Criteria abstracted from The Users' Guide to Medical Literature, from the Health Information Research Unit and Clinical Epidemiology and Biostatistics, McMaster University

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Article Reviewed:

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Aminophylline in the treatment of fluid overload

Pretzlaff RK, Vardis RJ, Pollack MM.

Crit Care Med 1999:27:2782-85. [abstract]

Reviewed by Patricia Jines, MD Rick Harrison, MD; UCLA

Review posted May 9, 2000

I. What is being studied?:

The study objective:

Evaluate aminophylline use as an adjunct diuretic in the treatment of fluid overload in critically ill children.

The study design:

Prospective controlled clinical trial. This is a repeated measures design in which subjects serve as their own controls.

The patients included:

Eight patients between the ages of 1 month to 6 years admitted to the pediatric ICU with a urinary catheter and a need for improved diuresis were included. A need for improved diuresis was defined as at least two of the following: positive fluid balance weight gain, worsening pulmonary edema or anasarca despite diuretic therapy. All patients were receiving a continuous infusion of furosemide (> 6 mg/kg/day).

The patients excluded:

Patients were ineligible for the study if they had hemodynamic instability, liver dysfunction, or rapid physiologic changes; if they were allergic to methylxanthine drugs or had taken methylxanthine drugs at any time in the month before enrolling in the study; or if they had a change in their furosemide infusion or had taken additional diuretics within six hours of the study.

The interventions compared:

A bolus of aminophylline (6 mg/kg) infused over 30 minutes in patients receiving a continuous infusion of furosemide.

The outcomes evaluated:

Urine flow rate, sodium and potassium excretion, and creatinine clearance 2 and 6 hours after the aminophylline bolus.

II. Are the results of the study valid?

1. Is there a strong, independent, consistent association between the surrogate end point and the clinical end point?

The authors describe that the consequences of fluid overload are increased mechanical ventilator, ICU and hospital days, and mortality. These are clinical outcomes we would be most interested in evaluating. In this study, the authors measured urine flow, sodium and potassium excretion, and creatinine clearance as surrogate outcomes.

A strong, independent, consistent association that improved diuresis is associated with improved patient outcome has been shown in only limited situations. In critically ill patients with pulmonary edema, a lower positive fluid balance has been associated with reduced extravascular lung water, ventilator days and ICU days (1). It also has been shown that in the early treatment of ARDS, fluid restriction/diuresis in euvolemic and hypervolemic patients can be pursued without deterioration of cardiac or renal function (2). In congestive heart failure, the combined use of diuretics has increased urine output but no significant effects on mortality and major cardiac events have been demonstrated (3)

2. Is there evidence from randomized trials in other drug classes that improvement in the surrogate end point has consistently led to improvement in the target outcome?

In the adult population, randomized clinical trials have shown in a few scenarios that urine output is associated with improvement in outcome. The use of loop diuretics given intermittently or by bolus can achieve negative fluid balances in patients with pulmonary edema and fluid overload (4). Randomized control trials in adults with pulmonary edema have shown that urine output was associated with an improvement in clinical outcome. Improved diuresis in oliguric renal failure, has not shown any difference in outcome in randomized, double blinded trials (5).

3. Is there evidence from randomized trials in the same drug class that improvement in the surrogate end point has consistently led to improvement in the target outcome?

There is no evidence from randomized trials with methylxanthines that improvement in urine output is associated with improvement in clinical outcome.

III. What were the results?

1. How large, precise, and lasting was the treatment effect?

The study showed an increase of urine output > 80%: from a baseline 5.3 ± 1.02 and at 2 hours 10.16 ± 1.96 mL/kg/hr (p=.004. Results are mean ± SEM). Also sodium excretion increased from 0.398 ± 0.129 mmol/kg/hr at baseline to 0.807 ± 0.208 mmol/kg/hr at 2 hours (p=.009). potassium excretion at baseline was 0.208 ± 0.065 mmol/kg/hr and increased to 0.435 ± 0.107 mmol/kg/hr at 2 hours (p=0.16). Creatinine clearance at baseline was 94.95 ± 20.75 and at 2 hours was 167.27 ± 39.38 mg/min/1.73 m² (p=0.029). After the sixth hour all variables returned to baseline levels. Hemodynamic variables such as heart rate changed < 10% and mean arterial pressure changed < 5% during the study time.

IV. Will the results help me in caring for my patients?

1. Can the results be applied to my patient care?

A typical PICU population frequently includes patients with fluid overload in spite of continuous furosemide therapy . The study demonstrates that a single dose of aminophylline does increase urine output and, although it may be useful in some cases, the results can not be applied to my patient care because of the characteristics of the study. It is a small size study and does not compare this therapy to other possible interventions such as the addition of another class of diuretic.

2. Were all clinically important outcomes considered?

Side effects of aminophylline were mentioned but toxicity was not reported in any patients. Changes in heart rate and blood pressure were systematically evaluated. Other potential side effects of theophylline such as nausea, vomiting and seizures are mentioned in the discussion only. With only eight patients it would be difficult to assess the frequency of these potential side effects after a single theophylline dose. However, side effects may become important with repeated or continuous dosing.

Although the patients selected were hemodynamically stable, the study did not consider the inter-individual variation in the rate of elimination of aminophylline, even with therapeutic doses (6). ICU patients would be expected to have different theophylline elimination rates based on their age and underlying disease. This would be important with repeated or continuous dosing. In addition, the outcomes of other subgroups might vary. For example, in cases of congestive heart failure (CHF) with concomitant renal failure, the use of aminophylline might not facilitate diuresis (7).

No information is given regarding duration of furosemide treatment in the patients at the time the aminophylline bolus was started. The use of previous diuretic combinations before the use of aminophylline were not reported.

There was no assessment of the use of dopamine as a confounding variable considering that three of the eight patients were on low dose dopamine. In CHF low doses of dopamine have been shown to have renal protective effect during vigorous diuresis (8). Diuretic effect may have been potentiated by the use of dopamine as demostrated in a previous study in oliguric children (9). The use of dopamine to enhance diuresis induced by furosemide is still controversial due to lack of large controlled studies that can show any positive effect in patient outcome or any effect in acute renal failure (10,11).

3. Are the likely treatment benefits worth the potential harms and costs?

The size of the study limits the ability to detect morbidity from aminophylline, but its use in other clinical situations has significant complications. The lack of a comparison group utilizing a more typical additional diuretic such as a thiazide limits the value of the study. This study should not form the basis for the use of aminophylline for fluid overload.

References

1. Mitchell JP, Schuller D, Calandrino FS, Schuster DP. Improved outcome based on fluid management in critically ill patients requiring pulmonary artery catheterization. Am Rev Respir Dis. 1992;145(5):990-8. [abstract]
2. Schuster DP. The case for and against fluid restriction and occlusion pressure reduction in adult respiratory distress syndrome. New Horiz. 1993;1(4):478-88. [abstract]
3. Follath F. Do diuretics differ in terms of clinical outcome in congestive heart failure? Eur Heart J. 1998;19 Suppl P:P5-8. Review. [abstract]
4. Schuller D, Lynch JP, Fine D. Protocol-guided diuretic management: comparison of furosemide by continuous infusion and intermittent bolus. Crit Care Med. 1997;25(12):1969-75. [abstract]
5. 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(12):2592-6. [abstract]
6. Rall TW: Drugs used in the treatment of asthma. In :Goodman & GilmanÕs The Pharmacologic Basis of Therapeutics. Ninth edition. Gilman AG, Rall TW, Nies AS, Taylor P. New York, Pergamon Press 1996, pp 672-680.
7. Kanda M, Yasuda S, Goto Y, Sumida H, Baba T, Noguchi T, Nonogi H. Diuretic effect of phosphodiesterase inhibitors depends on baseline renal function in patients with congestive heart failure. Am J Cardiol. 1999;83(8):1274-7, A9. [abstract]
8. Varriale P, Mossavi A. The benefit of low-dose dopamine during vigorous diuresis for congestive heart failure associated with renal insufficiency: does it protect renal function? Clin Cardiol. 1997;20(7):627-30. [abstract]
9. Bell M, Jackson E, Mi Z, McCombs E, Carcillo J. Low dose theophylline increases urine output in diuretic dependant critically ill children. Intensive Care Med. 1998 24: 1099-1105. [abstract]
10. Kindgen-Milles D, Tarnow J. Low dosage dopamine improves kidney function: current status of knowledge and evaluation of a controversial topic. Anasthesiol Intensivmed Notfallmed Schmerzther. 1997;32(6):333-42. Review. German. [abstract]
11. Vargo DL, Brater DC, Rudy DW, Swan SK. Dopamine does not enhance furosemide- induced natriuresis in patients with congestive heart failure. J Am Soc Nephrol. 1996;7(7):1032-7. [abstract]

 

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