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Biomedical subjects

F A Moore

Publications and source records attributed to F A Moore.

At least 73 records · Page 4Linked to original sources
PubMed1996

Interleukin-6 in the injured patient. Marker of injury or mediator of inflammation?

OBJECTIVE: The effects of interleukin (IL)-6 in the injured patient are examined in an attempt to clarify the potential pathophysiologic role of IL-6 in the response to injury. SUMMARY BACKGROUND DATA: Interleukin-6 is an integral cytokine mediator of the acute phase response to injury and infection. However, prolonged and excessive elevations of circulating IL-6 levels in patients after trauma, burns, and elective surgery have been associated with complications and mortality. The mechanistic role of IL-6 in mediating these effects is unclear. METHODS: A review of current literature is performed to summarize the origins, mechanisms of action, and biologic effects of IL-6 and to characterize the IL-6 response to injury. RESULTS: Interleukin-6 is a multifunctional cytokine expressed by a variety of cells after a multitude of stimuli, under complex regulatory control mechanisms. The IL-6 response to injury is uniquely consistent and related to the magnitude of the insult. Moreover, the early postinjury IL-6 response correlates with complications as well as mortality. CONCLUSIONS: Interleukin-6 appears to play an active role in the postinjury immune response, making it an attractive therapeutic target in attempts to control hyperinflammatory provoked organ injury.

Antigens, CD↗
PubMed1996

An increase in serum C18 unsaturated free fatty acids as a predictor of the development of acute respiratory distress syndrome.

OBJECTIVE: No means exist for predicting the acute respiratory distress syndrome (ARDS), which complicates sepsis, trauma, and a variety of clinical disorders. Because activation of phospholipid-signaling pathways involving the acyl chains oleate and linoleate may initiate and amplify the inflammatory response, and thereby lead to the development of ARDS, we examined whether serum concentrations of these bioactive lipids increase and are predictive of ARDS in at-risk patients. DESIGN: Part I: A prospective, single-blind trial. Part II: A prospective, randomized, double-blind trial. SETTING: General intensive therapy units in five university teaching hospitals. SUBJECTS: Part I: Thirty-nine healthy control patients were studied to determine normal distribution of serum acyl values, followed by 30 patients admitted with onset of sepsis, trauma, or development of ARDS (within 24 hrs of admission) over a 1-yr period. Part II: Eight patients admitted with sepsis syndrome over a 2-month period. INTERVENTIONS: Part II: Patients were randomized to receive the substituted methylxanthine, lisofylline (CT1501R), or an identically presented placebo. MEASUREMENTS AND MAIN RESULTS: We measured the serum free fatty acid concentrations in the 39 healthy control subjects, and then we prospectively examined the serum free fatty acid concentrations in 30 age-matched patients in samples obtained within 24 hrs from the onset of sepsis, trauma, or development of ARDS. We then prospectively studied eight septic, at-risk patients who were matched for age, Acute Physiology and Chronic Health Evaluation II scores, Multiple Organ Failure index, and Glasgow Coma Score, in a double-blind, placebo-controlled, pilot study. These patients included four patients who received no treatment and four patients who received lisofylline, a compound that decreases serum unsaturated free fatty acids and diminishes acute lung injury in animals caused by sepsis and/or trauma. The calculated ratios of serum free fatty acids (Le., the ratio of C18 unsaturated fatty acids linoleate and oleate to fully saturated palmitate, C16:0) increased and predicted the development of ARDS in at-risk patients. Serum samples from the 30 patients, obtained within 24 hrs from the onset of sepsis, trauma, or development of ARDS, had significantly increased mean acyl chain ratios (1.42 +/- 0.35 [SD]) compared with healthy control subjects (0.86 +/- 0.25; p < .01). Sera from 13 patients with sepsis or trauma who did not develop ARDS (group A [at-risk, non-pre-ARDS]) also had increased acyl ratios (1.23 +/- 0.27) compared with sera from healthy control subjects (0.86 +/- 0.25; p < .01). Sera from seven patients who subsequently developed ARDS (group B [at-risk, pre-ARDS]) had higher acyl ratios (1.70 +/- 0.21) than group A at-risk patients who did not develop ARDS (1.23 +/- 0.27; p < .01) or healthy control subjects (0.86 +/- 0.25; p < .001). Sera from ten group C patients with ARDS at the time of admission to the study had the highest acyl ratios (1.80 +/- 0.75), which exceeded values for healthy control subjects (p < .001) and group A at-risk patients without ARDS (p = .01), but were not significantly different then group B at-risk, pre-ARDS patients (p = .17). Prospective study of eight septic, at-risk patients demonstrated significantly (p < .05) increased serum acyl ratios in the four untreated patients (findings consistent with the first study) but a significantly (p = .02) reduced ratio in the four at-risk patients treated with lisofyline. CONCLUSIONS: Increases in unsaturated serum acyl chain ratios differentiate between healthy and seriously iII patients, and identify those patients likely to develop ARDS. Thus, the serum acyl ratio may not only prospectively identify and facilitate the assessment of new treatments in patients at highest risk for developing ARDS, but may also lead to new insights about the pathogenesis of ARDS.

Adult↗
PubMed1996

Nuclear factor-kappa B is activated in alveolar macrophages from patients with acute respiratory distress syndrome.

OBJECTIVE: The expression of proinflammatory cytokines is rapidly increased in experimental models of the acute respiratory distress syndrome (ARDS), in patients at risk for ARDS, and in patients with established ARDS. Because multiple cytokines are present in bronchoalveolar lavage fluid, a common, proximal activation mechanism may operate in these settings. The proinflammatory cytokines whose expression is increased in the lungs of patients with ARDS have binding sequences in their enhancer/promoter regions for transcriptional regulatory proteins, such as nuclear factor-kappa B (NF-kappa B), nuclear factor-IL6 (NF-IL6), cyclic adenosine monophosphate responsive element binding protein, serum protein-1, and activating protein-1. To test the hypothesis that activation of one or more of these nuclear transcriptional regulatory factors might provide a common mechanism for the simultaneous expression of multiple cytokine genes in the setting of ARDS, we measured activation of these factors in alveolar macrophages from patients with ARDS and from controls. DESIGN: Prospective, clinical study. SETTING: Medical and surgical intensive care units at a university hospital and a county hospital. PATIENTS: Twelve patients, six with established ARDS and six control patients without lung injury. INTERVENTIONS: Patients with ARDS and controls underwent fiberoptic bronchoscopy and bronchoalveolar lavage. Alveolar macrophages were isolated from lavage fluid and the nuclear proteins were extracted. Activation of transcriptional factors NF-kappa B, NF-IL6, cyclic adenosine monophosphate responsive element binding protein, activating protein-1, and serum protein-1 was determined using an electrophoretic mobility shift assay, followed by densitometry of the autoradiographed gels. MEASUREMENTS AND MAIN RESULTS: There were no significant differences in gender, age, tobacco smoking, Acute Physiology and Chronic Health Evaluation II score, quantity of lavage fluid, or number of alveolar macrophages in lavage specimens in the patient groups. Acute Lung Injury score and the Pao2/Fio2 ratio differed significantly between controls and ARDS patients: 0.46 +/- 0.17 vs. 2.74 +/- 0.14 (p < .0001) and 310 +/- 45 torr (41.3 +/- 6.0 kPa) vs. 150 +/- 11 torr (21.3 +/- 1.5 kPa) (p < .006), respectively. The mean Fio2 of the control patients was not significantly different from the mean Fio2 of ARDS patients: 0.47 +/- 0.11 vs. 0.55 +/- 0.6 (p = .53). Patients with ARDS had significantly (p < .02) increased activation of NF-kappa B in alveolar macrophages compared with patients without the syndrome. There was no evidence of increased activation of the transcriptional factors activating protein-1, serum protein-1, NF-IL6, or cyclic adenosine monophosphate responsive element binding protein in alveolar macrophages from ARDS vs. control patients. CONCLUSIONS: These experiments demonstrated increased in vivo activation of the nuclear transcriptional regulatory factor NF-kappa B (but not NF-IL6, cyclic adenosine monophosphate responsive element binding protein, activating protein-1, or serum protein-1) in alveolar macrophages from patients with ARDS. Because binding sequences for NF-kappa B are present in the enhancer/promoter sequences of multiple proinflammatory cytokines, activation of NF-kappa B may contribute to the increased expression of multiple cytokines in the lung in the setting of established ARDS.

Adult↗
PubMed1996

Endothelial cell activity varies in patients at risk for the adult respiratory distress syndrome.

OBJECTIVE: The endothelial cell produces many bioactive compounds that are presumed to play important roles in the pathogenesis of the adult respiratory distress syndrome (ARDS). We postulated that individuals with sepsis and trauma-two at-risk diagnoses for the development of ARDS--might demonstrate differences in the degree of endothelial cell activity. DESIGN: Prospective cohort study. SETTING: Intensive care unit patients in a tertiary, university-affiliated, city hospital. PATIENTS: Fifty-five intensive care unit patients (19 with sepsis and 36 trauma patients). INTERVENTIONS: Plasma measurements of three endothelial cell products--von Willebrand factor antigen, soluble intercellular adhesion molecule-1 (ICAM-1), and soluble E-selectin-were performed within 8 hrs of patients meeting our inclusion criteria, and at the clinical onset of ARDS. MEASUREMENTS AND MAIN RESULTS: Twenty-six percent of the septic patients and 25% of the trauma patients developed ARDS. The median (and 25% to 75% quartiles) concentrations of all three mediators measured in the sepsis patients (von Willebrand factor antigen 399% [375% to 452%], ICAM-1 573 ng/mL [470 to 980], and soluble E-selectin 180 ng/mL [81 to 340]) were significantly higher (p < .001 for each individual analysis) than in the trauma patients (von Willebrand factor antigen 256% [217% to 310%], ICAM-1 148 ng/mL [113 to 210], and soluble E-selectin 42 ng/mL [31 to 65 ng/ mL]). In addition, neither the ICAM-1 nor soluble E-selectin concentrations measured in the trauma patients were different (p = .17 and p = .24, respectively) from normal controls. In those patients who developed ARDS, the differences in the concentrations of all three endothelial cell mediators between the sepsis and trauma patients persisted (p = .008 for von Willebrand factor antigen, p = .003 for ICAM-1, and p = .003 for E-selectin). CONCLUSION: These findings suggest that differences in endothelial cell activity exist between sepsis and trauma patients who are at risk for the development of ARDS.

Adult↗
PubMed1996

Postinjury multiple organ failure: a bimodal phenomenon.

To better define the epidemiology of postinjury multiple organ failure (MOF), we prospectively evaluated 457 high-risk trauma patients who survived more than 48 hours. Overall, 70 (15%) developed MOF. In 27 (39%) patients, the occurrence was early, while in 43 (61%) patients the presentation was delayed. At presentation, early MOF had more cardiac dysfunction, while late MOF had greater hepatic failure. Indices of shock were more critical risk factors for early MOF, while advanced age was more important for late MOF. While early and late MOF had a similar high incidence of major infections, these appeared to be more important in precipitating late MOF. Finally, while mortality is similar, early MOF patients appear to succumb faster. In conclusion, postinjury MOF remains a significant challenge and appears to present in at least two patterns (i.e., early versus late). Better understanding of the relative roles of the dysfunctional inflammation and infections in early MOF versus late MOF may facilitate the development of new strategies for the prevention and treatment of morbid syndrome.

Adolescent↗
PubMed1996

Interleukin-6 delays neutrophil apoptosis via a mechanism involving platelet-activating factor.

BACKGROUND: Interleukin (IL)-6, an integral mediator of the physiologic acute phase response to injury, has been associated with adverse postinjury complications when present in excessive concentrations. The precise role of IL-6 is unclear, but may involve exacerbation of polymorphonuclear neutrophil leukocytes (PMN)-mediated hyperinflammation. We have shown that IL-6 delays PMN apoptosis, thereby inhibiting the resolution of inflammation. More recently we have found that IL-6 stimulates PMNs to generate platelet-activating factor (PAF). Given the evidence for PAF involvement in postinjury hyperinflammation, we hypothesized that IL-6 delayed apoptosis via a mechanism involving PAF. METHODS: PMNs were isolated from healthy human donors using plasma-Percoll gradients and were cultured in enriched RPMI 1640 media at 2 x 10(7) PMNs/mL for 24 hours (37 degrees C, 5% CO2). Subgroups were treated with IL-6 (0.1-10 ng/mL) or PAF (0.1-10 ng/mL) or pretreated with the PAF receptor antagonist WEB 2170 (20 microM) before IL-6 or PAF. Morphologic assessment and quantitation of apoptosis was performed with acridine orange/ethidium bromide stain. RESULTS: Both IL-6 and PAF suppressed PMN apoptosis. Pretreating PMNs with WEB 2170 abrogated the effects IL-6 as well as PAF. CONCLUSION: Interleukin-6 delays PMN apoptosis via a mechanism involving PAF. These observations may help elucidate the mechanisms of IL-6 and PAF in mediating postinjury hyperinflammation and secondary organ dysfunction, ultimately leading to effective therapeutic targets in patients at risk for multiple organ failure.

Apoptosis↗
PubMed1996

Neutrophil priming and activation in the pathogenesis of postinjury multiple organ failure.

The continuing study of multiple organ failure (MOF) has led to the development of inflammatory models of tissue injury in contrast to earlier infectious models. This change of focus is in response to more recent clinical observations suggesting that postinjury MOF frequently occurs in the absence of infection. In the alternative "two-hit" inflammatory model that has been proposed, the initial traumatic insult "primes" the inflammatory response such that a delayed, otherwise innocuous, inflammatory insult triggers an exaggerated response. The neutrophil (PMN), being uniquely equipped to cause oxidative tissue injury via the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system, has been implicated as an early pivotal player in this model of postinjury MOF. Similar to the "two-hit" inflammatory model, circulating PMNs respond to proinflammatory mediators by becoming primed for enhanced superoxide anion (O2.) production and by increasing adherence to endothelium of organs that are susceptible to PMN-mediated injury. Subsequent proinflammatory insults promote further neutrophil sequestration and activate them for enhanced release of O2.-. The resulting tissue injury can be perpetuated and lead to eventual end-organ damage and failure. In terms of the NADPH oxidase system, PMN priming and activation by various agonists have been well documented in vitro and lead to increased endothelial damage. PMN priming and activation are also operable in an in vivo model of gut ischemia/reperfusion, a surrogate of shock and trauma resuscitation, leading to distant organ damage. Finally, in clinical studies of severely injured trauma patients, PMN priming and activation sequences identify patients at risk for developing MOF with its associated high mortality. Further characterization of the mechanisms that regulate PMN priming and activation in the trauma patient is necessary for the development of new therapeutic interventions designed to block deleterious PMN responses which lead to MOF while not compromising beneficial PMN functions of host defense and tissue repair.

Animals↗
PubMed1996

Pulmonary consequences of severe chest trauma.

Combined flail chest and pulmonary contusion is a frequent problem in patients with blunt multisystem trauma admitted to the intensive care unit. These patients are at high risk for pneumonia and adult respiratory distress syndrome, which adds substantially to their morbidity and mortality rates. This article discusses the epidemiology and pathophysiology of this condition and the role of the respiratory care practitioner in the optimal management of these critically injured patients.

Adult↗
PubMed1995

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.

Apoptosis↗
PubMed1995

PMNs primed for superoxide release and increased CD11b expression do not sequester in normal lung.

Our previous work has implicated platelet activating factor (PAF)-induced neutrophil (PMN) priming and increased CD11b/CD18 receptor expression in the pathogenesis of lung injury following gut ischemia/reperfusion (I/R). In this model CD11b blockade abrogates lung injury but does not alter PMN priming or pulmonary leukosequestration. We, therefore, hypothesized that PAF-stimulated PMN priming and CD11b expression are insufficient to promote lung PMN sequestration. Normal rat PMNs, labeled with 51Cr, were incubated with PAF (10 ng/ml) to induce priming for superoxide (O2-) generation and enhance CD11b expression. Gut I/R animals underwent superior mesenteric artery occlusion for 45 min. 51Cr-labeled PMNs (2 x 10(7)) were injected iv. Study groups, consisting of (a) normal/control, (b) sham/laparotomy, and (c) gut I/R, were given either normal or PAF-treated PMNs. PAF-primed PMNs had increased 2- release and CD11b expression, but did not sequester in the lungs of normal rats. However, following gut I/R PAF-treated PMNs sequestered in the pulmonary bed. These data suggest that PAF priming for O2- generation and increased CD11b expression are insufficient alone to promote PMN sequestration in the lung. Rather, additional factors generated by gut I/R are necessary for this process.

Animals↗
PubMed1995

Reperfused gut elaborates PAF that chemoattracts and primes neutrophils.

Our in vivo model of mesenteric ischemia/reperfusion (I/R) has shown that the gut serves as a priming bed for neutrophils (PMN). Activation of phospholipase A2 (PLA2) during ischemia temporally precedes PMN sequestration in the gut and the appearance of primed PMN in the portal circulation. Therefore, we hypothesized that reperfused gut secretes platelet activating factor (PAF) via PLA2 activation that is responsible for increased PMN chemotaxis and priming for superoxide (O2-) generation. Sprague-Dawley rats underwent gut ischemia/reperfusion (45 min SMA occlusion/2 hr reperfusion) or sham laparotomy. Distal ileum was harvested, rinsed with bacteriostatic saline/neomycin, and incubated for 1 hr at 37 degrees C in RPMI 1640 and the cell-free supernatant was collected. Normal human PMNs, isolated by plasma-Percoll gradients, were pretreated with or without a PAF receptor antagonist (WEB 2170). Chemotaxis toward gut supernatant was then measured by the agarose method. Additionally, PMNs were preincubated with or without WEB 2170 and their O2- release in response to 1 microM FMLP was measured by the Vmax of SOD-inhibitable cytochrome c reduction. Reperfused gut produced a chemotactic index of 2.1 +/- 0.1 compared to 0.2 +/- 0.9 following sham laparotomy (P < 0.05); this was reduced to 0.4 +/- 0.9 with PAF receptor blockade. Similarly, gut I/R supernatant primed PMNs for O2- (P < 0.05) compared to laparotomy, and this effect was abrogated by a PAF antagonist. These data suggest that reperfused gut can elaborate PAF which chemoattracts and primes PMNs for O2- generation.

Animals↗
PubMed1995

Jack A. Barney Resident Research Award. Cardiopulmonary hazards of perihepatic packing for major liver injuries.

BACKGROUND: Perihepatic packing has been shown to result in pathologic intra-abdominal hypertension. Although now recognized as impairing abdominal organ perfusion, the extent to which perihepatic packing affects cardiopulmonary function has not been elucidated. METHODS: We analyzed a 3-year experience with 11 patients who sustained major hepatic injuries requiring perihepatic packing to control hemorrhage. Pertinent hemodynamic indices consisting of pulmonary capillary wedge pressure (PCWP), cardiac index (CI), oxygen delivery index (DO2), and systemic vascular resistance (SVR), and pulmonary indices consisting of peak airway pressure (PAP), mean airway pressure (MAP), static compliance (CST), and PaO2/FiO2 were measured in the surgical intensive care unit immediately before and after packs were removed. RESULTS: Unpacking resulted in a significant increase in CI (3.1 +/- 0.4 to 4.2 +/- 0.6 L/min/m2), DO2 (539 +/- 41 to 689 +/- 43 mL min/m2), CST (26 +/- 6 to 36 +/- 4 mL/cm H2O), and PaO2/FiO2 (162 +/- 44 to 237 +/- 53 cm H2O), as well as a significant decrease in PAP (47 +/- 9 to 29 +/- 6 cm H2O), MAP (34 +/- 4 to 27 +/- 3 cm H2O), PCWP (21 +/- 4 to 13 +/- 3 mm Hg), and SVR (1,239 +/- 162 to 887 +/- 130 dyne/cm5). CONCLUSIONS: Abdominal compartment syndrome following temporary perihepatic packing can result in significant cardiopulmonary compromise. While perihepatic packing can be an early life-saving procedure, timely alleviation of the secondary syndrome may be critical to the ultimate salvage of patients with marginal cardiopulmonary reserve.

Adolescent↗
PubMed1995

Are corticosteroids salvage therapy for refractory acute respiratory distress syndrome?

BACKGROUND: Late acute respiratory distress syndrome (ARDS), characterized by progressive pulmonary interstitial fibroproliferation, is associated with mortality > 80%. Although previous large prospective trials failed to show a benefit of steroids in early ARDS, recent small reports describe improved survival in patients with late ARDS. Recognizing the pathogenetic differences between early and late ARDS, we employed steroid therapy in patients with refractory late ARDS. PATIENTS AND METHODS: Over a 5-year period, we treated 6 patients who were dying of isolated refractory ARDS with methylprednisolone sodium succinate (1 to 2 mg/kg every 6 hours). Ventilatory parameters and lung injury scores were serially recorded, and steroids were weaned based on clinical response. RESULTS: Steroids were instituted after 16 days of advanced mechanical ventilatory support. By day 7 of steroid therapy, there was clinically significant improvement in PaO2/FiO2 ratios (84 to 172) and lung injury scores (3.6 to 2.9); 5 patients (83%) survived. CONCLUSIONS: Steroid therapy appears to be effective in patients with refractory late ARDS. Prospective trials are needed to define the indications, timing of intervention, dose and duration, and precautions of steroid therapy.

Acute Disease↗
PubMed1995

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.

Animals↗
PubMed1995

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.

Adolescent↗
PubMed1995

Evolving concepts in the pathogenesis of postinjury multiple organ failure.

Early epidemiologic studies concluded that infection with systemic sepsis was the common pathway for the development of ARDS and eventual MOF. As a consequence, research investigation from 1977 to 1987 focused on later clinical events (e.g., immunosuppression, persistent hypercatabolism, and bacterial translocation). Now, it is believed that an initial massive traumatic insult can create severe SIRS independent of infection (one-hit model). Alternatively, a less severe traumatic insult can create an inflammatory environment (i.e., primes the host) such that a later, otherwise innocuous, secondary inflammatory insult precipitates severe SIRS (two-hit model). As a result of these newer inflammatory models, research interest during the last 5 years has shifted to investigating earlier clinical events (e.g., unrecognized flow-dependent oxygen consumption, ischemia/reperfusion, and priming/activation of the inflammatory response).

Humans↗
PubMed1995

Extrapleural bupivacaine for amelioration of multiple rib fracture pain.

OBJECTIVE: The pain associated with multiple rib fractures can be surprisingly variable. The objective of this study was to determine the efficacy of an indwelling, percutaneously placed intercostal catheter in relieving the pain associated with multiple rib fractures. DESIGN: Prospective nonrandomized study setting: Surgical intensive care unit in a level 1 trauma center. SUBJECTS: Fifteen blunt chest trauma patients with a minimum of three rib fractures who had failed an intravenous patient controlled analgesia protocol. INTERVENTIONS: Insertion of an epidural catheter within the intercostal space. Bupivacaine 0.25% with epinephrine was injected in a volume of 20 mL. Subsequent doses were limited to a total of 400 mg per 24 hours. MEASUREMENTS AND MAIN RESULTS: Severity of injury was estimated by using the Injury Severity Score. For each patient a preinjection visual analogue scale (VAS) and incentive spirometry (IS) lung volume were determined. Fifteen minutes following injection of 0.25% bupivacaine with epinephrine the VAS and IS were repeated. The Injury Severity Score ranged from 9 to 32 (mean 19.0 +/- 1.6). Overall, mean VAS pain scores improved significantly following the initial bolus of bupivacaine (before VAS = 7.5 +/- 0.6, after VAS = 3.5 +/- 0.5, p < 0.05) and this was associated with significant increase in IS lung volumes (before IS = 0.77 +/- 0.09, after IS = 1.3 +/- 0.13, p < 0.05). No patient experienced either insertion-related or drug administration complications. CONCLUSIONS: These results confirm that an indwelling intercostal catheter provides a continuous nerve block resulting in a simple, safe procedure that can ameliorate the pain and splinting associated with multiple rib fractures. Although we experienced no complications, additional investigation is clearly needed.

Adult↗