Cardiopulmonary,histological, and inflammatory alterations after lung contusion in a novel mouse model of blunt chest trauma

Severe blunt chest trauma remains an important injury with high morbidity and mortality. However, the associated immunological alterations are poorly understood. Existing big animal models require large-scale settings, are often too expensive, and research products for immunological studies are limited. In this study we aimed to establish a new model of blunt, isolated and bilateral chest trauma in mice and to characterize its effects on physiological and inflammatory variables. Male C3H/HeN mice (n = 9-10/group) were anesthetized and a femoral artery was catheterized. The animals were subjected to trauma or sham procedure and monitored for 180 min. Blunt chest trauma was induced by a blast wave focused on the thorax. Trauma intensity was optimized by varying the exposure distance. Blood pressure, heart rate, respiratory rate, arterial blood gases and plasma cytokine levels were measured. Macroscopic and microscopic examinations were performed. In addition, outcome was evaluated in a 10-day survival study. Chest trauma caused a drop (P < 0.05) in blood pressure and heart rate, which partly recovered. Blood gases revealed hypoxemia and hypercarbia (P < 0.05) 180 min after trauma. There was marked damage to the lungs but none to abdominal organs. Histologically, the characteristic signs of a bilateral lung contusion with alveolar and intrabronchial hemorrhage were found. Plasma interleukin-6 and tumor necrosis factor alpha were considerably increased after 180 min. Blunt chest trauma resulted in an early mortality of 10% without subsequent death. On the basis of these findings, this novel mouse model of blunt chest trauma appears suitable for detailed studies on immunological effects of lung contusion.     

The role of C5a in the innate immune response after experimental blunt chest trauma

The inflammatory response after severe blunt chest trauma often leads to acute lung injury and acute respiratory distress syndrome which are associated with high mortality rates. Whereas the role of innate immunity in acute lung injury has been broadly investigated, the immune response after blunt chest trauma is still poorly understood. Therefore, the role of complement and neutrophils was determined in bilateral lung injury induced by a single blast wave. The following time-points were investigated posttrauma: sham, 1, 6, 12, and 24 h. There was a time-dependent systemic activation of complement as determined by CH-50 and presence of C5a-dependent chemotactic plasma activity. Moreover, factor H, a complement regulatory protein, was increased systemically and locally after injury. Anti-C5a treatment immediately after trauma ameliorated these peaks. After an initial systemic leukopenic phase, a marked leukocytosis occurred. The latter was normalized by C5a blockade. In parallel, white blood cell count in bronchioalveolar lavage fluids was increased as a function of time and was significantly decreased by anti-C5a treatment. Trauma-induced lung injury was also associated with dramatic changes in neutrophil function, namely early enhanced chemotaxis and phagocytosis, followed by prolonged functional defects-all of which were ameliorated by anti-C5a treatment. Furthermore, blockade of C5a ameliorated the buildup of the proinflammatory cytokine TNF-alpha, diminished the increase of cytokine-induced neutrophil chemoattractant 1, and altered the levels of the anti-inflammatory cytokine IL-10.These data suggest that blunt chest trauma leads to systemic activation of complement and robust C5a generation, which causes perturbations in defensive functions of neutrophils. Thus, C5a might represent a potential target for therapeutic immunomodulation to prevent immune dysfunctions post-trauma and thereby, perhaps, the progression to acute respiratory distress syndrome.     

Hemofiltration increases IL-6 clearance in early systemic inflammatory response syndrome but does not alter IL-6 and TNFα plasma concentrations

Objective: To test the hypothesis that continuous hemofiltration increases interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα) clearances and results in decreased cytokine plasma concentrations independent of renal function in patients with early SIRS. Design: Prospective, controlled, randomized study. Setting: Intensive care units at a university hospital. Patients: 28 consecutive patients who fulfilled the criteria of the systemic inflammatory response syndrome (SIRS). Interventions: Patients with SIRS were randomly assigned to either a hemofiltration or a control group irrespective of renal function. In patients of the hemofiltration group an isovolemic hemofiltration was initiated directly after the diagnosis of SIRS and maintained for at least 48 h. Measurements and results: A significant (p < 0.001) increase in total IL-6 clearance (hemofiltrate + urine), but not in TNFα clearance, was observed with hemofiltration. However, the plasma concentrations of both cytokines remained unchanged. Hemodynamic variables did not change significantly. Conclusions: Continuous hemofiltration increases IL-6 plasma clearance but not TNFα clearance. However, hemofiltration failed to decrease plasma concentrations of TNFα and IL-6 and, therefore, cannot be used effectively for cytokine elimination in SIRS. Accordingly, beneficial effects occasionally reported with hemofiltration are unlikely to be expected due to elimination of IL-6 or TNFα. Received: 12 November 1996 Accepted: 14 May 1997     

Alveolar macrophage phagocytosis is enhanced after blunt chest trauma and alters the posttraumatic mediator release

Blunt chest trauma is known to induce a pulmonary invasion of short-lived polymorphonuclear neutrophils and apoptosis of alveolar epithelial type 2 (AT2) cells. Apoptotic cells are removed by alveolar macrophages (AMΦ). We hypothesized that chest trauma alters the phagocytic response of AMΦ as well as the mediator release of AMΦ during phagocytosis. To study this, male Sprague-Dawley rats were subjected to blunt chest trauma. Phagocytosis assays were performed in AMΦ isolated 2 or 24 h after trauma with apoptotic cells or opsonized beads. Phagocytosis of apoptotic AT2 cells by unstimulated AMΦ was significantly increased 2 h after trauma. At 24 h, AMΦ from traumatized animals, stimulated with phorbol-12-myristate-13-acetate, ingested significantly more apoptotic polymorphonuclear neutrophils than AMΦ from sham animals. Alveolar macrophages after trauma released significantly higher levels of tumor necrosis factor α, macrophage inflammatory protein 1α, and cytokine-induced neutrophil chemoattractant 1 when they incorporated latex beads, but significantly lower levels of interleukin 1β and macrophage inflammatory protein 1α when they ingested apoptotic cells. In vivo, phagocytosis of intratracheally instilled latex beads was decreased in traumatized rats. The bronchoalveolar lavage concentrations of the phagocytosis-supporting surfactant proteins A and D after blunt chest trauma were slightly decreased, whereas surfactant protein D mRNA expression in AT2 cells was significantly increased after 2 h. These findings indicate that chest trauma augments the phagocytosis of apoptotic cells by AMΦ. Phagocytosis of opsonized beads enhances and ingestion of apoptotic cells downregulates the immunologic response following lung contusion. Our data emphasize the important role of phagocytosis during posttraumatic inflammation after lung contusion.     

Inhalation injury in severely burned children does not augment the systemic inflammatory response

Introduction  

Inhalation injury in combination with a severe thermal injury increases mortality. Alterations in inflammatory mediators, such as cytokines, contribute to the incidence of multi-organ failure and mortality. The aim of the present study was to determine the effect of inhalation injury on cytokine expression in severely burned children.     

Best evidence topic report. Use of troponin for the diagnosis of myocardial contusion after blunt chest trauma

Report by Lorna Jackson, SpR in Emergency Medicine
Checked by Alison Stewart, SHO III in Emergency Medicine     

常规心肌酶谱标记物在钝性胸部创伤后心肌挫伤的早期诊断价值

目的　探讨常规心肌酶谱标记物在钝性胸部创伤合并心肌挫伤早期的临床价值。方法　回顾性将钝性胸部创伤患者 14 2例依据心肌挫伤临床诊断标准分为钝性心肌挫伤组 (Ⅰ组 )和非钝性心肌挫伤组 (Ⅱ组 ) ,对入选病例 3d内心电图、超声心动图及创伤后 4 8h内心肌酶结果进行分析。结果　①钝性心肌挫伤 4 9例 ,占总病例数的 34 5 % ;②心肌挫伤以较高的创伤评分、胸部多部位损伤、肋骨骨折 (木连枷胸 )发生率高、心电图及超声心动图异常表现多为特点 ,组间比较差异显著 ;③CK≥ 10 0 0IU/L或CK -MB≥ 4 0IU/L是较理想检测指标 ,两者联合诊断可提高敏感性。结论　采用心肌酶谱联合指标早期诊断心肌挫伤可提高诊断的敏感性 ,结合病史、心电图、超声波结果可提高诊断的准确性     

Intensive insulin therapy does not alter the inflammatory response in patients undergoing coronary artery bypass grafting: a randomized controlled trial [ISRCTN95608630]

Introduction  

Strict control of plasma glucose in diabetic and non-diabetic patients has been shown to improve outcome in several clinical settings. There is extensive evidence that glucose can stimulate the production of pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α and IL-6, with no effect on the anti-inflammatory cytokine IL-10. We hypothesized that strict glucose regulation results in a change in cytokine balance from a pro-inflammatory state to a more balanced anti-inflammatory condition. In a randomized controlled trial we studied the effect of strict glycemic control on the local and systemic pro-inflammatory and anti-inflammatory balance in non-diabetic patients undergoing elective coronary artery bypass grafting with cardiopulmonary bypass.     

Effects of hydrogen sulfide on hemodynamics, inflammatory response and oxidative stress during resuscitated hemorrhagic shock in rats

Introduction

Hydrogen sulfide (H₂S) has been shown to improve survival in rodent models of lethal hemorrhage. Conversely, other authors have reported that inhibition of endogenous H₂S production improves hemodynamics and reduces organ injury after hemorrhagic shock. Since all of these data originate from unresuscitated models and/or the use of a pre-treatment design, we therefore tested the hypothesis that the H₂S donor, sodium hydrosulfide (NaHS), may improve hemodynamics in resuscitated hemorrhagic shock and attenuate oxidative and nitrosative stresses.

Methods

Thirty-two rats were mechanically ventilated and instrumented to measure mean arterial pressure (MAP) and carotid blood flow (CBF). Animals were bled during 60 minutes in order to maintain MAP at 40 ± 2 mm Hg. Ten minutes prior to retransfusion of shed blood, rats randomly received either an intravenous bolus of NaHS (0.2 mg/kg) or vehicle (0.9% NaCl). At the end of the experiment (T = 300 minutes), blood, aorta and heart were harvested for Western blot (inductible Nitric Oxyde Synthase (iNOS), Nuclear factor-κB (NF-κB), phosphorylated Inhibitor κB (P-IκB), Inter-Cellular Adhesion Molecule (I-CAM), Heme oxygenase 1(HO-1), Heme oxygenase 2(HO-2), as well as nuclear respiratory factor 2 (Nrf2)). Nitric oxide (NO) and superoxide anion (O₂ ^-) were also measured by electron paramagnetic resonance.

Results

At the end of the experiment, control rats exhibited a decrease in MAP which was attenuated by NaHS (65 ± 32 versus 101 ± 17 mmHg, P < 0.05). CBF was better maintained in NaHS-treated rats (1.9 ± 1.6 versus 4.4 ± 1.9 ml/minute P < 0.05). NaHS significantly limited shock-induced metabolic acidosis. NaHS also prevented iNOS expression and NO production in the heart and aorta while significantly reducing NF-kB, P-IκB and I-CAM in the aorta. Compared to the control group, NaHS significantly increased Nrf2, HO-1 and HO-2 and limited O₂ ^- release in both aorta and heart (P < 0.05).

Conclusions

NaHS is protective against the effects of ischemia reperfusion induced by controlled hemorrhage in rats. NaHS also improves hemodynamics in the early resuscitation phase after hemorrhagic shock, most likely as a result of attenuated oxidative stress. The use of NaHS hence appears promising in limiting the consequences of ischemia reperfusion (IR).     

Selective cyclooxygenase-2 inhibition does not alter keratinocyte wound responses in the mouse epidermis after abrasion

The cyclooxygenase isoforms, COX-1 and COX-2, are the rate limiting enzymes in the biosynthesis of prostaglandin E(2), a major prostaglandin involved in epidermal homeostasis and repair. Epidermal injury results in transient hyperplasia and induction of COX-2 expression. The role of COX-2 in this hyperplasia is unknown, however. In this study, we characterized the epidermal expression of COX isozymes following wounding by abrasion in SKH-1 mice using immunohistochemistry, in situ hybridization, and Western analysis. In addition, we evaluated pivotal keratinocyte functions necessary for the reparative hyperplasia, including proliferation by 5-bromo-2'deoxy-uridine labeling and differentiation by the expression of involucrin, keratin 1, and keratin 6. Although COX-1 expression in keratinocytes remained unchanged during wound healing, COX-2 expression was induced coincidentally with keratinocyte proliferation and keratin 6 expression, suggesting a role for COX-2 in epidermal repair. The role of COX-2 was also evaluated using the selective COX-2 inhibitor SC-791 and the traditional COX inhibitors indomethacin and diclofenac. Neither inhibitor altered keratinocyte proliferation or differentiation following abrasion, in contrast to dexamethasone, which delayed these responses. Our results indicated that, although COX-2 expression was coincident with transient epidermal hyperplasia and keratinocyte proliferation/differentiation during the healing of epidermal injury, it does not play a pivotal role in this repair process.     

Arginine vasopressin,but not epinephrine,improves survival in uncontrolled hemorrhagic shock after liver trauma in pigs

OBJECTIVE: Epinephrine is widely used for treatment of life-threatening hypotension, although new vasopressor drugs may merit evaluation. The purpose of this study was to determine the effects of vasopressin vs. epinephrine vs. saline placebo on hemodynamic variables, regional blood flow, and short-term survival in an animal model of uncontrolled hemorrhagic shock and delayed fluid resuscitation. DESIGN: Prospective, randomized, laboratory investigation that used a porcine model for measurement of hemodynamic variables and regional abdominal organ blood flow. SETTING: University hospital laboratory. SUBJECTS: A total of 21 pigs weighing 32 +/- 3 kg. INTERVENTIONS: The anesthetized pigs were subjected to a penetrating liver injury, which resulted in a mean +/- sem loss of 40% +/- 5% of estimated whole blood volume within 30 mins and mean arterial pressures of <20 mm Hg. When heart rate declined progressively, pigs randomly received a bolus dose and continuous infusion of either vasopressin (0.4 units/kg and 0.04 units.kg-1.min-1, n = 7), or epinephrine (45 microg/kg and 5 microg.kg(-1).min(-1), n = 7), or an equal volume of saline placebo (n = 7), respectively. At 30 mins after drug administration, all surviving animals were fluid resuscitated while bleeding was surgically controlled. MEASUREMENTS AND MAIN RESULTS: Mean +/- sem arterial blood pressure at 2.5 and 10 mins was significantly (p <.001) higher after vasopressin vs. epinephrine vs. saline placebo (82 +/- 14 vs. 23 +/- 4 vs. 11 +/- 3 mm Hg, and 42 +/- 4 vs. 10 +/- 5 vs. 6 +/- 3 mm Hg, respectively). Although portal vein blood flow was temporarily impaired by vasopressin, it was subsequently restored and significantly (p <.01) higher when compared with epinephrine or saline placebo (9 +/- 5 vs. 121 +/- 3 vs. 54 +/- 22 mL/min and 150 +/- 20 vs. 31 +/- 17 vs. 0 +/- 0 mL/min, respectively). Hepatic and renal artery blood flow was significantly higher throughout the study in the vasopressin group; however, no further bleeding was observed. Despite a second bolus dose, all epinephrine- and saline placebo-treated animals died within 15 mins after drug administration. By contrast, seven of seven vasopressin-treated animals survived until fluid replacement, and 60 mins thereafter, without further vasopressor therapy (p <.01). Moreover, blood flow to liver, gut, and kidney returned to normal values in the postshock phase. CONCLUSIONS: Vasopressin, but not epinephrine or saline placebo, improved short-term survival in a porcine model of uncontrolled hemorrhagic shock after liver injury when surgical intervention and fluid replacement was delayed.     

Rupture of the coronary artery after blunt nonpenetrating chest wall trauma detected by color Doppler echocardiography: a case report.

We report a rare case of a ruptured papillary muscle of the anterior leaflet of the tricuspid valve and the rupture of the septal branch of the left anterior descending coronary artery with drainage into the right ventricle after blunt nonpenetrating chest wall trauma. Both abnormalities were detected by transthoracic 2-dimensional and color Doppler echocardiography, and the septal branch rupture was confirmed by coronary angiography. The leading echocardiographic sign of the rupture of the coronary artery was intramyocardial mosaic-colored flow, representing the turbulent high-velocity flow in the ruptured coronary artery. Hypokinesis of the anteroseptal myocardial segments and the presence of Q waves in leads V1 through 4 on the electro-cardiogram were suggestive of anteroseptal myocardial infarction. We conclude that the history of chest trauma, the electrocardiographic changes, and wall motion abnormalities should be stimuli for a careful color Doppler flow "mapping" of the myocardium for possible identification of a coronary artery rupture.     

One size does not fit all in severe infection: obesity alters outcome,susceptibility, treatment,and inflammatory response

Introduction

Obesity is an increasingly common comorbidity in critically ill patients. Whether obesity alters sepsis outcome, susceptibility, treatment, and response is not completely understood.

Methods

We conducted a retrospective analysis comparing three group of septic shock patients based on the intervals of actual body mass index (BMI) in patients enrolled in the VASST (Vasopressin and Septic Shock Trial) cohort. Primary outcome measurement was 28-day mortality. We tested for differences in patterns of infection by comparing the primary site of infection and organism. We also compared the treatments (fluids and vasopressors) and inflammatory response, measuring adipose tissue-related cytokine concentrations (interleukin [IL]-6, monocyte chemotactic protein [MCP]-1, tumor necrosis factor [TNF]-α, and resistin) in plasma in a subset of 382 patients. Of the 778 patients in VASST, 730 patients who had body weight and height measurements were analyzed. Patients with BMI <25 kg/m² (n = 276) were grouped as a reference and compared to ''overweight'' (25< BMI <30 kg/m², n = 209) and ''obese'' (BMI >30 kg/m^2, n = 245) patients.

Results

Obese patients had the lowest 28-day mortality followed by overweight patients while patients with BMI <25 kg/m² had the highest mortality (p = 0.02). Compared to the patients with BMI <25 kg/m², obese and overweight patients also had a different pattern of infection with less lung (obese 35%, overweight 45%, BMI<25 kg/m² 50%, p = 0.003) and fungal infection (obese 8.2%, overweight 11%, and BMI<25 kg/m² 15.6%, p = 0.03). Per kilogram, obese and overweight patients received less fluid during the first four days (p<0.05) and received less norepinephrine (obese 0.14, overweight 0.21, BMI <25 kg/m² 0.26 µg/kg/min, p<0.0001) and vasopressin (obese 0.28, overweight 0.36, BMI <25 kg/m² 0.43 µU/kg/min, p<0.0001) on day 1 compared to patients with BMI <25 kg/m². Obese and overweight patients also had a lower plasma IL-6 concentration at baseline (obese 106 [IQR 34-686], overweight 190 [IQR 44-2339], BMI <25 kg/m² 235 [IQR 44-1793] pg/mL, p = 0.046).

Conclusions

Overall obesity was associated with improved survival in septic shock and differences in pattern of infection, fluids, and vasopressors. Importantly, the magnitude of inflammatory IL-6 response is muted in the obese.     

The antianginal agent, ranolazine, reduces myocardial infarct size but does not alter anatomic no-reflow or regional myocardial blood flow in ischemia/reperfusion in the rabbit

It has been suggested that ranolazine protects the ischemic/reperfused heart by reducing diastolic wall pressure during ischemia. However, there is limited information regarding the effect of ranolazine on the anatomic zone of no-flow in a model of acute myocardial occlusion/reperfusion. Before coronary artery occlusion (CAO), open-chest anesthetized rabbits were assigned to vehicle or ranolazine. Hearts received 60 minutes of CAO and 3 hours reperfusion. Ischemic risk zone was comparable in the 2 groups. Ranolazine significantly reduced infarct size. There was a non-significant trend for the no-reflow defect to be smaller in the ranolazine group. Regional myocardial blood flow was similar in both groups in the risk zone during ischemia and at 3 hours reperfusion. Heart rates were similar in both groups, whereas mean arterial pressure was reduced in the ranolazine group. While ranolazine was effective in reducing myocardial infarct size, the mechanism by which it did this was independent of improving perfusion during either ischemia or reperfusion, suggesting that ranolazine's effect of reducing infarct size involves alternative mechanisms.