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Manrai M, Dawra S, Singh AK, Jha DK, Kochhar R. Controversies in the management of acute pancreatitis: An update. World J Clin Cases 2023; 11:2582-2603. [PMID: 37214572 PMCID: PMC10198120 DOI: 10.12998/wjcc.v11.i12.2582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 01/22/2023] [Accepted: 03/29/2023] [Indexed: 04/25/2023] Open
Abstract
This review summarized the current controversies in the management of acute pancreatitis (AP). The controversies in management range from issues involving fluid resuscitation, nutrition, the role of antibiotics and antifungals, which analgesic to use, role of anticoagulation and intervention for complications in AP. The interventions vary from percutaneous drainage, endoscopy or surgery. Active research and emerging data are helping to formulate better guidelines. The available evidence favors crystalloids, although the choice and type of fluid resuscitation is an area of dynamic research. The nutrition aspect does not have controversy as of now as early enteral feeding is preferred most often than not. The empirical use of antibiotics and antifungals are gray zones, and more data is needed for conclusive guidelines. The choice of analgesic is being studied, and the recommendations are still evolving. The position of using anticoagulation is still awaiting consensus. The role of intervention is well established, although the modality is constantly changing and favoring endoscopy or percutaneous drainage rather than surgery. It is evident that more multicenter randomized controlled trials are required for establishing the standard of care in these crucial management issues of AP to improve the morbidity and mortality worldwide.
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Affiliation(s)
- Manish Manrai
- Department of Internal Medicine, Armed Forces Medical College, Pune 411040, India
| | - Saurabh Dawra
- Department of Medicine and Gastroenterology, Command Hospital, Pune 411040, India
| | - Anupam K Singh
- Department of Gastroenterology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Daya Krishna Jha
- Department of Gastroenterology, Army Hospital (Research and Referral), New Delhi 11010, India
| | - Rakesh Kochhar
- Department of Gastroenterology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
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D'Haese J, Werner J. Translational Research for Acute Pancreatitis - Which Results Have Really Influenced Our Therapy? Visc Med 2018; 34:436-438. [PMID: 30675489 DOI: 10.1159/000493890] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Acute pancreatitis is a common disease characterized by acinar cell destruction and acute inflammatory changes of the pancreas that lead to a systemic inflammatory response. A major research effort has been undertaken to unravel the underlying pathophysiology and to identify possible therapeutic targets. Still, only very few findings have influenced our clinical practice in the treatment of acute pancreatitis. Pancreatic microcirculation and capillary blood flow have long been suspected to play a major role in the course of the disease. It therefore seemed tempting to speculate that manipulation of the vasoconstrictor endothelin or its antagonist nitrogen monoxide could positively influence the outcome. We had to acknowledge, however, that these mechanisms take place very early in the disease course and that only prophylactic applications show an effect; this is useful in the setting of pancreas transplantation and endoscopic retrograde cholangiopancreatography but not applicable for clinical use in the therapy of acute pancreatitis. Research then focused on later pathophysiological stages of the disease, mainly on the process of adhesion and extravasation of leukocytes into the pancreatic tissue. Here, integrins and adhesion molecules like the intercellular adhesion molecule-1 (ICAM-1) were investigated in detail. A monoclonal antibody to ICAM-1 showed promising results in experimental models but was never further evaluated in the clinical setting. Hemodilution and fluid resuscitation was recognized to be an important therapeutic tool in acute pancreatitis. Here, initial experimental studies favored colloid solutions, and especially dextrans for isovolemic fluid resuscitation. It was recognized only later that colloid solutions are not effective and may even increase mortality in critically ill patients. Therefore, goal-directed infusion of Ringer's lactate solution at a moderate infusion rate to optimize volume status and hemoconcentration in acute pancreatitis is now advocated. In summary, out of the numerous experimental and translational studies, only very few have really influenced our daily clinical practice. Further research is therefore needed to find more specific and effective therapeutic agents for the treatment of acute pancreatitis.
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Affiliation(s)
- Jan D'Haese
- Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, University of Munich, LMU, Munich, Germany
| | - Jens Werner
- Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, University of Munich, LMU, Munich, Germany
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Hutchinson KM, Shaw SP. A Review of Central Venous Pressure and Its Reliability as a Hemodynamic Monitoring Tool in Veterinary Medicine. Top Companion Anim Med 2016; 31:109-121. [PMID: 27968811 DOI: 10.1053/j.tcam.2016.08.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2016] [Accepted: 08/04/2016] [Indexed: 01/05/2023]
Abstract
OBJECTIVE To review the current literature regarding central venous pressure (CVP) in veterinary patients pertaining to placement (of central line), measurement, interpretation, use in veterinary medicine, limitations, and controversies in human medicine. ETIOLOGY CVP use in human medicine is a widely debated topic, as numerous sources have shown poor correlation of CVP measurements to the volume status of a patient. Owing to the ease of placement and monitoring in veterinary medicine, CVP remains a widely used modality for evaluating the hemodynamic status of a patient. A thorough evaluation of the veterinary and human literature should be performed to evaluate the role of CVP measurements in assessing volume status in veterinary patients. DIAGNOSIS Veterinary patients that benefit from accurate CVP readings include those suffering from hypovolemic or septic shock, heart disease, or renal disease or all of these. Other patients that may benefit from CVP monitoring include high-risk anesthetic patients undergoing major surgery, trending of fluid volume status in critically ill patients, patients with continued shock, and patients that require rapid or large amounts of fluids. THERAPY The goal of CVP use is to better understand a patient's intravascular volume status, which would allow early goal-directed therapy. PROGNOSIS CVP would most likely continue to play an important role in the hemodynamic monitoring of the critically ill veterinary patient; however, when available, cardiac output methods should be considered the first choice for hemodynamic monitoring.
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Affiliation(s)
| | - Scott P Shaw
- VCA, Specialty Regional Medical Director; Northeast Los Angeles, CA, USA
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Mansfield C. Acute Pancreatitis in Dogs: Advances in Understanding, Diagnostics, and Treatment. Top Companion Anim Med 2012; 27:123-32. [DOI: 10.1053/j.tcam.2012.04.003] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2012] [Accepted: 04/30/2012] [Indexed: 12/26/2022]
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Abstract
OBJECTIVES Pancreatic necrosis is a serious complication of acute pancreatitis. The identification of simple laboratory tests to detect subjects at risk of pancreatic necrosis may direct management and improve outcome. This study focuses on the association between routine laboratory tests and the development of pancreatic necrosis in patients with acute pancreatitis. METHODS In a cohort of 185 patients with acute pancreatitis prospectively enrolled in the Severity of Acute Pancreatitis Study, patients with contrast-enhanced computerized tomography performed were selected (n=129). Serum hematocrit, creatinine, and urea nitrogen on admission and peak values within 48 h of admission were analyzed. The volume of intravenous fluid resuscitation was calculated for each patient. RESULTS Of 129 patients, 35 (27%) had evidence of pancreatic necrosis. Receiver operating characteristic curves for pancreatic necrosis revealed an area under the curve of 0.79 for admission hematocrit, 0.77 for peak creatinine, and 0.72 for peak urea nitrogen. Binary logistic regression yielded that all three tests were significantly associated with pancreatic necrosis (P<0.0001), with the highest odds ratio, 34.5, for peak creatinine. The volume of intravenous fluid resuscitation was similar in patients with and without necrosis. Low admission hematocrit (< or =44.8%) yielded a negative predictive value of 89%; elevated peak creatinine (>1.8 mg/dl) within 48 h yielded a positive predictive value of 93%. CONCLUSIONS We confirm that a low admission hematocrit indicates a low risk of pancreatic necrosis (PNec) in patients with acute pancreatitis. In contrast, an increase in creatinine within the first 48 h is strongly associated with the development of PNec. This finding may have important clinical implications and warrants further investigation.
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Volume assessment in patients with necrotizing pancreatitis: a comparison of intrathoracic blood volume index, central venous pressure, and hematocrit, and their correlation to cardiac index and extravascular lung water index. Crit Care Med 2008; 36:2348-54. [PMID: 18596637 DOI: 10.1097/ccm.0b013e3181809928] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
OBJECTIVE Volume depletion and/or increased hematocrit are associated with poor prognosis in necrotizing pancreatitis. Several studies suggest that intrathoracic blood volume index (ITBI) might be superior to central venous pressure (CVP) with regard to preload assessment. Therefore, the aim of our study was to evaluate the predictive value of CVP and hematocrit with regard to ITBI, and to correlate these parameters to cardiac index (CI). DESIGN Prospective study. SETTING Medical intensive care unit, university hospital. PATIENTS AND INTERVENTIONS Within 24 hrs of intensive care unit-admission, 96 hemodynamic measurements using the PiCCO system were performed in 24 patients with necrotizing pancreatitis. MAIN RESULTS Mean CVP (12.11 +/- 5.97 mm Hg; median 11.5 normal: 1-9 mm Hg) was elevated, whereas mean ITBI (822.8 +/- 157.0 mL/m2; median 836 mL/m2; normal: 850-1000 mL/m2) was decreased. Fifty-one of 96 ITBI values were decreased (prevalence of hypovolemia of 53%). No CVP value was decreased. Fifty-three CVP measurements were elevated despite simultaneous ITBI levels indicating a normal or decreased preload. Sensitivity, specificity, positive predictive value, and negative predictive value of CVP with regard to volume depletion (ITBI <850 mL/m2), were 0%, 100%, 0%, and 47%, respectively. An increase in hematocrit (hematocrit >40% [female] or >44% [male]) was found in 11 of 51 measurements with decreased ITBI. Sensitivity, specificity, positive predictive value, and negative predictive value of an increase in hematocrit with regard to volume depletion according to ITBI were 22%, 82%, 58%, and 48%, respectively. ITBI and delta-ITBI significantly correlated to CI and delta-CI (r = .566, p < 0.001; r = .603, p < 0.001), respectively. CVP and delta-CVP did not correlate to CI and delta-CI, respectively. There was a significant correlation between ITBI and extravascular lung water index (r = .392; p < 0.001), but no correlation between CVP and extravascular lung water index (r = .074; p = 0.473). CONCLUSIONS Volume depletion according to ITBI was found in more than half the patients. The predictive values of CVP and hematocrit with regard to volume depletion were low. ITBI and its changes significantly correlated to CI and its changes, which was not observed for CVP and delta-CVP. Therefore, ITBI appears to be more appropriate for volume management in necrotizing pancreatitis than CVP or hematocrit.
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Demirag A, Pastor CM, Morel P, Jean-Christophe C, Sielenkämper AW, Güvener N, Mai G, Berney T, Frossard JL, Bühler LH. Epidural anaesthesia restores pancreatic microcirculation and decreases the severity of acute pancreatitis. World J Gastroenterol 2006; 12:915-20. [PMID: 16521220 PMCID: PMC4066157 DOI: 10.3748/wjg.v12.i6.915] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effect of epidural anaesthesia (EA) on pancreatic microcirculation during acute pancreatitis (AP).
METHODS: AP was induced by injection of sodium taurocholate into the pancreatic duct of Sprague-Dawley rats. To realize EA, a catheter was introduced into the epidural space between T7 and T9 and bupivacaine was injected. Microcirculatory flow was measured by laser Doppler flowmetry. Arterial blood gas analyses were performed. At the end of the experiment (≤ 5 h), pancreas was removed for histology. The animals were divided into three groups: Group 1 (n = 9), AP without EA; Group 2 (n = 4), EA without AP; and Group 3 (n = 6), AP treated by EA.
RESULTS: In Group 1, pancreatic microcirculatory flow prior to AP was 141 ± 39 perfusion units (PU). After AP, microcirculatory flow obviously decreased to 9 ± 6 PU (P < 0.05). Metabolic acidosis developed with base excess (BE) of - 14 ± 3 mmol/L. Histology revealed extensive edema and tissue necrosis. In Group 2, EA did not significantly modify microcirculatory flow. BE remained unchanged and histological analysis showed normal pancreatic tissue. In Group 3, AP initially caused a significant decrease in microcirculatory flow from 155 ± 25 to 11 ± 7 PU (P < 0.05). After initiation of EA, microcirculatory flow obviously increased again to 81 ± 31 PU (P < 0.05). BE was -6 ± 4 mmol/L, which was significantly different compared to Group 1 (P < 0.05). Furthermore, histology revealed less extensive edema and necrosis in pancreatic tissue in Group 3 than that in Group 1.
CONCLUSION: AP caused dramatic microcirculatory changes within the pancreas, with development of metabolic acidosis and tissue necrosis. EA allowed partial restoration of microcirculatory flow and prevented development of tissue necrosis and systemic complications. Therefore, EA should be considered as therapeutic option to prevent evolution from edematous to necrotic AP.
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Affiliation(s)
- Alp Demirag
- Surgical Research Unit, Department of Surgery, University Hospital Geneva, 24, Rue Micheli-du-Crest, 1211, Geneva 14, Switzerland
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Strate T, Mann O, Kleinhans H, Rusani S, Schneider C, Yekebas E, Freitag M, Standl T, Bloechle C, Izbicki JR. Microcirculatory function and tissue damage is improved after therapeutic injection of bovine hemoglobin in severe acute rodent pancreatitis. Pancreas 2005; 30:254-9. [PMID: 15782104 DOI: 10.1097/01.mpa.0000157481.22155.2d] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVES Stasis of the pancreatic microcirculation initiates and aggravates acute pancreatitis. Bovine hemoglobin has been shown to improve microcirculation in acute pancreatitis if prophylactically infused 15 minutes after initiation of acute pancreatitis. The purpose of this study was to evaluate the therapeutic effectiveness of bovine hemoglobin on pancreatic microcirculation and tissue damage later in the course of experimental acute rodent pancreatitis. METHODS In Wistar rats, severe acute pancreatitis was induced by administration of glyco-deoxycholic-acid intraductally and cerulein intravenously. Pancreatic microcirculation was continuously monitored by intravital microscopy. Three hours after the initiation of acute pancreatitis, animals received either 0.8 mL bovine hemoglobin (Oxyglobin), hydroxyethyl starch (HES), or 2.4 mL 0.9% NaCl intravenously at random. After 6 hours, animals were killed, and histopathological damage of the pancreas was assessed using a validated histology score. RESULTS Pancreatic microcirculation assessed by leukocyte adherence was significantly improved by the administration of bovine hemoglobin in comparison with normal saline over time (mean difference, 51.6 +/- 9.2; P < 0.001) and HES (mean difference, 24.1 +/- 9.2; P = 0.037). This result was paralleled by decreased tissue damage in the bovine hemoglobin group as opposed to NaCl (6.75 vs. 12; range, 5.25-7.75 vs. 8.25-14; P < 0.001) and HES (6.75 vs. 9; range, 5.25-7.75 vs. 7.5-10.75; P < 0.001). CONCLUSION Therapeutic intravenous infusion of bovine hemoglobin improves pancreatic microcirculation and reduces pancreatic tissue damage in severe acute rodent pancreatitis but is not as effective as early (prophylactic) administration.
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Affiliation(s)
- Tim Strate
- Department of General Surgery, University Hospital Eppendorf, Martinistrasse 52, Hamburg, Germany.
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Plock JA, Schmidt J, Anderson SE, Sarr MG, Roggo A. Contrast-enhanced computed tomography in acute pancreatitis: does contrast medium worsen its course due to impaired microcirculation? Langenbecks Arch Surg 2005; 390:156-63. [PMID: 15711818 DOI: 10.1007/s00423-005-0542-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2004] [Accepted: 12/02/2004] [Indexed: 01/21/2023]
Abstract
BACKGROUND An early and accurate diagnosis of severe acute (necrotizing) pancreatitis is important to allow timely institution of therapy to limit the extra-pancreatic sequelae of this necrotizing process and to minimize the incidence of super-infection of the necrosis (i.e., progression to infected necrosis). Contrast-enhanced computed tomography (CECT) has become the cornerstone of diagnosis by confirming the clinical diagnosis of severe acute pancreatitis based on the various clinical scoring criteria. Moreover, CECT serves as an anatomic roadmap for guiding radiological and surgical interventions. However, still-controversial experimental studies in animals in the mid-1990s suggested that the use of intravenous radiographic contrast media early in the course of the disease might exacerbate the necrotizing process by further impairing the already compromised pancreatic microcirculation. A series of experimental and clinical studies followed that have both refuted and supported this claim; unfortunately, none is conclusive, and the topic remains, as yet, unresolved. AIMS Our objective was to review objectively the available literature found by a Medline search on this subject. METHODS Meta-analysis and review. RESULTS AND CONCLUSION Our conclusion, after analysis of these studies, is that there are no well-substantiated data that could resolve the controversy. However, several caveats will be offered.
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Affiliation(s)
- Jan A Plock
- Department of Surgery, University Hospital of Bern, Inselspital, 3010 Bern, Switzerland
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Abstract
Existing predictor systems of severe pancreatitis are cumbersome and can require up to 48 hr to complete. This study aimed to determine whether useful likelihood ratios exist for the prediction of severe pancreatitis, corresponding to various ranges of admission hematocrit. A retrospective cohort of 200 patients admitted with acute pancreatitis was identified. Likelihood ratios were calculated for a priori defined hematocrit ranges. Using multivariate logistic regression, initial hematocrit was evaluated as a predictor of severe pancreatitis as defined a priori by local and/or systemic complications (Atlanta criteria, 1992). Planned subgroup analysis was performed on those with a hematocrit >50%, stratified by 24-hr hematocrit. Fourteen patients (7%) developed severe pancreatitis. Likelihood ratios were 0.45, 0.70, and 7.5 for hematocrit ranges of < or =45, 45.1-49.9, and > or =50%, respectively. Hematocrit (as increases by 5%) was a significant predictor of severe pancreatitis (odds ratio [OR] = 2.8; P = 0.001), length of stay (P < 0.0001), necrosis (OR = 3.9; P = 0.001), and need for intensive care (OR 4.5; P = 0.002). The negative predictive value of the lowest range and positive predictive value of the highest range were 97% (95% CI: 92-99%) and 37% (16-62%), respectively. Lack of normalization of hematocrit by 24 hr did not predict severe pancreatitis. Initial hematocrit appears to be an early, simple, and useful predictor of severe pancreatitis. A normal 24-hr hematocrit does not appear to alter the prediction made by the initial hematocrit.
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Affiliation(s)
- S Ian Gan
- Department of Medicine, Advanced Therapeutic Endoscopy Centre Group, University of Calgary, Calgary, Alberta, Canada
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Affiliation(s)
- T Foitzik
- Department of Surgery, Benjamin Franklin Medical Center, Freie Universität Berlin, Germany.
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Abstract
Pancreatic microcirculatory disturbance plays an important role in the pathogenesis of acute pancreatitis, and it involves a series of changes including vasoconstriction, ischaemia, increased vascular permeability, impairment of nutritive tissue perfusion, ischaemia/reperfusion, leukocyte adherence, hemorrheological changes and impaired lymphatic drainage. Ischaemia possibly acts as an initiating factor of pancreatic microcirculatory injury in acute pancreatitis, or as an aggravating/continuing mechanism. The end-artery feature of the intralobular arterioles suggests that the pancreatic microcirculation is highly susceptible to ischaemia. Various vasoactive mediators, as bradykinin, platelet activating factor, endothelin and nitric oxide participate in the development of microcirculatory failure.
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Affiliation(s)
- Zong-Guang Zhou
- Department of Hepato-bilio-pancreatic Surgery & Institute of Microcirculation, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China.
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Abstract
In a previous retrospective case-control study, hemoconcentration was associated with the development of pancreatic necrosis. The aim of the present study was to determine in a cohort study whether hemoconcentration is a marker for both organ failure and necrotizing pancreatitis. A cohort study was performed on patients admitted with acute pancreatitis from February 1996 to April 1997. Pancreatic necrosis was defined by findings on dynamic contrast-enhanced computed tomography scan or magnetic resonance imaging. Of 128 total patients with acute pancreatitis, 53 underwent computed tomography or magnetic resonance imaging. Eighteen of 53 had necrotizing pancreatitis. Logistic regression identified an admission hematocrit > or = 44% and a failure of admission hematocrit to decrease at 24 hours as the best binary predictors of necrotizing pancreatitis and organ failure. By 24 hours, 17 of 18 patients with necrotizing pancreatitis versus 11 of 35 with interstitial pancreatitis met one or the other criterion for necrosis (p < 0.001). By 24 hours, 13 of 15 with organ failure versus 36 of 104 without organ failure met one or the other criterion (p < 0.001). The negative predictive value by 24 hours was 96% for necrotizing pancreatitis and 97% for organ failure. Hemoconcentration with an admission hematocrit > or = 44% and/or failure of admission hematocrit to decrease at approximately 24 hours was associated with the development of necrotizing pancreatitis and organ failure. Patients who did not experience hemoconcentration were very unlikely to develop pancreatic necrosis or organ failure.
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Affiliation(s)
- A Brown
- Center for Pancreatic Disease, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
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Baillargeon JD, Orav J, Ramagopal V, Tenner SM, Banks PA. Hemoconcentration as an early risk factor for necrotizing pancreatitis. Am J Gastroenterol 1998; 93:2130-4. [PMID: 9820385 DOI: 10.1111/j.1572-0241.1998.00608.x] [Citation(s) in RCA: 110] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE The aim of our study was to determine whether measurement of serum hematocrit during the first 24 h helps in distinguishing necrotizing from mild pancreatitis. METHODS From May 1992 to June 1996, a case-control study was performed with cases of patients with necrotizing pancreatitis. We selected as a control the next patient admitted with mild pancreatitis. RESULTS There were 32 patients in each group. Logistic regression identified an admission hematocrit of > or = 47% and a failure of admission hematocrit to decrease at 24 h as the best binary risk factors for necrotizing pancreatitis. At admission, more patients with necrotizing pancreatitis than with mild pancreatitis had a hematocrit > or = 47% (11/32 vs 3/32; p = 0.03). At 24 h, 15 additional patients with necrotizing pancreatitis versus only one with mild pancreatitis showed no decrease in admission hematocrit (p < 0.01). Thus, by 24 h, 26 of 32 patients with necrotizing pancreatitis versus only four of 32 patients with mild pancreatitis met one or the other criterion (p < 0.01). The sensitivity and specificity at admission were 34% and 91%; at 24 h, 81% and 88%. CONCLUSIONS Hemoconcentration with an admission hematocrit > or = 47% or failure of admission hematocrit to decrease at approximately 24 h were strong risk factors for the development of pancreatic necrosis.
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Affiliation(s)
- J D Baillargeon
- Center for Pancreatic Disease, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
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Dusetti NJ, Vasseur S, Ortiz EM, Romeo H, Dagorn JC, Burrone O, Iovanna JL. The pancreatitis-associated protein I promoter allows targeting to the pancreas of a foreign gene, whose expression is up-regulated during pancreatic inflammation. J Biol Chem 1997; 272:5800-4. [PMID: 9038194 DOI: 10.1074/jbc.272.9.5800] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
The pancreatitis-associated protein I (PAP I) is a pancreatic secretory protein expressed in pancreas during acute pancreatitis but not in the healthy pancreas. The promoter of the PAP I gene thus represents a potential candidate to drive expression of therapeutic molecules to the diseased pancreas. In this work, we have constructed recombinant adenoviruses harboring the chloramphenicol acetyltransferase (CAT) gene driven by several fragments of the PAP I promoter and have characterized their properties in vitro and in vivo. In vitro studies showed that the transduction of the pancreatic cell line AR-42J with these adenoviruses led to low levels of CAT activity in basal conditions. After stimulation with a combination of interleukin-6 and dexamethasone or after induction of oxidative stress, CAT activity was strongly induced, a characteristic of the endogenous PAP I gene. Stimulation was maximal when constructs comprised 1253 base pairs of the PAP I promoter, upstream from initiation of transcription, and decreased with shorter fragments of 317, 180, 118 or 61 base pairs. The recombinant adenovirus containing the CAT gene under the control of the PAP I promoter fragment (-1253/+10) was also tested in vivo. Following administration by intravenous injection into mice, CAT activity was measured in several tissues 96 h later. In healthy animals, low but significant CAT activity was detected in pancreas, compared with near background values observed in the other tissues. When experimental acute pancreatitis was induced, CAT expression was strongly enhanced only in pancreas. In control experiments with adenoviruses in which the CAT gene was driven by the cytomegalovirus promoter, higher levels of expression were observed in all tissues. Expression was not modified after induction of acute pancreatitis. In conclusion, this study shows that (i) a recombinant adenovirus containing a fragment of the PAP I promoter allows specific targeting of a reporter gene to the mouse pancreas and (ii) expression of the reporter gene in pancreas is induced during acute pancreatitis. Adenovirus-mediated gene therapy of acute pancreatitis is therefore conceivable.
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Affiliation(s)
- N J Dusetti
- U.315 INSERM, 46 boulevard de la Gaye, F 13009 Marseille, France
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