Stacey D. Moore-Olufemi

Resuscitation-induced gut edema and intestinal dysfunction

BACKGROUND Mesenteric venous hypertension and subsequent gut edema play a pivotal role in the development of intra-abdominal hypertension. Although gut edema is one cause of intra-abdominal hypertension, its impact on gut function is unknown. The purpose of this study was to create a model of acute hydrostatic gut edema and to evaluate its effect on gut motility and barrier function. METHODS The first study, group A, evaluated the effect of gut edema on transit over time using 20 mL/kg 0.9% saline. The second study, group B, focused on the 12-hour time period using 80 mL/kg 0.9% saline. Rats were randomized to superior mesenteric vein partial occlusion (venous hypertension) or sham surgery. At 6, 12, and 24 hours, group A underwent intestinal transit and tissue water weight measurements. At 12 hours, group B underwent tissue water, transit, ileal permeability and resistance, lactate and myeloperoxidase activity, and mucosal injury measurements. RESULTS Venous hypertension with fluid resuscitation caused acute hydrostatic gut edema, delayed intestinal transit, increased mucosal permeability to macromolecules, and decreased tissue resistance over time. Mucosal injury was minimal in mesenteric venous hypertension. CONCLUSION Acute mesenteric venous hypertension and resuscitation-induced gut edema, in the absence of ischemia/reperfusion injury, is associated with delayed intestinal transit and altered gut barrier function.

Ischemic preconditioning protects against gut dysfunction and mucosal injury after ischemia/reperfusion injury

Mesenteric ischemia/reperfusion (IR) damages the gastrointestinal epithelia and impairs gut function. Ischemic preconditioning (IPC) has been shown to protect organs against IR injury. We hypothesized that IPC protects the gut from IR injury. Rats were randomized to a sham group, a sham early IPC + IR group (sham IPC + SMA occlusion for 30 min and 6 h of reperfusion), an early IPC + IR group (IPC, three cycles of SMA occlusion for 4 min and reperfusion for 10 min) followed immediately by SMA occlusion for 30 min and 6 h of reperfusion), a sham 24-h group, a sham late IPC + IR group (sham IPC followed by additional reperfusion for 24 h + SMA occlusion for 30 min and 6 h of reperfusion), and a late IPC + IR group (IPC protocol followed by additional reperfusion for 24 h, and then SMA occlusion for 30 min followed by 6 h of reperfusion). At 6 h, transit was determined and expressed as the mean geometric center. Ileum was harvested for assessment of mucosal injury and myeloperoxidase (MPO) activity. Tissue water was determined using the wet-to-dry weight ratio to assess gut edema. Early IPC + IR significantly improved transit (3.9 ± 0.2), decreased MPO levels (3 ± 2), and lessened mucosal injury (1.2 ± 0.3) compared with animals subjected to sham early IPC + IR (transit, 2.9 ± 0.2; MPO levels, 9 ± 1; mucosal injury, 3.0 ± 0.6). Late IPC + IR also improved transit (6.0 ± 0.4) and decreased MPO levels (1 ± 1) compared with sham late IPC + IR (transit, 4.4 ± 0.2; MPO levels, 8 ± 1), however, there was no difference in the mucosal protection between late IPC + IR (1 ± 0.3) and sham late IPC + IR (1 ± 1). Our results suggest that early and late IPC improves intestinal dysfunction, decreases inflammation, and provides mucosal protection in the intestine after IR. Our results show that IR-induced gut dysfunction can be improved by IPC. Both phases of IPC can potentially be useful in the clinical setting of surgical patient care.

Outcomes in pediatric melanoma: Comparing prepubertal to adolescent pediatric patients

Objective:The aim of this study was to determine the influence of age on outcome in pediatric melanoma patients and to identify factors associated with positive lymph node status in this population. Methods:A retrospective review of a prospective pediatric melanoma database, using sentinel lymph node biopsy (SLNB), from 1992 to 2006, identified 109 patients with the primary diagnosis of melanoma. Patient age was dichotomized as prepubescent (<10 years of age) and adolescent (≥10–18 years of age). Factors investigated included patient race, sex, and lymph node status and tumor thickness, Spitzoid or Non-Spitzoid histology, radial growth phase, and vascular invasion. The Fishers exact test was used to compare patient groups. Time-to-event analysis was performed using the Kaplan-Meier method. Results:There were 25 prepubescent and 84 adolescent patients. Prepubescent patients were more often non-White, had greater tumor thickness, more spitzoid tumors and more vascular invasion. Ten-year overall survival (OS) was 89% and 10-year event-free survival (EFS) was 73%. Among 57 patients who had an SLNB, prepubertal patients had a higher percentage of sentinel lymph node positivity. The odds having a positive SLNB decreased by 13% each year with increasing age. Patients with a tumor thickness ≥2.01 mm had higher odds of having a positive lymph node compared with those patients with a tumor thickness ⩽1.0. Conclusions:This is the largest known study of prepubertal melanoma patients. Although OS and EFS did not differ by age groups, younger ages showed increased risk of lymph node metastasis and thicker tumors. This suggests that the younger pediatric patients may have a disease that differs biologically from that of the older pediatric patients.

Hypertonic saline resuscitation prevents hydrostatically induced intestinal edema and ileus

Objective:We have shown that acute edema induced by mesenteric venous hypertension (MV-HTN) impairs intestinal transit and reduces the standardized engineering measures of intestinal stiffness (elastic modulus) and residual stress (opening angle). We hypothesized that hypertonic saline (7.5%) would reverse these detrimental effects of acute edema. Design:Laboratory study. Setting:University laboratory. Subjects:Male Sprague Dawley rats (270–330 g). Interventions:Rats were randomized to five groups: sham, MV-HTN alone, MV-HTN with 4 mL/kg normal saline resuscitation (equal volume), MV-HTN with 33 mL/kg normal saline resuscitation (equal salt), and MV-HTN with 4 mL/kg hypertonic saline. Intestinal edema was measured by wet to dry tissue weight ratio. A duodenal catheter was placed and, 30 mins before death, fluorescein isothiocyanate Dextran was injected. At death, dye concentrations were measured to determine intestinal transit. Segments of distal ileum were hung to a fixed point in a tissue bath and to a force displacement transducer and stretched in increments of 1 mm; we recorded the new length and the corresponding force from the force displacement transducer to determine elastic modulus. Next, two transverse cuts were made yielding a 1- to 2-mm thick ring-shaped segment of tissue which was then cut radially to open the ring. Then the opening angle was measured. Measurements and Main Results:MV-HTN, MV-HTN with 4 mL/kg normal saline, and MV-HTN with 33 mL/kg normal saline caused a significant increase in tissue edema and a significant decrease in intestinal transit, stiffness, and residual stress compared with sham. Hypertonic saline significantly lessened the effect of edema on intestinal transit and prevented the changes in stiffness and residual stress. Conclusions:Hypertonic saline prevented intestinal tissue edema. In addition, hypertonic saline improved intestinal transit, possibly through more efficient transmission of muscle force through stiffer intestinal tissue.

Peroxisome proliferator-activated receptor gamma mediates protection against cyclooxygenase-2-induced gut dysfunction in a rodent model of mesenteric ischemia/reperfusion.

Cyclooxygenase (COX)-2 has been identified as an important mediator elaborated during ischemia/reperfusion, with pro- and anti-inflammatory properties having been reported. As the role of COX-2 in the small intestine remains unclear, we hypothesized that COX-2 expression would mediate mesenteric ischemia/reperfusion-induced gut injury, inflammation, and impaired transit and that these deleterious effects could be reversed by the selective COX-2 inhibitor, N-[2-(cyclohexyloxy)-4-nitrophenyl] methanesulphanamide (NS-398). Additionally, we sought to determine the role of peroxisome proliferator-activated receptor γ (PPARγ) in mediating protection by NS-398 in this model. Rats underwent sham surgery or were pretreated with NS-398 (3, 10, or 30 mg/kg) intraperitoneally 1 h before 60 min of superior mesenteric artery occlusion and 30 min to 6 h of reperfusion. In some experiments, NS-398 (30 mg/kg) was administered postischemia. Ileum was harvested for COX-2 mRNA and protein, PGE2, myeloperoxidase (inflammation), histology (injury), intestinal transit and PPARγ protein expression, and DNA-binding activity. COX-2 expression and PGE2 production increased after mesenteric ischemia/reperfusion and were associated with gut inflammation, injury, and impaired transit. Inhibition of COX-2 by NS-398 (30 mg/kg, but not 3 or 10 mg/kg) not only reversed the deleterious effects of COX-2, but additionally induced expression and nuclear translocation of PPARγ. NS-398 given postischemia was equally protective. In conclusion, COX-2 may function as a proinflammatory mediator in a rodent model of mesenteric ischemia/reperfusion. Reversal of gut inflammation, injury, and impaired transit by high-dose NS-398 is associated with PPAR activation, suggesting a potential role for PPAR-γ in shock-induced gut protection.

Immune-enhancing enteral nutrients differentially modulate the early proinflammatory transcription factors mediating gut ischemia/reperfusion.

BACKGROUND Recent reports suggest that enteral diets enriched with arginine may be harmful by enhancing inflammation. This is consistent with our gut ischemia/reperfusion (I/R) model in which arginine induced the proinflammatory mediator inducible nitric oxide synthase and resulted in injury and inflammation whereas glutamine was protective. We now hypothesize that arginine and glutamine differentially modulate the early proinflammatory transcription factors activated by gut I/R. METHODS At laparotomy, jejunal sacs were filled with either 60 mmol/L glutamine, arginine, or an iso-osmotic control followed by 60 minutes of superior mesenteric artery occlusion and 6 hours of reperfusion and compared with shams. Jejunum was harvested for nuclear factor (NF)-kappaB and activator protein-1 (AP-1) measured by electrophoretic mobility shift assay and c-jun and c-fos (AP-1 family) by supershift. RESULTS Both NF-kappaB and AP-1 were activated by gut I/R. Arginine and glutamine had no differential effect on NF-kappaB, whereas AP-1 expression (c-jun but not c-fos) was markedly enhanced by arginine and significantly lessened by glutamine. CONCLUSION Arginine enhanced expression of the early proinflammatory transcription factor AP-1 but not NF-kappaB. This represents a novel mechanism by which arginine may be harmful when administered to critically ill patients.

Hypertonic saline reverses stiffness in a Sprague-Dawley rat model of acute intestinal edema, leading to improved intestinal function

Introduction:Acute edema induced by resuscitation and mesenteric venous hypertension impairs intestinal transit and contractility and reduces intestinal stiffness. Pretreatment with hypertonic saline (HS) can prevent these changes. Changes in tissue stiffness have been shown to trigger signaling cascades via stress fiber formation. We proposed that acute intestinal edema leads to a decrease in intestinal transit that may be mediated by changes in stiffness, leading to stress fiber formation and decreased intestinal transit. Furthermore, HS administration will abolish these detrimental effects of edema. Results:Intestinal edema causes a significant increase in tissue water and a significant decrease in intestinal transit and stiffness compared with sham. HS reversed these changes to sham levels. In addition, tissue edema led to significant stress fiber formation and decreased numbers of focal contacts. HS preserved tissue stiffness, prevented stress fiber formation, and was associated with improved intestinal function. Conclusion:HS eliminates intestinal tissue edema formation and improves intestinal transit. In addition, the action of HS may be mediated through its preservation of tissue stiffness, which leads to prevention of signaling via stress fiber formation, leading to preserved intestinal function. Finally, intestinal edema may provide a novel physiologic model for examining stiffness and stress fiber signaling.

An Evidence-Based Review of a Lentinula edodes Mushroom Extract as Complementary Therapy in the Surgical Oncology Patient

The purpose of this review is to present the currently published evidence regarding the use, efficacy, potential mechanisms of action, and results of published clinical trials regarding the use of a Lentinula edodes mushroom-derived extract (active hexose correlated compound) as complementary therapy in patients with cancer. The authors explore the current preclinical and clinical evidence as it relates to this topic and its potential use in the surgical oncology patient. There has been a growing interest in stimulation of the immune system in trauma, cancer, and surgical patients in general. Little, however, has been written about some-of the supplements in widely used in Japan and China, but relatively unheard of in the United States.

Strategies for modulating the inflammatory response after decompression from abdominal compartment syndrome

BackgroundManagement of the open abdomen is an increasingly common part of surgical practice. The purpose of this review is to examine the scientific background for the use of temporary abdominal closure (TAC) in the open abdomen as a way to modulate the local and systemic inflammatory response, with an emphasis on decompression after abdominal compartment syndrome (ACS).MethodsA review of the relevant English language literature was conducted. Priority was placed on articles published within the last 5 years.Results/ConclusionRecent data from our group and others have begun to lay the foundation for the concept of TAC as a method to modulate the local and/or systemic inflammatory response in patients with an open abdomen resulting from ACS.

Pretreatment with bone morphogenetic protein-7 (BMP-7) mimics ischemia preconditioning following intestinal ischemia/reperfusion injury in the intestine and liver.

Intestinal ischemia/reperfusion (I/R) injury has been shown to cause intestinal mucosal injury and adversely affect function. Ischemic preconditioning (IPC) has been shown to protect against intestinal I/R injury by reducing polymorphonuclear leukocyte infiltration, intestinal mucosal injury, and liver injury, and preserve intestinal transit. Bone morphogenetic protein 7 (BMP-7) has been shown to protect against I/R injury in the kidney and brain. Recently, microarray analysis has been used to examine the possible IPC candidate pathways. This work revealed that IPC may work through upregulation of BMP-7. The purpose of this study was to examine if pretreatment with BMP-7 would replicate the effects seen with IPC in the intestine and liver after intestinal I/R. Rats were randomized to six groups: sham, I/R (30min of superior mesenteric artery occlusion and 6 h of R), IPC+R (three cycles of superior mesenteric artery occlusion for 4 min and R for 10 min), IPC+I/R, BMP-7+R (100 &mgr;m/kg recombinant human BMP-7), or BMP-7+I/R. A duodenal catheter was placed, and 30 min before sacrifice, fluorescein isothiocyanate-Dextran was injected. At sacrifice, dye concentrations were measured to determine intestinal transit. Ileal mucosal injury was determined by histology and myeloperoxidase activity was used as a marker of polymorphonuclear leukocyte infiltration. Serum levels of aspartate aminotransferase were measured at sacrifice to determine liver injury. Pretreatment with BMP-7 significantly improved intestinal transit and significantly decreased intestinal mucosal injury and serum aspartate aminotransferase levels, comparable to animals undergoing IPC. In conclusion, BMP-7 protected against intestinal I/R-induced intestinal and liver injury. Bone morphogenetic protein 7 may be a more logical surrogate to IPC in the prevention of injury in the setting of intestinal I/R.