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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Comparison of the renal effects of low to high doses of dopamine and dobutamine in critically ill patients: a single-blind randomized study.

Ichai C, Soubielle J, Carles M, Giunti C, Grimaud D.

Crit Care Med 2000;28(4):921-8. [abstract]

Reviewed by Umesh Narsinghani, MD, University of Arkansas for Medical Sciences/Arkansas Children's Hospital

Review posted July 27, 2000

I. What is being studied?:

The study objective:

To compare the effects of various doses of dopamine and dobutamine on renal function on a specific group of stable critically ill patients.

The study design:

Prospective, single blind, randomized study, in a 19 bed multidisciplinary intensive care unit of a university hospital.

The patients included:

1. Stable critically ill patients aged 18-70 years.
2. Hemodynamics: MAP 70 mmHg; Cardiac Index > 2.5 L/min/m2; pulmonary artery occlusion pressure 12 mmHg.
3. Mild renal impairment defined as creatinine clearance between 30-80 ml/min for 48 hours, before the study.

The patients excluded:

1. Hemodynamically unstable patients. (Not meeting criteria mentioned above)
2. Those with preexisting arterial hypertension or cardiac dysarrythmia.
3. Preexisting chronic renal insufficiency, or established acute renal failure, creatinine clearance 30 ml/min.
4. Patients receiving catecholamines, diuretics or antihypertensives prior to admission.

Withdrawal criteria:

1. Occurrence of sepsis during the infusion of dopamine or dobutamine as defined by classic Bone's criteria.
2. Development of cardiac dysarrythmia or arterial hypertension requiring specific drug therapy.
3. Oliguria urine output < 0.5ml/kg/hr.
4. Hemodynamic instability as mentioned above.

The interventions compared:

Each patient randomly received 4 different doses of dopamine and dobutamine (placebo, 3, 7, and 12 mcg/kg/min). Each infusion lasted for 4 hours.

The outcomes evaluated:

Hemodynamic variables: Cardiac output, mean pulmonary artery pressures, right atrial pressure, pulmonary artery pressure occlusion pressure, systemic and pulmonary vascular resistance indices were measured at the beginning of each time block (H0) and after 4 hrs (H4) of catecholamine administration.

Renal variables: Urine samples were collected at H4 for urine volume, urine sodium, potassium, creatinine and urea concentration. Blood samples were taken at H0 and at H4 of each infusion to determine plasma sodium, potassium, creatinine, and urea concentration. Fractional excretion of sodium (FeNa), fractional excretions of water (FeH2O) and creatinine clearances were evaluated.

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?

There is no evidence from the literature that improving renal function transiently makes any difference in mortality or improved renal morbidity. However, the presence of renal failure has consistently been associated with worse outcomes.

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?

No, the use of drugs from different classes has not suggested that improvement in the surrogate endpoint (transient improvement in renal function) has consistently led to improvement in target outcomes (e.g., mortality).

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?

No, several well-controlled studies have failed to demonstrate a better outcome with respect to improvement in renal function and/or survival. There is insufficient evidence that the administration of low-dose dopamine improves survival or obviates the need for dialysis in persons with acute renal failure. (1) It has been shown that renal effects of low-dose dopamine in patients with sepsis syndrome actually decreases with time. No renal effect of low-dose dopamine has been observed in patients with septic shock treated with catecholamines. (2) These findings in fact suggest a desensitization of renal dopaminergic receptors. The routine use of low-dose dopamine should be discouraged until a prospective, randomized, placebo-controlled trial establishes its safety and efficacy.

IIa. Validity Questions for Therapy Articles:

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes and no. Each patient in a single blind fashion randomly received all the infusions, with each patient serving as their own control. (Although there is no mention of the randomized order.)

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

Was followup complete? and were patients analyzed in the groups to which they were randomized?

Fourteen patients were screened to enter the study; 2 of them were not included because of the appearance of infection. 12 patients were included; 2 did not complete the study because they developed arterial hypertension during the dopamine and dobutamine infusion. Ten patients, 6 men and 4 women completed the study.

The follow up was complete. Patients were considered alive if they were discharged from the intensive care unit.

There was a single group wherein the subjects successively underwent each of the eight doses (dopamine and dobutamine) in a random order.

Secondary questions:

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

A single blind study design was implemented.

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

Since each patient served as their own control, there were no comparison groups.

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

Yes, the patients were treated equally, as respiratory support, sedation, standard daily fluid and sodium therapy was maintained throughout the study. During the infusion periods patients were not permitted to receive any other catecholamines, diuretics or any other treatment. Volume loading with hydroxyethyl starch was performed during the washout intervals to restore baseline hemodynamic condition. Patients remained in the supine position during the duration of the study.

III. What were the results?

1. How large, precise, and lasting was the treatment effect? (Effect should be large, precise, and lasting to consider a surrogate trial as possible basis for offering patients the intervention.)

Results for Hemodynamic data: Heart rate increased similarly with both drugs, p < 0.001 vs. control. Dopamine increased the MAP significantly during the 7 and 12 mcg/kg/min infusions. (p < 0.05 vs. control and 3 mcg/kg/min). Dobutamine on the other hand did not affect the MAP. Cardiac index increased with all dopamine and dobutamine infusions p < 0.001. However dobutamine during the 12 mcg/kg/min increased the cardiac index more than dopamine did. (p < 0.05). Dopamine did not significantly change the systemic vascular resistance index; on the other hand dobutamine significantly decreased the systemic vascular index at all comparable doses. The hemodynamics at each H0 did not differ amongst each other, and returned to baseline each time.

Results for Renal data: With dopamine urine volume increased significantly at all doses (p < 0.01); with a maximum increase of 102% at 7 and 12 mcg/kg/min. The urine volume did not change with dobutamine infusion. The creatinine clearance was increased by all doses of dopamine by a mean of 35% and there was no significant difference between the doses. Conversely dobutamine infusion did not significantly change the creatinine clearance. Similarly fractional excretion of sodium and water increased with dopamine but remained unchanged with dobutamine infusion.

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

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

This data was from an adult study and by the study design there was no way it could look at real outcomes. However, there was a convincing physiologic/pharmacologic effect seen.

2. Were all clinically important outcomes considered?

The study design prohibited any chance of seeing an effect on the most important outcomes - mortality, morbidity, length of stay, etc. Yes they measured all the pertinent physiologic variables, but the true clinical value was not studied.

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

The investigators did not look at harms or costs in this study. Two patients had to be withdrawn due to hypertension at the high doses of both drugs and the benefits were limited to physiologic improvements. The potential risk of high dose therapy cannot be overlooked (although since the same renal effect from dopamine was seen at the lowest dose, there should be no reason to use the high dose from a renal perspective).

References

1. Chertow GM, Sayegh MH, Allgren RL, Lazarus JM. Is the administration of dopamine associated with adverse or favorable outcomes in acute renal failure? Auriculin Anaritide Acute Renal Failure Study Group [see comments]. American Journal of Medicine. 1996; 101:49-53. [abstract]
2. Girbes AR, Smit AJ. Use of dopamine in the ICU. Hope, hype, belief and facts. Clinical & Experimental Hypertension (New York). 1997; 19:191-9.

 

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