NO-Donation Increases Visceral Circulation in a Porcine Model of Abdominal Hypertension.

Intraabdominal hypertension (IAH) is negative for outcome after intensive care. Little research has focused on medical intervention to improve visceral circulation during IAH. A nitric oxide (NO)-donor was compared with placebo in 25 pigs; each pig was randomized into three groups: PDNO (NO-donor), Control (placebo), or Sham. IAH was induced by CO2 insufflation to 30 mmHg. Sham group had surgical preparation only. Blood gases, invasive venous and arterial blood pressure, intestinal microcirculation and superior mesenteric blood flow were measured. The PDNO group had significantly increased intestinal microcirculation compared with Controls during IAH (last hour, P = 0.009). The mean arterial pressure and abdominal perfusion pressures (APP) were decreased, and the cardiac index were increased in the PDNO group. Also, systemic and pulmonary vascular resistances were lower in the PDNO group compared with Controls. These experimental findings indicate that NO should be further explored with potential application to improve intestinal microcirculation in IAH patients.

Fully covered self-expandable metal stent placed over a stapled colon anastomosis in an animal model: A pilot study of colon metabolism over the stent.

Background and Aim: Anastomotic leakage (AL) in colorectal resection and primary anastomosis is a common and feared complication. Fully covered self-expandable metal stents (FCSEMSs) have been used for the treatment of AL. It is still unknown whether FCSEMSs affect anastomosis healing negatively by causing ischemia. In an animal study, we investigated the metabolic effects over a FCSEMS covering a stapled colon anastomosis. Methods: Seven pigs were investigated using microdialysis after laparotomy, colon resection, and anastomosis with stent placement. Measurements were done at the proximal and distal ends of the anastomosis and at a reference catheter placed at the small intestine. Measurements of glucose, pyruvate, lactate, glycerol, and the lactate/pyruvate ratio (L/P) were carried out. Results: Lactate and L/P were significantly higher at the oral part of the anastomosis, while glucose showed a small declining tendency. At the distal part of the anastomosis, glucose decreased significantly after the resection but did not reach zero. Lactate increased significantly whereas L/P increased only slightly. Glycerol levels were stable. Conclusion: Colon resection caused initially hypermetabolism in the intestinal ends next to the resection site. This hypermetabolism neither deteriorated nor turned into ischemia during the initial postoperative course, but the start of hypoxemia could not be excluded during the study and after the placement of an FCSEMS.

Altered mRNA Expression Due to Rectal Perforation in a Porcine Model - A Pilot Study.

BACKGROUND: Anastomotic leakage is the most serious and unwelcome complication in rectal surgery. It has a great impact on postoperative morbidity and mortality. In this pilot study, changes of mRNA expression in blood were analyzed in an animal model designed to imitate anastomotic leakage. MATERIALS AND METHODS: Twelve pigs were randomized into two groups: A sham-operated control group and an experimental group in which iatrogenic rectal perforation was performed. The changes in the mRNA expression at 4 hours after creating the perforation were studied. Microarray analysis was performed using Gene Chip whole porcine genome array. mRNA expression of 19,124 genes was investigated. RESULTS: Significantly increased levels of genes with a fold change greater than 2 were found, including 276 coding for unknown proteins and 48 coding for known proteins. Eleven of those which coded for known proteins were up-regulated with a fold change >4. CONCLUSION: Eleven known genes were highly up-regulated after rectal perforation. These genes were mainly involved in inflammatory response, intracellular signaling and cell membrane regulation. Their corresponding proteins might potentially be clinical biomarkers of anastomotic leakage and should be evaluated in further clinical studies.

A Randomized Porcine Study in Low Cardiac Output of Vasoactive and Inotropic Drug Effects on the Gastrointestinal Tract.

BACKGROUND: Splanchnic vasodilation by inodilators is an argument for their use in critical cardiac dysfunction. To isolate peripheral vasoactivity from inotropy, such drugs were investigated, and contrasted to vasopressors, in a fixed low cardiac output (CO) model resembling acute cardiac dysfunction effects on the gastrointestinal tract. We hypothesized that inodilators would vasodilate and preserve the aerobic metabolism in the splanchnic circulation in low CO. METHODS: In anesthetized pigs, CO was lowered to 60% of baseline by partial inferior caval vein balloon inflation. The animals were randomized to placebo (n = 8), levosimendan (24 µg kg-1 bolus, 0.2 µg kg-1 min-1, n = 7), milrinone (50 µg kg-1 bolus, 0.5 µg kg-1 min-1, n = 7), vasopressin (0.001, 0.002 and 0.006 U kg-1 min-1, 1 h each, n = 7) or norepinephrine (0.04, 0.12, and 0.36 µg kg-1 min-1, 1 h each, n = 7). Hemodynamic variables including mesenteric blood flow were collected. Systemic, mixed-venous, mesenteric-venous, and intraperitoneal metabolites were analyzed. RESULTS: Cardiac output was stable at 60% in all groups, which resulted in systemic hypotension, low superior mesenteric artery blood flow, lactic acidosis, and increased intraperitoneal concentrations of lactate. Levosimendan and milrinone did not change any circulatory variables, but levosimendan increased blood lactate concentrations. Vasopressin and norepinephrine increased systemic and mesenteric vascular resistances at the highest dose. Vasopressin increased mesenteric resistance more than systemic, and the intraperitoneal lactate concentration and lactate/pyruvate ratio. CONCLUSION: Splanchnic vasodilation by levosimendan and milrinone may be negligible in low CO, thus rejecting the hypothesis. High-dose vasopressors may have side effects in the splanchnic circulation.

Early Metabolic and Inflammatory Intraperitoneal Changes After Rectum Perforation.

PURPOSE: Anastomotic leakage (AL) is the most dreaded complication in rectal surgery. It has a great impact on postoperative morbidity and mortality. This animal model, in which we have studied postoperative metabolic and inflammatory changes, is designed to imitate an AL. METHODS: Twelve pigs were randomized into 2 groups. In the experimental group, an iatrogenic rectal perforation was performed, with the control group having a sham operation. The 2 groups were followed for 10 hours after operation with regard to vital parameters, arterial lactate, and cytokines interleukin (IL) 1, IL6, and IL10 in the blood and intraperitoneally. Intraperitoneal microdialysis analyses of glucose, lactate, glycerol, and pyruvate were performed and the lactate/pyruvate ratio was calculated. RESULTS: Glucose levels were lower in the experimental group after 4 hours. After 7 hours, lactate and lactate/pyruvate ratio was higher in the experimental group. At the same time intraperitoneal cytokines IL6 and IL10 were higher in the experimental group. Blood samples showed higher IL6 after 7 hours in the experimental group. CONCLUSION: In this study, several significant differences between the groups in metabolic and inflammatory values were detected. Further clinical studies are recommended to evaluate the importance of intraperitoneal metabolic and inflammatory analyses as a diagnostic tool for early identification of an AL.

Results of postoperative microdialysis intraperitoneal and at the anastomosis in patients developing anastomotic leakage after rectal cancer surgery.

Introduction: Anastomotic leakage postoperatively in patients operated with rectum resection and primary anastomosis is a common and feared complication. We have studied seven patients with an anastomotic leakage after surgery and compared them with 13 patients without complications.Methods: Metabolic measurements with microdialysis were done during the first seven postoperative days, with measurements of glucose, pyruvate, lactate and glycerol. The lactate/pyruvate ratio was calculated. Measurements were performed subcutaneously, intraperitoneally and at the anastomosis. The inflammatory cytokines, IL 6 and IL 10, were measured intravenously and intraperitoneally 48 hours postoperatively.Results: Intravenous and intraperitoneal IL 6 were higher in the leakage group. Around the small intestine (intraperitoneally), we found that patients developing anastomotic leakage had higher lactate and lactate/pyruvate ratio immediately after surgery. They also showed lower glycerol levels. At the anastomosis, we found higher lactate and lactate/pyruvate ratio in anastomotic leak patients after the fourth postoperative day.Conclusions: The results indicate that a possible mechanism behind an anastomotic leakage is an impaired circulation and thus insufficient saturation to the small intestine peroperatively. This develops into an inflammation both intraperitoneally and intravenously, which, if not reversed, spread within the gastrointestinal tract .The colorectal anastomosis is the most vulnerable part of the gastrointestinal tract postoperatively and hypoxia and inflammation may occur there, and an anastomosis leakage will be the consequence.

Wound ballistics of military rifle bullets: An update on controversial issues and associated misconceptions.

The wound ballistics literature contains several misconceptions about the physical effects of penetrating projectiles in tissue and tissue simulants. These can adversely affect the proper management of gunshot injuries, particularly in view of the ongoing threat of terrorist and criminal acts using assault rifles against civilians. The understanding of the wounding effects by military rifle bullets can be founded on the concept of energy transfer to the wound as applied to high-energy missile trauma. A substantial component of high-energy transfer in assault rifle injuries is manifested by the dynamic phenomenon of temporary cavitation, which is extensively reviewed with respect to its impact on the wound production and the associated controversy surrounding its consequences in soft tissue wounds. Part of this controversy emanates from misinterpretation of experimental data regarding the magnitude of the temporary cavity induced by high-velocity projectiles and the different conceptions of the tissue response to cavitation. The interaction between the projectile and tissue can lead to tumbling and possibly to deformation and fragmentation of the bullet, all of which strongly influence the energy transfer characteristics affecting both the temporary cavitation and the size of the permanent wound channel. Awareness of these effects can enhance perception of clinical and radiological findings suggestive of the wounding mechanism by various projectiles. LEVEL OF EVIDENCE: Review/therapeutic, level V.

Proximal shift of colorectal cancer. A persistent phenomenon with multiple causes, patterns and clinical implications.

A considerable change in the anatomical distribution of colorectal cancer (CRC) towards more proximal sites has been observed in Western countries within the last 6-7 decades. As a result, tumors located proximally to the splenic flexure are now accounting for 30-40% (or even more) of overall CRC cases. This proximal migration is not always representing a true increase of proximal cancer, arising from various combinations of changes in the rates of proximal and distal cancer (e.g. proximal increase with distal stability/reduction, or decline in both sites albeit higher distally etc) in different areas and periods. Principal potential causes include ageing in Western populations (since proximal cancers are more common among the aged), various potentially site-specific exposures (lifestyle and medical) and systematic screening. Their effect is reflected in the particular shift patterns; for instance, widespread screening in USA has led to an overall CRC decline, more evident distally (for technical, anatomical and morphological reasons). Segmental disparities in particular characteristics (age, gender, morphology) and responses to various exposures are etiologically associated (for the most part) with underlying genetic differences between proximal and distal tumors. From clinical aspect, proximal shift necessitates a more generalized use of colonoscopy in screening programs. Potential interventions in treatment (segmental patient stratification) and prevention (identification of particular site-specific exposures) require further investigation.

Enoxaparin-induced spontaneous massive retroperitoneal hematoma with fatal outcome.

Spontaneous retroperitoneal hematoma (SRH) is a severe and potentially fatal complication of anticoagulation therapy. We describe a case of fatal spontaneous massive retroperitoneal hematoma in a female patient receiving bridging therapy with enoxaparin for atrial fibrillation. Physicians should be cautious when prescribing enoxaparin in elderly patients, in patients with impaired renal function, and in patients receiving concomitant oral anticoagulants. Emergency physicians should always consider SRH in the differential diagnosis in patients under enoxaparin therapy presenting with abdominal pain. Computed tomographic scan is the imaging modality of choice for evaluating SRH. Early diagnosis and aggressive treatment are of paramount importance as SRH is associated with high mortality and morbidity rates.

Intraperitoneal metabolic consequences of supraceliac aortic balloon occlusion in an experimental animal study using microdialysis.

BACKGROUND: To investigate the effects of supraceliac aortic balloon occlusion (ABO) and superior mesenteric artery (SMA) occlusion on abdominal visceral metabolism in an animal model using intraperitoneal microdialysis (IPM) and laser Doppler flowmetry. METHODS: A total of 9 pigs were subjected to ABO and 7 animals were subjected to SMA occlusion for 1 hour followed by 3 hours of reperfusion. Seven animals served as controls. Hemodynamic data, arterial blood samples, urinary output, and intestinal mucosal blood flow (IBF) were followed hourly. Intraperitoneal (i.p) glucose, glycerol, lactate, and pyruvate concentrations and lactate-to-pyruvate (l/p) ratio were measured using IPM. RESULTS: Compared with the baseline, ABO reduced IBF by 76% and decreased urinary output. SMA occlusion reduced IBF by 75% without affecting urinary output. ABO increased the i.p l/p ratio from 18 at baseline, peaking at 46 in early reperfusion. SMA occlusion and reperfusion tended to increase the i.p l/p ratio, peaking at 36 in early reperfusion. ABO increased the i.p glycerol concentration from 87 µM at baseline to 579 µM after 3 hours of reperfusion. SMA occlusion and reperfusion increased the i.p glycerol concentration but to a lesser degree. CONCLUSIONS: Supraceliac ABO caused severe hemodynamic, renal, and systemic metabolic disturbances compared with SMA occlusion, most likely because of the more extensive ischemia-reperfusion injury. The intra-abdominal metabolism, measured by microdialysis, was affected by both ABO and SMA occlusion but the most severe disturbances were caused by ABO. The i.p l/p ratios and the glycerol concentrations increased during ischemia and reperfusion and may serve as markers of these events and indicate anaerobic metabolism and cell damages respectively.

Clinicopathological differences of colorectal cancers according to tumor origin: Identification of possibly de novo lesions.

Colorectal cancer (CRC) is considered to develop through the conventional adenoma-carcinoma sequence. However, the existence of de novo carcinogenesis, without any intervening precursor lesions, has been suggested for certain morphologically different tumors lacking polypoid characteristics. The presence of such tumors, along with their correlation with cardinal clinicopathological parameters, such as stage, grade and site, was retrospectively investigated in a series of 119 surgically treated CRC cases. The absence of particular polypoid characteristics (adenomatous remnants or coexisting polyps in the tumor vicinity) in combination with an infiltrative (or ulceroinfiltrative) growth pattern, were the criteria defining the nonpolypoid origin. The recorded frequencies of remnants, coexisting polyps and infiltrative tumors were 7, 5, 9 and 32%, respectively. The incidence of cases meeting the above-mentioned criteria was 28.5%. These nonpolypoid lesions exhibited a predilection for proximal anatomical site (P=0.04), probably associated with their infiltrative pattern. Most importantly, de novo lesions (unlike polypoid) were rarely found among cases with indolent tumor characteristics (stage I or grade I, P=0.008), showing a considerably different overall pattern of distribution by stage and grade as compared to that of polypoid tumors (P=0.03). The fact that nonpolypoid CRCs appeared to be clinicopathologically different from their polypoid counterparts is supportive of possible de novo origin and suggestive of a likely worse clinical behavior. The impact of these findings should be investigated to determine potential applications in the diagnosis, treatment and surveillance of these lesions.

The pattern of epidermal growth factor receptor variation with disease progression and aggressiveness in colorectal cancer depends on tumor location.

The role of epidermal growth factor receptor (EGFR) in colorectal cancer (CRC) prognosis remains unclear despite the recent development of anti-EGFR treatments for metastatic disease. The heterogeneity of CRC may account for this discrepancy; proximal and distal CRC has been found to be genetically and clinicopathologically different. The aim of this study was to investigate the effect of tumor location on the association of EGFR with the conventional prognostic indicators (stage and grade) in CRC. Immunohistochemical assessment of EGFR was retrospectively performed in 119 primary CRC specimens and data were correlated with tumor stage and grade in the proximal and distal tumor subset. The molecular combination of EGFR with p53 (previously assessed in this sample) was similarly analyzed. EGFR positivity was detected in 34, 30 and 35% of the entire cohort, proximal and distal tumors, respectively. The pattern of EGFR clinicopathological correlation was found to differ by site. A reduction in the frequency of EGFR(+) with progression of stage and/or worsening of grade was observed proximally, whereas an opposite trend was recorded distally. Proximal tumors with stage I or with indolent features (stage I, well-differentiated) exhibited a significantly higher proportion of EGFR positivity than other tumors of this location (p=0.023 and p=0.022, respectively) or corresponding distal tumors (p=0.018 and p=0.035, respectively). Moreover, the co-existence of EGFR and high p53 staining (accounting for 11% of cases) was found in a significantly higher proportion of stage IV tumors compared to other stages (p=0.004), although only for the distal subset. Proximal and distal tumors showed various patterns of EGFR variation with disease progression and aggressiveness. This disparity provides further support to the hypothesis that these particular subsets of CRC are distinct tumor entities. It may also be suggestive of a potentially different therapeutic approach according to tumor site, particularly regarding anti-EGFR targeted treatment.

Disparate clinicopathological correlations of p53 and Bcl-2 in colorectal cancer.

p53 and Bcl-2 (both regulators of cell apoptosis) have been considered to be involved in the initiation and progression of the colorectal tumorigenic process, respectively. In this study, we investigated their association with tumor stage and grade -both substantially affecting prognosis. Immunohistochemical assessment of p53 and Bcl-2 was retrospectively conducted (using DO-7 and Ca-124 monoclonal antibodies, respectively) in 119 surgically resected colorectal carcinomas, and the results were correlated to tumor stage and grade. The proportion of tumors positively stained was 70% for p53 and 46% for Bcl-2, whereas co-expression of both markers was observed in 28% of cases. Tumors exhibiting the highest p53 staining (>60% stained cells) were more frequently found in disease stage IV (p=0.03), while Bcl-2 positivity showed a predilection for earlier stage (p=0.02) and better grade (p=0.028). The associations of both markers with stage, along with a reciprocal relationship between p53(+) and Bcl-2(+) tumors (p=0.02), stronger for cases with p53 staining >30% (p=0.007), remained significant only for distal tumors. The distinct correlations of p53 and Bcl-2 with disease progression and aggressiveness (being influenced by the extent of staining and tumor site) may be clinically useful in the determination of high-risk colorectal cancer cases.

Seprafilm: a retrospective preliminary evaluation of the impact on short-term oncologic outcome in colorectal cancer.

INTRODUCTION: Hyaluronate carboxymethylcellulose-based bioresorbable membrane (Seprafilm ) has been used as a method of postoperative adhesion prevention. However, its short-term effect on colorectal cancer recurrence remains unknown. METHODS: A retrospective chart review was undertaken of patients with colorectal cancer operated on with curative intent from 1996 to 1999. All patients who received Seprafilm during surgery were assigned to the Seprafilm group, whereas all patients who did not were placed in a control group. Tumor recurrence was defined as persistently elevated carcinoembryonic antigen levels, pathologic confirmation of endoscopic findings, or radiographically documented lesions in the liver, lung, or pelvis. RESULTS: There were 63 patients in the Seprafilm group and 93 in the control group. The two groups were well matched according to all standard clinical and pathologic characteristics. Adjuvant chemoradiotherapy was administered to 23 patients (36.5 percent) in the Seprafilm group and to 44 (47.3 percent) in the control group ( P= 0.24). At a mean follow-up of 11.4 +/- 7.3 months in the Seprafilm group and 14.2 +/- 11.9 months in the control group, there were 6 (9.5 percent) and 15 (16.1 percent) recurrences, respectively ( P= 0.33). The 1- and 2-year disease-free survival rates were 88 and 85 percent, respectively, in the Seprafilm group and 85 and 72 percent, respectively, in the control group (log-rank test, P= 0.44). CONCLUSION: Seprafilm did not adversely affect the short-term recurrence rate after curative resection of colorectal cancer. In addition, it did not appear to compromise the short-term oncologic outcome. However, with a short follow-up and a small denominator, a definitive conclusion cannot be drawn. This study does intimate that larger, longer-term, prospective, randomized studies may be safely conducted.