An increase in serum C18 unsaturated free fatty acids as a predictor of the development of acute respiratory distress syndrome.
OBJECTIVE
No means exist for predicting the acute respiratory distress syndrome (ARDS), which complicates sepsis, trauma, and a variety of clinical disorders. Because activation of phospholipid-signaling pathways involving the acyl chains oleate and linoleate may initiate and amplify the inflammatory response, and thereby lead to the development of ARDS, we examined whether serum concentrations of these bioactive lipids increase and are predictive of ARDS in at-risk patients.


METHODS
Part I: A prospective, single-blind trial. Part II: A prospective, randomized, double-blind trial.


METHODS
General intensive therapy units in five university teaching hospitals.


METHODS
Part I: Thirty-nine healthy control patients were studied to determine normal distribution of serum acyl values, followed by 30 patients admitted with onset of sepsis, trauma, or development of ARDS (within 24 hrs of admission) over a 1-yr period. Part II: Eight patients admitted with sepsis syndrome over a 2-month period.


METHODS
Part II: Patients were randomized to receive the substituted methylxanthine, lisofylline (CT1501R), or an identically presented placebo.


RESULTS
We measured the serum free fatty acid concentrations in the 39 healthy control subjects, and then we prospectively examined the serum free fatty acid concentrations in 30 age-matched patients in samples obtained within 24 hrs from the onset of sepsis, trauma, or development of ARDS. We then prospectively studied eight septic, at-risk patients who were matched for age, Acute Physiology and Chronic Health Evaluation II scores, Multiple Organ Failure index, and Glasgow Coma Score, in a double-blind, placebo-controlled, pilot study. These patients included four patients who received no treatment and four patients who received lisofylline, a compound that decreases serum unsaturated free fatty acids and diminishes acute lung injury in animals caused by sepsis and/or trauma. The calculated ratios of serum free fatty acids (Le., the ratio of C18 unsaturated fatty acids linoleate and oleate to fully saturated palmitate, C16:0) increased and predicted the development of ARDS in at-risk patients. Serum samples from the 30 patients, obtained within 24 hrs from the onset of sepsis, trauma, or development of ARDS, had significantly increased mean acyl chain ratios (1.42 +/- 0.35 [SD]) compared with healthy control subjects (0.86 +/- 0.25; p < .01). Sera from 13 patients with sepsis or trauma who did not develop ARDS (group A [at-risk, non-pre-ARDS]) also had increased acyl ratios (1.23 +/- 0.27) compared with sera from healthy control subjects (0.86 +/- 0.25; p < .01). Sera from seven patients who subsequently developed ARDS (group B [at-risk, pre-ARDS]) had higher acyl ratios (1.70 +/- 0.21) than group A at-risk patients who did not develop ARDS (1.23 +/- 0.27; p < .01) or healthy control subjects (0.86 +/- 0.25; p < .001). Sera from ten group C patients with ARDS at the time of admission to the study had the highest acyl ratios (1.80 +/- 0.75), which exceeded values for healthy control subjects (p < .001) and group A at-risk patients without ARDS (p = .01), but were not significantly different then group B at-risk, pre-ARDS patients (p = .17). Prospective study of eight septic, at-risk patients demonstrated significantly (p < .05) increased serum acyl ratios in the four untreated patients (findings consistent with the first study) but a significantly (p = .02) reduced ratio in the four at-risk patients treated with lisofyline.


CONCLUSIONS
Increases in unsaturated serum acyl chain ratios differentiate between healthy and seriously iII patients, and identify those patients likely to develop ARDS. Thus, the serum acyl ratio may not only prospectively identify and facilitate the assessment of new treatments in patients at highest risk for developing ARDS, but may also lead to new insights about the pathogenesis of ARDS.
Bursten
S L
SL
Division of Lipid Biology, Cell Therapeutics, Inc., Seattle, WA 98119, USA.
Federighi
D A
DA
Parsons
P
P
Harris
W E
WE
Abraham
E
E
Moore
E E
EE
Moore
F A
FA
Bianco
J A
JA
Singer
J W
JW
Repine
J E
JE
D000328:Adult; D004311:Double-Blind Method; D005230:Fatty Acids, Nonesterified / Q000097:blood*; D005231:Fatty Acids, Unsaturated / Q000097:blood*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010431:Pentoxifylline / Q000031:analogs & derivatives / Q000494:pharmacology; D011446:Prospective Studies; D012128:Respiratory Distress Syndrome / Q000175:diagnosis*; D018805:Sepsis / Q000097:blood; D016037:Single-Blind Method; D014947:Wounds and Injuries / Q000097:blood; D014970:Xanthines / Q000494:pharmacology
D005230:Fatty Acids, Nonesterified; D005231:Fatty Acids, Unsaturated; D014970:Xanthines; C008514:methylxanthine; C025189:lisofylline; D010431:Pentoxifylline