Emerging tropical diseases in Australia. Part 5. Hendra virus.

Hendra virus (HeV) was first isolated in 1994, from a disease outbreak involving at least 21 horses and two humans in the Brisbane suburb of Hendra, Australia. The affected horses and humans all developed a severe but unidentified respiratory disease that resulted in the deaths of one of the human cases and the deaths or putting down of 14 of the horses. The virus, isolated by culture from a horse and the kidney of the fatal human case, was initially characterised as a new member of the genus Morbillivirus in the family Paramyxoviridae. Comparative sequence analysis of part of the matrix protein gene of the virus and the discovery that the virus had an exceptionally large genome subsequently led to HeV being assigned to a new genus, Henipavirus, along with Nipah virus (a newly emergent virus in pigs). The regular outbreaks of HeV-related disease that have occurred in Australia since 1994 have all been characterised by acute respiratory and neurological manifestations, with high levels of morbidity and mortality in the affected horses and humans. The modes of transmission of HeV remain largely unknown. Although fruit bats have been identified as natural hosts of the virus, direct bat-horse, bat-human or human-human transmission has not been reported. Human infection can occur via exposure to infectious urine, saliva or nasopharyngeal fluid from horses. The treatment options and efficacy are very limited and no vaccine exists. Reports on the outbreaks of HeV in Australia are collated in this review and the available data on the biology, transmission and detection of the pathogen are summarized and discussed.

Erratum to: Antimicrobials: a global alliance for optimizing their rational use in intra-abdominal infections (AGORA).

[This corrects the article DOI: 10.1186/s13017-016-0089-y.].

Interleukin-6 suppression of neutrophil apoptosis is neutrophil concentration dependent.

Apoptosis of polymorphonuclear leukocytes (PMNs) is a critical step in the resolution of tissue inflammation. PMN apoptosis has been studied extensively in vitro, and diverse inflammatory mediators have been shown to modulate the process. The reported effects of interleukin-6 (IL-6) on PMN apoptosis are inconsistent; however, analysis of published studies reveals at least one discriminating factor--the use of varied concentrations of PMNs in the experimental design. Consequently, we hypothesized that the in vitro effects of IL-6 on PMN apoptosis varied with the concentration of PMNs in culture. PMNs isolated from healthy human donors were cultured at concentrations from 1 to 20 x 10(6)/mL, and incubated with IL-6 doses from 1 to 100 ng/mL. PMNs cultured at 1-5 x 10(6)/mL were unaffected by IL-6; in contrast, IL-6 inhibited apoptosis in PMNs cultured at 10-20 x 10(6)/mL, compared with untreated similarly concentrated PMNs. These data suggest caution in interpreting in vitro studies of apoptosis; on the other hand, appropriately designed experiments may help elucidate the regulation of apoptosis in vivo.

Interleukin-6 stimulates neutrophil production of platelet-activating factor.

Interleukin-6 (IL-6) is an integral mediator of the acute phase response to injury and infection; an exaggerated IL-6 response has been associated with adverse clinical events. The precise role of IL-6 is unclear, but it appears capable of modulating the functional repertoire of mature neutrophils (PMNs). Our previous work demonstrated that IL-6 -stimulated PMNs are primed by lower concentrations of platelet-activating factor (PAF) than nonstimulated PMNs. Recently, we have found that IL-6 suppresses PMN apoptosis via a PAF-like mechanism. We hypothesized that IL-6 stimulates PMNs to produce PAF. PMNs isolated from healthy human donors were incubated with IL-6 (0.1-100 ng/ml) at 37 degrees C. Lipid production was measured by use of thin-layer chromatography, and PAF quantitated with a scintillation proximity assay. IL-6 (1 and 10 ng/ml) stimulated PMNs to produce increase quantities of PAF. PAF production was associated with an increase in PMN cytosolic calcium. These data may provide mechanistic insight into IL-6 regulation of PMN-mediated cytotoxicity and the role of PAF in mediating IL-6 effects on PMNs.

Postinjury neutrophil priming and activation states: therapeutic challenges.

Both hyperactivity and hypoactivity of neutrophils (PMNs) have been implicated in the pathogenesis of postinjury multiple organ failure. In this paper, the cellular and molecular mechanisms involved in the regulation of PMN O2- production are reviewed. In addition, relevant research laboratory techniques for measuring both intracellular and extracellular O2- release are outlined. In a pilot study PMN O2- release in response to a battery of PMN agonists was determined, and four functional states of the NADPH were defined: resting, primed, activated, and unresponsive. PMNs from normal adult volunteers are in the resting state. In contrast, PMNs from patients with severe torso trauma are primed and activated in the first 24 h postinjury, but, after 48 h, become unresponsive to both receptor-dependent (platelet activating factor and N-formyl-methyl-leucyl-phenylalanine) and receptor-independent (phorbol 12-myristate 13-acetate) activation. The ability to identify at-risk patients and provide a rationale for ameliorating PMN-mediated tissue injury in patients with hyperinflammation syndromes are discussed. In addition, the importance of identifying patients with PMNs that are unresponsive, and the necessity for increasing PMN function in these patients in order to reduce the risk of sepsis, are also discussed.

Reduced PAF-acetylhydrolase activity is associated with postinjury multiple organ failure.

Our basic laboratory work has identified the postischemic gut as a source of platelet-activating factor (PAF), which primes circulating neutrophils for the production of reactive oxygen metabolites (ROMs) leading to distant organ injury. Circulating PAF-acetylhydrolase (PAF-AH) hydrolyzes PAF to lyso-PAF. Recently, ROMs have been shown to rapidly and irreversibly inactivate human PAF-AH. Consequently, our study hypothesis was that reduced levels of PAF-AH in severely injured patients would be associated with the development of multiple organ failure (MOF). Over a 16 mo period, 26 patients at known risk for MOF (Injury Severity Score (ISS) > or = 25 or an ISS > 15 with > or = 6 U of blood transfused within the first 6 h) had blood sampled on postinjury days 0, 1, 2, 3, and 5. PAF-AH activity was assessed by measuring the percentage of 3H-labeled PAF hydrolyzed. MOF was defined by a standard score. The mean age of the 26 study patients was 34 +/- 2 yr; 19 (73%) were male. The injury mechanism was blunt in 18 (69%), and the mean ISS was 31 +/- 2. Eight patients (31%) developed MOF. In the MOF patients, plasma PAF-AH activity was significantly lower on the day of injury and remained depressed throughout the ensuing 5 days compared with the non-MOF patients. Reduced PAF-AH activity is associated with the development of postinjury MOF. With the recent molecular cloning of human plasma PAF-AH, repleting this circulating, anti-inflammatory enzyme may represent useful therapy for these high risk patients.

Post-injury multiple organ failure: the role of the gut.

Despite intensive investigation, the pathogenesis of post-injury multiple organ failure (MOF) remains elusive. Laboratory and clinical research strongly suggests that the gastrointestinal tract (i.e., the gut) plays a pivotal pathogenic role. Since its inception in 1988, the Trauma Research Center (TRC) at the University of Texas-Houston Medical School (UTHMS) has focused its efforts on elucidating the role of the gut in post-injury MOF. On the basis of our observations and those of others, we believe that 1) shock with resulting gut hypoperfusion is an important inciting event, 2) the reperfused gut is a source of proinflammatory mediators that can amplify the early systemic inflammatory response syndrome (SIRS) and thus contribute to early MOF, 3) early gut hypoperfusion causes an ileus in both the stomach and small bowel that sets the stage for progressive gut dysfunction so that the proximal gut becomes a reservoir for pathogens and toxins that contribute to late sepsis-associated MOF, and 4) late infections cause further worsening of this gut dysfunction. Thus, the gut can be both an instigator and a victim of MOF. The purpose of this article is to provide the rationale behind these beliefs and to provide a brief overview of the ongoing research projects in the TRC at UTHMS.

Fivefold enlargement of implants in a splenic autotransplant recipient.

A 30-year-old patient underwent splenectomy for trauma with splenic autotransplantation. Four years later he survived a bout of pneumococcal sepsis with only oral penicillin therapy. Seven years after splenectomy, he underwent another laparotomy with the finding of fivefold enlargement of the splenic implants. Splenic autotransplants enlarge and probably function in human beings.

Phospholipase A2 inhibition decouples lung injury from gut ischemia-reperfusion.

BACKGROUND: Phospholipase A2 (PLA2) has recently been implicated as a key enzyme of local inflammation after gut ischemia-reperfusion (I/R). The hypothesis of this study is that PLA2 inhibition decouples remote organ injury from gut I/R. METHODS: Sprague-Dawley rats were pretreated with a PLA2 inhibitor, quinacrine (10 mg/kg, intravenously), before the induction of gut ischemia (45 minutes of superior mesenteric artery occlusion) followed by 6 hours of reperfusion. 125I-labeled albumin leak was employed as a marker of pulmonary endothelial permeability and myeloperoxidase as a monitor of neutrophil (PMN) traffic in the gut and lung. To further characterize the impact of PLA2 inhibition, PMNs were harvested at 6 hours of reperfusion and superoxide production was measured in the presence or absence of an activating stimulus, N-formyl-methionyl-leucyl-phenylalanine. RESULTS: Gut I/R increased gut PLA2 activity, elicited gut PMN influx, and produced lung leak; these events were prevented by PLA2 blockade. Gut I/R also markedly enhanced PMN superoxide production with N-formyl-methionyl-leucyl-phenylalanine, and this priming was ablated by PLA2 inhibition. CONCLUSION: These data suggest that PLA2 activation is a proximal step in the pathogenesis of distant organ injury after splanchnic hypoperfusion, a process that appears to involve PMN priming in the gut bed.

Disparate signal transduction in neutrophil CD18 adhesion receptor expression versus superoxide generation.

BACKGROUND: We have previously shown that platelet-activating factor (PAF) primes polymorphonuclear neutrophils (PMNs) for superoxide generation and, concurrently, increases CD11/CD18 receptor expression; both events appear central to the pathogenesis of postinjury multiple organ failure. Recently, the counterinflammatory role of the neuroendocrine response to trauma has been emphasized, and, specifically, beta-adrenergic stimulation has been found to inhibit PMN activation. METHODS: Normal human PMNs were primed with PAF (10(-9) mol/L for 5 minutes) or pretreated with beta-receptor stimulation (isoproterenol, 10(-7) mol/L) or adenylate cyclase (AC) activation (forskoklin, 10(-7) mol/L) for 5 minutes and then primed with PAF. Superoxide generation in response to N-formyl-methionyl-leucyl-phenylalanine (10(-6) mol/L) was measured by superoxide dismutase inhibitable reduction of cytochrome C and CD18 expression determined by flow cytometry. RESULTS: PAF primed PMNs for superoxide generation (229.5 +/- 42.3 nmol/10(6) cells/min versus 18.7 +/- 6.5), whereas pretreatment with beta-adrenoreceptor stimulation (112.9 +/- 20.6) or AC activation (115.3 +/- 12.6) dramatically attenuated this process (p < 0.0001). PAF also enhanced CD18 expression (6.1 +/- 1.1 mean fluorescence intensity versus 10.3 +/- 2.3), but beta-adrenoreceptor stimulation (10.1 +/- 2.1) and AC activation (9.7 +/- 1.9) had no discernible effect. CONCLUSIONS: PAF priming of PMNs for superoxide generation was inhibited by the beta-adrenergic signal transduction pathway, but CD18 expression was not regulated via this pathway.

Base deficit after major trauma directly relates to neutrophil CD11b expression: a proposed mechanism of shock-induced organ injury.

OBJECTIVE: To determine whether expression of neutrophil integrin receptors is related to the degree of post-traumatic shock. DESIGN: Data were collected prospectively on patients with major trauma admitted to the surgical intensive care unit. SETTING: Denver General Hospital, Colorado. PATIENTS AND PARTICIPANTS: 17 severely injured adults. MEASUREMENTS AND RESULTS: The mean fluorescence intensity and per cent positive of neutrophil integrin receptors CD11 b, CD18 and CD11 a, and systolic blood pressure, blood transfusion, lactate and base deficit as indices of shock. CD11 b expression on circulating neutrophils was increased 6 and 12 h after trauma. After correcting for the other shock indices, base deficit predicted CD11 b expression at 12 h. CD11 b expression was negatively correlated with the circulating neutrophil count. CONCLUSIONS: The degree of metabolic acidosis after trauma correlates directly with CD11 b receptor expression on circulating neutrophils. This relation may be the mechanism whereby post-traumatic shock results in neutrophil sequestration and neutrophil-mediated organ injury and failure.

Inadequate granulopoiesis after major torso trauma: a hematopoietic regulatory paradox.

Late postinjury sepsis is largely the result of defective host defense including failure to maintain an adequate number of functioning phagocytic cells. In this study we used stem cell culture techniques to measure colony-stimulating activity and have quantitated the number of circulating myeloid stem cells to see if defects in granulopoiesis occur after major torso trauma. Forty-two acutely injured patients (13 blunt and 29 penetrating injuries; mean age, 29.7 years) undergoing laparotomy with an abdominal trauma index of 15 to 40 were studied prospectively. Blood samples were obtained on days 1, 5, and 10. Patients were segregated by injury severity: abdominal trauma index less than 25 (n = 25) versus abdominal trauma index greater than or equal to 25 (n = 17). The more severely injured (abdominal trauma index greater than or equal to 25) patients had fewer circulating granulocytes and monocytes. Colony-stimulating activity was below normal control levels in all patients and was decreased further with increased injury severity. The more severely injured patients had a blunted bone marrow response (significantly fewer circulating myeloid stem cells) and suffered more major septic complications (24% vs 8%). In conclusion, major trauma to the torso causes a paradoxic depression in granulopoiesis that worsens with increased injury severity and may contribute to late septic morbidity. This colony-stimulating activity deficiency state is similar to that seen after major burns and may be amenable to future modulation.

Platelet-activating factor-induced polymorphonuclear neutrophil priming independent of CD11b adhesion.

BACKGROUND: Our previous studies have implicated phospholipase A2-dependent platelet-activating factor (PAF) production in the genesis of polymorphonuclear neutrophil (PMN)-mediated tissue injury after gut ischemia-reperfusion. Further, these studies have suggested a discordance of PMN sequestration and tissue injury. CD11B-dependent PMN-endothelial cell adhesion has been purported to play a dominant role in PMN-mediated tissue injury. We therefore undertook this study with the hypothesis that PAF-induced PMN superoxide production requires CD11B-mediated PMN-endothelial cell adherence. METHODS: Human PMNs, isolated by Percoll gradient centrifugation, were exposed to PAF (10 ng/ml). At fixed times of exposure during 120 minutes, (1) superoxide production, (2) CD11B receptor expression, and (3) PMN adhesion to unstimulated human umbilical vein endothelial cell cultures were assayed. RESULTS: PAF induced prompt changes in PMN priming (increased superoxide production after N-formyl-methyl-leucyl-phenylalanine activation), adhesion to unstimulated endothelial cells, and CD11B receptor expression. Priming was temporally concordant with the rise and fall of CD11B expression but appeared to precede adhesion. CD11B blockade (F(Ab') 2 anti-CD11B [60.1] antibodies), before or at maximal PAF priming, reduced PMN adhesion but had no effect on superoxide production. CONCLUSIONS: In summary, PAF-induced PMN priming occurs in temporal concordance with the expression of CD11B and subsequent endothelial cell adherence, but CD11B-mediated adherence is not essential for this process.

Soluble intercellular adhesion molecule-1 provokes polymorphonuclear leukocyte elastase release by CD18.

BACKGROUND: Elevated levels of soluble intercellular adhesion molecule-1 (sICAM-1) correlate with the development of postinjury multiple organ failure. Soluble ICAM-1 secretion is known to be induced in endothelial cells and monocytes by diverse inflammatory stimuli. We have found that incubation of quiescent polymorphonuclear leukocytes (PMNs) with sICAM-1 elicits elastase release and, more recently, that cross-linking CD18 receptors on PMNs also produces elastase release. Consequently, our study hypothesis was that sICAM-1 provokes PMN elastase release through its interaction with CD18. METHODS: To obtain sICAM-1, Chinese hamster ovarian cells transfected with human ICAM-1 were lysed and centrifuged at 150,000 g for 1 hour; the supernatant was passed over an ICAM-1 affinity column, eluted with 0.1 mmol/L glycine HCl, and concentrated with dialysis filter. Human PMNs (2.5 x 10(5)) were saturated with specific monoclonal antibodies for the beta 2 subunits (CD11a, CD11b, CD18) or nonspecific monoclonal antibodies for 30 minutes on ice before a 1-hour incubation with sICAM-1 (75 ng/ml) at 37 degrees C. Elastase activity was measured by the cleavage of n-methoxysuccinyl-A-A-P-V-p-nitroanilide. RESULTS: Neutrophil incubation with sICAM-1 resulted in 19.2% +/- 2.8% of total PMN elastase, compared with 2.4% +/- 0.5% in the controls. Blockade of CD18 abrogated sICAM-1 provoked elastase release with monoclonal antibodies to CD18 (TS1/18, 31H8) resulting in 4.3% +/- 1.0% and 5.5% +/- 1.4% elastase release, respectively. Blockade of CD11a, CD11b, and nonspecific antibody controls had no effect on sICAM-1 induced elastase release. CONCLUSIONS: In vitro, sICAM-1 provokes PMN elastase release through CD18. This may represent a mechanism by which elevated levels of circulating sICAM-1, released from local injury sites, provoke distal organ dysfunction.

Total enteral nutrition versus total parenteral nutrition after major torso injury: attenuation of hepatic protein reprioritization.

Reprioritization of hepatic protein synthesis, a process involving accelerated production of acute-phase proteins at the expense of constitutive proteins, accompanies major trauma. The impact of isocaloric, isonitrogenous total enteral nutrition (TEN) versus total parenteral nutrition (TPN) on hepatic reprioritization was investigated in a prospective, randomized trial. Of the 59 patients with an abdominal trauma index (ATI) greater than 15 but not more than 40, 45 evaluable patients were followed. Results from 36 (18 TEN, 18 TPN) evaluable patients revealed that mean serum levels of acute-phase proteins increased, whereas mean serum levels increased to a greater extent in the TPN group. The maximal increase from baseline for the acute-phase response in both groups occurred at postinjury day 5 and was significantly higher for alpha 1-antitrypsin (alpha 1AT, p = 0.03) and orosomucoid (p = 0.02) in the TPN group. Nonacute-phase proteins reached a nadir at day 10 in the TPN group and increased in the TEN group; significant differences between TEN and TPN groups appeared for albumin (p = 0.004) and retinol-binding protein (RBP, p = 0.03); alpha 2-macroglobulin (alpha 2M) approached significance at day 10 (p = 0.07). When change from baseline values was compared, day 10 increases in alpha 2M were significantly higher (p = 0.04) in the TEN group. These data suggest that postinjury TEN attenuates reprioritization of hepatic protein synthesis in patients sustaining major trauma.

Intercellular adhesion molecule-1 promotes neutrophil-mediated cytotoxicity.

BACKGROUND: Interaction of the CD11/CD18 complex on polymorphonuclear neutrophils (PMNs) and intercellular adhesion molecule (ICAM)-1 on endothelium is a critical event in PMN-mediated tissue injury. In addition, increased expression of ICAM-1 on type I pneumocytes has been identified in a variety of pulmonary disorders associated with PMN-induced inflammation. We hypothesized that ICAM-1 up-regulation is sufficient to promote cytotoxicity via activated PMNs. METHODS: The complementary DNA for human ICAM-1 was transfected into Chinese hamster ovarian (CHO) cells, which do not inherently express this adhesion receptor, by using the expression vector CD1.8. Fluorescence-activated cell sorter analysis revealed 62% CHO cell surface expression of ICAM-1. Wild type and transfected CHO cells were labeled with chromium 51 and exposed to quiescent or activated (1 mumol/L phorbol myristate acetate) PMNs for 4 hours. Subsets were pretreated with a monoclonal antibody to ICAM-1. PMN cytotoxicity was determined by specific percent 51Cr release. RESULTS: Incubation of quiescent PMNs with wild type and transfected CHO cells produced nominal cell lysis, 0.5% +/- 0.3% and 0.2% +/- 0.2%, respectively. Activated PMNs produced 13.6% +/- 3.2% versus 1.4% +/- 0.7% cell lysis, comparing transfected with wild type CHO cells, and 0.5% +/- 0.2% cell lysis after pretreatment with a monoclonal antibody to ICAM-1, p < 0.01. CONCLUSIONS: ICAM-1 up-regulation is sufficient to promote cytotoxicity via activated PMNs. This may represent a potential target for attenuating PMN-mediated injury to endothelial and other cell lines, including parenchyma.

Postinjury neutrophil priming and activation: an early vulnerable window.

BACKGROUND: Generation of extracellular, cytotoxic superoxide anion (O2-) by polymorphonuclear neutrophils (PMNs) contributes to an unbridled inflammatory response that can precipitate multiple organ failure (MOF). Release of O2- is markedly enhanced when activated PMNs have been previously "primed" by inflammatory mediators, such as those expressed after trauma. We therefore hypothesized that PMN priming occurs as an integral part of the early inflammatory response to trauma. METHODS: PMNs were obtained from 17 high-risk patients with torso trauma at 3, 6, 12, 24, 48, and 72 hours after injury, as well as from 10 healthy donors, and the in vitro release of O2- was quantitated with a kinetic, superoxide dismutase (SOD)-inhibitable cytochrome c reduction assay. PMN O2- release was measured in the presence and absence of 1 mumol/L N-formyl-methionyl-leucyl-phenylalanine (fMLP) and after priming and activation with 20 nmol/L platelet-activating factor (PAF) and 1 mumol/L fMLP, respectively. RESULTS: In vitro PMN O2- release was used to determine whether postinjury PMNs were (1) activated in vivo, (2) primed in vivo, or (3) primable in vitro. Unstimulated PMNs from trauma patients spontaneously expressed modest amounts of O2- in vitro from 6 to 48 hours after injury, suggesting endogenous activation. Also, fMLP-activated PMNs collected between 3 and 24 hours after injury expressed more O2- than controls (p < or = 0.02), indicating in vivo, trauma-related priming. Furthermore, postinjury PMNs were maximally primed in vivo (i.e., in vitro exposure to PAF before fMLP activation failed to significantly enhance O2- release) as compared to PMNs treated with fMLP. CONCLUSIONS: These data indicate that major torso trauma (first hit) primes and activates PMNs within 3 to 6 hours after injury. Consequently, we postulate that postinjury priming of PMNs may create an early vulnerable window during which a second hit (e.g., a secondary operation or delayed hemorrhage) activates exuberant PMN O2- release, rendering the injured patient at high risk for MOF.

Intravascular ultrasonography for the diagnosis of traumatic aortic disruption: a case report.

Thoracic aortic disruptions after blunt trauma are highly lethal injuries. Diagnosis of these injuries has traditionally been based on clinical suspicion, chest radiographs, and aortography. The roles of dynamic computed tomography and transesophageal echocardiography are currently under investigation. Intravascular ultrasonography is a new technology with potential as a diagnostic adjunct in the evaluation of these injuries. We present a case of traumatic aortic disruption identified by intravascular ultrasonography after nondiagnostic aortography and dynamic computed tomography studies.

Hypovolemic shock promotes neutrophil sequestration in lungs by a xanthine oxidase-related mechanism.

Our results suggest that xanthine oxidase (XO) contributes to lung neutrophil sequestration in hypovolemic shock. Catheterized rats subjected to shock by phlebotomy (approximately 30% blood loss) had decreased mean arterial blood pressures (P less than 0.05) and increased (P less than 0.05) lung myeloperoxidase (MPO) activities (indicative of lung neutrophil accumulation) compared with sham-treated normotensive rats. In contrast, rats depleted of lung and plasma XO activity by tungsten diet before phlebotomy had decreased (P less than 0.05) lung MPO activities compared with phlebotomized rats fed regular diets.

Blood transfusion. An independent risk factor for postinjury multiple organ failure.

OBJECTIVE: To determine if blood transfusion is a consistent risk factor for postinjury multiple organ failure (MOF), independent of other shock indexes. DESIGN: A 55-month inception cohort study ending on August 30, 1995. Data characterizing postinjury MOF were prospectively collected. Multiple logistic regression analysis was performed on 5 sets of data. Set 1 included admission data (age, sex, comorbidity, injury mechanism, Glasgow Coma Scale, Injury Severity Score, and systolic blood pressure determined in the emergency department) plus the amount of blood transfused within the first 12 hours. In the subsequent 4 data sets, other indexes of shock (early base deficit, early lactate level, late base deficit, and late lactate level) were sequentially added. Additionally, the same multiple logistic regression analyses were performed with early MOF and late MOF as the outcome variables. SETTING: Denver General Hospital, Denver, Colo, is a regional level I trauma center. PATIENTS: Five hundred thirteen consecutive trauma patients admitted to the trauma intensive care unit with an Injury Severity Score greater than 15 who were older than 16 years and who survived longer than 48 hours. INTERVENTIONS: None. MAIN OUTCOME MEASURES: The relationship of blood transfusions and other shock indexes with the outcome variable, MOF. RESULTS: A dose-response relationship between early blood transfusion and the later development of MOF was identified. Despite the inclusion of other indexes of shock, blood transfusion was identified as an independent risk factor in 13 of the 15 multiple logistic regression models tested; the odds ratios were high, especially in the early MOF models. CONCLUSIONS: Blood transfusion is an early consistent risk factor for postinjury MOF, independent of other indexes of shock.