Furosemide Continuous Infusion Was Stopped on 8th June
Continuous Diuretic Infusion
For hospitalized patients who are resistant to diuretic therapy, another approach is to infuse diuretics continuously. Continuous diuretic infusions have several potential advantages over bolus diuretic administration. First, because they avoid troughs of diuretic concentration, they prevent intermittent periods of positive NaCl balance (postdiuretic NaCl retention). When short acting diuretics, such as the loop diuretics, are administered by bolus infusion or by mouth once or twice a day, a period of natriuresis and diuresis lasting about 6 hr ensues. When diuretic serum concentrations decline, urine NaCl concentrations also decline to levels below basal (reviewed in Chapter IVB1 and above). Because 24-nr renal NaCl excretion is the composite of the natriuretic and anti-natriuretic periods, negative salt balance may be limited, especially when dietary salt intake is high. Clearly, a constant infusion that leads to constant serum diuretic concentrations will minimize periods of Na retention and might be expected to be more efficacious. Second, constant infusions appear to be more efficient than bolus therapy. In one study of patients with chronic renal failure a continuous infusion of bumetanide was 32% more efficient than a bolus of the same dose when the amount of NaCl excreted per milligram of administered diuretic was compared [36]. In a crossover study of nine patients with NYHA class III—IV congestive heart failure (see Fig. 8), 60-80 mg/day was more effective when given as a continuous infusion following a loading dose (30-40 mg) than when given as boluses three times daily (30-50 mg/ dose). Similar relations probably hold for other loop diuretics, although the efficiency ratios may depend in part in the half-lives of the drugs. Bumetanide has the shortest half-life, torsemide has a longer half-life, and furosemide is in between. It would be reasonable to expect that the ratio of the efficiency of bolus versus continuous infusion would be highest for torsemide and lowest for bumetanide. Thus, bolus torsemide may prove to be an alternative approach to continuous infusion in some patients. Third, some patients who are resistant to large doses of diuretics given by bolus have responded to continuous infusion [18, 41]. Most studies of efficacy in diuretic resistant patients have not compared strictly equivalent doses or administered them in a randomized manner. Yet several studies do provide suggestive evidence that continuous infusion may elicit diuresis in some patients resistant to large boluses. Van Meyel et ah, for example, showed satisfactory natriuresis during constant infusion in patients with congestive heart failure who had failed to respond to 250 mg furosemide given as a bolus [41], although the total daily doses of furosemide in that study were quite high. Fractional Na excretion varied in a linear manner with daily furosemide dose between 480 and 3840 mg/day. Fourth, diuretic response can be titrated; in the intensive care unit where obligate solute and fluid administration must be balanced by solute and fluid excretion, control of NaCl and water excretion can be obtained by tritration of diuretic dose. While this is important in every postoperative patient, it is especially important in patients who are hemodynamically compromised. Magovern and Magovern reported successful diuresis of hemodynamically compromised patients after cardiac surgery by continuous furosemide infusion [25]. Because continuous in-
FIGURE 8. Comparison of continuous infusion vs bolus furosemide treatment of patients with chronic congestive heart failure. The filled circles indicate Na excretion during infusion of 2.5-3.3 mg/hr following a loading dose of 30-40 mg furosemide. The open circles depict urinary Na excretion following 30-40 mg furosemide every 8 hr. Total urine output was 18.5% higher during continuous infusion than bolus administration. From [22].
FIGURE 8. Comparison of continuous infusion vs bolus furosemide treatment of patients with chronic congestive heart failure. The filled circles indicate Na excretion during infusion of 2.5-3.3 mg/hr following a loading dose of 30-40 mg furosemide. The open circles depict urinary Na excretion following 30-40 mg furosemide every 8 hr. Total urine output was 18.5% higher during continuous infusion than bolus administration. From [22].
fusion of loop diuretics may reduce the sympathetic discharge, activation of the renin/angiotensin system, and sudden massive solute and fluid losses that may occur following a large intravenous bolus (discussed above), continuous infusions may be the preferred mode of therapy for hemodynamically unstable patients in need of diuresis. Finally, drug toxicity from loop diuretics, such as ototoxicity (observed with all loop diuretics) and myopathies (with bumetan-ide), appear to be less common when the drugs are administered as continuous infusions. In fact, total daily furosemide doses exceeding 2 g have been tolerated well when administered over 24 hr. Dosage regimens for continuous intravenous diuretic administration are shown in Table 3. Of note, although natri-
| Infusion rate | ||
| Bolus (mg) | (mg/hr)" | |
| Furosemide | 20-80 | 2-80 |
| Bumetanide | 1 | 0.2 |
| Torsemide | 25 | 1-50 |
a In general, the lowest dose range for continuous infusion will be effective in patients with well preserved renal function and who have not previously been treated with loop diuretics. The highest doses should be reserved for patients with severe renal insufficiency and profound diuretic resistance. At high continuous doses, toxicity may develop, especially during furosemide infusion in patients with impaired renal function. Doses derived from [27].
uretic efficacy may vary linearly with loop diuretic dose, high infusion rates (2 g per day of furosemide, for example) might lead to toxic serum concentrations if continued for prolonged periods. This is especially true in patients with renal failure, in whom larger doses are often required to initiate diuresis. Special care should be taken when administering large daily doses of loop diuretics over prolonged periods; in patients with renal failure, a drug such as torsemide that is cleared, in part, by hepatic metabolism, may be preferred when high or prolonged therapy is attempted.
Most patients who were thought to be resistant to diuretics respond to one of these approaches. Side-effects of diuretic therapy such as prerenal azotemia and metabolic alkalosis, rather than resistance to diuretic therapy, usually limit the ability to reduce extracellular fluid volume further. Controlling extracellular fluid volume without provoking complications requires a thorough understanding of diuretic physiology and a commitment to using diuretics rationally and carefully. When medical diuresis fails despite addressing considerations discussed above, plasma ultrafiltration may be considered. Ultrafiltration, with or without accompanying hemodialysis, effectively removes extracellular fluid and many clinicians have observed surprisingly beneficial effects of ultrafiltration in diuretic resistant patients. Recent data suggest a possible rationale for the use of ultrafiltration in some diuretic resistant patients. Agostoni et al. [1] randomized patients with congestive heart failure to volume removal by ultrafiltration or furosemide. Regimens were devised to remove equal amounts of fluid. Whereas both approaches achieved the same volume depletion acutely, volume contraction was maintained significantly better following ultrafiltration than following medical diuresis (see Fig. 9). The secondary deterioration in extracellular fluid volume following furosemide treatment was associated with a brisk rise in renin and angiotensin II secretion. It may be speculated that
Baseline id 2d 3d 4d 1m
Baseline 1d 2d 3d 4d 1m 3m
FIGURE 9. Effects in patients with congestive heart failure of bolus furosemide (filled circles) vs plasma ultrafiltration (open circles) on body weight and plasma renin activity (PRA). The n in each group was 8. The differences were statistically significant. Data from [1].
Baseline id 2d 3d 4d 1m
Baseline 1d 2d 3d 4d 1m 3m
FIGURE 9. Effects in patients with congestive heart failure of bolus furosemide (filled circles) vs plasma ultrafiltration (open circles) on body weight and plasma renin activity (PRA). The n in each group was 8. The differences were statistically significant. Data from [1].
volume removal with loop diuretics, which stimulate renin secretion directly via their effects at the macula densa, leads to a more robust counterregulatory hormonal response that produces more rapid fluid reaccumulation. These interesting results highlight the important role that counterregulatory hormones play in attenuating the effectiveness of diuretics and suggest that ultrafiltration may have a role in the rare patient with extracellular fluid volume overload who cannot be controlled using one of the approaches described above.
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