Renal Protection Renal Protection During Cardiac During Cardiac

SurgerySurgeryAshraf Banoub, MD, MBAAshraf Banoub, MD, MBA

February 26, 2013February 26, 2013

►Renal PhysiologyRenal Physiology►Pathophysiology of CPBPathophysiology of CPB► Impact of AKIImpact of AKI►Risk and assessment for peri-operative Risk and assessment for peri-operative

AKIAKI► Interventions to provide renal Interventions to provide renal

protectionprotection

The Glomerulus (Renal Corpuscle)

► The glomerulus consists of five distinct components: capillary endothelium glomerular basement

membrane visceral epithelium parietal epithelium

(Bowman's capsule), mesangium

(interstitial cells

Glomerular ultrafiltration is Glomerular ultrafiltration is governed by the balance of governed by the balance of

Starling forces Starling forces

GFR=KGFR=Kufuf [(P[(Pgcgc-P-Pbsbs)-()-(ΠΠgcgc--ΠΠbsbs)])]

Anatomic relationships of the Anatomic relationships of the nephron and the renal vasculaturenephron and the renal vasculature

Renal Autoregulation Renal Autoregulation

►Autoregulation Autoregulation enables the enables the kidney to kidney to maintain solute maintain solute and water and water regulation regulation independently of independently of wide fluctuations wide fluctuations of arterial blood of arterial blood pressurepressure

(Based on the original work of Shipley and Study. From Pitts RF: Physiology of the Kidney and Body Fluids. Chicago, Year Book Medical Publishers, 1974.)

Renal Autoregulation Renal Autoregulation

►Two major mechanisms for renal Two major mechanisms for renal autoregulation.autoregulation. As mean arterial pressure decreases, As mean arterial pressure decreases,

renal vascular resistance decreases and renal vascular resistance decreases and renal blood flow (RBF) is maintained. renal blood flow (RBF) is maintained.

Tubuloglomerular feedback via the Tubuloglomerular feedback via the juxtaglomerular apparatus also plays a juxtaglomerular apparatus also plays a rolerole

Gong R, Dworkin LD, Brenner BM, et al: The renal circulations and glomerular ultrafiltration.   In: Brenner BM, ed. Brenner & Rector's The Kidney,  8th ed. Philadelphia: In; 2008:91-129.

Autoregulation is impaired by Autoregulation is impaired by

►calcium channel blockadecalcium channel blockade►chronic hypertensionchronic hypertension►diabetic kidney diabetic kidney ►acute renal failure acute renal failure ►cardiopulmonary bypass (CPB)cardiopulmonary bypass (CPB)►severe sepsissevere sepsisMackay JH, Feerick AE, Woodson LC, et al: Increasing organ blood flow during cardiopulmonary bypass in pigs: comparison of dopamine and perfusion pressure. Crit Care Med  1995; 23:1090-1098.

Cardiopulmonary Bypass Cardiopulmonary Bypass Management and Organ Management and Organ

ProtectionProtection ►The CPB circuit is designed to perform The CPB circuit is designed to perform

four major functions: four major functions: Oxygenation and carbon dioxide Oxygenation and carbon dioxide

eliminationelimination Circulation of bloodCirculation of blood Systemic cooling and rewarmingSystemic cooling and rewarming Diversion of blood from the heart to Diversion of blood from the heart to

provide a bloodless surgical field provide a bloodless surgical field

End-organ effects of End-organ effects of cardiopulmonary bypasscardiopulmonary bypass

►Modern cardiac surgery continues to Modern cardiac surgery continues to be challenged by the risk for organ be challenged by the risk for organ dysfunction and the morbidity and dysfunction and the morbidity and mortality that accompany it mortality that accompany it

Injurious Common Pathways Injurious Common Pathways Associated With Cardiac Associated With Cardiac

Surgery.Surgery.►CPB initiates a whole-body CPB initiates a whole-body

inflammatory response with the inflammatory response with the release of various injurious release of various injurious inflammatory mediators. inflammatory mediators.

►Preexisting patient comorbidities Preexisting patient comorbidities ►Embolization Embolization ►HypoperfusionHypoperfusion

Renal protection during cardiac surgery

►Impact of acute kidney injury In a study from the Duke University

database 2672 patients undergoing elective CABG

with CPB AKI requiring RRT occurred in only 0.7% of

patents but was associated with 28% mortality, compared with 1% in patients without AKIConlon PJ, Stafford-Smith M, White WD, et al. Acute renal failure following

cardiacsurgery. Nephrol Dial Transplant 1999;14:1158–62.

Renal protection during cardiac surgery

►Impact of acute kidney injury Prospective cohort study on 4118 patients

who underwent cardiac and thoracic aortic surgery in Austria

Increase of serum creatinine of more than 0.5 mg/dL at 48 hours after surgery was associated with a mortality of 32.5%, compared with 2.1% in patients who had a slight decrease

Lassnigg A, Schmidlin D, Mouhieddine M, et al. Minimal changes of serum creatinine predictprognosis in patients after cardiothoracic surgery: a prospective cohort study. JAmSocNephrol 2004;15:1597–605

Perioperative renal risk factors►Preoperative risk factors

Female gender Advanced age Diabetes mellitus Ventricular dysfunction left main coronary artery disease Chronic obstructive pulmonary disease Preexisting sepsis Liver disease Preexisting renal insufficiency Diastolic hypertension Genetic predisposition

Rosner MH, Okusa MD. Acute kidney injury associated with cardiac surgery. Clin J AmSoc Nephrol 2006;1:19–32Chew ST, Newman MF, White WD, et al. Preliminary report on the association of apolipoproteinE polymorphisms, with postoperative peak serum creatinine concentrations incardiac surgical patients. Anesthesiology 2000;93:325–31

Perioperative renal risk factors

►Intraoperative risk factors and pathogenesis of AKI Pre CPB During CPB Post CPB

Pre-CPB factors contributing to Pre-CPB factors contributing to AKIAKI

►Low MAP below limits of auto-Low MAP below limits of auto-regulationregulation ASCVDASCVD CKDCKD Chronic hypertensionChronic hypertension Recent MIRecent MI Severe valvular diseaseSevere valvular disease Reduced LVFReduced LVF

Pre-CPB factors contributing to Pre-CPB factors contributing to AKIAKI

►Drugs impacting auto-regulationDrugs impacting auto-regulation ACE-inhibitorsACE-inhibitors ARBsARBs Radio contrast agentsRadio contrast agents

►Low CO in the pre-CPB periodLow CO in the pre-CPB period Cardiogenic shockCardiogenic shock Inotropic supportInotropic support IABPIABP Hypotensive episodesHypotensive episodes

Kumar et al. Anesthesiology 2011

CPB factors contributing to AKI►Risk of perioperative AKI appears to be

increased prolonged duration of CPB and aortic

cross-clamping time complex procedures, such as combined

CABG and valve surgery hemodilution or anemia on CPB to a

hematocrit of less than 22%

Grayson AD, Khater M, Jackson M, et al. Valvular heart operation is an independent riskfactor for acute renal failure. Ann Thorac Surg 2003;75:1829–35Habib RH, Zacharias A, Schwann TA, et al. Adverse effects of low hematocrit duringcardiopulmonary bypass in the adult: should current practice be changed? J Thorac CardiovascSurg 2003;125:1438–50.

CPB factors contributing to AKI

► Risk of perioperative AKI appears to be increased Nonpulsatile flow contact activation on CPB

►vasoconstrictor hormones (epinephrine, angiotensin)► inflammatory cytokines (endotoxin, IL-1b, IL-6, IL-8 and

TNF-α)►Activates factor XII to XIIa (intrinsic pathway)►Activates kallikrein system►Activates fibrinolytic system►Activates complement system

Free iron released from heme leads to organic and inorganic oxygen radical reactions, lipid peroxidation and formation of hydroxyl radicals

Atheromatous embolism <40 μmGuYJ, MarianiMA,Boonstra PW, et al. Complement activation in coronary artery bypassgrafting patients without cardiopulmonary bypass: the role of tissue injury by surgicalincision. Chest 1999;116:892–8

Aprotinin►Administration of high doses of the

serine protease inhibitor aprotinin dramatically decreased blood loss after CPB

►When plasma concentrations of greater than 150 (KIU) per mL are achieved, kallikrein, plasmin, and CPB-induced fibrinolysis are effectively inhibited.

►Platelet activation and thromboxane release is prevented.

van Oeveren W, Jansen NJ, Bidstrup BP, et al. Effects of aprotinin on hemostatic mechanismsduring cardiopulmonary bypass. Ann Thorac Surg 1987;44:640–5.

Aprotinin►Numerous reports of an association between

aprotinin and elevation in postoperative serum creatinine

►Effects on kinin pathways that alter intrarenal hemodynamics

►Canadian BART Trial was halted by the Data Safety Monitoring Board because of increased 30-day mortality in patients receiving aprotinin.

►As a consequence, the Food and Drug Administration (FDA) suspended marketing of aprotinin in November 2007

http://www.fda.gov/cder/drug/early_comm/aprotinin.htm

Post CPB factors contributing Post CPB factors contributing to AKIto AKI

►Hemodynamic instabilityHemodynamic instability Low CO stateLow CO state Prolonged or repeated periods of Prolonged or repeated periods of

hypotensionhypotension HypovolemiaHypovolemia

►Nephrotoxic agentsNephrotoxic agents►Sepsis/SIRSSepsis/SIRS►Mechanical circulatory supportMechanical circulatory supportRosner et al. Clin J Am Soc Nephrol 2006; 1:19-32

Interventions to provide perioperative renal protection

►Hydration►Tight glycemic control►Dopaminergic agents►Furosemide►Mannitol►N-acetylcysteine►Calcium channel blockers►Natriuretic peptides

Interventions To Provide Perioperative Renal Protection

►Hydration It appears intuitive that judicious volume expansion

to maintain cardiac output and renal blood flow would provide perioperative renal protection.

The relationship between the volume of perioperative fluid administered and AKI has not been subjected to randomized, controlled trials.

No difference in markers of AKI whether 6% hydroxyethyl starch or 5% albumin was administered to 50 patients undergoing cardiac surgery

Boldt J, Brosch C, Ducke M, et al. Influence of volume therapy with a modern hydroxyethylstarchpreparation on kidney function in cardiac surgery patients with compromisedrenal function: a comparison with human albumin. Crit Care Med 2007;35(12):2740–6.

Interventions To Provide Perioperative Renal Protection►Tight glycemic control

1548 patients studied underwent cardiac surgery

demonstrated that tight postoperative glycemic control (blood sugar 80 to 110 mg/dL) decreased mortality by 50%

41% reduction in ARF requiring RRT

van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in the critically illpatients. N Engl J Med 2001;345:1359–67.Krinsley JS. Effect of an intensive glucose management protocol on the mortality of criticallyill adult patients. Mayo Clin Proc 2004;79:992–1000

Interventions To Provide Perioperative Renal Protection

►Tight glycemic control Intra-operative hyperglycemia (blood

sugar >200 mg/d) is associated with a sevenfold increase in the incidence of severe postoperative morbidity

A retrospective analysis of more than 3500 diabetic cardiac surgical patients observed a decrease in postoperative mortality from 5% to 2.5% when a subcutaneous insulin regimen was changed to continuous insulin infusionOuattara A, Lecomte P, Le Manach Y, et al. Poor intraoperative blood glucose control is

associated with a worsened hospital outcome after cardiac surgery in diabetic patients- Anesthesiology 2005;103:687–94.Furnary AP, Gao G, Grunkemeier GL, et al. Continuous insulin infusion reduces mortality in patients with diabetes undergoing coronary artery bypass grafting. J Thorac Cardiovasc Surg 2003;125:1007–21.

Dopaminergic agents►Dopamine►Fenoldopam

Dopaminergic agents►Dopamine is a naturally occurring

catecholamine that has dose-dependent effects on dopaminergic, beta1- and alpha-adrenergic receptors

► Its renoprotective role has been questioned and three systematic reviews found no evidence of benefit

►Dopamine may still be a useful inotropic agent that can improve renal perfusion and urine output by increasing cardiac contractility

Kellum JA. The use of diuretics and dopamine in acute renal failure: a systematic review of the evidence. Crit Care (Lond) 1997;1:53–9Marik PE. Low-dose dopamine: a systematic review. Intensive Care Med 2002;28:877–83

Dopaminergic agents►Fenoldopam

Fenoldopam, a synthetic phenol derivative of dopamine, is a selective DA1 receptor agonist that increases renal blood flow in a dosedependent manner

In several small prospective studies of cardiac surgery patients, low-dose fenoldopam infusion (0.3–0.5 mcg/kg/min) has been associated with preservation of GFR and serum creatinineHalpenny M, Lakshmi S, O’Donnell A, et al. Fenoldopam: renal and splanchnic

effects in patients undergoing coronary artery bypass grafting. Anaesthesia 2001;56:953–60.Ranucci M, Soro G, Barzaghi N, et al. Fenoldopam prophylaxis of postoperative acuterenal failure in high-risk cardiac surgery patients. Ann Thorac Surg 2004;78:1332–7

Dopaminergic agents►Fenoldopam

However, other studies in high-risk cardiac surgery or vascular surgery with aortic cross-clamping were unable to find a benefit of fenoldopam on renal function compared with dopamine or sodium nitroprusside

Oliver WC Jr, Nuttall GA, Cherry KJ, et al. A comparison of fenoldopam with dopamine and sodium nitroprusside in patients undergoing cross-clamping of the abdominal aorta. Anesth Analg 2006;103:833–40

Dopaminergic agents►Fenoldopam

Nonetheless, a recent meta-analysis of 16 studies on 1290 patients concluded that fenoldopam consistently and significantly reduced the risk for AKI, need for RRT, ICU length of stay and in-hospital mortality

Landoni G, Biondi-Zoccai GG, Tumlin JA, et al. Beneficial impact of fenoldopam incritically ill patients with or at risk for acute renal failure: a meta-analysis of randomized clinical trials. Am J Kidney Dis 2007;49:56–68

Furosemide

►Furosemide infusion (0.5 mg/kg/min), and saline placebo were administered throughout cardiac surgery and postoperatively in 126 patients

►Furosemide infusion was associated with an increase in serum creatinine twice as high as the other groups

Lassnigg A, Donner E, Grubhofer G, et al. Lack of renoprotective effects of dopamine and furosemide during cardiac surgery. J Am Soc Nephrol 2000;11:97–104

Mannitol►Mannitol is an osmotic diuretic and free

radical scavenger►Can prevent tubular obstruction by

sloughed proximal tubular cells and attenuate experimental ischemia-reperfusion injury

►Mannitol is routinely added to the priming solution on CPB but there is little evidence to support a renoprotective effect

Ip-Yam PC, Murphy S, Baines M, et al. Renal function and proteinuria after cardiopulmonary bypass: the effects of temperature and mannitol. Anesth Analg 1994;78:842–7.

N-acetylcysteine►Antioxidant that directly scavenges

reactive oxygen species, and there is considerable evidence to support its use to prevent contrast-induced nephropathy

►Similar benefit has not been found in cardiac surgery

Marenzi G, Assanelli E, Marana I, et al. N-acetylcysteine and contrast-induced nephropathy in primary angioplasty. N Engl J Med 2006;354:2773–82Sisillo E, Ceriani R, Bortone F, et al. N-acetylcysteine for prevention of acute renal failure in patients with chronic renal insufficiency undergoing cardiac surgery: a prospective, randomized, clinical trial. Crit Care Med 2008;36:81–6.

Calcium channel blockers►Calcium channel blockers promote renal

vasodilatation and increase renal blood flow and glomerular filtration rate

►They inhibit angiotensin action in the glomerulus and decrease circulating interleukin-2 receptors

►In one study, administration of intravenous diltiazem was associated with worsened function

Young EW, Diab A, KirshMM. Intravenous diltiazemand acute renal failure after cardiac operations. Ann Thorac Surg 1998;65:1316–9.

Natriuretic peptides►The natriuretic peptides are formed by

the endogenous synthesis of chains of 22 to 32 amino acids of similar structure.

►They specifically oppose the sympathoadrenal, renin-angiotensin, aldosterone, and arginine vasopressin systems via multiple mechanisms

Natriuretic peptides►Anaritide

Anaritide is the human recombinant formulation of ANP

After a 24-hour infusion of anaritide, patients with oliguric ATN (urine output <400 mL/day) had significantly improved dialysis- free survival, but outcome was actually worse in patients with non-oliguric renal failure (NORF)

Natriuretic peptides►Nesiritide

A meta-analysis of the use of nesiritide infusion in patients with advanced decompensated heart failure suggested that it is associated with worsening serum creatinine

In patients with left ventricular dysfunction (ejection fraction <40%) undergoing coronary revascularization or mitral valve surgery (n= 279)►a perioperative nesiritide infusion increased urine output►attenuated the postoperative increase in serum creatinine ►associated with a 6-month mortality benefit

MentzerRMJr, Oz MC, Sladen RN, et al. Effects of perioperative nesiritide in patients with left ventricular dysfunction undergoing cardiac surgery: the NAPA Trial. J Am Coll Cardiol 2007;49:716–26

ConclusionConclusion►AKI is a common and serious AKI is a common and serious

complication after cardiac surgerycomplication after cardiac surgery►Perioperative organ hypoperfusion is Perioperative organ hypoperfusion is

the most important factor leading to AKIthe most important factor leading to AKI►Co-morbid conditions in cardiac patients Co-morbid conditions in cardiac patients

place patients at increased risk place patients at increased risk ►No magic bullet for prevention of AKI No magic bullet for prevention of AKI

with the exception ofwith the exception of

Vigilance and attention to Vigilance and attention to hemodynamicshemodynamics