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.

ADAR1 is involved in the development of microvascular lung injury.

Deamination of adenosine on pre-mRNA to inosine is a recently discovered process of posttranscription modification of pre-mRNA, termed A-to-I RNA editing, which results in the production of proteins not inherent in the genome. The present study aimed to identify a role for A-to-I RNA editing in the development of microvascular lung injury. To that end, the pulmonary expression and activity of the RNA editase ADAR1 were evaluated in a mouse model of endotoxin (15 mg/kg IP)-induced microvascular lung injury (n=5) as well as in cultured alveolar macrophages stimulated with endotoxin, live bacteria, or interferon. ADAR1 expression and activity were identified in sham lungs that were upregulated in lungs from endotoxin-treated mice (at 2 hours). Expression was localized to polymorphonuclear and monocytic cells. These events preceded the development of pulmonary edema and leukocyte accumulation in lung tissue and followed the local production of interferon-gamma, a known inducer of ADAR1 in other cell systems. ADAR1 was found to be upregulated in alveolar macrophages (MH-S cells) stimulated with endotoxin (1 to 100 microg/mL), live Escherichia coli (5x10(7) colony-forming units), or interferon-gamma (1000 U/mL). Taken together, these data suggest that ADAR1 may play a role in the pathogenesis of microvascular lung injury possibly through induction by interferon.

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.

Effect of liposome-encapsulated hemoglobin on the development of endotoxin-induced shock in the rat.

Liposome-encapsulated hemoglobin (LEH) is an experimental oxygen-carrying resuscitation fluid. Because LEH is cleared from the circulation primarily by the reticuloendothelial system, its effect on the development of sepsis remains a major concern. Thus, the present study aimed to evaluate whether LEH modifies consequences of endotoxemia in the conscious normovolemic rat. LEH infusion at 10% of estimated blood volume (n = 10) did not affect mortality (30%, p < .05) and serum tumor necrosis factor-alpha levels (6204 +/- 414, p < .05) induced by 3.6 mg/kg Escherichia coli endotoxin administered (intravenous bolus) 22 h later. In contrast, when a shorter LEH-endotoxin time interval (<12 h, n = 10) or a higher dose of endotoxin (14.4 mg/kg, n = 20) was tested, LEH enhanced endotoxin-induced mortality (90% and 100%, respectively, p < .05) and broadened serum tumor necrosis factor-alpha response without modifying its peak levels. LEH (n = 20) did not exacerbate the endotoxin-induced tachycardia, leukopenia, and thrombocytopenia. Therefore, in this model, the effect of LEH on endotoxin-induced responses was dependent on the time interval between LEH and endotoxin administration as well as the endotoxin dose. The clinical relevance of these results should be further investigated.

The novel chemokine mob-1: involvement in adult respiratory distress syndrome.

BACKGROUND: Using differential display reverse transcriptase-polymerase chain reaction we have recently identified mob-1, the novel rat homologue of the human alpha-chemokine IP-10, as a highly inducible gene in adult respiratory distress syndrome (ARDS) lungs. The present study aimed to further implicate mob-1 in the pathogenesis of ARDS. METHODS: Pulmonary mob-1 mRNA up-regulation was confirmed by Northern blot analysis in three different rat models of ARDS-like lung injury and localized to pulmonary macrophages by using in situ hybridization. Also, Escherichia coli-derived recombinant mob-1 (rmob-1) was tested for its properties in relationship to lung injury. RESULTS: In vivo, intratracheal injection of rmob-1 (50 micrograms/rat) induced pulmonary leukosequestration (myeloperoxidase +93% +/- 8% versus control, p < 0.05) with preferential accumulation of neutrophils in bronchoalveolar lavage fluid (36.0% +/- 1.0% versus 0.1% +/- 0.1% in controls, p < 0.01). In vitro, transwell migration studies demonstrated chemotactic activity of rmob-1 (50 to 100 ng/ml) toward human monocytes (+151% +/- 34% versus rmob-1 vehicle, p < 0.01) and only weak chemotaxis for human neutrophils (+15% +/- 0% versus rmob-1 vehicle, p < 0.01). Utilizing a rat aortic ring model ex vivo, rmob-1 at 100 ng/ml exerted a very potent inhibitory effect on angiogenesis (-78.7% +/- 6.3% versus rmob-1 vehicle, p < 0.01), a major component of the resolution phase of ARDS. CONCLUSIONS: Taken together, these data support the involvement of mob-1 in the pathogenic mechanisms of ARDS possibly through chemotaclic actions on inflammatory cells and modulation of angiogenesis in the recovery phase of the disease.

ARDS-like lung injury produced by endotoxin in platelet-activating factor-primed rats.

We recently reported that the combined administration of lipopolysaccharide (LPS) and platelet-activating factor (PAF) in rats, at doses that are completely devoid of any effect when given alone, caused lung injury characterized by neutrophil adhesion to lung capillaries and postcapillary venules, neutrophil accumulation in the lung parenchyma, platelet-fibrin deposits in postcapillary venules, and pulmonary edema. A marked increase in lung myeloperoxidase activity and an elevation of serum tumor necrosis factor-alpha and thromboxane B2, along with leukopenia and thrombocytopenia, were also noticed. The present study aimed to examine whether repeated LPS-PAF stimulus can cause progressive lung injury reminiscent of adult respiratory distress syndrome (ARDS). A second LPS-PAF challenge, 4 h (n = 11) after the original challenge, induced mortality (69% at 24 h, P < 0.01) and some of the pathological changes seen in clinical ARDS, including severe pulmonary edema, alveolar proteinaceous exudates, monocytic infiltration, and a further increase in lung myeloperoxidase activity (700%, P < 0.01). Repeated LPS-PAF dosing also resulted in sustained increased serum tumor necrosis factor-alpha levels (1,610 +/- 470 pg/ml, P < 0.01) and further exacerbation of the leukopenia (-68 +/- 6%, P < 0.01) and thrombocytopenia (-65 +/- 8%, P < 0.01). These data suggest that repeated LPS-PAF actions are sufficient to elicit pathophysiology of ARDS-like lung injury.

Candida pericarditis: clinical profile and treatment.

BACKGROUND: Candida pericarditis is a rare medical and surgical emergency which, unless treated, leads to impaired cardiac function and death. To facilitate early diagnosis, the clinical features of this condition should be identified. METHODS: Twenty-five cases of Candida pericarditis reported in the last 30 years along with 1 new case were reviewed with regard to demographics, precipitating factors, diagnosis, treatment, and outcome. RESULTS: The syndrome occurred in immunocompromised (73%), antibiotic-treated (62%), or postpericardiotomy (54%) patients. The clinical presentation was frequently subtle and nonspecific. Nevertheless, unexplained fever, an increasing cardiac shadow on chest roentgenogram, or the development of cardiac tamponade may be suggestive. Positive culture for Candida in pericardial fluid or histologic evidence of yeast forms in pericardial tissue establishes the diagnosis. A combination of pericardiocentesis followed by operative drainage and antifungal agents is the usual treatment. Untreated, Candida pericarditis is 100% lethal, whereas prompt diagnosis and treatment lead to cure (mean follow-up, 19 months). CONCLUSIONS: Fever and evolving cardiac tamponade in immunocompromised or postpericardiotomy patients may be suggestive of Candida pericarditis; the presence of organisms in pericardial fluid is diagnostic. Pericardiocentesis followed by operative drainage and antifungal agents appears to be the treatment that is most likely to be curative.

Pharmacological profile of G619, a new platelet aggregation inhibitor.

G619, a 4-OH-isophthalic acid derivative, was studied for its capacity to inhibit platelet aggregation. G619 dose-dependently inhibited U46619, collagen, ADP, PAF, thrombin and epinephrine-induced platelet aggregation in vitro. The IC50 values for inhibition of U46619-induced human and rabbit platelet aggregation were 39 and 43 microM, respectively. G619, at 100 microM, inhibited high concentration collagen (10 micrograms/ml)-induced aggregation of rabbit platelets pretreated with indomethacin and increased the level of cAMP in washed rabbit platelets by 30% (p less than 0.01 vs basal). However, G619, did not inhibit fibrinogen binding to GPIIb/IIIa receptor, phosphodiesterase, U46619-induced contractile responses on canine saphenous vein or rabbit aorta, calcium-induced vasoconstriction and thrombin or PAF-induced elevation of [Ca++]i in platelets in vitro. In vivo, the U46619-induced maximal thrombocytopenia in rats was reduced from 40% (vehicle) to 22% and 18% by 10 and 30 mg/kg of G619 i.v., respectively. G619 (30 mg/kg) had no effect on the U46619-induced vasopressor response or sudden death in rats, and had no effect on TxB2 formation. Our results indicate that G619 is a broad-spectrum platelet aggregation inhibitor and may have its effect on a common mechanism for platelet aggregation besides an effect on the thromboxane A2 receptor.

Cystic duct carcinoma mimicking empyema of the gallbladder.

An 80-year-old woman underwent cholecystectomy because of a clinical and ultrasonic diagnosis of gallbladder empyema. Primary carcinoma of the cystic duct, which was completely removed, was incidentally found during pathologic examination. Although the prognosis following complete removal of this carcinoma is considered to be good, the patient died of the disease 7 months after the operation.

Thoracic duct injury in penetrating neck trauma.

Thoracic duct laceration from penetrating neck trauma is a rare injury associated with significant morbidity. Seventy-one cases published in the English literature in the last 50 years, along with one new case, were reviewed in an attempt to characterize the clinical profile, treatment, and outcome.

Platelet-activating factor in cardiovascular stress situations.

Since the elucidation of its chemical structure two decades ago, platelet-activating factor (PAF) has emerged as an important mediator of various cardiovascular stress situations. Most notably, PAF was implicated as a key factor in the septic shock syndrome, based on the similarities between endotoxin and PAF biological effects, the elevation of circulating and tissue levels of PAF during endotoxemia, and the protective effect of PAF antagonists in the septic state. In addition, accumulating data suggest the involvement of PAF in the pathophysiological processes associated with ischemia, hemorrhage and trauma, where PAF exerts its effects directly on cells and blood elements or indirectly through interactions with other mediators such as cytokines and prostaglandins. Nevertheless, the relative contribution of PAF to the pathophysiological processes in endotoxemia is still unknown and should await further investigations. The primary aims of this chapter are: to delineate the effects of PAF on the cardiovascular system, to summarize the data which suggest the involvement of PAF in stress situations of the cardiovascular system, and to identify areas where future experimental efforts should be focused.

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.

CT guided periaortic fluid aspiration diagnosing aortic graft infection.

CT guided diagnostic aspiration was performed on a patient suspected of aortic graft infection. The positive aspiration prompted aggressive successful surgical intervention.

Admission patterns of an urban level I trauma center.

Because trauma admission and hospitalization patterns have profound effects on the organization and utilization of urban trauma-care systems, the objective of this study was to identify and analyze these patterns. As an example, admissions to an urban Level I trauma center were reviewed. Retrospective review of all 2029 trauma admissions to a Level I trauma center was conducted from 1993 to 1996. The result was that most trauma patients were young (40% < 30 years of age) and male (74%). Mechanisms of injury were motor vehicle accident (36%), fall (27%), gunshot (17%), stab (7%), assault (6%), and swimming or diving accident (3%). Half of the patients were directly admitted from the scene. Injury Severity Score, length of stay, and mortality were 14.1 +/- 0.3, 10.5 +/- 0.3 days, and 5.1%, respectively. Admissions tended to occur more frequently between 4:00 PM and midnight (46%), between Friday and Sunday (52%), and between July and October (41%). The following patterns were identified: admissions per year decreased (-21%) because of reduced penetrating trauma (-43%, P < .01); pediatric patients (< 15 years) had similar incidence of penetrating trauma as adults (ages 15-45). Length of stay for all mechanisms of injury was not statistically different; most mortalities occurred within the first day (33%, P < .01) or after 6 days (36%, P < .01); early mortality was mainly due to penetrating injury (74%, P < .01), whereas late mortality was related to blunt trauma (92%, P < .01). The conclusion was that admission and demographic patterns were identified, which may be useful in the utilization, modification, and future design of trauma systems.

Nonoperative management of blunt splenic trauma in adults.

Forty-five adult patients with traumatic splenic injuries were treated during a 6-year period between 1980-1986 at Hadassah Hospital. The diagnosis was confirmed by splenic scintigraphy with 99mTc Tin-colloid. Fifteen patients (33%) who were stable on admission or after initial resuscitation were treated non-operatively and selected for this study. Treatment consisted of careful hemodynamic monitoring, strict bed rest, nasogastric suction, and i.v. fluids. In no case was emergency laparotomy necessary for deterioration of clinical condition or late complications. Splenic scans were repeated in 11 of the patients to assess resolution. In six of the patients, minimal residual defects were detected with no further complications. It is concluded that nonoperative treatment of splenic injuries in carefully selected patients is both safe and effective.

The status of hemoglobin-based red cell substitutes.

Red cell substitutes are currently under development for use in a variety of surgery and trauma-related clinical conditions. The need for artificial oxygen-carrying fluids continues to be driven by the shortage of donor blood, the complex logistics of blood banking, the risk of virally transmitted diseases, current transfusion practices, and the projected increased demand for blood products in the future. The effort to develop a replacement for the red cell component has evolved over the last century and has presented a number of significant challenges including safety and efficacy concerns. Recent progress in understanding the fundamental interactions of hemoglobin with the body at the molecular, cellular and tissue levels has led to the production of improved red cell substitutes suitable for clinical testing. Currently, seven products are being tested for a variety of applications including trauma, surgery, sepsis, cancer and anemia. Although some of these trials were unsuccessful, the majority of the available products exert no toxicity or only low level side effects. Encouraging results in early clinical trials with oxygen-carrying fluids support further development of these products and have increased the hope that a usable oxygen-carrying fluid will soon be available in the clinic. The purpose of this review is to provide up-to-date information on the status of these products with special emphasis on pre-clinical and clinical experience.

Sixty-Seven Consecutive Resuscitative Thoracotomies by A Single Surgeon.

BACKGROUND: Resuscitative thoracotomy is a dramatic operation performed in otherwise unsalvageable trauma patients. Analysis of its efficacy is based mostly on institutional series compiling the experience of multiple surgeons. This study aimed to report more consistent information by describing the resuscitative thoracotomy practice of a single surgeon and its evolution during more than two decades. METHODS: A retrospective review of consecutive patients who underwent resuscitative thoracotomy in July 1990 to December 2012. Demographics, mechanism of injury, signs of life, injuries, and outcomes were analyzed. Comparisons were made between penetrating and blunt trauma patients and between pre- and post-introduction of a selective resuscitative thoracotomy protocol. RESULTS: Sixty-seven resuscitative thoracotomies were performed. Most patients were males (84%), and mean age was 38 years. Mechanism of injury was stab wounds (54%, 36), blunt force (25%, 17), and gunshot wounds (21%, 14). Survival was 22% (8/36), 0% (0/17), and 7% (1/14), respectively. All nine survivors had signs of life upon admission, and survival in patients with signs of life on admission was 25% (8/32) in the stab wounds group and 8% (1/12) in the gunshot wounds group. Seven of the nine survivors (78%) were discharged neurologically intact. The most common injury in survivors was cardiac laceration with tamponade (6/9) and lung injury (3/9). Three survivors had a cardiac and lung injury, one had a lung hilum injury, and one had an abdominal inferior vena cava laceration. The switch to resuscitative thoracotomy protocol (2002) improved overall (31 vs 8%, p < 0.05) and penetrating trauma (45 vs 10%, p < 0.05) survival, eliminated resuscitative thoracotomy in patients presenting with no signs of life, and tended to reduce resuscitative thoracotomy utilization in blunt trauma patients. CONCLUSION: This single-surgeon series supports that resuscitative thoracotomy can be lifesaving in selected penetrating trauma patients in extremis. A switch to a selective evidence-based protocol increased overall and penetrating resuscitative thoracotomy survival and limited resuscitative thoracotomy performance to patients arriving with signs of life.

Resuscitative Thoracotomy: An Update.

BACKGROUND: Resuscitative thoracotomy is a heroic procedure that may offer the only survival hope for trauma patients in extremis. However, this operation has been the subject of much debate and its use, feasibility, outcomes, and cost are being continuously re-evaluated. METHODS: This is a review of the most current (after 2000) literature on resuscitative thoracotomy, based on computer database searches for studies on resuscitative thoracotomy, emergency department thoracotomy, and emergency thoracotomy. Studies were selected for inclusion in this review based on their relevance and contribution to our understanding of resuscitative thoracotomy. RESULTS: A total of 37 studies were included, and the following resuscitative thoracotomy-related topics were critically discussed: indications, biochemical profile, long-term outcome, organ donation, pre-hospital use, military use, international aspects, intra-aortic balloon occlusion, suspended animation, and cost and occupational exposure. CONCLUSIONS: This review demonstrates that the indications for resuscitative thoracotomy become clearer and that new information is available regarding its use in the pre-hospital urban environment and military settings. Furthermore, it points to new strategies to supplement resuscitative thoracotomy including intra-aortic balloon occlusion and suspended animation. Finally, it sheds light on the long-term outcomes, organ donation, and cost and occupational exposure following resuscitative thoracotomy.