Therapeutic hypothermia applicable to cardiac surgery

Veterinary Anaesthesia and Analgesia, 2015, 42, 559–569

doi:10.1111/vaa.12299

REVIEW ARTICLE

Therapeutic hypothermia applicable to cardiac surgery Klaus A Otto Central Laboratory Animal Facility, Hannover Medical School, Hannover, Germany

Correspondence: Klaus A Otto, Central Laboratory Animal Facility, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. E-mail: [email protected]

Abstract

Introduction

Objective To review the beneficial and adverse effects of therapeutic hypothermia (TH) applicable to cardiac surgery with cardiopulmonary bypass (CPB) in the contexts of various temperature levels and techniques for achieving TH.

Therapeutic hypothermia (TH), the intentional reduction of the body core temperature (Geurts et al. 2014), has long been applied as a neuroprotective measure during cardiac surgeries in humans and animals (Bigelow et al. 1950; Nathan et al. 2001; Aydemir et al. 2012). Other indications for TH include coronary artery bypass surgery (Boodhwani et al. 2007), surgical repair of thoracoabdominal (Bush et al. 1995; Griepp & Di Luozzo 2013) and intracranial (Todd et al. 2005; Nguyen et al. 2010) aneurysms, pulmonary thromboendarterectomy (Conolly et al. 2010) and surgery for cerebral arteriovenous malformations (Conolly et al. 2010), as well as arterial switch operations (ASO) in neonates (Aydemir et al. 2012). Deep hypothermic circulatory arrest (DHCA) has also been recommended for surgical procedures which carry a high risk for profound intraoperative haemorrhage, such as renal tumours with caval invasion (Conolly et al. 2010). Moreover, TH has become an integral part of treatment regimens for traumatic brain injury (TBI) (Mrozek et al. 2012; Adelson et al. 2013) and spinal cord injury (SCI) (Kwon et al. 2008; Batchelor et al. 2013; Ahmad et al. 2014), and in comatose human patients after successful cardiopulmonary resuscitation after out-of-hospital cardiac arrest (Kabon et al. 2003; Kelly & Nolan 2010; Diao et al. 2013) and for acute stroke (Berger et al. 2004; Lyden et al. 2006; Hennerici et al. 2013). Furthermore, systemic reviews have indicated that TH may reduce the risk for mortality and

Databases used Multiple electronic literature searches were performed using PubMed and Google for articles published from June 2012 to December 2014. Relevant terms (e.g. ‘hypothermia’, ‘cardiopulmonary bypass’, ‘cardiac surgery’, ‘neuroprotection’) were used to search for original articles, letters and reviews without species limitation. Reviews were included despite potential publication bias. References from the studies identified were also searched to find other potentially relevant citations. Abstracts, case reports, conference presentations, editorials and expert opinions were excluded. Conclusions Therapeutic hypothermia is an essential measure of neuroprotection during cardiac surgery that may be achieved most effectively by intravascular cooling using hypothermic CPB. For most cardiac surgical procedures, mild to modest (32–36 °C) TH will be sufficient to assure neuroprotection and will avoid most of the adverse effects of hypothermia that occur at lower body core temperatures. Keywords adverse effects, cardiopulmonary bypass, cardiovascular surgery, hypothermia, neuroprotection.

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Therapeutic hypothermia KA Otto neurodevelopmental disability in paediatric patients suffering from neonatal hypoxic-ischaemic encephalopathy (HIE) attributable to acute perinatal asphyxia or TBI (Shankaran et al. 2005; Shah 2010; Adelson et al. 2013). With respect to biomedical research, intentional hypothermia has been recommended as a method of achieving anaesthesia for surgery in neonatal rat and mouse pups (Phifer & Terry 1986; Danneman & Mandrell 1997), as well as in neonatal and early postnatal marsupial young (National Health and Medical Research Council 1990, 2014). Hypothermia has been shown to decrease anaesthetic needs in isoflurane-anaesthetized goats in a rectilinear fashion (Antognini 1993). The main rationale for using TH, however, has concerned the preservation of the brain, heart and kidneys from ischaemic injury (Wagner et al. 2001; Anttila et al. 2004). The brain is the organ most susceptible to ischaemia during circulatory arrest (Conolly et al. 2010), thus making neuroprotection most vital for a successful outcome (Bernard & Buist 2003). Hypothermia exerts its neuroprotective effects by acting via numerous pathways during ischaemia and the post-ischaemic reperfusion period (Zhao et al. 2007; Lampe & Becker 2011). More recently, however, the beneficial effects of TH have been discussed in the context of the numerous adverse effects reported for hypothermia, such as coagulopathy (Patt et al. 1988), cardiac dysrhythmias (Aslam et al. 2006) and wound infection (Sessler 2001). In view of such ongoing discussions, the intention of this review is to elucidate and contrast the advantages and disadvantages associated with different temperatures and techniques of TH with an emphasis on cardiac surgeries that require hypothermic cardiopulmonary bypass (CPB). Therefore, the pathophysiology of ischaemic injury will be addressed first and will be followed by an overview on the mechanisms of action of TH and the various techniques for achieving it. Ischaemic injury The initial, acute stage of cerebral ischaemic injury leads to pathophysiological changes (e.g. loss of transmembrane ionic gradients) that occur within the first 90 minutes of the onset of ischaemia (Siesj€ o 1992; Small et al. 1999). These changes are induced by reduced oxygen and substrate delivery that is inadequate to meet metabolic demands (Wu &

Grotta 2013). During hypoxia, intracellular adenosine-triphosphate (ATP) concentration decreases and the cellular metabolism switches into anaerobic glycolysis. Consequently, increases in hydrogen, inorganic phosphate and lactate ions occur in association with intracellular acidosis (Small et al. 1999; Sessler 2001). The depletion of ATP stores and subsequent Na+–K+–ATPase pump failure may be seen as one major cause of the loss of ionic gradients (Hansen 1985; Svyatets et al. 2010). Very early during this stage, an efflux of potassium (K+) ions occurs and is followed by an increase in Na+ and Ca2+ influxes (Small et al. 1999). In addition to ATP-sensitive K+ channels, Ca2+-gated K+ channels may be activated later during this stage when the intracellular calcium concentration ([Ca2+]i) is increased. The profound changes in the K+ gradient may cause swelling and lysis of astrocytes (Siesj€ o 1992; Small et al. 1999). Moreover, subsequent membrane depolarization initiates a marked increase in Ca2+ influx via voltage-gated calcium channels, which, in turn, further enhances membrane depolarization (Small et al. 1999). The consequences of the marked increase in intracellular Ca2+ concentration during the initial stage of ischaemic injury are as follows. Firstly, membrane depolarization causes an increased release of the excitatory neurotransmitter glutamate in the extracellular fluid (Siesj€ o et al. 1989; Choi 1990; Kempski 1994; Small et al. 1999). In addition, the reduced presynaptic glutamate reuptake attributable to the lack of energy-rich compounds (ATP, phosphocreatine) may further contribute to the high extracellular glutamate concentration (Benveniste et al. 1984). Secondly, Ca2+ influx via both voltage-sensitive calcium channels and the ligand-gated NMDA (N-methyl-D-aspartate) receptor channel results in intracellular Ca2+ overload and destruction of cellular Ca2+ homeostasis (Small et al. 1999). Thirdly, activation of phospholipases and proteases results in the generation of free fatty acids (e.g. arachidonic acid) and subsequent hydrolysis of mitochondrial and plasma membranes. Therefore, an intracellular Ca2+ overload has frequently been considered the major event in ischaemic brain cell death (Siesj€ o & Bengtsson 1989). Glutamate, a ligand at both ionotropic receptors [NMDA, AMPA (a-amino-3-hydroxy-5-methyl-4isoxazole propionic acid), KA (kainate)] and metabotropic receptors (Siesj€ o et al. 1989; Small et al.

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1999), further facilitates Ca2+ influx mainly via the NMDA receptor (Siesj€ o et al. 1989). Glutamate action on AMPA receptors facilitates Na+ influx and subsequent membrane depolarization, which, in turn, further increases the Ca2+ influx via voltagegated calcium channels (Small et al. 1999). Pathophysiological changes (e.g. neuroinflammation, oxidative stress, apoptosis) occurring in the second stage of cerebral ischaemic brain injury are mainly the sequelae of organ reperfusion. This stage may last for periods of hours to days after the injury occurs (Small et al. 1999; Ceulemans et al. 2010). The transient onset of oxidative metabolism and restoration of the mitochondrial membrane potential facilitates the sequestration and storage of Ca2+ from the cytoplasm in the mitochondria (Budd 1998). Although this Ca2+ shift helps to reduce the high cytoplasmic calcium concentration, it also causes a mitochondrial Ca2+ overload followed by mitochondrial swelling, generation of free radicals and apoptosis (Dux et al. 1987; Budd 1998; Small et al. 1999). Free radical species such as superoxide (O2 ), hydroxyl (OH ), hydrogen peroxide (H2O2) and peroxynitrite (N2O2 ) are generated at rates that far exceed the capacity of endogenous antioxidant systems, thus causing substantial damage to cellular DNA and lipid membranes (Flamm et al. 1978; Siesj€ o 1992; Bains & Hall 2012). In this stage, neuronal damage may be intensified by the generation of prostaglandins, thromboxanes, leukotrienes and inflammatory cytokines including interleukin1b (IL-1b) and tumour necrosis factor-a (Goss et al. 1995; Lampe & Becker 2011; Wu & Grotta 2013). Hypoxia inducible factor 1 (HIF-1), composed of an HIF-1a and HIF-1b subunit, is a transcription factor that mediates adaptive mechanisms during hypoxia and ischaemia (Semenza 2000; Kerendi et al. 2005; Han et al. 2014). During hypoxia, HIF-1 induces the expression of a variety of genes (e.g. erythropoietin, vascular endothelial growth factor) that allow the adaptation of cells to anaerobic conditions (Semenza 2000; Kerendi et al. 2005; Han et al. 2014).

order to prevent perioperative shivering in humans, midazolam (Bernard & Buist 2003), opioids such as fentanyl, hydromorphone (Scirica 2013) or meperidine (Kranke et al. 2002) and/or neuromuscular blocking drugs (NMDs) (e.g. vecuronium) (Bernard et al. 2002) have been used in addition to anaesthetics such as isoflurane or propofol (Sessler 1997). For the maintenance of a hypothermic CPB in laboratory sheep, a combination of isoflurane in an oxygen/air mixture, fentanyl and atracurium has been applied (Otto et al. 2011). Multiple mechanisms for hypothermia-induced neuroprotection have been identified including: 1) reduction of cerebral metabolic rate and energy depletion; 2) decrease of excitatory transmitter release; 3) inhibition of apoptosis; 4) reduction of free radical generation; 5) reduction of ion flux; 6) attenuation of neuroinflammatory response [i.e. reductions of vascular permeability, oedema formation and blood–brain barrier disruption (Churn et al. 1990; Colbourne et al. 1997; Ahmad et al. 2014)]; and 7) preservation of collagen integrity (Ning et al. 2007) and myocardial function (Dae et al. 2002; Zhao et al. 2008). Reduction of cerebral metabolic rate and energy depletion It is generally accepted that hypothermia protects organs from ischaemic injury by reducing the cerebral metabolic rate of oxygen (CMRO2) and glucose (CMRgluc) consumption (Michenfelder & Milde 1991). The decrease in CMRO2, however, is not linear (Svyatets et al. 2010). At temperatures between 37 °C and 22 °C, CMRO2 is reduced by 5% per 1 °C decrease in temperature. However, this reduction accelerates at temperatures below this range, with a 20% decrease per 1 °C at 20 °C and a 17% decrease per 1 °C at 18 °C (Kimura et al. 1994; Yenari et al. 2008). The decrease in cerebral metabolic demands slows enzymatic activity and helps to preserve ATP stores (Kwon et al. 2008). Accordingly, maintenance of Na+–K+–ATPase pump function and acid-base homeostasis will preserve cell membrane integrity and neuronal function (Kabon et al. 2003; Svyatets et al. 2010; Wu & Grotta 2013).

Hypothermia: presumed mechanisms of action

Decrease of excitatory transmitter release

Hypothermia in humans has been defined as a core body temperature of <36 °C (Hart et al. 2011). TH is accomplished with the pharmacological induction of poikilothermia and prevention of shivering in order to preserve ATP stores (Hildebrand et al. 2004). In

One important factor for the activation of NMDA receptors and the subsequent facilitation of the Ca2+ influx into cells is the presence of glycine, the level of which is depleted in the brain during hypothermia (Johnson & Ascher 1987; Baker et al. 1991).

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Therapeutic hypothermia KA Otto Moreover, hypothermia significantly reduces the temperature-dependent release of glutamate, thereby decreasing the risk for central nervous system (CNS) hyperexcitability (Takata et al. 2005; Campos et al. 2012). Inhibition of apoptosis Therapeutic hypothermia attenuates apoptotic neuronal cell death in the brain (Gonz alez-Ibarra et al. 2011; Ichinose et al. 2014; Suh et al. 2014). The obvious mechanisms underlying the effect of hypothermia on apoptotic cell death include both a decrease in caspase-3 expression and an increase in Bcl-2 protein expression (Ding et al. 2014). The neuroprotective effects of hypothermia are more pronounced at 30 °C than they are in mild hypothermia (33 °C) (Ding et al. 2014).

Preservation of collagen integrity and myocardial function Finally, hypothermia may preserve collagen integrity, increase survival proteins and promote signalling for cell survival (Ning et al. 2007). Myocardial function may also be supported by reduced cardiomyocyte fragility and improved viability (Sterz et al. 1991; Dae et al. 2002; Zhao et al. 2008), increased myocardial blood flow (Chien et al. 1994; Hamamoto et al. 2009), better microvascular integrity (Hamamoto et al. 2009) and reductions in the number of zones of no-reflow and myocardial necrosis (Chien et al. 1994). Even a small decrease (1 °C) in temperature can improve both microvascular blood flow and myocardial salvage (Hamamoto et al. 2009; Kanemoto et al. 2009). Hypothermia: adverse effects

Reduction of free radical generation The effects of hypothermia on free radical formation in the cerebral cortex were elucidated after experimental middle cerebral artery occlusion followed by hypothermic (33 °C) reperfusion (Karibe et al. 1994). Hypothermia blunted the consumption of endogenous antioxidants (e.g. ascorbate, gluthathione), indicating less free radical synthesis during hypothermia. Generally, hypothermia may affect free radical formation by attenuation of ischaemiainduced nitric oxide formation and a subsequent blockade of OH synthesis (Kader et al. 1994) and/ or a reduction in intracellular Ca2+ ion concentration resulting in a decrease in mitochondrial oxidative stress (Colbourne et al. 1997). The attenuation of intracellular Ca2+ overload may reduce the activity of various enzymes (e.g. phospholipases) involved in the formation of oxygen free radicals (Lei et al. 1994). Moreover, by decreasing the activity of superoxide dismutase, hypothermia may interfere with the generation of hydrogen peroxide and hydroxyl radicals which, in turn, reduces the rate of lipid peroxidation (Smith & Hall 1996). Post-traumatic hypothermia was also found to attenuate the usual rise in IL-1b (Goss et al. 1995) and IL-6 and to facilitate the increase in heat shock protein 70 (Chen et al. 2005). Because IL-10 increases during cooling, profound hypothermia may modulate the post-shock immune/inflammatory system by blocking the proinflammatory IL-6 response and by augmenting anti-inflammatory IL-10 and protective heat shock responses, respectively (Chen et al. 2005).

Coagulopathy Hypothermia-induced coagulopathy and surgical bleeding are multifactorial events. Platelet dysfunction, increased fibrinolytic activity and decreased activity of the coagulation cascade enzymes may all contribute to bleeding during both hypothermia and rewarming (Patt et al. 1988; Danzl & Pozos 1994). Prothrombin and partial thrombin times are increased (Rohrer & Natale 1992). Coagulopathy and thrombocytopenia, however, seem to occur more frequently in accidental hypothermia than during TH (Ahmad et al. 2014). Arrhythmias Electrocardiogram manifestations such as J (or Osborn) waves, prolonged PR, QRS, QT intervals and atrial arrhythmias are well-known adverse effects of hypothermia (Aslam et al. 2006; Marion & Bullock 2009). Hypothermia commonly causes sinus tachycardia followed by bradycardia (Danzl & Pozos 1994; Kabon et al. 2003), increased systemic vascular resistance (Bernard & Buist 2003), a high incidence of atrial and ventricular arrhythmias and prolonged asystole (Danzl & Pozos 1994; Tiainen et al. 2009). The likelihood of myocardial ischaemia in hypothermic patients is three times higher than in normothermic patients (Frank et al. 1997). Morbid cardiac events also include hypothermia-related increases in blood pressure, as well as an up to five-fold elevation in plasma norepinephrine level (Hart et al. 2011).

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Myocardial hypoxia Hypothermia shifts the oxyhaemoglobin dissociation curve to the left, resulting in increased oxygen binding to haemoglobin and reduced oxygen availability for tissues. Therefore, myocardial hypoxia can be expected when increased myocardial oxygen demand coincides with limited myocardial oxygen supply during a short diastolic filling time (e.g. tachycardia) (Hart et al. 2011). Decreased cardiac function Most arrhythmias, including brady- and tachyarrhythmias, as well as atrial or ventricular arrhythmias, are seen at body temperatures below 30–32 °C (Danzl & Pozos 1994; Dae et al. 2002; Polderman 2009; Kelly & Nolan 2010). Mild to moderate hypothermia (e.g. 32–33 °C) can reduce cardiac output and stroke volume by as much as 33% and 23%, respectively, without becoming clinically apparent (Gebauer et al. 2006). An impairment in both systolic and diastolic cardiac function that frequently resolves on rewarming may be caused by alterations in excitation–contraction coupling and actin–myosin interaction (Tveita et al. 1998), or by a hypothermia-induced reduction in the active transport mechanisms responsible for cytoplasmic Ca2+ concentration (Schr€ oder et al. 1994). Infections Hypothermia may increase the risk for infections by suppressing the inflammatory response, inhibiting neutrophil adhesion, promoting the anti-inflammatory T cell profile, causing thermoregulatory vasoconstriction with cutaneous hypoperfusion and by decreasing cytokine production (Hildebrand et al. 2005; Hart et al. 2011). Surgical wound infections, as well as respiratory and urinary tract infections, have been reported in conjunction with hypothermia (Polderman & Herold 2009; Ahmad et al. 2014). The risk for infections increases considerably when cooling time exceeds 48 hours (Marion & Bullock 2009). Impaired renal and hepatic functions During hypothermia, a reduced glomerular filtration rate, diminished renal and hepatic blood flow, metabolic acidosis, electrolyte disorders, prolonged drug clearance and insulin resistance with subsequent hyperglycaemia have been noticed (Aslam et al. 2006; Conolly et al. 2010; Hart et al. 2011). 563

A previous study in cats revealed that hypothermia (29 °C) prolongs the neuromuscular blockade from pancuronium (Miller et al. 1978). Pharmacokinetic and -dynamic data indicate that hypothermia reduces the elimination of pancuronium in both the urine and bile, leading to a prolonged plasma elimination half-life and a lower total plasma clearance of the drug than during normothermia. Moreover, it has been assumed that hypothermia decreases the metabolism of pancuronium. In addition, the lower plasma concentration required for twitch depression during hypothermia supports the hypothesis of an increased sensitivity to pancuronium. Reduced HIF-1a neosynthesis In vitro and in vivo investigations revealed that longlasting mild hypothermia (28–32 °C) lasting from 4 hours to as long as 24 hours will reduce HIF-1a synthesis (Tanaka et al. 2010). Thus, persistent hypothermia will interfere with the gene expression required for the adaptation of cells to hypoxia. Electrolyte depletion Finally, even mild hypothermia of 34 °C may cause marked diuresis, leading to electrolyte depletion, hypovolaemia and hypotensive episodes (Polderman et al. 2001a, b, 2002). Although K+ ion substitution may be indicated during cooling in order to avoid pronounced hypokalaemia caused by an intracellular K+ shift, the shift in K+ ions may reverse during rewarming, potentially leading to dangerous hyperkalaemia (Polderman et al. 2001b, 2002). Categories of hypothermia Hypothermia has been loosely categorized as ‘mild’ (33–36 °C), ‘modest’ (32–34 °C), ‘moderate’ (28– 32 °C), ‘severe’ (16–28 °C) and ‘profound’ (<15 °C) (Inamasu & Ichikizaki 2002; Kwon et al. 2008; Levi et al. 2009). Forty human neonates subjected to an ASO were treated under conditions of either mild (mean rectal temperature: 33.5 °C) or moderate (28.2 °C) hypothermic CPB (Aydemir et al. 2012). All patients in the ‘mild’ group were weaned safely from the CPB and required less dopamine, dobutamine and adrenalin. Intraoperative blood transfusion and postoperative lactate levels were also lower in the mild hypothermic group. In addition, mild hypothermia resulted in a shorter duration of inotropic support, shorter time to extubation, and shorter stays in the intensive care unit and in hospital.

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Therapeutic hypothermia KA Otto Mild hypothermia may also be effective and sufficient in providing substantial protection against cerebral ischaemia and myocardial infarction without causing severe cardiac arrhythmias (Kabon et al. 2003). Furthermore, brief periods of mild hypothermia may not be associated with increases in blood loss, wound infections or other medical complications (Kwon et al. 2008). Although more recent studies revealed mild hypothermia to have numerous beneficial effects in comparison with moderate to profound TH, DHCA (18 °C) is still favoured as the method of choice in aortic arch replacement surgeries and in elective surgeries shows a mortality rate of only 2% (Corvera & Fehrenbacher 2012; Ziganshin & Elefteriades 2013). One major advantage of DHCA is that the bloodless surgical area allows for a thorough examination for debris and thus helps to avoid complications arising from embolizations (Ziganshin & Elefteriades 2010). Although severe to profound TH has been recommended for elective surgeries such as the open repair of aortic dissections in adult human patients, neither profound nor extended cooling beyond 33.5 °C for 72 hours helped to reduce death rates in full-term human neonates with moderate or severe HIE (Shankaran et al. 2005, 2014). Therefore, future studies on TH with reference to optimum temperatures, duration of hypothermia, cooling and rewarming techniques and the efficacy of hypothermia are essential, particularly in the context of non-surgical applications including HIE, TBI and SCI. Techniques of cooling and rewarming Surface cooling is the most common method used to induce systemic hypothermia and involves the use of ice packs, alcohol baths, cooling blankets, cooling pads or gastric lavage with iced saline (Jordan & Carhuapoma 2007; Ahmad et al. 2014). With other surface cooling systems, a decrease in body temperature may be achieved by means of circulating cool air or cooling pads containing tubes through which cooled water is pumped (Hypothermia after Cardiac Arrest Study Group 2002; Kwon et al. 2008). Although these devices are easy to use, it may take several hours to achieve even mild levels of hypothermia, particularly in obese or oversized patients (Inamasu & Ichikizaki 2002; Bernard & Buist 2003). Therapeutic hypothermia may be established more rapidly and more effectively by intravenous

infusion of ice-cold saline solution or by means of extracorporal circulation in conjunction with a cooling/heating device (Rajek et al. 2000; Ziganshin & Elefteriades 2013). Infusion of 40 mL kg 1 of 4 °C cold saline solution into the superior vena cava resulted in a decrease in mean core temperature in adult anaesthetized human volunteers from a baseline of 35.7 °C to a temperature of 33.1 °C at the end of the 30 minutes infusion period (Rajek et al. 2000). Mean body core temperature at the end of the 90 minutes observation period was 33.9 °C. When CPB is established for aortic surgery, body core temperatures as low as 18 °C (probe in the urinary bladder) may be achieved within 30–40 minutes (Ziganshin & Elefteriades 2013). The gentle rewarming of the patient can be achieved over approximately 60 minutes (Ziganshin & Elefteriades 2013). Local cooling can be achieved using an epidural heat exchanger, by perfusion of the subarachnoid space or by irrigation of the spinal cord with ice-cold saline solution (Ahmad et al. 2014). Alternative approaches in surgery for aneurysms The majority of patients will tolerate up to 30 minutes of circulatory arrest at 18 °C without significant neurological impairment (Conolly et al. 2010; Griepp & Di Luozzo 2013). However, in order to prolong the period of safe circulatory arrest, DHCA may be combined with either selective antegrade cerebral perfusion (SACP) or retrograde cerebral perfusion (RCP) (Conolly et al. 2010; Tian et al. 2013). During SACP, the carotid arteries are perfused, whereas during RCP cold oxygenated blood is directed into the superior vena cava (Conolly et al. 2010). The disadvantages of SACP may include an increased risk for embolization and increased complexity of surgery, whereas risks for cerebral oedema and raised intracranial pressure have been reported for RCP (Khaladj et al. 2008; Conolly et al. 2010; Tian et al. 2013). Intraoperative monitoring of the cardiac patient during TH Monitoring of the body core temperature, which is assumed to reflect the temperature in the thoracic/ abdominal cavity and in the CNS (Hart et al. 2011), is mandatory when hypothermic CPB is established for cardiac surgery. Although many sites, such as

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the tympanic membrane, nasopharynx, oesophagus, urinary bladder, pulmonary artery and jugular venous bulb, have been recommended for measuring core temperature during general anaesthesia (Svyatets et al. 2010; Hart et al. 2011), an earlier study reported the nasopharynx, oesophagus and urinary bladder as providing the most accurate and precise measurements of core temperature (Cork et al. 1983). In adults with severe head injuries, brain temperature during surgery has been reported to be approximately half a degree lower than oesophageal, tympanic or bladder temperatures (Henker et al. 1998). For the maintenance of acid-base homoeostasis during TH, two different approaches have been recommended: alpha-stat management and pH-stat management (Hindman et al. 1995; Kurth et al. 1997; Priestley et al. 2001). During alpha-stat management, the arterial partial pressure of carbon dioxide (PaCO2) is kept within its normal range at 37 °C, whereas during pH-stat management, PaCO2 is corrected to the core temperature actually measured (Svyatets et al. 2010). Experimental studies in animals (piglets, rabbits) revealed that pH-stat management during CPB resulted in better neurological outcomes than alpha-stat management (Hindman et al. 1995; Kurth et al. 1997; Priestley et al. 2001). The improved neurological outcome with pH-stat management, as opposed to the alpha-stat approach, was characterized by a more pronounced decrease in CMRO2 at the same temperature (Hindman et al. 1995), more uniform brain cooling (Kurth et al. 1997) and less functional disability, as well as less neuronal cell damage (Priestley et al. 2001). By contrast, the adverse effects reported for pH-stat management included a greater risk for microembolism (Pl€ ochl & Cook 1999) and free radical-mediated damage (Rehncrona et al. 1989). For these reasons, in surgeries performed during DHCA, alpha-stat management should be preferred (Qian et al. 2013). With reference to monitoring of the depth of anaesthesia during hypothermic CPB, the effects of decreasing body temperature on brain anaesthetic requirements, volatile anaesthetics blood/gas solubility and duration of action of NMDs deserve thorough consideration in order to assure adequate surgical anaesthesia. A study in adult goats revealed that a decrease in body core temperature (cranial vena cava) from approximately 38.5 °C to 29.0 °C to 20.0 °C was 565

associated with a decrease in the mean minimum alveolar concentration (MAC) of isoflurane from 1.3% to 0.7% and finally to 0%, respectively, indicating the elimination of isoflurane requirements at 20.0 °C (Antognini 1993). Moreover, changes in liquid temperature that occur during both the cooling and rewarming phases of hypothermic CPB will, respectively, increase and decrease the liquid and tissue solubility of various anaesthetics (Nussmeier et al. 1989; Yu et al. 2001; Zhou & Liu 2001). Changes in liquid solubility may potentially cause corresponding changes in anaesthetic concentration readings during cooling and rewarming that must be considered when MAC multiples are used to monitor the depth of anaesthesia. Because hypothermia has been reported to prolong and intensify the action of NMDs such as pancuronium (Miller et al. 1978) and the clinical signs commonly used to determine the depth of anaesthesia are rarely available during hypothermic CPB (Schmidlin et al. 2001; Tiren et al. 2005), additional neuromonitoring [e.g. by electroencephalography (EEG)] may help to quantify the depth of anaesthesia, particularly during cardiac surgery (Otto et al. 2012). The maintenance of a high-voltage, low-amplitude EEG pattern or even EEG burst suppression during hypothermic CPB has been helpful for providing an adequate depth of surgical anaesthesia in laboratory sheep (Otto et al. 2011, 2012). Conclusions Therapeutic hypothermia is an essential measure of neuroprotection during cardiac surgeries that may be achieved most effectively by intravascular cooling using hypothermic CPB. For most cardiac surgical procedures, mild to modest (32–36 °C) TH will be sufficient to assure neuroprotection and will avoid most of the adverse effects of hypothermia that occur at lower core temperatures. As a reduction in body core temperature will also affect anaesthetic requirements, blood/gas solubility of anaesthetic gases and vapours, as well as the duration and intensity of the neuromuscular blockade, the employment of TH may require specific measures (e.g. EEG) in order to assure an adequate depth of surgical anaesthesia. References Adelson PD, Wisniewski R, Beca J et al. (2013) Comparison of hypothermia and normothermia after severe

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