Intermittent prone positioning was not able to reduce the duration of mechanical ventilation in this limited number of patients. However the oxygenation improved significantly over the first four days of treatment, and the prevalence of ARDS and pneumonia were reduced.

Ubiquitin is suggested to play a key role in essential intracellular functions, such as heat shock response, protein breakdown, and regulation of immune responses. Ubiquitin has also been detected in the extracellular space, but the function and biologic significance is unclear. We describe a new function of extracellular ubiquitin and show that extracellular ubiquitin specifically inhibits ex vivo secretion of tumor necrosis factor-␣ (TNF-␣) and TNF-␣ mRNA expression from peripheral blood mononuclear cells (PBMNCs) in response to endotoxin in a dose-dependent manner. In contrast, the TNF-␣ response to zymosan or Staphylococcus aureus as well as the interleukin-6 (IL-6) and IL-8 responses to endotoxin were unaffected by ubiquitin. Measurement of serum ubiquitin levels showed a significant 5-to 7-fold increase in sepsis and trauma patients, to the level required for inhibition of the PBMNC TNF-␣ response to endotoxin by ubiquitin. Elevated ubiquitin levels in serum were significantly correlated with a reduced TNF-␣ production. Antibodies to ubiquitin were able to (1) significantly increase (2-to 5-fold) the TNF-␣ response to endotoxin in whole blood from trauma and sepsis patients, (2) completely neutralize the inhibitory effect of trauma patients' serum on healthy donors' TNF-␣ production, and (3) partially neutralize the inhibitory effect of sepsis patients' serum on healthy donors' TNF-␣ production. Ubiquitin-depleted serum from trauma patients lost the inhibitory activity for TNF-␣ production, whereas extracted endogenous ubiquitin exerts the inhibitory activity. The results demonstrate that extracellular ubiquitin acts as a cytokinelike protein with anti-inflammatory properties and indicate that extracellular ubiquitin is involved in the regulation of immunodepression in critical

ObjectiveTo investigate the relation of the biallelic Nco1 restriction fragment length polymorphism in the first intron of the tumor necrosis factor (TNF) ␤ gene with the development of severe sepsis in multiply injured patients. Summary Background DataThe biallelic Nco1 polymorphism of the TNF␤ gene has been described to be associated with autoimmune diseases and with the mortality rate in severe sepsis. Therefore, the Nco1 polymorphism may be associated with the clinical finding that despite comparable risk factors, posttraumatic sepsis develops in some patients but not others. MethodsThe study group consisted of 110 patients with severe blunt trauma (Injury Severity Score Ն 17). Typing of each patient for the biallelic Nco1 polymorphism was performed by analyzing restriction fragments of an Nco1-digested DNA fragment obtained using polymerase chain reaction. Genotypes were then related to the occurrence of severe posttraumatic sepsis and TNF␣ serum concentrations. ResultsFifty-seven patients showed an uncomplicated posttraumatic recovery, and severe sepsis developed in 53 patients. The overall allele frequency (TNFB1 0.29, TNFB2 0.71) and genotype distribution (TNFB1 homozygous 7.3%, TNFB1/TNFB2 42.7%, TNFB2 homozygous 50%) were in agreement with the distribution in healthy volunteers. Genotype distribution in patients with an uncomplicated clinical course was significantly different from that in patients with severe posttraumatic sepsis. Development of severe posttraumatic sepsis was significantly increased in patients homozygous for the allele TNFB2. In patients with severe posttraumatic sepsis, TNF␣ serum concentrations were significantly higher in TNFB2-homozygous individuals compared with heterozygous and TNFB1-homozygous individuals. The age-and injury-matched odds ratio for the homozygous TNFB2 genotype compared with the heterozygous genotype was 5.22 (p ϭ 0.007, 95% confidence interval 1.6 to 17.9).

In severely injured patients, decreased levels of cellular and soluble HLA-DR appear as early indicators of an immune deviation associated with the development of severe sepsis. Moreover, immune alterations of different cell types may promote distinct kinds of septicemia.

We present a prospective study, designed to evaluate surfactant abnormalities in severely injured patients during the course of post-traumatic pulmonary dysfunction. Serially obtained bronchoalveolar lavage fluids from noncontused lung areas (in total, 132 samples from 17 patients) were analyzed for alveolar phospholipid composition and surfactant function in vitro during the first 14 days after trauma. The data were compared with those of 29 lavage samples obtained from 10 healthy control subjects and correlated to severity of respiratory failure. In the traumatized patients, the total lavage phospholipid content was unchanged, but there was a progressive decrease in the relative amounts of phosphatidylcholine (%PC) and phosphatidylglycerol and an increase in phosphatidylinositol, phosphatidylethanolamine, and sphingomyelin. These alterations were paralleled by a marked decrease in the hysteresis area of the surface tension isotherm. The decrease in %PC and reduction of hysteresis area were significantly correlated. The alterations in alveolar phospholipid composition and in vitro surfactant function were more pronounced in patients with severe respiratory failure. There was a significant inverse correlation between severity of respiratory dysfunction and %PC or hysteresis area for all traumatized patients. Protein leakage into the alveolar space was significantly higher in patients with severe respiratory failure and appeared to precede surfactant abnormalities in such patients. The neutrophil content in the alveolar space was markedly increased in all patients with multiple injuries however, no significant correlation with the noted alterations in alveolar phospholipid composition or surfactant function was found. We concluded that surfactant abnormalities occur during the course of post-traumatic pulmonary dysfunction and are correlated with the severity of respiratory failure.

Although MOF incidence remains unchanged, there is a significant fall in MOF-related mortality in patients with severe trauma, and death from single organ failure is virtually absent. Severe brain injury is now the leading cause of death in patients with severe multiple injuries admitted to the ICU.

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Ubiquitin is apparently safe and effective for reducing fluid requirements as a measure of diffuse capillary leak. This immunomodulatory property suggests a new therapeutic approach after injury in particular, and for infectious and noninfectious inflammation in general.