G. Mathiak

Platelet-activating factor (PAF) in experimental and clinical sepsis.

Despite considerable progress in understanding the pathogenic mechanisms of Gram-negative sepsis, the outcome of septic patients has not significantly improved. There are ample data that support a role for inflammatory mediators in sepsis that act in synergy with infectious agents to initiate and propagate the disease process. One such mediator is the glycerophospholipid platelet-activating factor (PAF). The objective of the present review is to summarize experimental and clinical evidence implicating PAF as a mediator in the pathomechanism of sepsis. This review is timely because many potent and selective PAF antagonists have matured for clinical development and a careful analysis of the data that support or refute the merit of clinical trials with such compounds may be important for both academic and pharmaceutical applications.

An improved clinically relevant sepsis model in the conscious rat

Objective To develop an improved small animal experimental paradigm that more closely mimics human sepsis. Design Prospective, randomized, controlled animal study. Setting Medical school research laboratory. Subjects Male Sprague-Dawley rats (280–320 g). Interventions We monitored the hemodynamic, hematologic, and biochemical consequences of abdominal sepsis produced by intraperitoneal implantation of a fibrin clot containing Escherichia coli in conscious, antibiotic-treated rats. Measurements and Main Results Similar to human sepsis, the implanted, infected clot (LD50 = 5–7 × 108 colony forming units/mL, n = 6) elevated cardiac index (>7% vs. sterile clot, p < .05, at 4 hrs), whereas mean arterial pressure and heart rate remained unaffected. The total peripheral resistance index and stroke volume index tended to decrease and increase, respectively. In contrast, an intravenous bolus injection of endotoxin (LD50 of E. coli lipopolysaccharide = 5.6 mg/kg, n = 7), the most commonly used sepsis model, induced profound hypodynamic responses manifested by a 27% decrease (vs. endotoxin vehicle, p < .01) in cardiac index, a 28% increase in the total peripheral resistance index (p < .01), and a 33% decrease in the stroke volume index (p < .01). The infectious peritonitis model also displayed dose-dependent thrombocytopenia (<61%, p < .05), leukopenia (<60%, p < .05), and mortality rate (50% at 5–7 × 108 colony forming units/mL, p < .05) with a minimally elevated serum tumor necrosis factor-&agr; level (145 vs. 12 ± 6 pg/mL in controls, p < .05). Conclusion This rodent model of antibiotic-treated, intra-abdominal infection features key characteristics of clinical sepsis. Although the hyperdynamic response observed in septic patients undergoing resuscitation was not clearly elicited, this paradigm better mimics clinical sepsis compared with the commonly used endotoxin model. Thus, utilization of this paradigm may provide additional opportunities to explore mechanisms of sepsis and to examine novel therapeutics.

Abdominal injuries associated with lumbar spine fractures in blunt trauma

BACKGROUND Specific analysis of the relationship between abdominal injuries and lumbar spine fractures has not yet been reported. METHODS A retrospective review of 258 blunt trauma patients with lumbar spine fractures treated between 1991 and 1996. RESULTS 26 patients sustained concomitant lumbar spine fractures and abdominal injuries. The mechanism of injury was motor vehicle collision (73%), pedestrian-struck (11%), fall (8%) and assault (8%) resulting in ISS, RTS and mortality of 27 +/- 4, 6.5 +/- 0.4 and 8%, respectively. Forty-four lumbar spine fractures were identified (1.7/pt) in association with splenic (54%), renal (41%), hepatic (32%) and small bowel (23%) injuries and no retroperitoneal involvement. Multilevel lumbar spine fractures were associated with a higher organ injury/fracture ratio compared with single level fractures (p < 0.01) including a twofold higher incidence of solid organ (spleen, liver and kidney) injury (p < 0.01). The level and type of fracture did not affect the incidence of total and individual organ injury. Patients with abdominal injuries were more severely injured mainly due to increased incidence of associated thoracic injuries although no significant difference in mortality was observed. CONCLUSION Abdominal injuries occurred only in the minority of blunt trauma patients with lumbar spine fractures. These injuries, which followed a similar distribution pattern as in blunt trauma in general, occurred most commonly due to motor vehicle collisions and in association with multilevel vertebral fractures. No correlation with fracture type or level was identified.

Chemokines and interleukin-18 are up-regulated in bronchoalveolar lavage fluid but not in serum of septic surgical ICU patients.

Our objective was to investigate the levels of chemokines (MIP1-alpha, MCP-1, and Gro-alpha), Interleukin-18 (IL-18), and Interleukin (IL-6) in bronchoalveolar lavage (BAL) fluid and serum at the onset and ongoing states of sepsis as defined by the American College of Chest Physicians/Society of Critical Care Medicine in septic surgical ICU patients. Our summary background data was to understand the significance of compartmentalized inflammatory mediator production in an immunologically active organ (lung) in comparison with levels in the systemic circulation. The study group consisted of 20 septic patients and 10 non-septic patients on surgical ICU. At the onset of sepsis, both BAL fluid and serum samples were taken and levels of MIP-1alpha, MCP-1, GRO-alpha, IL-18, and IL-6 were measured by ELISA. Furthermore, over a subsequent 8-day period, levels of these mediators were determined in serum. In some experiments, IL-18 mRNA levels were determined in peripheral blood lymphocytes (PBL) of septic and non-septic patients. At the onset of sepsis, MIP-1alpha, MCP-1, GRO-alpha, IL-18, and IL-6 levels were significantly up-regulated in BAL fluid as compared with non-septic controls. In marked contrast, with the exception of IL-18 mRNA and IL-6 peptide, there was no increase in serum levels of inflammatory mediators determined both at the onset and during the ongoing states of sepsis. Based on the present data, monitoring levels of serum chemokines and IL-18 protein as markers of sepsis might be misleading since despite their non-detection in serum, they were highly up-regulated in the lung tissue compartment. These data might underscore the role of MIP-1alpha, MCP-1, GRO-alpha, and IL-18 in the mediation of local tissue damage. Furthermore, these findings raise the notion that mediator measurement in immunologically active organs might serve as pivotal indicators of sepsis prior to the actual fulfillment of specific clinical criteria that defines the patient as being septic.

Effect of Liposome-Encapsulated Hemoglobin on Triglyceride, Total Cholesterol, Low-Density Lipoprotein, and High-Density Lipoprotein Cholesterol Measurements

The present study investigated the effect of liposome-encapsulated hemoglobin (LEH), an experimental oxygen-carrying resuscitation fluid, on triglyceride, total cholesterol, and low density lipoprotein (LDL), and high density lipoprotein (HDL) cholesterol measurements. In vivo, the intravenous infusion of LEH (5.6 mL/kg, n=6) elevated serum triglycerides (+92% vs. baseline, P<.05), total cholesterol (+25% vs. baseline, P<.01), LDL cholesterol (+72% vs. baseline, P<.01) and had no effect on serum HDL cholesterol. In addition, LEH did not alter the elevation in serum triglycerides (+302% vs. baseline, P<.01) and LDL cholesterol (+86% vs. baseline, P<.01) induced by lipopolysaccharide (3.6 mg/kg, i.v., n=6). Ex vivo, measurements of triglycerides and total cholesterol as well as LDL and HDL cholesterol in whole blood from naive rats were not changed by the addition of LEH (0–50%, n=6). In vitro, the addition of a fixed concentration of LEH (50%, n=6) to varying concentrations of cholesterol solution (0–50%), or vice versa, had no effect on cholesterol determination. It is therefore concluded that LEH only minimally affects serum levels of triglycerides, total cholesterol, LDL cholesterol, and HDL cholesterol and does not interfere with their measurement.