Effect of acute pancreatitis on porcine intestine: a morphological study.

AIM: The ultrastructural changes in the intestine were studied during experimental acute edematous and necrotizing porcine pancreatitis. The immunohistochemical expression of E-cadherin and ß-catenin in the jejunum and colon was assessed to characterize changes in the adherens junctions. METHODS: Twenty-four pigs were randomized to controls (n = 8) or to develop mild edematous (n = 8, saline infusion to pancreatic duct) or severe necrotizing pancreatitis (n = 8, taurocholic acid infusion). The ultrastructure of the mesenteric artery and the vein and epithelium of the jejunum and colon was analyzed at baseline and after 540 min with electron microscopy. The expression of E-cadherin and ß-catenin was assessed with immunohistochemistry. RESULTS: In the colon the microvilli and their glycocalyx shortened and reduced in density the most in necrotizing pancreatitis. In necrotizing pancreatitis adherens and tight junctions were occasionally open in the colon but rarely in the jejunum. Mitochondria in the colon epithelial cells were degenerated in necrotizing pancreatitis, swollen in edematous pancreatitis, and remained intact in the control case. In necrotizing pancreatitis, capillaries of the colon showed a broken endothelial lining with narrow lumens. The expression of E-cadherin immunoreactivity showed a trend toward a decrease in the colon in both edematous and necrotizing pancreatitis. CONCLUSION: Ultrastructural abnormalities in acute pancreatitis appear early in the colon, where they seem to be more damaging than in jejunum. Epithelial cell damage seems to include mitochondrial injury and an opening of tight and adherens junctions, which are more pronounced in necrotizing pancreatitis. Damage is seen in the mucosal and mesenteric endothelial cells.

Thymic neuroendocrine tumors in patients with multiple endocrine neoplasia type 1.

OBJECTIVE: MEN1 is associated with an increased risk of developing tumors in different endocrine organs. Neuroendocrine tumors of the thymus (TNETs) are very rare but often have an aggressive nature. We evaluated patients with MEN1 and TNET in three university hospitals in Finland. DESIGN/METHODS: We evaluated patient records of 183 MEN1-patients from three university hospitals between the years 1985-2019 with TNETs. Thymus tumor specimens were classified according to the new WHO 2021 classification of TNET. We collected data on treatments and outcomes of these patients. RESULTS: There were six patients (3.3%) with MEN1 and TNET. Five of them had the same common gene mutation occurring in Finland. They originated from common ancestors encompassing two pairs of brothers from sequential generations. The mean age at presentation of TNET was 44.7 ± 11.9 years. TNET was classified as atypical carcinoid (AC) in five out of six patients. One patient had a largely necrotic main tumor with very few mitoses and another nodule with 25 mitoses per 2 mm2, qualifying for the 2021 WHO diagnosis of large cell neuroendocrine carcinoma (LCNEC). In our patients, the 5-year survival of the TNET patients was 62.5% and 10-year survival 31.3%. CONCLUSION: In this study, TNETs were observed in one large MEN1 founder pedigree, where an anticipation-like earlier disease onset was observed in the most recent generation. TNET in MEN1 patients is an aggressive disease. The prognosis can be better by systematic screening. We also show that LCNEC can be associated with TNET in MEN1 patients.

Minimized and conventional cardiopulmonary bypass damage intestinal mucosal integrity.

OBJECTIVES: Previous studies have suggested that gastrointestinal integrity is compromised after cardiopulmonary bypass (CPB). We compared the effects of prolonged minimized (MCPB) and conventional CPB (CCPB) on intestinal mucosal integrity by determining mucosal damage, epithelial cell proliferation rate and distribution of tight junction proteins in a porcine model. DESIGN: Fourteen animals were randomly assigned to undergo 240 minutes of mild hypothermic MCPB or CCPB. Ileal and colonic biopsies were obtained prior and at the end of CPB. Mucosal damage was determined under light microscopic evaluation. Immunohistochemistry was used to investigate epithelial expression of Ki-67 as a measure of cell proliferation rate and claudin-1, 2, 3, 4, 5, and 7 as elements of tight junctions. RESULTS: In colonic biopsies, independent of the circuit type used, moderate mucosal damage was observed as indicated by focal epithelial damage, increased epithelial cell proliferation and decreased expression of tight junction protein claudin-4. CONCLUSIONS: Colonic mucosal damage was observed similarly in MCPB and CCPB. Based on these results, the effects of MCPB on intestinal mucosal stability are similar to those of CCPB.

Leukocyte filter enhances neutrophil activation during combined aortic valve and coronary artery bypass surgery.

OBJECTIVE: Cardiopulmonary bypass-induced systemic inflammatory reaction involving the expression of neutrophil surface adhesion molecules is the main mechanism leading to myocardial ischemia-reperfusion injury as well as multiorgan dysfunction. Patients undergoing prolonged cardiopulmonary bypass are especially at risk in this regard. The aim of this prospective, randomized study was to evaluate the impact of continuous leukocyte filtration on the perioperative expression of neutrophil adhesion molecules along with the markers of systemic inflammation during combined coronary artery revascularization and aortic valve surgery due to aortic stenosis. PATIENT AND METHODS: Twenty patients scheduled for combined coronary artery revascularization and aortic valve surgery due to aortic stenosis were randomized to undergo cardiopulmonary bypass with or without a leukocyte filter (LeukoGuard LG6). The expression of neutrophil adhesion molecules and proinflammatory cytokine response were measured. RESULTS: The use of the leukocyte filter significantly increased neutrophil CD11b expression (Pg = .003) compared to the control group, which was followed by a faster rise in interleukin-6 levels 5 minutes (median, 125 versus 34 pg/mL) and 2 hours after cardiopulmonary bypass (median, 158 versus 92 pg/mL, Pt x g < .001), respectively. No marked differences in terms of levels of CD11a, CD62L, cardiac troponin-I, or oxyhemodynamics were observed. CONCLUSIONS: The observed increased neutrophil activation and enhanced inflammatory response do not support the use of continuous leukofiltration in patients undergoing prolonged cardiopulmonary bypass.

Prolonged mild hypothermia after experimental hypothermic circulatory arrest in a chronic porcine model.

OBJECTIVES: We sought to evaluate the potential efficacy of prolonged mild hypothermia after hypothermic circulatory arrest. METHODS: Twenty pigs, after a 75-minute period of hypothermic circulatory arrest, were randomly assigned to be rewarmed to 37 degrees C (normothermia group) or to 32 degrees C and kept at that temperature for 14 hours from the start of rewarming (hypothermia group). RESULTS: The 7-day survival was 30% in the hypothermia group and 70% in the normothermia group (P =.08). The hypothermia group had poorer postoperative behavioral scores than the normothermia group. Prolonged hypothermia was associated with lower oxygen extraction and consumption rates and higher mixed venous oxygen saturation levels during the first hours after hypothermic circulatory arrest. Decreased cardiac index, lower pH, and higher partial pressure of carbon dioxide were observed in the hypothermia group. There was a trend for beneficial effect of prolonged hypothermia in terms of lower brain lactate levels until the 4-hour interval and of intracranial pressure until the 10-hour interval. Postoperatively, total leukocyte and neutrophil counts were lower, and creatine kinase BB was significantly increased in the hypothermia group. At extubation, the hypothermia group had higher oxygen extraction rates and lower brain tissue oxygen tension. CONCLUSIONS: A 14-hour period of mild hypothermia after 75-minute hypothermic circulatory arrest seems to be associated with poor outcome. However, the results of this study suggest that mild hypothermia may preserve its efficacy when it is used for no longer than 4 hours, but the potentials of a shorter period of postoperative mild hypothermia still require further investigation.

Potential neuroprotective benefits of erythropoietin during experimental hypothermic circulatory arrest.

OBJECTIVE: Recent studies have shown that erythropoietin protects neurons from glutamate toxicity and ischemia. This study was performed to evaluate the potential neuroprotective effect of erythropoietin during experimental hypothermic circulatory arrest. METHODS: Twenty pigs were randomized to receive intravenously either 500 IU/kg recombinant human erythropoietin or saline before a 75-minute period of hypothermic circulatory arrest at an intracerebral temperature of 18 degrees C. RESULTS: After the administration of erythropoietin, its concentration in the cerebrospinal fluid increased 4.5-fold 8 hours after the start of rewarming, whereas it did not increase in control animals. The 7-day survival rate was 60% in the erythropoietin group and 70% in the control group (P = 1.0). No significant differences were observed between the study groups in terms of electroencephalography, behavioral score, and histopathologic score. The erythropoietin group had higher vascular resistance and mean arterial pressure values, lower intracerebral concentrations of glutamate and glycerol, higher brain tissue oxygen tension, and lower apoptotic index. CONCLUSIONS: Administration of 500 IU/kg erythropoietin intravenously before hypothermic circulatory arrest was followed by an increased erythropoietin concentration in the cerebrospinal fluid. Although previous studies have demonstrated neuroprotective effects of erythropoietin during brain ischemia, the present study, using a chronic porcine model, failed to show any significant benefit after administration of erythropoietin in terms of mortality or brain histopathology. Lower intracerebral concentrations of glutamate and glycerol, higher brain tissue oxygen tension, and lower apoptotic index observed in the erythropoietin group, however, suggest that a distinct neuroprotective effect of erythropoietin might be achieved at different dosages and timing of administration.

Postoperative atrial fibrillation is a major cause of stroke after on-pump coronary artery bypass surgery.

BACKGROUND: Atrial fibrillation, occurring after coronary artery bypass grafting (CABG), has been suggested to be associated with the development of postoperative stroke. However, it is not clear what is the incidence of atrial fibrillation-related postoperative stroke, the timing of its occurrence, and the outcome. These issues have been investigated in a consecutive series of patients who have undergone on-pump coronary artery bypass grafting (ONCAB). METHODS: Among 2,630 patients who underwent ONCAB, 52 patients (2.0%) experienced postoperative stroke and form the basis of the present study. RESULTS: Twelve patients (23.1%) died postoperatively. The ischemic cerebral event occurred after a mean of 3.7 days (range, 0 to 33). In 19 patients (36.5%), atrial fibrillation preceded the occurrence of neurologic complication. These patients experienced a mean of 2.5 episodes of atrial fibrillation before the occurrence of neurologic complication. The cerebrovascular event occurred after a mean of 6.0 days in patients in whom atrial fibrillation preceded it, after a mean of 1.2 days in those with calcified ascending aorta, and after a mean of 3.1 days in those without calcified ascending aorta or in whom atrial fibrillation did not precede the cerebrovascular complication (p < 0.0001). Stroke occurred a mean of 21.3 hours after atrial fibrillation. CONCLUSIONS: This study confirmed that atrial fibrillation, occurring after CABG, is a major determinant of postoperative stroke. Prevention of postoperative atrial fibrillation, and of formation of clots into the left atrium, may dramatically reduce the risk of postoperative stroke.

Lamotrigine plus leukocyte filtration as a neuroprotective strategy in experimental hypothermic circulatory arrest.

BACKGROUND: Lamotrigine and leukocyte filtration seem to improve cerebral protection during experimental hypothermic circulatory arrest (HCA). This study was performed to evaluate whether their combined use may further improve cerebral protection. METHODS: Twenty-four pigs undergoing 75-minute period of HCA at 20 degrees C were randomly assigned to receive saline; lamotrigine (20 mg/kg) before HCA (L); or lamotrigine (20 mg/kg) before HCA plus leukocyte filtration before and after HCA (L + LF). RESULTS: Seven animals (87%) in the L + LF group, 4 (50%) in the L group, and 3 (37%) in the control group were alive on the seventh postoperative day. The median electroencephalogram burst recovery was 94% in the L + LF group (p = 0.024 versus control group), 81% in the L group, and 64% in the control group. Among the surviving animals, the median behavioral scores were 9, 9, and 6 at the seventh day, respectively (p = 0.005 between the L + LF group and the control group). The median histopathologic score was 14 in the L + LF group (p = 0.046 versus control group), 14.5 in the L group (p = 0.062 versus control group), and 21 in the control group. CONCLUSIONS: Lamotrigine has neuroprotective effect during HCA. The combined use of lamotrigine and LF may further improve the survival outcome.

Topical head cooling during rewarming after experimental hypothermic circulatory arrest.

BACKGROUND: The aim of this study was to evaluate the potential neuroprotective effect of topical head cooling during the first 2 postoperative hours after experimental hypothermic circulatory arrest. METHODS: Twenty pigs underwent a 75-minute period of hypothermic circulatory arrest and were randomly assigned to rewarming to 37 degrees C or to undergo topical cooling of the head for 2 hours from the start of rewarming followed by a period of external rewarming to 37 degrees C. RESULTS: The 7-day survival rate was 70% in the control group and 60% in the topical head cooling group. Despite brain tissue oxygenation, intracranial pressures, mixed oxygen venous saturation, oxygen consumption, and extraction tended to be favorable in the topical head cooling group as a clear effect of mild hypothermia. The latter group had significantly higher postoperative brain lactate and pyruvate ratios, and lactate and glucose ratios. Furthermore, the topical head cooling group had worse fluid balance throughout the postoperative period. Brain histopathologic scores were comparable with the study groups, but among 7-days survivors these scores tended to be worse in the topical head cooling group. CONCLUSIONS: Topical cooling of the head during the first 2 postoperative hours after experimental hypothermic circulatory arrest does not appear to provide any neuroprotective effect.

Minimized cardiopulmonary bypass reduces retinal microembolization: a randomized clinical study using fluorescein angiography.

BACKGROUND: The use of minimized cardiopulmonary bypass (MCPB) circuits has recently increased in an attempt to reduce the adverse effects of CPB. This prospective randomized study aimed to determine the effects of MCPB on retinal microembolization and related inflammatory, coagulation, and endothelial markers compared with conventional extracorporeal circulation (CCPB) among patients undergoing coronary artery bypass graft surgery. METHODS: Forty patients entered, and 37 patients completed the study. After the induction of anesthesia and immediately after the termination of CPB, standardized retinal fluorescein angiographs and digital images were obtained on both eyes and analyzed in a blinded fashion in terms of the CPB circuit. Blood samples for inflammatory, coagulation, and endothelial markers were collected at eight time points until the third postoperative day. RESULTS: Postperfusion retinal fluorescein angiographs revealed microembolic perfusion defects in 2 of 18 in the MCPB group and in 9 of 18 in the CCPB group (p=0.027 [11% vs. 50%, difference 39%, confidence interval: 0.087 to 0.613, p=0.029]). Activation of polymorphonuclear leukocytes as measured with polymorphonuclear elastase was significantly decreased in the MCPB group. Other markers of inflammation, coagulation, and endothelial dysfunction increased comparably in both groups during CPB. CONCLUSIONS: Retinal microembolization was found to be decreased after the use of minimized CPB compared with CCPB, suggesting a decreased embolic load to the brain after MCPB.

Bone marrow-derived mononuclear cell transplantation improves myocardial recovery by enhancing cellular recruitment and differentiation at the infarction site.

OBJECTIVE: Stem cell therapy in myocardial infarction is under intensive investigation; however, the mechanisms of recovery and the optimal transplantation technique remain controversial. The goal of this controlled and randomized study was to test the hypothesis that locally injected bone marrow-derived mononuclear cells can focus in on the damaged myocardium and improve cardiac function by means of active participation in remodeling. METHODS: Myocardial infarction was introduced through occlusion of the circumflex coronary artery for 90 minutes in 14 piglets (24.0 +/- 4.9 kg) that were randomized to a cell-therapy group (n = 7) and a control group (n = 7). At reperfusion, autologous purified prelabeled or unlabeled cells (10(8) cells/2 mL) or saline were injected into the myocardium. Cardiac function was measured by using echocardiography preoperatively and postoperatively and at 3 weeks, when hearts were collected for histopathologic examination. RESULTS: The ejection fraction recovered in the cell-therapy group (P = .02) but failed to recover in the control group, and at 3 weeks, it remained at the lower level compared with that in the cell-therapy group (P = .067). The number of living cells in the necrotic area was significantly greater in the cell-therapy group (P < .001). Labeled cells were detected in the infarcted area, and they showed signs of myocyte differentiation. Furthermore, the proportional area of muscle actin-positive cells at the granulation area was higher in the cell-therapy group (P = .035). CONCLUSIONS: Autologous bone marrow-derived mononuclear cells at the infarcted area localize in the myocardium. The exact mechanism of recovery remains to be determined, but our findings may give new information concerning the cellular events that occur during cell therapy-enhanced recovery.

Population-based audit of fresh-frozen plasma transfusion practices.

BACKGROUND: In contrast to decreasing red blood cell (RBC) consumption in Finland, the use of fresh-frozen plasma (FFP) has been increasing since the 1990s, suggesting that FFP use may not always be optimal. To improve transfusion practices, knowledge of current FFP use and regional, national, and international comparison is necessary. STUDY DESIGN AND METHODS: Nine (of 21) Finnish hospital districts participated. Data concerning FFP-transfused patients in the years 2002 and 2003 were collected from existing computerized medical records into a yearly updated database as part of a Finnish benchmarking project on blood component use. RESULTS: Data included 11,590 FFP-transfused patients and 60,240 FFP units (71.2% of Finnish FFP use) delivered to Finnish hospitals during the study period. FFP was transfused most often to surgery patients (62.8% of FFP transfusion hospital visits) with blood circulatory system problems (32.3% of surgically treated and FFP-transfused patients). In only 65.9 percent of FFP-transfused patients were coagulation variables measured at any point in the hospital episode, and FFP was usually transfused in paired doses. Mean FFP use in Finland is comparable to other countries. CONCLUSION: Although overall FFP use in Finland is similar to that of international figures, it does not ensure best practice. Perioperative staff, being the largest FFP user, should be encouraged to dose FFP based on coagulation variables and body weight. Improvement efforts should be directed to patient groups transfused with large amounts of FFP.

Leukocyte depleting filter attenuates myocardial injury during elective coronary artery bypass surgery.

BACKGROUND: Ischemia-reperfusion injury secondary to leukocyte activation has been widely recognized as one of the most relevant mechanism leading to postoperative organ dysfunction occurring after a period of ischemia. The aim of the present study was to evaluate in a prospective, randomized study, the value of leukocyte depleting filter in patients undergoing elective coronary artery bypass surgery. METHODS: Twenty patients scheduled for elective on-pump coronary artery bypass surgery were randomized to undergo cardiopulmonary bypass either with a leukocyte depleting filter incorporated in the extracorporeal circulation arterial line or without a filter. RESULTS: The main finding of this study was the significantly lower postoperative concentrations of cardiac troponin I in the leukocyte filter group (Tests of between-subjects effects: p = 0.024). There were also slightly better cardiac indices in the leukocyte filter group. A larger amount of blood units was infused intra- and postoperatively in patients undergoing cardiopulmonary bypass with leukocyte filtration (median, 600 [IQR, 0-1200] vs. 0 [IQR, 0-600], p = 0.08). Two patients in the leukocyte filter group underwent reoperation for bleeding but none in the control group (p = 0.48). Intra-and postoperative platelet count was lower in the leukocyte filter group (Tests of between-subjects effects: p = 0.08). Despite a significant increased concentration of C-reactive protein on the first postoperative day in the control group (p = 0.029), repeated-measures analysis failed to show any significant increase during the study period (p = 0.33). CONCLUSIONS: The results of this study suggest a myocardial protective effect of leukocyte filter in the setting of elective coronary artery bypass surgery.

EEG burst recovery is predictive of brain injury after experimental hypothermic circulatory arrest.

OBJECTIVE: To evaluate whether electroencephalography (EEG) recovery could be considered a reliable marker of brain injury after experimental hypothermic circulatory arrest (HCA). DESIGN: Cortical electrical activity was registered before and after a 75-min period of HCA in 27 pigs that survived 7 days after the experiment. The sum of EEG bursts was counted as a percentage of the sum of artifact-free bursts and suppressions, and this percentage was used as a measure of EEG activity in the analysis. RESULTS: Brain infarction developed in 13 animals (48.1%), in 12 cases (44.4%) having involved the cortex, in 1 case the thalamus (3.7%) and in another the hippocampus (3.7%). The mean EEG burst percentage significantly correlated with the total brain histopathological score (rho = -0.588, P = 0.001). EEG burst percentage from the 2 h 20 min to the 7 h 20 min interval correlated with the total brain histopathological score and with the cortex, brainstem and cerebellum scores. The mean EEG burst percentage rate was higher, but not significantly, among the animals without brain infarction (38.5% vs 32.4%), but such a difference was significant at the 3 h 20 min postoperative interval (P = 0.02). The mean EEG burst percentage significantly correlated with brain glucose concentration at the 1 h interval (rho = 0.387; P = 0.046), brain lactate concentration at the 2 h interval (rho = -0.431; P = 0.025), and the brain lactate/glucose ratio at the 1 h 30 min interval from the start of rewarming (rho = -0.433; P = 0.024). CONCLUSION: A decreased EEG burst percentage seems to be associated with an increased risk of developing histologically evident brain ischemic injury in the cortex, brainstem and cerebellum after experimental HCA.

Increase of intracranial pressure after hypothermic circulatory arrest in a chronic porcine model.

OBJECTIVE: An increase in intracranial pressure has been shown to threaten the outcome of patients with ischemic or traumatic brain injury. Its impact on the outcome of pigs undergoing hypothermic circulatory arrest has been evaluated in this study. DESIGN: Fifty-six pigs underwent a 75-min period of hypothermic circulatory arrest at 20 degrees C. Intracranial pressure, cerebral microdialysis, hemodynamic and metabolic parameters were monitored throughout the experiment. The animals were allowed to survive until the 7th postoperative day and, then, electively killed. RESULTS: The 7-day survival rate was 60.7%, and among survivors, 20 of them (58.8%) developed brain infarction. A significant increase in intracranial pressure as compared with the baseline level was observed since the end of cooling (p = 0.047) and the difference became larger during all the postoperative intervals (p < 0.0001). Animals that died postoperatively tended to have higher intracranial pressure levels during all the postoperative intervals, but such a difference reached significance only at the 4-h postoperative interval (p = 0.040). The same tendency was observed among animals that survived until the 7th postoperative day and that developed brain infarction or not, but the difference between these two groups did not reach statistical significance. The animals that died or developed postoperatively brain infarction had higher intracranial pressure values postoperatively as compared with those that survived without developing brain infarction and such a difference reached significance at the 2-h (p = 0.015) and 4-h postoperative intervals (p = 0.035). The peak intracranial pressure was 17.2 mmHg (IQR, 13.7-20.8) in animals that died or developed brain infarction and 14.1 mmHg (IQR, 11.8-16.4) in those that survived 7 days without developing brain infarction (p = NS). CONCLUSION: Intracranial pressure increases significantly after 75 min of experimental hypothermic circulatory arrest and such an increase is associated with a high risk of postoperative death and brain infarction.