Carlos A. Macias

Treatment With a Novel Hemigramicidin-TEMPO Conjugate Prolongs Survival in a Rat Model of Lethal Hemorrhagic Shock

Objective:We sought to develop a therapeutic agent that would permit prolongation of survival in rats subjected to lethal hemorrhagic shock (HS), even in the absence of resuscitation with asanguinous fluids or blood. Methods and Results:We synthesized a series of compounds that consist of the electron scavenger and superoxide dismutase mimic, 4-amino-2,2,6,6-tetramethylpiperidine-N-oxyl (4-NH2-TEMPO), conjugated to fragments and analogs of the membrane-active cyclopeptide antibiotic, gramicidin S. Using an in vivo assay, wherein isolated intestinal segments were loaded inside the lumen with various test compounds, we studied these compounds for their ability to prevent ileal mucosal barrier dysfunction induced by subjecting rats to profound HS for 2 hours. The most active compound in this assay, XJB-5-131, ameliorated peroxidation of the mitochondrial phospholipid, cardiolipin, in ileal mucosal samples from rats subjected to HS. XJB-5-131 also ameliorated HS-induced activation of the pro-apoptotic enzymes, caspases 3 and 7, in ileal mucosa. Intravenous treatment with XJB-5-131 (2 &mgr;mol/kg) significantly prolonged the survival of rats subjected to profound blood loss (33.5 mL/kg) despite administration of only a minimal volume of crystalloid solution (2.8 mL/kg) and the absence of blood transfusion. Conclusion:These data support the view that mitochondrially targeted electron acceptors and SOD mimics are potentially valuable therapeutics for the treatment of serious acute conditions, such as HS, which are associated with marked tissue ischemia.

The effects of trauma center care, admission volume, and surgical volume on paralysis after traumatic spinal cord injury.

Objective:To evaluate compliance with American College of Surgeons (ACS) guidelines and whether trauma center designation, hospital traumatic spinal cord injury (TSCI) case volume or spinal surgery volume is associated with paralysis. We hypothesized a priori that trauma center care, by contrast to nontrauma center care, is associated with reduced paralysis at discharge. Summary Background Data:Approximately 11,000 persons incur a TSCI in the United States annually. The ACS recommends all TSCI patients be taken to a level I or II trauma center. Methods:We studied 4121 patients diagnosed with TSCI by ICD-9-CM criteria in the 2001 hospital discharge files of 7 states (Florida, Massachusetts, New Jersey, New York, Texas, Virginia, Washington), who were treated in 100 trauma centers and 601 nontrauma centers. We performed multivariate analyses, including a propensity score quintile approach, adjusting for differences in case mix and clustering by hospital and by state. We also studied 3125 patients using the expanded modified Medicare Provider Analysis and Review records for the years 1996, 2001, and 2006 to assess temporal trends in paralysis by trauma center designation. Results:Mortality was 7.5%, and 16.3% were discharged with paralysis. Only 57.9% (n = 2378) received care at a designated trauma center. Trauma centers had a 16-fold higher admission caseload (20.7 vs. 1.3; P < 0.001) and 30-fold higher surgical volume (9.6 vs. 0.3; P < 0.001). In the multivariate propensity analysis, paralysis was significantly lower at trauma centers (adjusted odds ratio 0.67; 95% confidence interval, 0.53–0.85; P = 0.001). Higher surgical volume, not higher admission volume, was associated with lower risk of paralysis. Indeed, at nontrauma centers, higher admission caseload was associated with worse outcome. There was no significant difference in mortality. Conclusions:Trauma center care is associated with reduced paralysis after TSCI, possibly because of greater use of spinal surgery. National guidelines to triage all such patients to trauma centers are followed little more than half the time.

Hemigramicidin-tempo conjugates: Novel mitochondria-targeted antioxidants

Reactive oxygen species (ROS) are reactive, partially reduced derivatives of molecular oxygen. ROS are important in the pathogenesis of a wide range of acute pathologic processes, including ischemia/reperfusion injury, sepsis, and shock. Accordingly, effective ROS scavengers might be useful therapeutic agents for these conditions. Since mitochondria are the primary sites for ROS production within cells, it seems reasonable that targeting ROS scavengers to these organelles could be a particularly effective strategy. Indeed, a number of compounds or classes of compounds have been described that are based on this concept. One approach consists of coupling a payload--the portion of the molecule with ROS-scavenging activities--to a targeting moiety--the portion of the molecule that promotes selective accumulation within mitochondria. For example, the payload portion of XJB-5-131 consists of a stable nitroxide radical, which has been extensively investigated as a cytoprotective agent in a number of experimental models of oxidative stress. The targeting portion of XJB-5-131 consists of a portion of the membrane-active cyclopeptide antibiotic, gramicidin S. The gramicidin segment was used to target the nitroxide payload to mitochondria because antibiotics of this type have a high affinity for bacterial membranes and because of the close relationship between bacteria and mitochondria. In a rat model of hemorrhagic shock, delayed treatment with XJB-5-131 has been shown to prolong survival time in the absence of resuscitation with blood or a large volume of crystalloid fluid. Compounds like XJB-5-131 warrant further evaluation for the treatment of hemorrhagic shock as well as other acute conditions associated with increased mitochondrial production of ROS.

Survival in a rat model of lethal hemorrhagic shock is prolonged following resuscitation with a small volume of a solution containing a drag-reducing polymer derived from aloe vera.

Drag-reducing polymers (DRP) increase tissue perfusion at constant driving pressure. We sought to evaluate the effects of small-volume resuscitation with a solution containing a DRP in a rat model of hemorrhage. Anesthetized rats were hemorrhaged at a constant rate over 25 min. In protocol A, total blood loss was 2.45 mL/100 g, whereas in protocol B, total blood loss was 3.15 mL/100 g. Five minutes after hemorrhage, the animals were resuscitated with 7 mL/kg of either normal saline (NS) or NS containing 50 μg/mL of an aloe vera-derived DRP. In protocol B, a third group (CON) was not resuscitated. Whole-body O2 consumption (Vo2) and CO2 production (Vco2) were measured using indirect calorimetry. In protocol A, 5/10 rats in the NS group and 8/10 rats in the DRP group survived for 4 h (P = 0.14). Mean arterial pressure was higher in the DRP-treated group than in the NS-treated group 45 min after resuscitation (89 ± 8 vs. 68 ± 5 mmHg, respectively; P < 0.05). In protocol B, survival rates over 2 h in the DRP, NS, and CON groups were 5/15, 1/14, and 0/7, respectively (P < 0.05). Compared with NS-treated rats, those resuscitated with DRP achieved a higher peak Vo2 (9.0 ± 1.0 vs. 6,3 ± 1.0 mL/kg/min) and Vco2 (9.0 ± 1.1 vs. 6.0 ± 1.0 mL/kg/min) after resuscitation. We conclude that resuscitation with a small volume of DRP prolongs survival in rats with lethal hemorrhagic shock.