooling or detrimental by subjecting the brain to potentially increased embolic load. This uncoupling occurs at approximately 22 o C. Below this temperature, CBF becomes directly proportional to cerebral perfusion pressure (CPP) [4, 9]. The ratio of blood flow to metabolism increases from 20:1 at normothermia to 75:1 at deep hypothermia. This overprovision of CBF may be of great importance when determining the optimal conditions for brain protection at profound hypothermia during and after circulatory arrest. The rate of cooling is also important. Rapid cooling, particularly with large temperature gradients appears detrimental. This is presumably due to nonuniformity of brain cooling leaving some regions warmer and more vulnerable to ischemia. For this reason, a slow cooling period with a limited temperature gradient is desirable [10 12]. The acid-base environment also affects cerebral perfusion. The use of alpha-stat ph management allows ph to change with falling temperature as the buffering capacity for hydrogen ions increases, resulting in a relative alkalosis. Alpha-stat management preserves flow: metabolism (CBF: CMRO 2 ) matching during cooling until the temperature at which autoregulation is uncoupled. The alternative ph management approach is ph-stat, which maintains ph during cooling by adding CO 2. This uncouples cerebral autoregulation so that CBF varies directly with CPP. The addition of CO 2 during ph-stat management causes cerebral vasodilatation and increased CBF. This differentially increases relative perfu- 2007 by The Society of Thoracic Surgeons 0003-4975/07/$32.00 Published by Elsevier Inc doi:10.1016/j.athoracsur.2006.11.018

S800 AORTIC SURGERY SYMPOSIUM X HARRINGTON ET AL Ann Thorac Surg CEREBRAL PERFUSION 2007;83:S799 804 sion of deeper brain structures such as the thalamus, brainstem, and cerebellum. It may thus provide increased oxygen availability and cooling effect. Whereas this may be beneficial in children, it may increase the potential for edema and microembolization in adults [12 14]. During cooling to profound hypothermia, blood viscosity increases, which may reduce cerebral blood flow unless the hematocrit is reduced. This occurs in parallel with increasing hemoglobin oxygen avidity and O 2 solubility with gas exchange becoming more reliant on dissolved O 2. These phenomena led to the practice of aggressive hemodilution in patients undergoing profoundly hypothermic CPB [14, 15]. However, more recently, experimental evidence in pigs has shown improved cerebral capillary blood flow during reperfusion when the hematocrit is maintained at 30% compared with 20% during both cooling before and rewarming after hypothermic circulatory arrest. This also translates to improved brain outcomes [16, 17]. Hypothermic Circulatory Arrest Hypothermic circulatory arrest (HCA) has been a standard technique in arch surgery, and appears safe for short arrest durations. Its main premise is that cooling on CPB to profound hypothermia causes sufficient cerebral metabolic suppression enough to allow a period of total circulatory arrest during which aortic arch anastomoses may be performed. However, HCA is subject to a number of important physiologic and clinical consequences that differ from CPB with continuous perfusion. Experimental studies have consistently demonstrated a period of reactive hyperemia or cerebral hyperperfusion immediately after a period of HCA [6, 18, 19]. This is followed by a period of low cerebral blood flow with increased cerebrovascular resistance for several hours. During this socalled vulnerable interval, brain oxygen extraction is increased but CBF may be inadequate. Clinical studies, however, have shown conflicting results. In pediatric studies, the hyperemia demonstrated in animal models is not observed, but reduced cerebral blood flow and increased oxygen extraction after arrest do occur [4, 9]. In adults, increased transcranial oxygen extraction after arrest has also been demonstrated, together with an immediate increase in middle cerebral artery velocity after arrest detected by transcranial Doppler and indicative of relative hyperemia [20]. Other studies have also shown ongoing cerebral metabolic activity during HCA. resulting in an oxygen debt to be paid back after the ischemic period with a linear relationship between the duration of HCA and the impairment in cerebral oxygen metabolism [21]. Surgery utilizing HCA for aortic arch surgery carries a risk of permanent stroke of 5% to 7%, an incidence of transient neurologic deficit being as high as 20% and a risk of neuropsychological deficits in the majority of patients [1 3, 22 24]. The single largest operative determinant of neurologic outcome after HCA remains arrest duration. An arrest time over 25 minutes is associated with an increased risk of transient neurologic deficit and times 40 minutes increase the risk of stroke. Mortality increases sharply after one hour of arrest [25]. Continued research is required to define; the optimal perfusion conditions before arrest, the safest duration of cooling and the optimal circumstances of reperfusion and rewarming. The use of retrograde jugular bulb cannulae to monitor transcranial oxygen extraction and brain temperature should facilitate these enquiries. Proceeding to HCA before achieving jugular bulb oxygen saturations 95% or adequate cooling may be associated with adverse outcomes [4, 26]. There are no clinically proven pharmacologic adjuncts that reliably increase the safety of HCA. High dose barbiturates are now rarely used but many centers administer prearrest steroid and mannitol as putative adjuncts. The dosage and efficacy of these agents has not been standardized. Steroids may increase membrane stability but produce hyperglycemia exacerbating the insulin resistance of cooling [27] Neurohyperglycemia may exacerbate ischemic injury and the role of steroids requires clarification. The consistent finding of a high incidence of brain injury and the requirement for prolonged durations of ischaemia in order to facilitate complex aortic arch repairs led to the development of adjunctive cerebral perfusion techniques in an attempt to reduce mortality and morbidity. Retrograde Cerebral Perfusion Retrograde cerebral perfusion (RCP) through the superior vena cava has been used as a cerebral protective adjunct during aortic arch surgery since it was first described as an emergency treatment for massive air embolism during CPB [28]. The theoretical benefits of RCP are to maintain intracranial hypothermia, to flush out embolic debris and to provide metabolic support and removal of toxic metabolites and waste products, whilst potential disadvantages include causing cerebral edema thus exacerbating cerebral injury [29]. Experimental studies of RCP demonstrated true brain perfusion in some species but not others [30 32] with varying evidence of cerebral metabolic benefit [30, 33] and improvement in histologic and behavioral outcome compared with HCA alone [34, 35]. Such studies led to the widespread use of RCP during aortic arch surgery, and initially some large clinical series demonstrated good results [36 38]. More recently however, despite the demonstration of reversed transcranial Doppler ultrasound signals in the middle cerebral artery, clinical randomised trials have revealed no evidence of cerebral metabolic, neurologic or neuropsychological outcome benefit of RCP [20, 24]. Although it may be possible to increase true brain perfusion with RCP by increasing the driving perfusion pressure, this is likely to be counterproductive due to increased brain edema. Thus, the clinical pendulum has swung away from RCP in favor of antegrade perfusion techniques.

Ann Thorac Surg AORTIC SURGERY SYMPOSIUM X HARRINGTON ET AL 2007;83:S799 804 CEREBRAL PERFUSION S801 Selective Antegrade Cerebral Perfusion Selective antegrade cerebral perfusion (SACP) is now probably the most widely used adjunctive cerebral protective technique to supplement HCA. It was initially used as early as the 1950 s but was largely abandoned due to problems with embolic phenomena, neurologic deficit and vessel injury [39 41]. In the last 15 years there has been a resurgence of interest [42 44] and there is increasing experimental and clinical evidence that antegrade perfusion techniques afford superior brain protection during any HCA period. There are several different SACP techniques in clinical use, all comprising cannulation of some or all of the head and neck vessels to provide continued perfusion to the brain during a period of HCA. Notwithstanding the temperature related uncoupling of flow and metabolism, moderately hypothermic SACP may permit maintained cerebral autoregulation provided flows remain physiologic. This may allow the avoidance of profound corporeal hypothermia and the sequelae of long CPB times and coagulation disturbance. However, any advantages of warmer corporeal arrest have yet to be proven and if profoundly hypothermic SACP is used alongside moderately hypothermic corporeal arrest, there remains a risk of injury due to the large temperature gradients present at its initiation and discontinuation. For more complex arch repairs, particularly those with hybrid surgical and endovascular techniques, the longer corporeal arrest times that are necessary argue towards the use of more profoundly hypothermic techniques. Possible disadvantages of SACP include the dissection. manipulation and cannulation of the head and neck vessels, the set up of equipment which may be cumbersome and time consuming, and the requirement for further monitoring in order to assess the adequacy of the cerebral perfusion. Several different SACP techniques have been described, including cannulation of either the innominate or left common carotid artery or both, and either perfusing, or clamping or snaring the left subclavian artery in order to prevent a steal phenomenon. Perfusion temperatures also differ with some authors maintaining the brain and body at a single temperature, with varying degrees of hypothermia, and others perfusing the head cooler than the corporeal arrest temperature of the body. In most circumstances however, there remains by necessity a short period of total HCA during insertion and removal of the cannulae for cerebral perfusion [42, 44, 45]. Animal studies of SACP have demonstrated significant CBF and continued aerobic metabolism during the perfusion period with a less marked hyperemic response and reduced vulnerable interval [6, 46]. Both histologic and behavioral studies also demonstrate superior outcomes compared with both HCA alone or HCA with RCP [6, 47, 48]. Clinical studies of SACP have confirmed continued CBF and reduced transcranial oxygen extraction immediately post-arrest, amelioration of the oxygen debt otherwise accrued during HCA [49]. Excellent clinical outcomes with very low rates of both mortality and neurologic morbidity rates have also been reported in large series by several groups [50, 51]. Axillary Artery Cannulation Separate consideration should be given to the axillary site of arterial cannulation for CPB which may lead to superior results if used for antegrade brain perfusion during an arrest period. Historically, if the aortic arch was not suitable for cannulation, the second choice for arterial cannulation was the femoral artery thus perfusing the brain retrogradely from the descending aorta. This technique carries an increased risk of cerebral embolism, particularly in degenerative aneurysms with surface atheroma [52]. The use of axillary artery cannulation has become widespread as it allows antegrade perfusion of the brain without cannula repositioning. The axillary artery has lower rates of atherosclerotic change than either the aortic arch or femoral artery. Reduced risk of atheroembolism has been reported after axillary artery cannulation and it appears to be associated with a low risk of complications such as local dissection and brachial plexus injury compared with the risks of malperfusion and lower limb ischaemia associated with femoral artery cannulation [53 55]. There remains concern that axillaryinnominate perfusion alone will not necessarily afford adequate brain perfusion for those 15% of patients with an incomplete Circle of Willis. However, a second SACP cannula can be positioned in the left common carotid artery if back-bleed from this vessel during innominate perfusion appears inadequate. The Current Unknowns While there is clear evidence of the superiority of antegrade perfusion, its optimal delivery and perfusion characteristics are still unknown. The route of delivery of perfusion may be unilateral through the axillary artery or bilateral by cannulating both the innominate and left common carotid arteries separately or even all three epi-aortic vessels. These techniques have not been adequately compared [56]. The optimal flow rate of SACP is uncertain. Most authors use a flow of 10ml/kg/min as this roughly equates to normal normothermic brain blood flow. This achieves right radial or carotid artery pressures of 30 50 mm Hg. This flow rate is, however, probably significantly higher than that required under anaesthesia and at profound hypothermia. Higher flows might increase the risk of cerebral edema and embolic phenomena but whether lower flow rates with lower CPP are adequate is unclear. Studies using Near Infrared Spectroscopy (NIRS) have demonstrated apparently adequate cerebral perfusion at SACP flow rates of around 5 ml/kg/min although it is unknown whether this is advantageous [57, 58]. Several different perfusate temperatures have been utilized for SACP. Kazui et al. have achieved excellent clinical results using a perfusate temperature of 22 C but many authors still use lower temperature perfusion

S802 AORTIC SURGERY SYMPOSIUM X HARRINGTON ET AL Ann Thorac Surg CEREBRAL PERFUSION 2007;83:S799 804 (15 C) to ensure cerebral metabolic suppression [42]. A recent animal study reported improved cerebral metabolic outcome after SACP at 10 15 C compared with 20 25 C [59]. In addition, the temperature of corporeal arrest used for SACP is variable. Many centers use a uniform temperature for both cerebral perfusion and corporeal arrest. In our experience, utilization of a warmer corporeal arrest temperature with cold brain perfusion does not result in clinical benefit and may be responsible for the increased acidity, higher lactate levels and brain hyperemia post-arrest [49]. After the outcome of our randomized trial, we now perform cerebral perfusion and corporeal arrest at a uniform temperature of 15 C. For 52 patients undergoing proximal aortic arch reconstruction using this technique, the incidence of both mortality and permanent stroke was 3.8% (mean SACP time, 49 minutes, and HCA time, 9 minutes; unpublished data). As yet, we remain uncomfortable in submitting patients to obligatory albeit short arrest periods and SACP (with possible interruptions in flow during perfusion) without the safeguard of profound hypothermia. Some authors have advocated continued corporeal perfusion through a perfusion-occlusion cannula in the descending aorta to mitigate the effects of corporeal ischemia. The optimal acid base management strategy for aortic arch surgery in adults remains undetermined. While most use alpha-stat ph management [60], there is some evidence of benefit of ph stat management during cooling in pediatric surgery and some experimental studies of HCA and SACP [61 63]. The likelihood of increased embolic phenomena means that the ph-stat management technique has not been widely adopted in adult centers. Monitoring Cerebral Perfusion It is crucial to institute appropriate monitoring to ensure the adequacy of cerebral perfusion. Bilateral arterial line monitoring remains mandatory in aortic arch surgery, in order to detect malperfusion. In addition, radial arterial line pressure monitoring does not necessarily correlate with carotid pressure, particularly if axillary cannulation is used, and cannula-based perfusion pressure monitoring is essential. Some form of surrogate cerebral blood flow monitoring is also necessary, and we recommend the use of transcranial Doppler to monitor middle cerebral artery flow velocity. That is both harmless and easily instituted and may simultaneously monitor emboli. Other authors have used near-infrared spectroscopy (NIRS), which may be more sensitive in detecting perfusion in low flow states [64]. The adequacy of cerebral metabolic suppression should also be monitored either by use of jugular venous oxygen saturation measurements [26], or electroencephalographic monitoring [11]. Surrogate brain temperature monitoring is also a requirement. With controlled rates of cooling, nasopharyngeal temperature is a reliable indicator of brain temperature. It may, however, underestimate brain temperature during rewarming [65]. Table 1. Birmingham Protocol for Brain Perfusion During Arch Surgery Monitoring Bilateral radial artery pressure monitoring Jugular bulb temperature and O 2 saturation monitoring a In-cannula SACP pressure monitoring Trans-cranial Doppler middle cerebral artery velocity monitoring a Cooling Cannulation: distal arch or axillary (redo) Temperature gradient: 7 C Perfusion flow: 2.2 2.4 L min 1 min 2 Cooling duration 50 minutes Nasopharyngeal temperature at arrest: 15 C for 5 minutes Jugular bulb O 2 saturation at arrest: 95% a Pretreatment: mannitol 1 g kg 1 ; dexamethasone 100 mg (20 minutes prearrest) Hematocrit: 20% to 30% ph management: alpha-stat Glucose management: insulin sliding scale (WBG 10 mmol L 1 ) Arrest period Position: Trendelenberg 15 degrees HCA for anticipated arrest times 20 minutes SACP for other cases SACP Cannulation: balloon perfusion cannulae via innominate and left carotid arteries Left subclavian artery: occlusion with embolectomy catheter Perfusate temperature 15 C Hematocrit: 20% to 30% Flow rate 10 ml kg 1 min 1 Perfusion pressure 30 50 mm Hg Reperfusion Rigorous arch airdrill Perfusion flow: 2.2 2.4 L min 1 min 2 Reperfusion temperature 15 C for 5 minutes Rewarming Temperature gradient: 7 C Perfusion flow: 2.2 2.4 L min 1 min 2 Nasopharyngeal temperature maximum: 36.5 C Arterial outflow temperature maximum: 37 C Rewarming duration: nasopharyngeal temperature 36.5 C 10 20 minutes Hematocrit: 20% to 30% ph management: alpha-stat Glucose management: insulin sliding scale (WBG 10 mmol L 1 ) a Items are aspirational for nonresearch study patients. HCA hypothermic circulatory arrest; SACP selective antegrade cerebral perfusion; WBG whole blood glucose. Summary The performance of complex aortic arch surgery is now routinely possible with the addition of adjunctive antegrade cerebral perfusion techniques. Evidence suggests that perfusing the brain is better than not perfusing it,

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