*2.6.4. Impact of renal artery stenosis on CABG*

tery grafting in addition to SVGs in diabetic patients improved survival and decreased need for revascularization compared with single internal mammary artery grafting along with SVGs [28]. The strong correlation between diabetes and cardiovascular outcomes including survival and myocardial infarction is due to the diffusely extensive and rapidly progressive nature of atherosclerotic coronary artery disease (CAD) in this group of patients. Various other factors such as oxidized low-density lipoproteins (LDL), hyperglycemia causing ad‐ verse metabolic shifts, deranged fibrinolysis, increased coagulability, and advanced reno‐ vascular hypertension resulting in change in vessel architecture also contribute to the progressive nature of CAD in diabetics. There is increased tendency for LDL induced athe‐ rosclerotic plaque formation and there is greater predisposition to thrombosis due to in‐ creased blood viscosity secondary to high plasma protein levels. There is also platelet and endothelial dysfunction and increased production of thromboxane A2 and von- willebrand factor along with decreased production of prostacyclins which creates a procoagulant state. Coronary vasodilation is impaired as a result of loss of the hyperpolarizing mechanics nor‐ mally present in endothelial cells. Autonomic neuropathy in diabetes increases cardiac chrontropic workload and subsequently leads to greater oxygen demand even at rest. There is enhanced vascular tone in the coronary atherosclerotic plaque area leading to further re‐ duction in blood flow, producing orthostatic changes which leads to reduction in coronary perfusion pressure and mitigates warning signs of ischemia such as angina [27,29-32].

Hypertension has also been associated with worse post CABG outcomes. In a multi centre study of 2417 patients among whom patients were categorized into patients with normal preoperative blood pressure, isolated systolic hypertension (systolic blood pressure >140 mm Hg), diastolic hypertension (diastolic blood pressure >90 mm Hg), or a combination of systolic and diastolic hypertension. It was found that isolated systolic hypertension was as‐ sociated with a 40% greater risk of adverse outcomes such as stroke, renal failure, congestive heart failure and all cause mortality after CABG. Even after correction for confounding risk factor adjustment, the increased risk of adverse outcomes was significantly more pro‐

In a study of 936 hemodialysis patients to elucidate correlation of recognized risk factors in CKD patients, it was found that correlation with diabetes, smoking, African-American race and increasing age of above fifty- five years was strong. It is suspected that non-traditional risk factors like uremic environment and hemodialysis procedure using arteriovenous fistu‐ lae and high output state associated with these fistulae also impact the outcomes after

Dyslipidemia with a high LDL is a classic risk factor for development of CAD in the general population. However, it is likely not a major risk factor in patients with advanced renal dis‐ ease. In a study of 210 dialysis dependent patients compared with 223 control subjects with normal renal function, it was found that high density lipoprotein (HDL) levels were low

*2.6.2. Hypertension*

442 Artery Bypass

nounced in hypertensive patients [33].

*2.6.3. Impact of other risk factors*

CABG adversely [34].

Renal artery stenosis (RAS) can lead to refractory hypertension and gradual deterioration in kidney function. The presence of underlying RAS and its effect on CABG outcomes has been studied and variable results have been obtained. In a study of 798 patients undergoing iso‐ lated CABG with 18.7% having renal artery stenosis (>50% stenosis), acute renal failure de‐ veloped in 10.2% of patients post procedure. The mortality rate was 14% in patients who developed acute renal failure (ARF) post operatively, while it was 0.2% in patients who did not develop ARF. However, presence of RAS was not associated with development of ARF post-operatively [38].

In a series of eighteen patients undergoing CABG who also had varying degrees of RAS with mean serum creatinine of 2.6±2.7 mg/dl, RAS was not associated with adverse out‐ comes post-operatively [39].

### **2.7. Post-CABG complications in patients with CKD**

Besides relatively increased short-term mortality in patients with CKD undergoing CABG, they also encounter increased morbidity from infections, blood transfusions, and stroke. In a retrospective analysis of 3954 patients where 82.7% patients had creatinine <1.5 mg/dl, and 16% had a serum creatinine level between 1.5 and 3.0 mg/dl, it was demonstrated that pa‐ tients with a serum creatinine level >1.5 mg/dl had a mortality of 7% compared to 3% in pa‐ tients with serum creatinine <1.5 mg/dl. Additionally, patients with a higher serum creatinine level had a higher incidence of requiring prolonged mechanical ventilation (15% vs. 8%), risk of stroke (7% vs. 2%), and bleeding complications (8% vs. 3%). Three infectious complications (mediastinitis, graft harvest site infection, and chest wound infections) were not different among these groups, whereas the occurrence of pneumonia and endocarditis was significantly higher in patients with a higher serum creatinine [40].

#### *2.7.1. Prolonged mechanical ventilation*

It is believed that the prolonged mechanical ventilation and the need for re-intubation after CABG in patients with renal dysfunction are due to a compromised ability to eliminate fluid volume, thereby predisposing patients to impaired alveolar gas exchange. Additionally, re‐ nal failure would result in decreased metabolism and elimination of sedative, anxiolytic and analgesic drugs leading to impairment of respiratory drive.

ing with coronary bypass grafting. The mechanism of induction of cardioplegia involves prevention of repolarization of myocardial cell membrane due to the high potassium concentra‐ tion of the cardioplegic fluid causing inactivation of the sodium channels which initiate the ac‐ tion potential. The hypothermic fluid of cardioplegia induces asystole. When the solution is administered in the aortic root it is termed antegrade and when administered in the coronary si‐ nus, it is called retrograde. Myocardial protection with cardioplegia decreases the energy de‐ mands of the heart by arrest of the contractile apparatus. This is considered to be an extension of ischemia tolerance which is considered to minimize the deleterious effects of induced cardiac arrest. However, it still is desirable to keep duration of cardioplegia at a minimum as the aortic cross-clamp time is an important factor in predicting mortality in cardiac surgery and the lesser it is, the better the outcomes. The metabolic processes resulting from cardiac ischemia include sudden cessation of normal aerobic cardiac metabolic events, reduction in creatine phosphate, initiation of anaerobic glycolysis, and build-up of lactate and alpha glycerol phosphate as well as nucleotide metabolites. This is associated with contractile impairment and electrical path‐ way alterations consistent with typical EKG changes. The myocardial demand for high energy phosphate substrates is increased when the availability of adenosine triphosphate decreases. The predominant mode of energy derivation is switched to anaerobic glycolysis in the ischemic tissue. With early ischemic component, contractile activity and later on ion transport utilizes available adenosine triphosphate but gradually with the increase in ischemic time period, the metabolic demands undergo a compensatory reduction to prevent further ischemic damage. Ir‐ reversible injury in cardiac muscle is highlighted by very low levels of adenosine triphosphate, lack of energy production even by anaerobic mode, progressive accumulation of hydrogen ions, adenosine monophosphate, and lactic acid with a consequently high osmotic load, mito‐ chondrial swelling and amorphous densities in matrix, and loss of integrity of the sarcolemmal membrane. The precise mechanism of pathogenesis is still elusive. In animal models, severe is‐ chemia causes irreversible cell injury and death in one hour while with less severe ischemia in the mid and sub-epicardial myocardium, survival is possible up to six hours. Irreversible injury and cell death after six hours is inevitable. The ischemic injury changes reverse to a certain de‐ gree after reperfusion but how quickly and completely this transformation occurs is highly vari‐ able ranging from minutes to days. Aerobic metabolism is restored early while adenine

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Systolic dysfunction with reduction in LVEF <0.40 is also an indicator of poor prognosis in CKD patients undergoing CABG. In a comparison study of aortic cross clamp times in patients with normal versus reduced ejection fraction in 27,215 patients in which 99.8 % received antegrade, retrograde or combined cardioplegia, it was found that prolonged aortic cross clamp time was an independent predictor of mortality [43]. It was shown that a combination of reduced LVEF and prolonged aortic cross clamp time especially with CKD compounds the ischemic effects and increases overall risk of perioperative mortality. In this study, the mean aortic cross clamp time was 68± 20 minutes, number of distal grafts was 3.1± 1.4 and 68.7% of patients underwent grafting of the left internal mammary artery. The incidence of pulmonary complications was 12.2% and stroke was 2.27%. Fifty-two percent of the patients had baseline hypertension, 29%

It has been shown that patients undergoing CABG with off pump or beating heart technique experience improved post-operative outcomes and less perioperative mortality. In a study

nucleotide pool and stunning resolve slowly [42].

had diabetes and 7% were dialysis dependent.

A study showed that ventilatory complications such as need for greater than 48 hours of me‐ chanical ventilation and re- intubation is high in patients with significant renal dysfunction undergoing CABG, when compared to patients with normal or mild renal dysfunction [40]. Another study showed a stepwise increase in need for prolonged mechanical ventilation as the renal function deteriorates. In this study, the ventilator dependence rate greater than 24 hours was 8.6%, 14.7%, and 20.2%, as the stage of CKD increased [20].

#### *2.7.2. Bleeding complications post CABG*

Platelet dysfunction is a consequence of uremia in patients with CKD and they are more prone to bleeding complications requiring blood transfusion. A study showed that signifi‐ cant renal dysfunction (serum creatinine of 1.5 to 3.0 mg/dl) significantly increases bleeding complications such as disseminated intravascular coagulation, gastrointestinal hemorrhage, or thoracic hemorrhage sufficient to require reoperation, or result in cardiac complications such as cardiac arrest and low cardiac output [40].

The association of transfusion with mortality is particularly interesting. CKD impairs eryth‐ ropoiesis in the bone marrow due to reduced synthesis of erythropoietin, and is associated with pre-operative anemia of chronic disease and also leads to increased risk of bleeding af‐ ter CABG [41]. Strategies to optimize preoperative hemoglobin and to minimize post-opera‐ tive transfusion could possibly improve operative outcomes in patients with CKD. Transfusion needs are also increased as a result of uremia induced platelet dysfunction which can cause an increase in bleeding tendency in these patients.

### *2.7.3. Other post-CABG complications in CKD*

Interestingly, occurrence of post-operative atrial fibrillation has been shown to increase with worsening renal function as well. In a study, the occurrence of atrial fibrillation was 22.2%. 19.2% and 16.5% in severe, moderate and mild CKD patients respectively [20].

Different studies have demonstrated the increased incidence of stroke in patients with CKD. In an analysis on 2438 patients undergoing CABG, the incidence of stroke was 3%, 2.7% and 1.7% in severe, moderate and mild CKD groups [20].

Infectious complications occur more commonly in patients with CKD undergoing CABG as well. A study showed that deep sternal infection, pneumonia, septicemia, infection involv‐ ing a leg vein and overall infection rate was higher as the CKD stage increased (9.0%, 5.1%, and 3.5% in severe, moderate and mild CKD respectively) [20].

#### **2.8. Impact of aortic cross clamp time in CABG**

Aortic cross clamping time is the period during which an occlusive clamp is placed on the as‐ cending aorta close to the innominate artery as a part of achieving cardioplegia before proceed‐ ing with coronary bypass grafting. The mechanism of induction of cardioplegia involves prevention of repolarization of myocardial cell membrane due to the high potassium concentra‐ tion of the cardioplegic fluid causing inactivation of the sodium channels which initiate the ac‐ tion potential. The hypothermic fluid of cardioplegia induces asystole. When the solution is administered in the aortic root it is termed antegrade and when administered in the coronary si‐ nus, it is called retrograde. Myocardial protection with cardioplegia decreases the energy de‐ mands of the heart by arrest of the contractile apparatus. This is considered to be an extension of ischemia tolerance which is considered to minimize the deleterious effects of induced cardiac arrest. However, it still is desirable to keep duration of cardioplegia at a minimum as the aortic cross-clamp time is an important factor in predicting mortality in cardiac surgery and the lesser it is, the better the outcomes. The metabolic processes resulting from cardiac ischemia include sudden cessation of normal aerobic cardiac metabolic events, reduction in creatine phosphate, initiation of anaerobic glycolysis, and build-up of lactate and alpha glycerol phosphate as well as nucleotide metabolites. This is associated with contractile impairment and electrical path‐ way alterations consistent with typical EKG changes. The myocardial demand for high energy phosphate substrates is increased when the availability of adenosine triphosphate decreases. The predominant mode of energy derivation is switched to anaerobic glycolysis in the ischemic tissue. With early ischemic component, contractile activity and later on ion transport utilizes available adenosine triphosphate but gradually with the increase in ischemic time period, the metabolic demands undergo a compensatory reduction to prevent further ischemic damage. Ir‐ reversible injury in cardiac muscle is highlighted by very low levels of adenosine triphosphate, lack of energy production even by anaerobic mode, progressive accumulation of hydrogen ions, adenosine monophosphate, and lactic acid with a consequently high osmotic load, mito‐ chondrial swelling and amorphous densities in matrix, and loss of integrity of the sarcolemmal membrane. The precise mechanism of pathogenesis is still elusive. In animal models, severe is‐ chemia causes irreversible cell injury and death in one hour while with less severe ischemia in the mid and sub-epicardial myocardium, survival is possible up to six hours. Irreversible injury and cell death after six hours is inevitable. The ischemic injury changes reverse to a certain de‐ gree after reperfusion but how quickly and completely this transformation occurs is highly vari‐ able ranging from minutes to days. Aerobic metabolism is restored early while adenine nucleotide pool and stunning resolve slowly [42].

volume, thereby predisposing patients to impaired alveolar gas exchange. Additionally, re‐ nal failure would result in decreased metabolism and elimination of sedative, anxiolytic and

A study showed that ventilatory complications such as need for greater than 48 hours of me‐ chanical ventilation and re- intubation is high in patients with significant renal dysfunction undergoing CABG, when compared to patients with normal or mild renal dysfunction [40]. Another study showed a stepwise increase in need for prolonged mechanical ventilation as the renal function deteriorates. In this study, the ventilator dependence rate greater than 24

Platelet dysfunction is a consequence of uremia in patients with CKD and they are more prone to bleeding complications requiring blood transfusion. A study showed that signifi‐ cant renal dysfunction (serum creatinine of 1.5 to 3.0 mg/dl) significantly increases bleeding complications such as disseminated intravascular coagulation, gastrointestinal hemorrhage, or thoracic hemorrhage sufficient to require reoperation, or result in cardiac complications

The association of transfusion with mortality is particularly interesting. CKD impairs eryth‐ ropoiesis in the bone marrow due to reduced synthesis of erythropoietin, and is associated with pre-operative anemia of chronic disease and also leads to increased risk of bleeding af‐ ter CABG [41]. Strategies to optimize preoperative hemoglobin and to minimize post-opera‐ tive transfusion could possibly improve operative outcomes in patients with CKD. Transfusion needs are also increased as a result of uremia induced platelet dysfunction

Interestingly, occurrence of post-operative atrial fibrillation has been shown to increase with worsening renal function as well. In a study, the occurrence of atrial fibrillation was 22.2%.

Different studies have demonstrated the increased incidence of stroke in patients with CKD. In an analysis on 2438 patients undergoing CABG, the incidence of stroke was 3%, 2.7% and

Infectious complications occur more commonly in patients with CKD undergoing CABG as well. A study showed that deep sternal infection, pneumonia, septicemia, infection involv‐ ing a leg vein and overall infection rate was higher as the CKD stage increased (9.0%, 5.1%,

Aortic cross clamping time is the period during which an occlusive clamp is placed on the as‐ cending aorta close to the innominate artery as a part of achieving cardioplegia before proceed‐

19.2% and 16.5% in severe, moderate and mild CKD patients respectively [20].

analgesic drugs leading to impairment of respiratory drive.

*2.7.2. Bleeding complications post CABG*

444 Artery Bypass

such as cardiac arrest and low cardiac output [40].

*2.7.3. Other post-CABG complications in CKD*

1.7% in severe, moderate and mild CKD groups [20].

**2.8. Impact of aortic cross clamp time in CABG**

and 3.5% in severe, moderate and mild CKD respectively) [20].

hours was 8.6%, 14.7%, and 20.2%, as the stage of CKD increased [20].

which can cause an increase in bleeding tendency in these patients.

Systolic dysfunction with reduction in LVEF <0.40 is also an indicator of poor prognosis in CKD patients undergoing CABG. In a comparison study of aortic cross clamp times in patients with normal versus reduced ejection fraction in 27,215 patients in which 99.8 % received antegrade, retrograde or combined cardioplegia, it was found that prolonged aortic cross clamp time was an independent predictor of mortality [43]. It was shown that a combination of reduced LVEF and prolonged aortic cross clamp time especially with CKD compounds the ischemic effects and increases overall risk of perioperative mortality. In this study, the mean aortic cross clamp time was 68± 20 minutes, number of distal grafts was 3.1± 1.4 and 68.7% of patients underwent grafting of the left internal mammary artery. The incidence of pulmonary complications was 12.2% and stroke was 2.27%. Fifty-two percent of the patients had baseline hypertension, 29% had diabetes and 7% were dialysis dependent.

It has been shown that patients undergoing CABG with off pump or beating heart technique experience improved post-operative outcomes and less perioperative mortality. In a study of 638 patients with acute coronary syndrome undergoing emergency CABG out of which 240 were operated off pump and 398 had standard on-pump CABG. 14.5% of patients were in cardiogenic shock along with serum creatinine greater than 1.8 mg /dl. Follow-up was up to 5 years. The results showed that in the off pump CABG group, in-hospital outcomes were significantly better. With off-pump CABG, skin incision to culprit lesion revascularization time was significantly reduced. There was less requirement for prolonged mechanical venti‐ lation, less need for inotropic support, less incidence of atrial fibrillation, lower stroke rate (2.5 % vs. 6.7%), shorter intensive care unit stay and less sternal wound healing complica‐ tions (2.5% vs. 3.5%). The overall hospital mortality rate was also reduced (5.7%) as com‐ pared to those on cardiopulmonary bypass (8.6%) [44].

#### **2.9. Conclusion**

As we have discussed, numerous studies have shown that patients with CKD have worse outcomes including an increased mortality and other complications after undergoing CABG, when compared to patients without CKD. However, an increasing number of patients with ESRD continue to undergo CABG and additionally, these patients are getting more complex a higher presence of comorbidities including diabetes, hypertension and obesity [Figure 1]. However, fortunately, in-hospital mortality rates have declined remarkably from over 31% to 5.4% in patients with ESRD (versus 4.7% to 1.8% among patients without ESRD) [45]. However, the mortality in ESRD patients remains 3-fold higher which indicates the need of continued work to improve outcomes in these patients [Figure 2].

**Figure 2.** Graph depicting the constantly decreasing trend in mortality of patients with end-stage renal disease (ESRD) undergoing coronary artery bypass grafting (CABG) compared to patients without ESRD, over a 15-year period (Data from Parikh DS, Swaminathan M, Archer LE, et al. Perioperative outcomes among patients with end-stage renal dis‐

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Studies have shown that cardiovascular risk modification using ACC/AHA guideline rec‐ ommended therapies for CAD, such as aspirin, beta blockers, hydroxymethyl coenzyme A (HMG-Co A inhibitors popularly known as statins) and angiotensin converting enzyme (ACE) inhibitors are used less frequently in patients with CKD when compared to patients without CKD [14,46-48]. These medications have been shown to decrease the risk of cardio‐ vascular events across the population at risk. However, it is also true that many of those tri‐ als excluded patients with significant renal disease, which therefore poses a questions mark on their efficacy in patients with advanced CKD. Randomized trials to evaluate efficacy of

The presence of peripheral arterial disease (PAD) plays a significant role in the potential morbidity and mortality of patients undergoing CABG. Coexisting CAD and PAD signifi‐ cantly influences long term survival adversely [49,50]. In the Coronary Artery Surgery Study (CASS), PAD was found to carry a higher risk of mortality even when compared to patients who had previously experienced myocardial infarction and angina [51].PAD is in‐ cluded as a major risk factor when calculating risk of mortality in patients undergoing CABG [1,2]. Non-invasive diagnostic testing for PAD includes segmental pressure measure‐ ment, treadmill stress, and Doppler ultrasound with the most significant information pro‐ vided by the ankle-brachial index (ABI). Normally it is greater than 1.0 while <0.9 is considered abnormal. In patients with critical limb ischemia, the ABI is commonly <0.4. It is suspected that in PAD patients, poor surgical outcomes after CABG could be related to rap‐ id progression of atherosclerotic coronary artery disease and more extensive small vessel

ease following coronary artery bypass surgery in the USA. Nephrol. Dial. Transpl 2010; 25(7):2275-2283)..

these medications in patients with advanced renal dysfunction are warranted.

**3. Peripheral arterial disease and CABG outcomes**

**Figure 1.** Graph depicting the increasing trend in the number of patients with end-stage renal disease (ESRD) under‐ going coronary artery bypass grafting (CABG) over a 15-year period (Data from Parikh DS, Swaminathan M, Archer LE, et al. Perioperative outcomes among patients with end-stage renal disease following coronary artery bypass surgery in the USA. Nephrol. Dial. Transpl 2010; 25(7):2275-2283).

**Figure 2.** Graph depicting the constantly decreasing trend in mortality of patients with end-stage renal disease (ESRD) undergoing coronary artery bypass grafting (CABG) compared to patients without ESRD, over a 15-year period (Data from Parikh DS, Swaminathan M, Archer LE, et al. Perioperative outcomes among patients with end-stage renal dis‐ ease following coronary artery bypass surgery in the USA. Nephrol. Dial. Transpl 2010; 25(7):2275-2283)..

Studies have shown that cardiovascular risk modification using ACC/AHA guideline rec‐ ommended therapies for CAD, such as aspirin, beta blockers, hydroxymethyl coenzyme A (HMG-Co A inhibitors popularly known as statins) and angiotensin converting enzyme (ACE) inhibitors are used less frequently in patients with CKD when compared to patients without CKD [14,46-48]. These medications have been shown to decrease the risk of cardio‐ vascular events across the population at risk. However, it is also true that many of those tri‐ als excluded patients with significant renal disease, which therefore poses a questions mark on their efficacy in patients with advanced CKD. Randomized trials to evaluate efficacy of these medications in patients with advanced renal dysfunction are warranted.
