Excessive production of proinflammatory mediators is observed in patients undergoing hemorrhagic and septic shock. Here, we report the detection of cold-inducible RNA-binding protein (CIRP) in the blood of surgical ICU individuals. In animal models of hemorrhage and sepsis, CIRP is up-regulated in several organs and released into the circulation. Under hypoxic stresses, CIRP in macrophages is translocated from the nucleus to the cytosol and actively released. Recombinant CIRP stimulates TNF-α and HMGB1 release in macrophages as well as induces inflammatory responses and causes tissue injury in animals. Antisera to CIRP attenuate shock-induced inflammation, tissue injury, and lethality. Extracellular CIRP's activity is mediated through the TLR4/MD2 complex. Surface plasmon resonance analysis indicates that CIRP binds to the TLR4/MD2 complex as well as to individual TLR4 and MD2. The human CIRP amino-acid segment 106-125 binds to MD2 with high affinity. Collectively, CIRP is a new proinflammatory mediator of shock.

Necrotizing fasciitis has been associated with significant morbidity and mortality. Thirty-three patients were studied over a 3-year period. Predisposing factors included intravenous drug abuse (30%), diabetes (21%), and obesity (18%). Severe pain (94%) and abnormal temperature (88%) were present, whereas laboratory data and x-ray were nonspecific. Gram-positive organisms were most frequently recovered (B-hemolytic streptococcus 45%). Treatment consisted of antibiotics, surgical debridement, re-exploration 24 hours before surgery, nutritional support, and early soft tissue coverage as needed. Mean duration from admission to operation was 43 hours. The average number of operative debridements was three and the average length of hospitalization was 47 days. Patients operated on less than 12 hours from admission or greater than 48 hours had shorter hospital stays (36 and 38 days). The critical time period was 12-48 hours after admission; all deaths and amputations were in this group and the average hospital stay was 62 days (p less than 0.05). The number of operations did not correlate to hospital stay. Despite antibiotics and aggressive debridement, significant morbidity exists if operation is delayed more than 12 hours. Methods of early detection such as local bedside diagnostic incision and fascial inspection may be needed in high risk patients to further reduce the morbidity and mortality.

Several significant advances in the treatment of hepatic injuries have evolved over the past decade. These trends have been incorporated into the overall treatment strategy of hepatic injuries and are reflected in experiences with 411 consecutive patients. Two hundred fifty-eight patients (63%) with minor injuries (grades I to II) were treated by simple suture or hemostatic agents with a mortality rate of 6%. One hundred twenty-eight patients (31%) sustained complex hepatic injuries (grades III to V). One hundred seven patients (83.5%) with grades III or IV injury underwent portal triad occlusion and finger fracture of hepatic parenchyma alone. Seventy-three surviving patients (73%) required portal triad occlusion, with ischemia times varying from 10 to 75 minutes (mean, 30 minutes). The mortality rate in this group was 6.5% (seven patients) and was accompanied by a morbidity rate of 15%. Fourteen patients (11%) with grade V injury (retrohepatic cava or hepatic veins) were managed by prolonged protal triad occlusion (mean cross-clamp time, 46 minutes) and extensive finger fracture to the site of injury. In four of these patients an atrial caval shunt was additionally used. Two of these patients survived, whereas six of the 10 patients managed without a shunt survived, for an overall mortality rate of 43%. Over the past 4 years, six patients (4.7%) with ongoing coagulopathies were managed by packing and planned re-exploration, with four patients (67%) surviving and one (25%) developing an intra-abdominal abscess. One additional patient (0.8%) was managed by resectional debridement alone and survived. During the past 5 years, 25 hemodynamically stable and alert adult patients (6%) sustaining blunt trauma were evaluated by computed tomography scan and found to have grade I to III injuries. All were managed nonoperatively with uniform success. The combination of portal triad occlusion (up to 75 minutes), finger fracture technique, and the use of a viable omental pack is a safe, reliable, and effective method of managing complex hepatic injuries (grade III to IV). Juxtahepatic venous injuries continue to carry a prohibitive mortality rate, but nonshunting approaches seem to result in the lowest cumulative mortality rate. Packing and planned reexploration has a definitive life-saving role when used adjunctively in the presence of a coagulopathy. Nonoperative management of select hemodynamically stable adult patients, identified by serial computed tomography scans after sustaining blunt trauma is highly successful (95-97%).

Cold inducible RNA-binding protein (CIRP) is a nuclear protein which has been recently identified as a novel inflammatory mediator in hemorrhagic shock and sepsis. We hypothesized that CIRP acts as a potent inflammatory mediator in hepatic ischemia-reperfusion (I/R), and thus blocking CIRP protects against I/R-induced liver injury. Male C57BL/6 mice were subjected to 70% hepatic ischemia by microvascular clamping of the hilum of the left and median liver lobes for 60 min, followed by reperfusion. Anti-CIRP antibody (1 mg/kg body weight) or vehicle (normal saline) in 0.2 mL was injected via the internal jugular vein at the beginning of the reperfusion. Blood and liver tissues were collected 24 h after I/R for various measurements and a 10-day survival study was performed. CIRP released into the circulation was significantly increased 24 h after hepatic I/R. Anti-CIRP antibody treatment markedly reduced hepatocellular damage markers and significantly improved the liver microarchitecture. Anti-CIRP also reduced the systemic and local inflammation demonstrated by attenuation in both serum and hepatic levels of interleukin 6. The expression of neutrophil-attracting chemokine as well as liver neutrophil infiltration was reduced by anti-CIRP treatment. Anti-CIRP also dramatically decreased the amount of apoptosis and nitrosative stress, evidenced by decrease in TUNEL staining and inducible nitric oxide synthase and cyclooxygenase-2 levels, respectively. Finally, the 10-day survival rate was increased from 37.5% in the vehicle group to 75% in the anti-CIRP treatment group. Thus, targeting CIRP offers potential therapeutic implications in the treatment of hepatic I/R injury.