Inhaled Nitric Oxide Improves Outcomes in Mice Resuscitated with Stored Blood

Inhaled nitric oxide reduced the adverse effects of transfusing stored blood in mice, according to a study from the December issue of Anesthesiology. Researchers found that inhaled nitric oxide reduced tissue injury and improved short-term survival in mice that were resuscitated with a stored blood transfusion after hemorrhagic shock.

An estimated 40 percent of critically ill individuals receive at least one unit of packed red blood cells in the intensive care unit.¹ At Massachusetts General Hospital, the average human red cell storage duration is 16 days, and many units are stored for much longer, up to 42 days.

Transfusion of blood stored for longer durations is associated with increased morbidity and mortality, especially in patients with cardiovascular disease. Stored blood cells have reduced ability to transport oxygen, and many are destroyed after transfusion causing vascular nitric oxide, an important cellular messenger, to be scavenged.

“While blood transfusions help many patients, when red cells are stored for long periods before transfusion they can make some patients sicker,” said study senior author Warren M. Zapol, M.D. “Our research was modeled in mice to reproduce the adverse effects of stored blood transfusion and to learn which recipients might be more sensitive.”

About the Study
Mice were fed either a standard diet (10% calories from fat) or high-fat diet (60% calories from fat) for four to six weeks. They were then subjected to 90 minutes of hemorrhagic shock, followed by resuscitation and transfusion with either fresh blood (less than 24 hours old) or blood stored for two weeks. There was no immune response to transfusion because the mice were transfused with genetically-identical mouse blood.

Findings showed mice fed a standard diet, who received stored blood transfusion had increased tissue injury compared to those that received fresh blood transfusion. In addition, mice fed a high-fat diet that received stored blood transfusion had higher blood lactate levels and insufficient oxygen delivered via the blood stream, associated with a greater short-term mortality. 

Researchers found that when mice breathed nitric oxide, during and after transfusion, they had reduced tissue injury, lower lactate levels, and less inflammation and oxidative stress. Inhaled nitric oxide also improved the short-term survival rate of mice fed a high-fat diet, who were resuscitated with stored blood transfusion.

“Resuscitation with stored blood transfusion adversely impacts the outcomes of mice with hemorrhagic shock, an effect that is exacerbated by feeding mice a high-fat diet,” continued Dr. Zapol. “Our research also confirms that stored blood transfusion is bad for mice that have diabetes or are overweight, and the toxicity of stored blood in mice can be prevented with inhaled nitric oxide.”

Stored blood administration remains a critical component of the treatment of hemorrhage or anemia which results in inadequate oxygen delivery to tissues.

Dr. Zapol and his team hope their findings will help to better identify those patients who will be most susceptible to negative outcomes after a stored blood transfusion, as well as highlight the benefits of breathing nitric oxide when patients are transfused with stored red cells.

Dr. Zapol receives royalties from patents on inhaled nitric oxide licensed by Massachusetts General Hospital to Linde Corp., Munich, Germany and Ikaria Inc., Clinton, New Jersey.
 
For more information, visit the Anesthesiology website at anesthesiology.org.

¹Napolitano, L.M. et al. Crit. Care Med. 37, 3124-3157 (2009).