Inhibition of Intraluminal Pancreatic Enzymes With Nafamostat Mesilate Improves Clinical Outcomes After Hemorrhagic Shock in Swine

Kim, Hubert D.; Malinoski, Darren; Borazjani, Boris; Patel, Madhukar S.; Chen, Joseph; Slone, Johnathan A.; Nguyen, Xuan Mai T.; Steward, Earl; Schmid‐Schönbein, Geert W.; Hoyt, David B.

doi:10.1097/ta.0b013e3181da78b1

Cited by 8 publications

(8 citation statements)

References 23 publications

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“…In tandem with previous work demonstrating protection by gut pancreatic enzyme inhibition in experimental shock [3, 7, 17, 21, 27], these results further implicate digestive enzymes as a major mechanism in the pathogenesis of shock and the mucin layer as their principal deterrent. We propose that in shock, ischemia to the bowel results in an impairment in the proteolytically impermeable mucin layer with subsequent mucosal destruction by bowel pancreatic enzymes and deleterious systemic sequelae.…”

Section: Discussionsupporting

confidence: 82%

Impaired Small-Bowel Barrier Integrity in the Presence of Lumenal Pancreatic Digestive Enzymes Leads to Circulatory Shock

Kistler¹,

Alsaigh²,

Chang³

et al. 2012

Shock

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In bowel ischemia, impaired mucosal integrity may allow intestinal pancreatic enzyme products to become systemic and precipitate irreversible shock and death. This can be attenuated by pancreatic enzyme inhibition in the small bowel lumen. It is unresolved, however, whether ischemically-mediated mucosal disruption is the key event allowing pancreatic enzyme products systemic access, and whether intestinal digestive enzyme activity in concert with increased mucosal permeability leads to shock in the absence of ischemia. To test this possibility, the small intestinal lumen of non-ischemic rats was perfused for two hours with either digestive enzymes, a mucin disruption strategy (i.e., mucolytics) designed to increase mucosal permeability, or both, and animals were observed for shock. Digestive enzymes perfused included trypsin, chymotrypsin, elastase, amylase and lipase. Control (n=6) and experimental animals perfused with pancreatic enzymes only (n=6) or single enzymes (n=3 for each of the five enzyme groups) maintained stable hemodynamics. After mucin disruption using a combination of enteral N-acetylcysteine, atropine, and increased flow rates, rats (n=6) developed mild hypotension (p<0.001 compared to groups perfused with pancreatic enzymes only after 90 minutes) and increased intestinal permeability to intralumenally perfused FITC-dextrans-20kD (p<0.05) compared to control and enzyme-only groups, but there were no deaths. All animals perfused with both digestive enzymes and subjected to mucin disruption (n=6) developed hypotension and increased intestinal permeability (p<0.001 after 90 minutes). Pancreatic enzymes were measured in the intestinal wall of both groups subjected to mucin disruption, but not in the enzyme-only or control groups. Depletion of plasma protease inhibitors was found only in animals perfused with pancreatic enzymes plus mucin disruption, implicating increased permeability and intralumenal pancreatic enzyme egress in this group. These experiments demonstrate that increased bowel permeability via mucin disruption in the presence of pancreatic enzymes can induce shock and increase systemic protease activation in the absence of ischemia, implicating bowel mucin disruption as a key event in early ischemia. Digestive enzymes and their products, if allowed to penetrate the gut wall may trigger multiorgan failure and death.

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Section: Discussionsupporting

confidence: 82%

Impaired Small-Bowel Barrier Integrity in the Presence of Lumenal Pancreatic Digestive Enzymes Leads to Circulatory Shock

Kistler¹,

Alsaigh²,

Chang³

et al. 2012

Shock

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“…Irrespective of the particular (serine) protease inhibitor used, the mortality after shock is significantly reduced in these shock models (27). Animal mobility and responsiveness in the recovery phase after shock is also improved (60). Histologically, damage to the intestinal villi is significantly reduced, as well as injury to remote organs such as the lung, liver, and heart (27).…”

Section: Inhibition Of Digestive Protease Activitymentioning

confidence: 99%

Autodigestion

Altshuler

Kistler

Schmid‐Schönbein

2016

Shock

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There is currently no effective treatment for multiorgan failure following shock other than alleviation supportive care. A better understanding of the pathogenesis of these sequelae to shock is required. The intestine plays a central role in multiorgan failure. It was previously suggested that bacteria and their toxins are responsible for the organ failure seen in circulatory shock, but clinical trials in septic patients have not confirmed this hypothesis. Instead, we review here evidence that the digestive enzymes, synthesized in the pancreas and discharged into the small intestine as requirement for normal digestion, may play a role in multi-organ failure. These powerful enzymes are non-specific, highly concentrated and fully activated in the lumen of the intestine. During normal digestion they are compartmentalized in the lumen of the intestine by the mucosal epithelial barrier. However, if this barrier becomes permeable, e.g. in an ischemic state, the digestive enzymes escape into the wall of the intestine. They digest tissues in the mucosa and generate small molecular weight cytotoxic fragments such as unbound free fatty acids. Digestive enzymes may also escape into the systemic circulation and activate other degrading proteases. These proteases have the ability to clip the ectodomain of surface receptors and compromise their function; for example cleaving the insulin receptor causing insulin resistance. The combination of digestive enzymes and cytotoxic fragments leaking into the central circulation causes cell and organ dysfunction, and ultimately may lead to complete organ failure and death. We summarize current evidence suggesting that enteral blockade of digestive enzymes inside the lumen of the intestine may serve to reduce acute cell and organ damage and improve survival in experimental shock.

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“…Enteral treatment allows application of digestive enzyme inhibitors at concentrations that match the high concentrations of digestive enzymes inside the lumen of the intestine. The enteral administration of an enzyme inhibitor can be achieved by injection into an exposed intestine after an abdominal incision (14), or via infusion by a catheter (with an inflatable balloon) placed at the entry of the small intestine (24), or slow infusion into the intestine via a nasogastric tube in the lower part of the stomach (30). …”

Section: A New Opportunity: Inhibition Of Pancreatic Enzymes In the Lmentioning

confidence: 99%

“…2, 3) and attenuates inflammation in multiple shock models (including splanchnic artery occlusion, hemorrhagic and endotoxic shock) (2, 12, 18–20, 38–40) and can be demonstrated in multiple species (17, 24). Enteral blockade of digestive enzymes also significantly reduces the level of inflammatory markers in the intestine, liver, heart, lung and in the systemic circulation (14, 38) and attenuates plasma cytokine levels (19, 38).…”

Section: A New Opportunity: Inhibition Of Pancreatic Enzymes In the Lmentioning

confidence: 99%

The Autodigestion Hypothesis for Shock and Multi-organ Failure

Schmid‐Schönbein

Chang

2013

Ann Biomed Eng

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An important medical problem with high mortality is shock, sepsis and multi-organ failure. They have currently no treatments other than alleviation of symptoms. Shock is accompanied by strong markers for inflammation and involves a cascade of events that leads to failure in organs even if they are not involved in the initial insult. Recent evidence indicates that pancreatic digestive enzymes carried in the small intestine after mixing with ingested food are a major cause for multi-organ failure. These concentrated and relatively non-specific enzymes are usually compartmentalized inside the intestinal lumen as requirement for normal digestion. But after breakdown of the mucosal barrier they leak into the wall of the intestine and start an autodigestion process that includes destruction of villi in the intestine. Digestive enzymes also generate cytotoxic mediators, which together are transported into the systemic circulation via the portal venous system, the intestinal lymphatics and via the peritoneum. They cause various degrees of cell and organ dysfunction that can reach the point of complete organ failure. Blockade of digestive enzymes in the lumen of the intestine in experimental forms of shock serves to reduce breakdown of the mucosal barrier and autodigestion of the intestine, organ dysfunctions and mortality.

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Inhibition of Intraluminal Pancreatic Enzymes With Nafamostat Mesilate Improves Clinical Outcomes After Hemorrhagic Shock in Swine

Abstract: The inhibition of intraluminal pancreatic enzymes using enteroclysis with the serine protease inhibitor, NM, after hemorrhagic shock significantly improves the clinical outcome.

Cited by 8 publications

References 23 publications

Impaired Small-Bowel Barrier Integrity in the Presence of Lumenal Pancreatic Digestive Enzymes Leads to Circulatory Shock

Impaired Small-Bowel Barrier Integrity in the Presence of Lumenal Pancreatic Digestive Enzymes Leads to Circulatory Shock

Autodigestion

The Autodigestion Hypothesis for Shock and Multi-organ Failure

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