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Perioperative Considerations for the Patient at Risk for Altered Renal Perfusion John P. Maye CRNA PhD CAPT USNAssociate ProfessorGraduate School of NursingUniformed Services UniversityBethesda, Maryland

1Objectives Develop an appreciation for the numerous perioperative factors which influence renal perfusion Review the physiology of the renal system with regard to perfusion, elimination of fluid and waste and the maintenance of homeostasis. Review the renin angiotensin aldosterone system as it relates to renal perfusion and the influence of ACE Inhibitors on perioperative events Understand the importance of perfusion as it relates to renal physiology and the occurrence of Acute Kidney Injury and Tubular Necrosis

2 Clinical Questions What is intraoperative hypotension? When intraoperative hypotension occurs at what point should anesthesia providers become concerned with postoperative outcomes? Is intraoperative hypotension associated with Acute Kidney Injury (AKI)? Is ACE inhibitor therapy associated with the development of AKI ?Should ACE Inhibitors be continued until the day of surgery in all patients?

Intraoperative hypotension 133 different studies with 127 different definitions 3Non-cardiac surgical patients in a database of more than 33,000 patients at the Cleveland Clinic. Two main outcomes AKI and Myocardial injuryAcute Kidney Injury developed in 2478 patients The MAP threshold where the risk was increased was less than 55mmHgMAP less than 55mmHg for 1-5 min, 6-10 min, and 11-20 min and more than 20 min had graded increases in their outcomes.

Anesthesiology 2013:Extremely well done article which involved a complex statistical analysis with multiple regression models to control for many of the variables present to include day surgery cases, presence of preoperative kidney disease, missing follow up creatinine, surgeries for urinary obstruction, renal transplant, or nephrectomy or missing covariate data. Data base originally contained over 106,000 surgeries. January 2005 through September 2010.4 Clin J Am Soc Nephrol 2007Retrospective analysis of 504 patients who underwent gastric bypass procedures between 2003 and 2005 at University of Cincinnati Medical Center.AKI was defined as a greater than 50% increase from baseline serum creatinine during the first three postoperative daysA total of 42 patients (8.5%) developed postoperative AKI. Hyperlipidemia, preoperative use of ACE-Inhibitors, ARBs, intraoperative hypotension and higher BMIs were all associated with increased frequency of AKI.

5 Hospital for Special Surgery Journal (2011)65 year old female bilateral knee prosthesis under spinal anesthesia. (HTN, Obesity, hypercholesterolemia, CAD) on Lisinopril, beta blocker MAP greater than 60mmHg throughout the case. 1200ml of lactated ringers with 100ml blood loss.Intraoperative urine output 250ml over the 2 hour case POD1 Serum creatinine doubles 0.9mg/dl to 1.9 mg/dl (AKI as defined by the RIFLE Criteria)

Preoperative use of ACE-Inhibitors has thought to contribute to the development of postoperative AKI. The connection between the 2 has been orthopedic, cardiac and gastric bypass patient populations. The mechanisms by which ACE-I contribute to AKI are not completely understood but they are thought to be associated with impaired autoregulation of renal blood flow which may diminish the threshold at which renal injury can occur. Thus allowing for pre-renal AKI at MAPs that are normally associated with adequate perfusion. 6

57 year old male elective hip arthroplasty with a hx of rheumatoid arthritis, obesity, and hypertension.Medications: olmesartan 20mg combined with hydrochlorothiazide 12.5 mg daily (did take on the morning of surgery)Preoperative vital signs 140/70 heart rate of 70. Combined spinal/epidural with 2.2ml of 0.5% bupivicaine.Shortly after induction became profoundly hypotensive and bradycardic which rapidly progressed to asystoleAtropine 2mg, Epinephrine 5mg, and Vasopressin 40 units. Restoration of pulse and blood pressure after 9 minutes

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When hypotension, sodium depletion, or sympathetic stimulation occurs the juxtaglomerular cells of the kidney secrete the enzyme renin. Renin interacts with circulating angiotensinogen a serum glycoprotein produced by the liver to form the hormone angiotensin I. Angiotensin I is biologically inactive with the majority of angiotensin I converted to Angiotensin II in the lungs by Angiotensin Converting enzyme. Angiotensin II is a potent vasoconstrictor but also a stimulus for the release of aldosterone from the zona glowmareulosa cells of the adrenal cortex. Aldosterone the primary mineralcorticoid in the body promotes sodium reabsorption, water retention, and potassium secretion in the distal tubules and collecting ducts of the kidney. Thereby increasing mean arterial pressure. 8

Which are responsible for maintaining fluid and electrolyte homeostasis. The renal system is capable of filtering more than 7 liters of fluid per hour. Divided by 60 equals 116 ml/min. The renal system can alter the amount of and composition of urine to keep blood volume and electrolyte composition within normal limits. The kidneys are located in the retroperitoneal space under the diaphragm. The right kidney is slightly lower than the left. Costovertebral angle is an external landmark useful for locating the kidneys. The kidneys are protected by muscle, fascia and fat. They can be damaged by accident or trauma.

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Approximately 25% of the cardiac output is delivered to the kidneys. The majority of the blood supply is circulated through the outer cortex. Only 1 to 2 % perfuses the medulla. Total renal blood flow in both kidneys is approximately 1250 ml/min. Blood flows to the kidney from the abdominal aorta through the renal arteries which then divide into several interlobar arteries. The interlobar arteries travel in columns adjacent to the pyramids . When the interlobar arteries reach the border of the medulla and cortex they branch into the arcuate arteries. The arcuate arteries then travel along the cortical medullary border parallel to the renal capsule . The arcuate arteries then branch further to form small interlobular arteries which penetrate the cortex and branch extensively to form the afferent arterioles. The afferent arterioles divide to form glomerular capillaries which then coalesce to form the efferent arterioles. The efferent arterioles branch then again to form a second capillary bed. The peritubular capillaries wrap around the proximal and distal convulted tubules 10CompartmentsRBCs~1.5LIntravascular8% TBW~3.5 LExtracellualr 1/3 TBW (14L)Intracellular 2/3 TBW~28L

Interstitial25% TBW~10.5 L11

Components of the capillary pressure gradient. Filtration reflects the difference between the combined forces that move fluid out of the capillary ( capillary pressure (push) and interstitial fluid colloid osmotic pressure (pull). And those that attempt to hold fluid in the capillary (plasma colloid osmotic pressure (pull) and interstitial fluid pressure (push). A neurosurgical patient with cerebral edema and hypotension secondary to fluid volume loss will sometimes receive a colloid ( or blood) like albumin to pull fluid from the interstitium to the vascular space as opposed to crystalloid solutions which will quickly third space which is move from the intravascular to the interstitial spaces

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Cross section of the kidney demonstrating the renal pelvis, medullary pyramids, and cortex. Normal kidneys have 8 to 18 renal pyramids and a corresponding number of minor calices. The major calices drain urine into the ureter. Blood vessels , lymphatic vessels and nerves enter and exit through the hilum. The arterial blood supply to the kidney is derived from the renal arteries, which branch from the abdominal aorta and enter the kidney through the hilus. Interlobular arteries branch multiple times to provide the affrerent arterioles for each of the kidneys million nephrons

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Renal autoregulation maintains blood flow to the kidney over a wide range of mean arterial blood pressures from 75-160 mmhg. Blood flow to the kidneys remained constant at 1200 ml/min. Major factors controlling salt and water excretion include volume status, starling forces, the renin angiotensin-aldosterone system antidiuretic hormone (ADH), prostaglandins, catecholamines, and atrial natriuretic peptide.

14Major Functions of the NephronFiltration of water soluble substances from the bloodReabsorption of filtered nutrients, water, and electrolytesSecretion of wastes or excess substances into the filtrate

Most of the physiologic functioning of the kidney can be understood by examining the function of an individual nephron. The nephron is the functional unit of the kidney. Nephrons are organized in parallel such that each must accomplish all the necessary processing before releasing urine into the collecting ducts. Complex auto regulatory mechanisms ensure that the workload is evenly distributed among the kidneys many nephrons. Immunologic mechanisms trigger inflammation of the glomerulus as well as proliferation of glomerular tissue resulting into basement membrane, mesangium, and capillary endothelium damage.

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Each nephron is composed of a glomerulus (which includes capillary tuft and bowmans capsule). Proximal convoluted tubule, loop of henle, distal convoluted tubule and collecting duct. Cortical nephrons vs juxtamedullary nephrons

16Functions of the Nephron segmentsGlomerulusFilters fluid from blood into Bowman capsulePrevents passage of blood cells (erythrocytes, leukocytes, platelets) and plasma proteinsProteins and blood are not usually present in urine

epithelial cells of Bowman capsule. The basement membrane is an important selectivity barrier of the glomerulus, preventing plasma proteins, erythrocytes, leukocytes, and platelets from passing through. Cells are too large to pass through pores, and plasma proteins are negatively charged and repelled to some extent by the basement membrane. Proteins and blood cells are not usually present in the urine. Proteinuria is an important sign of basement membrane dysfunction. Another important component of the glomerulus is the mesangium, which includes the mesangial cells and mesangial matrix. Mesangial cells have a number of functions to include provision of structural support for glomerular capillaries, secretion of matrix proteins, phagocytosis and regulation of the Glomerular filtration rate or GFR.

17Functions of the Nephron segmentsProximal Convoluted TubuleTransports two thirds of filtered water and electrolytes for reabsorption by the peritubular capillariesTransports all of the filtered bicarbonate, glucose, amino acids, and vitamins from the filtrate to the interstitium

The Bowman capsule drains the glomerular filtrate directly into the proximal tubule segment, where two thirds of the water and electrolytes are rapidly transported from the filtrate to the interstitium for reabsorption by the peritubular capillaries. Nutrients, vitamins, and small proteins normally are reabsorbed completely in the early proximal tubule. The early proximal tubule is the site of most bicarbonate Ion reabsorption whereas chloride ion reabsorption in the late proximal tubule. Proximal tubule cells have high ATP requirements because most reabsorption utilizes active transport mechanisms that are dependent upon NA K ion pumps in the basolateral membrane. Water is reabsorbed passively through water channels in the tubule cell membranes. The reabsorption of solutes creates the osmotic force for passive water reabsorption.

18Functions of the Nephron segmentsDescending loop of HenleTransports water and delivers a concentrated filtrate to ascending loop of henlePermeable to waterWater drawn out by extra ions pumped into the Interstitium by ascending limb

19Functions of the Nephron segmentsAscending loop of HenleActively transports NA. K and CLNot permeable to water Results in hypoosmotic filtrate and a high interstitial osmolality

The thin descending limb is permeable to water but the thin and thick ascending part of the loop is not. The thick ascending segment contains powerful membrane pumps that co transport ions from the filtrate and deposit them in the interstitial fluid surrounding the loops of henle and collecting ducts. About 15 % of nephrons have extra long loops of henle that dip down into the medulla (juxtamedullary nephrons) . These nephrons are essential for creating concentrated urine. The loop formation of the loop of henle creates a countercurrent mechanism which allows the ascending limb of the loop of henle to create a high interstitial gradient in the medulla of the kidney. 20Functions of the Nephron segmentsDistal convoluted tubuleFiltrate that reaches the distal tubule is hypoosmotic (100mOsm/L) in comparison with plasma (280mOsm/L) Only 10% of the original glomerular filtrate remainsFurther reabsorption is under hormonal control

The filtrate that reaches the distal tubule is normally hypoosmotic (100mOsm/l) in comparison with plasma (280 mOsm/l) because electrolytes have been removed by the pumps in the ascending loop of henle. At this point in the nephron only 10% of the original glomerular filtrate volume remains, and further reabsorption in the distal tubule is largely under hormonal control. Aldosterone and angiotensin II stimulate the tubule cells to reabsorb sodium and water , whereas atrial natriuretic peptide (ANP) and urodilantin inhibit reabsorption. 21Functions of the Nephron segmentsCollecting ductDistal tubules of several nephrons empty into a single collecting tubuleMerge into larger and fewer collecting ductsCollecting ducts travel through high interstitial gradient of the medulla on the way to the renal pelvisCells in the collecting duct under the influence of ADH

The distal tubules of several nephrons empty into a single collecting tubule, which then merges into progressively larger and fewer collecting ducts that run parallel to the loops of henle. Eventually the collecting ducts form the medullary pyramids, which empty into the minor calices through the papilla. The collecting ducts travel through the high interstitial gradient of the medulla on their way to the renal pelvis. The collecting ducts have two cell types called principal cells or P cells and Intercalated cells or I cells. The majority of cells are the P type and respond to ADH. In the presence of ADH , more than 99% of the original filtrate is reabsorbed by the time it reaches the renal pelvis which creates 30 to 60 ml of concentrated urine per hour. 22

The separation of solute from water in the ascending limb of the loop of henle creates a dilute tubular fluid allowing the excretion of excess water by making dilute urine in the absence of ADH. NACL accumulation in the interstitium contributes to about half of the total osmolality. Urea particles in the interstitium contribute the other half of the particles that produce the normal interstitial gradient in the medulla.

23Acute Kidney InjuryAcute kidney injury is the sudden reduction of kidney function causing disruptions in fluid, electrolyte, and acid base balancesRetention of nitrogenous waste productsIncreased serum creatinine levelsDecreased glomerular filtration rates24RIFLE classification for staging Acute Kidney InjuryR Risk of injury (serum creatinine increased X 1.5 or GFR decreased by 25%)I Injury (serum creatinine increased x2 or GFR decreased by 50%).F Failure (serum creatinine increased by x3 or GFR decreased by 75%) or (serum creatinine greater than 4mg/dl with acute rise of 0.5mg/dl)L Loss persistent acute kidney failure complete loss of kidney function greater than 4 weeksE End stage complete loss of kidney function greater than 3 months. First three stages represent severity of kidney injury while the last tow stages are more related to outcome

25Epidemiology of AKIIncidence is 2 to 7% of hospitalized patients may be higher in the elderly40-60% of patients in the ICU ( rates increase with length of stay) Once diagnosed mortality rates range from 40-90%Risk of ESRD 8X compared to normal (Ishani et al J Am Soc Nephrol 2009) Studied medicare beneficiaries with AKI.AKI requiring HD were at a 28X risk for advanced CKD (Lo et al. Kidney Int 2009)

26Risk factors for AKIAge (greater than 75 years) CKD (GFR less than 60ml/min/1.73m 2)Cardiac failurePeripheral vascular diseaseLiver disease/cirrhosis-impairment of liver blood flowDiabetes mellitusSepsisHypovolemiaNephrotoxic medications27Etiology of AKIPrerenal AKI- hypovolemic states, CHF, Liver disease, blood loss, cardiogenic shock ( use of NSAIDS, ACE Inhibitors, AII receptor blockers may precipitate prenal AKI in the absence of hypoperfusion)Intrinsic/Intrarenal AKI- further classified by the specific anatomic area involved: vascular, interstitial, glomerular, tubular. (most common cause is acute tubular necrosis) (nephrotoxins with contrast medium the most offending agent) Postrenal AKI: Obstruction of the renal pelvis or ureters of both kidneys, of the bladder outlet, the urethra will result in discernible kidney disease. (obstruction increases retrograde pressure will result in ATN and AKI.

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30Acute Tubular Necrosis ATNAcute tubular necrosis (ATN) is the death of tubular cells, which may result when the tubular cells do not get enough oxygen (ischemic ATN) or when they have been exposed to a toxic drug or molecule (nephrotoxic ATN). New tubular cells can replace those that have died.The tubular cells of the kidneys undergo a continuous cycle of cell death and renewal, much like the cells of the skin31Acute Tubular Necrosis ATNATN accounts for nearly half of all cases of AKI in hospitalized patientsSepsis is the most common cause of ischemic ATN and may develop in about 50% of critically ill patients (profound vasodilation leads to hypoperfusion within the kidney)Elderly about 30% of ischemic cases are due to sepsis and another third are related to surgical interventionsProlonged prerenal kidney injury, perioperative and postoperative hypotension, hemorrhage and perioperative cardiac complications may also contribute

. 32Acute Tubular Necrosis ATNPathophysiologic processes Vascular process: As renal blood flow is decreased flow is shunted from the medulla to the cortex and medullary cells are further compromised. Local vasoconstrictors are released ( prostaglandins, leukotrienes) and stimulation of the SNS all produce further vasoconstriction. Tubular damage and hypoxia activate the inflammatory mediator cascadeTubular process: A reflection of the ischemia and inflammatory process. Damaged tubular epithelial cells are shed from the basement membrane and accumulate in the tubular filtrate where they eventually obstruct filtrate flow.

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Pathogenesis of Acute Tubular Necrosis34Phases of Acute Tubular Necrosis ATNProdromal phase: Normal or declining urine output, serum BUN and creatinine levels begin to rise (injury has occurred and duration of this phase is dependent upon cause and severity of injury)Oliguric phase: Most patients with ATN will develop oliguria. Accumulation of metabolic waste products, retained fluid, edema, HTN, pulmonary edema, heart failure, metabolic acidosis (impaired ability to excrete hydogen ions) accumulation of ureaPostoliguric Phase: Marked by renal recovery. Full recovery may take up to 1 year and is indicated when serum creatinine returns to normal range. 31% of elderly may not regain renal function.

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37 ACE Inhibitors: provide end organ protection independent of their blood pressure lowering properties in diseases such as congestive heart failure, post myocardial infarction, diabetes mellitus, and renal insufficiencyDrenger et al. 2012 Circulation: Withdrawal of an ACEI preoperatively is associated with an increase number of cardiovascular events mainly CHF and Postoperative MI.Observational nature of the study does not allow for definitive recommendations regarding perioperative ACEI use. Randomized clinical trials are recommended.

38 So what do we do? Pay attention to those patients who are taking ACEI and ARBs.Question them as to when the last dose was administered.Be aware of other antihypertensive medications that may be being administered concurrently (HCTZ)Maintain mean arterial blood pressures greater than 55mmhg at all times if possibleConsider vasopressin when patients on ACEI have hypotension that appears refractory to traditional vasopressors.

39 Clinical Questions What is intraoperative hypotension? When intraoperative hypotension occurs at what point should anesthesia providers become concerned with postoperative outcomes? Is intraoperative hypotension associated with Acute Kidney Injury (AKI)? Is ACE inhibitor therapy associated with the development of AKI ?Should ACE Inhibitors be continued until the day of surgery in all patients?

40Questions??

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