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Non-occlusive mesenteric ischemia and its associated intestinal gangrene in acute pancreatitis
Original Paper Pancreatology 2003;3:316–322 DOI: 10.1159/000071770
Received: May 21, 2002 Revised and accepted: April 25, 2003
Non-Occlusive Mesenteric Ischemia and Its Associated Intestinal Gangrene in Acute Pancreatitis Masahiko Hirota Kotaro Inoue Yu Kimura Takao Mizumoto Kinumo Kuwata Masaki Ohmuraya Takatoshi Ishiko Toru Beppu Michio Ogawa Department of Surgery II, Kumamoto University Medical School, Kumamoto City, Kumamoto, Japan
Key Words Acute pancreatitis W Non-occlusive mesenteric ischemia W Intestinal gangrene W Disseminated intravascular coagulation W Continuous regional arterial infusion
Abstract Background/Aims: Non-occlusive mesenteric ischemia (NOMI) has been defined as diffuse intestinal ischemia that often results in intestinal gangrene in the presence of a patent arterial trunk. The prevalence and nature of NOMI in acute pancreatitis was investigated. Methods: A total of 120 consecutive patients with acute pancreatitis managed in the Department of Surgery II, Kumamoto University Medical School, from April 1992 through December 2002, were investigated retrospectively. Among them, 60 patients had the severe form. Results: The overall mortality of acute pancreatitis patients was 8.3% (10/ 120). The prevalence and mortality of acute pancreatitis associated with NOMI were 6.7% (8/120) and 63% (5/8), respectively, while those of patients with NOMI-associated intestinal gangrene were 4.2% (5/120) and 100% (5/5), respectively. The mortality of patients with severe acute pancreatitis who did not develop NOMI was 10% (5/52).
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All patients with NOMI-associated intestinal gangrene quickly progressed and subsequently died of multiple organ failure. Plasma creatine phosphokinase (CPK) and lactate levels were elevated significantly in patients with NOMI. Conclusion: Acute pancreatitis associated with NOMI was extremely severe. If the plasma CPK and lactate levels are extremely high, NOMI should be suspected. Copyright © 2003 S. Karger AG, Basel and IAP
Introduction
Acute pancreatitis is a potentially fatal disease, with an overall mortality of 7–11% [1–3]. Severe acute pancreatitis is often associated with pancreatic necrosis or pancreatic infarction, which is associated with a higher mortality rate [4, 5]. Pancreatic necrosis may be the result of local vascular spasm and increased intravascular coagulability. Such vascular complications can also develop in other organs if the inflammatory insult is sufficiently strong [6]. The development of focal intestinal necrosis has been reported in several severe acute pancreatitis cases [7–11]. Two mechanisms have been proposed for
M. Hirota Department of Surgery II, Kumamoto University Medical School 1-1-1 Honjo, Kumamoto City, Kumamoto 860-8556 (Japan) Tel. +81 96 373 5212, Fax +81 96 371 4378 E-Mail [email protected]
these complications: (a) the direct diffusion of pancreatic enzymes, which leads to enzymatic digestion of the intestine, and (b) blood vessel obstruction caused by severe inflammation in the mesenterium, which leads to intestinal infarction. Non-occlusive mesenteric ischemia (NOMI), which is defined as diffuse intestinal ischemia in the presence of a patent arterial trunk, often results in intestinal gangrene [12, 13]. Progressive intestinal ischemia can lead to infarction, sepsis and death from multiple organ failure (MOF). NOMI is not rare, and comprises 20–30% of the total ischemic enteropathy cases. The focal intestinal necrosis described above might occur under similar pathological mechanisms. Hence, development of NOMI in severe acute pancreatitis patients should be a concern. Here we report the NOMI prevalence in acute pancreatitis patients, and discuss the nature of NOMI and its associated intestinal gangrene in acute pancreatitis.
Table 1. Etiology of acute pancreatitis
Etiology
Patients
Alcohol abuse Biliary Post-operative Drug Impaction of pancreatic stones ERCP Stenosis of pancreato-jejunal anastomosis ES Chronic renal failure Pancreas divism EPBD ESWL ENBD Fulminant hepatitis Hyperlipidemia Pancreato-biliary maljunction Posttraumatic Idiopathic
40 17 7 6 6 5 4 3 3 2 2 1 1 1 1 1 1 19
Total
Materials and Methods A total of 120 consecutive patients with acute pancreatitis managed in our department from April 1992 through December 2002 were investigated retrospectively. There were 83 men and 37 women ranging in age from 3 to 81 years (average 52). Diagnosis and severity classification of acute pancreatitis were based on the Japanese criteria [14, 15]. Among these patients, 60 were diagnosed with the severe form. In the Japanese criteria, severe acute pancreatitis does not always correspond to necrotizing pancreatitis. The cause of acute pancreatitis was related to alcohol abuse in 40 patients, biliary pancreatitis in 17 patients, and unknown (idiopathic pancreatitis) in 19 patients; the remaining causes are shown in table 1. Twenty-seven of the patients were primary admissions, and the remaining 93 were transferred from other hospitals. All patients with NOMI were transferred from other hospitals. The occurrence rate and nature of pancreatitis-associated NOMI were investigated, and the treatment modality and mortality were also analyzed. Diagnosis of NOMI was based on the angiographic appearance of the superior mesenteric artery (SMA) and/or the pathological evaluation of the intestine and mesenteric vessels. Angiography was performed on 31 patients with pancreatic necrosis to perform continuous regional arterial infusion (CRAI) therapy [16]. If there was no obstruction in the trunk of the SMA on pathological evaluation, extensive necrosis of the intestinal wall with microvascular thrombosis was considered to be the result of NOMI. The Student’s t-test was applied to compare the difference in creatine phosphokinase (CPK) and lactate levels at admission between patients with NOMI and those without NOMI. The normal range for CPK levels in our hospital is 57–284 U/l for men and 45– 176 U/l for women, while that for lactate levels is ! 1.1 mmol/l.
NOMI and Intestinal Gangrene in Acute Pancreatitis
120
ERCP = Endoscopic retrograde cholangiopancreatography; ES = endoscopic sphincterotomy; EPBD = endoscopic papillary balloon dilation; ESWL = extracorporeal shock-wave lithotripsy; ENBD = endoscopic nasobiliary drainage.
Results
Development of NOMI From April 1992 through December 2002, we treated a total of 120 consecutive patients with acute pancreatitis; 110 were cured (mortality 8.3%). The prevalence and mortality of acute pancreatitis associated with NOMI were 6.7% (8/120) and 63% (5/8), respectively, while those of patients with NOMI-associated intestinal gangrene were 4.2% (5/120) and 100% (5/5), respectively. All patients who developed NOMI had severe acute pancreatitis. The prevalence rate of NOMI in severe acute pancreatitis who developed NOMI was 63% (5/8), while that of severe acute pancreatitis who did not develop NOMI was 10% (5/52) (tables 2, 3). Nature of Pancreatic-Associated NOMI Macroscopic examination of NOMI patients revealed that most of the intestine was necrotic (table 2). However, there was no obstruction of the mesenteric arterial trunk as is seen in SMA thrombosis patients. Histological examination of intestinal specimens showed extensive necrosis
Pancreatology 2003;3:316–322
317
Table 2. Patients with NOMI CPK at admission U/l
Lactate Diagnostic procedure at admission of NOMI mmol/l
Part of intestinal necrosis
CRAI
Outcome
n.e.
18,290
8.9
Pa
Je–As
–
Died of MOF (at 28th day)
+ (?)
+ (2)
2,063
7.2
An+Pa
Je–Re
+ (CA)
Died of MOF (at 14th day)
–
+ (3)
+ (3)
8,280
7.1
An+Pa
Je–Re
+ (CA)
Died of MOF (at 9th day)
+ (2)
+ (2)
+ (2)
n.e.
3,528
8.1
Pa
Je–De
–
Died of MOF (at 28th day)
+ (3)
+ (1)
n.e.
+ (3)
n.e.
n.e.
18.1
Pa
Je–Re
–
Died of MOF (at 3rd day)
++ (2)
+ (2)
+ (3)
–
+ (8)
+ (2)
202
2.2
An
–
+ Survived (CA+SMA)
4
++ (5)
–
+ (6)
–
–
+ (5)
3,189
3.0
An
–
+ Survived (CA+SMA)
3
+ (3)
+ (3)
+ (3)
–
+ (28) + (3)
1,256
1.8
An
–
+ Survived (CA+SMA)
Case Age/ gender
Ran- Etiology son score
Duration of symp. at admission days
Complications panshock creatic necrosis1
DIC
portal sepsis venous gas
mesenteric arterial spasm
1
29/F
7
Idiopathic
2
++ (3)
+ (3)
+ (3)
–
+ (3)
2
54/M
8
Alcoholic
1
++ (2)
+ (2)
+ (2)
–
3
67/F
5
Biliary
2
+ (9)
+ (3)
+ (3)
4
55/M
8
Alcoholic
1
++ (2)
+ (2)
5
71/M
7
Hyperlipidemic
2
++ (3)
6
41/M
4
Alcoholic
1
7
44/M
4
Alcoholic
8
41/M
7
Biliary
An = Angiography; As = ascending colon; CA = celiac artery; CPK = creatine phosphokinase; CRAI = continuous regional arterial infusion; De = descending colon; DIC = disseminated intravascular coagulation; Je = jejunum; MOF = multiple organ failure; n.e. = not evaluated; NOMI = non-occlusive mesenteric ischemia; Pa = pathology; Re = rectum; SMA = superior mesenteric artery. Numbers in parentheses are the day when the corresponding complication was detected. 1 + = Small part of necrosis; ++ = massive necrosis.
Table 3. Mortality of acute pancreatitis patients
Severity
Patients
Patients who died (mortality)
Mild/moderate Severe without NOMI Severe with NOMI
60 52 8
0 (0%) 5 (10%) 5 (63%)
Total
120
10 (8%)
of the entire intestinal wall, consistent with NOMI(fig. 1). One patient (case 4) was complicated with portal venous gas (fig. 2), which is a marker of intestinal necrosis [17]. Five of 8 pancreatitis-associated NOMI patients were subjected to angiography, which revealed mesenteric arterial spasm, a finding that is specific to NOMI patients (fig. 3). All of 8 pancreatitis-associated NOMI patients had apparent pancreatic necrosis. However, 2 patients with NOMI who were subjected to CRAI with nafamostat
318
Pancreatology 2003;3:316–322
mesilate (240 mg/day) via the celiac artery (CA) for 7 days failed to show massive pancreatic necrosis (fig. 4). Most of the NOMI patients developed disseminated intravascular coagulopathy (DIC) and shock, both of which are speculated to be precipitative factors of NOMI (table 2). All gangrene patients had sepsis complications. In addition, CPK and lactate levels at admission were elevated significantly in patients with NOMI compared to patients without NOMI (5,258 B 2,227 vs. 441 B 158 U/l, p ! 0.001 for CPK; 7.1 B 1.9 vs. 2.8 B 0.7 mmol/l, p ! 0.01 for lactate). Treatment and Mortality All 5 patients with NOMI-associated intestinal gangrene, including 2 patients who received CRAI only to the CA-perfusing area, died between the 3rd and 28th day after onset of the disease. In contrast, the 3 NOMI patients who were treated with CRAI via the CA and SMA (patients 6–8) survived. Thus, the mortality of NOMI and NOMI-associated intestinal gangrene was 63% (5/8) and 100% (5/5), respectively. MOF was the cause of death in all patients with intestinal gangrene (ta-
Hirota/Inoue/Kimura/Mizumoto/Kuwata/ Ohmuraya/Ishiko/Beppu/Ogawa
Fig. 1. Microscopic appearance of NOMI-
associated intestinal gangrene. Histology of the intestine showed extensive necrosis of the entire intestinal wall, which is consistent with NOMI-associated gangrene. Case 3, colon. HE stain. !37.
Fig. 2. Portal venous gas on CT. Computed tomography (CT) of case 4 showed portal venous gas in the liver (arrow).
ble 2). We began to perform CRAI via only the CA in 1994, and CRAI via the CA and SMA in 1997. Hence, we did not perform CRAI on patient 1. We did not perform CRAI on patient 5, who was dead on admission, or on patient 4, who was operated on soon after admission.
NOMI and Intestinal Gangrene in Acute Pancreatitis
Discussion
NOMI has been defined as severe intestinal ischemia in the presence of a patent arterial tree. Eight cases of severe acute pancreatitis patients associated with NOMI are presented. Five of these cases showed marked progression and were fatal. Most of the patients developed both DIC and shock, which are speculated to be exaggerating factors of NOMI. Mesenteric arterial spasm was confirmed in all 5 patients who underwent angiography. Plas-
Pancreatology 2003;3:316–322
319
Fig. 3. Angiographic appearance of mesenteric vessels. Angiography of case 3 showed strong spasm in the CA (a) and SMA (b). Case 8, who received CRAI via the SMA in addition to the CA, showed apparent improvement of arterial spasm after 5 weeks (d) compared with appearance at admission (c).
Fig. 4. Macroscopic appearance of the pancreas in a patient that received CRAI therapy via the celiac artery. One patient (case 3) with NOMI (fig. 3a, b), who was subjected to CRAI with nafamostat mesilate (240 mg/ day) via the CA for 7 days, failed to show massive pancreatic necrosis. Patients with intestinal ischemia as the primary pathology may often have pancreatitis-like symptom and laboratory data. However, because the patient was first diagnosed with biliary pancreatitis without intestinal symptoms, which was exaggerated after endoscopic sphincterotomy, pancreatitis should be considered the primary pathology. Short arrow = Peripancreatic fat necrosis; long arrow = pancreatic necrosis; * = pancreatic parenchyma (head); ** = pancreatic parenchyma (body and tail).
320
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Hirota/Inoue/Kimura/Mizumoto/Kuwata/ Ohmuraya/Ishiko/Beppu/Ogawa
ma CPK and lactate levels at admission were elevated significantly in patients with NOMI. Because our patient group was selected by referral to our hospital, the incidence of NOMI in acute pancreatitis should be quantified in reference to this referral bias. Focal colonic necrosis, which is not as diffuse as that observed in NOMI patients, is estimated to comprise 1% of the total acute pancreatitis cases [7, 8] and 6–40% of the total necrotizing pancreatitis cases [8, 9]. A possible cause of this necrosis is an inflammatory extension into the mesocolon (vascular occlusion) and/or directly into the colon itself (severe pericolitis). The mortality of pancreatitis patients with focal colonic necrosis is 50–90% [10, 11]. Although NOMI is associated with the same intestinal complications as focal colonic necrosis, the underlying mechanisms are apparently different. Two major mechanisms are proposed for NOMI. Most investigators believe that it is caused by mesenteric vasoconstriction [18, 19], while others have postulated that it is a manifestation of DIC [20, 21]. Furthermore, shock, dehydration and/or increased abdominal pressure may also be associated with NOMI pathogenesis in pancreatitis patients. We propose that all of these factors may contribute to the development of NOMI. The vasoconstrictor endothelin is most likely the mediator for the vascular spasm observed in NOMI patients. Thrombin activates endothelin-converting enzyme-1 to produce endothelin-1 via proteinase-activated receptors [22]. The dynamic aspects of endothelin production in acute pancreatitis in rats are currently being investigated in our laboratory [23]. Mesenteric arterial spasm on angiography, which is commonly found in NOMI patients, was confirmed in 5 patients, 2 of whom died later of MOF. Because mesenteric arterial spasm was detected by angiography relatively early after the onset of acute pancreatitis (table 2), NOMI does not represent a terminal event. These results suggest that ischemic conditions of the intestine such as NOMI are significant steps in the development of MOF. One patient with NOMI (case 3), who showed apparent arterial spasm in both the CA and SMA (fig. 3a, b), was subjected to CRAI with nafamostat mesilate (240 mg/day) via the CA. She failed to show massive pancreatic necrosis at autopsy (fig. 4). Although this may have been a consequence of the severity of insult to the pancreas, it may indicate that CRAI blocks the development of pancreatic necrosis. Local administration of nafamostat mesilate may suppress the enhanced coagulative activity and inhibit the formation of microthrombosis, and therefore maintain pancreatic microcirculation. Because pancreatic necrosis manifests several days after the onset of acute
pancreatitis, improving pancreatic microcirculation may possibly prevent exaggeration from ischemia into necrosis. Maintenance of splanchnic microcirculation may also lead to a block in bacterial translocation through the intestinal mucosa. Hence, CRAI with nafamostat mesilate may inhibit the development and enlargement of necrosis (infarction) of the pancreas and intestine. Similarly, CRAI with nafamostat mesilate has been reported to be beneficial in the treatment of necrotizing pancreatitis [16]. We were able to inhibit the development of intestinal necrosis in some patients with spastic change in the CA and SMA (patients 6–8) by performing CRAI with nafamostat mesilate via both arteries. Thus, CRAI via the SMA may be a useful treatment modality for preventing intestinal gangrene by maintaining tissue microcirculation. If there is a NOMI-associated appearance in SMA angiography, we had better perform CRAI for the SMAperfusing area in addition to the CA-perfusing area. However, this is just speculative, and we need to further evaluate the effect of CRAI. In addition, administration of vasodilators, such as prostaglandin E1 and papaverine, may be another therapeutic modality for NOMI. CPK and lactate levels were extremely high in all patients with NOMI. Although some non-NOMI patients also showed high plasma CPK levels, those may be derived from inflamed back and abdominal wall skeletal muscles. Isozyme analysis of CPK may help differentiate these diagnosis. On the other hand, increased lactate levels may be a reflection of the microcirculatory disturbance. Consequently, an elevation in plasma CPK and lactate levels is indicative of extremely severe pancreatitis. If both CPK and lactate plasma levels are very high, angiography should be performed to check for the presence of NOMI or intestinal gangrene.
NOMI and Intestinal Gangrene in Acute Pancreatitis
Pancreatology 2003;3:316–322
Acknowledgements This study was supported by a Grant-in-Aid for the Research Committee on Intractable Pancreatic Diseases (Chairman: M. Ogawa) provided by the Ministry of Health, Welfare and Labor, Japan, and a Research Grant provided by the Pancreas Research Foundation of Japan.
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References 1 Brisinda G, Maria G, Ferrante A, Civello IM: Evaluation of prognostic factors in patients with acute pancreatitis. Hepatogastroenterology 1999;46:1990–1997. 2 Lankisch PG, Assmus C, Pflichthofer D, Struckmann K, Lehnick D: Which etiology causes the most severe acute pancreatitis? Int J Pancreatol 1999;26:55–57. 3 Toh SK, Phillips S, Johnson CD: A prospective audit against national standards of the presentation and management of acute pancreatitis in the south of England. Gut 2000;46:239–243. 4 Vesentini S, Bassi C, Talamini G, Cavallini G, Campedelli A, Pederzoli P: Prospective comparison of C-reactive protein level, Ranson score and contrast-enhanced computed tomography in the prediction of septic complications of acute pancreatitis. Br J Surg 1993;50:755– 757. 5 Kemppainen E, Sainio V, Haapiainen R, Kivisaari L, Kivilaakso R, Puolakkainen P: Early localization of necrosis by contrast-enhanced computed tomography can predict outcome in severe acute pancreatitis. Br J Surg 1996;83: 924–929. 6 Bradley EL III, Murphy F, Furguson C: Prediction of pancreatic necrosis by dynamic pancreatography. Ann Surg 1989;210:495–503. 7 Lukasch WM: Complications of acute pancreatitis. Arch Surg 1967;94:848–852. 8 Aldridge M, Francis ND, Glazer G, Dudley HA: Colonic complications of severe acute pancreatitis. Br J Surg 1989;76:362–367.
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9 Bouillot J, Alexandre JH, Vuong NP: Colonic involvement in acute necrotizing pancreatitis: Results of surgical treatment. World J Surg 1989;13:84–87. 10 Adams DB, Davis BR, Anderson MC: Colonic complications of pancreatitis. Am Surg 1994; 60:44–49. 11 Ravindra K, Sikora SS, Kumar A, Kapoor VK, Saxena R, Kanshik SP: Colonic necrosis is an adverse prognostic factor in pancreatic necrosis. Br J Surg 1995;82:109–110. 12 Haglund U, Lundgren O: Non-occlusive acute intestinal vascular failure. Br J Surg 1979;66: 155–158. 13 Howard TJ, Plaskon LA, Wiebke EA, Wilcox MG, Madura JA: Nonocclusive mesenteric ischemia remains a diagnostic dilemma. Am J Surg 1996;171:405–408. 14 Sunamura M, Lozonschi L, Takeda K, Kobari M, Matsuno S: Criteria for diagnosis of acute pancreatitis in Japan and clinical implications. Pancreas 1998;16:243–249. 15 Ogawa M, Hirota M, Hayakawa T, Matsuno S, Watanabe S, Atomi Y, Otsuki M, Kashima K, Koizumi M, Harada H, Yamamoto M, Nishimori I: Development and use of a new staging system for severe acute pancreatitis in Japan using a new staging system. Pancreas 2002;25: 325–330. 16 Takeda K, Matsuno S, Sunamura M, Kakugawa Y: Continuous regional arterial infusion of protease inhibitor and antibiotics in acute pancreatitis. Am J Surg 1996;171:394–398.
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17 Kinoshita H, Shinozaki M, Tanimura H, Umemoto Y, Sakaguchi S, Takifuji K, Kawasaki S, Hayashi H, Yamaue H: Clinical features and management of hepatic portal venous gas. Arch Surg 2001;136:1410–1414. 18 Boley SJ, Regan JA, Tunnick PA: Persistent vasoconstriction – A major factor in nonocclusive mesenteric ischemia. Curr Top Surg Res 1971;3:425–433. 19 Bassiounty HS: Nonocclusive mesenteric ischemia. Surg Clin North Am 1997;77:319–326. 20 Whitehead R: Ischaemic enterocolitis: An expression of the intravascular coagulation syndrome. Gut 1971;12:912–917. 21 Margaretten W, McKay DC: Thrombotic ulcerations of the gastrointestinal tract. Arch Intern Med 1971;127:250–252. 22 Eto M, Barandier C, Rathgeb L, Kozai T, Joch H, Yang Z, Luscher TF: Thrombin suppresses endothelial nitric oxide synthase and upregulates endothelin-converting enzyme-1 expression by distinct pathways: Role of Rho/ROCK and mitogen-activated protein kinase. Circ Res 2001;89:583–590. 23 Inoue H, Hirota M, Kimura Yu, Kuwata K, Ohmuraya M, Ogawa M: Further evidence for endothelin as an important mediator of pancreatic and intestinal ischemia in severe acute pancreatitis. Pancreas 2003;26:218–223.
Hirota/Inoue/Kimura/Mizumoto/Kuwata/ Ohmuraya/Ishiko/Beppu/Ogawa
Received: May 21, 2002 Revised and accepted: April 25, 2003
Non-Occlusive Mesenteric Ischemia and Its Associated Intestinal Gangrene in Acute Pancreatitis Masahiko Hirota Kotaro Inoue Yu Kimura Takao Mizumoto Kinumo Kuwata Masaki Ohmuraya Takatoshi Ishiko Toru Beppu Michio Ogawa Department of Surgery II, Kumamoto University Medical School, Kumamoto City, Kumamoto, Japan
Key Words Acute pancreatitis W Non-occlusive mesenteric ischemia W Intestinal gangrene W Disseminated intravascular coagulation W Continuous regional arterial infusion
Abstract Background/Aims: Non-occlusive mesenteric ischemia (NOMI) has been defined as diffuse intestinal ischemia that often results in intestinal gangrene in the presence of a patent arterial trunk. The prevalence and nature of NOMI in acute pancreatitis was investigated. Methods: A total of 120 consecutive patients with acute pancreatitis managed in the Department of Surgery II, Kumamoto University Medical School, from April 1992 through December 2002, were investigated retrospectively. Among them, 60 patients had the severe form. Results: The overall mortality of acute pancreatitis patients was 8.3% (10/ 120). The prevalence and mortality of acute pancreatitis associated with NOMI were 6.7% (8/120) and 63% (5/8), respectively, while those of patients with NOMI-associated intestinal gangrene were 4.2% (5/120) and 100% (5/5), respectively. The mortality of patients with severe acute pancreatitis who did not develop NOMI was 10% (5/52).
ABC
© 2003 S. Karger AG, Basel and IAP 1424–3903/03/0034–0316$19.50/0
Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com
Accessible online at: www.karger.com/pan
All patients with NOMI-associated intestinal gangrene quickly progressed and subsequently died of multiple organ failure. Plasma creatine phosphokinase (CPK) and lactate levels were elevated significantly in patients with NOMI. Conclusion: Acute pancreatitis associated with NOMI was extremely severe. If the plasma CPK and lactate levels are extremely high, NOMI should be suspected. Copyright © 2003 S. Karger AG, Basel and IAP
Introduction
Acute pancreatitis is a potentially fatal disease, with an overall mortality of 7–11% [1–3]. Severe acute pancreatitis is often associated with pancreatic necrosis or pancreatic infarction, which is associated with a higher mortality rate [4, 5]. Pancreatic necrosis may be the result of local vascular spasm and increased intravascular coagulability. Such vascular complications can also develop in other organs if the inflammatory insult is sufficiently strong [6]. The development of focal intestinal necrosis has been reported in several severe acute pancreatitis cases [7–11]. Two mechanisms have been proposed for
M. Hirota Department of Surgery II, Kumamoto University Medical School 1-1-1 Honjo, Kumamoto City, Kumamoto 860-8556 (Japan) Tel. +81 96 373 5212, Fax +81 96 371 4378 E-Mail [email protected]
these complications: (a) the direct diffusion of pancreatic enzymes, which leads to enzymatic digestion of the intestine, and (b) blood vessel obstruction caused by severe inflammation in the mesenterium, which leads to intestinal infarction. Non-occlusive mesenteric ischemia (NOMI), which is defined as diffuse intestinal ischemia in the presence of a patent arterial trunk, often results in intestinal gangrene [12, 13]. Progressive intestinal ischemia can lead to infarction, sepsis and death from multiple organ failure (MOF). NOMI is not rare, and comprises 20–30% of the total ischemic enteropathy cases. The focal intestinal necrosis described above might occur under similar pathological mechanisms. Hence, development of NOMI in severe acute pancreatitis patients should be a concern. Here we report the NOMI prevalence in acute pancreatitis patients, and discuss the nature of NOMI and its associated intestinal gangrene in acute pancreatitis.
Table 1. Etiology of acute pancreatitis
Etiology
Patients
Alcohol abuse Biliary Post-operative Drug Impaction of pancreatic stones ERCP Stenosis of pancreato-jejunal anastomosis ES Chronic renal failure Pancreas divism EPBD ESWL ENBD Fulminant hepatitis Hyperlipidemia Pancreato-biliary maljunction Posttraumatic Idiopathic
40 17 7 6 6 5 4 3 3 2 2 1 1 1 1 1 1 19
Total
Materials and Methods A total of 120 consecutive patients with acute pancreatitis managed in our department from April 1992 through December 2002 were investigated retrospectively. There were 83 men and 37 women ranging in age from 3 to 81 years (average 52). Diagnosis and severity classification of acute pancreatitis were based on the Japanese criteria [14, 15]. Among these patients, 60 were diagnosed with the severe form. In the Japanese criteria, severe acute pancreatitis does not always correspond to necrotizing pancreatitis. The cause of acute pancreatitis was related to alcohol abuse in 40 patients, biliary pancreatitis in 17 patients, and unknown (idiopathic pancreatitis) in 19 patients; the remaining causes are shown in table 1. Twenty-seven of the patients were primary admissions, and the remaining 93 were transferred from other hospitals. All patients with NOMI were transferred from other hospitals. The occurrence rate and nature of pancreatitis-associated NOMI were investigated, and the treatment modality and mortality were also analyzed. Diagnosis of NOMI was based on the angiographic appearance of the superior mesenteric artery (SMA) and/or the pathological evaluation of the intestine and mesenteric vessels. Angiography was performed on 31 patients with pancreatic necrosis to perform continuous regional arterial infusion (CRAI) therapy [16]. If there was no obstruction in the trunk of the SMA on pathological evaluation, extensive necrosis of the intestinal wall with microvascular thrombosis was considered to be the result of NOMI. The Student’s t-test was applied to compare the difference in creatine phosphokinase (CPK) and lactate levels at admission between patients with NOMI and those without NOMI. The normal range for CPK levels in our hospital is 57–284 U/l for men and 45– 176 U/l for women, while that for lactate levels is ! 1.1 mmol/l.
NOMI and Intestinal Gangrene in Acute Pancreatitis
120
ERCP = Endoscopic retrograde cholangiopancreatography; ES = endoscopic sphincterotomy; EPBD = endoscopic papillary balloon dilation; ESWL = extracorporeal shock-wave lithotripsy; ENBD = endoscopic nasobiliary drainage.
Results
Development of NOMI From April 1992 through December 2002, we treated a total of 120 consecutive patients with acute pancreatitis; 110 were cured (mortality 8.3%). The prevalence and mortality of acute pancreatitis associated with NOMI were 6.7% (8/120) and 63% (5/8), respectively, while those of patients with NOMI-associated intestinal gangrene were 4.2% (5/120) and 100% (5/5), respectively. All patients who developed NOMI had severe acute pancreatitis. The prevalence rate of NOMI in severe acute pancreatitis who developed NOMI was 63% (5/8), while that of severe acute pancreatitis who did not develop NOMI was 10% (5/52) (tables 2, 3). Nature of Pancreatic-Associated NOMI Macroscopic examination of NOMI patients revealed that most of the intestine was necrotic (table 2). However, there was no obstruction of the mesenteric arterial trunk as is seen in SMA thrombosis patients. Histological examination of intestinal specimens showed extensive necrosis
Pancreatology 2003;3:316–322
317
Table 2. Patients with NOMI CPK at admission U/l
Lactate Diagnostic procedure at admission of NOMI mmol/l
Part of intestinal necrosis
CRAI
Outcome
n.e.
18,290
8.9
Pa
Je–As
–
Died of MOF (at 28th day)
+ (?)
+ (2)
2,063
7.2
An+Pa
Je–Re
+ (CA)
Died of MOF (at 14th day)
–
+ (3)
+ (3)
8,280
7.1
An+Pa
Je–Re
+ (CA)
Died of MOF (at 9th day)
+ (2)
+ (2)
+ (2)
n.e.
3,528
8.1
Pa
Je–De
–
Died of MOF (at 28th day)
+ (3)
+ (1)
n.e.
+ (3)
n.e.
n.e.
18.1
Pa
Je–Re
–
Died of MOF (at 3rd day)
++ (2)
+ (2)
+ (3)
–
+ (8)
+ (2)
202
2.2
An
–
+ Survived (CA+SMA)
4
++ (5)
–
+ (6)
–
–
+ (5)
3,189
3.0
An
–
+ Survived (CA+SMA)
3
+ (3)
+ (3)
+ (3)
–
+ (28) + (3)
1,256
1.8
An
–
+ Survived (CA+SMA)
Case Age/ gender
Ran- Etiology son score
Duration of symp. at admission days
Complications panshock creatic necrosis1
DIC
portal sepsis venous gas
mesenteric arterial spasm
1
29/F
7
Idiopathic
2
++ (3)
+ (3)
+ (3)
–
+ (3)
2
54/M
8
Alcoholic
1
++ (2)
+ (2)
+ (2)
–
3
67/F
5
Biliary
2
+ (9)
+ (3)
+ (3)
4
55/M
8
Alcoholic
1
++ (2)
+ (2)
5
71/M
7
Hyperlipidemic
2
++ (3)
6
41/M
4
Alcoholic
1
7
44/M
4
Alcoholic
8
41/M
7
Biliary
An = Angiography; As = ascending colon; CA = celiac artery; CPK = creatine phosphokinase; CRAI = continuous regional arterial infusion; De = descending colon; DIC = disseminated intravascular coagulation; Je = jejunum; MOF = multiple organ failure; n.e. = not evaluated; NOMI = non-occlusive mesenteric ischemia; Pa = pathology; Re = rectum; SMA = superior mesenteric artery. Numbers in parentheses are the day when the corresponding complication was detected. 1 + = Small part of necrosis; ++ = massive necrosis.
Table 3. Mortality of acute pancreatitis patients
Severity
Patients
Patients who died (mortality)
Mild/moderate Severe without NOMI Severe with NOMI
60 52 8
0 (0%) 5 (10%) 5 (63%)
Total
120
10 (8%)
of the entire intestinal wall, consistent with NOMI(fig. 1). One patient (case 4) was complicated with portal venous gas (fig. 2), which is a marker of intestinal necrosis [17]. Five of 8 pancreatitis-associated NOMI patients were subjected to angiography, which revealed mesenteric arterial spasm, a finding that is specific to NOMI patients (fig. 3). All of 8 pancreatitis-associated NOMI patients had apparent pancreatic necrosis. However, 2 patients with NOMI who were subjected to CRAI with nafamostat
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mesilate (240 mg/day) via the celiac artery (CA) for 7 days failed to show massive pancreatic necrosis (fig. 4). Most of the NOMI patients developed disseminated intravascular coagulopathy (DIC) and shock, both of which are speculated to be precipitative factors of NOMI (table 2). All gangrene patients had sepsis complications. In addition, CPK and lactate levels at admission were elevated significantly in patients with NOMI compared to patients without NOMI (5,258 B 2,227 vs. 441 B 158 U/l, p ! 0.001 for CPK; 7.1 B 1.9 vs. 2.8 B 0.7 mmol/l, p ! 0.01 for lactate). Treatment and Mortality All 5 patients with NOMI-associated intestinal gangrene, including 2 patients who received CRAI only to the CA-perfusing area, died between the 3rd and 28th day after onset of the disease. In contrast, the 3 NOMI patients who were treated with CRAI via the CA and SMA (patients 6–8) survived. Thus, the mortality of NOMI and NOMI-associated intestinal gangrene was 63% (5/8) and 100% (5/5), respectively. MOF was the cause of death in all patients with intestinal gangrene (ta-
Hirota/Inoue/Kimura/Mizumoto/Kuwata/ Ohmuraya/Ishiko/Beppu/Ogawa
Fig. 1. Microscopic appearance of NOMI-
associated intestinal gangrene. Histology of the intestine showed extensive necrosis of the entire intestinal wall, which is consistent with NOMI-associated gangrene. Case 3, colon. HE stain. !37.
Fig. 2. Portal venous gas on CT. Computed tomography (CT) of case 4 showed portal venous gas in the liver (arrow).
ble 2). We began to perform CRAI via only the CA in 1994, and CRAI via the CA and SMA in 1997. Hence, we did not perform CRAI on patient 1. We did not perform CRAI on patient 5, who was dead on admission, or on patient 4, who was operated on soon after admission.
NOMI and Intestinal Gangrene in Acute Pancreatitis
Discussion
NOMI has been defined as severe intestinal ischemia in the presence of a patent arterial tree. Eight cases of severe acute pancreatitis patients associated with NOMI are presented. Five of these cases showed marked progression and were fatal. Most of the patients developed both DIC and shock, which are speculated to be exaggerating factors of NOMI. Mesenteric arterial spasm was confirmed in all 5 patients who underwent angiography. Plas-
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Fig. 3. Angiographic appearance of mesenteric vessels. Angiography of case 3 showed strong spasm in the CA (a) and SMA (b). Case 8, who received CRAI via the SMA in addition to the CA, showed apparent improvement of arterial spasm after 5 weeks (d) compared with appearance at admission (c).
Fig. 4. Macroscopic appearance of the pancreas in a patient that received CRAI therapy via the celiac artery. One patient (case 3) with NOMI (fig. 3a, b), who was subjected to CRAI with nafamostat mesilate (240 mg/ day) via the CA for 7 days, failed to show massive pancreatic necrosis. Patients with intestinal ischemia as the primary pathology may often have pancreatitis-like symptom and laboratory data. However, because the patient was first diagnosed with biliary pancreatitis without intestinal symptoms, which was exaggerated after endoscopic sphincterotomy, pancreatitis should be considered the primary pathology. Short arrow = Peripancreatic fat necrosis; long arrow = pancreatic necrosis; * = pancreatic parenchyma (head); ** = pancreatic parenchyma (body and tail).
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ma CPK and lactate levels at admission were elevated significantly in patients with NOMI. Because our patient group was selected by referral to our hospital, the incidence of NOMI in acute pancreatitis should be quantified in reference to this referral bias. Focal colonic necrosis, which is not as diffuse as that observed in NOMI patients, is estimated to comprise 1% of the total acute pancreatitis cases [7, 8] and 6–40% of the total necrotizing pancreatitis cases [8, 9]. A possible cause of this necrosis is an inflammatory extension into the mesocolon (vascular occlusion) and/or directly into the colon itself (severe pericolitis). The mortality of pancreatitis patients with focal colonic necrosis is 50–90% [10, 11]. Although NOMI is associated with the same intestinal complications as focal colonic necrosis, the underlying mechanisms are apparently different. Two major mechanisms are proposed for NOMI. Most investigators believe that it is caused by mesenteric vasoconstriction [18, 19], while others have postulated that it is a manifestation of DIC [20, 21]. Furthermore, shock, dehydration and/or increased abdominal pressure may also be associated with NOMI pathogenesis in pancreatitis patients. We propose that all of these factors may contribute to the development of NOMI. The vasoconstrictor endothelin is most likely the mediator for the vascular spasm observed in NOMI patients. Thrombin activates endothelin-converting enzyme-1 to produce endothelin-1 via proteinase-activated receptors [22]. The dynamic aspects of endothelin production in acute pancreatitis in rats are currently being investigated in our laboratory [23]. Mesenteric arterial spasm on angiography, which is commonly found in NOMI patients, was confirmed in 5 patients, 2 of whom died later of MOF. Because mesenteric arterial spasm was detected by angiography relatively early after the onset of acute pancreatitis (table 2), NOMI does not represent a terminal event. These results suggest that ischemic conditions of the intestine such as NOMI are significant steps in the development of MOF. One patient with NOMI (case 3), who showed apparent arterial spasm in both the CA and SMA (fig. 3a, b), was subjected to CRAI with nafamostat mesilate (240 mg/day) via the CA. She failed to show massive pancreatic necrosis at autopsy (fig. 4). Although this may have been a consequence of the severity of insult to the pancreas, it may indicate that CRAI blocks the development of pancreatic necrosis. Local administration of nafamostat mesilate may suppress the enhanced coagulative activity and inhibit the formation of microthrombosis, and therefore maintain pancreatic microcirculation. Because pancreatic necrosis manifests several days after the onset of acute
pancreatitis, improving pancreatic microcirculation may possibly prevent exaggeration from ischemia into necrosis. Maintenance of splanchnic microcirculation may also lead to a block in bacterial translocation through the intestinal mucosa. Hence, CRAI with nafamostat mesilate may inhibit the development and enlargement of necrosis (infarction) of the pancreas and intestine. Similarly, CRAI with nafamostat mesilate has been reported to be beneficial in the treatment of necrotizing pancreatitis [16]. We were able to inhibit the development of intestinal necrosis in some patients with spastic change in the CA and SMA (patients 6–8) by performing CRAI with nafamostat mesilate via both arteries. Thus, CRAI via the SMA may be a useful treatment modality for preventing intestinal gangrene by maintaining tissue microcirculation. If there is a NOMI-associated appearance in SMA angiography, we had better perform CRAI for the SMAperfusing area in addition to the CA-perfusing area. However, this is just speculative, and we need to further evaluate the effect of CRAI. In addition, administration of vasodilators, such as prostaglandin E1 and papaverine, may be another therapeutic modality for NOMI. CPK and lactate levels were extremely high in all patients with NOMI. Although some non-NOMI patients also showed high plasma CPK levels, those may be derived from inflamed back and abdominal wall skeletal muscles. Isozyme analysis of CPK may help differentiate these diagnosis. On the other hand, increased lactate levels may be a reflection of the microcirculatory disturbance. Consequently, an elevation in plasma CPK and lactate levels is indicative of extremely severe pancreatitis. If both CPK and lactate plasma levels are very high, angiography should be performed to check for the presence of NOMI or intestinal gangrene.
NOMI and Intestinal Gangrene in Acute Pancreatitis
Pancreatology 2003;3:316–322
Acknowledgements This study was supported by a Grant-in-Aid for the Research Committee on Intractable Pancreatic Diseases (Chairman: M. Ogawa) provided by the Ministry of Health, Welfare and Labor, Japan, and a Research Grant provided by the Pancreas Research Foundation of Japan.
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