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Abstract

  1. Top of page
  2. Abstract
  3. Sodium and water handling and diuretic activity
  4. Diuretic resistance
  5. Mechanisms of diuretic resistance in heart failure
  6. Management of diuretic resistance
  7. Inotropic support
  8. Conclusion
  9. References

Congestive heart failure is a complex clinical hemodynamic disorder characterized by chronic and progressive pump failure and fluid accumulation. Although the overall impact of diuretic therapy on congestive heart failure mortality remains unknown, diuretics remain a vital component of symptomatic congestive heart failure management. Over time, sodium and water excretion are equalized before adequate fluid elimination occurs. This phenomenon is thought to occur in one out of three patients with congestive heart failure on diuretic therapy and is termed diuretic resistance. In congestive heart failure, both pharmacokinetic and pharmacodynamic alterations are thought to be responsible for diuretic resistance. Due to disease chronicity, symptomatic management is vital to improved quality of life and enhancing diuretic response is therefore pivotal.

Congestive heart failure (CHF) is a complex clinical hemodynamic disorder characterized by chronic and progressive pump failure. As CHF progresses, the myocardium becomes incapable of meeting tissue metabolic demands, and compensatory mechanisms, specifically the activation of the reninangiotensin-aldosterone system (RAAS) and the sympathetic nervous system, attempt to correct the metabolic imbalance and normalize organ perfusion. 1–3 Sodium and water retention are entwined with the RAAS. As a result, attenuated cardiac output and renal perfusion seen with chronic heart failure may lead to decreased sodium delivery to the macula densa cells in the nephron, stimulating renin release. This, in turn, leads to the activation of the RAAS, with efferent arteriolar vasoconstriction secondary to angiotensin II production, peripheral vasoconstriction, and aldosterone secretion, resulting in sodium and water retention.1–4

A cardinal manifestation of CHF is fluid retention and fluid accumulation that causes congestion of the lungs, liver, intestines, and peripheral compartments. Treatment with diuretics is quite effective in relieving the congestive symptoms that occur due to excess fluid accumulation.5,6 However, the overall impact of diuretics on prognosis remains unknown, as outcome trials evaluating solely diuretic-related benefits are not available. To date, spironolactone is the only diuretic that has been shown, in combination with standard therapy, to decrease morbidity and mortality, and these cardioprotective effects of spironolactone are thought not to be directly related to its diuretic actions, but rather to its blocking of the action of aldosterone at cellular and myocardial levels. 7 Despite definitive diuretic outcome data, the majority of patients in large morbidity and mortality trials were on diuretic therapy as part of their standard treatment regimen, demonstrating that diuretics are a vital component in CHF management.8–11

Sodium and water handling and diuretic activity

  1. Top of page
  2. Abstract
  3. Sodium and water handling and diuretic activity
  4. Diuretic resistance
  5. Mechanisms of diuretic resistance in heart failure
  6. Management of diuretic resistance
  7. Inotropic support
  8. Conclusion
  9. References

Sodium and water regulation by the kidney is dependent on arterial volume, which constitutes about 1.25% of the total body volume.4,12 In nonedematous patients, expansion of the extracellular fluid volume triggers the kidney to excrete excess sodium and water, reverting fluid status to its origin. In certain edematous states, such as CHF, the homeostatic mechanism is altered and retention of sodium and water persists, despite extracellular fluid volume expansion.12 In addition, the maximum attainable amount of sodium excretion may be reduced in CHF, lessening the degree of natriuresis.13,14

In patients with normal renal function, 99% of the filtered sodium is reabsorbed.14 Approximately 66% of sodium is reabsorbed in the proximal tubule of the nephron, with an additional 25% being reabsorbed in the thick ascending limb of the loop of Henle. Nephron segments past the thick ascending limb do not maintain a prominent reabsorptive capacity.15

After proximal tubule excretion, loop diuretics exert their action in the lumen of the thick ascending limb of the loop of Henle. Inhibition of the Na+ K+ 2Cl cotransport system causes sodium, chloride, potassium, and hydrogen ions to be excreted in the urine. Diuretic efficacy is directly related to urinary excretion rates, rather than to plasma drug concentrations.16

It has been demonstrated that continuous infusion of loop diuretics produces greater natriuresis than intermittent doses, despite identical amounts of drug at the site of action.17 A good adjudicator of this response is the time course of delivery of loop diuretics in the proximal tubule.18 Loop diuretic effectiveness is related not only to the amount of drug at the site of action but also to the amount of time the drug remains at the site of action. Due to the sigmoidal shape of the dose-response curve, a threshold or dose-response quantity of drug must be reached.19 If the threshold quantity is not achieved, diuretic efficacy is curtailed, despite large amounts of total drug in the urine.20 Furthermore, the natriuretic activity of loop diuretics is related to the amount of sodium present in the loop of Henle. Decreased sodium delivery to that part of the nephron, as seen with renal insufficiency and/or decreased renal perfusion due to low cardiac output, will diminish natriuresis.14

Diuretic resistance

  1. Top of page
  2. Abstract
  3. Sodium and water handling and diuretic activity
  4. Diuretic resistance
  5. Mechanisms of diuretic resistance in heart failure
  6. Management of diuretic resistance
  7. Inotropic support
  8. Conclusion
  9. References

Although difficult to quantify, diuretic resistance is thought to occur in one of three patients with CHF. Heart failure represents the most common clinical situation in which diuretic resistance is observed. In mild CHF, diuretic resistance is not commonly encountered, as long as renal function is preserved. However, in moderate and severe CHF patients, diuretic resistance occurs more frequently and often becomes a clinical problem.21,22

Despite its frequency, the term “diuretic resistance” remains inadequately defined. In general, failure to decrease the extracellular fluid volume despite liberal use of diuretics is often termed diuretic resistance. In clinical settings, diuretic resistance in edematous patients has been defined as a clinical state in which sodium intake and excretion are equalized before adequate elimination of fluid occurs.22 More technically, diuretic resistance has been expressed as a fractional sodium excretion (FENa+) of <0.2%. (FENa+) represents the amount of sodium excreted (mmol/time) as a percentage of filtered load [plasma Na+ concentration × glomerular filtration rate].)23 Finally, Epstein et al.24 defined diuretic resistance as a failure to excrete at least 90 mmol of sodium within 72 hours of a 160 mg oral furosemide dose given twice daily.

Mechanisms of diuretic resistance in heart failure

  1. Top of page
  2. Abstract
  3. Sodium and water handling and diuretic activity
  4. Diuretic resistance
  5. Mechanisms of diuretic resistance in heart failure
  6. Management of diuretic resistance
  7. Inotropic support
  8. Conclusion
  9. References

Physiologic alterations in CHF, such as changes in absorption, distribution, metabolism, and elimination of drugs, can indeed alter loop diuretic pharmacokinetics; however, these effects do not fully explain diuretic resistance.25 If pharmacokinetic alterations were solely responsible for diuretic resistance, then increasing the dose or altering the route of administration should surmount the resistance. Instead, a parallel between pharmacokinetic and pharmacodynamic changes affecting the time course of delivery may clarify diuretic resistance. Enhancing the diuretic response should be the focal point.

Haller et al.26 described a 29-year-old patient with dilated cardiomyopathy who was refractory to diuresis despite high-dose furosemide (250 mg orally three times a day). The authors concluded that diuretic resistance was a result of the combination of cardiac pump failure, hyperaldosteronism, and dietary indiscretion.

Delayed and weakened diuresis in patients with CHF may be secondary to gastrointestinal edema, even though diuretic bioavailability is unaltered.20 Referring to the principle of time course of delivery of diuretics, the rate of absorption is lessened and the time to achieve a threshold dose is delayed in patients with heart failure as compared to healthy volunteers, translating into diuretic resistance.27,28

In CHF and renal insufficiency, insufficient concentrations of diuretics intraluminally may cause diuretic resistance. This can occur due to decreased plasma blood flow and impaired secretion by the proximal tubule.20,29

Drug-drug interactions have been associated with diuretic failure and, ultimately, resistance. Nonsteroidal anti-inflammatory agents (NSAIDs) may alter renal hemodynamics by decreasing renal blood flow.20 In severe heart failure, prostaglandins play an important role in renal perfusion. Prostaglandins promote sodium and water excretion, and prostaglandin inhibition with aspirin or other NSAIDs has been shown to attenuate diuretic efficacy. Hall30 noted an impressive reduction in diuretic requirements when daily administration of as small a dose as 100 mg of aspirin was stopped.

In healthy patients, the RAAS may be reflexively activated by acute administration of loop diuretics, further increasing sodium and water retention and thus curtailing the diuretic effect.31 In severe CHF, this should not be prominent because loop diuretics usually do not further increase neurohormones in a pre-existing neurohormonally activated state. Additionally, the use of medications that inhibit the RAAS, as is often done in patients with CHF, should offset the effects of any further activation of the RAAS with acute administration of loop diuretics.32

Physiologically, diuretic effects may be overcome with high sodium intake, misleading the clinician to determine diuretic resistance. Dietary noncompliance, although not a form of diuretic resistance, can be associated with diuretic failure. Initially, loop diuretics result in a pronounced natriuresis; however, with dietary indiscretion, avid sodium reabsorption occurs post-diuresis.33 If a net negative sodium balance is not attained, dietary sodium negligence should be investigated.

It has also been suggested that long-term administration of loop diuretics, as seen in CHF, may be associated with pharmacologic changes within the nephron, resulting in heightened response to sodium. Data in hypertensive patients suggest that blocking sodium reabsorption in the loop of Henle results in larger amounts of sodium delivery to the early distal tubule causing cell hypertrophy.31 Cell hypertrophy of the distal convoluted tubule results in augmented sodium reabsorption and subsequent diminished natriuretic response.

Management of diuretic resistance

  1. Top of page
  2. Abstract
  3. Sodium and water handling and diuretic activity
  4. Diuretic resistance
  5. Mechanisms of diuretic resistance in heart failure
  6. Management of diuretic resistance
  7. Inotropic support
  8. Conclusion
  9. References

Before diuretic resistance is confirmed, CHF management must be optimized. General approaches include attenuating neurohormonal compensation with combinations of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, β blockers, and spironolactone; improving contractility with inotropes (when clinically necessary in the acute decompensated state); regulating dietary fluid and sodium intake; avoiding NSAIDs; and bed rest.34,35 Elucidating the resistance mechanism is the answer to optimal treatment. Common clinical approaches to diuretic resistance include sequential diuretic blockade and continuous infusion loop diuretic therapy (CILT).

One mechanism for overcoming diuretic resistance is by sequential nephron blockade.14 Concurrent use of diuretics acting upon different segments of the nephron and loop diuretics with either proximal or distal tubule diuretics may produce an additive or synergistic diuretic response.36 For example, acetazolamide inhibits sodium reabsorption, proximally causing increased sodium concentrations in the loop of Henle whereby loop diuretics may exert their natriuretic action. With short-term combination acetazolamide and furosemide, diuretic resistance can be surmounted. However, this strategy is short-lived due to the risk of metabolic acidosis with long-term acetazolamide therapy. Another approach would be blockage of sodium reabsorption at the distal tubule by coadministering a thiazide (hydrochlorothiazide) or a thiazide-like (metolazone) diuretic that may restore diuresis in resistant states.31 Concurrent administration of longer-acting distal tubule diuretics prevents post-loop diuretic sodium reabsorption. The distal tubule diuretics prevent the adaptive process of cell hypertrophy that occurs with long-term loop diuretic use. Utilization of collecting tubule diuretics, such as spironolactone, alone or in combination with loop diuretics may be more effective when circulating aldosterone concentrations are increased (which is usually the case in more advanced CHF, such as New York Heart Association classes III and IV).7

As previously reviewed, the dose response to diuretic therapy in patients with CHF is altered, often resulting in diuretic resistance.13,21,22 Although large, well designed studies are not available, small studies and case reports evaluating the use of CILT, particularly with furosemide, suggest that CILT is an effective strategy to combat resistant edema in CHF.29,37–40 From available data, the administration of loop diuretics (furosemide in particular) by continuous infusion may provide greater diuresis and natriuresis than bolus administration and can be considered a therapeutic option for patients with moderate to severe CHF.

Due to their short duration of action, intermittent doses of loop diuretics can produce rebound sodium retention amid dosing intervals. Similar to sequential blocking, CILT may curtail rebound sodium reabsorption.41 The usefulness of CILT has been demonstrated by Lahav et al.,37 who concluded that preceding a bolus dose, continuous infusion of furosemide produced constant and significant diuresis and natriuresis, as compared to intermittent administration.

One of the earliest clinical reports of CILT was published by Lawson et al.38 In the setting of refractory edema (inadequate diuretic response after 120 mg oral furosemide), 10 CHF patients were administered furosemide infusions titrated to clinically adequate diuresis. Infusion doses ranged from 4–16 mg/hour, and satisfactory response was achieved in all patients evaluated. Although only an observational study with many limitations, this early evaluation provided the foundation for CILT in CHF.

Subsequent studies in patients with CHF, diuretic resistance, and/or concomitant renal dysfunction validated the results of Lawson et al. These studies evaluated the use of continuous-infusion furosemide (48–4000 mg/24 hr) to more traditional oral (120–2500 mg/24 hr) and intravenous bolus (120–1000 mg/24 hr) administration.29,37,39,40 The outcome of these studies demonstrated that continuous-infusion furosemide with or without a loading dose resulted in amplified urine output and natriuresis without increased side effects.29,37,39,40 Frequently reported side effects were mild hypomagnesemia and hypokalemia that were managed with replacement therapy. Although not critically evaluated by audiometric studies, temporary hearing loss and tinnitus occurred more frequently with high-dose bolus administration than with other administration modes. This finding suggested that ototoxicity is mainly due to high, rapid peak concentrations observed with large bolus doses. Despite study limitations, the literature supports the relative safety and efficacy of CILT at daily doses up to 4000 mg.

None of the above studies of CHF addresses standard dose regimens, making evaluations and recommendations of CILT difficult. However, Schuller et al.42 observed that protocol-guided, continuous-infusion furosemide was an effective and reasonable strategy for managing fluid overload in intensive care patients. Published data utilizing protocol-guided therapy in patients with CHF are not readily available, leaving many unanswered questions as to the optimal dosing strategy.

Data evaluating the use of continuous infusion of torsemide and bumetanide are limited.43–45 Conceptually, both agents should be effective and well tolerated; however, severe musculoskeletal side effects have occurred with continuous infusion of bumetanide. This may limit the utility of bumetanide in settings where a high dose is required.43

Inotropic support

  1. Top of page
  2. Abstract
  3. Sodium and water handling and diuretic activity
  4. Diuretic resistance
  5. Mechanisms of diuretic resistance in heart failure
  6. Management of diuretic resistance
  7. Inotropic support
  8. Conclusion
  9. References

In critical illness and CHF, dobutamine and renal dose dopamine have been demonstrated to improve both cardiorenal hemodynamics and renal function. 46–48 However, few studies have evaluated the effectiveness of this strategy in diuretic resistance and its efficacy is uncertain due to conflicting results.49,50 In addition, there is some concern over the increased mortality observed with the use of these agents in advanced stages of heart failure.51 Finally, most of the information available remains anecdotal, and the true efficacy of inotropes in diuretic resistance remains to be fully elucidated.

Conclusion

  1. Top of page
  2. Abstract
  3. Sodium and water handling and diuretic activity
  4. Diuretic resistance
  5. Mechanisms of diuretic resistance in heart failure
  6. Management of diuretic resistance
  7. Inotropic support
  8. Conclusion
  9. References

Fluid accumulation producing edematous states is a common problem encountered in patients with CHF. Management of the edematous state usually includes diuresis in combination with fluid and sodium restriction. However, this standard approach often fails as CHF progresses and diuretic resistance occurs. In the management of diuretic resistance, appropriate attention should first be given to optimizing CHF therapy utilizing ACE inhibitors, β blockers, angiotensin receptor blockers, spironolactone, and digoxin in combination with sodium and fluid restriction. Strategies to combat diuretic resistance include sequential nephron blockade with combination loop and thiazide or thiazide-like diuretics. In addition, favorable outcomes have been demonstrated with continuous infusion of loop diuretics. From the available literature, it could be recommended that sequential nephron blockade with a combination of furosemide and metolazone or CILT is appropriate. As most of the CILT literature concerns furosemide, a bolus dose of 40–80 mg of intravenous furosemide followed by a continuous infusion of 0.05–0.1 mg/kg/hr, titrated hourly to a net fluid balance of at least −1 mL/kg, may prove useful.

Finally, new therapeutic options in the management of CHF are being evaluated. These new therapeutic options—endothelin antagonists, dual angiotensin-converting enzyme-endopeptidase or vasopeptide inhibitors, and recombinant preparations of human brain natriuretic peptide—may offer further approaches to the management of CHF as well as diuretic resistance.

References

  1. Top of page
  2. Abstract
  3. Sodium and water handling and diuretic activity
  4. Diuretic resistance
  5. Mechanisms of diuretic resistance in heart failure
  6. Management of diuretic resistance
  7. Inotropic support
  8. Conclusion
  9. References