DIURETIC THERAPY

George HigginsPharmacology

Renal Anatomy

The kidneys (average weight ~ 135 gms) are located in the retro-peritoneum just below the diaphragm; the midline of the kidneys is at the second lumbar vertebra.

There are three regions: cortex, outer medulla and inner medulla. The functional unit is the nephron, classified as superficial (85%) or juxta-

medullary (15%), based on its location and length of tubular structures. Blood supply: aorta renal artery interlobar artery afferent arteriole

glomerular capillaries efferent arteriole vasa recta (peritubular capillaries) venules arcuate vein interlobar vein renal vein IVC.

Tubular system: Bowman’s capsule proximal tubule loop of Henle distal tubule collecting duct renal pelvis ureter bladder.

Hemodynamics : kidneys receive an inordinate blood supply (25% of cardiac output); only 10% of this renal blood flow is filtered, yielding a GFR of 125 ml/min and an average urine output of 2 ml/min. Eighty percent of blood is utilized in the cortex, with 15% perfusing the outer medulla and only 1-3% received by the inner medulla (necessary for urinary concentration in the counter-current mechanism).

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Total filtration volume (180 L/day) contrasts with total urine volume (1-2 L/day); 99% of filtrate is reabsorbed by the tubules and collecting ducts.

Renal Physiology

Kidneys perform these four important physiologic functions:

1. filtration – hydrostatic pressure inside the glomerular capillaries causes expression of filtrate (essentially plasma without proteins) into Bowman’s capsule which leads into the proximal tubule. The primary factor is renal perfusion pressure, which is influenced by mean arterial pressure (auto-regulated between 60-180 mm Hg), cardiac output and sympathetic nervous system activity.

2. reabsorption – as the filtrate moves through the tubules and collecting ducts, water and solutes are reabsorbed from the tubular lumen into the peritubular interstitial fluid and then into the blood. The principle factors regulating sodium and water reabsorption are aldosterone, ADH, renal prostaglandins and atrial natriuretic factor (ANF).

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Renal Physiology (cont’d)

3. secretion - tubular epithelial cells transport or secrete substances into the lumens of the renal tubules. Examples of substances secreted are excess hydrogen and potassium ions, ammonium, toxic metabolic products and foreign substances such as drugs.

4. minor functions – regulatory mechanisms such as renin production and endocrine functions such as the creation of erythropoietin.

Tubular System Mechanisms

The reabsorptive and secretory capabilities of the various portions of the renal tubules are different, as illustrated in the characteristics of the epithelial cells in the various tubular segments.

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Tubular System Mechanisms (cont’d)

Proximal tubules have large number of mitochondria to support extremely rapid active transport processes of reabsorption and secretion. Additionally, there are “loose” junctions between cells, allowing excess fluid and small molecular solutes to leak back into the tubular lumens to achieve a balance.

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Loop of Henle thin segment has a thin wall with few mitochondria, indicating limited metabolic activity. The descending portion is highly permeable to water and moderately permeable to urea, sodium and other ions. The ascending portion is far less permeable to water but more permeable to urea. These differences are important in the counter-current mechanism for concentrating urine.

Loop of Henle thick segment begins where epithelial cells start to thicken in the ascending limb. The cells of this segment are similar to the proximal tubule cells, except the junctions are much “tighter” and very impermeable to water and urea. This segment rises back to its glomerulus of origin and passes between the afferent and efferent arterioles, forming the juxta-glomerular complex. The interplay between this complex and the macula densa cells controls the release of renin into the circulation where it controls effective circulating volume.

Tubular System Mechanisms (cont’d)

The distal tubule, which begins at the juxta-glomerular complex, has two functional segments. The diluting segment is almost entirely impermeable to both water and urea, but allows ion exchange freely. The late distal tubule and cortical collecting tubule have three characteristics: (1) impermeable to urea (so urea passes to urine); (2) capable of balancing potassium and sodium extracellular levels by either absorption or secretion under the influence of aldosterone; (3) variably permeable to water under the influence of ADH.

The collecting ducts have epithelial cells with few mitochondria. They adjust water and sodium reabsorption as guided by levels of ADH, and secrete hydrogen ions and transport HCO3 ions to control the acid-base balance of the extracellular fluid.

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Counter-current Mechanism

A counter-current system is one in which blood inflow runs parallel and in the opposite direction to outflow. In the kidneys, the arrangement of the peritubular capillaries, the vasa recta and the thin segment of the loop of Henle make this mechanism possible. The loops of Henle operate as a counter-current multiplier (of osmolality) and the vasa recta maintains the operation as a counter-current exchanger.

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Counter-current Mechanism (cont’d)

The steps involved in the formation of concentrated urine with minimal water excretion:

1. formation of highly osmolal (up to 1200 mOsm/L at the tip of the vasa recta) renal interstitial fluid by active transport of ions (NaCL) and passive diffusion of urea from the loop of Henle into the medullary interstitium.

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2. sluggish medullary blood flow in the vasa recta preventing the washout of solutes and increasingly concentrating interstitial osmolality.

3. diffusion of sodium chloride and urea into the interstitial fluid and water diffusion back into the blood in the ascending limb of the vasa recta.

4. according to the level of ADH, water is either reabsorbed or allowed to pass on as urine in the late distal tubules and collecting ducts

Hormonal Regulation of Renal Function

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Anti-diuretic hormone (ADH; vasopressin) is released from the posterior pituitary gland in response to several factors: increased plasma osmotic pressure (primarily determined by sodium concentration), decreased extracellular volume, hypotension, stress, nausea/vomiting, standing, angiotensin II, clofibrate, carbamazepine. ADH increases collecting duct permeability to water, leading to water retention and a low-volume, concentrated urine. The volume of urine can vary 100-fold, according to ADH concentration.

Hormonal Control (cont’d)

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Aldosterone is a mineral-corticoid secreted by the adrenal cortex in response to angiotensin II (AII), a part of the renin-angiotensin system. Aldosterone acts directly on the kidney to decrease the rate of sodium-ion excretion (thereby retaining water) and to increase the rate of potassium-ion secretion.

The renin-angiotensin system regulates blood volume, arterial pressure, cardiac and vascular functions. Sympathetic stimulation (SNS), renal artery hypotension and decreased sodium delivery to the distal tubules (sensed at the macula densa) stimulates the release of renin from the juxta-glomerular apparatus (see page 5). Renin is an enzyme that cleaves angiotensin I (AI) from angiotensinogen. Angiotensin converting enzyme (ACE) forms angiotensin II (AII) that has several important functions: (1) causes systemic vasoconstriction (increasing BP and SVR); (2) causes release of aldosterone (above) to increase sodium and fluid retention; (3) stimulates ADH release (page 9) to conserve fluid; (4) stimulates thirst centers in the brain; (5) enhances SNS function by releasing norepinephrine; and (6) stimulates cardiac and vascular hypertrophy.

Hormonal Regulation (cont’d)

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Atrial natriuretic peptide (ANP) is released from the cardiac atria in response to increased NaCl intake and ECF volume. ANP increases Na+ excretion by dilating afferent arterioles (increasing GFR) and inhibiting Na+ reabsorption. Other effects are systemic vasodilation, renin inhibition and blocking of catecholamines and angiotensin II (AII).

The kidneys, along with the lungs, are a major site of prostaglandin synthesis. Intra-renal release of prostaglandins and kinins may be important mechanisms for modulating renal blood flow and GFR. Prostaglandins may increase blood in the renal cortex and decrease flow in the renal medulla. Kinins may be a component in renal vasodilation, although the mechanism has not been proven.

Epinephrine/nor-epinephrine in low concentrations result in elevated blood pressure, decreased RBF and no change in GFR, suggesting equal constriction of both afferent and efferent arterioles. High concentrations cause a marked fall in both RBF and GFR, as blood flow is shunted away from the renal cortex. These conditions are seen in hypoxia, syncope, strenuous exercise, pain, hemorrhage and general anesthesia.

Dopamine, as the immediate precursor of nor-epinephrine, reduces renal and mesenteric vascular resistance by stimulating specific dopamine receptors in these vascular beds at low does (1-3 ucg/kg/min). This causes increases in RBF, GFR and sodium ion excretion. At 1-10 ucg/kg/min, dopamine acts as a ß1 – adrenergic agonist, increasing blood pressure. At doses greater than 10 ucg/kg/min, the alpha-adrenergic agonism predominates, causing vasoconstriction. Responses to epinephrine/nor-epinephrine and renin greatly outweigh responses to dopamine.

Responses to Anesthesia

In general, all anesthetic and surgical techniques cause diverse changes in extra-renal systems that can have renal effects. Examples include cardiac depression, changes in intravascular volume and SVR, catecholamine secretion, electrolyte imbalance, surgical positioning, inappropriate baroreceptor-sensing due to PEEP, and infusions of vasopressors or hypertonic solutions.

Inhaled agents: earlier agents, especially methoxyflurane and to a lesser degree enflurane, cause direct nephrotoxicity due to fluoride ion, a metabolite. The ion interferes with active transport in the loop of Henle by preventing ATP hydrolysis and also destroying mitochondria in the proximal tubules. The metabolism of the common inhaled anesthetics is listed in Table 15-8. (page 13)

Responses to Anesthesia (cont’d)

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Table 15-8. Metabolism of Inhaled Anesthetics to Fluoride ionDrug % MetabolizedMethoxyflurane 40-50Halothane 15-20Sevoflurane 3Enflurane 2Isoflurane 0.2Desflurane 0.02

Sevoflurane may be degraded by soda lime and baralyme, yielding compound A. This compound can cause renal tubular necrosis. The conditions of low-flow technique in a circle system with dry soda lime accentuate the risk.

The primary effect of inhaled agents on the kidney is mediated through their effects on renal circulation. Renal blood flow is usually preserved through auto-regulation and reductions in renal vascular resistance. Any decrease in blood flow and GFR is of little concern in healthy individuals, but can be pivotal in patients with impaired renal function prior to surgery.

Intravenous agents, such as thiopental or propofol, do not alter renal blood flow. Despite the hemodynamic changes seen in extremes of dosage, factors such as autoregulation, reduced SNS tone and direct renal artery dilation maintain adequate flow. Other intravenous agents have not been fully studied in the human model. In general, ketamine, diazepam, and morphine do not reduce renal blood flow directly. Fentanyl decreases GFR and urine output. In chronic renal failure, the use of morphine and meperidine is limited due to renally excreted metabolites.

Regional techniques of spinal and epidural blockade produce little changes in GFR and renal blood flow. Thoracic epidurals with epinephrine-containing local anesthetics reduce renal flood flow and GFR in relation to the magnitude of reduction in systemic blood pressure and also by blockade of SNS control of the efferent and afferent arterioles.

In summary, all agents and techniques have the possibility to decrease renal function. In healthy individuals, there appears to be limited if any insult. In those patients with baseline renal dysfunction, additional measures to support the kidneys during surgery may be necessary.

Diuretic Classification

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Diuretics are organic anionic compounds that increase the urinary salt excretion, and water just happens to follow the sodium. They increase the rate of urine formation. It cannot be forgotten that water may be the only true physiologic diuretic and is an easily corrected and common deficit in the surgical patient.

Diuretics have been used since the 16th century for the treatment of edema. One of the earliest used was mercurous chloride, now listed as a poison. It acted by interfering with chloride reabsorption. In 1930, it was discovered that the antimicrobial sulfanilamide could be used to treat patients with congestive heart failure due to an increase in renal excretion of sodium. Most modern diuretics were developed when side effects of antibacterial drugs were noted. In fact, nearly all diuretics are derivatives of sulfa drugs. Diuretics are the most commonly prescribed drugs in the U.S. and can be quite helpful but they can also have an extremely wide range of adverse effects.

Diuretic Classification (cont’d)

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Osmotic diuretics are solutes that have the following characteristics:

freely filterable at the glomerulus undergo limited reabsorption from the renal tubules pharmacologically inert resistant to metabolic alteration

They are usually administered in very large quantities to alter the osmolarity of the plasma, glomerular filtrate and renal tubular fluid, resulting in osmotic diuresis. This also draws fluid out of the intracellular spaces, decreasing cellular bulk.

Mannitol is the most frequently used osmotic diuretic. It is a six-carbon sugar that is not metabolized. It increases the osmolarity of renal tubular fluid and prevents reabsorption of water. Sodium is diluted in this retained water. The increased osmolarity causes water, sodium, chloride and bicarbonate ions to be excreted.

Indications: prophylaxis against acute renal failure; treatment of increased intracranial pressure; differential diagnosis of acute oliguria; reduction of intraocular pressure; controversial antidote for ciguatera (food) poisoning; possible use in rhabdomyolysis.

Side effects: pulmonary edema in patients prone to congestive heart failure.

Other osmotic diuretics include urea, isosorbide and glycerin. Urea is rarely used due to issues of venous thrombosis and tissue necrosis in the case of extravasation; isosorbide and glycerin are uncommon but possible in reducing intra-ocular pressure prior to eye surgery.Diuretic Classification (cont’d)

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Carbonic Anhydrase Inhibitors are weak diuretics that act by limiting the secretion of hydrogen ions into the proximal tubule and increasing the loss of bicarbonate ions. Chloride is retained by the kidneys to offset the loss of bicarbonate. Potassium is excreted in exchange for sodium. The net effect is an excretion of an alkaline urine and development of hyperchloremic metabolic acidosis with hypokalemia.

Acetazolamide (DIAMOX) is the most commonly used CA-inhibitor, both in oral and intravenous preparations. Dichlorphenamide (Daranide) and Methazolamide (Neptazine) are infrequently used oral forms.

Indications: reduction of intra-ocular pressure for glaucoma or in eye surgery; adjuvant therapy for petit mal and grand mal epilepsy; treatment of high-altitude sickness; alkalinization of urine for treatment of certain drug-overdoses and hyperuricemia; elevated intra-cranial pressure; treatment of familial periodic paralysis.

Side effects: hyperchloremic metabolic acidosis; hypokalemia; renal calculi formation; paresthesia and encephalopathy with coma. It should not be used in renal or hepatic dysfunction or in cirrhosis. Facial and extremity tingling are common as are taste disturbances.

Loop Diuretics

Loop Diuretics (cont’d)

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Although chemically different from each other, ethacrynic acid (Edecrin), furosemide (Lasix), bumetanide (Bumex) and torsemide (Demadex) all act in a similar manner. At the tubular level, they act primarily by inhibiting active chloride transport in the thick ascending limb of Henle’s loop. Because of this area’s crucial role in the countercurrent multiplication, the loop diuretics increase urinary water, sodium, calcium and magnesium excretion. The net result is a hypokalemic metabolic alkalosis.

Furosemide and ethacrynic acid also cause renal vasodilation apparently due to increased prostaglandin production and decreased degradation. NSAID’s and cyclooxygenase-2 (COX-2) inhibitors may suppress prostaglandin action, blocking or attenuating the diuresis of these agents.

Indications: mobilization of edema due to renal, hepatic or cardiac dysfunction; increased intracranial pressure; differential diagnosis of acute oliguria; treatment of symptomatic hypercalcemia.

Side effects: hypokalemia with resultant dysrhythmias; calcium and magnesium depletion; metabolic alkalosis; digitalis toxicity; hypochloremia; hyperuricemia; hyperglycemia; potentiation of NDMR’s; aminoglycoside nephrotoxicity; acute increases in lithium plasma concentrations; and temporary or permanent deafness seen in large dose chronic therapy with furosemide, torsemide and ethacrynic acid.

Aldosterone antagonists (often classified as potassium-sparing diuretics) prevent the aldosterone-mediated augmentation of renal tubular reabsorption of sodium and chloride ions. Spironolactone (Aldactone) and eplerenone (Inspra) are currently used as competitive antagonists of aldosterone.

Aldosterone Antagonists (cont’d)

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Spironolactone (Aldactone)

The net effect of aldosterone antagonism is a small diuresis in comparison to other diuretics. These drugs are usually administered in combination with other agents that block sodium re-absorption more proximally in the nephron. As a selective aldosterone receptor antagonist, eplerenone, may offer advantages over currently available non-selective aldosterone antagonists (spironolactone) in terms of reduced side effects (gynecomastia and impotence).

Indications: hypertension; refractory edema; fluid overload due to hepatic cirrhosis.

Side effects: hyperkalemia, especially when used in combination therapy with a thiazide diuretic in renal failure; gynecomastia; dysmenorrhea and sexual dysfunction.

Potassium-sparing Diuretics are loosely grouped according to their pharmaco-dynamic effects. While spironolactone and eplerenone have steroidal structures, triamterene (Dyrenium) and amiloride (Midamor) are organic bases and do not depend on aldosterone for their effect. Triamterene and amiloride not only antagonize the renal tubular effects of aldosterone but also inhibit the secretion of potassium and hydrogen ions in the distal renal tubule.

Indications: Combination therapy in hypertension (Maxide) and edema.

Side effects: hyperkalemia; metabolic acidosis; nausea/vomiting.Thiazide Diuretics

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(DIURIL) (HYDRODIURIL) (EXNA)

Thiazide diuretics were developed by the altering the basic sulfonamide structure. These agents are the more commonly prescribed class of all diuretics. Their primary action is to inhibit reabsorption of sodium and chloride ions, principally in the cortical portion of the ascending loops of Henle and, to a lesser extent, in the proximal and distal renal tubules. The net result is a marked increase in urinary excretion of sodium, chloride and bicarbonate ions. Magnesium is commonly lost, along with any of the halides (fluorine, chlorine, bromine, or iodine). Another common finding is hypochloremic, hypokalemic metabolic alkalosis.

The anti-hypertensive result of these diuretics is initially due to decreased extracellular fluid volume, reducing cardiac output. The sustained effect is the development of peripheral vasodilation, which requires several weeks to develop.

There are some other sulfonamide-based diuretics that differ chemically from the thiazides, but are indistinguishable in their pharmacodynamic effects.

(LOZOL) (HYDROMOX) (ZAROXOLYN) (HYGROTON)

Indications: hypertension; CHF; nephrotic syndrome; nephrogenic diabetes insipidus; bromide toxicity; prevention of calcium-based kidney stones.

Side effects: metabolic alkalosis; cardiac dysrhythmias; skeletal muscle weakness; ileus; nephropathy; hyperglycemia and aggravation of diabetes mellitus (by inhibition of insulin release); hyperuricemia leading to gout; photosensitivity; pancreatitis; renal and hepatic dysfunction.

Xanthines

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These drugs occur in plants widely distributed throughout the world, and are often ingested in diet or taken as a prescription. They stimulate the CNS and cardiac muscle, relax smooth muscle and act as diuretics. Although there is increased renal blood flow and GFR due in increased cardiac output, there is also in increase in the rate of excretion of sodium and chloride. Carbonic anhydrase inhibitors potentiate this effect. A common example is a chronic asthmatic (on theophylline) who drinks coffee and uses Diamox for glaucoma.

Intraoperative Diuretic Therapy

Intracranial (ICP) reduction:

1. 20% Mannitol 0.25 – 2 Grams/kg IV over 30-60 minutes2. Furosemide 0.25 – 2 mg/kg IV for patients with risk of CHF3. Torsemide 0.25 – 2 mg/kg IV for patients with risk of CHF

Intraocular (IOP) reduction:

Acetazolamide 250 – 500 mg over 20 minutes

Renal failure prophylaxis:

1. Dopamine infusion @ 1-3 ucg/kg/min2. Fenoldopam infusion @ 0.1 ucg/kg/min3. 20% Mannitol 0.25 – 0.5 Grams/kg iv prior to insult OR4. 20% Mannitol infusion @ 5 – 10 Grams / hour

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Intraoperative Diuretic Therapy (cont’d)

Oliguria (less than 0.5 ml/kg/hr of urine formation)

- pre-renal : low intravascular volume, low cardiac output or renal blood flow

symptoms: urine osmolarity > 400 mOsm/L; urine sodium < 20 mEq/Ltreatment: volume, dopamine, inotropes

- intra-renal : ATN due to ischemia or drugs

symptoms: before diuretics, low urine osmolarity; urine sodium > 20 mEq/Ltreatment: removal of cause; fluids; low-dose diuretics and dopamine PA catheter data-directed therapy

- post-renal : ureteral obstruction (stones, stenosis, surgical clips or suture)

symptoms: anuriatreatment: remove obstruction surgically

General strategies:

1. limit magnitude and duration of acute renal failure2. promote solute excretion (restore perfusion and volume)3. consider diagnostic data with caution (except urine output)4. early aggressive diuresis guided by pulmonary artery catheter

Rhabdomyolysis (striated muscle breakdown)

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When muscle tissue is damaged, myoglobin is released into the bloodstream. Initially haptoglobin can absorb moderate amounts, but as this mechanism is overloaded, the myoglobin breaks down into ferrihemate and globulin. As intravascular fluid is sequestered in the injured muscle, acidosis from hemorrhage and hypo-perfusion results in direct toxicity from the iron in ferrihemate and formation of casts (combined muco-proteins and the breakdown sediment in acidic urine environment) in the distal tubules. These effects are also enhanced by reflex renal vaso-constriction, and, left untreated, result in acute tubular necrosis in 10-30% of patients.

Formation of casts in distal tubules

Under anesthesia, most of the cardinal features of this condition (myalgias, weakness, confusion, compartment syndrome, nausea/vomiting and neuropathy) are masked, leaving only two signs commonly monitored: peaked t-waves and myoglobinuria.

If rhabdomyolysis remains unrecognized, acidosis, hypotension, oliguria and disseminated intravascular coagulopathy (DIC) can frequently develop.

Rhabdomyolysis (cont’d)

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Causative factors:

Muscle trauma/compression: MVA, earthquake, physical restraint, fractures. Muscle ischemia: embolism, surgical clamps, shock, sickle cell crisis, burns. Muscle exertion: marathons, military recruits, epilepsy, DT’s, psychic agitation. Substance abuse: ectasy, cocaine, PCP, heroin and alcohol. Medication: statins, anti-malarials, colchicine, AZT, haloperidol, phenothiazines,

cyclosporine, steroid abuse and licorice (hypermineralocorticoidism). Toxins: snake/insect venom, hemlock (from eating quail), buffalo fish. Electrical muscle injury: shock, lightning, repeated cardioversion. Hyperthermia: succinylcholine, tranquilizers, neuroleptic malignant syndrome,

central anticholinergic syndrome. Infections: HIV, influenza, pneumonia, Legionnaires, salmonella/shigella, tetanus. Electrolyte disorders: especially in DKA and hyperosmolar states. Massive blood transfusions. Mushroom poisoning.

Genetic predisposition for exertional rhabdomyolysis, especially in children, is present with these hereditary disorders:

Glycolysis and glycogenolysis defects such as McArdle’s disease. Lipid metabolism defects. Mitochondrial myopathies. Muscular dystrophies, and g6pd deficiency. Collagen vascular disorders: polymyositis, dermatomyositis.

Diagnosis

Early recognition of patients with a susceptible history (trauma, crush injury, unconsciousness resulting in prolonged immobilization) along with deteriorating kidney function and tea-colored urine is crucial. Serum creatinine kinase is usually elevated (10,000-100,000 U/L), and chemistry analysis often reveals hyperkalemia, hypocalcemia, lactic acidosis, hyperphosphatemia, rising creatinine, and positive urine hemoglobin and pigmented casts. EKG may show peaked t-waves. There may be thrombocytopenia, and evidence of DIC. Further diagnostic tests may delay treatment, which usually has a six-hour window of therapeutic opportunity.

Rhabdomyolysis (cont’d)

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Treatment

Initial treatment is generous IV fluids (usually NS, but LR may be recommended) to correct hypovolemia and preserve kidney function. The goal is urinary output of at least 100 cc/hr. In adults, this usually requires 1 liter in the first hour, followed by 500 cc/hr for the first 24 hours. A pulmonary artery catheter may be indicated in patients prone to cardiac failure. Sodium bicarbonate bolus or infusion may be indicated to correct acidosis and to alkalinize the urine to prevent formation of urinary casts. This may worsen hypocalcemia, however. Arterial blood gases should be followed for acid-base analysis. Furosemide or mannitol may be used to increase urinary output, but there are conflicting studies to support this treatment.

In those patients with persistent anuria, hemodialysis, continuous hemofiltration or peritoneal dialysis may be required. Underlying problems such as DIC, thrombocytopenia, and compartment syndrome need attention. The mortality rate can approach 20% in those patients who develop renal impairment with Rhabdomyolysis.

Adjuvant Therapy Related To Renal Threat or Dysfunction

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Fenoldopam (Corlopam®)

Fenoldopam mesylate is the first commercially available selective dopamine-1 receptor agonist. It acts predominantly as a vasodilator in peripheral arteries and as a diuretic in the kidneys. More specifically, agonism of peripheral dopamine -1 receptors results in arterial vasodilation, increased cyclic AMP release, natriuresis and diuresis in renal tubules and renin release in the juxto-glomerular apparatus. It is currently approved for in-hospital, short-term management of severe hypertension at doses ranging from 0.1 – 0.16 ucg/kg/min.

In view of its renal actions, fenoldopam has been empirically used (off label) as a protective agent in situations known to lead to impaired renal function, such as vascular surgery, shock or use of contrast media. The usual starting dose is 0.1 ucg/kg/min. Unlike dopamine, renal vasodilation increases with larger doses, with hypotension often determining the end-point.

Side effects include hypotension, increased intra-ocular pressure, headache, flushing, dizziness, bradycardia or tachycardia. There are reports of flattening of the T waves in anterior and lateral leads, and overall T-wave inversion.

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N-acetylcysteine (Mucomyst®, Acetadote®, Parvolex®)

N-acetylcysteine (NAC) is the N-acetyl derivative of the amino acid L-cysteine, and is a precursor in the formation of the antioxidant glutathione in the body. Inhaled NAC (Mucomyst®) is used as mucolytic in conditions of thickened respiratory secretions. Intravenous NAC (Parvolex®) is used to treat acetaminophen overdosage.Adjuvant Therapy Related To Renal Threat or Dysfunction (cont’d)

Contrast-induced nephrotoxicity (CIN) is a important cause of acute renal failure, and is the third leading cause of new episodes of acute renal failure in hospitalized patients. CIN primarily results from renal vasoconstriction, hyperosmolar renal blood flow sludging and direct cellular toxicity from the iodine-based contrast agent. Previous generations of contrast agents (e.g. Isovue®) were more damaging than the newest agent, iodixanol (Visipaque®). Proven preventive measures to reduce the indicidence of CIN include hydration, use of iodixanol in limited quantities and the elimination of NSAID use. Stategies that may work are: (1) the use of an infusion of 130 mEq/L of sodium bicarbonate @ 1 ml/kg/hour before, during and after the study period; (2) 600 mg of N-acetylcysteine b.i.d. the day before and the day of the study and (3) hemofiltration or hemodialysis in high risk patients.

Side effects of intravenous NAC include rash, urticaria and pruritis. Oral preparations have vitually no side effects, except decreasing the absorption of magnesium if taken at the same time.

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Nesiritide (Natrecor®)

Nesiritide is a purified preparation of human B-type natriuretic peptide (hBNP) and is manufactured from E. coli using recombinant DNA technology. hBNP binds to guanylate cyclase receptors of vascular smooth muscle and endothelial cells, increasing cGMP and smooth muscle relaxation. cGMP acts as a second messenger to dilate veins and arteries. Some studies document a mixed effect (+/-) on aldosterone and renin activity.Adjuvant Therapy Related To Renal Threat or Dysfunction (cont’d)

Nesiritide is indicated for the IV treatment of patients with acutely decompensated CHF who have either dypsnea at rest or with minimal activity. It is contraindicated in patients in cardiogenic shock, patients with low filling pressures or such conditions such as valvular stenosis and cardiac tamponade that rely upon venous return for appropriate cardiac output. The loading dose in 2 ucg/kg followed by an infusion starting at 0.01 ucg/kg/min. Side effects are hypotension, abdominal pain, nausea and headache.

There is much controversy among providers regarding use of nesiritide, especially in outpatient infusion centers, where CHF patients receive “tune ups” covered by Medicare. The cost of nesiritide is estimated at approximtely $500/dose compared with $10/dose for nitroglycerin. Outcome and mortality studies suggest that nesiritide may have an adverse effect upon 30-day mortality (7.1 vs 4.8 % in placebo group). Additionally, there has been no increase in urine output with nesiritide, and further studies have shown that this drug has no natriuretic or diuretic effects in decompensated CHF patients. Finally, a retrospective study suggests that there is an increase in renal failure with the use of this agent.

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In summary, there are many new therapies for renal function. Although not in the realm of conventional anesthesia management, knowledge of these agents can offer the anesthesia provider a basis of discussion with surgeons and others who frequently request that we administer these drugs during the course of an anesthetic.

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References

1. Guyton, AC. Textbook of Medical Physiology, 7th ed. Chapters 33, 34, 35, 36 & 38. WB Saunders, 1986.

2. Ganong, WF. Review of Medical Physiology, 21st ed. Chapters 20, 24, 27, 38 & 39. McGraw-Hill, 2003.

3. Barash, PG. Clinical Anesthesia, 3rd ed. Chapters 13, 15, 26, 36 & 41. Lippincott-Raven, 1997.

4. Stoelting, RK. Pharmacology & Physiology in Anesthetic Practice, 3 rd ed. Chapters 2, 3, 4, 6, 20, 22, 23, 25, 40, 44, 51 & 53. Lippincott-Raven, 1999.

5. Gilman, AG. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 10th ed. Chapters 29, 30, 31 & 33. McGraw-Hill, 2001.

6. Abay, MC et al. Current Literature Questions the Routine Use of Low-dose Dopamine. AANA Journal. 2007; 75: 57-63.

7. Murphy, MB et al. Fenoldopam – A Selective Peripheral Dopamine-Receptor Agonist for the Treatment of Severe Hypertension. New England Journal of Medicine. 2001; 345: 1548-1557.

8. Rudnick, MR et al. Contrast-induced nephropathy: How it develops, how to prevent it. Cleveland Clinic Journal of Medicine. 2006; 73: 75-87.

9. Topol, EJ. Nesiritide – Not Verified. New England Journal of Medicine. 2005; 353: 113-116.

10. Brown, C et al. Preventing Renal Failure in Patients with Rhabdomyolysis: Do Bicarbonate and Mannitol Make a Difference? J Trauma 2004; 56: 1191-1196.

11. Cho YS et al. Comparison of lactated Ringer’s solution and 0.9% saline in the treatment of Rhabdomyolysis induced by doxylamine intoxication. Emerg Med J 2007; 24: 276-280.

12. Bosch X et al. Rhabdomyolysis and Acute Kidney Injury. N Engl J Med 2009; 361: 62-72.

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