Anda di halaman 1dari 12

60378_CCC05_sw

9/10/07

2:47 PM

Page 1

CONTEMPORARY CRITICAL CARE


A MONTHLY PUBLICATION FOR CONTINUING MEDICAL EDUCATION IN CRITICAL CARE

VOLUME 5 NUMBER 5 October 2007

Diuretics in Critical Care


Ellen C. Omi, MD, and Walter A. Boyle III, MD
Learning Objectives: After reading this issue, the participant should be able to: 1. Describe the mechanism of action of the various classes of diuretics. 2. Recall the utilities of diuretics in the intensive care unit and their limitations. 3. Describe some of the evidence and lack of evidence supporting the use of diuretics as therapy in the intensive care unit setting. Diuretics are commonly used to maintain or adjust fluid balance in critically ill and injured patients. In this review, we focus on the common diuretics used in the ICU, their mechanisms of action, and some of the evidence supporting their use in several important clinical conditions. We attempt to include those aspects of diuretic use that are of greatest importance to the practicing intensivist, including a discussion of diuretic dependence and resistance, and the recent controversies surrounding the use of diuretics in the prevention of renal failure and in patients with renal insufficiency and oliguria. classes explains both the primary effects of these drugs and the secondary adaptive actions that limit their potency.
Table 1. Common Classes of Diuretics and Their Use Class Osmotic Mannitol Common ICU Indications Dosing Guidelines Brain Injury/cerebral edema 0.51.0 g/kg Renal failure prior to 0.3 g/kg aortic cross-clamp Rhabdomyolysis 500 mg PO once equivalent to 250 mg PO q6h 4 doses 2080 mg PO/IV intermittently; 4 mg/hr infusion 600800 mg/day IV maximum 20100 mg IV intermittently until effect 0.51.0 mg IV; 10 mg/day maximum 25100 mg PO daily in one or divided doses 0.520 mg PO daily

Classes of Diuretics
The five common classes of diuretics are listed in Table 1. All promote the excretion of sodium (natruresis or saluresis) and water (diuresis) via different mechanisms.2 As shown in Figure 1, their actions also occur at differing anatomic locations in the nephron. The anatomic location of action is a major determinant of potency of the various classes of diuretics, and adaptations in the segments that are not affected by the diuretic, particularly those sites distal to the site of action, result in diuretic resistance and dependence. Thus, the arrangement of the specialized pumps and transporters affected by the various diuretic
Dr. Omi is Assistant Professor of Surgery, Division of Trauma, Surgical Critical Care, and Burns, Loyola University Health System, Chicago, IL; and Dr. Boyle is Professor of Anesthesiology and Surgery, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110; E-mail: boylew@wustl.edu. The authors have disclosed that they have no significant relationship with or financial interests in any commercial organizations pertaining to this educational activity. Lippincott CME Institute, Inc., has identified and resolved all faculty conflicts of interest in any commercial organizations pertaining to this educational activity.

Carbonic anhydrase inhibitors Acetazolamide Metabolic alkalosis

Loop diuretics Furosemide

Fluid overload, renal failure hyperkalemia

Bumetanide

Hypercalcemia

Thiazide diuretics Hydrochlorothiazide Fluid overload, edema, hypertension Metolazone Fluid overload, edema, hypertension Potassium-sparing diuretics Triamterene Edema, hypertension, potassium sparing Spironolactone Liver failure-associated ascites and fluid overload

50100 mg PO twice daily; maximum dose 300 mg/day 25-400 mg PO daily; maximum dose 400 mg/day

The continuing education activity in Contemporary Critical Care is intended for clinical and academic intensivists, critical care residents, and other practitioners with an interest in the care of the critically ill and critically injured patient. 1

60378_CCC05_sw

9/10/07

2:47 PM

Page 2

Contemporary Critical Care

October 2007

EDITOR-IN-CHIEF
Todd Dorman, MD* Associate Professor Departments of Anesthesiology/ Critical Care Medicine, Internal Medicine, Surgery and Nursing Johns Hopkins Hospital Meyer 291 600 N. Wolfe Street Baltimore, MD 21287-7294 tdorman@jhmi.edu

Aa GI DCT
JG Osmotic Diuretics

CT

Aldosterone Antagonists
Na+ K+

PCT

Ea TAL

Thiazides

Amiloridesensitive Na+ channel lumen

EDITORIAL BOARD
Yaniv Almog, MD Soroka University Medical Center Beer Sheva, Israel Sean M. Berenholtz, MD, MHS Johns Hopkins University School of Medicine Baltimore, MD Daniel R. Brown, MD, PhD Mayo Clinic Rochester, MN Walter A. Boyle III, MD Washington University School of Medicine St. Louis, MO Judith Jacobi, PharmD Methodist Hospital/Clarian Health Indianapolis, IN Z. Leah Harris, MD Johns Hopkins University School of Medicine Baltimore, MD Pamela A. Lipsett, MD Johns Hopkins University School of Medicine Baltimore, MD Gerald A. Maccioli, MD Critical Health Systems, Inc. Raleigh, NC Marek A. Mirski, MD, PhD Johns Hopkins University School of Medicine Baltimore, MD Dan Mullany, MBBS, MMedSc(Clin Epi) The Prince Charles Hospital Queensland, Australia Ronald Pauldine, MD Johns Hopkins Bayview Medical Center Baltimore, MD Jonathan E. Sevransky, MD Johns Hopkins University School of Medicine Baltimore, MD Dr. Dorman has disclosed that he is a stock shareholder in Visicu, Inc.
*

Na+ Loop diuretics K+ 2 ClOAT


interstitium Na+ ATP K+ HCO3H+ CA H2O + CO2 H+ + HCO3CA CO2 + H2O Na+ lumen

Na+ K+ interstitium Na+

TLH

Carbonic Anhydrase Inhibitors

Figure 1. Diagram of the nephron and the site of action of diuretics. Water, as a rule, follows sodium movement in the nephron. The glomerulus and the proximal convoluted tubule is the site of action for osmotic diuretics. The proximal convoluted tubule is also the site of action for carbonic anhydrase inhibitors. The thick ascending limb of the loop of Henle is the site of action of loop diuretics. The distal convoluted tubule is the site of action for thiazides, and the collecting tubule is the site of aldosterone antagonists and other potassium-sparing diuretics. The organic acid transporter in the proximal tubule is also important in secretion of diuretics into their tubular site of action. A, aldosterone; Aa, afferent arteriole; CA, carbonic anhydrase; CT, connecting tubule; DCT, distal convoluted tubule; Ea, efferent arteriole; Gl, glomerulus; JG, juxtaglomerular complex; OAT, organic acid transporter; PCT, proximal convoluted tubule; TAL, thick ascending limb; TLH, thin loop of Henle.

As shown in Figure 1, the hydraulic pressure in the glomerular capillaries results in ultrafiltrate deposition into Bowmans space and the proximal tubule. As a general rule, the directional movement of the sodium ion is accompanied by movement of water out of the tubule and into the surrounding interstitium. The proximal tubule contains sodium/potassium adenosine triphosphatase (ATPase), which is involved in the active transport of

sodium out of the ultrafiltrate and with it chloride, bicarbonate, and water. Generally, 60% to 70% of the ultrafiltrate sodium and water is reabsorbed at this site. Reabsorption of sodium bicarbonate via the action of extracellular and intracellular carbonic anhydrase is shown Figure 1. The proximal tubule is the major site of action of carbonic anhydrase inhibitors, and this is the site of the nonsteroidal anti-inflammatory drug (NSAID)-sensitive, organic acid

Contemporary Critical Care (ISSN 1543-9003) is published monthly by Lippincott Williams & Wilkins, Inc., 16522 Hunters Green Parkway, Hagerstown, MD 21740-2116. Customer Service Manager, Audrey Dyson: Phone (800) 787-8981 or call (410) 528-8572. 24-Hour Fax (410) 528-4105 or E-mail audrey.dyson@wolterskluwer.com. Visit our website at LWW.com. Publisher, Daniel E. Schwartz: Phone (410) 528-4020, Fax (410) 528-4105.
Copyright 2007 Lippincott Williams & Wilkins. Priority Postage paid at Hagerstown, MD, and at additional mailing offices. POSTMASTER: Send address changes to Contemporary Critical Care, Subscription Dept., Lippincott Williams & Wilkins, P.O. Box 1600, 16522 Hunters Green Parkway, Hagerstown, MD 21740-2116. PAID SUBSCRIBERS: Current issue and archives are available FREE online at www.lwwnewsletters.com. COPYING: Contents of Contemporary Critical Care are protected by copyright. Reproduction, photocopying, and storage or transmission by magnetic or electronic means are strictly prohibited.Violation of copyright will result in legal action, including civil and/or criminal penalties. Permission to reproduce in any way must be secured in writing from: Permissions Dept., Lippincott Williams & Wilkins, 351 W. Camden Street, Baltimore, MD 21201; Email: arnetta.queen@wolterskluwer.com. For commercial reprints, E-mail matt.westcoat@ wolterskluwer.com. Opinions expressed do not necessarily reflect the views of the Publisher, Editor, or Editorial Board. A mention of products or services does not constitute endorsement. All comments are for general guidance only; professional counsel should be sought for specific situations.

60378_CCC05_sw

9/10/07

2:47 PM

Page 3

October 2007

Contemporary Critical Care

transporter. As shown in the figure, this transporter is involved in the active transport of organic acids, as well as both loop and thiazide diuretics into the proximal tubular lumen. It should be noted that every diuretic (except for the aldosterone receptor antagonist spironolactone) acts on channels and pumps located in the apical membrane (i.e., on luminal side of the tubular cells). Thus, ultrafiltration and active transport of diuretics into luminal fluid are essential for these drugs to be delivered in effective concentrations to their sites of action in the tubular lumen. The decreased efficacy of diuretics with decreased glomerular filtration is related not just to decreased delivery of sodium and water to diuretic-sensitive sites of action, and increased sodium reabsorption at distal sites, but also to decreased amounts of filtered and secreted diuretic.3 The distal tubule has two segments: the thick ascending limb, and the distal convoluted tubule. The thick ascending limb of the loop of Henle contains the sodium-potassium-2 chloride pump (NKCC2), which is inhibited by loop diuretics, thereby promoting loss of sodium, potassium, chloride, and water. The decrease in electrolyte reabsorption at this site is also critical for the countercurrent mechanism to produce the medullary concentration gradient. Thus, loop diuretics, in particular, result in loss of ability to maximally concentrate urine and retain water. The macula densa, located in the thick ascending limb, is a component of the juxtaglomerular apparatus involved in tubuloglomerular feedback and increased proximal sodium absorption with increased distal sodium delivery. The distal convoluted tubule is capable of reabsorption of sodium via the thiazide-sensitive sodium/potassium exchanger. A smaller amount of carbonic anhydrase activity is also present in this segment, which accounts for some bicarbonate reabsorption and acid secretion. Ammonium ion transport into the urine also occurs in this segment and further buffers luminal hydrogen ions. In the connecting duct, sodium (and chloride and water passively) is reabsorbed through the amiloride- and triamterene-sensitive sodium channel and potassium/hydrogen transport-linked mechanism that is controlled by aldosterone.4
Carbonic Anhydrase Inhibitors

Carbonic anhydrase inhibitors, of which the most commonly used in the class is acetazolamide, inhibit the enzyme carbonic anhydrase. Carbonic anhydrase is involved in the conversion of carbonic acid, formed spontaneously in the presence of bicarbonate and hydrogen to water and carbon dioxide. In the lumen of the nephron, this mechanism is dependent on the secretion of hydrogen ion by the sodium/hydrogen exchanger. After carbon dioxide and water are generated in the lumen, carbon dioxide diffuses back into the cell where it again combines with water to form carbonic acid via the action of intracellular carbonic anhydrase, with regeneration of the bicarbonate and hydrogen ion. The bicarbonate diffuses passively into the interstitial space, driven by sodium efflux (via the sodium/potassium ATPase). Inhibition of carbonic anhydrase thus prevents the effective secretion of hydrogen ion and reabsorption of sodium bicarbonate. This
3

enzyme is found prominently in the proximal tubule as well as in the thick ascending limb of the loop of Henle.3 Administration of a carbonic anhydrase inhibitor results in both delivery of increased sodium to the more distal segments, together with bicarbonate. The result is natruresis and diuresis of alkaline urine. Secretion of other organic acids and ammonium ion are also inhibited by carbonic anhydrase inhibitors which may thereby result in significant systemic acidemia and decreases in plasma pH. Generally, potassium secretion is increased due to increased activity of the sodium/potassium exchangers in the distal tubule. However, in the presence of acidemia, increased efflux of hydrogen in place of potassium with exchange for sodium blunts the potassium loss. Hypokalemia is thus rarely experienced with carbonic anhydrase inhibitors.3 Carbonic anhydrase inhibitors are generally viewed as relatively weak diuretics in terms of sustained natruresis and diuresis. This is largely related to the fact that the decreased sodium reabsorption in the proximal tubule is largely reabsorbed in the more distal segments, although the action on carbonic anhydrase in the distal tubule allows for continued secretion of some sodium bicarbonate and alkaline urine. These drugs are frequently used in the treatment of patients with significant metabolic alkalosis, which may be due to prior use of loop or thiazide diuretics, excessive gastric losses of hydrogen ion, or because of metabolic compensation for respiratory acidosis. In this regard, it should be noted that it may be difficult to distinguish primary and secondary metabolic alkalosis in the presence of respiratory acidosis, particularly in critically ill patients with complex acid base disturbances. This distinction can be important, however, as a significant primary respiratory acidosis component can result in a dangerous decrease in pH with carbonic anhydrase inhibitors. Nevertheless, acetazolamide appears to be relatively safe and effective in the treatment of metabolic alkalosis in critically ill and ventilator dependent patients.5,6 Mazur et al.7 studied the use of acetazolamide for chloride unresponsive metabolic alkalosis in critically ill medical patients with chronic obstructive pulmonary disease or asthma. They found a single 500-mg dose of acetazolamide was generally safe and was equally effective as four 250-mg doses given every 6 hours in both diuresis and the decrease in bicarbonate concentration at 72 hours. Other studies have similarly demonstrated that acetazolamide has a long biological half-life. Carbonic anhydrase inhibitors are also used to decrease ocular fluid production and treat glaucoma, and these drugs also have been used to prevent altitude sickness, ostensibly by inducing a compensatory metabolic acidosis and increasing oxygen delivery. Side effects of carbonic anhydrase inhibitors include metabolic acidosis; unmasking primary respiratory acidosis; increased retention of ammonium ion, which may exacerbate encephalopathy in patients with impaired liver function; and increased risk of nephrolithiasis.3
Osmotic Diuretics

Mannitol, the most commonly used osmotic diuretic, is a small, inert, sugar-alcohol that is cell impermeant and therefore

60378_CCC05_sw

9/10/07

2:47 PM

Page 4

Contemporary Critical Care

October 2007

acts as an osmotic agent to draw water from cells. This thereby decreases intracellular water and increases both extracellular and intracellular osmolarity. Osmotic diuretics are freely filtered in the nephron, but poorly reabsorbed, if at all. Thus, these agents appear in high concentrations in the tubular fluid, accompanied by water. The fact that these agents also increase extracellular fluid (by the amount of water leaving the intracellular space) tends to augment glomerular filtration and thereby increase their relative diuretic effect. These agents are generally relatively weak natriuretics and often result in hypernatremia. In addition, in renal failure or in the presence of significant volume depletion and decreased ultrafiltration, they can accumulate and be measured as unmeasured osmos, or the osmolar gap. Mannitol is commonly used to treat patients with increased intracranial pressure and cerebral edema due to brain injury or liver failure. In addition, although data from clinical trials are somewhat conflicting and scant, mannitol has been used to promote diuresis and prevent acute renal failure in patients undergoing renal transplantation or abdominal aortic aneurysm repair and in patients with rhabdomyolysis.8-18 The mechanism for the protective effect is unknown but has been postulated to be related to the free radical scavenger properties of mannitol, prevention of tubular swelling, flushing of the tubule by increasing urine output, and increased renal blood flow due to volume expansion.16 Complications of mannitol therapy commonly include volume depletion, hypernatremia, and hyperosmolarity. In addition, mannitol has been reported to produce renal failure, which impairs mannitol clearance and can result in signs or symptoms of fluid overload.19 The only therapy effective in the removal of mannitol in this situation is hemodialysis.
Loop Diuretics

Loop agents inhibit the NKCC2 pump in the thick ascending loop of Henle. This class of drugs has been in use for a long time, with FDA approval of the sulfonamide derivative furosemide in 1966.20 The sulfonamide loop agents all have a high therapeutic index, are potent, and are available to be administered parenterally. These features provide distinct advantages, and thus account for the widespread use of these as the diuretics of choice, especially furosemide, in the ICU. Other drugs in the class include bumetanide, torsemide, and ethacrynic acid. As already mentioned, the clearance and secretion of the active, unmetabolized drug into the tubule determines the concentration at the site of action and thus is an important factor in the diuretic action. Poor glomerular filtration or high concentrations of organic acids, such as may occur with renal failure, or use of NSAIDs, results in decreased responsiveness to furosemide. Such patients also usually have poor delivery of sodium to the site of action of the diuretic, which also impairs diuretic responsiveness. Finally, there are adaptive mechanisms that occur both acutely, such as the so-called braking phenomenon, and after chronic use, including increased expression of the distal convoluted tubule thiazide-sensitive sodium/potassium exchanger, tubular hypertrophy, and hyperaldosteronism. These mechanisms contribute to decreased responsiveness to furosemide and furosemide dependence.21
4

The action of furosemide is independent of acid-base status or urinary pH, and it can result in metabolic alkalosis related to both chloride and potassium deficiency and increased absorption of sodium chloride and bicarbonate in the proximal tubule. Furosemide also possesses wellknown but poorly understood systemic vasodilating, particularly venodilating, actions that result in decreases in end diastolic ventricular pressure. This latter action is thought to account for the immediate relief reported in patients with fluid overload. Furosemide also produces renal vasodilatation, with decreases in renal vascular resistance, and an increase in the renal blood flow, which may further enhance its diuretic and natruretic effects.22 Continuous infusions of furosemide are used often in the ICU. From a theoretical standpoint, infusions compared with bolus injections should be better tolerated hemodynamically, produce less of the furosemide concentration-dependent ototoxicity, and result in a more continuous diuresis with less acute resistance due to diuretic braking (Figure 2).21 Several small studies generally support these potential benefits, particularly greater efficacy and decreased toxicity.23 Schuller et al.24 investigated a fluid balance-driven protocol using either intermittent or continuous dosing of furosemide in 33 medical and cardiac patients with pulmonary edema. They found no difference in the doses of furosemide required to produce an equivalent diuresis in the two groups. However, the authors noted that the urine output in both protocol groups was substantially better than in the nonrandomized patients, who received intermittent furosemide boluses that were not constrained by ins and outs as in the protocol, and urine output was less variable and better sustained in the continuous infusion group. Similarly, in another small study in which 22 fluid-overloaded patients were randomized to an intermittent versus continuous furosemide-dosing protocol, there were no significant differences in hemodynamics or the amount of diuresis, but lower doses of furosemide were required, and serum potassium was better maintained in the continuous infusion group.25 Taken together, available data suggest that continuous infusion compared with intermittent bolus dosing produces better results in terms of more predictable hourly urine output, and fewer complications associated with the drug. The most common problems associated with loop diuretics are related to volume depletion and electrolyte abnormalities, particularly hypokalemia and metabolic alkalosis; as well as hyponatremia, hypochloremia, hypocalcemia, and hypomagnesemia. Care should thus be exerted while giving these drugs without accounting for potassium and magnesium losses, particularly in patients taking digitalis or prone to atrial arrhythmias. Conversely, the thick ascending limb is a site for calcium and potassium reabsorption, and these agents can be particularly useful in inducing calciuresis or kaliuresis in patients with hypercalcemia or hyperkalemia. Loop diuretics are well known to produce significant ototoxicity related to actions on cochlear hair cell channels, which is also concentration dependent and usually completely reversible. In general, this is only an issue when very large bolus doses are given. One study suggested that bumetanide may be less toxic than furosemide at equipotent doses, but

60378_CCC05_sw

9/10/07

2:47 PM

Page 5

October 2007

Contemporary Critical Care

105 95 300 60

50

UNaVmmol/6 hours

200

UNaVmmol/6 hours

40

30

100

20

10 0 Control Days Furosemide Day 1 Furosemide Day 2 Furosemide Day 3

0 Control Days Furosemide Day 1 Furosemide Day 2 Furosemide Day 3

A-High salt intake (270 mmol/day)

B-Low salt intake (20 mmol/day)

Figure 2.The diuretic braking phenomenongraph showing the effect of daily administration of furosemide on sodium excretion (UNaV) measured every 6 hours in healthy subjects on (A) a high-salt diet (270 mmol/day), and (B), a low-salt diet (20 mmol/day). As can be seen in both groups, each dose of furosemide results in a large increase in UNaV, shown as the solid bars. On the highsalt diet, UNaV declines significantly (shaded areas) compared with the control average (shown as the horizontal dashed line) for each of the UNaV subsequent 6 hour intervals after Lasix. The result is no change in daily sodium balance or natruresis on the highsalt diet (i.e. diuretic braking). By comparison, although furosemide is less effective in patients on the low-salt diet, there is no room for significant decreases in UNaV, thus positive sodium balance cannot offset the effect of furosemide, and there is net natruresis (i.e., no braking, or broken braking). (Graph adapted from Wilcox et al.40 Used with permission.)

other studies do not support this contention. Although ethacrynic acid is rarely used except in patients allergic to sulfonamides, it should be remembered that ototoxicity with that drug appears to be much more severe and may not be as reversible compared with furosemide and bumetanide.2
Thiazide Diuretics

Thiazide diuretics are another class of sulfonamide diuretics that act on the distal convoluted tubular sodium/potassium exchanger to produce decreased sodium reabsorption. Although hydrochlorothiazide is the most common thiazide used in the outpatient setting, metolazone is another potent thiazide diuretic that is often used in conjunction with a loop diuretic to potentiate natruresis and diuresis. Most of these drugs are only available in oral form, with the exception of chlorothiazide, which is available for oral and parenteral administration. Loop diuretics and thiazides have a welldescribed synergistic effect owing in part to the fact that the renal adaptations that counter the effects of the loop diuretics involve increased sodium reabsorption in the relatively high capacity thiazide-sensitive proximal convoluted tubule.21 Thus, resistance to loop diuretics may be overcome by the addition of a thiazide diuretic; conversely, patients who become unresponsive to thiazides may have sensitivity to thiazides restored when they are given in combination with a loop diuretic.2 As with loop diuretics, treatment with thiazide diuretics may be associated with significant electrolyte abnormalities,
5

hypokalemia and hyponatremia being most common. Hypokalemia is due in large part to increased potassium excretion in the aldosterone-sensitive hydrogen/potassium transporter in the collecting tubule. Patients on thiazides who become volume depleted can develop hyperreninemic hyperaldosteronism that can result in both thiazide resistance and thiazide dependence (known as thiazide addiction). Aldosterone antagonists or angiotensin-converting enzyme (ACE) inhibitors can potentially prevent or treat this condition. Additionally, unlike loop diuretics, thiazide diuretics result in increased calcium reabsorption, not calciuresis. Thus, thiazides should not be used to treat hypercalcemia, and they can potentially exacerbate it. Another potential problem with the thiazides is the increased reabsorption of uric acid, resulting in significant elevations of plasma urate and increased risk of developing gout. Thiazides also have been reported to produce some worsening of glucose intolerance due to increased insulin resistance and decreased insulin release secondary to hypokalemia. Thiazides may also cause mild increases in serum cholesterol levels. There have been no compelling data, however, to suggest that there is any significant increased morbidity associated with any of these adverse effects in patients chronically taking thiazide diuretics.2
Potassium-Sparing Diuretics

The potassium-sparing diuretics are generally used to avoid or limit the hypokalemia that accompanies diuresis with loop agents or thiazides. They act by inhibiting sodium

60378_CCC05_sw

9/10/07

2:47 PM

Page 6

Contemporary Critical Care

October 2007

entry via an amiloride-sensitive, apical sodium channel in the collecting tubule, which provides the electrochemical gradient that drives potassium and hydrogen ion secretion into the lumen. Because of the relatively limited amount of sodium normally delivered to the collecting tubule, these drugs are generally weak diuretics. However, as this is also the most distal mechanism, they may be critical to breaking the back of diuretic resistance and sodium retention in patients on loop or thiazide diuretics. This mechanism is under the genomic control of aldosterone, which acts through a specific receptor and a complex signaling pathway to increase expression of pumps and transporter proteins involved in sodium reabsorption and secretion of potassium and hydrogen ion at this site (Figure 1). Aldosterone synthesis and secretion is in turn driven by increases in renin and angiotensin production, as well as by increases in serum potassium. As discussed earlier, patients taking thiazide diuretics may develop hyperaldosteronism that contributes to diuretic resistance and diuretic dependence. Additionally, primary hyperaldosteronism is being increasingly recognized as an important entity that can prevent natruresis and diuresis in normoreninemic hypertensive patients. Such patients may be resistant to angiotensin converting enzyme inhibitors, although the sodium retention will be sensitive to aldosterone antagonists.3 The exchange of luminal sodium moving down its electrochemical gradient for intracellular potassium at this site is the major mechanism responsible for the potassium wasting effects of loop and thiazide diuretics. Thus, blockade of this mechanism accounts for the potassiumsparing effects of inhibitors of this aldosterone-sensitive mechanism. Hyperkalemia can occur, however, with these agents, particularly in the presence of a high potassium diet or potassium supplementation and when given together with NSAIDs or ACE inhibitors. These drugs should not be given to patients at risk of developing hyperkalemia.2 Both amiloride and triamterene act directly on the apical (luminal) sodium channel and must be delivered in the tubular fluid as with other diuretics. However, spironolactone competitively inhibits the intracellular aldosterone receptor and is thus not dependent on glomerular filtration or secretion. In addition to hyperkalemia, these drugs decrease secretion of hydrogen ion into the filtrate (by the same sodium influx-linked mechanism involved in potassium secretion) and can thus result in metabolic acidosis. Spironolactone also blocks aldosterone-mediated ammonia production in the kidney, which also contributes to decreased removal of the hydrogen ion, although this effect could be potentially advantageous in patients with liver failure.2
Other Diuretics

mechanism. Fenoldopam mesylate is a dopamine-1 receptor agonist that selectively binds the receptor without the cardiac effects of dopamine. Both dopamine and fenoldopam are poor diuretics and their role, or lack of a role, in preventing or treating acute renal failure is discussed in more detail below.

Diuretic Therapy in the Management of Fluid Balance


Diuretic therapy is clearly important in the ICU in the treatment of fluid overload and edema, particularly in patients with underlying cardiac or liver failure. Additionally, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), pulmonary contusion, and postoperative or postresuscitation fluid overload are commonly encountered problems that are frequently treated with diuretic therapy. Diuretics are also used in the management of patients with oliguria. Although diuretics clearly improve signs and symptoms of fluid overload, however, their use per se has not been shown to improve mortality in the ICU. One recent study suggested that diuretic use may have contributed to increased mortality in patients with oliguric renal insufficiency.26 Thus, diuretics should be used cautiously and with the recognition that diuresis that is too aggressive can result in decreased cardiac output, tissue perfusion, and well as hypotension. This can lead to precipitation of acute renal failure, a serious complication that markedly increases mortality. Overdiuresis and volume depletion can increase activity of the adrenergic-renin-angiotensinaldosterone axis and arginine vasopressin release, which may produce unwanted side effects and be counterproductive in producing the desired natruresis and diuresis. Common sense dictates that the lowest effective dose of a diuretic should be used. The volume status of the patient and responsiveness to the diuretic should be monitored closely. Continuous infusions of loop diuretics or combinations of loop diuretics and either thiazides or potassium-sparing diuretics may be more effective in the prevention of diuretic resistance, thereby avoiding counterproductive responses associated with higher doses.21 Although there are no specific evidence-based recommendations as to fluid management in patients with lung injury (ALI, ARDS, pulmonary trauma), the available literature for more than 20 years has suggested that keeping intravascular volume at a low level, while still maintaining adequate perfusion of vital organs, results in improved lung function and survival.2730 Thus, although identifying and treating the underlying cause is of greatest importance in ALI and ARDS, efforts are usually made to minimize pulmonary interstitial fluid.31 Furosemide, in particular, may contribute by decreasing pulmonary vascular resistance and pulmonary capillary hydrostatic pressure and thereby further decrease efflux of fluid into the lung interstitium. Animal and human studies have shown that lowering left atrial pressures decreases the degree of lung edema.2830 A small study performed in hypoproteinemic ICU patients (n = 40) with ALI and ARDS demonstrated that furosemide combined with albumin, compared with either placebo or furosemide alone,
6

Dopamine is natruretic in low doses (13 mcg/kg/min) due to an increase in renal blood flow and glomerular filtration rate, as well as cAMP-induced inhibition of the sodium/hydrogen exchanger in the proximal tubule. Aminophylline, which also increases cAMP via phosphodiesterase inhibition, has similar weak diuretic properties that are likely related to a similar

60378_CCC05_sw

9/10/07

2:47 PM

Page 7

October 2007

Contemporary Critical Care

were superior in both improved oxygenation and net negative fluid balance.32 There was no decrease in mortality and the effects on oxygenation and fluid balance are clearly relevant in sicker patients requiring high FiO2. Similarly, pulmonary contusion from blunt chest trauma is also managed with fluid restriction and diuretics to maintain low cardiac filling pressure. Again, this is based primarily on evidence that such strategies improve oxygenation.31 Increased interstitial water in virtually every organ is often encountered in the ICU, particularly after aggressive fluid resuscitation to manage severe hemorrhage, septic shock, acute traumatic injury, or major surgery. In fact, such patients may meet the PaO2/FiO2 criteria for ALI and ARDS due to the increased interstitial lung water.27 With little evidence to the contrary, and recent evidence suggesting that fluid restriction may be beneficial in surgical patients, diuretics are often used to maintain fluid and electrolyte balance or remove excess interstitial fluid. There is, however, an ongoing debate regarding whether over-resuscitation of surgical patients in the perioperative period has a detrimental effect on outcomes in terms of complications and return of bowel function.33 In one study of colorectal surgical patients, a restrictive fluid resuscitation protocol resulted in significantly fewer cardiopulmonary and tissue-healing complications in the fluid restricted group.34 Similarly, in another small study of colorectal surgical patients, restrictive compared with liberal volume resuscitation resulted in significantly faster recovery of bowel function.35 Finally, in a recent randomized study of patients undergoing elective intra-abdominal surgery, the patients randomized to the restrictive fluid resuscitation had a significantly lower rate of total complications compared with the liberal fluid control group.36 On the other side, however, recent studies also indicate the partial pressure of oxygen at the tissue level is improved with supplemental perioperative fluid, although the improvement in tisTable 2. Mechanisms of Diuretic Resistance and Dependence Acute and chronic adaptations to diuretic use Increased sodium resorption by downstream transporters Acute tolerance Dependent on capacity of existing transporters Compensatory sodium retention (diuretic braking) Chronic tolerance/dependence Hypertrophy and increased production of distal transporters Increased proximal tubular sodium resorption Decreased sodium delivery to more distal diuretic-sensitive transporters Release of sodium and water retentive hormones Increased activity of renin-angiotensin-aldosterone axis Increased release of antidiuretic hormone Pharmacokinetic factors affecting diuretic availability in the tubule Decreased renal perfusion Reduced filtration of diuretic Hypotension/low cardiac output Impaired diuretic secretion by the tubule Metabolic acidosis Nonsteroidal anti-inflammatory drugs Large volume of distribution Increased interstitial fluid Hypoproteinemia Diuretic binding by protein in the tubule Nephrotic syndrome

sue oxygenation did not translate to fewer complications.37 Presently, there are no data to strongly support either view, and no available data to suggest that routine diuretic use to maintain negative or less-positive fluid balance has benefit in the routine fluid management of surgical patients. Taken together, cumulative knowledge and conventional wisdom suggest that over-resuscitation may be detrimental, particularly in patients with lung injury, and diuretics may be useful to decrease obvious interstitial edema and improve pulmonary gas exchange in over-resuscitated, post-shock, or post-injury patients. However, adequate resuscitation is still a primary concern and, in the absence of some of the conditions discussed below, use of diuretics in the resuscitation phase appears counterintuitive. Nevertheless, we have clearly moved away from give em fluids till they froth, then back off to a position well articulated in the concept of goal-directed therapy. An example of this is illustrated in the surviving sepsis guidelines that fluid resuscitation should continue until specific cardiac filling pressure and oxygen delivery endpoints are met, then back off.38 Once cardiac filling pressure and cardiac output/perfusion parameters have been met, and the patient remains oliguric, diuretics may increase urine output and potentially decrease the incidence of oliguric renal failure. However, there are no strong data in support of that position. Diuretics in this case may potentially produce harm. Ideally, there will be future studies assessing the value of diuretics to achieve defined outcomes in the ICU including time on the ventilator, ICU and hospital length of stay, and survival.

Diuretic Dependence and Diuretic Resistance


With administration of a loop or thiazide diuretic, increased sodium is delivered to more distal segments, with compensatory increases in distal sodium reabsorption that offset the action of the diuretic. Additionally, as intravascular volume decreases, glomerular filtration is decreased and proximal tubular reabsorption of sodium is increased. Both result in decreased delivery of sodium and diuretic to the more distal diuretic-sensitive sites. Increases in aldosterone and antidiuretic hormone further decrease the natruretic and diuretic effects of these drugs. Prolonged exposure to diuretics also leads to tubular remodeling and cellular hypertrophy, with increased expression of the pumps and channels that oppose the action of the diuretic.39 Separately and together, these adaptations to diuretic use limit diuretic potency, and lead to both diuretic resistance and diuretic dependence. The factors listed in Table 2 may all contribute to diuretic resistance and diuretic dependence in the ICU. Diuretic braking describes the acute adaptation to the sodium- and fluid-depleting actions of diuretics. An example of this, also called acute tolerance, is shown in Figure 2. In this experiment, loop diuretics were administered to six normal subjects daily over 3 days. As shown in Figure 2A, each dose of furosemide produces a brisk diuresis. However, after each dose, the kidneys increase sodium retention during the interval following the diuretic-induced natruresis such that sodium balance is unchanged over each of the three 24-hour intervals. Only when the subject is placed on a restricted sodium diet
7

60378_CCC05_sw

9/10/07

2:47 PM

Page 8

Contemporary Critical Care

October 2007

(Figure 2B) can negative sodium and fluid balance be achieved.40 In the ICU, this acute tolerance or diuretic braking during the period between doses could be an important cause of diuretic resistance. This braking phenomenon makes an additional argument for use of continuous diuretic infusions to achieve effective diuresis and natruresis more easily, particularly in patients who receive substantial amounts of obligatory sodium throughout the day with medications and in their diet. There is no period during a continuous infusion where the nephron is absent of the diuretic and the braking phenomenon should thus be eliminated.21 Molecular and cellular remodeling in the tubules and tubular cell hypertrophy also occur in patients who take diuretics chronically, which may render such patients both diuretic resistant as well as diuretic dependent, even for maintenance of normal fluid and electrolyte balance under basal conditions.39 In one study, the natruretic response to furosemide in patients was significantly blunted after a month of therapy. In an animal model, this blunted response lasted up to 2 weeks.41 The decreased responsiveness to furosemide in these studies was class specific (i.e., it did not occur with spironolactone or thiazides). Additionally, patients taking loop diuretics may have increased sensitivity to the more distally acting thiazide diuretics. Similarly, sensitivity to thiazide diuretics, which may be lost with chronic use or renal failure due to decreased glomerular filtration and increased proximal sodium reabsorption, can be recovered by the addition of a loop diuretic. Diuretics that act on different mechanisms may, when used in combination, produce greater than predicted efficacy.21 In addition to diuretic adaptations, important pharmacokinetic factors listed in Table 2 also may contribute to diuretic resistance. The action of all diuretics, with the exception or spironolactone, is dependent on binding to pumps and channels on the luminal side of the tubular membrane. Thus, it is the amount of diuretic in the filtrate, not the plasma, which determines the delivery to the site of diuretic action. Patients with impaired renal perfusion or glomerular filtration, for any reason, would thus be expected to display some diuretic resistance due to impaired delivery of the diuretic into the tubular fluid. Additionally, patients with metabolic acidosis or patients receiving NSAIDs have decreased transport of the diuretic into the tubular lumen.21 Finally, diuretics are highly bound to plasma proteins. Thus, edematous patients who are hypoalbuminemic display an increase in the volume of distribution of diuretics. In patients with proteinuria, diuretic binding in the tubule decreases the effective concentration of the drug at the site of action.42

Diuretics as Therapy
Renal Failure and Diuretic Therapy

Acute renal failure is an independent risk factor for death in postoperative and critically ill patients, with mortality rates for patients who develop renal failure of 38% to 70%.26,4345 Renal failure is thus generally viewed as one of the most serious complications contributing to mortality in the ICU. In postcardiac surgery patients, for example, acute renal failure
8

is a potent predictor of outcome with an operative mortality in patients requiring dialysis of 63.7% compared with 4.3% in patients without renal failure.46 It is also widely recognized that oliguric renal failure is associated with increased need for dialysis and increased mortality.47 Thus there has been considerable interest in methods to both prevent acute renal failure from developing and convert oliguric to nonoliguric renal failure using diuretics. Low-dose (renal dose) dopamine, which induces both increases in renal blood flow and urine output, has been advocated for both the prevention and treatment of acute renal insufficiency, largely based on small, observational, noncontrolled trials.48 Multiple prospective trials have not demonstrated this benefit of dopamine, however, either in preventing or treating renal failure in patients undergoing cardiovascular surgery, receiving intravenous contrast agents, or in the general critical care population.44,4851 Indeed, dopamine may be harmful by delaying recognition of renal insufficiency, by decreasing splanchnic mucosal blood flow and potentially precipitating mesenteric ischemia, and by producing unwanted cardiac stimulation and tachyarrhythmias.52,53 Fenoldopam mesylate, a selective dopamine-1 receptor agonist, increases renal blood flow without the adverse cardiac effects seen with dopamine. This drug has been studied extensively to determine its potential to prevent acute renal failure or decrease the need for dialysis. Again, as with dopamine, there are no convincing data from any single study that there is a benefit in the prevention of acute renal failure in the setting of radiocontrast agent administration, renal failure secondary to septic shock, or renal failure in critically ill patients.5456 As with dopamine, there appears to be nonsustained improvements in renal function in some patients, but no significant long-term benefit in terms of decreased renal failure, the need for dialysis, or mortality. However, a recent meta-analysis of 16 pooled data sets from studies of fenoldopam use in the critically ill, suggested that fenoldopam did decrease both the need for dialysis and mortality in critically ill patients at risk of acute renal failure.57 At this point, a large prospective study will probably be needed before fenoldopam is widely used in critically ill patients at increased risk for developing renal failure. Furosemide was also thought to have a renal protective effect attributed to its ability to decrease energy-dependent sodium chloride uptake at the vulnerable cortical medullary border and induce adequate tubular urine flow. Pretreatment with furosemide appeared to have a renal protective effect in animal models of acute renal failure.58,59 However, prospective trials of furosemide in the prevention of renal failure have failed to demonstrate any benefit. In a recent study with patients undergoing cardiac surgery, perioperative furosemide actually resulted in a significant increase in the incidence of acute renal injury.49 Diuretics, particularly furosemide, are also commonly used in the treatment of oliguric renal insufficiency. Again, this is largely based on data indicating that nonoliguric renal failure is associated with a decrease in the need for dialysis and a better outcome. However, this association is based on

60378_CCC05_sw

9/10/07

2:47 PM

Page 9

October 2007

Contemporary Critical Care

spontaneous urine output, irrespective of diuretic use; it is unclear whether conversion of oliguric to nonoliguric renal failure can occur with diuretics, and if it does, whether diuretic-induced conversion provides the same benefit. Shilliday et al.47 studied the use of furosemide, torsemide, and placebo in acute renal failure. There was no difference in need for hemodialysis, time to renal recovery, or mortality with the use of diuretics. Interestingly, there was no difference in the mortality of nonoliguric patients who received placebo versus those that received loop diuretics. A recent prospective observational study of 552 ICU patients with new onset renal failure published by Mehta et al.26 suggested that furosemide use in patients with renal failure was associated with a 68% increase in hospital mortality and a 77% increase in the odds of death or nonrecovery of renal function. It is important to note, however, that the use of furosemide in this study was not controlled, and that the increased risk of diuretics was again entirely borne by the subgroup that had little response to high doses of diuretics. Additionally, the group that was not treated with diuretics had significantly higher urine outputs than the diuretic nonresponder group, suggesting that the administration of higher doses of diuretics were potentially driven by low urine output and lack of response to lower doses, as would be expected. The diuretic-treated group was also significantly older, had higher incidences of cardiac and respiratory failure, and experienced a longer interval until receiving initial renal replacement therapy. Finally, the increased mortality associated with diuretics in the Mehta et al.26 report, which was largely based on a statistical model of propensity scoring to adjust for differences in risk factors (e.g., age, cardiac, and respiratory failure) between the two groups, was apparently not found in a much larger multicenter, multinational study of 1743 patients using three similar but more complex statistical models to adjust for the differences in the measured variables among the groups.43 However, all three statistical models in this latter study demonstrated a nonsignificant increased risk of mortality (odds ratio: 1.2), which was comparable to that in the Mehta et al. study. At this point, although the data indicating that diuretics produce harm may be weak, there does not appear any strong indication for diuretic use in oliguric renal failure. There may be some potential advantage to converting oliguric to nonoliguric renal failure, but the effectiveness or value of diuretics for this purpose has not been clearly established.47 More investigation seems warranted. A multicenter prospective randomized trial that would evaluate potential risk and benefit of diuretics in oliguric hypervolemic patients, controlling for all apparently confounding variables including time to initial renal replacement therapy, would be ideal to determine the true impact of diuretic use on need for dialysis, recovery of renal function, and mortality in oliguric patients with renal insufficiency.
Rhabodomyolysis and Diuretic Therapy

because of muscle injury are freely filtered into the glomerulus, with myoglobinuria-induced renal failure occurring through a number of proposed mechanisms. Myoglobin binds nitric oxide, resulting in renal vasoconstriction, and it produces heme protein-induced renal tubular cell toxicity and interluminal cast formation that leads to tubular obstruction. Myoglobin solubility is increased in alkaline solutions and standard therapy thus consists of volume loading and forced diuresis of alkaline urine to dilute the myoglobin and increase myoglobin solubility. Intravenous fluid hydration is the mainstay of therapy, but diuretics, most commonly mannitol, together with sodium bicarbonate infusions, are used to maintain a high output of alkaline urine. Administration of acetazolamide to alkalinize the urine has not been shown to be beneficial.60 In a nonrandomized study of mannitol and bicarbonate therapy in 382 trauma patients with elevated creatinine phosphokinase (CPK) levels, the patients with CPK levels of more than 5000 U/L had significantly increased incidence of renal failure (19%) compared with those with lower CPK levels (8%).61 However, the incidence of renal failure, need for dialysis, and mortality were not changed in the 40% of patients who received mannitol and bicarbonate using an established protocol. In a subgroup analysis, however, there was a clear trend toward decreases in renal failure, need for dialysis, and mortality in the patients with CPK levels greater than 15,000 U/L. In the 32 patients with CPK levels of more than 30,000 U/L, 24 patients (75%) received mannitol and bicarbonate, and these patients, compared with the untreated group, had decreases in renal failure (46% vs. 63%), need for dialysis (13% vs. 38%) and mortality (29% versus 63%). It seems that if mannitol and urine alkalinization with bicarbonate infusions have benefit, then this might be seen best in patients with higher CPK levels. A randomized trial with more of these high-risk patients will need to be performed to answer the question definitively.
Contrast Nephropathy and Diuretic Therapy

Diuretics are often used as therapeutic agents to aid in the preservation of renal function in critically ill patients with rhabdomyolysis. Myoglobin and heme proteins released
9

Diagnostic imaging studies requiring administration of nephrotoxic intravenous radiocontrast agents are often necessary in critically ill patients. There has been considerable interest in the potential use of diuretics to attenuate renal injury and thereby decrease morbidity and mortality associated with radiocontrast-induced nephropathy. In a recent prospective randomized trial of patients undergoing cardiac angiography, the efficacy of saline hydration alone versus saline hydration plus either furosemide or mannitol was evaluated. Notably, the mean serum creatinine concentration was significantly higher 24 hours after angiography in both diuretic treated groups, and the difference was sustained at the 48-hour time point in the furosemide-treated group.62 It has subsequently been argued that this study may have been flawed because fluid losses in the diuretic-treated groups were not replaced. However, another recent trial with even higher basal rates of renal failure showed no beneficial effect of diuretic treatment prior to administration of intravenous radiocontrast agents even when fluid losses

60378_CCC05_sw

9/10/07

2:47 PM

Page 10

Contemporary Critical Care

October 2007

were replaced.63 In summary, there are no compelling data to suggest that furosemide or mannitol are beneficial in protecting renal function following radiocontrast agents, and some studies suggest a detrimental effect. Dopamine also has been studied for this indication. No beneficial effect has been demonstrated in the prevention of renal insufficiency following exposure to intravenous radiocontrast agents.64
Brain Injury and Diuretic Therapy

The osmotic diuretic mannitol has clearly been shown to be an effective modality in the treatment of intracranial hypertension. Mannitol is superior to barbiturates and is best used continuously as opposed to being used for intracranial pressure goal-directed therapy.65,66 Despite the lack of a randomized trial demonstrating that mannitol decreases the area of brain injury or improves long term outcomes, the presumed benefit of reducing intracranial pressure alone has led the Brain Trauma Foundation and the American Association of Neurological Surgeons to recommend the use of mannitol in the treatment of intracranial hypertension.67 There appear to be two fundamentally distinct mechanisms of action of mannitol that are important in the injured or edematous brain. First, the osmotic effect decreases intracellular volume. Thus, although mannitol has an initial volume expanding and hemodiluting effect that may actually increase cerebral blood flow, the overall effect is a decrease in intracranial volume and pressure. Second, the diuretic effect of mannitol reduces intravascular volume, further decreasing intracranial volume and pressure. If mannitol is given in high doses over extended periods of time or in the presence of renal failure, it accumulates in the interstitial space and may result in fluid retention or overload, thereby potentially increasing cerebral edema.67 Animal cell culture studies suggest that mannitol versus hypertonic saline results in more rebound swelling when the blood brain barrier is disrupted by brain injury, presumably related to mannitol accumulation.68 Taken together, there remains strong general support for the use of mannitol in the control of increased intracranial pressure; however, mannitol should be used in caution in patients with renal failure, as it will accumulate rapidly and result in fluid retention and may cause rebound edema. The residual mannitol that is not cleared between doses can be measured as the osmolar gap, as described previously. Finally, although mannitol has been used in the prevention of renal failure (as in myoglobinuria, for example), several reports suggest prolonged use of high doses of mannitol can be nephrotoxic and result in renal insufficiency due to so-called osmotic nephrosis.19

pharmacokinetic mechanisms may also limit delivery of diuretics to their site of action in the tubular lumen. With the exception of mannitol, the concept that diuretics can be renal protective in the perioperative period or following radiocontrast administration has been disproved by several studies, which demonstrate that administration of loop diuretics, in particular, may be counterproductive and increase the degree of renal injury in these settings. Additional recent retrospective studies have suggested that diuretic use may increase the risk of mortality or chronic renal failure in the ICU, although available retrospective data also suggest that this may not be due to the diuretic use per se. These studies suggest both that diuretics are used in oliguric patients at increased risk of poorer outcomes, and that diuretic use may delay initiation of renal replacement therapy. Some evidence suggests that mannitol may have a renal protective effect in patients with severe rhabdomyolysis or patients undergoing aortic surgery, and there is no evidence suggesting that mannitol can produce harm in these situations. Mannitol excess, however, has been associated with a unique renal injury termed osmotic nephrosis. Overall, despite frequent and widespread use of diuretics, the evidence that diuretics improve outcomes in critically ill patients is generally lacking. However, we still view their use as a mainstay in the management of fluid overload; in lung protection strategies; as well as for treatment of acute renal failure, rhabdomyolysis, and brain injury.
REFERENCES 1. 2. 3. 4. Adler SM, Verbalis JG. Disorders of body water homeostasis in critical illness. Endocrinol Metab Clin North Am 2006;35:873-894, xi. Greenberg A. Diuretic complications. Am J Med Sci 2000;319:10-24. Wilcox CS. Diuretics. In: Brenner BM, ed. Brenner & Rectors The Kidney. Philadelphia: Elsevier, 2004, pp 2345-2380. Tisher CC. Structure and function of the kidneys. In: Goldman L, Ausiello D, eds. Goldman: Cecil Textbook of Medicine. 22nd ed. Philadelphia, PA: W.B. Saunders; 2004:663-668. Marik PE, Kussman BD, Lipman J, et al. Acetazolamide in the treatment of metabolic alkalosis in critically ill patients. Heart Lung 1991;20:455-459. Dickinson GE, Myers ML, Goldbach M, et al. Acetazolamide in the treatment of ventilatory failure complicating acute metabolic alkalosis. Anesth Analg 1981;60:608-610. Mazur JE, Devlin JW, Peters MJ, et al. Single versus multiple doses of acetazolamide for metabolic alkalosis in critically ill medical patients: a randomized, double-blind trial. Crit Care Med 1999;27:1257-1261. Lane NJ, Thorniley MS, Manek S, et al. Effect of mannitol and polyethylene glycol on the action of furosemide during renal storage and transplantation. Transplantation 1996;62:575-582. Salahi H, Malek Hosseini SA, Ahmad E, et al. Mannitol infusion and decreased incidence of allograft acute renal failure. Transplant Proc 1995;27:2569. Homsi E, Barreiro MF, Orlando JM, et al. Prophylaxis of acute renal failure in patients with rhabdomyolysis. Ren Fail 1997;19:283-288. Zager RA, Foerder C, Bredl C. The influence of mannitol on myoglobinuric acute renal failure: functional, biochemical, and morphological assessments. J Am Soc Nephrol 1991;2:848-855. Lauzurica R, Teixido J, Serra A, et al. Hydration and mannitol reduce the need for dialysis in cadaveric kidney transplant recipients treated with CyA. Transplant Proc 1992;24:46-47. van Valenberg PL, Hoitsma AJ, Tiggeler RG, et al. Mannitol as an indispensable constituent of an intraoperative hydration protocol for the prevention of acute renal failure after renal cadaveric transplantation. Transplantation 1987;44:784-788. Barry KG, Cohen A, Leblanc P. Mannitolization. I. The prevention and therapy of oliguria associated with cross-clamping of the abdominal aorta. Surgery 1961;50:335-340. Barry KG, Cohen A, Knochel JP, et al. Mannitol infusion. II. The prevention of acute functional renal failure during resection of an aneurysm of the abdominal aorta. N Engl J Med 1961;264:967-971.

5. 6.

7.

8.

9.

10. 11.

Conclusion
Five classes of diuretics are available for use in critically ill patients. The loop diuretic furosemide is used most commonly for removal of sodium and water (diuresis), whereas the osmotic diuretic mannitol is used commonly to treat cerebral edema. Acetazolamide is also used commonly to treat refractory metabolic alkalosis. There is now considerable evidence for resistance to diuretics related to both acute adaptations, evidenced by diuretic braking phenomenon, and chronic adaptations related to increased expression of downstream channels and pumps to resorb the increased sodium delivered. Additionally, several
10
12. 13.

14.

15.

60378_CCC05_sw

9/10/07

2:47 PM

Page 11

October 2007
16. Nicholson ML, Baker DM, Hopkinson BR, et al. Randomized controlled trial of the effect of mannitol on renal reperfusion injury during aortic aneurysm surgery. Br J Surg 1996;83:1230-1233. 17. Holt SG, Moore KP. Pathogenesis and treatment of renal dysfunction in rhabdomyolysis. Intensive Care Med 2001;27:803-811. 18. Better OS, Stein JH. Early management of shock and prophylaxis of acute renal failure in traumatic rhabdomyolysis. N Engl J Med 1990;322:825-829. 19. Visweswaran P, Massin EK, Dubose TD, Jr. Mannitol-induced acute renal failure. J Am Soc Nephrol 1997;8:1028-1033. 20. MD Conult. Furosemide. Gold Standard, Inc., 2007. Available at: www. mdconsult.com. 21. Ellison DH. The physiologic basis of diuretic synergism: its role in treating diuretic resistance. Ann Intern Med 1991;114:886-894. 22. Dikshit K, Vyden JK, Forrester JS, et al. Renal and extrarenal hemodynamic effects of furosemide in congestive heart failure after acute myocardial infarction. N Engl J Med 1973;288:1087-1090. 23. Martin SJ, Danziger LH. Continuous infusion of loop diuretics in the critically ill: a review of the literature. Crit Care Med 1994;22:1323-1329. 24. Schuller D, Lynch JP, Fine D. Protocol-guided diuretic management: comparison of furosemide by continuous infusion and intermittent bolus. Crit Care Med 1997;25:1969-1975. 25. Mojtahedzadeh M, Salehifar E, Vazin A, et al. Comparison of hemodynamic and biochemical effects of furosemide by continuous infusion and intermittent bolus in critically ill patients. J Infus Nurs 2004;27:255-261. 26. Mehta RL, Pascual MT, Soroko S, et al. Diuretics, mortality, and nonrecovery of renal function in acute renal failure. JAMA 2002;288:2547-2553. 27. Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med 2000;342:1334-1349. 28. Prewitt RM, McCarthy J, Wood LD. Treatment of acute low pressure pulmonary edema in dogs: relative effects of hydrostatic and oncotic pressure, nitroprusside, and positive end-expiratory pressure. J Clin Invest 1981;67:409-418. 29. Simmons RS, Berdine GG, Seidenfeld JJ, et al. Fluid balance and the adult respiratory distress syndrome. Am Rev Respir Dis 1987;135:924-929. 30. Humphrey H, Hall J, Sznajder I, et al. Improved survival in ARDS patients associated with a reduction in pulmonary capillary wedge pressure. Chest 1990;97:1176-1180. 31. Allen GS, Coates NE. Pulmonary contusion: a collective review. Am Surg 1996;62:895-900. 32. Martin GS, Moss M, Wheeler AP, et al. A randomized, controlled trial of furosemide with or without albumin in hypoproteinemic patients with acute lung injury. Crit Care Med 2005;33:1681-1687. 33. Boldt J. Fluid management of patients undergoing abdominal surgery more questions than answers. Eur J Anaesthesiol 2006;23:631-640. 34. Brandstrup B, Tonnesen H, Beier-Holgersen R, et al. Effects of intravenous fluid restriction on postoperative complications: comparison of two perioperative fluid regimens: a randomized assessor-blinded multicenter trial. Ann Surg 2003;238:641-648. 35. Lobo DN, Bostock KA, Neal KR, et al. Effect of salt and water balance on recovery of gastrointestinal function after elective colonic resection: a randomised controlled trial. Lancet 2002;359:1812-1818. 36. Nisanevich V, Felsenstein I, Almogy G, et al. Effect of intraoperative fluid management on outcome after intraabdominal surgery. Anesthesiology 2005;103:25-32. 37. Arkilic CF, Taguchi A, Sharma N, et al. Supplemental perioperative fluid administration increases tissue oxygen pressure. Surgery 2003;133:49-55. 38. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001;345:1368-1377. 39. Kaissling B, Stanton BA. Adaptation of distal tubule and collecting duct to increased sodium delivery. I. Ultrastructure. Am J Physiol 1988;255:F1256-1268. 40. Wilcox CS, Mitch WE, Kelly RA, et al. Response of the kidney to furosemide. I. Effects of salt intake and renal compensation. J Lab Clin Med 1983;102:450-458. 41. Loon NR, Wilcox CS, Unwin RJ. Mechanism of impaired natriuretic response to furosemide during prolonged therapy. Kidney Int 1989;36:682-689. 42. Inoue M, Okajima K, Itoh K, et al. Mechanism of furosemide resistance in analbuminemic rats and hypoalbuminemic patients. Kidney Int 1987;32:198-203.

Contemporary Critical Care


43. Uchino S, Doig GS, Bellomo R, et al. Diuretics and mortality in acute renal failure. Crit Care Med 2004;32:1669-1677. 44. Nair P, Bihari D. Acute renal failure in the ICU in the 1990sanything goes? Intensive Care Med 1997;23:1193-1196. 45. Levy EM, Viscoli CM, Horwitz RI. The effect of acute renal failure on mortality. A cohort analysis. JAMA 1996;275:1489-1494. 46. Chertow GM, Levy EM, Hammermeister KE, et al. Independent association between acute renal failure and mortality following cardiac surgery. Am J Med 1998;104:343-348. 47. Shilliday IR, Quinn KJ, Allison ME. Loop diuretics in the management of acute renal failure: a prospective, double-blind, placebo-controlled, randomized study. Nephrol Dial Transplant 1997;12:2592-2596. 48. Denton MD, Chertow GM, Brady HR. Renal-dose dopamine for the treatment of acute renal failure: scientific rationale, experimental studies and clinical trials. Kidney Int 1996;50:4-14. 49. 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. 50. Gare M, Haviv YS, Ben-Yehuda A, et al. The renal effect of low-dose dopamine in high-risk patients undergoing coronary angiography. J Am Coll Cardiol 1999;34:1682-1688. 51. Vendegna TR, Anderson RJ. Are dopamine and/or dobutamine renoprotective in intensive care unit patients? Crit Care Med 1994;22:1893-1894. 52. Duke GJ, Briedis JH, Weaver RA. Renal support in critically ill patients: lowdose dopamine or low-dose dobutamine? Crit Care Med 1994;22:1919-1925. 53. Thadhani R, Pascual M, Bonventre JV. Acute renal failure. N Engl J Med 1996;334:1448-1460. 54. Stone GW, McCullough PA, Tumlin JA, et al. Fenoldopam mesylate for the prevention of contrast-induced nephropathy: a randomized controlled trial. JAMA 2003;290:2284-2291. 55. Morelli A, Ricci Z, Bellomo R, et al. Prophylactic fenoldopam for renal protection in sepsis: a randomized, double-blind, placebo-controlled pilot trial. Crit Care Med 2005;33:2451-2456. 56. Tumlin JA, Finkel KW, Murray PT, et al. Fenoldopam mesylate in early acute tubular necrosis: a randomized, double-blind, placebo-controlled clinical trial. Am J Kidney Dis 2005;46:26-34. 57. Landoni G, Zangrillo A, Franco A, et al. Long-term outcome of patients who require renal replacement therapy after cardiac surgery. Eur J Anaesthesiol 2006;23:17-22. 58. Heyman SN, Brezis M, Greenfeld Z, et al. Protective role of furosemide and saline in radiocontrast-induced acute renal failure in the rat. Am J Kidney Dis 1989;14:377-385. 59. Brezis M, Rosen S, Silva P, et al. Transport activity modifies thick ascending limb damage in the isolated perfused kidney. Kidney Int 1984;25:65-72. 60. Visweswaran P, Guntupalli J. Rhabdomyolysis. Crit Care Clin 1999;15: 415-428, ix-x. 61. Brown CV, Rhee P, Chan L, et al. Preventing renal failure in patients with rhabdomyolysis: do bicarbonate and mannitol make a difference? J Trauma 2004;56:1191-1196. 62. Solomon R, Werner C, Mann D, et al. Effects of saline, mannitol, and furosemide to prevent acute decreases in renal function induced by radiocontrast agents. N Engl J Med 1994;331:1416-1420. 63. Stevens MA, McCullough PA, Tobin KJ, et al. A prospective randomized trial of prevention measures in patients at high risk for contrast nephropathy: results of the P.R.I.N.C.E. Study. Prevention of Radiocontrast Induced Nephropathy Clinical Evaluation. J Am Coll Cardiol 1999;33:403-411. 64. Gerlach AT, Pickworth KK. Contrast medium-induced nephrotoxicity: pathophysiology and prevention. Pharmacotherapy 2000;20:540-548. 65. Smith HP, Kelly DL, Jr., McWhorter JM, et al. Comparison of mannitol regimens in patients with severe head injury undergoing intracranial monitoring. J Neurosurg 1986;65:820-824. 66. Schwartz ML, Tator CH, Rowed DW, et al. The University of Toronto head injury treatment study: a prospective, randomized comparison of pentobarbital and mannitol. Can J Neurol Sci 1984;11:434-440. 67. The Brain Trauma Foundation. Guidelines for the Management of Severe Traumatic Brain Injury: Management and Prognosis of Severe Traumatic Brain Injury. New York: The Brain Trauma Foundation, 2000. 68. McManus ML, Soriano SG. Rebound swelling of astroglial cells exposed to hypertonic mannitol. Anesthesiology 1998;88:1586-1591.

11

60378_CCC05_sw

9/10/07

2:47 PM

Page 12

Contemporary Critical Care

October 2007

CME QUIZ: Volume 5, Number 5


To earn CME credit, you must read the CME article and complete the quiz on the enclosed answer form, answering at least seven of the 10 quiz questions correctly. Select the best answer and use a blue or black pen to completely fill in the corresponding box on the enclosed answer form. Please indicate any name and address changes directly on the answer form. If your name and address do not appear on the answer form, please print that information in the blank space at the top left of the page. Make a photocopy of the completed answer form for your own files and mail the original answer form in the enclosed postage-paid business reply envelope. Your answer form must be received by Lippincott CME Institute, Inc., by September 30, 2008. For more information, call (800) 787-8981. Online quiz instructions: To take the quiz online, go to http://cme.LWWnewsletters.com, and enter your username and password.Your username will be the letters LWW (case sensitive) followed by the 12-digit account number on your mailing label. You may also find your account number on the paper answer form mailed with your issue. Your password will be 1234; this password may not be changed. Follow the instructions on the site. You may print your official certificate immediately. Please note: Lippincott CME Institute, Inc., will not mail certificates to online participants. Lippincott Continuing Medical Education Institute, Inc., is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Lippincott Continuing Medical Education Institute, Inc., designates this educational activity for a maximum of 2 AMA PRA Category 1 Credits. Physicians should only claim credit commensurate with the extent of their participation in the activity. 1. Which one of the following diuretics does not have a site of action from within the tubule? A. Furosemide B. Spironolactone C. Acetazolamide D. Metolazone 2. Carbonic anhydrase inhibitors act on the A. proximal tubule B. glomerulus C. proximal tubule and thick ascending limb of the loop of Henle D. proximal tubule and thin loop of Henle 3. Which one of the following diuretics generally is considered a weak natruretic and diuretic, yields alkaline urine, and may cause metabolic acidosis? A. Mannitol B. Spironolactone C. Amiloride D. Acetazolamide 4. One of the signs of mannitol overdose in the patient with renal insufficiency is A. pulmonary edema and fluid overload B. cardiac arrhythmia C. metabolic acidosis and hyperglycemia D. hepatic failure 5. Loop diuretics act on the A. sodium/potassium exchanger in the distal convoluted tubule B. sodium-potassium-2 chloride pump in the thick ascending limb of the loop of Henle C. hydrogen/potassium transporter in the proximal convoluted tubule D. sodium channel in the collecting tubule 6. Which one of the following is a mechanism of diuretic resistance? A. Downregulation of thiazide-sensitive pumps in the distal convoluted tubule B. Increased secretion of diuretic into the tubule C. Increased binding of diuretic to proteins in the lumen of the tubule D. Use of intermittent dosing of diuretic versus continuous intravenous infusion 7. Which one of the following diuretics has an action downstream of the action of furosemide and thus can act synergistically for a bigger diuretic response? A. Acetazolamide B. Ethacrynic acid C. Dopamine D. Hydrochlorothiazide 8. Which one of the following agents is typically used in the treatment of contrast nephropathy? A. Furosemide B. Mannitol C. Spironolactone D. None of the above 9. In which one of the following disease processes is the use of thiazide diuretics contraindicated? A. Hypercalcemia B. Hyperkalemia C. Congestive heart failure D. Hypertension 10. Which one of the following adaptive mechanisms augments the effect of thiazide diuretics in patients taking loop diuretics on a chronic basis? A. Increased concentration of thiazides in the tubule B. Synergistic binding of the loop diuretic and the thiazide diuretic C. Hypertrophy of the tubule cells and increased number of sodium/potassium exchangers in the distal convoluted tubule D. Inhibition of the amiloride-sensitive sodium channel causing efflux of sodium out of the tubule

12