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Biomedical subjects

T Foitzik

Publications and source records attributed to T Foitzik.

65 records · Page 4Linked to original sources
PubMed1993

Isovolemic hemodilution with dextran 60 as treatment of pancreatic ischemia in acute pancreatitis. Clinical practicability of an experimental concept.

OBJECTIVE: This phase-I study transferred the concept of isovolemic hemodilution, which has been proven beneficial in the treatment of experimental acute pancreatitis to the patient. SUMMARY BACKGROUND DATA: Pancreatic ischemia represents one main mechanism in the pathogenesis of necrotizing pancreatitis. Isovolemic hemodilution with dextran 60 has been shown experimentally to limit the progression of pancreatic necrosis by improving pancreatic microcirculation. METHODS: Thirteen patients with clinically severe nonbiliary pancreatitis and CT-classification E according to Balthazar were enrolled. Exclusion criteria were anemia, coronary heart disease, chronic obstructive pulmonary disease, coagulopathies, and secondary referral. The volume of blood to be exchanged for dextran 60 was calculated from a nomogram based on body surface. Isovolemic hemodilution aimed at a hematocrit of 30%. Independent from the exchange procedure conventional fluid resuscitation was performed to adjust the central venous pressure at 6 +/- 2 mm Hg. RESULTS: Whole blood (750-1,700 mL) was exchanged for dextran 60 during 45 to 70 minutes. No adverse effect was encountered; central hemodynamics were not affected. Considering a mean Ranson score of 5, mortality was low (7.7%). Progression of pancreatic necrosis was registered in only two patients subsequently undergoing surgical treatment (15%). CONCLUSIONS: Isovolemic hemodilution is practicable in patients. A randomized trial has to prove whether isovolemic hemodilution can substantially alter the course of acute pancreatitis as anticipated from animal studies.

Acute Disease↗
PubMed1991

[The value of classification for therapy and prognosis of acute pancreatitis. Analysis of a patient sample of the Heidelberg Surgical University Clinic 1986-1989].

116 patients admitted for acute pancreatitis were analysed. In 80% of patients presenting biliary pancreatitis cholecystectomy and bile duct exploration was the prevalent treatment, in 7.8% pancreatic necrosis was removed. Indications to operate on patients with non-biliary pancreatitis included enhancement of pancreatic inflammation revealed by computed tomography and multi-organ-failure or sepsis complicating the course of the disease (incidence of laparotomy 20.3%, incidence of necrosectomy 12.3%). According to this concept 2 out of 3 patients presenting partial pancreatic necrosis recovered without operation. Lethality of patients with acute necrotizing pancreatitis (6.9%) was accounted 25%, over-all mortality 6%. Methods used for classification of severity of acute pancreatitis (Mainz classification, Ranson criteria) turned out to be not reliable. Clinical staging of pancreatitis was not in accordance with intraoperative findings in 51.9% of cases. As a prerequisite for stage-dependent therapy new objective data to access severity and clinical course of acute pancreatitis have to be worked out.

Acute Disease↗
PubMedDate not supplied

Minitracheotomy: a new interventional technique for treatment of sputum retention.

Sputum retention causing pulmonary atelectasis, secondary pneumonia, and respiratory failure is a frequent complication particularly in patients recovering from abdominal and thoracic surgery. Physiotherapy and conventional therapeutic means like blind tracheobronchial and bronchoscopic suction applied to prevent and treat postoperative respiratory complications have been shown to not be completely effective. Minitracheotomy is a new alternative method for the treatment of sputum retention. Endobronchial suction can be performed as often as required, using a thin uncuffed tube (ID 4.5 mm) which is inserted into the trachea through the cricothyroid membrane under local anaesthesia. Since respiration occurs normally through the nose, mouth, and larynx these patients retain speech and the ability to cough. Complications are rare. Endobronchial suction via minitracheotomy is minimally invasive, more comfortable, and at least as effective as conventional bronchoscopic suction. It therefore has become a routine method used in the treatment of postoperative sputum retention in high-risk patients in many intensive-care units.

Humans↗
PubMedDate not supplied

Glutamine stabilizes intestinal permeability and reduces pancreatic infection in acute experimental pancreatitis.

Intestinal barrier failure and subsequent translocation of bacteria from the gut play a decisive role in the development of systemic infections in severe acute pancreatitis. Glutamine (GLN) has been shown to stabilize gut barrier function and to reduce bacterial translocation in various experimental settings. The aim of this study was to evaluate whether GLN reduces gut permeability and bacterial infection in a model of acute necrotizing pancreatitis. Acute necrotizing pancreatitis was induced in 50 rats under sterile conditions by intraductal infusion of glycodeoxycholic acid and intravenous infusion of cerulein. Six hours after the induction of pancreatitis, animals were randomly assigned to one of two groups: standard total parental nutrition (TPN) or TPN combined with GLN (0.5 g/kg(-1)/day(-1)). After 96 hours, the animals were killed. The pancreas was prepared for bacteriologic examination, and the ascending colon was mounted in a Ussing chamber for determination of transmucosal resistance and mannitol flux as indicators of intestinal permeability. Transmucosal resistance was 31% higher in the animals treated with GLN- supplemented TPN compared to the animals given standard TPN. Mannitol flux through the epithelium was decreased by 40%. The prevalence of pancreatic infections was 33% in animals given GLN-enriched TPN as compared to 86% in animals receiving standard TPN (P < 0.05). Adding GLN to standard TPN not only reduces the permeability of the colon but decreases pancreatic infections in acute necrotizing pancreatitis in the rat. This confirms previous reports that GLN decreases bacterial translocation by stabilizing the intestinal mucosal barrier. The present findings provide the first evidence suggesting that stabilizing the intestinal barrier can reduce the prevalence of pancreatic infection in acute pancreatitis and that GLN may be useful in preventing septic complications in clinical pancreatitis.

Acute Disease↗
PubMedDate not supplied

Therapy for microcirculatory disorders in severe acute pancreatitis: comparison of delayed therapy with ICAM-1 antibodies and a specific endothelin A receptor antagonist.

Many of the complications in severe acute pancreatitis result from the amplifying effects of microcirculatory disruption. The pathogenesis of these microcirculatory disorders is multifactorial and involves various vasoactive mediators. Thus questions arise as to which vasoactive mediators are most important and how long after the onset of disease vasoactive mediator blockade may be effective. The present study compares the effect of delayed therapy with two vasoactive mediator antagonists, previously tested with promising results in other studies in a well-established rodent model of severe acute pancreatitis. Twelve hours after induction of acute pancreatitis, rats were randomized to therapy with intracellular adhesion molecule-1 (ICAM-1) antibody (2 mg/kg IA-29), endothelin A receptor antagonist (ET-RA) (40 mg/kg LU 135252), or saline solution (volume equivalent). After 12 hours of fluid resuscitation, animals underwent repeat laparotomy for intravital microscopic determination of capillary blood flow, leukocyte rolling, and capillary permeability in the pancreas and colon. Other measurements included cardiorespiratory parameters, hematocrit, pleural effusions, ascites, urine production, and survival. Compared to saline treatment, both ICAM antibody and ET-RA significantly enhanced capillary blood flow in the pancreas and colon, reduced leukocyte rolling, and stabilized capillary permeability. These beneficial effects on microcirculation were associated with decreased fluid loss into the third space and improved renal function and survival. Although both antagonists likewise enhanced capillary blood flow and reduced leukocyte rolling, ET-RA was significantly more effective than ICAM antibody in counteracting capillary leakage, thereby further reducing fluid sequestration. The present study confirms the beneficial effects of endothelin and ICAM antagonists in severe acute pancreatitis, even with delayed therapy, suggesting that both compounds are candidates for further clinical testing. Selective endothelin A receptor blockade appears to be especially attractive for clinical use not only because it was superior to ICAM antibody in the present study but also because of its favorable pharmacologic properties and (preliminary) positive results in clinical phase 2 studies currently underway for other diseases.

Acute Disease↗
PubMedDate not supplied

Angiogenesis inhibitor TNP-470 reduces human pancreatic cancer growth.

In this study we investigated the effects of the angiogenesis inhibitor TNP-470 on human pancreatic cancer cells in vitro and in vivo. The action of TNP-470 on vascular endothelial growth factor (VEGF) was also assessed. In vitro human pancreatic cancer cells (MIAPaCa-2, AsPC-1, and Capan-1), and human umbilical vein endothelial cells (HUVEC) were exposed to increasing concentrations (1 pg/ml to 100 microg/ml) of TNP-470. Cell proliferation was assessed after 3 days by cell count and MTT assay. In vivo, 5 x 10(6) pancreatic cancer cells were injected subcutaneously into nude mice. Four weeks later, 1 mm3 fragments of the resulting tumors were implanted into the pancreas of other mice. Animals received either TNP-470 (30 mg/kg every other day) or vehicle subcutaneously for 14 weeks. The volume of the primary tumor and metastatic spread were determined at autopsy. Concentrations of VEGF were determined in serum (VEGF(S)) and ascites (VEGF(A)) by enzyme-linked immunosorbent assay. Microvessel density was analyzed by immunohistochemistry in CD31-stained tumor sections. In vitro, proliferation and viability of the human pancreatic cancer cell lines were significantly inhibited at high concentrations of TNP-470 (> 1 microg/ml). In contrast, TNP-470 effectively decreased the growth of HUVEC at 100 pg/ml. In vivo, tumor volume and dissemination scores were significantly lower in all three pancreatic cancer cell lines. VEGF(S) and VEGF(A) were not different between treated groups. Treatment with TNP-470 significantly reduced neoangiogenesis in tumors of all three human pancreatic cancer cell lines: MIAPaCa-2 = 74.8 +/- 7.8/0.74 mm2 vs. 24.8 +/- 3.7/0.74 mm2; AsPC-1 = 65.3 +/- 5.0/0.74 mm2 vs. 26.0 +/- 3.4/0.74 mm2; and Capan-1 = 82.2 +/- 5.8/0.74 mm2 vs. 26.9 +/- 2.5/0.74 mm2 (P < 0.001). However, survival was not statistically different between groups. TNP-470 reduced tumor growth and metastatic spread of pancreatic cancer in vivo. This was probably due to the antiproliferative effect of the agent on endothelial cells rather than to the direct inhibition of pancreatic cancer cell growth. TNP-470 activity was not associated with alteration of VEGF secretion.

Adenocarcinoma↗
PubMedDate not supplied

Intestinal microcirculation and gut permeability in acute pancreatitis: early changes and therapeutic implications.

Translocation of bacteria from the intestine causes local and systemic infection in severe acute pancreatitis. Increased intestinal permeability is considered a promoter of bacterial translocation. The mechanism leading to increased gut permeability may involve impaired intestinal capillary blood flow. The aim of this study was to evaluate and correlate early changes in capillary blood flow and permeability of the colon in acute rodent pancreatitis of graded severity. Edematous pancreatitis was induced by intravenous cerulein; necrotizing pancreatitis by intravenous cerulein and intraductal glycodeoxycholic acid. Six hours after induction of pancreatitis, the permeability of the ascending colon was assessed by the Ussing chamber technique; capillary perfusion of the pancreas and colon (mucosal and subserosal) was determined by intravital microscopy. In mild pancreatitis, pancreatic capillary perfusion remained unchanged (2.13 c 0.06 vs. 1.98 +/-0.04 nl x min(-1) x cap(-1) [control]; P = NS), whereas mucosal (1.59 +/-0.03 vs. 2.28 +/-0.03 nl x min(-1) x cap((-1))[control]; P <0.01) and subserosal (2.47 +/-0.04 vs. 3.74 +/-0.05 nl x min(-1) x cap((-1))[control]; P <0.01) colonic capillary blood flow was significantly reduced. Severe pancreatitis was associated with a marked reduction in both pancreatic (1.06 +/-0.03 vs. 1.98 +/-0.04 nl x min(-1) x cap(-1) [control]; P <0. 01) and colonic (mucosal: 0.59 +/-0.01 vs. 2.28 +/-0.03 nl x min(-1) x cap((-1))[control], P <0.01; subserosal: 1.96 +/-0.05 vs. 3.74 +/-0.05 nl x min(-1) x cap(-1) [control], P <0.01) capillary perfusion. Colon permeability tended to increase with the severity of the disease (control: 147 +/-19 nmol x thr(-1) x cm(-2); mild pancreatitis: 158 +/-23 nmol x hr(-1) x cm(-2); severe pancreatitis: 181 +/-33 nmol x hr(-1) x cm(-2); P = NS). Impairment of colonic capillary perfusion correlates with the severity of pancreatitis. A decrease in capillary blood flow in the colon, even in mild pancreatitis not associated with significant protease activation and acinar cell necrosis or impairment of pancreatic capillary perfusion, suggests that colonic microcirculation is especially susceptible to inflammatory injury. There was no significant change in intestinal permeability in the early stage of pancreatitis, suggesting a window of opportunity for therapeutic interventions to prevent the later-observed increase in gut permeability, which could result in improved intestinal microcirculation.

Acute Disease↗
PubMedDate not supplied

Endothelin-1 mediates the alcohol-induced reduction of pancreatic capillary blood flow.

Increased plasma endothelin-1 (ET-1) levels in rats after alcohol administration and increased endothelin receptor expression in the pancreas in chronic alcoholic pancreatitis have led to the hypothesis that ET-1 may play a critical role in the pathogenesis of ethanol-induced pancreatic injury through impairment of perfusion. To further test the hypothesis that ET-1 mediates an alcohol-induced reduction of pancreatic perfusion, the present study compares the effect of intravenous alcohol and ET-1 on pancreatic capillary blood flow (PCBF) and investigates whether endothelin receptor blockade prevents the alcohol-induced reduction in PCBF. Anesthetized rats were randomly assigned to receive one of the following: a 1-hour infusion of 2 g/kg alcohol or the volume equivalent of saline solution plus ET-1 (1.25 microgram/kg), a specific endothelin-A receptor antagonist (50 mg/kg), or saline solution (volume equivalent). The pancreas was exposed for intravital microscopy; PCBF was determined at the same location before the test solutions were given, after the infusion, and 1 hour thereafter. Alcohol and ET-1 significantly decreased PCBF from 2.0 nl/min/cap to 1.7 nl/min/cap. The reduction in PCBF was even more pronounced when alcohol and ET-1 were combined (1.5 nl/min/cap), whereas the ET receptor antagonist increased PCBF in saline-treated rats to 2.2 nl/min cap and maintained stable PCBF in alcohol-treated animals. The observation that PCBF is reduced by both alcohol and ET-1 and that the alcohol-induced reduction of PCBF can be aggravated by ET-1 and prevented by a specific endothelin-1 antagonist supports the hypothesis that ET-1 is the mediator of the alcohol-associated reduction of pancreatic perfusion.

Animals↗
PubMedDate not supplied

Therapy for microcirculatory disorders in severe acute pancreatitis: effectiveness of platelet-activating factor receptor blockade vs. endothelin receptor blockade.

Many of the complications of severe acute pancreatitis are the result of the amplifying effects of microcirculatory disruption. The factors causing microcirculatory disorders in acute pancreatitis involve vasoactive mediators such as platelet-activating factor (PAF) and endothelin-1 (ET) activated during the inflammatory response to pancreatic injury. To further evaluate the potential therapeutic role of specific receptor antagonists (RA) to these mediators, the present study compares the effect of PAF and ET receptor blockade on microcirculation and organ function in a well-established rodent model of severe acute pancreatitis. Six hours after acute pancreatitis induction, rats were randomized to therapy with ET-RA (50 mg/kg LU-135252), PAF-RA (82 microg/kg WEB-2170), or NaCl 0.9% (volume equivalent). After 18 hours of fluid resuscitation, animals were relaparotomized for intravital microscopic determination of capillary blood flow, leukocyte rolling, and capillary permeability in the pancreas and colon. Other measurements included cardiorespiratory parameters, hematocrit, pleural effusions, ascites, urine production, and survival. Compared to saline treatment both ET-RA and PAF-RA significantly improved capillary blood flow in the pancreas and colon, reduced leukocyte rolling, and stabilized capillary permeability. The beneficial effects of receptor antagonist treatment on microcirculation were associated with decreased fluid loss into the third space, improved renal and respiratory function, and survival. Although both receptor antagonists likewise improved capillary blood flow, ET-RA was significantly more effective in counteracting leukocyte rolling and capillary leakage, thereby further reducing fluid sequestration. The present study confirms the beneficial effects of PAf and ET receptor blockade on microcirculation inside and outside the pancreas, organ function, and survival when given at the early stage of severe pancreatitis. Because ET-RA was more effective in stabilizing capillary permeability and avoiding subsequent fluid loss into the third space, we propose that ET-RA should be tested in a clinical trial (either in comparison or in addition to PAF-RA).

Animals↗
PubMedDate not supplied

Pulmonary microcirculation in mild and severe experimental pancreatitis.

BACKGROUND: Research aimed at elucidating the pathogenesis of pancreatitis-associated lung injury and evaluating novel strategies for preventing respiratory complications in acute pancreatitis (AP) has not yet involved intravital microscopic (IVM) studies of pulmonary microcirculation in animals with severe disease. OBJECTIVE: To characterize and compare pulmonary microcirculation in severe/necrotizing (NP) and mild/edematous pancreatitis (EP) in the rat. METHODS: EP was induced by intravenous cerulein infusion (n = 10) and NP by a standardized intraductal infusion of glycodeoxycholic acid followed by intravenous cerulein (n = 10). After 24 h a left-sided thoracotomy was performed for IVM examination of pulmonary capillary blood flow, permeability, leukocyte sticking and the thickness of alveolar septi. Further measurements included monitoring of arterial blood gases and histological evaluation of lung injury. RESULTS: In animals with NP, histology revealed severe pulmonary edema together with clustering of polymorphonuclear leukocytes in pulmonary microvessels and alveoli. IVM showed a greater number (n) of leukocytes sticking on the endothelium of pulmonary capillaries (9.4 +/- 0.7 vs. 1.8 +/- 0.2 in healthy control animals) and increased capillary permeability (260 +/- 14 vs. 136 +/- 6% relative fluorescein intensity) while capillary blood flow was decreased (0.41 +/- 0.05 vs. 0.57 +/- 0.03 mm/s). In comparison, changes in EP were significantly less pronounced (flow 0.5 +/- 0.04 mm/s, permeability 156 +/- 4%, leukocyte sticking n = 4.6 +/- 0.7). CONCLUSIONS: These findings suggest that deterioration of pulmonary microcirculation in AP correlates with disease severity and that a model featuring NP may therefore be more suitable to further study pancreatitis-associated pulmonary injury.

Animals↗