Predicting Organ Failure Severity in Sepsis

A new study has found that the severity of organ failure, inflammation, and presence of early shock in severe sepsis are associated with increased levels of asymmetrical dimethyl arginine (ADMA).

Researchers from Trinity College (Dublin, Ireland) and St. James Hospital (Dublin, Ireland) conducted a prospective observational study of 47 intensive care unit (ICU) patients at St. James with severe sepsis, and 10 healthy controls from among staff members. Serum ADMA--an endogenous non-selective inhibitor of the nitric oxide synthase (NOS) enzyme--and interleukin-6 (IL-6) were assayed on admission to the ICU and seven days later. Allelic genetic variation for a polymorphism was assessed in each patient. Blood samples were available from 40 patients on day one and 35 patients on day seven. Twenty-eight patients were available for blood samples at both time points. Fourteen (30%) of the patients died prior to ICU discharge.

On day one, more ADMA was detectable in the ICU group than in the control group. Levels subsequently increased during the first week in the ICU. ADMA levels were associated with vasopressor requirements on day one. ADMA levels and sequential organ failure assessment (SOFA) scores were directly associated on day one and day seven, with the degree of acidemia and lactemia directly correlating with ADMA levels at both time points. On day seven, IL-6 directly correlated with ADMA levels. The G allele at position -449 in the regulatory gene DDAH II gene was associated with increased ADMA concentrations at both time points. The results were published in Critical Care, a peer-reviewed journal published by BioMed Central, on September 26, 2006.

"We have confirmed the association between ADMA levels and the extent of multiple organ failure in sepis,” concluded Dr. Michael J. O'Dwyer and colleagues. "We suggest that ADMA levels may be regulated via a genetic component. We propose that polymorphism at position -449 in the DDAH II gene may be functional and has the potential to be used as a marker for the susceptibility to, and the severity of, an inflammatory response secondary to an infective insult.”

ADMA levels may be genetically determined by a promoter polymorphism in the DDAH II gene that functions by metabolizing ADMA to citrulline.



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Trinity College
St. James Hospital
Critical Care