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Inflammatory Mediators in Human Acute Pancreatitis

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Inflammatory Mediators in Human Acute Pancreatitis 546 Gut 2000;47:546–552 Inflammatory mediators in human acute pancreatitis: clinical and pathophysiological Gut: first published as 10.1136/gut.47.4.546 on 1 October 2000. Downloaded from implications J Mayer, B Rau, F Gansauge, H G Beger Abstract sources during the course of the disease.1 Background—The time course and rela- Studies on AP have demonstrated that these tionship between circulating and local mediators are produced in a variety of tissues in cytokine concentrations, pancreatic in- a predictable sequence, initiated by local flammation, and organ dysfunction in release of proinflammatory mediators such as acute pancreatitis are largely unknown. interleukin (IL)-1â, IL-6, and IL-8, which Patients and methods—In a prospective induce a systemic inflammatory response clinical study, we measured the pro- reflected by increased levels of soluble inter- inflammatory cytokines interleukin (IL)- leukin 2 receptor (sIL-2R), neopterin, or 1â, IL-6 and IL-8, the anti-inflammatory tumour necrosis factor á (TNF-á). This results cytokine IL-10, interleukin 1â receptor in inflammatory infiltration of distant organs antagonist (IL-1RA), and the soluble IL-2 with multiorgan failure and death.1 receptor (sIL-2R), and correlated our The systemic inflammatory response is kept findings with organ and systemic compli- at bay by local and systemic release of anti- cations in acute pancreatitis. In 51 pa- inflammatory mediators such as interleukin 1â tients with acute pancreatitis admitted receptor antagonist (IL-1RA) and IL-10 which within 72 hours after the onset of symp- were shown to reduce the severity of pancreatitis 2–5 toms, these parameters were measured and pancreatitis associated organ failure. daily for seven days. In addition, 33 These observations demonstrate the potential of aspirates from ascites and the lesser sac immunomodulation in preventing pancreatitis were measured. associated organ failure. Results—Sixteen patients had mild acute However, little is known of the relationship pancreatitis (AP) and 35 severe AP between the clinical course of AP in humans (Atlanta classification); 18 patients devel- and the dynamics of the major cytokines, both http://gut.bmj.com/ oped systemic complications requiring locally and in the systemic circulation, in the treatment. All mediators were increased presence or absence of distant organ complica- in AP. sIL-2R, IL-10, and IL-6 were tions. Therefore, we examined the relationship significantly elevated in patients with dis- between local and systemic mediators in early tant organ failure. An imbalance in IL-1â/ AP in a prospective clinical trial. IL-1RA was found in severe AP and pulmonary failure. Peak serum sIL-2R Patients and methods predicted lethal outcome and IL-1RA was DEFINITIONS on September 27, 2021 by guest. Protected copyright. an early marker of severity. IL-6 was the Mild acute pancreatitis (MAP) was defined best prognostic parameter for pulmonary according to the Atlanta classification6 as con- failure. firmed acute pancreatitis without development Conclusion—Our results suggest that of one or more major local or systemic compli- local mediator release, with a probable cations caused by pancreatitis. Severe acute IL-1â-IL-1RA imbalance in severe cases, pancreatitis (SAP) was defined as AP associ- is followed by the systemic appearance of ated with one or more major local or systemic pro- and anti-inflammatory mediators. complications caused by pancreatitis. Local The pattern of local and systemic media- complications include pancreatic necrosis, Department of tors in complicated AP suggests a role for acute pancreatic fluid collection, pancreatic General Surgery, systemic lymphocyte activation (triggered pseudocyst, or pancreatic abscess. Systemic University Hospital of by local release of mediators) in distant complications include respiratory failure (pO2 Ulm, Ulm, Germany organ complications in severe AP. <60 mm Hg requiring oxygen therapy for J Mayer (Gut 2000;47:546–552) B Rau longer than 24 hours or mechanical ventila- F Gansauge tion), cardiocirculatory failure (systolic blood Keywords: pancreatitis; cytokines; lymphocyte H G Beger pressure <80 mm Hg for more than 15 activation; pancreatic necrosis; organ complications minutes), renal failure (serum creatinine Correspondence to: Dr H G Beger Department of General Surgery, Morbidity and mortality in acute pancreatitis Abbreviations used in this paper: IL, interleukin; University Hospital of Ulm, (AP) is largely determined by distant organ IL-1RA, interleukin 1â receptor antagonist; sIL-2R, Steinhövelstr. 9, D-89075 soluble interleukin 2 receptor; AP, acute pancreatitis; Ulm/ Germany. Email: failure in severe attacks. These systemic mani- hans.beger@ festations of a disease initially limited to the MAP, mild AP; SAP, severe AP; TNF-á, tumour medizin.uni-ulm.de necrosis factor á; SIRS, systemic inflammatory pancreas are thought to be mediated by a vari- response syndrome; CRP, C reactive protein; LR, Accepted for publication ety of pro- and anti-inflammatory mediators likelihood ratio; ERCP, endoscopic retrograde 4 April 2000 released from the pancreas and various other cholangiopancreatography. www.gutjnl.com Cytokines in pancreatitis 547 Table 1 Complications of mild and severe acute pancreatitis (AP) Infected Necrosis Pulmonary Renal Death Sepsis Shock necrosis Gut: first published as 10.1136/gut.47.4.546 on 1 October 2000. Downloaded from Mild AP (n=16) 0 2 without ventilation 1 without dialysis – – – – Severe AP (n=35) 34 12 without ventilation, 18 with 8 without dialysis 6 with 13 11 7 without catecholamines 9 ventilation dialysis 12 with catecholamines >2 mg% in the absence of prior renal with severe AP, 34 had pancreatic necrosis and insuYciency), or the presence of gastro- one patient with interstitial pancreatitis suf- intestinal haemorrhage. Bacteria negative sep- fered from renal failure. Thirteen patients with sis was defined as the systemic inflammatory pancreatic necrosis died during their hospital response syndrome (SIRS) without positive stay, resulting in an overall hospital mortality of blood culture according to the definitions of 25.5%. Of the patients who died, six (46%) the ACCP/SCCM consensus conference suVered from infected necroses, while in the committee.7 Sepsis was defined as blood survivor group only three patients (15.8%) had culture positive SIRS. bacterial infection. In severe AP, 19 patients suVered from cardiocirculatory failure PATIENTS (“shock”), 12 of whom were treated with intra- Patients with confirmed AP (clinical symp- venous catecholamines. Only two patients with toms, amylase/lipase greater than three times pancreatic necrosis did not develop any sys- the upper limit, and pancreatitis on ultrasound temic complications; 14 developed systemic or computed tomography scan) who were complications but needed no intervention admitted to our hospital as primary or second- while 18 developed systemic complications ary referrals within 72 hours after the onset of requiring mechanical ventilation (n=18), dialy- symptoms were prospectively entered into the sis (n=6), or surgical intervention (n=10) study. The study was performed according to (table 1). local ethics committee regulations and in- formed consent was obtained. Exclusion crite- ria were age <18 years, infection with hepatitis METHODS or human immunodeficiency virus, pregnancy, The cytokines IL-1â, IL-6, IL-10, the antag- and refusal of consent. A total of 51 patients onist IL-1RA, and the soluble IL-2 receptor were included in the study; 16 suVered from (sIL-2R) were measured in serum at intervals mild AP (MAP) and 35 from severe AP (SAP) using commercially available ELISA kits (DPC according to the Atlanta classification.6 Of the Biermann, Bad Nauheim, Germany and R&D patients with MAP, seven were male and nine System, Oxford, UK) on a standard ELISA reader according to the manufacturer’s instruc- were female (median age 65 years (range http://gut.bmj.com/ 19–83)). The aetiology in MAP was biliary tions. IL-8 was measured by a chemilumines- (n=10),alcoholic (n=4),post-endoscopic retro- cent immunoassay using the Immulite auto- grade cholangiopancreatography (ERCP) mated Luminometer (DPC Biermann, Bad (n=1), and idiopathic (n=1). Twenty four Nauheim, Germany). The cytokines were patients with SAP were male and 11 were chosen based on experience obtained in previ- female (median age 46 years (range 32–79)). ous studies. As markers for pancreatic and The aetiology in SAP was alcoholic (n=20), monocyte/macrophage cytokine release,8–10 the biliary (n=11), post-ERCP (n=3), and idio- proinflammatory IL-1â and its receptor an- on September 27, 2021 by guest. Protected copyright. pathic (n=1). Median Ranson scores were 3 for tagonist IL-1RA were chosen. TNF-á was not MAP and 6 for SAP, and median admission measured as it is unstable, diYcult to measure APACHE II scores were 7 for MAP and 14 for in the clinical setting, and is expressed in the SAP. Both scores were significantly higher in pancreas in a similar manner as IL-1â.11 As a SAP than in MAP (p<0.05). marker of lymphocyte activation, we measured All patients with mild AP suVered from the soluble cleaved interleukin 2 receptor interstitial pancreatitis; two of these patients CD25, sIL-2R. IL-6 was determined as a lym- developed pulmonary insuYciency but did not phocyte activating cytokine and IL-8 as a neu- require mechanical ventilation. Of 35 patients trophil activating chemokine. IL-10 was Table 2 Peak values of routine chemical parameters in serum in mild and severe acute pancreatitis (AP) (mean
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