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Controlled randomized multicenter trial of urgent endoscopic papillotomy for acute biliary pancreatitis
April 1995
Pancreatic
*A.Szlachcic, *S.J.Konturek, W.Domschke. Department of Medicine B, University of MOnster, MOnster, Germany and *Institute of Physiology, University of Krakow, Krakow, Poland.
Ho.spital, Free Univ.of Berlin and 2Univ.of Heidelberg, Germany We have previously demonstrated that the combination of alcohol (ALC) and exocrine hyperstimulation (ES) causes acinar cell injury which is not found when the pancreas is exposed to ALC or ES alone (Arch Surg 1994). The mechanism for this synergistic adverse effect is not known. Since ALC reduces oxygen delivery to the pancreas we speculated that impairment of pancreatic microcirculation may be involved although ES is known to increase pancreatic blood flow. To evaluate this possibility we measured capillary pancreatic blood flow (PBF) by means of intravital microscopy and pancreatic tissue oxygen saturation (SOs) by means of pulse oximetry in rats before and after exposure to ALC and ES. After exposure of the pancreas for either intravital microscopy or pulse oximetry anesthetized rats were randomly allocated for iv. infusion of a) [ALC] 2g/kg/h ethanol (n= 14); b) [ES] 5#g/kg/h cerulein (n= 14); c) [ALC+ES] (n=14); or d) [CONTR] NaCl 0.9% (n=10). Mean arterial pressure (MAP) and arterial blood gases (ABG) were monitored, and PBF and pancreatic SO2 determined at the same location before (BL) and 1 hr after the start of the test solutions. There were no significant changes in MAP and ABG during the experiment and no differences between test groups at any time point. PBF and SOs did not change in control animals given NaC10.9 %, whereas ALC decreased PBF (BL: 2.0_+0.05 nllmin/cap; after lhr: 1.6_+0.1hi/rain/cap; p < 0.05; paired t-test) and pancreatic SO2 (92_+1% vs 88_+1% ; p < 0.05); ES alone increased PBF (1.8_+0.1 vs 2.2+0.1 hi/rain/cap; p<0.05), SOs did not change. In contrast, we found decreased PBF (1.9_+0. l vs 1.4_+0~2 hi/rain/cap; p<0.05) and SO2 (93_+1 vs 90_+1%; p<0.05) in animals subjected to ALC+ES. The present data in conjunction with our previous observation that ALC and ES (but not ALC or ES alone) cause acinar cell necrosis suggest that the synergistic adverse effect of alcohol and exocrine hyperstimulation on the pancreas is linked by regional ischemia and hypoxemia.Alcohol-induced reduction of pancreatic microperfusion may be especially harmful in this situation because pancreatic oxygen demand is likely to be increased in the state of exocrine hyperstimulation.
The decrease in pancreatic exocrine secretion during the course of acute pancreatitis is a well documented process. However, t h e mechanisms underlying this reduced pancreatic function are not fully understood. To analyze pancreatic protein synthesis and secretion during and after caerulein-induced pancreatitis we performed the plasma amino acid consumption test on conscious rats. After stimulation with 1 IJg caeruleirdkg/h s.c. for 1 hour, the control group with intact pancreas exhibited a decrease in plasma amino acids by about 15% . and this decrease could be abolished by the administration of the specific CCK-receptor antagonist, Ioxiglumide. Protein and amylase secretion were augmented by caerulein to about 400% of control values. Upon supramaximal stimulation of the pancreas with caerulein (20 pglkg/h s.c. for 5 h) we observed a decrease of pancreatic secretion, which was accompanied by a more prolonged and more pronounced decrease of plasma amino acids (25%). Two hours after cessation of the supramaximal stimulation of pancreatic secretion (to induce pancreatitis), the administration of 1 pg/kg/h of caerulein for one hour resulted in a further decrease of plasma amino acid level whereas no stimulation of exocrine pancreatic secretion was observed. Eighteen hours later, repeated administration of 1 pg/kg/h of caerulein was still able to induce amino acid decrease by 20 percent, but again, no stimulation of exocrme pancreatic secretior7 was detectable. We conclude that in the time course of acute caerulein-induced pancreatitis there might be an imbalance between synthesis of Pthancreatic enzymes (reflected by amino acid consumption) and e release of exocrine pancreatic secretion into the duodenum, which may be explained by discharge of proteolytic enzymes into the extracellular space of the pancreas.
CONTROLLED RANDOMIZED MULTICENTER TRIAL OF URGENT ENDOSCOPIC PAPILLOTOMY FOR ACUTE BILIARY PANCREATITIS U.R. Fglsch, R. Nitsche, R. LOdtke, R.A. Hilgers, W. Creutzfeldt and the German Study Group of Acute Biliary Pancreatitis, Depts of Medicine, University of Kiel and of Medical Statistics, University of GOttingen, FRG In two monocenter trials the impact of urgent endoscopicretrograde cholanginpancreatography (ERCP) with endoscopic papiilntomy (EPT) in case of bile duct stones on lethality and local and systemic complications in acute biliary pancreatitis (ABP) remained controversial (Lancet 979,1988; NEJM 328,228,t993). Therefore, we conducted a multicenter trial of urgent ERCP in patients (pts) with ABP but without obstructive jaundice. In 22 German hospitals 238 pts have been randomized between 1989 and 1994 either to receive urgent ERCP within 72 hours since the beginning of abdominal pain (107 pts) or conventional management (99 pts). 32 pts had to be excluded because inclusion criteria had not been followed. In the conventional group ERCP was only performed in case of a) persistent biliary colics, b) septical fever, or c) increase of serum bilirubin of more than 3 mg % (51 mmol/I) within 5 days. If common bile duct stones~ (CGS) were identified at ERCP, EPT was undertaken and the stones extracted. Results: In the invasive treatment group urgent ERCP was successfulin 102 (95%) of the 107 pts. In 51 pts (50%) CBS were detected and EPT performed. EPT was successfulin 49 pts and in 44 pts stones were successfully removed. Local and systemic complications as well as iethality in both treatment groups are given in the table.
Resp, Renal Fail. Fail.
ChoL cyst.
A353
ADVERSE EFFECT OF ALCOHOL AND EXOCRINE HYPERSTIMULATION ON PANCREATIC MICROCIRCULATION AND TISSUE OXYGENATION. Th,Foitzik t, I-I.G.Hotz1, B.Forgacs 2' W.Schratt 2, E.Klar ~, H.J.Buhr L. Depts.of Surgery/Benjamin Franklin
PLASMA AMINO ACID CONSUMPTION AND PANCREATIC SECRETION DURING AND AFTER CAERULEIN-INDUCED PANCREATITIS IN RATS. H.Fischer, J.W.Konturek,
•
Disorders
Cholan- Icterus Sepsis Lethality
gitis
Invasjve group n - 107
12
7
10
1t
1
10
7
Conventional group
5
4
16
11
8*
13
4
n - 99 *p
•
EFFECTS OF C H O L E C Y S T O K I N I N (CCK) O N C A L C I U M O U T F L U X FROM PANCREATIC ACINI IS M E D I A T E D BY THE HIGH AFFINITY S T A T E OF THE CCK RECEPTOR A N D IS N O T C A U S E D BY INCREASED INOSlTOL PHOSPHATE. K.P. Fortune, V.D.Talkad, S.N.Joshi, d.D.Gardner. Saint
Louis University, St.Louis, MO. 63104 The pancreatic CCK receptor exists in 3 different affinity states for CCK-8 - high affinity, low affinity and very low affinity. The effects of CCK-8 on cytosolic Ca measured in a stirred cuvette or on outflux of 4~Ca are thought to reflect interaction of CCK-8 with the low or very low affinity state of the CCK receptor. The major findings that supported this conclusion were obtained using CCK-JMV-180, which appeared to have a high affinity for the high affinity state of the CCK receptor where it acted as an agonist and a low affinity for the low affinity state of the CCK receptor where it acted as an antagonist. Recently, using a variety of state-selective ligands we have demonstrated that CCK-JMV-180 actually has a high affinity for the low affinity state of the CCK receptor and a low affinity for the high affinity state of the CCK receptor (BBA 1224,103,1994). We have reanalyzed our previous results for outflux of 4~Cawith CCK-8 and CCK-JMV-1 80 (Am.J.Physiol. 257,G202,1989). We have also tested the effects of two receptor antagonists, L-364,718, which has the same affinities for the 3 different states of the CCK receptor, and CCK-JMV-179, which has different affinities for each different state of the CCK receptor on outflux of *SCa and formation of [3HIinositol phosphate stimulated by CCK-8. We have compared these effects with those of the antagonists on CCK-8 occupation of the different CCK receptor affinity states determined from binding of ~251CCK-8 and [5H]L-364,718. CCK-8 caused a 5-fold increase in 46Caoutflux and CCK-JMV-180 was 60% as efficacious as CCK-8. The effects of these two peptides alone and in combination were superimposable with their effects predicted from occupation of the high affinity state of the CCK receptor. The effects of L-364,718 and CCK-JMV-179 on CCK-8stimulated outflux of 46Ca were consistent with CCK-8 occupation of the high affinity state. The effects of these antagonists on CCK-8-stimulated formation of [ZHIinositol phosphate were consistent with CCK-8 occupation of the low affinity state.The present results indicate that outflux of 45Ca from pancreatic acini is mediated by agonists occupying the high affinity state of the CCK receptor. Since CCK-8-induced formation of inositol phosphate is mediated bythe low affinity state of the CCK receptor, agonist-induced formation of inositol phosphate does not produce the increased outflux of 45Ca.
Pancreatic
*A.Szlachcic, *S.J.Konturek, W.Domschke. Department of Medicine B, University of MOnster, MOnster, Germany and *Institute of Physiology, University of Krakow, Krakow, Poland.
Ho.spital, Free Univ.of Berlin and 2Univ.of Heidelberg, Germany We have previously demonstrated that the combination of alcohol (ALC) and exocrine hyperstimulation (ES) causes acinar cell injury which is not found when the pancreas is exposed to ALC or ES alone (Arch Surg 1994). The mechanism for this synergistic adverse effect is not known. Since ALC reduces oxygen delivery to the pancreas we speculated that impairment of pancreatic microcirculation may be involved although ES is known to increase pancreatic blood flow. To evaluate this possibility we measured capillary pancreatic blood flow (PBF) by means of intravital microscopy and pancreatic tissue oxygen saturation (SOs) by means of pulse oximetry in rats before and after exposure to ALC and ES. After exposure of the pancreas for either intravital microscopy or pulse oximetry anesthetized rats were randomly allocated for iv. infusion of a) [ALC] 2g/kg/h ethanol (n= 14); b) [ES] 5#g/kg/h cerulein (n= 14); c) [ALC+ES] (n=14); or d) [CONTR] NaCl 0.9% (n=10). Mean arterial pressure (MAP) and arterial blood gases (ABG) were monitored, and PBF and pancreatic SO2 determined at the same location before (BL) and 1 hr after the start of the test solutions. There were no significant changes in MAP and ABG during the experiment and no differences between test groups at any time point. PBF and SOs did not change in control animals given NaC10.9 %, whereas ALC decreased PBF (BL: 2.0_+0.05 nllmin/cap; after lhr: 1.6_+0.1hi/rain/cap; p < 0.05; paired t-test) and pancreatic SO2 (92_+1% vs 88_+1% ; p < 0.05); ES alone increased PBF (1.8_+0.1 vs 2.2+0.1 hi/rain/cap; p<0.05), SOs did not change. In contrast, we found decreased PBF (1.9_+0. l vs 1.4_+0~2 hi/rain/cap; p<0.05) and SO2 (93_+1 vs 90_+1%; p<0.05) in animals subjected to ALC+ES. The present data in conjunction with our previous observation that ALC and ES (but not ALC or ES alone) cause acinar cell necrosis suggest that the synergistic adverse effect of alcohol and exocrine hyperstimulation on the pancreas is linked by regional ischemia and hypoxemia.Alcohol-induced reduction of pancreatic microperfusion may be especially harmful in this situation because pancreatic oxygen demand is likely to be increased in the state of exocrine hyperstimulation.
The decrease in pancreatic exocrine secretion during the course of acute pancreatitis is a well documented process. However, t h e mechanisms underlying this reduced pancreatic function are not fully understood. To analyze pancreatic protein synthesis and secretion during and after caerulein-induced pancreatitis we performed the plasma amino acid consumption test on conscious rats. After stimulation with 1 IJg caeruleirdkg/h s.c. for 1 hour, the control group with intact pancreas exhibited a decrease in plasma amino acids by about 15% . and this decrease could be abolished by the administration of the specific CCK-receptor antagonist, Ioxiglumide. Protein and amylase secretion were augmented by caerulein to about 400% of control values. Upon supramaximal stimulation of the pancreas with caerulein (20 pglkg/h s.c. for 5 h) we observed a decrease of pancreatic secretion, which was accompanied by a more prolonged and more pronounced decrease of plasma amino acids (25%). Two hours after cessation of the supramaximal stimulation of pancreatic secretion (to induce pancreatitis), the administration of 1 pg/kg/h of caerulein for one hour resulted in a further decrease of plasma amino acid level whereas no stimulation of exocrine pancreatic secretion was observed. Eighteen hours later, repeated administration of 1 pg/kg/h of caerulein was still able to induce amino acid decrease by 20 percent, but again, no stimulation of exocrme pancreatic secretior7 was detectable. We conclude that in the time course of acute caerulein-induced pancreatitis there might be an imbalance between synthesis of Pthancreatic enzymes (reflected by amino acid consumption) and e release of exocrine pancreatic secretion into the duodenum, which may be explained by discharge of proteolytic enzymes into the extracellular space of the pancreas.
CONTROLLED RANDOMIZED MULTICENTER TRIAL OF URGENT ENDOSCOPIC PAPILLOTOMY FOR ACUTE BILIARY PANCREATITIS U.R. Fglsch, R. Nitsche, R. LOdtke, R.A. Hilgers, W. Creutzfeldt and the German Study Group of Acute Biliary Pancreatitis, Depts of Medicine, University of Kiel and of Medical Statistics, University of GOttingen, FRG In two monocenter trials the impact of urgent endoscopicretrograde cholanginpancreatography (ERCP) with endoscopic papiilntomy (EPT) in case of bile duct stones on lethality and local and systemic complications in acute biliary pancreatitis (ABP) remained controversial (Lancet 979,1988; NEJM 328,228,t993). Therefore, we conducted a multicenter trial of urgent ERCP in patients (pts) with ABP but without obstructive jaundice. In 22 German hospitals 238 pts have been randomized between 1989 and 1994 either to receive urgent ERCP within 72 hours since the beginning of abdominal pain (107 pts) or conventional management (99 pts). 32 pts had to be excluded because inclusion criteria had not been followed. In the conventional group ERCP was only performed in case of a) persistent biliary colics, b) septical fever, or c) increase of serum bilirubin of more than 3 mg % (51 mmol/I) within 5 days. If common bile duct stones~ (CGS) were identified at ERCP, EPT was undertaken and the stones extracted. Results: In the invasive treatment group urgent ERCP was successfulin 102 (95%) of the 107 pts. In 51 pts (50%) CBS were detected and EPT performed. EPT was successfulin 49 pts and in 44 pts stones were successfully removed. Local and systemic complications as well as iethality in both treatment groups are given in the table.
Resp, Renal Fail. Fail.
ChoL cyst.
A353
ADVERSE EFFECT OF ALCOHOL AND EXOCRINE HYPERSTIMULATION ON PANCREATIC MICROCIRCULATION AND TISSUE OXYGENATION. Th,Foitzik t, I-I.G.Hotz1, B.Forgacs 2' W.Schratt 2, E.Klar ~, H.J.Buhr L. Depts.of Surgery/Benjamin Franklin
PLASMA AMINO ACID CONSUMPTION AND PANCREATIC SECRETION DURING AND AFTER CAERULEIN-INDUCED PANCREATITIS IN RATS. H.Fischer, J.W.Konturek,
•
Disorders
Cholan- Icterus Sepsis Lethality
gitis
Invasjve group n - 107
12
7
10
1t
1
10
7
Conventional group
5
4
16
11
8*
13
4
n - 99 *p
•
EFFECTS OF C H O L E C Y S T O K I N I N (CCK) O N C A L C I U M O U T F L U X FROM PANCREATIC ACINI IS M E D I A T E D BY THE HIGH AFFINITY S T A T E OF THE CCK RECEPTOR A N D IS N O T C A U S E D BY INCREASED INOSlTOL PHOSPHATE. K.P. Fortune, V.D.Talkad, S.N.Joshi, d.D.Gardner. Saint
Louis University, St.Louis, MO. 63104 The pancreatic CCK receptor exists in 3 different affinity states for CCK-8 - high affinity, low affinity and very low affinity. The effects of CCK-8 on cytosolic Ca measured in a stirred cuvette or on outflux of 4~Ca are thought to reflect interaction of CCK-8 with the low or very low affinity state of the CCK receptor. The major findings that supported this conclusion were obtained using CCK-JMV-180, which appeared to have a high affinity for the high affinity state of the CCK receptor where it acted as an agonist and a low affinity for the low affinity state of the CCK receptor where it acted as an antagonist. Recently, using a variety of state-selective ligands we have demonstrated that CCK-JMV-180 actually has a high affinity for the low affinity state of the CCK receptor and a low affinity for the high affinity state of the CCK receptor (BBA 1224,103,1994). We have reanalyzed our previous results for outflux of 4~Cawith CCK-8 and CCK-JMV-1 80 (Am.J.Physiol. 257,G202,1989). We have also tested the effects of two receptor antagonists, L-364,718, which has the same affinities for the 3 different states of the CCK receptor, and CCK-JMV-179, which has different affinities for each different state of the CCK receptor on outflux of *SCa and formation of [3HIinositol phosphate stimulated by CCK-8. We have compared these effects with those of the antagonists on CCK-8 occupation of the different CCK receptor affinity states determined from binding of ~251CCK-8 and [5H]L-364,718. CCK-8 caused a 5-fold increase in 46Caoutflux and CCK-JMV-180 was 60% as efficacious as CCK-8. The effects of these two peptides alone and in combination were superimposable with their effects predicted from occupation of the high affinity state of the CCK receptor. The effects of L-364,718 and CCK-JMV-179 on CCK-8stimulated outflux of 46Ca were consistent with CCK-8 occupation of the high affinity state. The effects of these antagonists on CCK-8-stimulated formation of [ZHIinositol phosphate were consistent with CCK-8 occupation of the low affinity state.The present results indicate that outflux of 45Ca from pancreatic acini is mediated by agonists occupying the high affinity state of the CCK receptor. Since CCK-8-induced formation of inositol phosphate is mediated bythe low affinity state of the CCK receptor, agonist-induced formation of inositol phosphate does not produce the increased outflux of 45Ca.