All concepts, explanations, trials, and studies have been re-written in plain English and may contain errors. I am not a doctor ----------------------------------------------------------- NOTE: You can make the print bigger with the font button on your browser! (It's usually a big "A") ----------------------------------------------------------- DIURETIC RESISTANCE In healthy people, an increase in extra fluid inside the body triggers the kidneys to get rid of extra sodium and water. Heart failure screws this whole process up, and edema (see chfpatients.com/faq/edema.htm) results. In HF, the RAS (see chfpatients.com/text/RAS.txt) is too active. Swelling from sodium and water retention are linked to the RAS. Reduced heart output can lead to reduced kidney function. That reduces sodium delivery to cells in the kidneys, stimulating release of renin. Renin encourages over-activation of the RAS, which leads to arteries tightening up (vasoconstriction) from too much angiotensin 2 and aldosterone. All this causes sodium and water retention. Also, if you have CHF, your body probably cannot get rid of as much sodium as a healthy body. In patients with normal kidney function, 99% of filtered sodium is reabsorbed. About 2/3 of this sodium is reabsorbed in a part of the kidney called the proximal tubule of the kidney's nephron. The rest is reabsorbed in a part of the kidney called the loop of Henle. After sodium is passed on by the proximal tubule, loop diuretics act on it in the inside passage of the loop of Henle - thus the name "loop" diuretics. These drugs inhibit the transport system for sodium, potassium, and chloride. This causes sodium, chloride, potassium, and hydrogen ions to be eliminated through the urine. In other words, regardless of how much diuretic you take, it won't help unless you are peeing a lot! WHAT STOPS DIURETICS FROM WORKING LIKE THEY SHOULD? Loop diuretic effectiveness is not just from the amount of drug that makes it to the kidney, but also from how long the drug stays there to do its thing. This means that a certain amount of drug must be used before it is truly effective. If this "threshold" dose is not reached, diuretics won't work as well, even with high doses of drug in the body. The effectiveness of loop diuretics is also related to the amount of sodium in the kidney's loop of Henle. If there is no sodium to be eliminated in the area where the drug does its work, the drug is not going to help. Reduced blood flow to the kidneys can reduce the amount of sodium delivered to the loop of Henle. WHAT IS DIURETIC RESISTANCE? Diuretic resistance is thought to happen in one of 3 CHFers. In mild CHF, this problem is rarely seen. In moderate and severe CHF, diuretic resistance happens more often. Failure to get rid of edema despite high dose diuretic use is often called diuretic resistance. Epstein defined diuretic resistance as failure to pee out at least 90 mmol of sodium within 72 hours of a 160 mg oral furosemide dose given twice daily. Technically, diuretic resistance is fractional sodium excretion (FENa+) of less than 0.2%. (FENa+) is the amount of sodium excreted (mmol/time) as a percentage of filtered load (blood Na+ concentration 5 times glomerular filtration rate). WHAT CAUSES DIURETIC RESISTANCE? One report described a 29 year old DCM patient who stayed swollen despite 250 mg Lasix 3 times a day. The author discovered that this was a result of a weakened heart - AND - not following a low-sodium diet. Diuretic effects may be offset by high sodium intake. Not following a low-sodium diet is often linked to diuretic failure. At first, loop diuretics may work very well, but with too-high sodium diet intake, sodium reabsorption occurs quickly. Weak diuretic effectiveness may be partly from edema in the stomach and intestines. This reduces the absorption of diuretic pills since they are absorbed in that area. Lots of fluid there prevents full absorption. Torsemide is absorbed better than Lasix is such patients. Drug-drug interactions have also been linked to diuretic failure. NSAIDs can reduce kidney blood flow. In severe CHF, prostaglandins may play a part. Prostaglandins encourage your body to pee out sodium and water, so inhibiting them with aspirin or other NSAIDs can reduce diuretic effectiveness. Hall noted an impressive reduction in diuretic requirements when people taking only 100mg aspirin per day stopped the aspirin. Studies of high blood pressure patients suggest that blocking sodium reabsorption in the loop of Henle (as in loop diuretic use) causes larger amounts of sodium to enter the early distal tubule, causing cell enlargement. Such cell enlargement causes more sodium reabsorption - less diuretic effect. WHAT TO DO ABOUT IT? Before diuretic resistance is diagnosed, CHF treatment must be maxed out. This means combinations of ACE inhibitors, ARBs, beta-blockers, possibly Inspra, and spironolactone with inotropes if necessary (see chfpatients.com/inotropes.htm) ; restricting fluid and sodium intake ; and avoiding NSAIDs. Managing CHFers with diuretic resistance may include using multiple diuretics and CILT - Continuous Infusion Loop Diuretic Therapy. You can use different diuretics that act on different parts of the kidney to get more effect. For example, acetazolamide inhibits sodium reabsorption. This increases sodium levels in the loop of Henle where loop diuretics work so there is more sodium in the right place for diuretics to get rid of it, taking extra water with it. However, this strategy is short-term due to the risk of metabolic acidosis with long-term acetazolamide use. Another way is to block sodium reabsorption at the distal tubule by giving a thiazide or thiazide-like (metolazone) diuretic. This may prevent sodium re- absorption after the loop diuretic does its thing. This may also prevent the cell enlargement that can occur with long-term loop diuretic use. In advanced heart failure, aldosterone levels in the blood may be high. Diuretics like spironolactone, with loop diuretics, help fight this "hyperaldosteronism." IV DIURETIC USE Small studies - especially using furosemide - suggest that CILT is effective. Giving furosemide by continuous infusion (IV) may be a good option for CHFers suffering diuretic resistance. Due to their short time of action, intermittent IV loop diuretic doses may cause rebound sodium retention between doses. CILT prevents this. CILT's usefulness was shown by Lahav, who concluded that giving continuous IV furosemide gave significant diuretic action compared to intermittent dosing. An early clinical report by Lawson included 10 CHFers who showed little response to 120 mg oral furosemide, so IV furosemide was used. IV dose ranged from 4 to 16 mg per hour. All patients got good results. Later studies confirmed the effect. Those trials compared continuous IV furosemide at 48 to 4000 mg per 24 hours to oral Lasix at 120 to 2500 mg per 24 hours. They also compared continuous IV Lasix to a one-time IV "bolus" dose at 120 to 1000 mg per 24 hours. These studies showed that continuous IV furosemide with or without a big first "loading" dose increased urination without increased side effects. Reported side effects included mild reduction in magnesium and potassium levels. Temporary hearing loss and ringing in the ears happened more often with large single IV doses than with other dosing methods. The medical literature supports the relative safety and effectiveness of CILT at daily doses up to 400 mg per 24 hours. There are, however, many unanswered questions about best dose and timing. Information on continuous IV torsemide (Demadex) and bumetanide (Bumex) is limited. Theoretically, both should be effective and well tolerated. However, severe musculoskeletal side effects have been seen with continuous IV Bumex. IN CONCLUSION In managing diuretic resistance, CHF therapy should first be maximized using ACE inhibitors, beta-blockers, ARBs, Inspra, spironolactone, and digoxin in combination with sodium and fluid intake restrictions. Strategies to combat diuretic resistance include using combinations of loop and thiazide (or thiazide-like) diuretics. Continuous infusion of loop diuretics may be another option. From the available literature, a first bolus dose of 40 to 80 mg of IV furosemide followed by continuous infusion of 0.05 to 0.1 mg/kg/hr may prove useful. Title: Diuretic Resistance and Strategies to Overcome Resistance in Patients With Congestive Heart Failure Editors: Susan Ravnan, Marcus Ravnan, Prakash Deedwania, Domenic Sica, Prakash Deedwania Source: CHF 8(2):80-85, 2002 Source: http://www.medscape.com/viewarticle/433219_print.