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Christoph Thiemermann - One of the best experts on this subject based on the ideXlab platform.
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dopexamine can attenuate the inflammatory response and protect against Organ Injury in the absence of significant effects on hemodynamics or regional microvascular flow
Critical Care, 2013Co-Authors: Mansoor N Bangash, Nimesh S A Patel, Elisa Benetti, Massimo Collino, C J Hinds, Christoph Thiemermann, Rupert M PearseAbstract:Introduction: The effects of dopexamine, a b2-agonist, on perioperative and sepsis-related hemodynamic, microvascular, immune, and Organ dysfunction are controversial and poorly understood. We investigated these effects in a rodent model of laparotomy and endotoxemia. Methods: In two experiments, 80 male Wistar rats underwent laparotomy. In 64 rats, this was followed by administration of endotoxin; the remainder (16) underwent sham endotoxemia. Endotoxemic animals received either dopexamine at 0.5, 1, or 2 μg/kg/min or 0.9% saline vehicle (controls) as resuscitation fluid. The effects of dopexamine on global hemodynamics, mesenteric regional microvascular flow, renal and hepatic function and immune activation were evaluated. Results: Endotoxin administration was associated with a systemic inflammatory response (increased plasma levels of tumor necrosis factor (TNF)-a, interleukin (IL)-1b, IL-6, and IL-10, as well as cell-adhesion molecules CD11a and CD11b), and increased pulmonary myeloperoxidase (MPO) activity (indicating pulmonary leukocyte infiltration), whereas biochemical changes demonstrated lactic acidosis with significant renal and hepatic Injury. Dopexamine administration was associated with less-severe lactic acidosis (pooled dopexamine versus controls, (lactate, 2.2 mM ± 0.2 mM versus 4.0 mM ± 0.5 mM; P < 0.001) and reductions in the systemic inflammatory response (pooled dopexamine versus control, 4 hour (TNF-a): 324 pg/ml ± 93 pg/ml versus 97 pg/ml ± 14 pg/ml, p < 0.01), pulmonary myeloperoxidase (MPO) activity, and hepatic and renal Injury (pooled dopexamine versus control (ALT): 81 IU/L ± 4 IU/L versus 138 IU/L ± 25 IU/L; P < 0.05; (creatinine): 49.4 μM ± 3.9 μM versus 76.2 μM ± 9.8 μM; P < 0.005). However, in this study, clinically relevant doses of dopexamine were not associated with clinically significant changes in MAP, CI, or gut regional microvascular flow. Conclusions: In this model, dopexamine can attenuate the systemic inflammatory response, reduce tissue leukocyte infiltration, and protect against Organ Injury at doses that do not alter global hemodynamics or regional microvascular flow. These findings suggest that immunomodulatory effects of catecholamines may be clinically significant when used in critically ill surgical patients and are independent of their hemodynamic actions.
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sphingosylphosphorylcholine reduces the Organ Injury dysfunction and inflammation caused by endotoxemia in the rat
Critical Care Medicine, 2008Co-Authors: Oliver Murch, Elisa Benetti, Massimo Collino, Maha Abdelrahman, Margherita Gallicchio, Emanuela Mazzon, Roberto Fantozzi, Salvatore Cuzzocrea, Christoph ThiemermannAbstract:OBJECTIVE Sphingosylphosphorylcholine (SPC) has been reported to activate a variety of G-protein coupled receptors, including S1P(1-5), G2A, GPR4, and OGR1 (GPR68). Interestingly, other structurally related lysophospholipid agonists of these receptors have been shown to exhibit immunomodulatory properties both in vitro and in vivo. These include prevention of tumor necrosis factor-alpha-induced monocyte adhesion to aortic endothelium in mice (sphingosine-1-phosphate via S1P(1-5) receptors) and reduction of Organ Injury and/or mortality in animal models of sepsis and endotoxemia (lysophosphatidylcholine via G2A). Here, we investigate the effects of SPC on the Organ Injury/dysfunction caused by systemic administration of lipopolysaccharide and the mechanisms underlying the observed effects of SPC. DESIGN Prospective, randomized study. SETTING University-based research laboratory. SUBJECTS Sixty-one anesthetized male Wistar rats. INTERVENTIONS Rats received either SPC (10 mg/kg intravenously) or vehicle (phosphate-buffered saline 1 mL/kg intravenously) 15 mins before or 15 mins after induction of endotoxemia with lipopolysaccharide (6 mg/kg intravenously). MEASUREMENTS AND MAIN RESULTS Treatment with SPC significantly reduced the Organ/dysfunction Injury caused by lipopolysaccharide. SPC pretreatment significantly reduced the circulating levels of interleukin-1beta and interleukin-6, the expression of CD11b (ligand for intercellular adhesion molecule-1) on circulating polymorphonuclear cells, the expression of proteins of intercellular adhesion molecule-1 (Western blot and immunohistochemistry), cyclooxygenase-2 and nuclear translocation of nuclear factor-kappaB (Western blot analysis), and inducible nitric oxide synthase (immunohistochemistry) as well as the lung Injury caused by endotoxemia in the rat. CONCLUSIONS SPC reduced the Organ Injury/dysfunction caused by endotoxin in the rat. These beneficial effects of SPC are associated with potent anti-inflammatory effects.
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muramyl dipeptide enhances the response to endotoxin to cause multiple Organ Injury in the anesthetized rat
Shock, 2007Co-Authors: Oliver Murch, Maha Abdelrahman, Amar Kapoor, Christoph ThiemermannAbstract:: Nucleotide oligomerization domain (NOD) proteins recognize peptidoglycan fragments, resulting in up-regulation of transcription factors, and may enhance the inflammatory response to infection. Specifically, NOD2 has been shown to sense muramyl dipeptide (MDP), which is released during bacterial cell growth and replication. Activation of NOD2 by MDP enhances the inflammatory response caused by LPS (endotoxin). Here, we investigated the effects of MDP on the Organ Injury/dysfunction caused by systemic administration of a low dose of LPS. Male Wistar rats were coadministered with either MDP (1 - 10 mg kg(-1), i.v.) or vehicle (0.5 mL kg(-1) saline, i.v.), and a low dose of LPS (1 mg kg(-1), i.v.) or vehicle (1 mL kg(-1), saline, i.v.). MAP and heart rate were continuously monitored for 6 h. Markers of Organ dysfunction/Injury, plasma cytokine levels, and lung myeloperoxidase activity were measured 6 h after MDP and LPS coadministration. In a separate study, MDP (3 or 10 mg kg(-1), i.v.) or vehicle (0.5 mL kg(-1) saline, i.v.) was administered 24 h before LPS infusion. When compared with animals receiving low-dose LPS alone, coadministration of MDP (10 mg kg(-1), i.v.) and LPS, or administration of MDP (10 mg kg(-1), i.v.) 24 h before LPS resulted in a significant increase in the degree of Organ Injury, cytokine release, and lung Injury caused by LPS alone. Thus, our results demonstrate that the two bacterial wall components MDP and LPS work in concert to cause multiple Organ Injury and systemic inflammation. We hope that our results stimulate other studies designed to evaluate the effects of NOD ligands in animal models of inflammation.
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inhibition of endogenous hydrogen sulfide formation reduces the Organ Injury caused by endotoxemia
British Journal of Pharmacology, 2005Co-Authors: Marika Collin, Madhav Bhatia, Farhana Anuar, Oliver Murch, Philip K Moore, Christoph ThiemermannAbstract:Hydrogen sulfide (H2S) is a naturally occurring gaseous transmitter, which may play important roles in normal physiology and disease. Here, we investigated the role of H2S in the Organ Injury caused by severe endotoxemia in the rat. Male Wistar rats were subjected to acute endotoxemia (Escherichia coli lipopolysaccharide (LPS) 6 mg kg−1 intravenously (i.v.) for 6 h) and treated with vehicle (saline, 1 ml kg−1 i.v.) or DL-propargylglycine (PAG, 10–100 mg kg−1 i.v.), an inhibitor of the H2S-synthesizing enzyme cystathionine-γ-lyase (CSE). PAG was administered either 30 min prior to or 60 min after the induction of endotoxemia. Endotoxemia resulted in circulatory failure (hypotension and tachycardia) and an increase in serum levels of alanine aminotransferase and aspartate aminotransferase (markers for hepatic Injury), lipase (indicator of pancreatic Injury) and creatine kinase (indicator of neuromuscular Injury). In the liver, endotoxemia induced a significant increase in the myeloperoxidase (MPO) activity, and in the expression and activity of the H2S-synthesizing enzymes CSE and cystathionine-β-synthase. Administration of PAG either prior to or after the injection of LPS dose-dependently reduced the hepatocellular, pancreatic and neuromuscular Injury caused by endotoxemia, but not the circulatory failure. Pretreatment of rats with PAG abolished the LPS-induced increase in the MPO activity and in the formation of H2S and in the liver. These findings support the view that an enhanced formation of H2S contributes to the pathophysiology of the Organ Injury in endotoxemia. We propose that inhibition of H2S synthesis may be a useful therapeutic strategy against the Organ Injury associated with sepsis and shock. British Journal of Pharmacology (2005) 146, 498–505. doi:10.1038/sj.bjp.0706367
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gsk 3β inhibitors attenuate the Organ Injury dysfunction caused by endotoxemia in the rat
Critical Care Medicine, 2005Co-Authors: Laura Dugo, Nimesh S A Patel, Muhammad M. Yaqoob, Marika Collin, David A Allen, Inge Bauer, Eero Mervaala, Marjut Louhelainen, Simon J Foster, Christoph ThiemermannAbstract:OBJECTIVE Serine-threonine protein kinase glycogen synthase kinase (GSK)-3 is involved in regulation of many cell functions, but its role in regulation of inflammatory response is unknown. Here we investigate the effects of GSK-3beta inhibition on Organ Injury/dysfunction caused by lipopolysaccharide or coadministration of lipopolysaccharide and peptidoglycan in the rat. DESIGN Prospective, randomized study. SETTING University-based research laboratory. SUBJECTS Ninety-nine anesthetized male Wistar rats. INTERVENTIONS Study 1: Rats received either intravenous Escherichia coli lipopolysaccharide (6 mg/kg) or vehicle (1 mL/kg; saline). Study 2: Rats received either intravenous E. coli lipopolysaccharide (1 mg/kg) and Staphylococcus aureus peptidoglycan (0.3 mg/kg) or vehicle. The potent and selective GSK-3beta inhibitors TDZD-8 (1 mg/kg intravenously), SB216763 (0.6 mg/kg intravenously), and SB415286 (1 mg/kg intravenously) or vehicle (10% dimethyl sulfoxide) was administered 30 mins before lipopolysaccharide or lipopolysaccharide and peptidoglycan. MEASUREMENTS AND MAIN RESULTS Endotoxemia resulted in increases in the serum levels of creatinine (indicator of renal dysfunction), aspartate aminotransferase, alanine aminotransferase (markers for hepatocellular Injury), lipase (indicator of pancreatic Injury), and creatine kinase (indicator of neuromuscular Injury). Coadministration of lipopolysaccharide and peptidoglycan resulted in hepatocellular Injury and renal dysfunction. All GSK-3beta inhibitors attenuated the Organ Injury/dysfunction caused by lipopolysaccharide or lipopolysaccharide and peptidoglycan. GSK-3beta inhibition reduced the Ser536 phosphorylation of nuclear factor-kappaB subunit p65 and the messenger RNA expression of nuclear factor-kappaB-dependent proinflammatory mediators but had no effect on the nuclear factor-kappaB/DNA binding activity in the lung. GSK-3beta inhibition reduced the increase in nuclear factor-kappaB p65 activity caused by interleukin-1 in human embryonic kidney cells in vitro. CONCLUSIONS The potent and selective GSK-3beta inhibitors TDZD-8, SB216763, and SB415286 reduced the Organ Injury/dysfunction caused by lipopolysaccharide or lipopolysaccharide and peptidoglycan in the rat. We propose that GSK-3beta inhibition may be useful in the therapy of the Organ Injury/dysfunction associated with sepsis, shock, and other diseases associated with local or systemic inflammation.
Yousheng Jiang - One of the best experts on this subject based on the ideXlab platform.
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multiple Organ Injury in male c57bl 6j mice exposed to ambient particulate matter in a real ambient pm exposure system in shijiazhuang china
Environmental Pollution, 2019Co-Authors: Daochuan Li, Rong Zhang, Haiyan Zhang, Lixiao Zhou, Liping Chen, Shen Chen, Shejun Chen, Jian Zhen Yu, Jianqing Zhang, Yousheng JiangAbstract:Abstract The development of a rodent ambient particulate matter (PM) inhalation system is critical for drawing causal inferences between PM exposure and the onset of human diseases. In this study, we constructed a real-ambient PM exposure system to investigate multi-Organ Injury and the reversibility of the impairments in C57BL/6 J male mice exposed to PM with a duration of up to three months in Shijiazhuang, a city with the highest PM2.5 concentration in China. This unique exposure system provided an optimal scenario for round-the-clock PM exposure absent a change in the physiochemical properties of PM and minimized the disturbance to the mice habitat. The mean concentration of PM2.5 in the exposure chambers was 89.95, 79.98, and 87.87 μg/m3 at three different time points, respectively: weeks 1–3, week 1–6, and week 1–12. The Injury in multiple Organs, including lung, brain, heart, testis, and intestine, was profound and was evident by the significant pathological and functional alterations. Pulmonary pathological examination revealed severe interstitial inflammatory and alveolar hemorrhage throughout the exposure, which was in line with the reduced lung function and the increased cytokine excretion in bronchoalveolar lavage fluid and blood plasma. Notably, the PM-mediated inflammatory response in different systems was correlated with the severity of the Injury and the attenuation of pulmonary lesions in the recovery group. Thus, the PM2.5-induced inflammatory response, the chemical components-induced cytotoxicity, genetic damage, and oxidative stress might be implicated in the impairment of multiple murine Organs. These findings revealed the severity, sensitivity, and reversibility of multi-Organ Injury in response to a real-ambient PM exposure.
Ping Wang - One of the best experts on this subject based on the ideXlab platform.
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sirtuin 1 activator srt1720 protects against Organ Injury induced by intestinal ischemia reperfusion
Shock, 2015Co-Authors: Laura W Hansen, Ping Wang, Adam Khader, Weng Lang Yang, Jose M Prince, Jeffrey Nicastro, Gene F CoppaAbstract:Intestinal ischemia-reperfusion (I/R) occurs in various clinical situations and causes local and remote Organ Injury, especially in the lungs, leading to significant morbidity and mortality. The maintenance of mitochondrial biogenesis is essential for cell survival and is regulated in part by sirtuin 1 (SIRT1), an energy-sensing enzyme. We hypothesized that SIRT1 activation with SRT1720 would reduce local and remote Organ Injury after intestinal I/R. Intestinal I/R was induced by the occlusion of the superior mesenteric artery of adult male C57BL/6 mice for 45 min, followed by reperfusion for 4 h. SRT1720 or vehicle was injected intravenously at the time of reperfusion. Blood, small intestine, and lung tissues were collected for analysis. The SRT1720 treatment of I/R mice resulted in a 57% increase in protein levels of succinate dehydrogenase, an index of mitochondrial mass, and a 120% increase in messenger RNA levels of mitochondrial transcription factor A, a marker for mitochondrial biogenesis. The microscopic architecture and apoptosis of the gut tissue was improved in the SRT1720-treated I/R mice. SRT1720 decreased intestinal messenger RNA levels of tumor necrosis factor-α by 60% and inducible nitric oxide synthase to baseline after I/R. Systemic inflammation, as determined by serum interleukin-6, was reduced in treated mice. Lung Injury, as measured by histological architecture and myeloperoxidase activity, and lung apoptosis were also improved after the SRT1720 treatment. SRT1720 preserved mitochondrial biogenesis and mass, leading to inhibition of inflammation and oxidative stress, thereby protecting against intestinal I/R-induced Injury. Thus, the SIRT1-mediated pathway is a promising target for the treatment of intestinal I/R Injury.
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orexigenic hormone ghrelin attenuates local and remote Organ Injury after intestinal ischemia reperfusion
PLOS ONE, 2008Co-Authors: Weifeng Dong, Mian Zhou, Corrado P Marini, Thanjavur S Ravikumar, Ping WangAbstract:Background Gut ischemia/reperfusion (I/R) Injury is a serious condition in intensive care patients. Activation of immune cells adjacent to the huge endothelial cell surface area of the intestinal microvasculature produces initially local and then systemic inflammatory responses. Stimulation of the vagus nerve can rapidly attenuate systemic inflammatory responses through inhibiting the activation of macrophages and endothelial cells. Ghrelin, a novel orexigenic hormone, is produced predominately in the gastrointestinal system. Ghrelin receptors are expressed at a high density in the dorsal vagal complex of the brain stem. In this study, we investigated the regulation of the cholinergic anti-inflammatory pathway by the novel gastrointestinal hormone, ghrelin, after gut I/R. Methods and Findings Gut ischemia was induced by placing a microvascular clip across the superior mesenteric artery for 90 min in male adult rats. Our results showed that ghrelin levels were significantly reduced after gut I/R and that ghrelin administration inhibited pro-inflammatory cytokine release, reduced neutrophil infiltration, ameliorated intestinal barrier dysfunction, attenuated Organ Injury, and improved survival after gut I/R. Administration of a specific ghrelin receptor antagonist worsened gut I/R-induced Organ Injury and mortality. To determine whether ghrelin's beneficial effects after gut I/R require the intact vagus nerve, vagotomy was performed in sham and gut I/R animals immediately prior to the induction of gut ischemia. Our result showed that vagotomy completely eliminated ghrelin's beneficial effect after gut I/R. To further confirm that ghrelin's beneficial effects after gut I/R are mediated through the central nervous system, intracerebroventricular administration of ghrelin was performed at the beginning of reperfusion after 90-min gut ischemia. Our result showed that intracerebroventricular injection of ghrelin also protected the rats from gut I/R Injury. Conclusions These findings suggest that ghrelin attenuates excessive inflammation and reduces Organ Injury after gut I/R through activation of the cholinergic anti-inflammatory pathway.
Fredric M Pieracci - One of the best experts on this subject based on the ideXlab platform.
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hypercoagulability following blunt solid abdominal Organ Injury when to initiate anticoagulation
American Journal of Surgery, 2013Co-Authors: Brandon C Chapman, Ernest E Moore, Gregory J Jurkovich, Carlton C Barnett, Robert T Stovall, Walter L Biffl, Clay Cothren Burlew, Denis D Bensard, Fredric M PieracciAbstract:Background The optimal time to initiate venous thromboembolism pharmacoprophylaxis after blunt abdominal solid Organ Injury is unknown.
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hypercoagulability following blunt solid abdominal Organ Injury when to initiate anticoagulation
American Journal of Surgery, 2013Co-Authors: Brandon C Chapman, Ernest E Moore, Gregory J Jurkovich, Carlton C Barnett, Robert T Stovall, Walter L Biffl, Clay Cothren Burlew, Denis D Bensard, Fredric M PieracciAbstract:Abstract Background The optimal time to initiate venous thromboembolism pharmacoprophylaxis after blunt abdominal solid Organ Injury is unknown. Methods PostInjury coagulation status was characterized using thromboelastography (TEG) in trauma patients with blunt abdominal solid Organ injuries; TEG was divided into 12-hour intervals up to 72 hours. Results Forty-two of 304 patients (13.8%) identified underwent multiple postInjury thromboelastographic studies. Age ( P = .45), gender ( P = .45), and solid Organ Injury grade ( P = .71) were similar between TEG and non-TEG patients. TEG patients had higher Injury Severity Scores compared with non-TEG patients (33.2 vs 18.3, respectively, P P Conclusions Patients sustaining blunt abdominal solid Organ injuries transition to a hypercoagulable state approximately 48 hours after Injury. In the absence of contraindications, pharmacoprophylaxis should be considered before this time for effective venous thromboembolism prevention.
David H Livingston - One of the best experts on this subject based on the ideXlab platform.
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resistance of the female as opposed to the male intestine to i r mediated Injury is associated with increased resistance to gut induced distant Organ Injury
Shock, 2007Co-Authors: Elizabeth A Deitch, Sergey B. Zaets, Tamara L. Berezina, Eleonora Feketeova, George W Machiedo, Carl J Hauser, David H LivingstonAbstract:We tested the hypothesis that the female intestine is more resistant to gut I/R Injury than the male intestine by comparing the effects of the isolated pure gut I/R superior mesenteric artery occlusion (SMAO) model on gut morphology and whether SMAO-induced distant Organ Injury (lung, bone marrow [BM], neutrophils, and red blood cells [RBCs]) would differ between male and proestrus female rats. At 6 or 24 h after SMAO or sham SMAO, gut Injury, lung permeability, pulmonary neutrophil sequestration, RBC deformability, and BM RBC and white blood cell progenitor growth were measured, as was the ability of the plasma from these rats to activate naive rat neutrophils. At both 6 and 24 h after SMAO, the female rats had significantly less intestinal Injury and reduced gut-induced lung Injury, BM suppression, RBC dysfunction, and neutrophil activation than male rats subjected to SMAO. These results indicate that the resistance of proestrus female rats to gut Injury and gut-induced distant Organ Injury is greater than that observed in male rats.
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Management of Trauma to the Male External Genitalia: The Usefulness of American Association for the Surgery of Trauma Organ Injury Scales
Journal of Urology, 2003Co-Authors: Alicia M. Mohr, Robert F Lavery, Annette M. Pham, Ziad C. Sifri, Vladislav Bargman, David H LivingstonAbstract:ABSTRACTPurpose: Injury to the male external genitalia is rare and, therefore, there are little data in the literature regarding the options for nonoperative management and outcome. To assist in defining the indications for nonoperative management the usefulness of the American Association for the Surgery of Trauma (AAST) Organ Injury scales for these injuries was examined.Materials and Methods: We retrospectively reviewed the medical records of 116 male patients with trauma to the external genitalia in a 10-year period and classified injuries according to the Organ Injury severity scales (scrotum, testis, penis and urethra) of the AAST. Based on AAST grading management and outcome was reviewed.Results: Mean patient age was 28 years and 79% of the injuries were due to gunshot wounds. A total of 87 patients (75%) underwent surgery, while 27 penile injuries and 8 scrotal/testicular injuries were managed nonoperatively. There were 54 scrotal explorations, 33 testicular injuries and 20 orchiectomies (bilatera...
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free fluid on abdominal computed tomography without solid Organ Injury after blunt abdominal Injury does not mandate celiotomy
American Journal of Surgery, 2001Co-Authors: David H Livingston, Robert F Lavery, Marian R Passannante, Joan Skurnick, Stephen R Baker, T C Fabian, Donald E Fry, Mark A MalangoniAbstract:Abstract Background: Mandatory celiotomy has been proposed for all patients with unexplained free fluid on abdominal computed tomography (CT) scanning after blunt abdominal Injury. This recommendation has been based upon retrospective data and concerns over the potential morbidity from the late diagnosis of blunt intestinal Injury. This study examined the rate of intestinal Injury in patients with free fluid on abdominal CT after blunt abdominal trauma. Methods: This study was a multicenter prospective series of all patients with blunt abdominal trauma admitted to four level I trauma centers over 22 months. Data were collected concurrently at the time of patient enrollment and included demographics, Injury severity score, findings on CT scan, and presence or absence of blunt intestinal Injury. This database was specifically queried for those patients who had free fluid without solid Organ Injury. Results: In all, 2,299 patients were evaluated. Free fluid was present in 265. Of these, 90 patients had isolated free fluid with only 7 having a blunt intestinal Injury. Conversely, 91% of patients with free fluid did not. All patients with free fluid were observed for a mean of 8 days (95% confidence interval 6.1 to 10.4, range 1 to 131). There were no missed injuries. Conclusions: Free fluid on abdominal CT scan does not mandate celiotomy. Serial observation with the possible use of other adjunctive tests is recommended.
