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

Trzeciak, Stephen; Glaspey, Lindsey J.; Dellinger, R Phillip; Durflinger, Paige; Anderson, Keith; Dezfulian, Cameron; Roberts, Brian W.; Chansky, Michael E.; Parrillo, Joseph E.; Hollenberg, Steven M.

doi:10.1097/ccm.0000000000000549

Cited by 52 publications

(37 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Unfortunately, NO signaling is highly complex, with context-specific functions that can be both homeostatic and pathologic 54–56 . Human studies of NO-targeted microvascular therapeutics have accordingly been disappointing 57,58 , potentially reflecting broad, nonspecific effects of NO manipulation 59 . These challenges (and opportunities) of NO-based therapies have been reviewed in detail elsewhere 60 .…”

Section: Pathogenesis Of Microvascular Dysfunction During Sepsismentioning

confidence: 99%

Endothelial and Microcirculatory Function and Dysfunction in Sepsis

Colbert

Schmidt

2016

Clinics in Chest Medicine

View full text Add to dashboard Cite

SYNOPSISThe microcirculation is a series of arterioles, capillaries, and venules that performs essential functions of oxygen and nutrient delivery, customized to the unique physiologic needs of the supplied organ. The homeostatic microcirculatory response to infection, which includes barrier hyperpermeability, leukocyte adhesion, and coagulation activation, can become harmful if overactive and/or dysregulated, contributing to the organ failure characteristic of sepsis. In humans, pathologic microcirculatory dysfunction can be directly visualized by intravital microscopy or indirectly measured via detection of circulating biomarkers, such as endothelial glycocalyx fragments. While several treatments have been shown to protect the microcirculation during sepsis, these therapies have not improved patient outcomes when applied indiscriminately. Future outcomes-oriented studies are needed to test the utility of sepsis therapeutics when applied in a manner "personalized" to a patient's microcirculatory dysfunction.

show abstract

Section: Pathogenesis Of Microvascular Dysfunction During Sepsismentioning

confidence: 99%

Endothelial and Microcirculatory Function and Dysfunction in Sepsis

Colbert

Schmidt

2016

Clinics in Chest Medicine

View full text Add to dashboard Cite

show abstract

“…(46) To date, there have been 2 randomized clinical trials in adults of inhaled nitric oxide for the treatment of existing microcirculatory disease. (47) (48) In both adult studies, no difference between the treatment and control arms was reported. In addition, none of the inhaled nitric oxidebronchopulmonary dysplasia prophylaxis, randomized clinical trials found any effect on the risk of periventricular leukomalacia, intraventricular hemorrhage, NEC, or longterm neurodevelopmental outcome.…”

Section: Can the Effect Of Hypoxic Vasodilation Be Augmented?mentioning

confidence: 79%

Red Blood Cell Storage in Transfusion-Related Acute Gut Injury

et al. 2015

View full text Add to dashboard Cite

and The iNO-TRAGI Trial. This commentary does contain a discussion of an unapproved/ investigative use of a commercial product/ device. Educational Gaps1. Transfusion-associated gut injury is the occurrence of necrotizing enterocolitis 48 hours or less after packed red blood cell transfusion given for anemia in low-risk infants born at extremely low gestational age. 2. Blood storage alters the red blood cells, creating a storage lesion that may affect infants born at extremely low gestational ages who are at the cusp of an oxygen delivery-consumption imbalance. AbstractTransfusion-related acute gut injury is defined as the occurrence of necrotizing enterocolitis 48 hours or less after a packed red blood cell (PRBC) transfusion for marked anemia in older, low-risk infants born at extremely low gestational ages (<28 weeks' gestational age) who are no longer experiencing any historically associated risk factors except enteral feeding. As oxygen delivery decreases with advancing anemia, growing premature neonates compensate by redistribution of blood flow, increased cardiac output, and elevated oxygen extraction. Further adjustments to microvascular blood flow arise from nitric oxide-based hypoxic vasodilation, which eventually becomes limiting for sustaining oxygen consumption. Among many effects on red blood cells (RBC), storage lowers donor RBC nitric oxide content and increases free hemoglobin nitric oxide scavenging, whereas low oxygenation reduces nitric oxide production by endothelial nitric oxide synthase; these varied mechanisms collectively result in mitigation of hypoxic vasodilation. Because the adverse effect of packed RBCs on neonatal gut oxygenation appears primarily in association with extreme anemia, a sudden reduction in mucosal blood flow during periods of increased oxygen demand (enteral feeding) presumably results in injury to the physical barrier, enabling bacterial invasion and necrotizing enterocolitis. In infants born at extremely low gestational ages, PRBC transfusions for iatrogenic or developmentally acquired anemia are common and will persist even after all conservation techniques, microassay methods, and use of erythropoietin have been implemented. A fixed need for transfusions exists because of additional biologic restrictions imposed by normal rates of human somatic growth coupled with limits of RBC production to accommodate the need for an expanding RBC mass. Improved understanding of etiologic mechanisms of microvascular injury with transfusion should be instructive to clinicians in managing this dilemma.Objectives After completing this article, readers should be able to:1. Define and identify the risk factors associated with transfusion-related acute gut injury (TRAGI). 2. Outline the mechanisms by which blood transfusions might be implicated in the occurrence of TRAGI. 3. Explain the concept of hypoxic vasodilation and its value in the maintenance of microvascular circulation under hypoxic conditions. 4. Discuss potential strategies to decrease the risk of TRAGI in infants born at ...

show abstract

“…However, this strategy did not improve the sublingual microcirculation or organ function in a recent series of septic shock patients [49]. Of note, inhaled NO has major biological effects in the pulmonary network but only marginally increases plasma NO 2 - levels (up to 0.41 µ M , while normal values range between 0.05 and 0.30 µ M [20]) for use in peripheral hypoxic regions.…”

Section: Discussionmentioning

confidence: 99%

Oral Nitrate Increases Microvascular Reactivity and the Number of Visible Perfused Microvessels in Healthy Volunteers

Kolb¹,

Orbegozo²,

Créteur³

et al. 2017

J Vasc Res

View full text Add to dashboard Cite

Nitric oxide (NO) plays an important role in controlling microcirculatory function, but the effects of exogenous administration of nitrate (NO₃^-) on the microcirculation have not been well studied. We evaluated whether NO₃^- could influence the microvascular response to hypoxia in 17 healthy volunteers. We used a vascular occlusion test (VOT) to assess the response of near-infrared spectroscopy-derived indexes to hypoxic stress before and 2 h 15 min after oral administration of 800 mg potassium nitrate. We also monitored changes in the sublingual microcirculation using side-stream dark-field (SDF) video microscopy. The descending (7.3 [6.8-8.1] to 8.2 [7.9-9.8] %/min, p = 0.01) and ascending (201 [180-233] to 240 [197-285] %/min, p = 0.01) thenar oxygen saturation (StO₂) slopes were significantly greater during VOT after nitrate administration than before. Sublingual SDF measurements showed increases in the total number of visible perfused vessels (i.e., from 14.1 [13.2-15.5] to 16.3 [15.4-16.7] vessels/mm, p < 0.01) and in the number of visible perfused small vessels (i.e., from 12.2 [11.5-13.7] to 14.2 [13.5-15.3] vessels/mm, p < 0.01) after nitrate administration but no changes in the microvascular flow index or in the proportion of visible perfused vessels, which were already maximal at baseline. Oral administration of nitrate therefore significantly influenced the response to a hypoxic challenge, increasing the number of visible perfused vessels and thus possibly limiting the O₂ diffusion distance.

show abstract

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

Abstract: 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.

Cited by 52 publications

References 63 publications

Endothelial and Microcirculatory Function and Dysfunction in Sepsis

Endothelial and Microcirculatory Function and Dysfunction in Sepsis

Red Blood Cell Storage in Transfusion-Related Acute Gut Injury

Oral Nitrate Increases Microvascular Reactivity and the Number of Visible Perfused Microvessels in Healthy Volunteers

Contact Info

Product

Resources

About