Citrulline and intestinal fatty acid-binding protein as biomarkers for gastrointestinal dysfunction in the critically ill

Currently there is no reliable tool available to monitor gastrointestinal function in the critically ill. Biomarkers are therefore of great interest in this field as the lack of monitoring tools impedes any interventional studies. The potential biomarkers citrulline and intestinal fatty acid-binding protein (I-FABP) are the present focus. Targeted literature searches were undertaken for physiology and pathophysiology, sampling, measurement methods and clinical use of citrulline and I-FABP as biomarkers of intestinal function and injury. Physiology and pathophysiology, specific aspects of sampling and different laboratory assays are summarized and respective pitfalls outlined. Studies in animals and patients outside the ICU support the rationale for these biomarkers. At the same time, evidence in critically ill patients is not yet convincing, several specific aspects need to be clarified, and methodology and interpretation to be refined. We conclude that there are good physiological rationales for citrulline as a marker of enterocyte function and for I-FABP as a marker of intestinal injury, but further studies are needed to clarify whether and how they could be used in daily practice in caring for critically ill patients

Citrulline as a marker of intestinal function and absorption in clinical settings: A systematic review and meta-analysis

Background: Citrulline has been described as a marker of intestinal function or absorption but evidence varies according to clinical settings. Objective: The objective of this article is to examine the evidence of plasma citrulline as a marker of intestinal function and absorption in various clinical settings. Methods: Studies were examined for p values, means and standard deviations, correlation coefficients or other metrics depicting the association of citrulline with intestinal function. A random effects model was used to produce a pooled estimate. A hierarchical summary receiver operating curve model was fitted for diagnostic accuracy measures. Results: Citrulline levels are correlated strongly with small bowel length in short bowel syndrome patients (r = 0.67). Citrulline is strongly negatively correlated (r = –0.56) with intestinal disease severity with regards to enteropathies (coeliac disease, tropical enteropathy, Crohn’s disease, mucositis, acute rejection in intestinal transplantation). Citrulline cut-off levels have an overall sensitivity and specificity of 80% and 84% respectively. Citrulline levels in untreated coeliac patients compared to controls were reduced by 10 µmol/l. Citrulline levels increase with gluten-free diet and with improvement of enteropathy. Citrulline is decreased in critical illness and sepsis. Conclusion: These findings allow us to advocate quite reasonably that citrulline is a marker of acute and chronic intestinal insufficiency

ACUTE INTESTINAL NECROSIS: THE PREOPERATIVE DIAGNOSTIC APPROACH:PARTICULARLY REFERENCES TO ACUTE VASCULAR INTESTINAL NECROSIS

”…occlusion of the mesenteric vessels is apt to be regarded asone of those conditions of which diagnosis is impossible, theprognosis hopeless and the treatment almost useless.”A. J. Cokkinis, 192

Preclinical evaluation of common markers and iohexol for the development of intestinal permeability tests in dogs : Studies on laboratory Beagle dogs and Sprague-Dawley rats

Intestinal permeability testing is the specific method to assess for a defective intestinal epithelial barrier. Intestinal permeability measurements are considered helpful and non-invasive means to evaluate intestinal mucosal damage for both scientific (particularly) and clinical purposes, and have been widely used in laboratory rodents and humans. Despite their many advantages, permeability tests have not gained widespread use as a testing option for the detection and management of canine intestinal disorders in veterinary clinical research. The main reasons for this may include the lack of an optimal biomarker for permeability testing, impracticalities involving current testing methodologies, and inconsistencies in test results that have been found by investigators using these tests. Chromium 51-labeled ethylenediamine tetra-acetic acid (51Cr-EDTA) is widely considered the most accurate intestinal permeability probe, but the use of radioactivity is a major drawback. Sugar biomarkers such as lactulose and rhamnose have been more commonly used in the recent years, but they have been associated with marked inconsistencies in the test results. Iohexol is a contrast medium commonly used in radiology for diagnostic purposes in human and veterinary patients, but this molecule has more recently been successfully used for the screening of gut mucosal damage in laboratory rats and humans. The main advantage of iohexol is that its use does not involve radioactivity, nor is it degraded in the intestinal lumen. Furthermore, it has the potential to be quantified by different analytical techniques. The main objective of this project was to improve the methodology of the intestinal permeability tests in dogs in order to make the testing simpler, more practical and accurate for veterinarians and researchers using this approach to investigate intestinal mucosal damage and disorders associated with a defective intestinal epithelial barrier. An additional objective was to preliminarily assess the use of iohexol as a novel intestinal permeability marker for use in dogs. The work consisted of preclinical comparisons of the most relevant intestinal permeability markers including 51Cr-EDTA, lactulose and rhamnose, and iohexol performed in both urine and blood tests using laboratory dog and rat models. In conclusion, studies on the percentage urinary recovery of 51Cr-EDTA, lactulose, and rhamnose, as well as D-xylose, 3-O-methyl-D-glucose, and sucrose after their oral simultaneous administration provided normative data for healthy adult male Beagle dogs. The analysis revealed a discrepancy in the percentage urinary recovery between 51Cr-EDTA and lactulose, suggesting that these two markers are not as equivalent as has so far been believed based on previous studies in humans and cats. It was also concluded that the use of a single marker provides comparable test results to the use of two markers, as evidenced by a comparison of recovery values from 51Cr-EDTA and lactulose versus their correspondent ratio against rhamnose. This supports the hypothesis that, in contrast to the dual sugar test, the use of one inert larger probe may be sufficient for permeability testing, and the testing procedure may consequently be considerably simplified. The studies also demonstrated that the 51Cr-EDTA permeability blood test based on the collection of at least two serum or plasma specimens gives comparable results to the 6-h cumulative urine test. The blood approach is much easier than the urine-based test, as it avoids the constraints associated with urine collection in dogs. Iohexol was shown to have a clear relationship with 51Cr-EDTA in serum levels when they were simultaneously administered to Beagle dogs. When it was used as an intestinal permeability probe in laboratory rats before and after the induction of a well-characterized experimental form of inflammatory bowel disease, it was also possible to clearly discriminate between healthy animals and rats with intestinal mucosal damage. The iohexol blood test can therefore be considered a promising tool for assessing canine intestinal permeability in veterinary clinical research. Nevertheless, further studies using iohexol as intestinal permeability blood marker, particularly in diseased dogs, are warranted before firm conclusions can be made on the validity of this test.Yleisten merkkiaineiden ja joheksolin laboratorioarviointi ja koiran suolen läpäisevyystutkimusten kehittäminen beaglekoirilla ja Sprague–Dawley-rotilla. Suolen läpäisevyystesteillä tutkitaan, onko suolen pintaepiteelissä vaurio. Näitä testejä on käytetty runsaasti laboratoriojyrsijöillä ja ihmisillä ja ne ovat hyödyllisiä ja kajoamattomia suolen limakalvovaurion tutkimuskeinoja sekä (etenkin) tutkimuksessa että hoidossa. Monista eduista huolimatta näitä testejä ei vielä käytetä laajasti koirien suolistosairauksien diagnosointiin ja hoitoon. Tämä johtunee lähinnä siitä, että testaukseen sopivaa optimaalista biomarkkeria ei ole, nykyiset testausmenetelmät ovat hankalia ja tulosten on huomattu vaihtelevan. 51Cr-EDTAa pidetään tarkimpana suolen läpäisevyyden markkerina, mutta se on radioaktiivista. Sokeribiomarkkereiden kuten laktuloosin ja ramnoosin käyttö on laajentunut viime vuosina, mutta testitulokset ovat vaihdelleet huomattavasti. Joheksoli on ihmisillä ja eläimillä yleisesti käytetty röntgenvarjoaine, jota on käytetty myös suolen limakalvovaurioiden seulontaan laboratoriorotilla ja ihmisillä. Joheksoli ei ole radioaktiivista eikä hajoa suolessa, ja sen määrä pystytään mittaamaan eri tekniikoilla. Tutkimuksen päätavoitteena oli kehittää suolen läpäisevyystestausta, jotta koirat voitaisiin tutkia aiempaa helpommin, kätevämmin ja tarkemmin suolen limakalvovaurioiden ja suolen epiteeliä vaurioittavien tautien varalta. Tutkimuksessa arvioitiin myös alustavasti joheksolin käyttöä uutena suolen läpäisevyyden merkki-aineena koirilla. Tutkimuksessa verrattiin prekliinisesti tärkeimpiä suolen läpäisevyyden merkkiaineita, mm. 51Cr-EDTAa, laktuloosia, ramoosia ja joheksolia, laboratoriokoirien ja rottien virtsa- ja verinäytteiden avulla. Tulokset 51Cr-EDTAn, laktuloosin, ramnoosin, D-ksyloosin, 3-O-metyyli-D-glukoosin ja sakkaroosin erittymisestä virtsaan tuottivat tietoa terveiden aikuisten urosbeaglejen viitearvoista. 51Cr-EDTAn ja laktuloosin prosentuaalisessa erittymisessä virtsaan havaittiin eroja, joten nämä merkkiaineet saattavat erota toisistaan enemmän kuin ihmis- ja kissakokeiden perusteella on luultu. 51Cr-EDTAn ja laktuloosin erittymisen ja niiden ja ramnoosin erittymissuhteen vertailu osoitti, että yhdellä merkkiaineella saadaan yhtä hyvät tulokset kuin kahdella. Tämä tukee käsitystä, että testaus voidaan toteuttaa kahden sokerin sijasta vain yhdellä inertillä, suurimolekyylisellä merkkiaineella, mikä voi helpottaa suuresti testausta. Tutkimukset osoittivat myös, että 51Cr-EDTAn määritys vähintään kahdesta verinäytteestä tuottaa yhtä hyvät tulokset kuin 6 tunnin virtsankeräykseen perustuva koe. Veritestaus on huomattavasti helpompaa kuin koirien virtsan kerääminen ja testaus. Seerumin joheksoli- ja 51Cr-EDTA-pitoisuuksien todettiin korreloivan selvästi, kun beagleille annettiin molempia. Kun laboratoriorottien suolen läpäisevyyttä tutkittiin joheksolilla sekä ennen kokeellisen tulehduksellisen suolistosairauden induktiota ja sen jälkeen, tuloksista nähtiin selvästi, oliko suolen limakalvo terve vai vaurioitunut. Joheksoliverikoe on siis lupaava työkalu koiran suolen läpäisevyyden arviointiin. Joheksoliverikokeen käyttöä suolen läpäisevyyden tutkimiseen on silti hyvä arvioida tarkemmin etenkin sairailla koirilla ennen kuin kokeen luotettavuudesta tehdään varmoja johtopäätöksiä

Luminally expressed gastrointestinal biomarkers

Introduction: A biomarker is a measurable indicator of normal biologic processes, pathogenic processes or pharmacological responses. The identification of a useful biomarker is challenging, with several hurdles to overcome before clinical adoption. This review gives a general overview of a range of biomarkers associated with inflammatory bowel disease or colorectal cancer along the gastrointestinal tract. Areas covered: These markers include those that are already clinically accepted, such as inflammatory markers such as faecal calprotectin, S100A12 (Calgranulin C), Fatty Acid Binding Proteins (FABP), malignancy markers such as Faecal Occult Blood, Mucins, Stool DNA, Faecal microRNA (miRNA), other markers such as Faecal Elastase, Faecal alpha-1-antitrypsin, Alpha2-macroglobulin and possible future markers such as microbiota, volatile organic compounds and pH. Expert commentary: There are currently a few biomarkers that have been sufficiently validated for routine clinical use at present such as FC. However, many of these biomarkers continue to be limited in sensitivity and specificity for various GI diseases. Emerging biomarkers have the potential to improve diagnosis and monitoring but further study is required to determine efficacy and validate clinical utility

Measurement of gut permeability using fluorescent tracer agent technology

Abstract The healthy gut restricts macromolecular and bacterial movement across tight junctions, while increased intestinal permeability accompanies many intestinal disorders. Dual sugar absorption tests, which measure intestinal permeability in humans, present challenges. Therefore, we asked if enterally administered fluorescent tracers could ascertain mucosal integrity, because transcutaneous measurement of differentially absorbed molecules could enable specimen-free evaluation of permeability. We induced small bowel injury in rats using high- (15 mg/kg), intermediate- (10 mg/kg), and low- (5 mg/kg) dose indomethacin. Then, we compared urinary ratios of enterally administered fluorescent tracers MB-402 and MB-301 to urinary ratios of sugar tracers lactulose and rhamnose. We also tested the ability of transcutaneous sensors to measure the ratios of absorbed fluorophores. Urinary fluorophore and sugar ratios reflect gut injury in an indomethacin dose dependent manner. The fluorophores generated smooth curvilinear ratio trajectories with wide dynamic ranges. The more chaotic sugar ratios had narrower dynamic ranges. Fluorophore ratios measured through the skin distinguished indomethacin-challenged from same day control rats. Enterally administered fluorophores can identify intestinal injury in a rat model. Fluorophore ratios are measureable through the skin, obviating drawbacks of dual sugar absorption tests. Pending validation, this technology should be considered for human use

Enteraalne toitmisravi, seedetrakti düsfunktsioon ja soole biomarkerid intensiivravipatsientidel

Väitekirja elektrooniline versioon ei sisalda publikatsiooneOrganpuudulikkuste diagnoosimine ja ravi on üks intensiivravi nurgakividest, kuid seedetrakti puudulikkus on ebapiisavalt defineeritud ning diagnoosimine põhineb siiani peamiselt subjektiivsel kliinilisel läbivaatusel. Võimalikud ravimeetodid seedetrakti probleemide lahendamiseks intensiivravipatsientidel ning nende tõenduspõhisus on vähesed. Uurimistöö keskendus enteraalse toitmisravi läbiviimisele ja jälgimisele, seedetrakti düsfunktsiooni ja puudulikkuse diagnoosimisele ja mõju selgitamisele ning kõrgenenud kõhukoopasisese rõhu ravivõimaluste uurimisele intensiivravihaigetel. Leidsime, et pärast enteraalse toitmise protokolli kasutuselevõttu manustati intensiivravipatsientidele esimese nädala jooksul oluliselt rohkem toiduenergiat enteraalse toitmise teel ilma komplikatsioonide sagenemiseta. Samaaegselt aga vähenes veenisisene toitmine ning kokkuvõttes ka nädala summaarne toiduenergia hulk. Tulemused viitavad vajadusele toitmisravi komplekssemalt planeerida. Järgmises uuringus järeldasime, et soole funktsiooni peegeldava biomarkeri tsitrulliini ning kahjustuse markeri I-FABP-i määramine ei võimalda enteraalse toitmisravi edukust hinnata ning nende roll toitmisravi juhtimisel on hetkel ebaselge. Kõrgenenud kõhukoopasisene rõhk on intensiivravipatsientidel sage probleem, mille ilmnemine on seotud kehvemate ravitulemustega, kuid ravivõtted on piiratud. Meie uurimistöö osutab ühe ravimeetodi, sedatsiooni süvendamise, vähesele toimele ja võimalikele kõrvaltoimetele. Kuivõrd ligi veerandil patsientidest on raviefekt siiski hea, võib seda ravivõtet vajaduse korral kaaluda. Seedetrakti puudulikkuse teke on seotud halvemate ravitulemustega. Nii primaarne, st kõhukoopa patoloogiaga seotud, kui sekundaarne, muu põhjusega seedetrakti puudulikkus on seotud kõrge suremusega. Sekundaarse põhjusega seedetrakti puudulikkuse juhud leiavad sagedamini aset hilisemal intensiivraviperioodil, patsientide seisund on raskem ning ravitulemused võivad olla kehvemad. Töötasime välja seedetrakti sümptomite ja kõrgenenud kõhukoopasisese rõhu raskusastmete kombinatsioonil põhineva kliinilise skoori seedetrakti düsfunktsiooni hindamiseks, mis on vajalik nii kliinilises kui teadustöös. Skoori võime ennustada suremust oli hea ning järgmise sammuna on vajalik valideerimisuuring.The diagnosis and treatment of organ failures is a cornerstone of intensive care. Gastrointestinal failure is insufficiently defined and diagnosis is mostly based on subjective clinical assessment. Treatment options of gastrointestinal problems are limited and the underlying evidence poor. Research in this dissertation focused on the management of enteral nutrition, the diagnosis and impact of gastrointestinal dysfunction and the treatment of intra-abdominal hypertension. After implementing an enteral feeding protocol, significantly more calories were delivered via the enteral route during the first week of intensive care without an increase in complications. In parallel, the delivery of parenteral calories decreased and overall less calories were provided during the first week. This highlights the need to plan for more comprehensive planning of nutritional interventions. Intra-abdominal hypertension is frequent in intensive care patients and associated with worse outcomes. Deepening of sedation as a treatment option has an overall small effect on intra-abdominal pressure, but may cause hemodynamic disturbances. Nevertheless, deeper sedation decreases intra-abdominal pressure by a greater amount in some patients and therefore this method can be considered if treatment is needed. Development of gastrointestinal failure is associated with poor treatment outcomes. Both primary and secondary gastrointestinal failure are related to high mortality. Secondary gastrointestinal failure tends to occur later in the course of critical illness in more severely ill patients and may carry a worse prognosis. A clinical score to quantify gastrointestinal dysfunction was developed based on gastrointestinal symptoms and intra-abdominal hypertension. The ability of the score to predict mortality was good and as a next step, validation studies are needed.https://www.ester.ee/record=b546596

Guidelines for pre-operative cardiac risk assessment and perioperative cardiac management in non-cardiac surgery : the Task Force for Preoperative Cardiac Risk Assessment and Perioperative Cardiac Management in Non-cardiac Surgery of the European Society of Cardiology (ESC) and endorsed by the European Society of Anaesthesiology (ESA)

Non-cardiac surgery; Pre-operative cardiac risk assessment; Pre-operative cardiac testing; Pre-operative coronary artery revascularization; Perioperative cardiac management; Renal disease; Pulmonary disease; Neurological disease; Anaesthesiology; Post-operative cardiac surveillanc

Intestinal injury in cardiac arrest is associated with multiple organ dysfunction: A prospective cohort study

Background - The impact of intestinal injury in cardiac arrest is not established. The first aim of this study was to assess associations between clinical characteristics in out-of-hospital cardiac arrest (OHCA) and a biomarker for intestinal injury, Intestinal Fatty Acid Binding Protein (IFABP). The second aim was to assess associations between IFABP and multiple organ dysfunction and 30-day mortality. Methods - We measured plasma IFABP in 50 patients at admission to intensive care unit (ICU) after OHCA. Demographic and clinical variables were analysed by stratifying patients on median IFABP, and by linear regression. We compared Sequential Organ Failure Assessment (SOFA) score, haemodynamic variables, and clinical-chemistry tests at day two between the “high” and “low” IFABP groups. Logistic regression was applied to assess factors associated with 30-day mortality. Results - Several markers of whole body ischaemia correlated with intestinal injury. Duration of arrest and lactate serum concentrations contributed to elevated IFABP in a multivariable model (p Conclusion - Cardiac arrest duration and lactate serum concentrations were risk factors for intestinal injury. High levels of IFABP at admission were associated with multiple organ dysfunction and mortality