Randomized Controlled Trial of Inhaled Nitric Oxide for the ... : Critical Care Medicine (original) (raw)

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Randomized Controlled Trial of Inhaled Nitric Oxide for the Treatment of Microcirculatory Dysfunction in Patients With Sepsis*

Trzeciak, Stephen MD, MPH1; Glaspey, Lindsey J. BA1; Dellinger, R. Phillip MD1; Durflinger, Paige RRT1; Anderson, Keith RRT, MBA1; Dezfulian, Cameron MD2; Roberts, Brian W. MD3; Chansky, Michael E. MD3; Parrillo, Joseph E. MD3,4; Hollenberg, Steven M. MD4

1Division of Critical Care Medicine, Department of Medicine, Cooper University Hospital, Cooper Medical School of Rowan University, Camden, NJ.

2Department of Critical Care Medicine and The Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA.

3Department of Emergency Medicine, Cooper University Hospital, Cooper Medical School of Rowan University, Camden, NJ.

4Division of Cardiovascular Disease, Department of Medicine, Cooper University Hospital, Cooper Medical School of Rowan University, Camden, NJ.

* See also p. 2628.

Trial registration: ClinicalTrials.gov (NCT00608322).

Dr. Trzeciak is responsible for all aspects of the study, had full access to all of the data, and takes responsibility for the integrity of this study as a whole. Ms. Glaspey contributed to data acquisition and critical revision of the article. Dr. Dellinger contributed to study concept and design and critical revision of the article, and he received funding and administrative support. Mr. Durflinger contributed to data acquisition and critical revision of the article. Mr. Anderson contributed to data acquisition and critical revision of the article. Dr. Dezfulian contributed to intellectual content, data acquisition, and critical revision of the article. Dr. Roberts contributed to data analysis, intellectual content, and drafting of the article. Dr. Chansky contributed to critical revision of the article and received funding and administrative support. Dr. Parrillo contributed to study concept and design and critical revision of the article, and he received funding and administrative support. Dr. Hollenberg contributed to study concept and design, intellectual content, critical revision of the article, and study oversight. All authors approved this article prior to submission for publication.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal).

Ikaria provided study drug and Masimo provided point-of-care methemoglobin monitors for this clinical trial. These funding sources had no role in the design, conduct, or interpretation of this clinical trial and no role in article preparation.

This study and Dr. Trzeciak were supported by a grant (K23GM083211) from the National Institutes of Health (NIH) (National Institute of General Medical Sciences). Dr. Trzeciak, Ms. Glaspey, Dr. Dellinger, Mr. Durflinger, Mr. Anderson, Dr. Roberts, Dr. Chansky, and Dr. Hollenberg received support for article research from the NIH. Dr. Dezfulian received grant support from National Institute of Neurological Disorders and Stroke K08 (funded study on nitrite therapy after cardiac arrest) and received support for article research from the NIH. Dr. Parrillo served as board member for Artisian, Sangart, Cytosorbents, and National Heart, Lung, and Blood Institute, and he received support for article research from the NIH. His institution received grant support from the Salem Foundation.

For information regarding this article, E-mail: [email protected]

Abstract

Objectives:

Sepsis treatment guidelines recommend macrocirculatory hemodynamic optimization; however, microcirculatory dysfunction is integral to sepsis pathogenesis. We aimed to test the hypothesis that following macrocirculatory optimization, inhaled nitric oxide would improve microcirculation in patients with sepsis and that improved microcirculation would improve lactate clearance and multiple organ dysfunction.

Design:

Randomized, sham-controlled clinical trial.

Setting:

Single urban academic medical center.

Patients:

Adult patients with severe sepsis and systolic blood pressure less than 90 mm Hg despite intravascular volume expansion and/or serum lactate greater than or equal to 4.0 mmol/L.

Interventions:

After achievement of macrocirculatory resuscitation goals, we randomized patients to 6 hours of inhaled nitric oxide (40 ppm) or sham inhaled nitric oxide administration. We administered study drug via a specialized delivery device that concealed treatment allocation so that investigators and clinical staff remained blinded.

Measurements and Main Results:

We performed sidestream dark-field videomicroscopy of the sublingual microcirculation prior to and 2 hours after study drug initiation. The primary outcome measure was the change in microcirculatory flow index. Secondary outcomes were lactate clearance and change in Sequential Organ Failure Assessment score. We enrolled 50 patients (28 of 50 [56%] requiring vasopressor agents; 15 of 50 [30%] died). Although inhaled nitric oxide significantly raised plasma nitrite levels, it did not improve microcirculatory flow, lactate clearance, or organ dysfunction. In contrast to previous studies conducted during the earliest phase of resuscitation, we found no association between changes in microcirculatory flow and lactate clearance or organ dysfunction.

Conclusions:

Following macrocirculatory optimization, inhaled nitric oxide at 40 ppm did not augment microcirculatory perfusion in patients with sepsis. Further, we found no association between microcirculatory perfusion and multiple organ dysfunction after initial resuscitation.