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Does use of dopamine versus Levophed change mortality in shock?

This issue's column is based on the peer-reviewed article by Daniel De Backer MD, PhD, Patrick Biston MD and Jacques Devriendt MD, et al, titled, "Comparison of dopamine and norepinephrine in the treatment of shock." It was published in the March 4, 2010 issue of the New England Journal of Medicine (Volume 362, Number 9, pages 779-89).

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We'll review this article by sections to teach the scientific method for a research project: Background or Introduction, Question, Hypothesis, Methods, Results, Discussion, Reflections, Future Research, Conclusions, Acknowledgements, Conflicts of Interest and Bibliography.

Background

The authors explain that circulatory shock is a life-threatening emergency that results in death in approximately 50 percent of all patients. Intravenous fluids are the first step in resuscitation, but often an intravenous adrenergic agent as a continuous infusion is added as the next step. The authors note that either of two adrenergic agents, dopamine or norepinephrine (Levophed) is recommended as first-line vasopressors in the treatment of circulatory shock.

There is continuing controversy about whether one agent is superior to the other, based on their differences in alpha-adrenergic, beta-adrenergic and dopaminergic properties. Growing observational evidence among Intensivist indicate that norepinephrine compared to dopamine may be associated with better outcomes.

The authors chose to design a study to evaluate these two drugs in patients with shock. Their study was designed to evaluate whether the choice of norepinephrine over dopamine as the first-line vasopressor could reduce the rate of death among patients in shock. A secondary goal of their study was to determine if a difference exists in the adverse effects of the drugs.

The Question and Hypothesis

The question being asked by the authors was, "Can the choice of norepinephrine over dopamine as the first-line vasopressor agent reduce the mortality among patients in shock?" The authors hypothesized that norepinephrine as the first-line vasopressor agent would reduce the mortality among patients in shock.

The Methods

This project was a multicenter, prospective, blinded, comparative study conducted in eight centers in Belgium, Austria and Spain. It was approved by the Ethics Committee of each participating center with a written informed consent required for each subject to be enrolled.

In this study, shock was defined as a systolic blood pressure of less than 100 mm Hg or a mean blood pressure of less than 70 mm Hg. Intensive care unit patients were eligible for the study if they were 18 years or older, in shock after receiving an adequate amount of intravenous fluids, required a vasopressor agent and showed signs of tissue hypoperfusion such as mottled skin, decreased urine output, or elevated serum lactate.

Randomization of patients to either dopamine versus norepinephrine was stratified at each center using sealed envelopes opened only by study pharmacists. The nurses and physicians were unaware of the treatment assignments. The dose of the vasopressor was increased or decreased according to the physician in charge of each case. The maximum dose permitted by the pharmacist was 20 micrograms/kg/minute for dopamine and 0.19 micrograms/kg/minute for norepinephrine.

The primary end-point was mortality at 28 days. A secondary end-point was adverse effects. For statistical considerations, the authors reviewed their first SOAP study from 2006. They decided to analyze data as each 100 patients were enrolled, closing the study at approximately 1,600 patients or when statistical significance was obtained. A predefined subgroup analysis was performed according to the type of shock: hypovolemic, septic, or cardiogenic. Mortality was compared between dopamine and norepinephrine using chi-squared tests with a level of significance p < .05 for all statistical tests. Software was SPSS version 13.3 (SPSS, Chicago, IL).

Results

There were 1,679 patients enrolled in the study. Of the total, 858 patients were randomized to receive dopamine and 821 patients to receive norepinephrine. The baseline characteristics of the two groups of patients were similar. There was no significant difference in mortality between the two groups: 53% for patients receiving dopamine and 49% for patients receiving norepinephrine.

For subgroup analyses, the population in this study consisted of patients with septic shock (n = 1044; 62%), hypovolemic shock (n = 280; 16%) and cardiogenic shock (n = 263; 17%). For patients with cardiogenic shock, dopamine, as compared to norepinephrine, was associated with a significantly higher mortality. Additionally, in all patients as a secondary finding, dopamine was associated with more dysrhythmias than norepinephrine.

Discussion, Reflections and Future Research

The authors first noted that their study showed an overall mortality approximately 50 percent as noted in other studies. They also noted that the increased mortality in cardiogenic shock patients receiving dopamine, as compared to norepinephrine, was unexpected, as dopamine might be expected to improve cardiac output in such patients.

Also, the minimal amount of administered fluids, 1,000 mL of crystalloid or 500 mL of colloid, may have been inadequate for some subjects and may have affected outcomes. The authors noted that their adverse findings on dopamine strongly challenge the American College of Cardiology - American Heart Association guideline for the use of dopamine for treatment of patients with cardiogenic shock.

Conclusion, Acknowledgements and Conflicts of Interest

The authors demonstrated that there was no significant difference in mortality between all patients with shock treated with dopamine versus those treated with norepinephrine. The proposed hypothesis was incorrect. However, the data demonstrated a secondary finding that dopamine was associated with a higher number of cardiac dysrhythmias compared to norepinephrine.

Acknowledgements credit those who assisted a research project by time, effort and financial support. The European Society of Intensive Care, through the European Critical Care Research Network, supported part of the study. The study author Cesar Aldecoa MD has received consulting fees from Covidien, a maker of health care products. All other study authors disclosed no relevant financial relationships.

Bibliography

For this research project, there were 28 references. An accompanying editorial to the article was included on pages 841-843 in the same issue of the New England Journal of Medicine. It is titled, "Treating Shock--Old Drugs, New Ideas" by Jerrold H. Levy MD, from the Department of Anesthesiology at Emory University School of Medicine and Cardiothoracic Anesthesiology, Atlanta. The ClinicalTrials.gov registration number for this study was NCT00314704.

Herbert Patrick, M.D., M.S.E.E., is an Intensivist and member of the Active Staff at Hahnemann University Hospital, Philadelphia, PA. Dr. Patrick can be contacted at hpatrick2@gmail.com.

by Herbert Patrick MD
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Title Annotation:RESPIRATORY RESEARCH
Author:Patrick, Herbert
Publication:FOCUS: Journal for Respiratory Care & Sleep Medicine
Date:May 1, 2010
Words:1056
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