Jerome Vernick

Serum tumor necrosis factor-alpha profile in trauma patients.

Tumor necrosis factor-alpha (TNF-alpha) has been implicated in several late consequences of trauma such as sepsis, multiple organ failure, and ischemia-reperfusion injury. However, no data are available to indicate whether TNF-alpha is involved in the initial pathophysiologic response to trauma. To address this issue, serum TNF-alpha was determined (by ELISA) longitudinally (first blood sample on admission) in 100 randomly selected trauma patients admitted to the emergency department and trauma division at Jefferson Medical Center, Philadelphia. The TNF-alpha levels were detectable at one or more time points in 35 patients. Mean values tended to be elevated (50.3 +/- 11.5 pg/mL) during the first 5 days, but this trend did not differ statistically from that in healthy controls (n = 12) and did not correlate with the severity of injury (Injury Severity Score and Glasgow Coma Scale score). The TNF-alpha response was not dependent on the mechanism and site of injury, the presence of shock (systolic blood pressure < 90 mm Hg), and the need for emergent surgery. Also, serum TNF-alpha levels were not significantly elevated in patients who subsequently developed multiple organ failure (n = 4), septic shock (n = 5), or both (n = 3). Taken together, these data do not support a role for circulating TNF-alpha in the initial acute inflammatory response to trauma.

Lyophilized liposome encapsulated hemoglobin: evaluation of hemodynamic, biochemical, and hematologic responses.

ObjectiveTo characterize the hemodynamic, biochemical, and hematologic responses to the administration of the oxygen-carrying fluid lyophilized liposome-encapsulated hemoglobin in the conscious, normovolemic rat. DesignProspective, randomized trial. SettingAnimal laboratory, Jefferson Medical College. SubjectsEighty-four male Sprague-Dawley rats. InterventionsCatheters were introduced into the right atrium (through the jugular vein) and both femoral arteries of test animals, and a thermistor was placed in the ascending aorta through the left common carotid artery for infusion of lyophilized liposome-encapsulated hemoglobin, blood collection, and blood pressure (BP) and cardiac output determinations. Measurements and Main ResultsLyophilized liposome-encapsulated hemoglobin (n = 8) infusion (1 mL/min iv) at 1 or 6 mL/kg (10% of estimated blood volume) had no detectable effect on BP, cardiac output, total peripheral resistance, and heart rate during the 5-hr observation period. The infusion also had no effect on hematocrit, leukocyte count, and serum tumor necrosis factor-α concentrations. Survival at 7 days was 100% (n = 20). Lyophilized liposomeencapsulated hemoglobin caused transient (2-hr) thrombocytopenia (-24 ± 9% vs. a Ringers lactate control group, p < .01), and marginally increased serum thromboxane B2 concentrations (14.6 ± 6 pg/100 μL, p < .01). ConclusionsThese data suggest that lyophilized liposome-encapsulated hemoglobin can be safely administered to conscious rats, supporting the development of this substance as a potential blood substitute. (Crit Care Med 1994; 22:480–485)

A new salutary resuscitative fluid: liposome encapsulated hemoglobin/hypertonic saline solution.

Low-volume resuscitation with hypertonic (7.5%) saline (HTS) is an evolving therapeutic modality for patients with hemorrhagic shock. This solution has been shown to exert protective hemodynamic effects in models of controlled hemorrhagic shock and in several clinical trials. However, HTS has no oxygen-carrying capacity and therefore does not improve oxygen delivery directly. One of the leading strategies in developing an oxygen-carrying resuscitative fluid is the encapsulation of hemoglobin within phospholipid vesicles (LEH). This preparation has the advantage of being blood type and antigen free, easily adaptable to scale-up production, and remarkably stable with a long shelf life. We therefore tested the hypothesis that lyophilized LEH reconstituted with HTS will improve tissue oxygenation and survival in rats exposed to a lethal controlled hemorrhagic shock. Shock was induced by withdrawal of 70% of blood volume and therapy (n = 10-16) with HTS (5 mL/kg), LEH (5 mL/kg), lactated Ringers solution (vol:vol = 1:3), LEH-HTS (5 mL/kg), or oxygen (100%) was initiated 15 minutes later. The LEH-HTS improved skeletal muscle oxygen tension directly measured using a thin-film chamber oxygen sensor (PO2 87 +/- 13 mm Hg vs. 40-50 mm Hg in other groups, p < 0.05). This was associated with improved blood pressure, reduced acidosis, and increased survival at 24 hours (75% vs. 6%-25% in other groups, p < 0.05). In conclusion, the study demonstrates a remarkably salutary effect of LEH reconstituted with HTS as a blood substitute in the treatment of hemorrhagic shock.

Response to Blunt Chest Injury: A New Experimental Model

Abstract : Pulmonary insufficiency continues to be a major cause of death following trauma of many types. In combat casualties, direct injury to the lung is the most common cause of arterial hypoxemia, though contusion of the chest wall by a high velocity bullet may actually produce a greater pulmonary injury than when the lung is penetrated. Similarly, the familiar civilian injuries that occur when the chest is crushed against the steering wheel may produce severe contusion of the underlying pulmonary parenchyma while the chest wall remains intact. An experimental method for producing a standard injury to the lung through the intact chest wall was developed, and the acute changes in cardiopulmonary function following injury have been studied. The physiologic changes associated with healing of the injury were documented.

Platelet activating factor mediates interleukin-2-induced lung injury in the rat

Interleukin-2 was recently shown to cause acute lung injury characterized by microvascular permeability defect, interstitial edema, and leukosequestration. Similar responses can also be produced by platelet activating factor (PAF). Thus, the present study aimed to examine whether PAF plays a key role in the development of IL-2-induced lung injury in the anesthetized rat. Intravenous infusion (60 min) of recombinant human IL-2 at 10(5)-10(6) U/rat (n = 7-9) dose-dependently elevated lung water content (27 +/- 1%, P less than 0.01), myeloperoxidase activity (+84 +/- 23%, P less than 0.05), and serum thromboxane B2 (990 +/- 70%, P less than 0.01), but failed to alter blood pressure, hematocrit, serum tumor necrosis factor-alpha, and circulating leukocytes and platelets. Pretreatment (-30 min) with a potent and specific PAF antagonist, BN 50739 (10 mg/kg, intraperitoneally, n = 6) prevented the pulmonary edema (P less than 0.05) and thromboxane B2 production (P less than 0.01), and attenuated the elevation of lung myeloperoxidase activity (+18 +/- 16%, P less than 0.05) induced by IL-2. These data suggest that PAF is involved in the pathophysiological processes leading to IL-2-induced lung injury, and point to the potential therapeutic capacity of PAF antagonists in preventing pulmonary edema during IL-2 therapy.

Aspiration-induced lung injury: Role of complement

OBJECTIVES To examine the role of complement in the development of acid aspiration-induced lung injury in the rat. It was postulated that inhibition or depletion of complement attenuates aspiration-induced lung injury. DESIGN Controlled animal trial. SETTING Animal Laboratory, Jefferson Medical College, Philadelphia, PA. SUBJECTS Anesthetized rats. INTERVENTIONS Aspiration was induced by the intratracheal administration of 0.2 mL of 0.1 N hydrochloric acid (n = 7) and lung injury was evaluated by determining water content, myeloperoxidase activity, protein concentration, and leukocyte count in bronchoalveolar lavage fluid. Muscle PO2 was directly measured using a thin-film chamber oxygen sensor and serum tumor necrosis factor-alpha was assayed by enzyme-linked immunosorbent assay. The effect of complement inhibition by recombinant human soluble complement receptor type 1 (n = 8) or complement depletion by cobra venom factor (n = 7) on lung injury was evaluated. MEASUREMENTS AND MAIN RESULTS Acid aspiration induced pulmonary leukosequestration, edema, and a microvascular permeability defect, along with tissue hypoxia. Pretreatment with soluble complement receptor type 1 (complement inhibition) or cobra venom factor (complement depletion) significantly reduced lung edema (-61 +/- 7%; p < .05), eliminated protein accumulation in bronchoalveolar lavage fluid (p < .01), and improved (p < .05) tissue oxygenation. In contrast, there was no effect of soluble complement receptor type 1 or of cobra venom factor on leukosequestration. CONCLUSIONS Acid aspiration induces lung injury through a complement-dependent mechanism that leads to microvascular permeability defects. Therefore, the possibility that complement inhibitors may have a salutary effect in humans with aspiration-induced lung injury should be investigated.

Surgical management of severe liver trauma: a role for liver transplantation

Severe devascularizing liver injuries continue to carry a high mortality. Rapid operative intervention to achieve hemostasis and debride devitalized tissue remains essential to salvaging these patients. For those with unsalvageable liver injuries liver transplantation can be employed. Careful support of the patient in the anhepatic state, reversal of coagulopathy, and use of venous bypass intraoperatively permit successful transplantation.

Interleukin-2-induced lung injury. The role of complement.

Pulmonary edema and sepsis-like syndrome are grave complications of interleukin-2 (IL-2) therapy. Recent animal studies have suggested IL-2-induced microvascular injury as the underlying mechanism. Since complement factors have been shown to mediate increased vascular permeability in diverse conditions that lead to pulmonary injury and recombinant human IL-2 is known to activate the complement system in patients undergoing IL-2 therapy, we hypothesized that complement factors play a pivotal role in the development of increased vascular permeability after IL-2 treatment. To test this hypothesis, we evaluated the capacity of recombinant soluble human complement receptor type 1 (sCR1, BRL 55730), a new highly specific complement inhibitor, to attenuate IL-2-induced lung injury in the rat. Recombinant human IL-2 (intravenously for 60 minutes) at 10(6) U per rat (n = 4) elevated lung water content (37 +/- 6%, P < .05), myeloperoxidase activity (162 +/- 49%, P < .05), and serum thromboxane B2 (30 +/- 1 pg/100 microL, P < .01) and had no effect on serum tumor necrosis factor-alpha sCR-1 at 30 mg/kg (n = 5), but not at 10 mg/kg (n = 6), attenuated the elevation of lung water content (18 +/- 2%, P < .05) and myeloperoxidase activity (42 +/- 9%, P < .05) but failed to alter serum thromboxane B2 response to IL-2. These data suggest the involvement of complement in the pathogenesis of IL-2-induced pulmonary microvascular injury and point to the potential therapeutic capacity of complement inhibitors in combating this toxic effect of IL-2 therapy.

PAF and TNFα Interactions in the Pathophysiology of Septic Shock

The septic shock syndrome is a medical emergency caused in part by the release into the circulation of bacterial lipopolysaccharide (LPS) endotoxin. The evolving concept in the pathophysiology of septic shock suggests that endotoxin induces its detrimental effects indirectly through the production of multiple mediators among which platelet activating factor (PAF) and tumor necrosis factor-a (TNFa) play a major role. The role of PAF and TNFa in endotoxemia was inferred from the following observations: 1 ) many of the manifestations of septic shock such as hypotension, hemoconcentration, thrombocytopenia and leukopenia can be produced by PAF and TNFa (Table 1 ); 2) elevated levels of PAF and TNFa were found in various septic conditions (Table 2); and 3) PAF antagonists and anti-TNFa neutralizing antibodies were shown to convey significant protection in animal models of septic shock (Table 3).