Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Jul 15, 2016; 8(7): 526-531
Published online Jul 15, 2016. doi: 10.4251/wjgo.v8.i7.526
Pancreatic injury in patients with septic shock: A literature review
Anis Chaari, Karim Abdel Hakim, Kamel Bousselmi, Mahmoud Etman, Mohamed El Bahr, Ahmed El Saka, Eman Hamza, Mohamed Ismail, Elsayed Mahmoud Khalil, Vipin Kauts, William Francis Casey
Anis Chaari, Karim Abdel Hakim, Kamel Bousselmi, Mahmoud Etman, Mohamed El Bahr, Ahmed El Saka, Eman Hamza, Mohamed Ismail, Elsayed Mahmoud Khalil, Vipin Kauts, William Francis Casey, Department of Intensive Care, King Hamed University Hospital, Al Muharaq 24343, Bahrain
Author contributions: All authors equally contributed to this paper with conception and design of the study, literature review and analysis, drafting and critical revision and editing, and final approval of the final version.
Conflict-of-interest statement: All the authors declare they have no conflict of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Anis Chaari, MD, Department of Intensive Care, King Hamed University Hospital, Bilding 234, Road 2835, Block 228, Bussaiteen, Al Muharaq 24343, Bahrain.
Telephone: +973-38073955 Fax: +973-17766428
Received: March 16, 2016
Peer-review started: March 18, 2016
First decision: April 18, 2016
Revised: April 26, 2016
Accepted: May 17, 2016
Article in press: May 27, 2016
Published online: July 15, 2016


Sepsis and septic shock are life threatening condition associated with high mortality rate in critically-ill patients. This high mortality is mainly related to the inadequacy between oxygen delivery and cellular demand leading to the onset of multiorgan dysfunction. Whether this multiorgan failure affect the pancreas is not fully investigated. In fact, pancreatic injury may occur because of ischemia, overwhelming inflammatory response, oxidative stress, cellular apoptosis and/or metabolic derangement. Increased serum amylase and/or lipase levels are common in patients with septic shock. However, imaging test rarely reveal significant pancreatic damage. Whether pancreatic dysfunction does affect the prognosis of patients with septic shock or not is still a matter of debate. In fact, only few studies with limited sample size assessed the clinical relevance of the pancreatic injury in this group of patients. In this review, we aimed to describe the epidemiology and the physiopathology of pancreatic injury in septic shock patients, to clarify whether it requires specific management and to assess its prognostic value. Our main finding is that pancreatic injury does not significantly affect the outcome in septic shock patients. Hence, increased serum pancreatic enzymes without clinical features of acute pancreatitis do not require further imaging investigations and specific therapeutic intervention.

Key Words: Septic shock, Pancreas, Lipase, Amylase, Prognosis

Core tip: Pancreatic injury is common in septic shock patients. Tissue hypoperfusion is the main leading cause of pancreatic insult. Other factors such as oxidative stress and cellular apoptosis have been reported to enhance the pancreatic damage. The clinical relevance of increased level of pancreatic enzymes is not well established. In fact, hyperamylasemia and/or hyperlipasemia are not associated with higher mortality. Moreover, most of the imaging investigations do not show significant morphological changes of the pancreas. Hence, disturbed serum pancreatic enzymes without clinical evidence of acute pancreatitis should not trigger any specific therapy.


Severe sepsis and septic shock are common life-threatening conditions in critically-ill patients[1-3]. Despite recent therapeutic advances and the establishment of internationally accepted guidelines regarding the management of patients suffering from septic shock, the overall mortality in these patients ranges from 30% to 60%[2,4,5]. This high mortality is usually associated with the onset of multiple organ dysfunction. In fact, a few studies have reported that the worsening of organ function as well as the increase in the number of the failing organs is significantly associated with poor outcome in both adult and pediatric patients[6,7]. Accordingly, it has been reported that the onset of acute kidney injury is associated with a significant rise in the intensive care unit (ICU) mortality up to 50%-70% and that the highest mortality has been in patients with a high score on the severity of illness scale and/or in those who require renal replacement therapy[2,8-10]. Similarly, hypoxic liver injury in patients with septic shock has been reported to be associated with a mortality as high as 50%[11,12]. Experimental and clinical studies also suggest that gut ischemia is one of the hallmarks of septic shock[13-15]. However, whether pancreatic exocrine function is also impaired in septic shock patients has not been fully investigated. Moreover, there is still debate regarding the optimum modality for management of pancreatic insult as well as its prognostic value.

The aim of this review is to describe the epidemiology and the physiopathology of pancreatic injury in septic shock patients, to clarify whether it requires specific management and to assess its prognostic value.


A systematic literature search was conducted through Pubmed by using the following Medical Subheadings terms: Septic shock, sepsis, lipase, amylases and acute pancreatitis. Different Boolean operator combinations (AND/OR) were attempted. Overall, 97 articles were selected for this review. We didn’t proceed to any language restriction and only the studies published between 1996 and 2016 were considered.


The incidence of pancreatic injury in critically-ill patients is extremely variable according to the used definition. High levels of amylase levels have been reported in 32% to 79% of patients admitted in medical or surgical ICUs[16-19]. However, most of these studies have concluded that this elevation is not always due to pancreatic insults[16-18]. In fact, the proportion of non-pancreatic isoamylase in patients with hyperamylasemia has been reported to range from 30% to 74% of the total serum amylase[16,18]. Hence, other markers have been used to assess the exocrine pancreatic dysfunction in critically-ill patients. Lipase is one such marker which is more specific for the diagnosis of pancreatitis[20]. Similar to hyperamylasemia, increased lipase serum level is also common in critically-ill patients. In fact, Manjuck et al[21] reported that hyperlipasemia is found in 40% of the patients requiring ICU admission. Similarly, Denz et al[19] reported increased serum lipase levels in 57% of critically-ill patients. Recent guidelines have highlighted that the rise of one or both of these two enzymes should be higher than three times the upper limit of normal range to be considered as a useful criterion for acute pancreatitis[22]. However, only a limited number of patients admitted to the ICU with a diagnosis other than pancreatitis fulfill this definition[23] and/or have significant morphological changes in pancreatic anatomy on imaging tests[19,21]. Only a few studies have focused on the exocrine pancreatic dysfunction in the subgroup of critically-ill patients with septic shock[23-25]. Hence, epidemiological data regarding the pancreatic function impairment in this group of patient is lacking.


The pathophysiology of pancreatic injury in septic shock patients is not fully understood. The most commonly accepted hypothesis is pancreatic ischemia[26,27]. However, few experimental and human studies have suggested that other mechanisms might also be involved such as cell apoptosis[28,29], increased release of nitric oxide by the endothelial cells[30], platelets activation[31], ischemia - reperfusion phenomenon[32], elevated triglyceride levels and the development of biliary sludge[33].

Pancreatic ischemia

Severe hypotension and tissue hypoperfusion are the main hallmarks of septic shock[34,35]. Experimental studies have shown that gut perfusion is severely impaired in the early stages of septic shock[14,36]. In a porcine model of septic shock caused by fecal peritonitis, ljungdahl et al[14] have reported that the oxygen consumption of the gut, including that of pancreas, is markedly increased in this condition. This is accompanied by a significant decrease in the gut intramucosal pH which occurs even before the lactate rises in the arterial blood. The pancreas is particularly sensitive to hypotension. In fact, a temporary ischemia for 40 min has been shown to be sufficient to cause significant pancreatic injury on histological examination, presenting mainly as peripheral necrosis of the lobules[37]. Several studies have suggested that the impairment of pancreatic perfusion is more pronounced in septic shock. In fact, in an experimental animal model study, Raper et al[26] reported that the cardiac output is increased during the hyper dynamic phase of septic shock. Concomitantly, the systemic blood flow is increased in the gallbladder and the colon whereas it is markedly decreased in the pancreas. This demonstrates that the oxygen delivery to the pancreatic cells is significantly decreased despite the considerable increase of their oxygen requirement[26].

Beside these macro-circulatory abnormalities, pancreatic injury related to septic shock can also be explained by micro-circulatory and cellular dysfunctions[38]. In fact, severe sepsis and septic shock are commonly associated with coagulation abnormalities, usually manifested as disseminated intravascular coagulation[39,40]. Several forensic studies have reported ischemic and necrotic changes in various organs. These include occlusion and fibrin deposition in small and mid-size vessels, observed in patients who die from septic shock[41]. These abnormalities are triggered mainly by an overwhelming inflammatory reaction which is orchestrated by the immune host defense in response to the endotoxinic aggression[34,39]. The expression of the tissue factor by the mononuclear, polymorphonuclear and endothelial cells activates the coagulation cascade[42,43]. Activation of platelets, down-regulation of anticoagulant pathways and reduced fibrin removal due to inhibition of fibrinolysis enhances microvascular thrombosis[39]. Experimental studies have shown that the pancreatic microcirculation is deeply disturbed in septic shock. In fact, in a model of fecal peritonitis, Hiltebrand et al[27] reported that the microcirculatory flow is reduced by 50% in various splanchnic organs within 240 min. The flow normalizes after fluid resuscitation in all the organs, except in the pancreas.

Although the most widely accepted hypothesis used to explain pancreatic dysfunction in patients with septic shock is pancreatic ischemia, significant pancreatic injury has also been reported in normotensive sepsis model. This suggests that other mechanisms may also be responsible for causing pancreatic ischemia[44].

Cellular apoptosis

Delayed and inappropriate management of septic shock is associated with a worse outcome due to multiple organ dysfunction syndrome (MODS)[45-48]. The main cause of MODS in this condition is the uncontrolled inflammatory storm caused by overwhelming host immune response[49]. Beside the deleterious effect of this reaction on the macrocirculation and microcirculation, as described above, the pro-inflammatory cytokines- mainly interleukine (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α - also activate the NF-κB pathway. This causes cellular self-destruction and apoptosis[50]. This has been demonstrated in the hepatocytes and the immune cells with severe Gram-negative bacterial infection[50,51]. Experimental studies have shown that the exposure of pancreatic cells to lipopolysaccharide is associated with apoptosis and increased release of TNF-α, IL-1β and IL-8. Damage to the Acinar cells consists of nuclear fragmentation, abnormal cytoplasmic vacuoles and cellular swelling[28,29,52,53]. Unlike these experimental studies, there is no evidence to suggest that apoptosis is a major cause of exocrine pancreatic dysfunction in patients suffering from septic shock. In fact, histological studies performed in patients who died from septic shock and multiorgan failure have shown that the apoptosis of acinar cells is seen only in a scattered manner[54].

Other mechanisms

Other hypothesis that may explain pancreatic injury in patients suffering from septic shock.

The oxidative stress: Oxidative stress has been demonstrated in patients suffering from septic shock patients[55]. The main causes of mitochondrial dysfunction and increased release of reactive oxygen species are ischemia/reperfusion phenomenon and inflammation[55,56]. Other factors, such as the activation of the phagocytic cells and the production of nitric oxide by the endothelial cells, have been shown to aggravate the oxidative stress[57]. The cellular damage in sepsis is enhanced by the depletion of antioxidants and scavenger enzymes such as glutathione and thiamine in the plasma[56,58]. Several studies have suggested that the oxidative stress can induce pancreatic damage in septic shock[32,59].

Triglycerides: Serum triglyceride level has been reported to be significantly increased in septic shock[60,61]. Moreover, compared to those patients who survived septic shock, patients who died from it have been found to have a higher serum triglyceride level over the first 7 d of their illness[62]. Whether the high level of serum triglyceride seen in patients with septic shock is enough to induce pancreatic cell damage need to be investigated.


The clinical relevance of increased amylase and/or lipase in patient with septic shock has been poorly investigated. Whether pancreatic injury is only a satellite phenomenon or a major condition affecting the prognosis of this group of patients is still a matter of debate. In fact, only a few studies, most of them with a small number of patients, have investigated pancreatic dysfunction in critically-ill patients[19,21,23-25,44]. Pezzilli et al[23] have reported that amylase and lipase levels are significantly increased in patients with septic shock in comparison to a control group. However, none of the included patients met the criteria of acute pancreatitis and no significant correlation was found with mortality. These findings have been corroborated by post-mortem pancreatic tissue sample examination which has not shown significant morphological changes[24].

Available data suggest that imaging tests should not be requested for all critically-ill patients with deranged pancreatic enzymes as long as the clinical assessment does not suggest acute pancreatitis. In fact, Denz et al[19] reported that contrast enhanced computed tomography performed for all patients with a serum lipase level higher than 450 U/L was positive only in 35% of the patients. None of these patients had severe necrotizing pancreatitis which required specific management. However, the authors have reported that imaging abnormalities are more common in patients with increased blood levels of pancreatitis-associated protein. This raises the question: Which marker can be considered as a reliable test to assess the pancreatic dysfunction?

Even though the available data shows that the increase in the levels of pancreatic enzymes does not affect the mortality in critically-ill patients, the pancreatic dysfunction may cause malnutrition in patient with prolonged stay in intensive care units. In fact, the pancreatic secretory function is important for the digestion and absorption of fats, protein and carbohydrates[63]. In a prospective cross-sectional study of 563 critically-ill patients, Wang et al[64] reported that the prevalence of exocrine pancreatic insufficiency in these patients is 52.2% although only 34.9% of these patients had increased serum lipase levels and only 30.2% had increased serum amylase levels. The definition of exocrine pancreatic insufficiency in their study was based on decreased fecal elastase-1 concentration (< 200 mcg/g). The authors have also found that both shock and sepsis are independent factors which predict exocrine pancreatic insufficiency. Tribl et al[25] have reported similar results as they found that the concentration of amylase and chymotrypsin in the duodenal juice is significantly lower in patients with sepsis or septic shock than in healthy volunteers. Moreover, the concentration of trypsin is significantly lower in septic shock patients than sepsis patients without shock. The therapeutic implications of these findings need to be investigated by further studies.


Pancreatic injury is common in patients suffering from septic shock. Increase in levels of pancreatic enzymes does not significantly affect the outcome. Only those patients who show clinical features of acute pancreatitis need to undergo further radiological investigations. However, pancreatic dysfunction may affect the nutritional state of patients receiving enteral feeding and requiring prolonged ICU stay. Whether specific treatment should be considered to avoid malnutrition in these patients need to be investigated further.


Manuscript source: Invited manuscript

P- Reviewer: Kleeff J, Tjora E, Wan QQ S- Editor: Gong ZM L- Editor: A E- Editor: Lu YJ

1.  Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med. 2008;36:296-327.  [PubMed]  [DOI]
2.  Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001;29:1303-1310.  [PubMed]  [DOI]
3.  Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med. 2003;348:1546-1554.  [PubMed]  [DOI]
4.  Sasse KC, Nauenberg E, Long A, Anton B, Tucker HJ, Hu TW. Long-term survival after intensive care unit admission with sepsis. Crit Care Med. 1995;23:1040-1047.  [PubMed]  [DOI]
5.  Annane D, Aegerter P, Jars-Guincestre MC, Guidet B. Current epidemiology of septic shock: the CUB-Réa Network. Am J Respir Crit Care Med. 2003;168:165-172.  [PubMed]  [DOI]
6.  Moemen ME. Prognostic categorization of intensive care septic patients. World J Crit Care Med. 2012;1:67-79.  [PubMed]  [DOI]
7.  Leteurtre S, Duhamel A, Deken V, Lacroix J, Leclerc F. Daily estimation of the severity of organ dysfunctions in critically ill children by using the PELOD-2 score. Crit Care. 2015;19:324.  [PubMed]  [DOI]
8.  Honore PM, Jacobs R, Hendrickx I, Bagshaw SM, Joannes-Boyau O, Boer W, De Waele E, Van Gorp V, Spapen HD. Prevention and treatment of sepsis-induced acute kidney injury: an update. Ann Intensive Care. 2015;5:51.  [PubMed]  [DOI]
9.  Bagshaw SM, Uchino S, Bellomo R, Morimatsu H, Morgera S, Schetz M, Tan I, Bouman C, Macedo E, Gibney N. Septic acute kidney injury in critically ill patients: clinical characteristics and outcomes. Clin J Am Soc Nephrol. 2007;2:431-439.  [PubMed]  [DOI]
10.  Gurjar M, Baronia AK, Azim A, Prasad N, Jain S, Singh RK, Poddar B, Bhadauria D. Septic acute kidney injury in critically ill Indian patients. Indian J Crit Care Med. 2013;17:49-52.  [PubMed]  [DOI]
11.  Horvatits T, Trauner M, Fuhrmann V. Hypoxic liver injury and cholestasis in critically ill patients. Curr Opin Crit Care. 2013;19:128-132.  [PubMed]  [DOI]
12.  Fuhrmann V, Kneidinger N, Herkner H, Heinz G, Nikfardjam M, Bojic A, Schellongowski P, Angermayr B, Schöniger-Hekele M, Madl C. Impact of hypoxic hepatitis on mortality in the intensive care unit. Intensive Care Med. 2011;37:1302-1310.  [PubMed]  [DOI]
13.  Ji MH, Yang JJ, Wu J, Li RQ, Li GM, Fan YX, Li WY. Experimental sepsis in pigs--effects of vasopressin on renal, hepatic, and intestinal dysfunction. Ups J Med Sci. 2012;117:257-263.  [PubMed]  [DOI]
14.  Ljungdahl M, Rasmussen I, Haglund U. Intestinal blood flow and intramucosal pH in experimental peritonitis. Shock. 1999;11:44-50.  [PubMed]  [DOI]
15.  Levy B, Bollaert PE, Charpentier C, Nace L, Audibert G, Bauer P, Nabet P, Larcan A. Comparison of norepinephrine and dobutamine to epinephrine for hemodynamics, lactate metabolism, and gastric tonometric variables in septic shock: a prospective, randomized study. Intensive Care Med. 1997;23:282-287.  [PubMed]  [DOI]
16.  Rattner DW, Gu ZY, Vlahakes GJ, Warshaw AL. Hyperamylasemia after cardiac surgery. Incidence, significance, and management. Ann Surg. 1989;209:279-283.  [PubMed]  [DOI]
17.  Vitale GC, Larson GM, Davidson PR, Bouwman DL, Weaver DW. Analysis of hyperamylasemia in patients with severe head injury. J Surg Res. 1987;43:226-233.  [PubMed]  [DOI]
18.  Weaver DW, Busuito MJ, Bouwman DL, Wilson RF. Interpretation of serum amylase levels in the critically ill patient. Crit Care Med. 1985;13:532-533.  [PubMed]  [DOI]
19.  Denz C, Siegel L, Lehmann KJ, Dagorn JC, Fiedler F. Is hyperlipasemia in critically ill patients of clinical importance? An observational CT study. Intensive Care Med. 2007;33:1633-1636.  [PubMed]  [DOI]
20.  Treacy J, Williams A, Bais R, Willson K, Worthley C, Reece J, Bessell J, Thomas D. Evaluation of amylase and lipase in the diagnosis of acute pancreatitis. ANZ J Surg. 2001;71:577-582.  [PubMed]  [DOI]
21.  Manjuck J, Zein J, Carpati C, Astiz M. Clinical significance of increased lipase levels on admission to the ICU. Chest. 2005;127:246-250.  [PubMed]  [DOI]
22.  Working Group IAP/APA Acute Pancreatitis Guidelines. IAP/APA evidence-based guidelines for the management of acute pancreatitis. Pancreatology. 2013;13:e1-15.  [PubMed]  [DOI]
23.  Pezzilli R, Barassi A, Imbrogno A, Fabbri D, Pigna A, Morselli-Labate AM, Corinaldesi R, Melzi d’Eril G. Is the pancreas affected in patients with septic shock?--a prospective study. Hepatobiliary Pancreat Dis Int. 2011;10:191-195.  [PubMed]  [DOI]
24.  Tribl B, Madl C, Mazal PR, Schneider B, Spitzauer S, Vogelsang H, Gangl A. Exocrine pancreatic function in critically ill patients: septic shock versus non-septic patients. Crit Care Med. 2000;28:1393-1398.  [PubMed]  [DOI]
25.  Tribl B, Sibbald WJ, Vogelsang H, Spitzauer S, Gangl A, Madl C. Exocrine pancreatic dysfunction in sepsis. Eur J Clin Invest. 2003;33:239-243.  [PubMed]  [DOI]
26.  Raper RF, Sibbald WJ, Hobson J, Rutledge FS. Effect of PGE1 on altered distribution of regional blood flows in hyperdynamic sepsis. Chest. 1991;100:1703-1711.  [PubMed]  [DOI]
27.  Hiltebrand LB, Krejci V, Banic A, Erni D, Wheatley AM, Sigurdsson GH. Dynamic study of the distribution of microcirculatory blood flow in multiple splanchnic organs in septic shock. Crit Care Med. 2000;28:3233-3241.  [PubMed]  [DOI]
28.  Laine VJ, Nyman KM, Peuravuori HJ, Henriksen K, Parvinen M, Nevalainen TJ. Lipopolysaccharide induced apoptosis of rat pancreatic acinar cells. Gut. 1996;38:747-752.  [PubMed]  [DOI]
29.  Kimura K, Shimosegawa T, Abe R, Masamune A, Satoh A, Takasu A, Koizumi M, Toyota T. Low doses of lipopolysaccharide upregulate acinar cell apoptosis in cerulein pancreatitis. Pancreas. 1998;17:120-126.  [PubMed]  [DOI]
30.  Ruetten H, Southan GJ, Abate A, Thiemermann C. Attenuation of endotoxin-induced multiple organ dysfunction by 1-amino-2-hydroxy-guanidine, a potent inhibitor of inducible nitric oxide synthase. Br J Pharmacol. 1996;118:261-270.  [PubMed]  [DOI]
31.  Emanuelli G, Montrucchio G, Dughera L, Gaia E, Lupia E, Battaglia E, De Martino A, De Giuli P, Gubetta L, Camussi G. Role of platelet activating factor in acute pancreatitis induced by lipopolysaccharides in rabbits. Eur J Pharmacol. 1994;261:265-272.  [PubMed]  [DOI]
32.  Sakorafas GH, Tsiotos GG, Sarr MG. Ischemia/Reperfusion-Induced pancreatitis. Dig Surg. 2000;17:3-14.  [PubMed]  [DOI]
33.  Steinberg W, Tenner S. Acute pancreatitis. N Engl J Med. 1994;330:1198-1210.  [PubMed]  [DOI]
34.  Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med. 2013;369:2063.  [PubMed]  [DOI]
35.  Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013;39:165-228.  [PubMed]  [DOI]
36.  Grum CM. Tissue oxygenation in low flow states and during hypoxemia. Crit Care Med. 1993;21:S44-S49.  [PubMed]  [DOI]
37.  Spormann H, Sokolowski A, Letko G. Effect of temporary ischemia upon development and histological patterns of acute pancreatitis in the rat. Pathol Res Pract. 1989;184:507-513.  [PubMed]  [DOI]
38.  Zhou ZG, Chen YD. Influencing factors of pancreatic microcirculatory impairment in acute panceatitis. World J Gastroenterol. 2002;8:406-412.  [PubMed]  [DOI]
39.  Levi M, van der Poll T. Inflammation and coagulation. Crit Care Med. 2010;38:S26-S34.  [PubMed]  [DOI]
40.  Levi M, Schultz M, van der Poll T. Disseminated intravascular coagulation in infectious disease. Semin Thromb Hemost. 2010;36:367-377.  [PubMed]  [DOI]
41.  Kojima M, Shimamura K, Mori N, Oka K, Nakazawa M. A histological study on microthrombi in autopsy cases of DIC. Bibl Haematol. 1983;95-106.  [PubMed]  [DOI]
42.  Ferkau A, Gillmann HJ, Mischke R, Calmer S, Ecklebe S, Abid M, Minde JW, Echtermeyer F, Theilmeier G. Infection-associated platelet dysfunction of canine platelets detected in a flow chamber model. BMC Vet Res. 2013;9:112.  [PubMed]  [DOI]
43.  Rauch U, Bonderman D, Bohrmann B, Badimon JJ, Himber J, Riederer MA, Nemerson Y. Transfer of tissue factor from leukocytes to platelets is mediated by CD15 and tissue factor. Blood. 2000;96:170-175.  [PubMed]  [DOI]
44.  Tribl B, Bateman RM, Milkovich S, Sibbald WJ, Ellis CG. Effect of nitric oxide on capillary hemodynamics and cell injury in the pancreas during Pseudomonas pneumonia-induced sepsis. Am J Physiol Heart Circ Physiol. 2004;286:H340-H345.  [PubMed]  [DOI]
45.  Dhainaut JF, Yan SB, Joyce DE, Pettilä V, Basson B, Brandt JT, Sundin DP, Levi M. Treatment effects of drotrecogin alfa (activated) in patients with severe sepsis with or without overt disseminated intravascular coagulation. J Thromb Haemost. 2004;2:1924-1933.  [PubMed]  [DOI]
46.  Simmons J, Pittet JF. The coagulopathy of acute sepsis. Curr Opin Anaesthesiol. 2015;28:227-236.  [PubMed]  [DOI]
47.  Bai X, Yu W, Ji W, Lin Z, Tan S, Duan K, Dong Y, Xu L, Li N. Early versus delayed administration of norepinephrine in patients with septic shock. Crit Care. 2014;18:532.  [PubMed]  [DOI]
48.  Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E, Tomlanovich M. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345:1368-1377.  [PubMed]  [DOI]
49.  Rossaint J, Zarbock A. Pathogenesis of Multiple Organ Failure in Sepsis. Crit Rev Immunol. 2015;35:277-291.  [PubMed]  [DOI]
50.  Kim SM, Sakai T, Dang HV, Tran NH, Ono K, Ishimura K, Fukui K. Nucling, a novel protein associated with NF-κB, regulates endotoxin-induced apoptosis in vivo. J Biochem. 2013;153:93-101.  [PubMed]  [DOI]
51.  Roger PM, Hyvernat H, Ticchioni M, Kumar G, Dellamonica J, Bernardin G. The early phase of human sepsis is characterized by a combination of apoptosis and proliferation of T cells. J Crit Care. 2012;27:384-393.  [PubMed]  [DOI]
52.  Li YY, Lu S, Li K, Feng JY, Li YN, Gao ZR, Chen CJ. Down-regulation of HSP60 expression by RNAi increases lipopolysaccharide- and cerulein-induced damages on isolated rat pancreatic tissues. Cell Stress Chaperones. 2010;15:965-975.  [PubMed]  [DOI]
53.  Wang XL, Li Y, Kuang JS, Zhao Y, Liu P. Increased heat shock protein 70 expression in the pancreas of rats with endotoxic shock. World J Gastroenterol. 2006;12:780-783.  [PubMed]  [DOI]
54.  Hotchkiss RS, Swanson PE, Freeman BD, Tinsley KW, Cobb JP, Matuschak GM, Buchman TG, Karl IE. Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. Crit Care Med. 1999;27:1230-1251.  [PubMed]  [DOI]
55.  Crimi E, Sica V, Slutsky AS, Zhang H, Williams-Ignarro S, Ignarro LJ, Napoli C. Role of oxidative stress in experimental sepsis and multisystem organ dysfunction. Free Radic Res. 2006;40:665-672.  [PubMed]  [DOI]
56.  Costa NA, Gut AL, de Souza Dorna M, Pimentel JA, Cozzolino SM, Azevedo PS, Fernandes AA, Zornoff LA, de Paiva SA, Minicucci MF. Serum thiamine concentration and oxidative stress as predictors of mortality in patients with septic shock. J Crit Care. 2014;29:249-252.  [PubMed]  [DOI]
57.  Oldham KM, Bowen PE. Oxidative stress in critical care: is antioxidant supplementation beneficial? J Am Diet Assoc. 1998;98:1001-1008.  [PubMed]  [DOI]
58.  Huet O, Cherreau C, Nicco C, Dupic L, Conti M, Borderie D, Pene F, Vicaut E, Benhamou D, Mira JP. Pivotal role of glutathione depletion in plasma-induced endothelial oxidative stress during sepsis. Crit Care Med. 2008;36:2328-2334.  [PubMed]  [DOI]
59.  Wray GM, Hinds CJ, Thiemermann C. Effects of inhibitors of poly(ADP-ribose) synthetase activity on hypotension and multiple organ dysfunction caused by endotoxin. Shock. 1998;10:13-19.  [PubMed]  [DOI]
60.  Wendel M, Paul R, Heller AR. Lipoproteins in inflammation and sepsis. II. Clinical aspects. Intensive Care Med. 2007;33:25-35.  [PubMed]  [DOI]
61.  Murch O, Collin M, Hinds CJ, Thiemermann C. Lipoproteins in inflammation and sepsis. I. Basic science. Intensive Care Med. 2007;33:13-24.  [PubMed]  [DOI]
62.  Lee SH, Park MS, Park BH, Jung WJ, Lee IS, Kim SY, Kim EY, Jung JY, Kang YA, Kim YS. Prognostic Implications of Serum Lipid Metabolism over Time during Sepsis. Biomed Res Int. 2015;2015:789298.  [PubMed]  [DOI]
63.  Domínguez-Muñoz JE. Pancreatic exocrine insufficiency: diagnosis and treatment. J Gastroenterol Hepatol. 2011;26 Suppl 2:12-16.  [PubMed]  [DOI]
64.  Wang S, Ma L, Zhuang Y, Jiang B, Zhang X. Screening and risk factors of exocrine pancreatic insufficiency in critically ill adult patients receiving enteral nutrition. Crit Care. 2013;17:R171.  [PubMed]  [DOI]