Open Payments Data Analysis of General and Fellowship-trained Surgeons Receiving Industry General Payments From 2016 to 2020: Payment Disparities and COVID-19 Pandemic Impact.

OBJECTIVE: To characterize industry nonresearch payments made to general and fellowship-trained surgeons between 2016 and 2020. BACKGROUND: The Centers for Medicare & Medicaid Services Open Payments Data (OPD) reports industry payments made to physicians related to drugs and medical devices. General payments are those not associated with research. METHODS: OPD data were queried for general and fellowship-trained surgeons who received general payments from 2016 to 2020. Payments' nature, amount, company, covered product, and location were collected. Surgeons' demographics, subspecialty, and leadership roles in hospitals, societies, and editorial boards were evaluated. RESULTS: From 2016 to 2020, 44,700 general and fellowship-trained surgeons were paid $535,425,543 in 1,440,850 general payments. The median payment was $29.18. The most frequent payments were for food and beverage (76.6%) and travel and lodging (15.6%); however, the highest dollar payments were for consulting fees ($93,128,401; 17.4%), education ($88,404,531; 16.5%), royalty or license ($87,471,238; 16.3%), and travel and lodging ($66,333,149; 12.4%). Five companies made half of all payments ($265,654,522; 49.6%): Intuitive Surgical ($128,517,411; 24%), Boston Scientific ($48,094,570; 9%), Edwards Lifesciences ($41,835,544, 7.8%), Medtronic Vascular ($33,607,136; 6.3%), and W. L. Gore & Associates ($16,626,371; 3.1%). Medical devices comprised 74.7% of payments ($399,897,217), followed by drugs and biologicals ($33,945,300; 6.3%). Texas, California, Florida, New York, and Pennsylvania received the most payments; however, the top dollar payments were in California ($65,702,579; 12.3%), Michigan ($52,990,904, 9.9%), Texas ($39,362,131; 7.4%), Maryland ($37,611,959; 7%), and Florida ($33,417,093, 6.2%). General surgery received the highest total payments ($245,031,174; 45.8%), followed by thoracic surgery ($167,806,514; 31.3%) and vascular surgery ($60,781,266; 11.4%). A total of 10,361 surgeons were paid >$5000, of which 1614 were women (15.6%); in this group, men received higher payments than women (means, $53,446 vs $22,571; P <0.001) and thoracic surgeons received highest payments (mean, $76,381; NS, P =0.14). A total of 120 surgeons were paid >$500,000 ($203,011,672; 38%)-5 non-Hispanic White (NHW) women (4.2%) and 82 NHW (68.3%), 24 Asian (20%), 7 Hispanic (5.8%), and 2 Black (1.7%) men; in this group, men received higher payments than women (means, $1,735,570 vs $684,224), and NHW men received payments double those of other men (means, $2,049,554 vs $955,368; NS, P =0.087). Among these 120 highly paid surgeons (>$500,000), 55 held hospital and departmental leadership roles, 30 were leaders in surgical societies, 27 authored clinical guidelines, and 16 served on journal editorial boards. During COVID-19, 2020 experienced half the number of payments than the preceding 3 years. CONCLUSIONS: General and fellowship-trained surgeons received substantial industry nonresearch payments. The highest-paid recipients were men. Further work is warranted in assessing how race, gender, and leadership roles influence the nature of industry payments and surgical practice. A significant decline in payments was observed early during the COVID-19 pandemic.

Anesthesia-related cardiac arrest.

BACKGROUND: Much is still unknown about the actual incidence of anesthesia-related cardiac arrest in the United States. METHODS: The authors identified all of the cases of cardiac arrest from their quality improvement database from 1999 to 2009 and submitted them for review by an independent study commission to give them the best estimate of anesthesia-related cardiac arrest at their institution. One hundred sixty perioperative cardiac arrests within 24 h of surgery were identified from an anesthesia database of 217,365 anesthetics. An independent study commission reviewed all case abstracts to determine which cardiac arrests were anesthesia-attributable or anesthesia-contributory. Anesthesia-attributable cardiac arrests were those cases in which anesthesia was determined to be the primary cause of cardiac arrest. Anesthesia-contributory cardiac arrests were those cases where anesthesia was determined to have contributed to the cardiac arrest. RESULTS: Fourteen cardiac arrests were anesthesia-attributable, resulting in an incidence of 0.6 per 10,000 anesthetics (95% CI, 0.4 to 1.1). Twenty-three cardiac arrests were found to be anesthesia-contributory resulting in an incidence of 1.1 per 10,000 anesthetics (95% CI, 0.7 to 1.6). Sixty-four percent of anesthesia-attributable cardiac arrests were caused by airway complications that occurred primarily with induction, emergence, or in the postanesthesia care unit, and mortality was 29%. Anesthesia-contributory cardiac arrest occurred during all phases of the anesthesia, and mortality was 70%. CONCLUSION: As judged by an independent study commission, anesthesia-related cardiac arrest occurred in 37 of 160 cardiac arrests within the 24-h perioperative period.

Data driven linear algebraic methods for analysis of molecular pathways: application to disease progression in shock/trauma.

MOTIVATION: Although trauma is the leading cause of death for those below 45years of age, there is a dearth of information about the temporal behavior of the underlying biological mechanisms in those who survive the initial trauma only to later suffer from syndromes such as multiple organ failure. Levels of serum cytokines potentially affect the clinical outcomes of trauma; understanding how cytokine levels modulate intra-cellular signaling pathways can yield insights into molecular mechanisms of disease progression and help to identify targeted therapies. However, developing such analyses is challenging since it necessitates the integration and interpretation of large amounts of heterogeneous, quantitative and qualitative data. Here we present the Pathway Semantics Algorithm (PSA), an algebraic process of node and edge analyses of evoked biological pathways over time for in silico discovery of biomedical hypotheses, using data from a prospective controlled clinical study of the role of cytokines in multiple organ failure (MOF) at a major US trauma center. A matrix algebra approach was used in both the PSA node and PSA edge analyses with different matrix configurations and computations based on the biomedical questions to be examined. In the edge analysis, a percentage measure of crosstalk called XTALK was also developed to assess cross-pathway interference. RESULTS: In the node/molecular analysis of the first 24h from trauma, PSA uncovered seven molecules evoked computationally that differentiated outcomes of MOF or non-MOF (NMOF), of which three molecules had not been previously associated with any shock/trauma syndrome. In the edge/molecular interaction analysis, PSA examined four categories of functional molecular interaction relationships--activation, expression, inhibition, and transcription--and found that the interaction patterns and crosstalk changed over time and outcome. The PSA edge analysis suggests that a diagnosis, prognosis or therapy based on molecular interaction mechanisms may be most effective within a certain time period and for a specific functional relationship.

Effects of ketamine on endotoxin and traumatic brain injury induced cytokine production in the rat.

BACKGROUND: Endotoxemia from lipopolysaccharide (LPS) induces systemic cytokine production, whereas traumatic brain injury (TBI) increases intracerebral cytokine production. In anesthetic doses, ketamine has potent anti-inflammatory properties. However, its anti-inflammatory effects at subanesthetic doses and its effects on TBI-induced inflammation have not been fully investigated. We hypothesized that ketamine would attenuate both LPS- and TBI-induced inflammatory responses. METHODS: Male rats received intraperitoneal (i.p.) ketamine (70 mg/kg, 7 mg/kg, or 1 mg/kg) or saline 1 hour before LPS (20 mg/kg i.p.) or saline. Five hours after LPS, rats were killed. Serum was collected for cytokine analysis. In other experiments, male rats were given ketamine (7 mg/kg i.p.) or saline 1 hour before induction of TBI with controlled cortical impact (or sham). One hour and 6 hours after injury, brain was extracted for analysis of cerebral edema and cytokine production. RESULTS: LPS increased the serum concentrations of interleukin (IL)-1α, IL-1ß, IL-6, IL-10, tumor necrosis factor-α, and interferon-γ. Ketamine dose dependently attenuated these changes. TBI caused cerebral edema and increased concentrations of cerebral IL-1α, IL-1ß, IL-6, IL-10, and tumor necrosis factor-α. However, ketamine had minimal effect on TBI-induced inflammation. CONCLUSIONS: Although ketamine did not seem to exert any beneficial effects against TBI in the rat, it did not exacerbate cytokine production or enhance cerebral edema as some studies have suggested.

Laparotomy attenuates lipopolysaccharide-induced gastric bleeding in the rat.

Lipopolysaccharide (LPS) increases systemic inflammation and causes duodenogastric reflux of bile and gastric bleeding. Laparotomy prevents gastric injury from the luminal irritant bile, but its effects on LPS-induced gastric injury are unknown. We hypothesized that laparotomy would diminish inflammation and attenuate gastric bleeding caused by LPS. In the rat, laparotomy, done either before or after administration of LPS, attenuated LPS-induced bile reflux, gastric bleeding, and cyclooxygenase-2, but not inducible nitric oxide synthase, expression when compared to controls given LPS. Laparotomy also blunted LPS-induced changes in serum cytokine production. These data suggest that laparotomy has gastroprotective effects by preventing LPS-induced bile reflux and gastric bleeding and by a mechanism mediated, at least in part by cyclooxygenase-2.

Ketamine suppresses LPS-induced bile reflux and gastric bleeding in the rat.

BACKGROUND: Although ketamine has many beneficial effects in a rat model of noninfectious inflammation with lipopolysaccharide (LPS), its effects on gut ileus are unknown. We hypothesized that ketamine would improve LPS-induced ileus and therefore examined its effects on gastric emptying and intestinal transit as well as duodenogastric bile reflux and associated gastric bleeding. METHODS: Male rats received saline or ketamine (7 mg/kg ip) 1 hour before saline or LPS (20 mg/kg ip) for 5 hours. Thirty minutes before killing, rats received orogastric rhodamine B isothiocyanate-labeled dextran and 5 minutes later fluorescein isothiocyanate-labeled dextran via a duodenal catheter. GI contents were collected for dye, bile acid, and hemoglobin (index of bleeding) determinations. RESULTS: LPS significantly impaired intestinal transit and increased duodenogastric bile reflux and gastric luminal hemoglobin content. Ketamine improved intestinal transit, prevented LPS-induced bile reflux, and diminished gastric bleeding. In mechanistic studies, ketamine also attenuated LPS-induced upregulation of the proinflammatory genes inducible nitric oxide synthase and cyclo-oxygenase-2 in the stomach but preserved expression of the anti-inflammatory gene heme-oxygenase-1 (Western blot). CONCLUSIONS: These data suggest that ketamine may prevent LPS-induced gastric bleeding by decreasing bile reflux through improved intestinal transit or by local changes in nitric oxide, prostaglandin, and carbon monoxide metabolism.

Fasting exacerbates and feeding diminishes LPS-induced liver injury in the rat.

INTRODUCTION: Enteral nutrition improves clinical outcomes. The effects of feeding on LPS induced liver injury are unknown. We hypothesized that feeding would attenuate liver injury from LPS. METHODS: Fasted or fed rats were given LPS (20 mg/kg i.p.) or saline for 5 h and sacrificed. Serum aminotransferases and cytokines (immunoassay) were measured. Oxidative stress protein (iNOS, COX2, and HO1) assessments (Western immunoblot) were also obtained. RESULTS: In fasted rats, LPS significantly increased serum aminotransferase levels, enhanced hepatic COX2, iNOS, and HO1 immunoreactivity, and increased serum cytokine levels when compared to controls. While feeding diminished liver enzymes, attenuated expression of COX2 and iNOS, and blunted production of pro-inflammatory cytokines, it did not modulate LPS-induced expression of the anti-inflammatory markers HO1 and IL-10. CONCLUSION: These data suggest that feeding decreases liver injury by attenuating expression of pro-inflammatory mediators while maintaining expression of anti-inflammatory mediators, both systemically and locally.

Alpha-melanocyte stimulating hormone in critically injured trauma patients.

BACKGROUND: Alpha-melanocyte stimulating hormone (alpha-MSH) is a neuropeptide which modulates inflammation. Prior studies have documented decreased alpha-MSH concentrations in patients with acute traumatic brain injury and subarachnoid hemorrhage. We hypothesized that alpha-MSH levels would be decreased in critically injured patients and that this would correlate with poor outcome. METHODS: We performed a retrospective review of prospectively collected data more than 12 months ending December 2005. alpha-MSH concentrations were measured in major torso trauma patients (excluding severe head injuries) who underwent standardized shock resuscitation. alpha-MSH concentrations were measured every 4 hours for the first 24 hours of intensive care unit admission and daily thereafter for hospital days 2 to 5. Controls were similarly aged, healthy volunteers. Outcomes measured included lengths of stay, infectious morbidity, and the incidence of multiple organ failure (MOF) and mortality. RESULTS: Fifty-one trauma patients were studied with a median age of 33 (22-54) years. Seventy-five percent were male and 82% sustained blunt trauma. The median Injury Severity Score was 25 (16-34). Eighteen percent of the patients developed MOF, 18% died, and 24% developed MOF and died. The mean initial (first value on the first day) alpha-MSH concentration was significantly lower than in controls (15.9 pg/mL +/- 7.6 pg/mL vs. 26.1 pg/mL +/- 7.4 pg/mL, p = 0.0008) and did not change significantly during the 5-day study period. On univariate and adjusted multivariate analyses, initial alpha-MSH concentrations did not predict either MOF or mortality. CONCLUSIONS: The current study is the first to document significantly decreased alpha-MSH concentrations in critically injured trauma patients as compared with controls. Furthermore, alpha-MSH concentrations remained so throughout the study period.

Training future surgical scientists: realities and recommendations.

OBJECTIVE: To examine factors influencing surgical research and assess the current state of training future surgical scientists. SUMMARY BACKGROUND DATA: The number of surgeons actively engaged in research seems to be decreasing. Training future surgical scientists to increase these numbers depends on a variety of factors that are constantly changing. Current trends at the National Institutes of Health (NIH) and changes in graduate medical education make the training of the next generation of surgical scientists more challenging than ever. METHODS: Recent literature in surgical education, surgical research, and funding patterns at the NIH were reviewed. RESULTS: Quantitative and qualitative deficiencies exist in surgical research. Although an increasing number of students are becoming interested in surgery, the burden of debt from medical school may preclude them from pursuing research during or after residency. Research training is complicated by the fact that no formal curriculum exists for training in research and oversight is lacking. Junior faculty face increased demands for clinical revenue, which decreases time for research. In addition, surgeons are less successful at obtaining NIH funding when compared with nonsurgeons and seem to be at a disadvantage. CONCLUSIONS: Development of the next generation of surgical scientists begins by attracting the best students into surgery and by providing a structured research curriculum with appropriate oversight. Senior surgical faculty need to become more active at the NIH and provide appropriate financial support and mentorship for residents and junior faculty engaged in research.

Cyclooxygenase-1 suppresses lipopolysaccharide-induced changes in rat gastric inducible nitric oxide synthase.

OBJECTIVE: Both nitric oxide synthase (NOS) and cyclooxygenase (COX) have inducible isoforms that are up-regulated during inflammatory states. However, the interaction between these enzymes is not clearly understood. The objective was to clarify the interactions between NOS and COX in the rat gastric mucosa in the presence and absence of lipopolysaccharide. DESIGN: Laboratory study. SETTING: Medical school laboratory. SUBJECTS: Female Sprague-Dawley rats. INTERVENTIONS: We used nonselective and selective COX inhibitors to determine the role of COX on inducible NOS (iNOS) expression in the gastric mucosa. MEASUREMENTS AND MAIN RESULTS: The nonselective COX inhibitors salicylate and indomethacin enhanced the expression of iNOS in the rat gastric mucosa and exacerbated gastric injury in the presence of lipopolysaccharide, effects reversed by exogenous prostaglandin E2. Selective COX-1 inhibition with SC560 similarly increased gastric iNOS expression and exacerbated gastric injury, while the selective COX-2 inhibitor NS398 had no effect on iNOS expression or gastric injury in the presence of lipopolysaccharide. CONCLUSIONS: These data suggest that COX-1 derived prostaglandins exert an inhibitory effect on gastric iNOS during endotoxemia, and this may represent a potential cytoprotective mechanism not previously recognized for this enzyme, since up-regulation of iNOS is deleterious in some tissues.

Differential effects of luminal arginine and glutamine on metalloproteinase production in the postischemic gut.

BACKGROUND: Matrix metalloproteinases (MMPs) are a group of endopeptidases induced under inflammatory conditions in the intestine which possess the capacity to degrade components of the extracellular matrix. We have previously demonstrated that MMP-2 expression correlates with increased inducible nitric oxide synthase (iNOS) production in the stomach and that iNOS is upregulated in the postischemic gut by the luminal nutrient arginine and repressed by luminal glutamine. We therefore hypothesized that arginine would enhance expression of MMP-2 in the postischemic gut. METHODS: Jejunal sacs were created in rats at laparotomy and filled with either 60 mM glutamine, arginine, or magnesium sulfate (osmotic control) followed by 60 minutes of superior mesenteric artery occlusion (SMAO) and 6 hours of reperfusion and compared with shams. Jejunum was harvested, and membrane type-1 matrix metalloproteinase (MT1-MMP), MMP-2, and iNOS protein expression was determined by Western analysis and MMP-9 production by gelatin zymography. RESULTS: MMP-2, MT1-MMP, MMP-9, and iNOS were all increased after SMAO compared with shams. Arginine maintained while glutamine inhibited the increase in iNOS, MT1-MMP, and MMP-2 expression in the postischemic gut. Pretreatment of the arginine group with a selective iNOS inhibitor blunted the induction of MMP-2 in the postischemic gut. There was no differential modulation of MMP-9 by the luminal nutrients. CONCLUSIONS: The arginine-induced upregulation of iNOS may contribute to increased activity of MT1-MMP and MMP-2. The mechanism for this differential regulation by arginine warrants further investigation.

Effects of anesthesia on lipopolysaccharide-induced changes in serum cytokines.

BACKGROUND: The pathophysiology of sepsis is incompletely understood, however alterations in systemic inflammation and serum cytokines are thought to play a central role. In the rat, ketamine, but not isoflurane, prevents hepatic injury from lipopolysaccharide (LPS). The effect of these anesthetics on the systemic inflammatory response and other organs remains to be fully elucidated. We hypothesized that ketamine, but not isoflurane, would blunt the cytokine response to LPS administration. METHODS: Male rats received no anesthesia, intraperitoneal ketamine (70 mg/kg), or inhalational isoflurane. One hour later, LPS (20 mg/kg, intraperitoneal) or saline was given for 5 hours and rats were killed. Gastric fluid volumes were determined as an index of gastric emptying. Serum was collected and cytokines measured via a multiplexed suspension immunoassay. RESULTS: In nonanesthetized rats, LPS increased gastric luminal fluid accumulation and serum levels of proinflammatory cytokines when compared with saline controls. Anesthesia with either ketamine or isoflurane caused a significant reduction in LPS-induced changes in serum cytokines, although ketamine had a more dramatic reduction in tumor necrosis factor alpha levels than did isoflurane. Both anesthetics reduced the interleukin IL-6/IL-10 ratio in response to LPS when compared with LPS alone. Ketamine, but not isoflurane, prevented LPS-induced gastric luminal fluid accumulation. CONCLUSIONS: These data indicate that both ketamine and isoflurane diminish the systemic inflammatory response to LPS in the rat as measured by serum cytokines and a reduced IL-6/IL-10 ratio. However, only ketamine improves LPS-induced gastric dysfunction, perhaps secondary to its ability to reduce serum tumor necrosis factor alpha levels more effectively.

Gastric alkalinization after major trauma.

BACKGROUND: Gastric function in trauma patients is poorly understood. In animals, shock causes gastric luminal alkalinization and bile reflux. In trauma patients, studies of stress gastritis prophylaxis demonstrated with continuous gastric pH monitoring that the stomach became alkaline even without antisecretory therapy. Therefore, we hypothesized that trauma patients have an alkaline gastric environment that may be because of bile reflux. METHODS: A prospective observational study at an urban Level I trauma center was performed. All major torso trauma patients (severe head injuries excluded) who met the criteria for standardized shock resuscitation were eligible for inclusion. A 12.5 Fr silastic pH probe (Sandhill Scientific) was placed in the stomach and the gastric pH continuously monitored for 7 days. Patients received no stress gastritis prophylaxis. Gastric samples were obtained each day and assayed for total bile acids and pH. RESULTS: Twelve patients were entered into the study. Mean age was 31 years +/- 4 years, 67% men, 75% blunt mechanism of injury, and mean Injury Severity Score 28 +/- 3. Three patients (25%) developed multiple organ failure and four acquired ventilator-associated pneumonia. During the first day of continuous pH monitoring, 9 of 12 patients had a gastric pH >4 for the majority of the day with 7 patients having essentially no acid production. During subsequent days, gastric pH began to drop and by the 4th day the majority of each day was spent at a pH <4. Additionally, gastric pH of patients with ventilator-associated pneumonia or multiple organ failure tended to be more alkaline. Bile acid was present in the gastric fluid of all patients in varying amounts. However, there was no significant correlation between gastric pH and bile acid concentration. CONCLUSIONS: Traumatic injury causes gastric luminal alkalinization that may be related, only in part, to bile acid reflux. Other alkalinizing factors remain to be elucidated.

Effect of NOS inhibition on rat gastric matrix metalloproteinase production during endotoxemia.

UNLABELLED: Matrix metalloproteinases (MMPs) degrade the extracellular matrix and contribute to LPS-induced gastric injury. MMPs are closely modulated by their activators, membrane type-MMP (MT-MMPs) and their endogenous inhibitors, the tissue inhibitors of metalloproteinases (TIMPs). As LPS-induced gastric injury is mediated in part by iNOS, and NO modulates MMP production in vitro, we hypothesized that NOS inhibition would similarly modulate LPS-induced gastric MMP production. Therefore, the purpose of these studies was to compare the effects of selective and nonselective NOS inhibition on LPS-induced gastric MMP production. METHODS: Sprague-Dawley rats were given either the nonselective NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 5 mg/kg, s.c.), a selective iNOS inhibitor, aminoguanidine (45 mg/kg, i.p.) or L-N-iminoethyl-lysine (L-NIL; 10 mg/kg, i.p.), or vehicle 15 min before saline or LPS (20 mg/kg, i.p.) and killed 24 h after LPS administration. Stomachs were assessed for macroscopic injury (computed planimetry), and gastric mucosal MMP production was assessed by gelatin zymography, in situ zymography, and Western analysis for MMP-2, MT1-MMP, and TIMP-2. (n > or = 4/group; ANOVA). RESULTS: Aminoguanidine treatment decreased LPS-induced macroscopic gastric injury as well as MMP-2 and MT1-MMP protein production while having no effect on TIMP-2 protein levels. L-NIL similarly attenuated the induction of MMP-2 and MT1-MMP by LPS. L-NAME failed to attenuate LPS induced gastric injury or MT1-MMP protein induction and increased MMP-2 levels. L-NAME similarly had no effect on gastric TIMP-2 production. CONCLUSIONS: Selective iNOS inhibition decreases gastric MMP-2 activity after LPS administration, whereas nonselective inhibition increases MMP-2 levels. The ability of selective iNOS inhibition to ameliorate LPS-induced gastric injury may be due in part to its inhibition of active MMP-2 production, whereas nonselective NOS inhibitors increase MMP-2 levels and maintain gastric injury after LPS administration.

Ketamine attenuates liver injury attributed to endotoxemia: role of cyclooxygenase-2.

BACKGROUND: Endotoxic shock can cause end-organ dysfunction and liver injury. Critically ill patients frequently require surgical intervention under general anesthesia for source control. However, the effects of anesthetics on organ function during sepsis and their influence on inflammatory mediators such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) remain to be fully elucidated. Because ketamine anesthesia has anti-inflammatory effects in some tissues, we hypothesized that it would attenuate lipopolysaccharide (LPS)-induced liver injury. METHODS: Adult rats were given no anesthesia (saline), continuous isoflurane inhalation, or intraperitoneal (i.p.) injection of ketamine 70 mg/kg. One hour later, the rats received saline or LPS (20 mg/kg i.p.) for 5 hours. The rats were killed, and serum hepatocellular enzymes, liver COX-2, iNOS protein (Western immunoblot), and nuclear factor kappa B (NF-kappaB)-binding activity (electrophoretic mobility shift assay) determined. In a separate study, the role of COX-2 in LPS-induced liver injury was examined by pretreating rats with the selective COX-2 inhibitor NS-398 (3 mg/kg, i.p.) and the role of iNOS examined with the use of the selective inhibitor aminoguanidine (45 mg/kg, i.p.) 1 hour before LPS. RESULTS: LPS increased serum aspartate aminotransferase and alanine aminotransferase levels, hepatic iNOS and COX-2 protein, and nuclear factor NF-kappaB. Ketamine, but not isoflurane, attenuated these effects caused by LPS. COX-2 inhibition with NS-398 as well as iNOS inhibition with aminoguanidine diminished LPS-induced changes in aspartate aminotransferase and alanine aminotransferase levels. CONCLUSIONS: These data indicate that anesthetics differ in their effects on liver injury caused by LPS. Ketamine has hepatoprotective effects, while isoflurane does not. Moreover, the protective effects of ketamine are mediated, at least in part, through a reduction in COX-2 and iNOS protein that could be regulated via changes in NF-kappaB-binding activity.

Rat gastric injury after lipopolysaccharide: role of inducible nitric oxide synthase.

BACKGROUND: Short-term treatment with lipopolysaccharide (LPS) causes morphologic, but not macroscopic, gastric injury and decreases gastric injury caused by a subsequent challenge with a luminal irritant. This effect is abrogated by inducible nitric oxide synthase (iNOS) inhibition. The effects of long-term treatment with LPS on gastric injury are unknown as is the role of iNOS. We hypothesized that LPS would cause macroscopic gastric injury at later time points through an iNOS-dependent pathway. METHODS: Conscious rats were given saline or LPS (1 or 20 mg/kg intraperitoneal) as a single intraperitoneal injection and killed 24 to 72 hours after injection. Macroscopic gastric injury (computerized planimetry), gastric luminal fluid volume and pH, and iNOS protein levels were assessed. RESULTS: When compared with saline, high-dose but not low-dose LPS caused macroscopic gastric injury, increased gastric luminal fluid and pH, and up-regulated iNOS at 24 and 48 hours. All assessments returned to baseline by 72 hours. Inhibition of iNOS with 1400W (1 mg/kg intraperitoneal) given 15 minutes before saline or LPS (20 mg/kg) attenuated the deleterious effects of LPS on gastric injury and pH, but not fluid accumulation. CONCLUSIONS: These data suggest that prolonged treatment with high-dose LPS causes gastric injury through an iNOS-mediated pathway.

The impact of diabetes in patients with necrotizing soft tissue infections.

BACKGROUND: Given the association of diabetes with necrotizing soft tissue infections (NSTIs) and hyperglycemia with mortality in critically ill patients, this study investigates the impact of diabetes and hyperglycemia in NSTI patients. METHODS: This is a retrospective review of NSTI patients at LBJ General Hospital between January 1995 and December 2002, assessing infectious morbidity, mortality, and length of hospital stay. RESULTS: There was a trend towards increased infectious complications, defined as a hospital-acquired (not present within 48 h of presentation) infection at a secondary site, amongst diabetic patients (RR 2.1, 95% CI 0.7-6.8) and patients with admission hyperglycemia greater than 200 mg/dL (OR 1.9, 95% CI 0.7-5.7) but not with admission hyperglycemia greater than 120 mg/dL (OR 1.6, 95% CI 0.3-8.7). Patients with an infectious complication had a longer hospital stay (median, interquartile range [IQR]; 36, 30-44 days vs. 10, 7-20 days, p < 0.001), increased mortality (29% vs. 7%, p = 0.05), and poorer outcome defined as death, amputation, or hospital stay exceeding the 75th percentile for length of stay (79% vs. 20%, p < 0.001). CONCLUSIONS: Diabetes mellitus and admission hyperglycemia may increase infectious complications in NSTI patients, predicting a longer and more complicated hospital course. Further study is required to define the optimal metabolic target in this patient population.

Effects of ketamine/xylazine on expression of tumor necrosis factor-alpha, inducible nitric oxide synthase, and cyclo-oxygenase-2 in rat gastric mucosa during endotoxemia.

Some anesthetics attenuate expression of endotoxin-induced production of proinflammatory genes. The anesthetic combination of ketamine/xylazine (K/X) decreases lipopolysaccharide (LPS)-induced liver injury in rats. However, the effects of K/X on gut function and gene expression are unknown. The purpose of this study was to examine the effect of K/X on LPS-induced gastric fluid accumulation, and gastric tumor necrosis factor (TNF)-alpha, inducible nitric oxide synthase (iNOS), and cyclo-oxygenase (COX)-2 expression, as well as serum TNF-alpha protein levels over time. We hypothesized that K/X would attenuate these LPS-induced endpoints. Rats were given either intraperitoneal saline or K (70 mg/kg) and X (6 mg/kg) 1 h before saline or LPS (20 mg/kg i.p.) treatment of 1, 3, or 5 h. Serum and gastric fluid and mucosa were collected and TNF-alpha, iNOS, and COX-2 expression were determined. LPS caused a significant increase in early serum and gastric mucosal TNF-alpha protein expression at 1 h, an effect that was significantly attenuated by K/X pretreatment. LPS caused significant gastric stasis and increased iNOS and COX-2 mRNA expression and iNOS protein expression in the stomach when compared with controls. K/X attenuated LPS-induced gastric fluid accumulation and upregulation of iNOS mRNA and protein, but not COX-2. These data indicate that K/X inhibits some proinflammatory genes and pathophysiologic responses in the serum and stomach during endotoxemia. The effects of K/X appear to inhibit transcriptional events in iNOS expression, which may be dependent on K/X-induced inhibition of early TNF-alpha expression. Furthermore, in rat models of endotoxemia, especially those evaluating the stomach, careful consideration needs to be given if anesthetic combinations with ketamine and/or xylazine are used, as they alter LPS-induced responses.

Lipopolysaccharide-induced gastrointestinal injury in rats: role of surface hydrophobicity and bile salts.

Sepsis of gastrointestinal origin can lead to life-threatening complications in vital organs due to bacterial overgrowth and/or translocation from the lumen into the blood. In a rat model of endotoxemia, changes in surface hydrophobicity (associated with barrier integrity) of the gastrointestinal mucosa were examined. Rats were treated with Escherichia coli lipopolysaccharide (LPS), and gastric and ileal tissue were collected for determination of surface hydrophobicity by contact angle analysis. A role for bile salts in hydrophobicity changes was tested by quantifying bile salts in the lumen of both the stomach and ileum after LPS and by the administration of LPS to bile duct-ligated rats. A single intraperitoneal dose of LPS induced a dose- and time-dependent reduction in hydrophobicity of both the stomach and ileum, with the stomach showing greater sensitivity at an earlier time than the ileum. LPS also induced gastric bleeding, reflux of bile acid into the gastric lumen, and decreased levels of bile salt in the ileum. The LPS-induced reductions in surface hydrophobicity of the stomach were prevented by prior bile duct ligation. We conclude that LPS disrupts gastrointestinal barrier integrity, in part by mechanisms involving bile constituents and an attenuation in the mucosa's hydrophobic characteristics.

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 N(G)-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.