**4.3.1 Risk factors of neurocognitive dysfunction**

**Patient Risk Factors;** Neuroprotective anesthetic, surgical and perfusion techniques should be the key element in the management of these procedures guided by the identification of the high risk patients in the preoperative period.

*Patient risk factors (Lombard et al,2010;Grigore et al,2009)* 


*Surgical risk factors;* 


#### **4.3.2 Prevention of adverse neurological outcome**

**CPB;** Cerebral hypoperfusion, temperature fluctuations, high incidence of cerebral embolism, inflammatory response, brain swelling and elevated levels of biomarkers of brain injury explains the potential of CABG surgeries for the development of POCD. However, in

In the preoperative period, brain imaging can detect the prior brain infarction, white matter lesions and/or lacunar infarcts that are clinically asymptomatic and also abnormal brain perfusion areas can be detected by SPECT prior to the operation; demonstrating the high-

There are several factors that have been associated with neurological problems such as patient risk factors including aortic atherosclerosis and surgical risk factors including type

**Patient Risk Factors;** Neuroprotective anesthetic, surgical and perfusion techniques should be the key element in the management of these procedures guided by the identification of

History of cerebrovascular disease with symptoms or silent infarctions (presence of one

 Genetic predisposition (minor alleles of C-reactive protein (CRP; 3'UTR 1846C/T), IL-6;- 174G/C, platelet glycoprotein IIb/IIIa receptor variants are the candidates requiring

**CPB;** Cerebral hypoperfusion, temperature fluctuations, high incidence of cerebral embolism, inflammatory response, brain swelling and elevated levels of biomarkers of brain injury explains the potential of CABG surgeries for the development of POCD. However, in

of surgery, temperature control, glucose control and intraoperative hemodynamics.

or more lacunar infarcts on preoperative magnetic resonance imaging)

risk patients for the development of POCD.

**4.3.1 Risk factors of neurocognitive dysfunction** 

the high risk patients in the preoperative period. *Patient risk factors (Lombard et al,2010;Grigore et al,2009)* 

Non-coronary manifestations of atherosclerosis;

Advanced age (>70 yr)

*Surgical risk factors;* 

 Blood gas management Cerebral embolism Cell salvage Valve surgery Temperature control Hemodilution Oxygen delivery Glucose control

Intraoperative hemodynamics

Systemic inflammatory response

**4.3.2 Prevention of adverse neurological outcome**

Aortic atherosclerosis

CPB

Peripheral vascular disease Chronic neurologic illness Congestive heart failure Fewer years of education Limited social support

Insulin-dependent diabetes mellitus

further knowledge)(Grogan et al,2008)

recent trials the cardiac surgical patients with or without CPB were investigated and no difference was described between them in terms of neurological outcome (Lombard et al,2010; Grigore et al,2009).

**Blood gas management;** Although there are controversies about the technique to be used during CPB period, α-stat has been shown to preserve pressure autoregulation and recommended for the technique to be used in adults (see also management during CPB).

**Cerebral Embolism;** Long-term dysfunctions might be mostly related to macroemboli from aortic lesions due to aortic manipulation, rather than gaseous microemboli which is the predominant type of microemboli during bypass period (Wahrborg et al,2004). However, the macroemboli to be a major cause of cognitive dysfunction is unlikely that it has been defined to be more associated with stroke (Bar-Yosef et al,2004). As being the most common type of cerebral emboli detected by transcranial Doppler during CPB are air emboli; in order to increase the rate of absorbtion of intravascular emboli, CO2 has been used for wound insufflation to replace air in the pericardium, as it is more soluble than air. Although it reduced the number of arterial emboli, it has not been investigated for the brain protection, and also this technique is not without risks (Grogan et al,2008). The imaging techniques improves every year and one of them is the magnetic resonance diffusion-weighted imaging (DWI), which identifies regions of cerebral ischemia with a high sensitivity and specificity differentiating the acute from chronic infarction. 25-50% of patients undergoing cardiac surgery develop new lesions on DWI, however, very few of them show clinically significant infarction. On the other hand there are trials reporting significant correlation between the lesions on DWI and cognitive impairment proving that for the development of cognitive dysfunction, necrosis is not necessary, whereas other trials did not reveal any correlation (Knipp et al,2005;Cook et al,2007). More sensitive imaging techniques such as functional MRI may be used for assessing neurocognitive dysfunction after cardiac surgery.

**Cell Salvage;** Continuous flow cell saver when compared with conventional cardiotomy suction, may reduce the lipid microemboli (resulting in small arteriolar capillary dilatations) by processing the shed blood a major source of lipid microparticulates, thus reduce the cognitive decline after cardiac surgery (Grogan et al 2008, as cited in Djaiani et al,2007). Simply discarding the pericardial aspirate, when the shed blood is low, is an acceptable choice; and on the other hand using the cell-saver may cause thrombocytopenia and decrease the concentration of coagulation factors leading to bleeding and high rates of transfusion. Thrombocytopenia is a major concern because transfusion of platelets increases the risk of stroke in cardiac surgical patients. The increased requirement for transfusion has been shown by both Rubens et al. (Grogan et al,2008 as cited in Rubens et al,2007) and Djaiani et al. (Grogan et al 2008, as cited in Djaiani et al,2007), although their results in terms of the effects of cell-saver and cardiotomy suction on neurocognitive dysfunction are conflicting.

**Valve Surgery;** The valve surgeries have an increased incidence of cognitive dysfunction, because of the open heart chambers during the procedure. Furthermore the cognitive dysfunction following valve surgery lasts longer than CPBG surgeries most probably because of the ongoing microemboli (Lombard et al,2010).

**Temperature Control;** Hypothermia has been the major intervention that is used for cerebral protection. Moderate and mild hypothermia were not dissimilar in terms of POCD, however hyperthermia has been proven clearly to be associated with adverse neurologic outcome. The potential benefit of hypothermia is clearly offset by inappropriate rewarming, which leads to cerebral hyperthermia. Mild hypothermia (32-34 C), slow rewarming, avoiding hyperthermia are the current recommendations (Grigore et al,2009;Grogan et al,2008) (see also management during CPB).

**Hypothermic Circulatory Arrest:** Moderate or profound hypothermia with periods of circulatory arrest combined with selective anterograde or retrograde brain perfusion periods has become an acceptable technique. Selective anterograde perfusion has been proven to be comparable or better than hypothermic circulatory arrest alone or retrograde perfusion; furthermore it has been reported that shortened period of brain ischemia via selective anterograde perfusion and use of less profound hypothermia is associated with good clinical outcomes (Reich et al,2010).

**Hemodilution;** In order to avoid the adverse effects of hypothermia on blood viscosity, hemodilution is used, which also reduces blood requirement during cardiac surgery. As hematocrit level decreases, oxygen carrying capacity decreases which in turn increases CBF leading to a high risk of cerebral emboli. Although a definitive recommendation is not available, transfusion of blood products are supported to be reserved for patients with hemoglobin level of <6 gr/dl during CPB and <7 gr/dl after surgery (Ferraris et al,2007) (see also management during CPB).

**Oxygen Delivery;** Delivery of oxygen during CPB period is less than in awake and anesthetized patients; particularly because of the hemodilution at the onset of bypass reducing the arterial oxygen content. During CPB, delivery of oxygen to the brain is preserved at low pump flow rates at the expense of other organs. A critical DO2 value should be targeted to preserve organ functions (Murphy et al;2009) (see also management during CPB).

**Glucose Control;** Moderate glycemic control is recommended instead of tight glycemic control, given a Class IIa, LOE C indication for insulin therapy when the glucose level exceeds 140-185 mg/dl (Adams et al,2007;Finfer et al,2009).

**Intraoperative Hemodynamics;** The patients with pre-existing cerebrovascular diseases (CVD) are more vulnerable to cerebral hypoperfusion during CPB. Considering the increased age of these patients, most of them already have a symptomatic or asymptomatic CVD, which requires maintenance of pre-CPB cerebral perfusion pressures. MAP>70 mmHg is supported to be the goal especially in the elderly (Grogan et al,2008). Although there is no clear data, pump flow rates of 1-2.4 L/min/m2 have been shown to preserve CBF (Murphy et al,2009).

**Aortic Atherosclerosis;** As being an important risk factor for the development of cognitive dysfunction, detection of atherosclerosis of the ascending aorta provides risk stratification in the preoperative period that may lead to a decision of 'off-pump' CAB or 'no touch' approach to ascending aorta in order to prevent any adverse neurological outcome. Avoiding ascending aorta manipulations or searching for the atherosclerosis free areas may be beneficial, however after CPB it has been shown that CPB itself (due to sandblasting effect) may result in new mobile lesions on the sites where previously was mild-to-moderate atherosclerosis; at the sites of aortic cannulation and clamping (Reich et al,2010) .

**Systemic Inflammatory Response;** It is well-known that CPB causes a profound systemic inflammatory response. High baseline level of CRP was found to be associated with greater risk of neurocognitive decline. Cerebral ischemia-reperfusion injury also produces a profound inflammatory response; p-selectin expression on platelets resulting in platelet accumulation, rendering the brain vulnerable to microthrombosis, leading to ischemia (Lombard et al,2010). According to recent guidelines it is not unreasonable to use reduced

avoiding hyperthermia are the current recommendations (Grigore et al,2009;Grogan et

**Hypothermic Circulatory Arrest:** Moderate or profound hypothermia with periods of circulatory arrest combined with selective anterograde or retrograde brain perfusion periods has become an acceptable technique. Selective anterograde perfusion has been proven to be comparable or better than hypothermic circulatory arrest alone or retrograde perfusion; furthermore it has been reported that shortened period of brain ischemia via selective anterograde perfusion and use of less profound hypothermia is associated with good

**Hemodilution;** In order to avoid the adverse effects of hypothermia on blood viscosity, hemodilution is used, which also reduces blood requirement during cardiac surgery. As hematocrit level decreases, oxygen carrying capacity decreases which in turn increases CBF leading to a high risk of cerebral emboli. Although a definitive recommendation is not available, transfusion of blood products are supported to be reserved for patients with hemoglobin level of <6 gr/dl during CPB and <7 gr/dl after surgery (Ferraris et al,2007) (see

**Oxygen Delivery;** Delivery of oxygen during CPB period is less than in awake and anesthetized patients; particularly because of the hemodilution at the onset of bypass reducing the arterial oxygen content. During CPB, delivery of oxygen to the brain is preserved at low pump flow rates at the expense of other organs. A critical DO2 value should be targeted to preserve organ functions (Murphy et al;2009) (see also

**Glucose Control;** Moderate glycemic control is recommended instead of tight glycemic control, given a Class IIa, LOE C indication for insulin therapy when the glucose level

**Intraoperative Hemodynamics;** The patients with pre-existing cerebrovascular diseases (CVD) are more vulnerable to cerebral hypoperfusion during CPB. Considering the increased age of these patients, most of them already have a symptomatic or asymptomatic CVD, which requires maintenance of pre-CPB cerebral perfusion pressures. MAP>70 mmHg is supported to be the goal especially in the elderly (Grogan et al,2008). Although there is no clear data, pump flow rates of 1-2.4 L/min/m2 have been shown to preserve CBF (Murphy

**Aortic Atherosclerosis;** As being an important risk factor for the development of cognitive dysfunction, detection of atherosclerosis of the ascending aorta provides risk stratification in the preoperative period that may lead to a decision of 'off-pump' CAB or 'no touch' approach to ascending aorta in order to prevent any adverse neurological outcome. Avoiding ascending aorta manipulations or searching for the atherosclerosis free areas may be beneficial, however after CPB it has been shown that CPB itself (due to sandblasting effect) may result in new mobile lesions on the sites where previously was mild-to-moderate

**Systemic Inflammatory Response;** It is well-known that CPB causes a profound systemic inflammatory response. High baseline level of CRP was found to be associated with greater risk of neurocognitive decline. Cerebral ischemia-reperfusion injury also produces a profound inflammatory response; p-selectin expression on platelets resulting in platelet accumulation, rendering the brain vulnerable to microthrombosis, leading to ischemia (Lombard et al,2010). According to recent guidelines it is not unreasonable to use reduced

atherosclerosis; at the sites of aortic cannulation and clamping (Reich et al,2010) .

al,2008) (see also management during CPB).

clinical outcomes (Reich et al,2010).

also management during CPB).

management during CPB).

et al,2009).

exceeds 140-185 mg/dl (Adams et al,2007;Finfer et al,2009).

circuit surface and biocompatible surface-modified circuits which are useful and effective in reducing systemic inflammatory response (Class IIa, LOE B) (Shann et al,2006).

**Pharmacological Interventions;** One of the methods that is investigated for the prevention of neurological dysfunction after CPB, is pharmacological protection, though remains controversial. It has been reported that the incidence of neurocognitive dysfunction can be lowered by using short-acting anesthetic and analgesic agents, providing a faster recovery from general anesthesia (Chen et al,2001). Shorter emergence times can be achieved by using low blood-gas partition coefficient and rapidly eliminated volatile anesthetics such as sevoflurane and desflurane (Frink et al,1992;Tsai et al,1992). In their preliminary report, Kanbak et al. reported that isoflurane and propofol were similar in terms of neuropsycological test scores and neurological examination after CPB, despite increased levels of S100BP in the propofol group (Kanbak et al,2004). Kanbak et al. also investigated the effects of isoflurane, desflurane and sevoflurane on cognitive function after CABG, comparing them in terms of neurological tests and S100BP levels. Isoflurane has been reported to provide better cognitive outcome (Kanbak et al,2007).

Pexelizumab, lidocaine, magnesium, ketamine, 17β-estradiol, donepezil, aprotinin are the pharmacological agents that are investigated for their efficacy on neurocognitive functions after cardiac surgery, however, all require further evaluation. There are no ideal pharmacological agent for neuroprotection during cardiac surgery (Lombard et al,2010; Grogan et al,2008).

*Recommendations to reduce brain injury during cardiac surgery (Grogan et al,2008)* 


#### **4.4 Acute kidney injury (AKI)**

Acute kidney injury known to be an independent predictor of mortality in cardiac surgery, has an incidence of 50% by some defnitions, doubling the postoperative and intensive care unit costs (Park et al,2010). The pathophysiologic processes of cardiac-surgery associated AKI (CSA-AKI) were concluded to be; exogenous and endogeneous toxins, metabolic factors, ischemia-reperfusion, neurohormonal activation, inflammation and oxidative stress, which are interrelated and probably synergistic (Garwood,2010).

A common terminology and definition is necessary to determine the high-risk patients for the development of CSA-AKI. The term acute renal injury reflects the entire spectrum of the disease process; from minimal changes in serum creatinin to anuric renal failure, from functional deviations to structural changes and from prerenal azotemia to acute tubular necrosis (Dennen et al,2010). The Second International Cosensus Conference of the Acute Dialysis Quality Initiative (ADQI) group published a classification system for AKI based on the changes in serum creatinin and/or urine output. In this 5-stage classification, first 3 describes the risk, injury and failure for the severity of the AKI based on the changes in serum creatinin, glomerular filtration rate (GFR) and urine output. Last 2 stages describe outcome as loss and end-stage kidney disease, making the acronym RIFLE classification (Bellomo et al,2004). Acute Kdney Injury Network (AKIN) proposed a modification to this classification and used a time frame of 48 hours in which the AKI has to occur and included lesser degrees of serum creatinin elevation. ADQI subdivided this classification into stages as early (within the first 7 days) and late (occuring between 7 and 30 days after cardiac surgery) (Hoste et al,2008).

In order to prevent cardiac surgery associated acute kidney injury (CSA-AKI) the most important approach is providing adequate renal perfusion throughout the surgery. Although there is no guide for any specific fluid or vasoactive agent to improve renal function, it is important to identify patients who are at increased risk such as patients in volume depletion and have congestive heart failure (Tolwani et al,2008). However it should be kept in mind that pathophysiological events other than changes in RBF are also responsible for development of AKI (Garwood,2010,as cited in Bonventre et al,2004 & Friedewald et al,2004). The patients known to have renal disease are more prone to have systemic acidosis and electrolyte disturbances mainly hyperkalemia, requiring more frequent blood gas and electrolyte sampling. Intraoperatively adequate fluid and medication management should be done for the dialysis patients ensuring that they have a recent dialysis with an adequate serum potassium level (London et al,2008). The ongoing investigations have a goal to define a single or a panel of early biomarkers to prospectively identify the potential for developing AKI after cardiac surgeries (Garwood,2010).

Cardiac surgery patients are particularly at risk of volume-responsive AKI; which is the term used more favorably than prerenal azotemia, emphasizing that despite the reversibility of early stages of AKI, even minor increases above baseline may result in adverse outcomes and any degree of renal insufficiency no matter how small may result in significant clinical consequences even in the absence of complete loss of function (Garwood,2010).

The non-volume responsive AKI also may occur in cardiac surgical patients. Ischemic period which has been clearly defined in experimental models, is also clearly defined to be associated with multiple injurious events in humans during the perioperative period. The key sign is a rapid, progressive and profound decline in GFR, which continue and progress even after return of renal perfusion to baseline (Garwood,2010).

Acute kidney injury known to be an independent predictor of mortality in cardiac surgery, has an incidence of 50% by some defnitions, doubling the postoperative and intensive care unit costs (Park et al,2010). The pathophysiologic processes of cardiac-surgery associated AKI (CSA-AKI) were concluded to be; exogenous and endogeneous toxins, metabolic factors, ischemia-reperfusion, neurohormonal activation, inflammation and oxidative stress,

A common terminology and definition is necessary to determine the high-risk patients for the development of CSA-AKI. The term acute renal injury reflects the entire spectrum of the disease process; from minimal changes in serum creatinin to anuric renal failure, from functional deviations to structural changes and from prerenal azotemia to acute tubular necrosis (Dennen et al,2010). The Second International Cosensus Conference of the Acute Dialysis Quality Initiative (ADQI) group published a classification system for AKI based on the changes in serum creatinin and/or urine output. In this 5-stage classification, first 3 describes the risk, injury and failure for the severity of the AKI based on the changes in serum creatinin, glomerular filtration rate (GFR) and urine output. Last 2 stages describe outcome as loss and end-stage kidney disease, making the acronym RIFLE classification (Bellomo et al,2004). Acute Kdney Injury Network (AKIN) proposed a modification to this classification and used a time frame of 48 hours in which the AKI has to occur and included lesser degrees of serum creatinin elevation. ADQI subdivided this classification into stages as early (within the first 7 days) and late (occuring between 7 and 30 days after cardiac

In order to prevent cardiac surgery associated acute kidney injury (CSA-AKI) the most important approach is providing adequate renal perfusion throughout the surgery. Although there is no guide for any specific fluid or vasoactive agent to improve renal function, it is important to identify patients who are at increased risk such as patients in volume depletion and have congestive heart failure (Tolwani et al,2008). However it should be kept in mind that pathophysiological events other than changes in RBF are also responsible for development of AKI (Garwood,2010,as cited in Bonventre et al,2004 & Friedewald et al,2004). The patients known to have renal disease are more prone to have systemic acidosis and electrolyte disturbances mainly hyperkalemia, requiring more frequent blood gas and electrolyte sampling. Intraoperatively adequate fluid and medication management should be done for the dialysis patients ensuring that they have a recent dialysis with an adequate serum potassium level (London et al,2008). The ongoing investigations have a goal to define a single or a panel of early biomarkers to prospectively identify the potential for developing AKI after cardiac surgeries

Cardiac surgery patients are particularly at risk of volume-responsive AKI; which is the term used more favorably than prerenal azotemia, emphasizing that despite the reversibility of early stages of AKI, even minor increases above baseline may result in adverse outcomes and any degree of renal insufficiency no matter how small may result in significant clinical

The non-volume responsive AKI also may occur in cardiac surgical patients. Ischemic period which has been clearly defined in experimental models, is also clearly defined to be associated with multiple injurious events in humans during the perioperative period. The key sign is a rapid, progressive and profound decline in GFR, which continue and progress even after return of renal perfusion to baseline (Garwood,2010).

consequences even in the absence of complete loss of function (Garwood,2010).

which are interrelated and probably synergistic (Garwood,2010).

**4.4 Acute kidney injury (AKI)** 

surgery) (Hoste et al,2008).

(Garwood,2010).

Pathophysiological events other than changes in RBF are also responsible for the development of AKI (Garwood,2010,as cited in Molitoris et al,2004Bonventre et al,2004 & Friedewald et al,2004 ).

As the AKI is a multifactorial adverse consequence, it is crucial to address these interreacting factors for the prevention and treatment of CSA-AKI. The disease process includes ischemia, endothelial and epithelial dysfunction and tubular injury (Garwood,2010). Despite their limitations and variabilities in the AKI definitions and targeting mostly the prevention rather than treatment, there are many trials investigating the effects of vasodilators-primarily increasing the renal blood flow (dopamine, dopexamine, fenoldopam, angiotensin-converting enzyme inhibitors (ACEI) (captopril, enalaprilat), diltiazem, prostacyclin, nifedipine, PGE-1, sodium nitroprusside, theophylline), interventions inducing natriuresis or diuresis or both (atrial natriuretic peptid, brain natriuretic peptid, urodilatin, diuretic agents (loop diuretics and mannitol), antiinflammatory agents (N-acetyl cyctein, aspirin, glutathion, corticosteroids, leukodepletion), clonidine, albumin infusion, isotonic saline infusion, insulin therapy, early continous venovenous hemofiltration and also off vs on-pump technique. Fenoldopam, ACEI, atrial natriuretic peptide (nesiritide), B-natriuretic peptid, urodilatin were associated with reduction in the incidence of CSA-AKI. Off-pump surgical technique and pulsatile flow techniques also were reported to reduce the incidence (Park et al,2010). The recent trials are investigating reactive oxygen molecule scavengers, anti-inflammatory agents and antiapoptotic agents. AKIN also identifies the antiapoptotic agents (e.g.tetracyclines, human recombinant erythropoietin (HrEPO)) as potentially useful for AKI, though further researchs are needed (Garwood,2010).
