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Labelled granulocytes scanning for the diagnosis of infected necrosis in acute pancreatitis (AP): What kind of labelling should be used?
April 1 9 9 5
ENDOGENOUS ANTICYTOKINES DETERMINE THE PROGNOSIS OF SEVERE ACUTE PANCREATITIS A, HeinLsch. C. BalM, R. Kadow, S: Mann', U. Mann', H. Messmann, J. Schmidt', K. Voelkel', H. ZimgibP, H.-G. Loser. J. Schoelmerich. Depts. of Internal Medicine I and Surgery', University of Regensburg, FRG tptroductioo: Severe acute pancreatitis represents a who(e body inflammation. Mediators of inflammation as agonLsts of systemic inflammatory reactions can be measured in peripheral blood as well as endogenous antagonistic mediators produced by white blood cells. Our prospective controlled study is intended to investigate the pathophysiningy of intiammatory mediators in mild (MAP) and severe acute pancrestitis (SAP). Methods: Serum levels of eytokines (IL-1, tL.6. tL-8, TNF) as agonLstic and TNF receptors (TNFRp55, TNFRp75) as antagonistic mediators of the systemic inflammatory response and (Ll-receptor antagonist (IL1-RA) were measured during the course of MAP and SAP. SAP was defined when necroses of the pancreas in contrast enhanced computed tomography were associated with the failure of at least one organ system (cardiovascular, kidney or respiratory) Patients with SAP were given a standardized intensive care treatment. They were randomized for piasmapheresLs or standard treatment. Results: Initially enhanced cytoldne levels were higher in SAP (TNF 42,4 +29,0; IL-6 500.~340; IL-8 192~-200) than in MAP ('rNF 8,6 ±6,2; IL-6 37±30; IL.8 32,*30). The levels of endogenous antagonists rose to high values in patients with SAP (TNFRp55 10459`*2870; TNFR p75 13796±8077) whereas there was no pronounced increase of TNFR levels in patients with MAP (p55 3924±1547:p75 4447±1543). During the follow up cytoldne and TNFR levels decreased in both. SAP with conservative treatment (p55 11983±1614:p75 10765,.1886) and MAP (p55 2541.,136; p75 3716 `*368). In contrast Patients with SAP treated with piasrnapharesis showed an increase of TNFR's (p55 12628 `.1631; p75 16011±6672) and a better survival rate (75%). in patients with SAP without piasmapheresis TNF receptors decreased in the course of the disease and none survived. Conclusions: initially enhanced cytokine levels reflect the severity of the disease and correlate to the clinical course. Levels of TNF receptors as endogenous antagonLsts could be of prognostic value initially and in particular in the later course of SAP. Piasmapheresis in patients with SAP seemes to further increase the enhanced TNF receptor levels whereas eytokine levels decreased. In SAP with multiple Organ failure release of antagonistic mediators seems to be impaired. The further increase of TNF receptors in patients with SAP and plasrnapheresLs seems to restitute the balance between agon~stic and antagonistic factors either by eliminating agonistic mediators or by stimulating the TNF receptor producing white blood cells.
THE EFFECT OF BLOOD-PURIFIKATION IN THE INITIAL TREATMENT OF SEVERE ACUTE HEMORRHAGIC-NECROTIZINGPANCREATITISOF THE RAT Th. Heller. B. Hornei, J. Emmrich, University of Rostock, Dept. of Internal Medicine Th~ AIM of our study was to evaluate the effect of extracorporal detoxication on the survival time in the treatment of the early vasoactiv-toxic stage of the severe acute pancreatitis. Because of the purification characteristics we choosed the blood-exchange-transfusion (BET), p e r f o r m e d as cross circulation and the plasmapheresis (PP) as membranplasmapheresis. Both methods are very sufficient in eliminating large molecules and proteinbounder substances in contrast to the established peritoneal lavage or dialysis. Especially such substances like activated enzymes (e,g. phospholipase A2, elastase, trypsin) and mediators (e.g. kinin-kallikJ'einsystem, complement-system) or toxic products (e,g. lysolecithin) play an important role in the pathogenesis of the initial ignition of the systemic inflammation. METHOD: We used Wistar~strain rats of 270 to 330 g bodyweight kept under standard conditions with nutrition and aqua ad libitum. First we established the extracorporal circulation by introducing permanent catheters in the arteria carotis communis sinistra and the vena jugularis interna dextra. An acute pancreatitis was induced 24 hrs, later by instillation of 0,1 ml olive-oil/lO0 g body-weight in the pancreatic duct system with a constant volume flow of 10 ml/hr, via transduodenal cannulation of the papilla vateri. One PP treatment was performed another two hrs. later lasting two hrs.. The separated plasma was reinfused in the control-group (ctrl.-gr.) (n=6). We replaced it by fresh separated plasma from healthy animals in the therapy-group (th.-gr.) (n=5), In the other therapy study we performed a blood-purifikation by blood-exchange using a cross-circulation-system. We carried out the circulation four hrs. after induction of the pancreatitis about two hrs,; in the ctTL-gr, between two pancreatitis rats and in the th.-gr, between one healthy and one ill animal. RESULTS: Both methods of extracorporal blood-purification showed a positiv effect on the mean survival time: PP: 9 hrs. in the th.-gr, vs. 3 hrs in the ctrl.-gr.; p < 0,05, BET: 35 hrs. in the th.-gr, vs. 10 hrs. in the ctrL-gr.; p < 0,05. Interestingly the histomorphological exploration of the blood-donor animals in the th.-gr, of the BET showed no effect of the polluted blood on the liver, pancreas, ren and lung. All pancreatitis-rats in the groups died in a full developed severe acute hemorrhagic-necroticing pancreatitis (serumparameters, macroscopic and histopathological findings). CONCLUSION: Our results indicate the benefitial effect of PP and BET in the early stage af a severe pancreatitis independent of an one- or multi-organ-failure,
Pancreatic
Disorders
A359
PLASMAPHERESIS IN SEVERE ACUTE PANCREATITiS A NEW THERAPEUTIC OPTION? A. Heiniach, C. Ball~, R, Kadow, S. Mann*, U. Mann*, H. Messmann, J, Schmidt*, K. Voelkel*, H. Zirngibl% H.-G. Leser, J, Schnelmerich. Depts. of Internal Medicine and Surgery*, University of Regensburg , FRG Introduction: Severe acute pancreatitis (SAP) has still a high mortalitiy due to the frequent developement of multiple organ failure. The prefered treatment is conservative (intensive care, interventionel methods); surgical treatment in desperate cases shows an even higher mortality. Since a positive effect of plasmapheresis has been described in some case reports but has not been proved yet, our prospective controlled study intended to evaluate the benefit of plasmepheresis in patients with SAP. Methods: Pancreatitis was defined as severe acute pancreatitis by 1) clinical and laboratory parameters, 2) the presence of necroses in the contrast enhanced computed tomography and 3 ) failure of at least one organ system (cardiovascular failure, kidney failure, respiratory fai(ure). Patients with SAP were given a standardized intensive care treatment and randomized for plasmapheresis or conservative treatment. Results" So far 5 patients with SAP were included in our study. In the group without plasmapheresis (n=41 ell patients died whereas in the group with plasmapheresis (n=4) only one patient died. Plasmaage sex hospital stay pheresis mean (range} mean (range) with 56 (37-70) 2f, 2m 36,5 (17-70) wthout 71 (59-84 2f, 2m 37 12-123) Plasma-
] disease days number of initial complications | before complications during h~.spitelization follow up Iwith 14 ~ 1,5(1-3) 1,8(1-3) Lwithout 4_2,3 (1-4) 1,8 (1-4) 2,5 (1-3) Conclusion: Our data show a trend to better survival in the group of patients with SAP and plasmaphe~'esis. Further patients have to be included in the study to assess the beneficial effect of plasmapheresis statistically.
• LABELLED GRANULOCYTES SCANNING FOR THE DIAGNOSIS OF INFECTED NECROSIS IN ACUTE PANCREATITIS (AP): WHAT KIND OF LABELLING SHOULD BE USED ? D H e r e s b a o h 1, AF Robot 1, A Devillers 2, A Moisan 2, P Bourguet2, JF Bretagne I, Gosselin M 1 - Depts of Gastroenterology (1) & Nuclear Medicine (2) CHRU Pontchaillou - 35033 Rennes, France. Diagnosis of infected necrosis in AP is rarely based on clinical or radiological features, but mainly on the results of fine needle aspiration of fluid collections. The interest of HMPAO-99mTc (To) labelled leukocyte scintiscan (SC) has been recently mentioned, but the technical conditions of this test must be precised because of the early digestive elimination of To. T h e aim of the present study was to determine sensitivity and specificity of simultaneous 111-Indium (In) and To-labelled leukocyte SC for the diagnosis of infected necrosis. Patients & M e t h o d s : 32 studies were performed in 31 consecutive padents (M/F = 18/6, aged 56 + 2 yrs). They underwent CT scan within 20+_2 days following the onset of AP, which were classified into class A , B or C (n = 9) and D or E (n = 23) according to Balthazar's classification. SC (23+_3 days following the onset of AP) comprised a 40 minutes (mini long tomography, a 5 rain long anterior static imaging performed 1 hour (S1) and 4 hours ($2) respectively after the administration of To- labelled granulocytes, and a 5 and 10 min long anterior and posterior static imaging performed 4 hours ($3) and 2,1 hours ($4) after the administration of Inlabelled granulocytes. The uptake was evaluated semi-quantitatively by two independent investigators. The fall in splenic area activity (FSA) between $3 and $4 was also determined. The final diagnosis of infection (n = 10) was J~ased on the results of fine needle aspiration (n = 16) performed 9+_2"days after SC, or of the subsequent clinical course (n = 16, 7 -+ 1 months). Results : Sensitivity and specificity of SC were 80% and 77% respectively for S1, and 100% and 56% for $2. They were 90% and 73% for $3, 100% and 68% for $4. Comparing false positives to true negatives for $1, antibiotherapy was not more frequent (2/5 vs 8]17) bu more longer (12+_1 vs 5+_1 d respectively) in false positives. False positiv{ cases for $2, $3 and $4 may be explained by a colonic activity observed In cases of infected and sterile necrosis, FSA was equal to 22+_3% an, 13+2% (p < 0.01), respectively. Same data in term of sensitivity an specificity were observed if we considered only the 16 patients explore by fine needle aspiration. Conclusions : The diagnosis of infected necrosis in AP is made at be on early (1 hour) Tc- labelled granulocyte SC,or on a 4 hours In SC. fall in splenic activity higher than 20% is also of predictive value.
ENDOGENOUS ANTICYTOKINES DETERMINE THE PROGNOSIS OF SEVERE ACUTE PANCREATITIS A, HeinLsch. C. BalM, R. Kadow, S: Mann', U. Mann', H. Messmann, J. Schmidt', K. Voelkel', H. ZimgibP, H.-G. Loser. J. Schoelmerich. Depts. of Internal Medicine I and Surgery', University of Regensburg, FRG tptroductioo: Severe acute pancreatitis represents a who(e body inflammation. Mediators of inflammation as agonLsts of systemic inflammatory reactions can be measured in peripheral blood as well as endogenous antagonistic mediators produced by white blood cells. Our prospective controlled study is intended to investigate the pathophysiningy of intiammatory mediators in mild (MAP) and severe acute pancrestitis (SAP). Methods: Serum levels of eytokines (IL-1, tL.6. tL-8, TNF) as agonLstic and TNF receptors (TNFRp55, TNFRp75) as antagonistic mediators of the systemic inflammatory response and (Ll-receptor antagonist (IL1-RA) were measured during the course of MAP and SAP. SAP was defined when necroses of the pancreas in contrast enhanced computed tomography were associated with the failure of at least one organ system (cardiovascular, kidney or respiratory) Patients with SAP were given a standardized intensive care treatment. They were randomized for piasmapheresLs or standard treatment. Results: Initially enhanced cytoldne levels were higher in SAP (TNF 42,4 +29,0; IL-6 500.~340; IL-8 192~-200) than in MAP ('rNF 8,6 ±6,2; IL-6 37±30; IL.8 32,*30). The levels of endogenous antagonists rose to high values in patients with SAP (TNFRp55 10459`*2870; TNFR p75 13796±8077) whereas there was no pronounced increase of TNFR levels in patients with MAP (p55 3924±1547:p75 4447±1543). During the follow up cytoldne and TNFR levels decreased in both. SAP with conservative treatment (p55 11983±1614:p75 10765,.1886) and MAP (p55 2541.,136; p75 3716 `*368). In contrast Patients with SAP treated with piasrnapharesis showed an increase of TNFR's (p55 12628 `.1631; p75 16011±6672) and a better survival rate (75%). in patients with SAP without piasmapheresis TNF receptors decreased in the course of the disease and none survived. Conclusions: initially enhanced cytokine levels reflect the severity of the disease and correlate to the clinical course. Levels of TNF receptors as endogenous antagonLsts could be of prognostic value initially and in particular in the later course of SAP. Piasmapheresis in patients with SAP seemes to further increase the enhanced TNF receptor levels whereas eytokine levels decreased. In SAP with multiple Organ failure release of antagonistic mediators seems to be impaired. The further increase of TNF receptors in patients with SAP and plasrnapheresLs seems to restitute the balance between agon~stic and antagonistic factors either by eliminating agonistic mediators or by stimulating the TNF receptor producing white blood cells.
THE EFFECT OF BLOOD-PURIFIKATION IN THE INITIAL TREATMENT OF SEVERE ACUTE HEMORRHAGIC-NECROTIZINGPANCREATITISOF THE RAT Th. Heller. B. Hornei, J. Emmrich, University of Rostock, Dept. of Internal Medicine Th~ AIM of our study was to evaluate the effect of extracorporal detoxication on the survival time in the treatment of the early vasoactiv-toxic stage of the severe acute pancreatitis. Because of the purification characteristics we choosed the blood-exchange-transfusion (BET), p e r f o r m e d as cross circulation and the plasmapheresis (PP) as membranplasmapheresis. Both methods are very sufficient in eliminating large molecules and proteinbounder substances in contrast to the established peritoneal lavage or dialysis. Especially such substances like activated enzymes (e,g. phospholipase A2, elastase, trypsin) and mediators (e.g. kinin-kallikJ'einsystem, complement-system) or toxic products (e,g. lysolecithin) play an important role in the pathogenesis of the initial ignition of the systemic inflammation. METHOD: We used Wistar~strain rats of 270 to 330 g bodyweight kept under standard conditions with nutrition and aqua ad libitum. First we established the extracorporal circulation by introducing permanent catheters in the arteria carotis communis sinistra and the vena jugularis interna dextra. An acute pancreatitis was induced 24 hrs, later by instillation of 0,1 ml olive-oil/lO0 g body-weight in the pancreatic duct system with a constant volume flow of 10 ml/hr, via transduodenal cannulation of the papilla vateri. One PP treatment was performed another two hrs. later lasting two hrs.. The separated plasma was reinfused in the control-group (ctrl.-gr.) (n=6). We replaced it by fresh separated plasma from healthy animals in the therapy-group (th.-gr.) (n=5), In the other therapy study we performed a blood-purifikation by blood-exchange using a cross-circulation-system. We carried out the circulation four hrs. after induction of the pancreatitis about two hrs,; in the ctTL-gr, between two pancreatitis rats and in the th.-gr, between one healthy and one ill animal. RESULTS: Both methods of extracorporal blood-purification showed a positiv effect on the mean survival time: PP: 9 hrs. in the th.-gr, vs. 3 hrs in the ctrl.-gr.; p < 0,05, BET: 35 hrs. in the th.-gr, vs. 10 hrs. in the ctrL-gr.; p < 0,05. Interestingly the histomorphological exploration of the blood-donor animals in the th.-gr, of the BET showed no effect of the polluted blood on the liver, pancreas, ren and lung. All pancreatitis-rats in the groups died in a full developed severe acute hemorrhagic-necroticing pancreatitis (serumparameters, macroscopic and histopathological findings). CONCLUSION: Our results indicate the benefitial effect of PP and BET in the early stage af a severe pancreatitis independent of an one- or multi-organ-failure,
Pancreatic
Disorders
A359
PLASMAPHERESIS IN SEVERE ACUTE PANCREATITiS A NEW THERAPEUTIC OPTION? A. Heiniach, C. Ball~, R, Kadow, S. Mann*, U. Mann*, H. Messmann, J, Schmidt*, K. Voelkel*, H. Zirngibl% H.-G. Leser, J, Schnelmerich. Depts. of Internal Medicine and Surgery*, University of Regensburg , FRG Introduction: Severe acute pancreatitis (SAP) has still a high mortalitiy due to the frequent developement of multiple organ failure. The prefered treatment is conservative (intensive care, interventionel methods); surgical treatment in desperate cases shows an even higher mortality. Since a positive effect of plasmapheresis has been described in some case reports but has not been proved yet, our prospective controlled study intended to evaluate the benefit of plasmepheresis in patients with SAP. Methods: Pancreatitis was defined as severe acute pancreatitis by 1) clinical and laboratory parameters, 2) the presence of necroses in the contrast enhanced computed tomography and 3 ) failure of at least one organ system (cardiovascular failure, kidney failure, respiratory fai(ure). Patients with SAP were given a standardized intensive care treatment and randomized for plasmapheresis or conservative treatment. Results" So far 5 patients with SAP were included in our study. In the group without plasmapheresis (n=41 ell patients died whereas in the group with plasmapheresis (n=4) only one patient died. Plasmaage sex hospital stay pheresis mean (range} mean (range) with 56 (37-70) 2f, 2m 36,5 (17-70) wthout 71 (59-84 2f, 2m 37 12-123) Plasma-
] disease days number of initial complications | before complications during h~.spitelization follow up Iwith 14 ~ 1,5(1-3) 1,8(1-3) Lwithout 4_2,3 (1-4) 1,8 (1-4) 2,5 (1-3) Conclusion: Our data show a trend to better survival in the group of patients with SAP and plasmaphe~'esis. Further patients have to be included in the study to assess the beneficial effect of plasmapheresis statistically.
• LABELLED GRANULOCYTES SCANNING FOR THE DIAGNOSIS OF INFECTED NECROSIS IN ACUTE PANCREATITIS (AP): WHAT KIND OF LABELLING SHOULD BE USED ? D H e r e s b a o h 1, AF Robot 1, A Devillers 2, A Moisan 2, P Bourguet2, JF Bretagne I, Gosselin M 1 - Depts of Gastroenterology (1) & Nuclear Medicine (2) CHRU Pontchaillou - 35033 Rennes, France. Diagnosis of infected necrosis in AP is rarely based on clinical or radiological features, but mainly on the results of fine needle aspiration of fluid collections. The interest of HMPAO-99mTc (To) labelled leukocyte scintiscan (SC) has been recently mentioned, but the technical conditions of this test must be precised because of the early digestive elimination of To. T h e aim of the present study was to determine sensitivity and specificity of simultaneous 111-Indium (In) and To-labelled leukocyte SC for the diagnosis of infected necrosis. Patients & M e t h o d s : 32 studies were performed in 31 consecutive padents (M/F = 18/6, aged 56 + 2 yrs). They underwent CT scan within 20+_2 days following the onset of AP, which were classified into class A , B or C (n = 9) and D or E (n = 23) according to Balthazar's classification. SC (23+_3 days following the onset of AP) comprised a 40 minutes (mini long tomography, a 5 rain long anterior static imaging performed 1 hour (S1) and 4 hours ($2) respectively after the administration of To- labelled granulocytes, and a 5 and 10 min long anterior and posterior static imaging performed 4 hours ($3) and 2,1 hours ($4) after the administration of Inlabelled granulocytes. The uptake was evaluated semi-quantitatively by two independent investigators. The fall in splenic area activity (FSA) between $3 and $4 was also determined. The final diagnosis of infection (n = 10) was J~ased on the results of fine needle aspiration (n = 16) performed 9+_2"days after SC, or of the subsequent clinical course (n = 16, 7 -+ 1 months). Results : Sensitivity and specificity of SC were 80% and 77% respectively for S1, and 100% and 56% for $2. They were 90% and 73% for $3, 100% and 68% for $4. Comparing false positives to true negatives for $1, antibiotherapy was not more frequent (2/5 vs 8]17) bu more longer (12+_1 vs 5+_1 d respectively) in false positives. False positiv{ cases for $2, $3 and $4 may be explained by a colonic activity observed In cases of infected and sterile necrosis, FSA was equal to 22+_3% an, 13+2% (p < 0.01), respectively. Same data in term of sensitivity an specificity were observed if we considered only the 16 patients explore by fine needle aspiration. Conclusions : The diagnosis of infected necrosis in AP is made at be on early (1 hour) Tc- labelled granulocyte SC,or on a 4 hours In SC. fall in splenic activity higher than 20% is also of predictive value.