Early organ dysfunction affects long-term survival in acute pancreatitis patients

Skouras, Christos; Hayes, Alastair; Williams, Linda; Garden, O. James; Parks, Rowan W.; Mole, Damian J.

doi:10.1111/hpb.12259

Cited by 15 publications

(13 citation statements)

References 37 publications

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“…AP is associated with a high mortality, shortens overall life expectancy in survivors22 and constitutes a considerable healthcare resource burden 7–913 Specifically, the evolution of persistent organ dysfunction requiring CC support has the most deleterious short-term and long-term consequences in AP.…”

Section: Discussionmentioning

confidence: 99%

Identifying risk factors for progression to critical care admission and death among individuals with acute pancreatitis: a record linkage analysis of Scottish healthcare databases

et al. 2016

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ObjectivesAcute pancreatitis (AP) can initiate systemic complications that require support in critical care (CC). Our objective was to use the unified national health record to define the epidemiology of AP in Scotland, with a specific focus on deterministic and prognostic factors for CC admission in AP.SettingHealth boards in Scotland (n=4).ParticipantsWe included all individuals in a retrospective observational cohort with at least one episode of AP (ICD10 code K85) occurring in Scotland from 1 April 2009 to 31 March 2012. 3340 individuals were coded as AP.MethodsData from 16 sources, spanning general practice, community prescribing, Accident and Emergency attendances, hospital in-patient, CC and mortality registries, were linked by a unique patient identifier in a national safe haven. Logistic regression and gamma models were used to define independent predictive factors for severe AP (sAP) requiring CC admission or leading to death.Results2053 individuals (61.5% (95% CI 59.8% to 63.2%)) met the definition for true AP (tAP). 368 patients (17.9% of tAP (95% CI 16.2% to 19.6%)) were admitted to CC. Predictors of sAP were pre-existing angina or hypertension, hypocalcaemia and age 30–39 years, if type 2 diabetes mellitus was present. The risk of sAP was lower in patients with multiple previous episodes of AP. In-hospital mortality in tAP was 5.0% (95% CI 4.1% to 5.9%) overall and 21.7% (95% CI 19.9% to 23.5%) in those with tAP necessitating CC admission.ConclusionsNational record-linkage analysis of routinely collected data constitutes a powerful resource to model CC admission and prognosticate death during AP. Mortality in patients with AP who require CC admission remains high.

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Section: Discussionmentioning

confidence: 99%

Identifying risk factors for progression to critical care admission and death among individuals with acute pancreatitis: a record linkage analysis of Scottish healthcare databases

et al. 2016

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“… Acute pancreatitis (AP) is a common and devastating inflammatory condition of the pancreas that is considered to be a paradigm of sterile inflammation leading to systemic multiple organ dysfunction syndrome (MODS) and death1,2 Acute mortality from AP-MODS exceeds 20%3 and for those who survive the initial episode, their lifespan is typically shorter than the general population4. There are no specific therapies available that protect individuals against AP-MODS.…”

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confidence: 99%

“…The development of MODS (and particularly ARDS) is a key determinant of outcome in critically ill individuals regardless of the initiating event4. AP serves as a paradigm for sterile systemic inflammation, and this work builds on a rapidly expanding body of work uncovering the potential role of the kynurenine pathway in several inflammatory and degenerative disease states, and is the first to demonstrate therapeutic efficacy of KMO inhibition to protect against MODS.…”

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confidence: 99%

Kynurenine-3-monooxygenase inhibition prevents multiple organ failure in rodent models of acute pancreatitis

Mole

Webster

Uings

et al. 2016

Nat Med

134

151

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Acute pancreatitis (AP) is a common and devastating inflammatory condition of the pancreas that is considered to be a paradigm of sterile inflammation leading to systemic multiple organ dysfunction syndrome (MODS) and death1,2 Acute mortality from AP-MODS exceeds 20%3 and for those who survive the initial episode, their lifespan is typically shorter than the general population4. There are no specific therapies available that protect individuals against AP-MODS. Here, we show that kynurenine-3-monooxygenase (KMO), a key enzyme of tryptophan metabolism5, is central to the pathogenesis of AP-MODS. We created a mouse strain deficient for Kmo with a robust biochemical phenotype that protected against extrapancreatic tissue injury to lung, kidney and liver in experimental AP-MODS. A medicinal chemistry strategy based on modifications of the kynurenine substrate led to the discovery of GSK180 as a potent and specific inhibitor of KMO. The binding mode of the inhibitor in the active site was confirmed by X-ray co-crystallography at 3.2 Å resolution. Treatment with GSK180 resulted in rapid changes in levels of kynurenine pathway metabolites in vivo and afforded therapeutic protection against AP-MODS in a rat model of AP. Our findings establish KMO inhibition as a novel therapeutic strategy in the treatment of AP-MODS and open up a new area for drug discovery in critical illness.

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“…12 Recently published data from a retrospective analysis of patients with AP has shown that the early development of MODS is associated with an increased mortality rate up to 10 years after the index presentation. 6 This strongly suggests that MODS in acute pancreatitis (AP-MODS) has a persistent and deleterious impact on patients' physiological status, though the exact nature of this pathology remains to be characterised. Existing studies indicate that most deaths are the result of cardiovascular, pulmonary, digestive or malignant disease.…”

Section: Strengths and Limitations Of This Studymentioning

confidence: 99%

Study protocol for resolution of organ injury in acute pancreatitis (RESORP): an observational prospective cohort study

et al. 2020

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IntroductionSurvivors of acute pancreatitis (AP) have shorter overall survival and increased incidence of new-onset cardiovascular, respiratory, liver and renal disease, diabetes mellitus and cancer compared with the general population, but the mechanisms that explain this are yet to be elucidated. Our aim is to characterise the precise nature and extent of organ dysfunction following an episode of AP.Methods and analysisThis is an observational prospective cohort study in a single centre comprising a University hospital with an acute and emergency receiving unit and clinical research facility. Participants will be adult patient admitted with AP. Participants will undergo assessment at recruitment, 3 months and 3 years. At each time point, multiple biochemical and/or physiological assessments to measure cardiovascular, respiratory, liver, renal and cognitive function, diabetes mellitus and quality of life. Recruitment was from 30 November 2017 to 31 May 2020; last follow-up measurements is due on 31 May 2023. The primary outcome measure is the incidence of new-onset type 3c diabetes mellitus during follow-up. Secondary outcome measures include: quality of life analyses (SF-36, Gastrointestinal Quality of Life Index); montreal cognitive assessment; organ system physiological performance; multiomics predictors of AP severity, detection of premature cellular senescence. In a nested cohort within the main cohort, individuals may also consent to multiparameter MRI scan, echocardiography, pulmonary function testing, cardiopulmonary exercise testing and pulse-wave analysis.Ethics and disseminationThis study has received the following approvals: UK IRAS Number 178615; South-east Scotland Research Ethics Committee number 16/SS/0065. Results will be made available to AP survivors, caregivers, funders and other researchers. Publications will be open-access.Trial registration numbersClinicalTrials.gov Registry (NCT03342716) and ISRCTN50581876; Pre-results.

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Early organ dysfunction affects long-term survival in acute pancreatitis patients

Abstract: Early organ dysfunction in AP is an independent predictor of long-term survival even when in-hospital deaths are accounted for. Negative predictors also include age, and idiopathic and alcohol-related aetiologies.

Cited by 15 publications

References 37 publications

Identifying risk factors for progression to critical care admission and death among individuals with acute pancreatitis: a record linkage analysis of Scottish healthcare databases

Identifying risk factors for progression to critical care admission and death among individuals with acute pancreatitis: a record linkage analysis of Scottish healthcare databases

Kynurenine-3-monooxygenase inhibition prevents multiple organ failure in rodent models of acute pancreatitis

Study protocol for resolution of organ injury in acute pancreatitis (RESORP): an observational prospective cohort study

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