Biomedical subjects
Publications and source records attributed to Brian G Harbrecht.
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BACKGROUND: Most minor splenic injuries are readily treated nonoperatively but controversy exists regarding the role of nonoperative management for higher-grade injuries. The infrequency of these injuries has made evaluation of factors critical to their management difficult. METHODS: Through the National Trauma Data Bank, 3,085 adults sustaining severe (Abbreviated Injury Scale score > or = 4) blunt splenic injury from 1997 to 2003 were retrospectively reviewed. Patient management, demographic information, physiologic data, procedures performed, and outcomes were analyzed. RESULTS: Nonoperative management was attempted in 40.5% of patients but ultimately failed in 54.6% of those. Failure of nonoperative management was associated with increased age, low admission systolic blood pressure, higher injury severity score, and increased hospital and intensive care unit length of stay. Mortality associated with failure of nonoperative management (12.3%) and successful observation (13.8%) was similar. CONCLUSIONS: Nonoperative management of higher-grade splenic injuries is associated with a high rate of failure and prolonged hospital stay. Careful judgment must be exercised in applying nonoperative management to patients with severe splenic injuries.
Nitric oxide (NO) is a reactive radical produced by the enzyme nitric oxide synthase (NOS) and it plays an important role in a large number of biological pathways. NO can be produced under normal physiologic conditions and contribute to homeostasis but, when produced in excess, it may lead to tissue injury and organ dysfunction. The regulation of NOS activity and expression is becoming increasingly understood. NOS enzyme inhibitors as tools to decrease excessive NO synthesis have received the most attention and have been subjected to the greatest experimental study. Compounds that scavenge excessive NO have been developed and have shown promise in a number of experimental models but have received considerably less attention as potential therapeutic agents. In this article, the use of NO scavengers in two conditions in which excessive NO appears to be pathophysiologically significant, shock and sepsis, is reviewed. The relevant biology of NO in these disease states is presented and the therapeutic potential of NO scavengers in clinical care is explored.
Several decades ago, a shift occurred in the management of adult splenic injuries. Influenced by the experience in pediatric trauma patients, adult trauma surgeons began turning from mandatory operative treatment of all splenic injuries toward nonoperative management. Nonoperative treatment is now the most common method of management for patients with splenic injuries and is the most common method of splenic salvage. However, controversy exists about how to appropriately select patients for nonoperative treatment since bleeding from splenic injuries can incur significant morbidity and mortality. Recent refinements in the management of adult blunt splenic injuries will be reviewed.
BACKGROUND: The Eastern Association for the Surgery of Trauma Multiinstitutional Workgroup reported a failure rate for nonoperative management of blunt splenic injury in adults of 10.8%. Sixty percent of the failures occurred within 24 hours of admission. The purpose of this multiinstitutional study by the Eastern Association for the Surgery of Trauma was to determine common variables in failure of nonoperative management of blunt splenic injury in adults. STUDY DESIGN: Medical records were reviewed in a blinded fashion on 78 patients in whom nonoperative management failed. Statistical analysis was performed with ANOVA, extended chi-square, and Fisher's exact test; statistical significance was p<0.05. RESULTS: The 78 patients were categorized based on hemodynamic status. Forty-four percent were stable; 31% had transient hypotension or tachycardia that resolved with fluid infusion (responders); and 25% were unstable. Two-thirds of the unstable patients required laparotomy within 12 hours of admission; all had laparotomy within 72 hours. Mortality was significantly different when comparing the unstable to the stable and responder groups: stable (3%), responders (8%), and unstable (37%), despite similar age and only modest differences in Injury Severity Score. Eight CT scans were misinterpreted initially. Of 26 Focused Abdominal Sonography for Trauma (FAST) studies, 11 (42.3%) were false negative. Abnormal abdominal findings were noted in 67.7% of patients on admission. Ten patients died (12.8%). Sixty percent of the deaths were caused largely by delayed treatment of splenic or other abdominal injuries; one patient died in the responder group and five unstable patients died. CONCLUSIONS: Thirty percent to 40% of the patients who had unsuccessful nonoperative management in this study were selected inappropriately, with hemodynamic instability or initial misinterpretation of diagnostic studies. As a consequence, the majority of the deaths were from delayed treatment of intraabdominal injuries. This article suggests that written protocols, better adherence to sound clinical judgment, and experienced and timely interpretation of radiologic studies would reduce the incidence of failure of nonoperative management of blunt splenic injury in adults.
OBJECTIVE: To assess whether changes in cytochrome P-450 (CYP) activity of specific CYP enzymes occur in severely injured patients and to assess changes in CYP activity during recovery. DESIGN: Prospective clinical study. SETTING: University-affiliated, level I trauma center and trauma critical care unit. PATIENTS: Twenty-three multiply injured patients admitted to a trauma critical care unit were compared with healthy volunteers. INTERVENTIONS: CYP metabolizing activity was assessed using the probe drugs mephenytoin (CYP-2C19), chlorzoxazone (CYP-2E1), dapsone (multiple CYP enzymes), and flurbiprofen (CYP-2C9). MEASUREMENTS AND MAIN RESULTS: Mephenytoin metabolism was profoundly suppressed after injury and increased during postinjury recovery, whereas chlorzoxazone metabolism was suppressed to a lesser degree. Measures of dapsone and flurbiprofen metabolism were elevated throughout the study. Chlorzoxazone and mephenytoin metabolism correlated with the multiple organ dysfunction score and with the multiple organ failure score. CONCLUSIONS: CYP isoform activity is differentially altered by shock and trauma in injured patients. The metabolic activity of selected CYP isoforms may have potential for evaluating acute hepatic dysfunction in critically ill trauma patients.
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An association between outcome and case volume has been demonstrated for selected complex operations. The relationship between trauma center volume and patient outcome has also been examined, but no clear consensus has been established. The American College of Surgeons (ACS) has published recommendations on optimal trauma center volume for level 1 designation. We examined whether this volume criteria was associated with outcome differences for the treatment of adult blunt splenic injuries. Using a state trauma database, ACS criteria were used to stratify trauma centers into high-volume centers (>240 patients with Injury Severity Score >15 per year) or low-volume centers, and outcome was evaluated. There were 1,829 patients treated at high-volume centers and 1,040 patients treated at low-volume centers. There was no difference in age, gender, emergency department pulse, emergency department systolic blood pressure, or overall mortality between high- and low-volume centers. Patients at low-volume centers were more likely to be treated operatively, but the overall success rate of nonoperative management between high- and low-volume centers was similar. These data suggest that ACS criteria for trauma centers level designation are not associated with differences in outcome in the treatment of adult blunt splenic injuries in this regional trauma system.
The cyclic AMP response element (CRE) has been implicated in the regulation of the expression of many genes and cellular processes important in hepatocyte function. CRE sites exist in the promoter regions of several genes expressed during inflammation. Numerous studies on the role of CRE in hepatocyte gene expression have been performed in resting hepatocytes, but the role of CRE during inflammation is unknown. To evaluate the regulation of CRE-mediated transcription during sepsis, cultured hepatocytes were exposed to proinflammatory cytokines and lipopolysaccharide (LPS) was injected into rats. Nuclear proteins were collected and CRE binding activity measured by electromobility shift assay (EMSA) using a consensus CRE oligonucleotide. CRE binding activity was increased in vitro by cytokines and in vivo by LPS administration but CRE-dependent reporter activity was decreased by cytokine stimulation. A c-jun N-terminal kinase (JNK) inhibitor reversed the cytokine-induced increase in CRE binding and increased CRE-dependent reporter activity. Supershift assays indicated that cyclic AMP response element binding protein (CREB) and c-Jun proteins were included in the CRE binding complex. CREB induced and c-Jun suppressed reporter activity using a CRE-dependent construct transfected into cultured primary hepatocytes. In conclusion, these data demonstrate that proinflammatory cytokines regulate CRE binding and activity in cultured hepatocytes and suggest that sepsis-induced changes in CRE binding may participate in the cellular response to inflammation.
cAMP significantly inhibits IL-1beta+IFNgamma-induced iNOS gene expression in hepatocytes, but the signaling pathways responsible for the effect are not known. PKA inhibitors, H89, PKI, and KT5720, had no effect on the recovery of the inhibitory effects of cAMP on cytokine-induced hepatocyte iNOS expression and activity. The JNK inhibitor, SP 600125, effectively reversed the inhibitory effects of cAMP on iNOS expression and significantly increased iNOS promoter activity. A cAMP analogue, dbcAMP, significantly induced JNK signaling and increased AP-1 binding activity in hepatocytes. The JNK activator, anisomycin, inhibited iNOS expression and transcription in hepatocytes as well as AP-1 binding activity; and SP600125 reversed this effect of anisomycin. Overexpression of c-Jun in hepatocytes inhibited IL-1beta+IFNgamma-induced nitrite accumulation and iNOS promoter activity while dominant negative c-Jun partially reversed the inhibitory effects of cAMP on nitrite accumulation. We conclude that JNK signaling plays an important role in the inhibitory effects of cAMP on IL-1beta+IFNgamma-induced iNOS gene expression in cultured hepatocytes.
BACKGROUND: The factors important in determining outcome when managing adult blunt splenic injuries continue to be debated. Whether trauma center level designation (Level I versus Level II) affects patient management has not been evaluated. STUDY DESIGN: We conducted a retrospective analysis of prospectively gathered data from the Pennsylvania Trauma Outcome Study database that collected information from 27 statewide trauma centers (Level I [15], Level II [17]). Adult patients (ages > or = 16 years) with blunt splenic injuries (ICD-9-CM 865) were evaluated. Demographic data, injury data, and trauma center level designation were collected, and patient management, length of stay, and mortality were analyzed. RESULTS: There were 2,138 adult patients who suffered blunt splenic injuries during the study period (1998-2000). Patients treated at Level II trauma centers (n = 772) had a higher rate of operative treatment (38.2% versus 30.7%) (p < 0.001), but a shorter mean length of stay (10.1 +/- 0.4 versus 12.0 +/- 0.4 days) (p < 0.01) compared with patients in Level I trauma centers (n = 1,366). The rate of failure of nonoperative treatment was lower at Level II trauma centers (13.0% versus 17.6%) (p < 0.05), but the mortality for patients managed nonoperatively was higher (8.4% versus 4.5%) (p < 0.05). Splenorrhaphy was performed more frequently in Level I trauma centers. CONCLUSIONS: Management differences exist in the treatment of adult blunt splenic injuries between institutions of different trauma center level designation. Multicenter studies should account for this finding in design and implementation.
The inducible nitric oxide synthase (iNOS) is stimulated to produce large quantities of nitric oxide (NO) by proinflammatory stimuli, hemorrhagic shock, and a variety of cytokines. We have previously shown that cAMP profoundly inhibits hepatocyte iNOS expression in vitro. In this study, we tested whether glucagon, a hormone that increases cAMP in hepatocytes, could regulate hepatic iNOS expression and activity in vivo. Rats were injected intraperitoneally with lipopolysaccharide (LPS, 10 mg/kg) and treated with either saline or glucagon (500 microg/kg i.p.). Plasma and liver tissue were obtained 6 and 24 h after LPS. LPS induced increased iNOS mRNA, iNOS protein, and plasma levels of nitrite/nitrate that were all significantly decreased by glucagon treatment. The reduction in iNOS expression produced by glucagon was associated with a reduction in plasma AST and LDH levels, suggesting decreased LPS-induced hepatic injury. These data suggest that glucagon may participate in the in vivo regulation of hepatic iNOS expression after proinflammatory stimuli.
In hemorrhagic shock (HS), increased cytokine production contributes to tissue inflammation and injury through the recruitment of neutrophils [polymorphonuclear cells (PMN)]. HS stimulates the early expression of inducible nitric oxide synthase (iNOS) that modulates proinflammatory activation after hemorrhage. Experiments were performed to determine the contribution of iNOS to gut inflammation and dysmotility after HS. Rats subjected to HS (mean arterial pressure 40 mmHg for 2.5 h followed by resuscitation and death at 4 h) demonstrated histological signs of mucosal injury, impairment of intestinal smooth muscle contractility, extravasation of PMN, and increased gut mRNA levels of ICAM-1, IL-6, and granulocyte colony-stimulating factor (G-CSF). In addition, DNA binding activity of NF-kappaB and Stat3, an IL-6 signaling intermediate, was significantly increased. In shocked rats treated with the selective iNOS inhibitor l-N(6)-(1-iminoethyl)lysine at the time of resuscitation, histological signs of intestinal injury and PMN infiltration were reduced and muscle contractility was almost completely restored. Selective iNOS inhibition in shocked animals reduced the binding activity of NF-kappaB and Stat3 and reduced mRNA levels of ICAM-1, IL-6, and G-CSF. The results of studies using iNOS knockout mice subjected to HS were similar. We propose that early upregulation of iNOS contributes to the inflammatory response in the gut wall and participates in the activation of signaling cascades and cytokine expression that regulate intestinal injury, PMN recruitment, and impaired gut motility.
We examined effects of cyclic AMP on adenovirus mediated inducible nitric oxide synthase expression in primary rat hepatocytes. In AdCMV-hiNOS infected hepatocytes, dbcAMP at a concentration of 1-100 microM inhibited nitrite and nitrate accumulation, iNOS protein and iNOS mRNA expression. At a concentration of 1-5mM, dbcAMP increased iNOS activity and expression. Both the inhibitory and stimulatory effects of cAMP on adenovirus mediated iNOS expression were dose dependent. This dual effect of cAMP on iNOS activity and expression can be accounted by its effect on CMV promoter activity since dbcAMP significantly inhibited CMV promoter activity in hepatocytes at low concentration and induced it at high concentration. We concluded that dbcAMP can regulate adenovirus-mediated human iNOS expression in primary hepatocytes by the mechanisms regulating the CMV promoter used in the adenovirus vector.
OBJECTIVE: To review the epidemiology and characteristics of patients who died or underwent colectomy secondary to fulminant Clostridium difficile colitis. SUMMARY BACKGROUND DATA: In patients with C. difficile colitis, a progressive, systemic inflammatory state may develop that is unresponsive to medical therapy; it may progress to colectomy or death. METHODS: The authors reviewed 2,334 hospitalized patients with C. difficile colitis from January 1989 to December 2000. Sixty-four patients died or underwent colectomy for pathologically proven C. difficile colitis. RESULTS: In 2000, the incidence of C. difficile colitis in hospitalized patients increased from a baseline of 0.68% to 1.2%, and the incidence of patients with C. difficile colitis in whom life-threatening symptoms developed increased from 1.6% to 3.2%. Forty-four patients required a colectomy and 20 others died directly from C. difficile colitis. Twenty-two percent had a prior history of C. difficile colitis. A recent surgical procedure and immunosuppression were common predisposing conditions. Lung transplant patients were 46 times more likely to have C. difficile colitis and eight times more likely to have severe disease. Abdominal computed tomography scan correctly diagnosed all patients, whereas 12.5% of toxin assays and 10% of endoscopies were falsely negative. Patients undergoing colectomy for C. difficile colitis had an overall death rate of 57%. Significant predictors of death after colectomy were preoperative vasopressor requirements and age. CONCLUSIONS: C. difficile colitis is a significant and increasing cause of death. Surgical treatment of C. difficile colitis has a high death rate once the fulminant expression of the disease is present.
OBJECTIVE: Hypotension is associated with increased mortality, however previous studies have failed to account for the depth and duration of hypotension. We evaluated the effect of the duration of hypotension on outcome in injured patients. METHODS: Trauma patients admitted to the intensive care unit (ICU) from 1999 to 2000 were prospectively evaluated. Patients transferred to a ward </= 48 hours after admission were excluded. The lowest systolic blood pressure and duration of all episodes of systolic blood pressure below 90 mm Hg were recorded along with the total ICU length of stay and discharge status. The Kruskal-Wallis test, Pearson chi2, and test for trend were used for analysis. RESULTS: Patients with hypotension during the first 24 hours of ICU care had an increased mortality rate. A brief (</= 10 minutes) episode of hypotension was associated with increased mortality that increased with duration of hypotension (p = 0.0001). ICU length of stay also increased with duration of hypotension (p = 0.0001). CONCLUSION: Brief episodes of hypotension are associated with an increased risk of death in patients requiring admission to the ICU after injury and a longer ICU recovery for those who survive.