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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Albumin and furosemide therapy in hypoproteinemic patients with acute lung injury.

Martin GS, Mangialardi RJ, Wheeler AP, Dupont WD, Morris JA, Bernard GR.

Crit Care Med 2002;30(10):2175-82 [abstract]

Reviewed by Diane Godorov, DO, Children's Healthcare of Atlanta

Review posted June 24, 2003

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I. What is being studied?:

The study objective:

Does diuresis and colloid replacement in hyproteinemic patients with acute lung injury improve pulmonary physiology?

The study design:

prospective, randomized, double blind placebo-controlled

The patients included:

Those that met each of the following criteria at study entry:

1. the American-European Consensus Conference definition for ALI (bilateral infiltrates on frontal radiograph, PaO2/FiO2 ratio of less than or equal to 300 mm Hg, no evidence of left atrial hypertension, or pulmonary artery wedge pressure less than or equal to 18 mm Hg, if available,
2. serum total protein level of less than or equal to 5.0 g/dL,
3. ongoing nutritional support, and
4. mechanical ventilation greater than or equal to 48 hours

The patients excluded:

1. hemodynamic instability (defined as > 1 L of intravenous fluid boluses or transfusion of > 2 units PRBCs for hemodynamic support within 24 hours before eligibility, or vasopressor requirements, defined as dopamine exceeding 5 micrograms/kg/min, any dose of epinephrine, phenylephrine, or norepinephrine, or use of more than one vasoactive infusion),
2. renal disease (serum creatinine of greater than or equal to 3.0 mg/dL or urine output of < 400 mL per 24 hours
3. hepatic failure (documented cirrhosis, total bilirubin of > 2.0 mg/dL, or international normalized ratio of > 1.8 not attributable to anticoagulant medications),
4. allergies to albumin or furosemide,
5. pregnancy,
6. serum sodium of > 150 meq/L or potassium of < 2.5 meq/L.

The existence of exclusion criteria did not preclude subsequent enrollment once the criteria resolved.

The interventions compared:

5 day protocol of administration of 25 gm of serum albumin every 8 hours with a continuous infusion of furosemide, or dual placebo control group

The outcomes evaluated:

A change in weight (primary outcome variable), serum total protein, fluid balance, hemodynamics, respiratory system compliance and oxygenation, and decreased time on the ventilator

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes, by a computer generated list.

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

Was followup complete?

Yes, thirty seven patients were enrolled and completed the study protocol (treatment group included 19 patients and control included 18). Data was collected each day during the treatment period and out to 30 days after enrollment for outcome measures; all patients were followed to discharge or to death

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

Yes, there were no crossovers between the groups

Secondary questions:

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

Patients were blinded. The single radiologist reading daily films was blinded; the investigational pharmacy at each hospital was responsible for study drug preparation, camouflage, blinding and dispensation. The clinicians caring for the patients were also unaware of treatment assignment.

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

The groups did not differ in age, sex, race, APACHE III, LIS, or SOFA scores. About 75% of the patients enrolled were from the surgical ICUs, where the lung injuries in both groups was related to trauma.

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

No data or text is presented to allow comment on this question. Since the clinicians were unaware of group assignment, we may presume they were otherwise treated equally, but we cannot be certain.

III. What were the results?

1. How large was the treatment effect?

Primary outcomes:

All patients in the treatment group demonstrated a fluid loss with a mean 3.3 L net diuresis and higher urine output, whereas the control group demonstrated a mean weight gain of 0.5 L (p=0.14). (NOTE: The protocol design called for the infusion of study drug to be titrated every eight hours to achieve a net diuresis and daily weight loss of > 1 kg/day. The results show that they were able to follow their protocol fairly well but didn't reach the goal of 5 L negative after day five. The control group did not have this as part of their protocol, so did not have as much weight loss.) The treatment group had more of a weight loss than the control group; a mean of 10.0 kg versus 4.7 kg (p=0.04). (There is no explanation for this apparent discrepancy, how the total fluid balance can be positive in the controls yet they lost almost 5 kg.)

Patients in the treatment group had an increase in serum total protein (mean of 1.9 g/dL) versus the control group's increase (mean 0.7 g/dL). A rise in serum albumin was also seen (mean of 1.5 g/dL vs 0.3 g/dL) (P < 0.001 for both.) (NOTE: Again, this result shows that if you give albumin, the albumin and the total protein will go up. The results show that they were able to follow the protocol well. They showed that nearly all of the change in serum total protein was due to changes in serum albumin.)

Patients in the treatment group experienced more rapid improvements in oxygenation with a decreased oxygenation index; -3.4 vs. -0.8 in the control group. (this effect was seen only during the first 24 hours of the infusion, admittedly prior to any significant increased diuresis, potentially implicating the non-diuretic effect of furosemide?) and were ventilated for a shorter duration (5.5 more vent-free days but 95% CI -1.8 to 12.8) than control group patients However, there were no significant changes in LIS, SOFA scores, standard chest x-ray scores, reintubation rates or shock free survival within or between groups.

Secondary outcomes:

Regardless of group, patients who lost weight during the 5 day study period were much less likely to die during subsequent follow-up than those who gained weight (p=0.001). No statistically significant difference was noted in overall outcomes, with positive trends toward decreased ventilator time, ICU stay and hospital stay in the treatment group.

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

Although the treatment effect had a positive impact on the patient's weight and fluid balance, the study was not designed (powered) sufficiently to detect differences in clinically important outcomes such as survival or length of stay.

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

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

It is not known whether, similar results can be achieved with hypoalbuminemic pediatric patients with ALI/ARDS. All the patients in this study were adults, the majority of which were trauma victims. It appears that if one adopted the strategy of this protocol, one could successfully improve diuresis and raise the total protein in your patients. How this impacts outcome is clearly not answered in this study.

2. Were all clinically important outcomes considered?

In this small trial that was designed only to evaluate physiologic changes, the important clinical outcomes (mortality, length of stay, etc.) were considered but there was insufficient power to detect any meaningful differences.

All patients in the treatment group had an increase Na+, an increased bicarbonate, and a drop in K+. Also, 5 of 19 had to have the diuretic infusion stopped because of electrolyte problems. In addition, by day 5, 53% in the treatment group had their albumin stopped because the TP was greater than 6.0.

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

Possibly, since there were no significant adverse effects associated with the treatment protocol except for the electrolyte abnormalities related to the diuretic therapy. Overall costs are reduced if the patient requires fewer days on mechanical ventilation (but that was not shown), despite the cost of the albumin; in this study estimated cost of one day in the ICU and on the ventilator was $3000, and a maximum of 375 mg of albumin over the 5 day period was less than $1200.00. However, a more definitive study designed to evaluate important clinical outcomes, including costs and complications, is indicated prior to widespread adoption of this approach.

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