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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Comparison of continuous versus intermittent furosemide administration in postoperative pediatric cardiac patients.

Singh NC, Kissoon N, Mofada SA, Bennett M, Bohn DJ.

Crit Care Med 1992; 20:17-21. [abstract]

Reviewed by Patricia Jines MD and Jonathan D. Feldman MD, UCLA Children's Hospital

Review posted February 2, 2000

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I. What is being studied?:

The study objective:

To compare the effects of furosemide administered by intermittent iv infusion vs. continuous iv infusion on urinary output, hemodynamic variables, and serum electrolyte concentrations

The study design:

Prospective, randomized trial.

The patients included:

Twenty postoperative pediatric cardiac patients that met the criteria of adequate Intravascular volume as determined by clinically acceptable heart rate, peripheral pulses, and perfusion (capillary refill < 3 secs), BP (> 5% for age), and CVP, which was determined for the individual patients by at least two physicians who considered:

• CVP at the time of maximum hemodynamic stability
• Cardiac lesion
• Surgical repair
• Cross-clamp and by-pass time
• Urine output < 1mL/kg/hr,
• Normal serum potassium concentration (> 3.5 mmol/L)
• No receipt of any other diuretic within 12 hours of surgery or during the study period.

The patients excluded:

Patients that did not meet the above criteria, although no exclusion criteria was defined.

The interventions compared:

Continuous intravenous furosemide infusion vs. intermittent intravenous furosemide bolus dosing.

The continuous infusion was a initial dose of 0.1 mg/kg IV (minimum 1 mg) and started at 0.1 mg/kg/hr. The infusion rate was doubled every 2 hours (to a maximum of 0.4 mg/kg/hr) if the urine output continued to be < 1 ml/kg/hr.

The intermittent dose was 1 mg/kg of furosemide IV every 4 hours and, if the urine output was < 1 ml/kg/hr in the preceding 4 hours, the dose was increased by 0.25 mg/kg IV to a maximum of 1.5 mg/kg.

The outcomes evaluated:

Furosemide dose, urine output, CVP, serial serum and urinary electrolytes measurements and cardiac index were evaluated.

This study looks at a surrogate endpoint (dose and mode of furosemide given in 24 hours to achieve a certain urine output) instead of a clinical endpoint (mortality, length of stay, etc). In this case the surrogate is not valid because there is no independent, strong or consistent association between the surrogate endpoint and a clinical outcome endpoint. In addition, there is no evidence from randomized trials in the same drug class or in other drug classes that links urine output or urine output variance with outcome.

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

The assignment of patients to treatments was randomized but it is not explained how it was performed.

2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?

Was followup complete?

Study period was 24 hours postoperative; no further follow up was applicable.

Were patients analyzed in the groups to which they were randomized?

Yes, therapy was completed and all patients remained in their assigned groups

Secondary questions:

3. Were patients, health workers, and study personnel "blind" to treatment?

Neither patients nor health workers were blinded.

4. Were the groups similar at the start of the trial?

As per a student t-test, no differences were found in the two groups when comparing sex, weight, cross-clamp time, bypass time, fluid intake, and serum sodium, chloride and potassium values. Although due to the small number of patients it was difficult to show any differences.

Cardiac procedures in the two groups cannot be compared in a quantitative way. Also no data about use of vasoactive drugs or renal baseline function was mentioned in the study.

5. Aside from the experimental intervention, were the groups treated equally?

Although for each group there was a similar 24 hr average observation in urine output, CVP, urine and serum electrolytes, the studies were done by two teams in two different medical centers (Toronto and London). No standardized care was delineated for any aspect of the postoperative care including fluid management and use of other diuretics during the study time. A priori, the study protocol was designed in the way that the continuous infusion group received less furosemide/kg compared to the bolus infusion group.

III. What were the results?

1. How large was the treatment effect?

The study only shows that a higher dose of furosemide was administered to the intermittent bolus group (mean 6.23 ± 0.62 mg/kg/day) compared to the continuous infusion group (mean 4.90 ± mg/kg/day); p = 0.0045. Urine output was similar overall (p = NS), as are the CVP and urinary K+ concentrations. In addition, less variability in the urine output was seen in the continuous infusion group (2.19 ± 1.92 ml/kg/day) than the intermittent group (13.07 ± 14.56 ml/kg/day); (expressed as mean log variance ± variance) p = 0.045. Urinary Na+ loss was reported higher (p = 0.007) in the intermittent group (0.29 ± 0.15 mmol/kg/day) compared to the continuous bolus group (0.20 ± 0.06 mmol/kg/day) without a significance serum electrolyte difference. We cannot assess the treatment effect in terms of relative risk or relative risk reduction of the therapy.

2. How precise was the estimate of the treatment effect?

We cannot assess the precision of treatment effect; as this was not a binary outcome study.

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

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

The postoperative cardiac patients presented in this study are similar to the patients seen in our unit (although in our hospital, during the first 24 hours they remain in a cardiac unit different from the general PICU).

2. Were all clinically important outcomes considered?

No assessment of drug tolerance or adverse effects as oto- or nephrotoxicity, cardiac arrhythmias or calcium status were reported.

Cardiac procedures were listed but the degree of postoperative hemodynamic support or preoperative severity of illness could not be determined from the data. No data about the need of further interventions (electrolyte replacement, use of other diuretics, dialysis) to maintain diuresis was reported. The study duration was 24 hours and no further follow up was given. The most clinically relevant outcomes, such as mortality or length of stay, were not recorded. However, one could not anticipate significant clinical outcome differences from this intervention.

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

There are no significant clinical benefits and no harms or adverse outcomes were identified. Loop diuretics are already used in post-cardiac surgical patients to reduce fluid overload. The outcomes of the study provide no striking findings to support any change in the usual way that diuretics are given. The impact of the treatment in relation to a specific clinical outcome cannot be assessed. There appears to be little additional risk of adverse outcome if the bolus dose modality is performed instead of the continuous infusion of furosemide. Since less drug is used in the continuous group as designed by the protocol, the potential toxicity or whether less drug is needed is not evaluated by this study.

References

1. Bucher H, Guyatt GH, Cook DJ, et al. Applying Clinical Trial Results A. How to Use an Article Measuring the Effect of an Intervention on Surrogate End Points. JAMA 1999; 282:771-778. [citation] [full-text for limited time]
2. Detorre MD, Stidman GL, Watson DC, Ring JC. Enhanced diuresis with continuous furosemide infusion in post operative pediatric cardiac surgery patients (abstract). Critical Care Medicine 1994 22:A183
3. Eades SH, Christensen ML. The clinical pharmacology of loop diuretics in the pediatric patient. Pediatric Nephrology 1998; 12:603-616. [abstract]
4. Luciani GB, Nichani S, Chang AC, et al. Continuous versus intermittent furosemide infusion in critically ill infants after open heart operations. Annals of Thoracic Surgery 1997; 64:1133-1139. [abstract]
5. Yelton SL, Gaylor M, Murray MM. The role of continuous infusion loop diuretics. The Annals of Pharmacotherapy 1995; 29:1010-1014. [abstract]

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