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-l (ICAM-1) antibody (2 mg/kg b&29), endothelin A receptor antagonist (ET-RA) (40 mg/kg LU 135252), or saline solution (volume equivalent). After 12 hours of fluid resuscitation, animals under-went 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. Presented at the Fortieth Annual Meeting of The Society for Surgery of the Alimentary Tract, Orlando, Fla., May 16–19, 1999.     

Treatment of acute pancreatitis with beta-adrenergic agonist drugs

An increase in microvascular permeability may be important in the pathogenesis of acute pancreatitis. beta-adrenergic receptor agonist drugs are known to inhibit the increase in microvascular permeability induced by histamine and related vasoactive substances. These inflammatory mediators have been shown to be released during the course of experimental and human pancreatitis. We investigated the effect of isoproterenol and terbutaline sulfate on the development of acute edematous (AEP) and acute hemorrhagic (AHP) pancreatitis in a feline model of biliary pancreatitis. When given at the time of pancreatic insult, isoproterenol prevented the development of both AEP and AHP. Both isoproterenol and terbutaline sulfate reduced the severity of pancreatic inflammation, even when given up to 12 hours after the onset of AEP. Although neither drug was effective in treating established AHP, our findings suggest that, if given early in the course of the disease, they may be useful in preventing the progression of AEP to AHP.     

血管活性物质在急性胰腺炎微循环障碍中的作用

目的 探讨血管活性物质在急性胰腺炎微循环障碍中的作用。方法 采用文献回顾的方法,对涉及血管活性物质的代谢、受体,作用机理和在急性胰腺炎中所起作用的研究进行了综述。结果 缓激肽、内皮素、血小板活化因子、一氧化氮等在急性胰腺炎局部微循环障碍中起一定作用。但实验结果并不一致。结论 影响血管活性物质发挥其微血管效应的因素较多,其在急性胰腺炎局部微循环障碍中的作用值得进一步研究。     

Microcirculatory derangement and ischemia of the pancreas]

We present a review of the microvascular morphology of the pancreas and microstructure of the pancreatic lobule, and introduce our experimental results on pancreatic microcirculation following acute pancreatitis. Impairment of pancreatic microcirculation in the early phase of acute pancreatitis may play a key role in the progression of this disease. Possible contributory mechanisms include increased vascular permeability, reduced blood flow, leukocyte-endothelial cell interaction, and intravascular thrombus formation. We achieved direct-visualization and quantification of changes in microvascular permeability and leukocyte behavior in the pancreas with acute pancreatitis using an in vivo microscope system and off-line computer analysis. Bradykinin and oxygen radicals have been demonstrated to be involved in the increased vascular permeability in the early stage of cerulein pancreatitis. Gabexate mesilate (FOY) prevents the increase in vascular permeability, resulting in a decreased number of rolling leukocytes. Leukocyte adherence to the pancreatic microcirculation is a secondary event following permeability changes in acute pancreatitis. Leukocyte infiltration during aggravation of acute pancreatitis is mediated by leukocyte-endothelial cell interaction via leukocyte integrin CD11b/18. The diamino-pyridine derivative IS-741 inhibits the progression of pancreatic inflammation by down-regulating the expression of CD11b/18.     

Pancreatic microcirculation in acute pancreatitis

We present a review of the microvascular morphology of the pancreas and microstructure of the pancreatic lobule, and report our experimental results of the investigation of pancreatic microcirculation following acute pancreatitis. Impairment of pancreatic microcirculation in the early phase of acute pancreatitis may play a key role in the progression of this disease. Possible contributory mechanisms include increased vascular permeability, reduced blood flow, leukocyte-endothelial cell interaction and intravascular thrombus formation. Using an in-vivo microscope system and off-line computer analysis, we achieved direct visualization and quantification of changes in microvascular permeability and leukocyte behavior in pancreas with acute pancreatitis. Bradykinin and oxygen radicals have been demonstrated to be involved in the increase of vascular permeability in the early stage of caerulein pancreatitis. Leukocyte adherence to the vessels in the pancreatic microcirculation is a secondary event following permeability changes in acute pancreatitis. Leukocyte infiltration during exacerbation of acute pancreatitis is mediated by leukocyte-endothelial cell interaction via leukocyte integrin CD11b/18. Received for publication on Jan. 29, 1997; accepted on April 24, 1997     

Effect of ethanol on pancreatic interstitial pH and blood flow in cats with chronic pancreatitis.

OBJECTIVE: The objective of this study was to investigate the effects of ethanol on pancreatic blood flow and interstitial pH in chronic pancreatitis. BACKGROUND: Ethanol is known to contribute to the development of both acute and chronic pancreatitis. However, it is unclear how ethanol precipitates episodes of acute pancreatic inflammation in the setting of chronic pancreatitis. In a model of chronic pancreatitis in cats, it is known that pancreatic blood flow is abnormally low and decreases further after ethanol ingestion. Because it is possible that this reduction in blood flow might be damaging to the pancreas, we investigated the effects of ethanol on pancreatic interstitial pH, an index of pancreatic ischemia. METHODS: In normal cats and cats with obstructive chronic pancreatitis, pancreatic blood flow and interstitial pH were measured using the hydrogen gas clearance technique and pH microelectrode, respectively. RESULTS: In normal cats, intragastric, but not intravenous, ethanol reduced both pancreatic blood flow by 62% (p < 0.05) and interstitial pH (7.38 +/- 0.03 to 7.20 +/- 0.03, p < 0.05). In cats with chronic pancreatitis in which basal pancreatic blood flow was already only 60% of normal flow, both intragastric and intravenous ethanol decreased both pancreatic blood flow (intragastric, 40% decrease, p < 0.05; intravenous, 34% decrease, p < 0.05) and interstitial pH (intragastric, 7.24 +/- 0.04 to 7.08 +/- 0.04, p < 0.05; intravenous 7.20 +/- 0.08 to 7.07 +/- 0.07, p < 0.05). CONCLUSIONS: This profound decrease in pH, lasting up to 2 hours after ethanol exposure in the chronic pancreatitis animals, suggests the possibility of ischemic cellular damage to the pancreas. These findings may explain the pathogenesis of bouts of acute pancreatic inflammation after ethanol ingestion in the setting of chronic disease.     

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 μg/kg WEB-2170), or NaCl 0.9% (volume equivalent). After 18 hours of fluid resuscitation, animals were relaparototnized 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). Presented at the Thirty-Ninth Annual Meeting of The Society for Surgery of the Alimentary Tract, New Orleans, La., May 17–20, 1998.     

Disturbances of the microcirculation in acute pancreatitis

BACKGROUND: Severe acute pancreatitis is characterized by pancreatic necrosis, resulting in local and systemic inflammation. Pancreatitis affects both the systemic and pancreatic vasculature. This review focuses on the underlying processes involved in the changes of microvascular anatomy following acute pancreatitis. METHODS: A Medline/PubMed search (January 1966 to December 2005) with manual cross-referencing was conducted. All relevant articles investigating the pancreatic microcirculatory anatomy and the effect of pancreatitis on the microcirculation were included. RESULTS: The pancreas is susceptible to ischaemic insult, which can exacerbate acute pancreatitis. There is also increasing evidence of pancreatic and systemic microvascular disturbances in the pathogenesis of pancreatitis, including vasoconstriction, shunting, inadequate perfusion, and increased blood viscosity and coagulation. These processes may be caused or exacerbated by ischaemia-reperfusion injury and the development of oxygen-derived free radicals. CONCLUSION: Acute pancreatitis impairs the pancreatic and systemic microcirculation, which is a key pathological process in the development of severe necrotizing disease.     

The influence of ethanol on pancreatic blood flow in cats with chronic pancreatitis.

BACKGROUND. The mechanism by which ethanol predisposes to acute pancreatitis, especially in established chronic pancreatitis, is not known. Here we studied the effects of acute ethanol ingestion on pancreatic blood flow in chronic pancreatitis, a setting characterized by diminished basal blood flow to the pancreas. METHODS. Obstructive pancreatitis was created by partial duct ligation for 3 weeks in nine cats. Controls (n = 8) were not operated on. Blood flow was measured in anesthetized animals with a hydrogen gas clearance technique and an intraductal electrode. Pancreatic interstitial pressure, systemic and portal blood pressures, and serum ethanol levels were recorded, and pancreatic vascular resistance was calculated. Measurements were made before and for 2 hours after 20 cc of 40% (wt/vol) ethanol was instilled into the stomach. RESULTS. Basal flow was reduced in the obstructed pancreas to 51% of normal. Both groups showed an acute decrease in blood flow when ethanol was given. A more steep (50% of baseline) and a more prolonged (120 minutes) fall was observed in the pancreatitis group than in controls (31% and 60 minutes, respectively). The decline in blood flow correlated with increases in interstitial pressure and vascular resistance. CONCLUSIONS. Acute ethanol ingestion sharply reduces pancreatic blood flow, especially in glands with chronic pancreatitis.     

Evidence against a role for polymorphisms at tumor necrosis factor, interleukin-1 and interleukin-1 receptor antagonist gene loci in the regulation of disease severity in acute pancreatitis

BACKGROUND: Cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) and their endogenous antagonists such as IL-1 receptor antagonist (IL-1RA) are important mediators of disease severity in acute pancreatitis. Because the level of secretion of these cytokines is determined in part by genetic factors, the aim of this study was to examine the influence of genetically determined cytokine secretion upon disease severity in acute pancreatitis. METHODS: TNF (TNF-308, TNFB), IL-1beta, and IL-1 receptor antagonist (IL-1RA) genotypes were determined for 190 patients with acute pancreatitis and 102 healthy volunteers. To further assess the influence of genetic factors, the cytokine phenotype for TNF-alpha, IL-1beta, and IL-1RA was determined by using a whole blood culture technique in 51 patients after recovery. RESULTS: The distributions of TNF-308, TNFB, IL-1beta, and IL-1RA gene polymorphisms were similar in patients with mild or severe acute pancreatitis. Further, no difference in gene polymorphism frequencies was observed between patients with acute pancreatitis and healthy controls. With respect to phenotype, the secretion of TNF-alpha was similar in patients with previous mild and severe acute pancreatitis; however, the IL-1beta: IL-1RA ratio was significantly lower in patients with previous severe acute pancreatitis than in those with mild disease. CONCLUSIONS: Our observations suggest that genetic factors are not important in determining TNF-alpha secretion in patients with acute pancreatitis. However, a predetermined imbalance between IL-1beta and its antagonist IL-1RA would appear to exist in patients with severe acute pancreatitis, although the genetic basis for this altered relationship could not be determined.     

重症急性胰腺炎心脏损伤的发病机制

重症急性胰腺炎早期炎症介质使微循环血管通透性增加,组织间隙积液,胰腺组织水肿、坏死,腹腔内大量体液积蓄,二者导致有效循环血量急剧下降,回心血量下降.随着有效循环血量进行性下降,冠脉血流不足,心肌细胞缺血,心肌受到不同程度的损伤,心脏负担相对过重,心肌纤维被动拉长易位,导致心肌细胞膜的损伤.炎症介质连锁反应和放大效应使机体大量释放细胞因子如TNF-α、细胞介素、氧自由基等活性物质,导致心肌细胞的完整性受损,心肌细胞凋亡,心脏功能障碍甚至衰竭.此外,腹腔间隔综合征、胰腺炎相关性腹水、电解质紊乱等也是参与其发生的重要因素.     

Renal function in experimentally induced acute pancreatitis in dogs: How it is affected by the nephrotoxic substance in pancreatic exudate from ascitic fluid

Renal failure occurring in dogs during experimental acute pancreatitis and the effect on renal function of intravenous injections of ascitic fluid which accumulated during the acute pancreatitis were studied. Five hours after the induction of acute pancreatitis, the accumulation of 200 to 400 ml of ascitic fluid, and an elevation in hematocrit as well as a decreased mean arterial pressure were observed, which suggested hypovolemia due to plasma loss. At the same time, the renal blood flow, glomerular filtration rate, and urinary output decreased significantly. Hypovolemia was observed to be the main cause of renal failure in accordance with previous reports. When the sterile ascitic fluid was injected into healthy dogs, temporary hypotension was observed without changes in the hematocrit. However, the renal blood flow, glomerular filtration rate and urinary output decreased, together with an elevation in renal vascular resistance, even after the hypotension had returned to normal. This study shows that renal failure associated with acute pancreatitis occurred mainly as a direct result of hypovolemia but also that the sterile ascitic fluid contained nephrotoxic substances which were suspected to be unrelated to vasoactive substances or protease. Their removal is therefore necessary for the treatment and prevention of renal failure complicating acute pancreatitis.     

Renal function in experimentally induced acute pancreatitis in dogs: how it is affected by the nephrotoxic substance in pancreatic exudate from ascitic fluid

Renal failure occurring in dogs during experimental acute pancreatitis and the effect on renal function of intravenous injections of ascitic fluid which accumulated during the acute pancreatitis were studied. Five hours after the induction of acute pancreatitis, the accumulation of 200 to 400 ml of ascitic fluid, and an elevation in hematocrit as well as a decreased mean arterial pressure were observed, which suggested hypovolemia due to plasma loss. At the same time, the renal blood flow, glomerular filtration rate, and urinary output decreased significantly. Hypovolemia was observed to be the main cause of renal failure in accordance with previous reports. When the sterile ascitic fluid was injected into healthy dogs, temporary hypotension was observed without changes in the hematocrit. However, the renal blood flow, glomerular filtration rate and urinary output decreased, together with an elevation in renal vascular resistance, even after the hypotension had returned to normal. This study shows that renal failure associated with acute pancreatitis occurred mainly as a direct result of hypovolemia but also that the sterile ascitic fluid contained nephrotoxic substances which were suspected to be unrelated to vasoactive substances or protease. Their removal is therefore necessary for the treatment and prevention of renal failure complicating acute pancreatitis.     

Pathogenesis and mechanisms of pain in chronic pancreatitis

虽然慢性胰腺炎的病理已经十分清楚，但其早期的致病机制尚不明确。慢性胰腺炎的一般特点为纤维化，慢性炎症和胰腺实质的消失，这些特征会随着疾病的发展而逐渐出现，同时还伴有急性胰腺炎的症状。一些专家认为慢性胰腺炎继发于急性胰腺炎。另一些则认为慢性胰腺炎首先发生，急性胰腺炎则在此基础上发生。慢性胰腺炎所引起的疼痛可通过许多机制发生。增高的胰腺压力可干扰神经，影响血流，改变pH值，并引起有毒物质的潴留，激活动作电位。组织的破坏和炎症介质的释放可刺激传入神经。甚至，炎症可直接破坏神经，引起神经性疼痛。掌握疼痛在外周和中枢神经系统中的神经冲动传递路径才能找出减轻胰性疼痛的有效方法。疼痛可以通过内脏、迷走、脊神经和膈神经等外周神经传递。它也可通过脊髓的背侧神经束和脊髓丘脑束中继传递。因此寻找到新的治疗胰性疼痛的方法是可能的。     

Renal microcirculation in experimental acute pancreatitis of dogs--the effect of pancreatic protease inhibitor and dopamine

To understand the renal microcirculation in acute pancreatitis is important to know the pathophysiology of renal insufficiency frequently observed as one of multiple organ failures in severe acute pancreatitis. In mongrel dogs acute pancreatitis was experimentally introduced by autologous bile added trypsin injection into the pancreatic duct. The effect of new synthesized pancreatic protease inhibitor (PATM) and dopamine in a dose of 3mg/kg/hr and 10 micrograms/kg/min were investigated, respectively. In acute pancreatitis dogs, renal arterial blood flow and renal tissue blood flow immediately fell and gradually decreased in time course of experiment and renal vascular resistance increased from 2 hours after onset of pancreatitis. When pancreatic protease inhibitor (PATM) was infused in acute pancreatitis dogs, blood pressure and pulse pressure relatively preserved during the experiment. Renal blood flow and renal tissue blood flow were maintained during the first 1 hour and thereafter slightly decreased, however which was less than that of no PATM treated dogs. When dopamine was infused in acute pancreatitis dogs, blood pressure was maintained during the first 90 minutes thereafter remarkably decreased. Renal blood flow was maintained within 60 minutes, however it remarkably decreased at the end of the experiment. This study suggested that renal microcirculation was disturbed from early period of acute pancreatitis in dogs and pancreatic protease inhibitor (PATM) had a beneficial effect of maintain the renal microcirculation.     

A Nonpancreatic Source of the Proteolytic-enzyme Amidase and Bacteriology in Experimental Acute Pancreatitis

In previous studies of human and experimental acute pancreatitis, three main assumptions have been made. First, that the disease is due to activation of pancreatic proteolytic enzymes in the pancreas with resulting “autodigestion” of the gland. Second, that interstitial pancreatitis is a mild form of hemorrhagic pancreatitis into which it may progress, and third, that bacteria play little part, if any, in the initiation of the disease. These assumptions are now questioned. In the present study in dogs, levels of proteolytic enzymes in blood, thoracicduct lymph and peritoneal fluid were measured using benzoylarginine amide. Raised levels of amidase were found in hemorrhagic, but not with interstitial, pancreatitis, and biochemical examination of amidase suggested it was not a pancreatic protease, but with its broad specificity and stability derived from bacteria. Addition of antibiotic to the blind duodenal loop in hemorrhagic pancreatitis reduced the level of blood amidase, but Trasylol given intravenously did not, nor did it inhibit amidase in vitro. In all animals, histological examination was made of the pancreas at time of death. On bacteriology, it is concluded that experimental interstitial pancreatitis results from damage to the pancreatic duct system without infection, and haemorrhagic pancreatitis mainly from reflux of bacteria into the pancreatic ducts from the duodenum. Only bacteria such as Escherichia coli and Clostridium welchii that produce proteolytic enzymes and cytotoxins appear to be able to cause haemorrhagic pancreatitis, and these bacteria may explain the release of vasoactive polypeptides and the vascular effects. In hemorrhagic pancreatitis such bacteria were found in the pancreas, but none in interstitial pancreatitis. Evidence is given to suggest that pancreatic proteolytic enzymes are unlikely to cause the cell necrosis which is a pathological feature of hemorrhagic pancreatitis, and that “autodigestion” is likewise unlikely to be a cause of this condition. An extrapancreatic source of proteolytic enzymes from bacteria is now suggested in haemorrhagic pancreatitis, and more attention to bacteriology in human acute pancreatitis is urgently needed. Amidase levels were highest in peritoneal fluid, suggesting a rationale for peritoneal lavage in the treatment of acute pancreatitis, and it is unlikely that Trasylol can give any benefit. The assessment of treatment of acute pancreatitis will be unsatisfactory as long as the proportion of haemorrhagic to interstitial pancreatitis in any series is not known accurately.     

Microcirculatory derangements in acute pancreatitis

During the past decade, a considerable number of experimental studies have confirmed the hypothesis that microcirculatory derangements play a pivotal role in the pathogenesis of acute pancreatitis, including the process of conversion from edematous to necrotizing injury. Predominant microcirculatory disorders are nutritive capillary perfusion failure, with the consequence of prolonged focal hypoxia or anoxia, and inflammation-associated microvascular leukocyte recruitment, CD11b- and intercellular adhesion molecule (ICAM)-1-mediated leukocyte-endothelial cell interaction and loss of endothelial integrity, which may result in both edema formation and necrosis. A variety of proinflammatory mediators, such as oxygen radicals, leukotrienes, platelet-activating factor, and interleukins, but also bradykinin and endothelins, seem to be involved in triggering the manifestations of these microcirculatory disorders. In contrast, the anti-inflammatory interleukin-10, as well as nitric oxide, are thought to be capable of protecting from these pancreatitis-associated microvascular injuries. This knowledge may be encouraging for the development of novel therapeutic strategies, aiming at the attenuation of microcirculatory disorders, and, thus, preventing tissue injury in acute pancreatitis. Received: July 4, 2000 / Accepted: December 28, 2000     

Treatment of pancreatic pseudocysts.

According to the Atlanta classification an acute pseudocyst is a collection of pancreatic juice enclosed by a wall of fibrous or granulation tissue, which arises as a consequence of acute pancreatitis or pancreatic trauma, whereas a chronic pseudocyst is a collection of pancreatic juice enclosed by a wall of fibrous or granulation tissue, which arises as a consequence of chronic pancreatitis and lack an antecedent episode of acute pancreatitis. It is generally agreed that acute and chronic pseudocysts have a different natural history, though many reports do not differentiate between pseudocysts that complicate acute pancreatitis and those that complicate chronic disease. Observation--"conservative treatment"--of a patient with a pseudocyst is preponderantly based on the knowledge that spontaneous resolution can occur. It must, however, be admitted that there is substantial risk of complications or even death; first of all due to bleeding. There are no randomized studies for the management protocols for pancreatic pseudocysts. Therefore, today we have to rely on best clinical practice, but still certain advice may be given. First of all it is important to differentiate acute from chronic pseudocysts for management, but at the same time not miss cystic neoplasias. Conservative treatment should always be considered the first option (pseudocysts should not be treated just because they are there). However, if intervention is needed, a procedure that is well known should always be considered first. The results of percutaneous or endoscopic drainage are probably more dependent on the experience of the interventionist than the choice of procedure and if surgery is needed, an intern anastomosis can hold sutures not until several weeks (if possible 6 weeks).     

Pathophysiology of acute pancreatitis: Evaluation of the effects and mode of action of indomethacin in experimental pancreatitis in dogs

Prostaglandins are known to affect vascular flow and the inflammatory response. Since acute pancreatitis involves both of these phenomena, we undertook studies using anesthetized mongrel dogs to investigate changes in blood pressure, cardiac output and pancreatic arterial flow for 6 hr in both normal animals (10 dogs) and following induction of acute pancreatitis (15 dogs). Indomethacin (5 mg/kg), which inhibits synthesis of prostaglandins, was then injected intravenously, and the animals were subsequently monitored for 2 hr. Results showed: (1) A significant fall in pancreatic arterial flow, relative to cardiac output, over the first 6 hr of the disease in the acute pancreatitis animals (P < 0.001). (2) A further significant decrease in relative pancreatic arterial flow following indomethacin in these animals (P < 0.001). A similar reduction in pancreatic arterial flow was observed following indomethacin administration in the control animals (P < 0.001). Conclusions: (1) Relative pancreatic arterial flow falls during experimental acute pancreatitis. (2) Indomethacin reduces both basal and compromised pancreatic arterial flow in the anesthetized dog; this suggests that prostaglandins may participate in the maintainance of basal acid-compromised pancreatic blood flow in the anesthetized dog.     

Chronic resuscitation after trauma-hemorrhage and acute fluid replacement improves hepatocellular function and cardiac output.

OBJECTIVE: To determine whether prolonged (chronic) resuscitation has any beneficial effects on cardiac output and hepatocellular function after trauma-hemorrhage and acute fluid replacement. BACKGROUND DATA: Acute fluid resuscitation after trauma-hemorrhage restores but does not maintain the depressed hepatocellular function and cardiac output. METHODS: Male Sprague-Dawley rats underwent a 5-cm laparotomy (i.e., trauma was induced) and were bled to and maintained at a mean arterial pressure of 40 mmHg until 40% of maximal bleed-out volume was returned in the form of Ringer's lactate (RL). The animals were acutely resuscitated with RL using 4 times the volume of maximum bleed-out over 60 minutes, followed by chronic resuscitation of 0, 5, or 10 mL/kg/hr RL for 20 hours. Hepatocellular function was determined by an in vivo indocyanine green clearance technique. Hepatic microvascular blood flow was assessed by laser Doppler flowmetry. Plasma levels of interleukin-6 (IL-6) were determined by bioassay. RESULTS: Chronic resuscitation with 5 mL/kg/hr RL, but not with 0 or 10 mL/kg/hr RL, restored cardiac output, hepatocellular function, and hepatic microvascular blood flow at 20 hours after hemorrhage. The regimen above also reduced plasma IL-6 levels. CONCLUSION: Because chronic resuscitation with 5 mL/kg/hr RL after trauma-hemorrhage and acute fluid replacement restored hepatocellular function and hepatic microvascular blood flow and decreased plasma levels of IL-6, we propose that chronic fluid resuscitation in addition to acute fluid replacement should be routinely used in experimental studies of trauma-hemorrhage.