Sonlee D. West

Does upregulation of inducible nitric oxide synthase play a role in hepatic injury

Lipopolysaccharide (LPS) and gut ischemia/reperfusion (I/R) injury cause reversible liver injury. Because nitric oxide (NO) can have both beneficial and deleterious effects in the gastrointestinal tract, and because the role of NO in gut I/R-induced hepatic injury is unknown, this study examined its role in LPS and gut I/R-induced hepatic injury in the rat. Both LPS and gut I/R caused a similar increase in serum hepatocellular enzymes. LPS but not gut I/R caused a significant increase in upregulation of hepatic inducible NO synthase (iNOS) according to quantitative real-time RT-PCR and Western immunoblot analysis. Aminoguanidine, a selective iNOS inhibitor, attenuated LPS-induced hepatic injury and hypotension, but did not prevent gut I/R-induced hepatic injury. In contrast, the non-selective NOS inhibitor NG-nitro-L-arginine methyl ester aggravated liver damage from both LPS and gut I/R. These data indicate that iNOS plays a role in mediating LPS-induced hepatic injury, but not gut I/R-induced hepatic injury. The data also suggest that the constitutive isoforms of NOS play a hepatoprotective role in both models of hepatic injury.

Transforming Growth Factor-β, Macrophage Colony-Stimulating Factor and C-Reactive Protein Levels Correlate with CD14highCD16+ Monocyte Induction and Activation in Trauma Patients

Severe injury remains a leading cause of death and morbidity in patients under 40, with the number of annual trauma-related deaths approaching 160,000 in the United States. Patients who survive the initial trauma and post-traumatic resuscitation are at risk for immune dysregulation, which contributes to late mortality and accounts for approximately 20% of deaths after traumatic injury. This post-traumatic immunosuppressed state has been attributed to over-expression of anti-inflammatory mediators in an effort to restore host homeostasis. We measured a panel of monocyte markers and cytokines in 50 severely injured trauma patients for 3 days following admission. We made the novel observation that the subpopulation of monocytes expressing high levels of CD14 and CD16 was expanded in the majority of patients. These cells also expressed CD163 consistent with differentiation into alternatively activated macrophages with potential regulatory or wound-healing activity. We examined factors in trauma plasma that may contribute to the generation and activation of these cells. The percentage of CD14highCD16+ monocytes after trauma correlated strongly with plasma C-reactive protein (CRP) transforming growth factor-β (TGF-β), and macrophage colony-stimulating factor (M-CSF) levels. We demonstrate a role for TGF-β and M-CSF, but not CRP in generating these cells using monocytes from healthy volunteers incubated with plasma from trauma patients. CD16 is a receptor for CRP and IgG, and we showed that monocytes differentiated to the CD14highCD16+ phenotype produced anti-inflammatory cytokines in response to acute phase concentrations of CRP. The role of these cells in immunosuppression following trauma is an area of ongoing investigation.

Family presence during brain death evaluation: a randomized controlled trial

Objective:To evaluate if a family presence educational intervention during brain death evaluation improves understanding of brain death without affecting psychological distress. Design:Randomized controlled trial. Setting:Four ICUs at an academic tertiary care center. Subjects:Immediate family members of patients suspected to have suffered brain death. Interventions:Subjects were group randomized to presence or absence at bedside throughout the brain death evaluation with a trained chaperone. All randomized subjects were administered a validated “understanding brain death” survey before and after the intervention. Subjects were assessed for psychological well-being between 30 and 90 days after the intervention. Measurements and Main Results:Follow-up assessment of psychological well-being was performed using the Impact of Event Scale and General Health Questionnaire. Brain death understanding, Impact of Event Scale, and General Health Questionnaire scores were analyzed using Wilcoxon nonparametric tests. Analyses were adjusted for within family correlation. Fifty-eight family members of 17 patients undergoing brain death evaluation were enrolled: 38 family members were present for 11 brain death evaluations and 20 family members were absent for six brain death evaluations. Baseline understanding scores were similar between groups (median 3.0 [presence group] vs 2.5 [control], p = 0.482). Scores increased by a median of 2 (interquartile range, 1–2) if present versus 0 (interquartile range, 0–0) if absent (p < 0.001). Sixty-six percent of those in the intervention group achieved perfect postintervention “understanding” scores, compared with 20% of subjects who were not present (p = 0.02). Median Impact of Event Scale and General Health Questionnaire scores were similar between groups at follow-up (Impact of Event Scale: present = 20.5, absent = 23.5, p = 0.211; General Health Questionnaire: present = 13.5, absent = 13.0, p = 0.250). Conclusions:Family presence during brain death evaluation improves understanding of brain death with no apparent adverse impact on psychological well-being. Family presence during brain death evaluation is feasible and safe.

Bombesin-Induced Gastroprotection

Abstract:Bombesin is an endogenous gut peptide that is prominent in the stomach. In addition to its effects on modulating acid and gut peptide secretion, recent evidence indicates that bombesin is a potent gastroprotective agent. This review article examines the ability of bombesin to prevent gastric injury. Its protective actions appear to be mediated primarily via the release of endogenous gastrin, as gastroprotection is negated by blockade of gastrin receptors. Bombesin-induced gastroprotection and gastrin release are modified by somatostatin. Immunoneutralization of endogenous somatostatin increases the ability of bombesin to prevent gastric injury by increasing gastrin release. In mechanistic studies, ablation of capsaicin-sensitive afferent neurons abolishes bombesin-induced gastroprotection while cyclo-oxygenase inhibition partially reverses this effect. Nitric oxide synthase inhibition also negates bombesin-induced gastroprotection as well as the ability of bombesin to increase gastric mucosal blood flow. Taken together, the available evidence indicates that bombesin causes release of endogenous gastrin that activates sensory neurons located in the gastric mucosa. Activation of sensory neurons causes increased production of nitric oxide through activation of constitutive nitric oxide synthase, which leads to a resultant increase in gastric mucosal blood flow and renders the stomach less susceptible to damage from luminal irritants.

Lipopolysaccharide-Induced Changes in Rat Gastric H/K-ATPase Expression

Objective:To evaluate lipopolysaccharide (LPS)-induced inhibition of gastric acid secretion. Summary Background Data:Endotoxemia from LPS inhibits gastric acid secretion by an unknown mechanism. Bacterial overgrowth in the stomach caused by decreased acid secretion could be responsible for nosocomial pneumonia developing in critically ill intensive care unit patients. Because acid secretion is via the H/K-ATPase and the effects of LPS on this enzyme are unknown, we hypothesized that LPS causes inhibition of gastric acid secretion by down-regulating the H/K-ATPase Methods:A rat model to study gastric acid secretion was created. Saline or LPS (0.05–20 mg/kg IP) was given for 1 hour, after which basal acid secretion was determined for 1 hour. Pentagastrin (PG; 10 &mgr;g/kg IV) or saline was then given and gastric acid output collected for another 2 hours Results:LPS dose dependently inhibited basal and PG stimulated acid secretion. LPS increased &agr;- and &bgr;-H/K-ATPase subunit mRNA expression (Northern blot) in the absence of PG compared with saline. In the presence of PG, LPS did not have this effect. Western blot analysis did not show any difference in &agr;- or &bgr;-subunit immunoreactivity. Immunofluorescence analysis demonstrated that PG increased staining in the secretory membranes for H/K-ATPase subunits whereas in all LPS-treated rats, it appeared that H/K-ATPase subunits remained within the tubulovesicles. Furthermore, changes in H/K-ATPase mRNA expression may not be related to changes in NF-&kgr;B activity Conclusions:These data suggest that inhibition of gastric acid secretion by LPS is due to inhibition of H/K-ATPase enzymatic function or changes in cytoskeletal rearrangements in H/K-ATPase subunits rather than by down-regulation of transcriptional or translational events.

Cholecystokinin-Induced Gastroprotection: A Review of Current Protective Mechanisms

Cholecystokinin (CCK) is a member of a family of gastrointestinal peptides known to physiologically regulate pancreatic protein secretion, gallbladder contractility, and gut motility. In addition, CCK has been found to play important roles in endocrine and neural systems in the periphery as well as in the central nervous system. CCK has been proposed to play a role in satiety, anxiety, and intestinal transit in addition to its well-described effects in coordinating digestion of a meal. We and others have shown that exogenous and endogenous CCK prevent gastric injury from luminal irritants. These data suggest that the release of CCK may represent an important component of the intrinsic gastric mucosal defense system. This review focuses on the ability of CCK to render the stomach more resistant to injury from luminal insults and will summarize recent studies that examine the possible mechanisms involved.

Evaluation of a Device Combining an Inferior Vena Cava Filter and a Central Venous Catheter for Preventing Pulmonary Embolism Among Critically Ill Trauma Patients

PURPOSE To evaluate efficacy and safety of a novel device that combines an inferior vena cava (IVC) filter and central venous catheter (CVC) for prevention of pulmonary embolism (PE) in critically ill patients. MATERIALS AND METHODS In a multicenter, prospective, single-arm clinical trial, the device was inserted at the bedside without fluoroscopy and subsequently retrieved before transfer from the intensive care unit (ICU). The primary efficacy endpoint was freedom from clinically significant PE or fatal PE 72 hours after device removal or discharge, whichever occurred first. Secondary endpoints were incidence of acute proximal deep venous thrombosis (DVT), catheter-related thrombosis, catheter-related bloodstream infections, major bleeding events, and clinically significant thrombus (occupying > 25% of volume of filter) detected by cavography before retrieval. RESULTS The device was placed in 163 critically ill patients with contraindications to anticoagulation; 151 (93%) were critically ill trauma patients, 129 (85%) had head or spine trauma, and 102 (79%) had intracranial bleeding. The primary efficacy endpoint was achieved for all 163 (100%) patients (95% confidence interval [CI], 97.8%-100%, P < .01). Diagnosis of new or worsening acute proximal DVT was time dependent with 11 (7%) occurring during the first 7 days. There were no (0%) catheter-related bloodstream infections. There were 5 (3.1%) major bleeding events. Significant thrombus in the IVC filter occurred in 14 (8.6%) patients. Prophylactic anticoagulation was not initiated for a mean of 5.5 days ± 4.3 after ICU admission. CONCLUSIONS This novel device prevented clinically significant and fatal PE among critically ill trauma patients with low risk of complications.

Nosocomial Infections after Severe Trauma Are Associated With Lower Apolipoproteins B and AII

BACKGROUND Infection after severe trauma is a significant cause of morbidity and mortality days to weeks after the initial injury. Apolipoproteins play important roles in host defense and circulating concentrations are altered by the acute inflammatory response. The purpose of this study was to determine if patients who acquire infection after severe trauma have significantly lower apolipoprotein levels than trauma patients who do not become infected. METHODS We conducted a case–control study on a prospectively identified cohort of adult patients admitted to our intensive care unit after severe trauma (Injury Severity Score ≥ 16). We compared plasma apolipoprotein levels between patients who acquired an infection within 30 days after trauma (cases) and those that remained infection free (controls). RESULTS Of 40 patients experiencing severe trauma, we identified 22 cases that developed an infection within 30 days after injury. Cases had significantly lower posttrauma plasma levels of apolipoprotein B (p = 0.02) and apolipoprotein AII (p = 0.02) compared with controls. Consistent with previous studies, cases also received greater volumes of crystalloid infusions (p < 0.01) and blood transfusions (p < 0.01). Cases also had a more profound inflammatory response as measured by interleukin 6 levels (p = 0.02). CONCLUSION Infection after severe trauma is associated with decreased circulating apolipoproteins as compared with uninfected controls. Profoundly decreased plasma apolipoproteins B and AII could potentially contribute to the impaired immunity after severe trauma. Apolipoproteins are potential targets for identifying those patients at risk of infection after trauma and for interventions aimed at preventing nosocomial infections. LEVEL OF EVIDENCE Prognostic study, level III.

Effects of lipopolysaccharide on gastric stasis: role of cyclooxygenase.

This study was done to examine the role of cyclooxygenase (COX) in lipopolysaccharide (LPS)-induced gastroprotection and gastric stasis. In conscious rats, LPS dose and time dependently increased gastric luminal fluid accumulation. LPS decreased blood flow (laser Doppler) and prevented gastric injury from acidified ethanol at time points before significant fluid accumulation occurred. LPS increased COX-2 but not COX-1 expression. In contrast, LPS decreased gastric mucosal prostaglandin synthesis. LPS-induced gastric luminal fluid accumulation was negated by both nonselective COX inhibition with salicylate and selective COX-2 inhibition with NS-398 but not by selective COX-1 inhibition with SC-560. Neither salicylate nor NS-398 blocked LPS-induced gastroprotection. LPS-induced gastroprotection does not depend entirely on accumulation of luminal fluid and is independent of COX-1 and COX-2. However, the ability of LPS to cause gastric stasis and increase gastric luminal fluid accumulation involves COX-2.

Effects of ethnicity on deceased organ donation in a minority-majority state.

Objective:To define how ethnicity affects donation rates in New Mexico when compared with the United States. We hypothesized that deceased donation rates in New Mexico would reflect the ethnic rates of the population. Design:We performed a retrospective review of the Organ Procurement Database for New Mexico from 2009 to June 2012. Methods:Rates for donors and transplant candidates were calculated relative to 2010 census population estimates by ethnicity for non-Hispanic Whites, Hispanics, and American Indians. Poisson regression analyses were used to test whether United States and New Mexico rates differed. Rates were scaled to 100,000 patient-years for reporting. Setting:State of New Mexico population compared to United States population. Subjects:Reported deaths to New Mexico Donor Services and United Network for Organ Sharing from 2009 to 2012. Interventions:None. Measurements and Main Results:Non-Hispanic White age-adjusted donor rates per 100,000 patient-years were 2.58 in New Mexico versus 2.60 in the United States, Hispanic donor rates were 1.98 in New Mexico versus 2.03 nationwide, and American Indian donor rates in New Mexico were 0.26 versus 1.23 nationwide (rate ratio = 0.21; 95% CI, 0.05–0.86). American Indians have significantly lower donor rates in New Mexico compared to non-Hispanic Whites (rate ratio = 0.11) and Hispanics (rate ratio = 0.13) and nationally (non-Hispanic Whites: rate ratio = 0.32 and Hispanics: rate ratio = 0.43). Hispanics and non-Hispanic Whites had similar donor rates regardless of geographic strata (Hispanics vs non-Hispanic Whites, New Mexico: 0.83; United States: 0.75). In New Mexico, Hispanic patients were 1.43 times more likely to be listed as transplant candidates than non-Hispanic Whites and American Indians were 3.32 times more likely to be listed than non-Hispanic Whites. In the United States, Hispanic patients were 1.90 times more likely to be listed as transplant candidates than non-Hispanic Whites and American Indians were 1.55 times more likely to be listed than non-Hispanic Whites. Conclusions:Donor and transplant candidate rates did not show strong differences by geographic strata. These findings suggest that further work is needed to elucidate the causes for ethnic differences in rates of consent and donation, particularly in the American Indian population.