Skip to main content
SpringerLink
Log in

Acute intestinal failure in critically ill patients: is plasma citrulline the right marker?

  • Review
  • Published:
Intensive Care Medicine Aims and scope Submit manuscript

Abstract

Introduction

Small bowel functions are more complex than colon functions, and short bowel conditions are associated with increased mortality. Gastrointestinal dysfunction in critically ill patients is common, probably underestimated, and associated with a poor prognosis. However, a validated definition of acute intestinal failure is lacking, in absence of a marker to measure it. Consequently, small bowel dysfunction is not clearly integrated into the overall approach used to treat ICU patients.

Materials and Methods

Review of the literature on gastrointestinal dysfunction in critically ill patients, and proposition of a definition of acute intestinal failure.

Conclusion

On the one hand, small bowel ischemia is related to acute reduction of enterocyte mass and loss of gut barrier function by epithelial lifting of villi. On the other hand, systemic inflammatory response syndrome (SIRS) and sepsis could be linked to an acute dysfunction of enterocytes without enterocyte reduction. Citrulline is an amino acid mainly synthesized by small bowel enterocytes. Various contexts of chronic and acute reduction of enterocyte mass have been correlated with low plasma citrulline concentration. Critically ill patients with shock have an acute reduction of enterocyte mass and reduced gut citrulline synthesis, leading to a low plasma citrulline concentration. Acute intestinal failure could be defined as an acute reduction of enterocyte mass and/or acute dysfunction of enterocytes, associated or not with loss of gut barrier function. The influence of SIRS and acute renal failure on plasma citrulline concentration and the value of this concentration as an indicator of acute intestinal failure in critically ill patients must be further evaluated.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Abbreviations

ICU:

Intensive care unit

SIRS:

Systemic inflammatory response syndrome

CRP:

C-reactive protein

IAH:

Intra-abdominal hypertension

AIDS:

Acute intestinal distress syndrome

GIF:

Gastrointestinal failure

References

  1. Abu-Elmagd KM (2006) Intestinal transplantation for short bowel syndrome and gastrointestinal failure: current consensus, rewarding outcomes, and practical guidelines. Gastroenterology 130:S132–S137

    Article  PubMed  CAS  Google Scholar 

  2. Lloyd DA, Vega R, Bassett P, Forbes A, Gabe SM (2006) Survival and dependence on home parenteral nutrition: experience over a 25 year period in a UK referral centre. Aliment Pharmacol Ther 24:1231–1240

    Article  PubMed  CAS  Google Scholar 

  3. Messing B, Joly F (2006) Guidelines for management of home parenteral support in adult chronic intestinal failure patients. Gastroenterology 130:S43–S51

    Article  PubMed  Google Scholar 

  4. Jones BA, Gores GJ (1997) Physiology and pathophysiology of apoptosis in epithelial cells of the liver, pancreas, and intestine. Am J Physiol 273:G1174–G1188

    PubMed  CAS  Google Scholar 

  5. Mayhew TM, Myklebust R, Whybrow A, Jenkins R (1999) Epithelial integrity, cell death and cell loss in mammalian small intestine. Histol Histopathol 14:257–267

    PubMed  CAS  Google Scholar 

  6. Reintam A, Parm P, Kitus R, Kern H, Starkopf J (2009) Gastrointestinal symptoms in intensive care patients. Acta Anaesthesiol Scand 53:318–324

    Article  PubMed  CAS  Google Scholar 

  7. Gaussorgues P, Gueugniaud PY, Vedrinne JM, Salord F, Mercatello A, Robert D (1988) Bacteremia following cardiac arrest and cardiopulmonary resuscitation. Intensive Care Med 14:575–577

    Article  PubMed  CAS  Google Scholar 

  8. Deitch EA (1992) Multiple organ failure. Pathophysiology and potential future therapy. Ann Surg 216:117–134

    Article  PubMed  CAS  Google Scholar 

  9. Fiddian-Green RG (1988) Splanchnic ischaemia and multiple organ failure in the critically ill. Ann R Coll Surg Engl 70:128–134

    PubMed  CAS  Google Scholar 

  10. Hallback DA, Hulten L, Jodal M, Lindhagen J, Lundgren O (1978) Evidence for the existence of a countercurrent exchanger in the small intestine in man. Gastroenterology 74:683–690

    PubMed  CAS  Google Scholar 

  11. Lundgren O (1974) The circulation of the small bowel mucosa. Gut 15:1005–1013

    Article  PubMed  CAS  Google Scholar 

  12. Chang JX, Chen S, Ma LP, Jiang LY, Chen JW, Chang RM, Wen LQ, Wu W, Jiang ZP, Huang ZT (2005) Functional and morphological changes of the gut barrier during the restitution process after hemorrhagic shock. World J Gastroenterol 11:5485–5491

    PubMed  Google Scholar 

  13. Leung FW, Su KC, Passaro E Jr, Guth PH (1992) Regional differences in gut blood flow and mucosal damage in response to ischemia and reperfusion. Am J Physiol 263:G301–G305

    PubMed  CAS  Google Scholar 

  14. Ahren C, Haglund U (1973) Mucosal lesions in the small intestine of the cat during low flow. Acta Physiol Scand 88:541–550

    Article  PubMed  CAS  Google Scholar 

  15. Chiu CJ, McArdle AH, Brown R, Scott HJ, Gurd FN (1970) Intestinal mucosal lesion in low-flow states. I. A morphological, hemodynamic, and metabolic reappraisal. Arch Surg 101:478–483

    PubMed  CAS  Google Scholar 

  16. Haglund U, Hulten L, Ahren C, Lundgren O (1975) Mucosal lesions in the human small intestine in shock. Gut 16:979–984

    Article  PubMed  CAS  Google Scholar 

  17. Derikx JP, Matthijsen RA, de Bruine AP, van Dam RM, Buurman WA, Dejong CH (2009) A new model to study intestinal ischemia-reperfusion damage in Man. J Surg Res. doi:10.1016/j.jss.2009.09.046

  18. Kanda T, Fujii H, Tani T, Murakami H, Suda T, Sakai Y, Ono T, Hatakeyama K (1996) Intestinal fatty acid-binding protein is a useful diagnostic marker for mesenteric infarction in humans. Gastroenterology 110:339–343

    Article  PubMed  CAS  Google Scholar 

  19. Rahman SH, Ammori BJ, Holmfield J, Larvin M, McMahon MJ (2003) Intestinal hypoperfusion contributes to gut barrier failure in severe acute pancreatitis. J Gastrointest Surg 7:26–35 discussion 35–26

    Article  PubMed  Google Scholar 

  20. Besselink MG, van Santvoort HC, Renooij W, de Smet MB, Boermeester MA, Fischer K, Timmerman HM, Ahmed Ali U, Cirkel GA, Bollen TL, van Ramshorst B, Schaapherder AF, Witteman BJ, Ploeg RJ, van Goor H, van Laarhoven CJ, Tan AC, Brink MA, van der Harst E, Wahab PJ, van Eijck CH, Dejong CH, van Erpecum KJ, Akkermans LM, Gooszen HG (2009) Intestinal barrier dysfunction in a randomized trial of a specific probiotic composition in acute pancreatitis. Ann Surg 250:712–719

    Article  PubMed  Google Scholar 

  21. van Haren FM, Pickkers P, Foudraine N, Heemskerk S, Sleigh J, van der Hoeven JG (2010) The effects of methylene blue infusion on gastric tonometry and intestinal fatty acid binding protein levels in septic shock patients. J Crit Care 25(358):e351–e357

    Google Scholar 

  22. Derikx JP, Matthijsen RA, de Bruine AP, van Bijnen AA, Heineman E, van Dam RM, Dejong CH, Buurman WA (2008) Rapid reversal of human intestinal ischemia-reperfusion induced damage by shedding of injured enterocytes and reepithelialisation. PLoS One 3:e3428

    Article  PubMed  Google Scholar 

  23. Fleming C (1981) Remington M Nutrition and the surgical patient. In: Hill GL (ed) Intestinal failure. Churchill Livingstone, New York, pp 219–235

    Google Scholar 

  24. Nightingale J (2001) Introduction: definition and classification of intestinal failure. In: Nightingale JMD (ed) Intestinal failure. GMM, London, p XIX

    Google Scholar 

  25. Le Gall JR, Lemeshow S, Saulnier F (1993) A new simplified acute physiology score (SAPS II) based on a European/North American multicenter study. Jama 270:2957–2963

    Article  PubMed  CAS  Google Scholar 

  26. Vincent JL, Moreno R, Takala J, Willatts S, De Mendonca A, Bruining H, Reinhart CK, Suter PM, Thijs LG (1996) The SOFA (sepsis-related organ failure assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med 22:707–710

    Article  PubMed  CAS  Google Scholar 

  27. Fagon JY, Chastre J, Novara A, Medioni P, Gibert C (1993) Characterization of intensive care unit patients using a model based on the presence or absence of organ dysfunctions and/or infection: the ODIN model. Intensive Care Med 19:137–144

    Article  PubMed  CAS  Google Scholar 

  28. Malbrain ML, De Laet I (2008) AIDS is coming to your ICU: be prepared for acute bowel injury and acute intestinal distress syndrome. Intensive Care Med 34:1565–1569

    Article  PubMed  Google Scholar 

  29. Malbrain ML, Cheatham ML, Kirkpatrick A, Sugrue M, Parr M, De Waele J, Balogh Z, Leppaniemi A, Olvera C, Ivatury R, D’Amours S, Wendon J, Hillman K, Johansson K, Kolkman K, Wilmer A (2006) Results from the international conference of experts on intra-abdominal hypertension and abdominal compartment syndrome. I. definitions. Intensive Care Med 32:1722–1732

    Article  PubMed  Google Scholar 

  30. Reintam A, Parm P, Kitus R, Starkopf J, Kern H (2008) Gastrointestinal failure score in critically ill patients: a prospective observational study. Crit Care 12:R90

    Article  PubMed  Google Scholar 

  31. Khadaroo RG, Marshall JC (2008) Gastrointestinal dysfunction in the critically ill: can we measure it? Crit Care 12:180

    Article  PubMed  Google Scholar 

  32. Curis E, Nicolis I, Moinard C, Osowska S, Zerrouk N, Benazeth S, Cynober L (2005) Almost all about citrulline in mammals. Amino Acids 29:177–205

    Article  PubMed  CAS  Google Scholar 

  33. Crenn P, Messing B, Cynober L (2008) Citrulline as a biomarker of intestinal failure due to enterocyte mass reduction. Clin Nutr 27:328–339

    Article  PubMed  CAS  Google Scholar 

  34. Crenn P, Coudray-Lucas C, Thuillier F, Cynober L, Messing B (2000) Postabsorptive plasma citrulline concentration is a marker of absorptive enterocyte mass and intestinal failure in humans. Gastroenterology 119:1496–1505

    Article  PubMed  CAS  Google Scholar 

  35. Crenn P, Vahedi K, Lavergne-Slove A, Cynober L, Matuchansky C, Messing B (2003) Plasma citrulline: a marker of enterocyte mass in villous atrophy-associated small bowel disease. Gastroenterology 124:1210–1219

    Article  PubMed  CAS  Google Scholar 

  36. Papadia C, Sherwood RA, Kalantzis C, Wallis K, Volta U, Fiorini E, Forbes A (2007) Plasma citrulline concentration: a reliable marker of small bowel absorptive capacity independent of intestinal inflammation. Am J Gastroenterol 102:1474–1482

    Article  PubMed  CAS  Google Scholar 

  37. Tizianello A, De Ferrari G, Garibotto G, Gurreri G, Robaudo C (1980) Renal metabolism of amino acids and ammonia in subjects with normal renal function and in patients with chronic renal insufficiency. J Clin Invest 65:1162–1173

    Article  PubMed  CAS  Google Scholar 

  38. Olde Damink SW, Jalan R, Redhead DN, Hayes PC, Deutz NE, Soeters PB (2002) Interorgan ammonia and amino acid metabolism in metabolically stable patients with cirrhosis and a TIPSS. Hepatology 36:1163–1171

    Article  PubMed  CAS  Google Scholar 

  39. Herbers AH, Feuth T, Donnelly JP, Blijlevens NM (2010) Citrulline-based assessment score: first choice for measuring and monitoring intestinal failure after high-dose chemotherapy. Ann Oncol 21:1706–1711

    Article  PubMed  CAS  Google Scholar 

  40. Wedlake L, McGough C, Hackett C, Thomas K, Blake P, Harrington K, Tait D, Khoo V, Dearnaley D, Andreyev HJ (2008) Can biological markers act as non-invasive, sensitive indicators of radiation-induced effects in the gastrointestinal mucosa? Aliment Pharmacol Ther 27:980–987

    Article  PubMed  CAS  Google Scholar 

  41. Ruiz P, Tryphonopoulos P, Island E, Selvaggi G, Nishida S, Moon J, Berlanga A, Defranc T, Levi D, Tekin A, Tzakis AG (2010) Citrulline evaluation in bowel transplantation. Transplant Proc 42:54–56

    Article  PubMed  CAS  Google Scholar 

  42. Herbers AH, Blijlevens NM, Donnelly JP, de Witte TJ (2008) Bacteraemia coincides with low citrulline concentrations after high-dose melphalan in autologous HSCT recipients. Bone Marrow Transplant 42:345–349

    Article  PubMed  CAS  Google Scholar 

  43. van Vliet MJ, Tissing WJ, Rings EH, Koetse HA, Stellaard F, Kamps WA, de Bont ES (2009) Citrulline as a marker for chemotherapy induced mucosal barrier injury in pediatric patients. Pediatr Blood Cancer 53:1188–1194

    Article  PubMed  Google Scholar 

  44. Pan L, Wang X, Li W, Li N, Li J (2010) The intestinal fatty acid binding protein diagnosing gut dysfunction in acute pancreatitis: a pilot study. Pancreas 39:633–638

    Article  PubMed  CAS  Google Scholar 

  45. Hietbrink F, Besselink MG, Renooij W, de Smet MB, Draisma A, van der Hoeven H, Pickkers P (2009) Systemic inflammation increases intestinal permeability during experimental human endotoxemia. Shock 32:374–378

    Article  PubMed  CAS  Google Scholar 

  46. Piton G, Manzon C, Monnet E, Cypriani B, Barbot O, Navellou JC, Carbonnel F, Capellier G (2010) Plasma citrulline kinetics and prognostic value in critically ill patients. Intensive Care Med 36(4):702–706

    Article  PubMed  CAS  Google Scholar 

  47. Hersch M, Scott JA, Izbicki G, McCormack D, Cepinkas G, Ostermann M, Sibbald WJ (2005) Differential inducible nitric oxide synthase activity in circulating neutrophils vs. mononuclears of septic shock patients. Intensive Care Med 31:1132–1135

    Article  PubMed  Google Scholar 

  48. Kao CC, Bandi V, Guntupalli KK, Wu M, Castillo L, Jahoor F (2009) Arginine, citrulline and nitric oxide metabolism in sepsis. Clin Sci (Lond) 117:23–30

    Article  CAS  Google Scholar 

  49. Luiking YC, Poeze M, Ramsay G, Deutz NE (2009) Reduced citrulline production in sepsis is related to diminished de novo arginine and nitric oxide production. Am J Clin Nutr 89:142–152

    Article  PubMed  CAS  Google Scholar 

  50. Le Boucher J, Charret C, Coudray-Lucas C, Giboudeau J, Cynober L (1997) Amino acid determination in biological fluids by automated ion-exchange chromatography: performance of Hitachi L-8500A. Clin Chem 43:1421–1428

    PubMed  CAS  Google Scholar 

  51. Demacker PN, Beijers AM, van Daal H, Donnelly JP, Blijlevens NM, van den Ouweland JM (2009) Plasma citrulline measurement using UPLC tandem mass-spectrometry to determine small intestinal enterocyte pathology. J Chromatogr B Analyt Technol Biomed Life Sci 877:387–392

    Article  PubMed  CAS  Google Scholar 

  52. van Waardenburg DA, de Betue CT, Luiking YC, Engel M, Deutz NE (2007) Plasma arginine and citrulline concentrations in critically ill children: strong relation with inflammation. Am J Clin Nutr 86:1438–1444

    PubMed  Google Scholar 

  53. Freund H, Atamian S, Holroyde J, Fischer JE (1979) Plasma amino acids as predictors of the severity and outcome of sepsis. Ann Surg 190:571–576

    Article  PubMed  CAS  Google Scholar 

  54. Luiking YC, Deutz NE (2007) Exogenous arginine in sepsis. Crit Care Med 35:S557–S563

    Article  PubMed  CAS  Google Scholar 

Download references

Conflicts of interest

None.

Author information

Authors and Affiliations

  1. Intensive Care Unit, Besançon University Hospital, Besançon, France

    Gaël Piton, Cyril Manzon & Gilles Capellier

  2. Clinical Chemistry Unit, Besançon University Hospital, Besançon, France

    Benoit Cypriani

  3. Hepatology and Gastroenterology Unit, University Hospital of Bicêtre, Le Kremlin Bicêtre, France

    Franck Carbonnel

  4. EA 3920 and INSERM IFR 133, University of Franche Comté, Besançon, France

    Gaël Piton & Gilles Capellier

  5. Service de Réanimation Médicale, Hôpital Jean Minjoz, Université de Franche Comté, Boulevard Fleming, 25030, Besançon, France

    Gaël Piton

Authors
  1. Gaël Piton
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cyril Manzon
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Benoit Cypriani
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Franck Carbonnel
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gilles Capellier
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gaël Piton.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Piton, G., Manzon, C., Cypriani, B. et al. Acute intestinal failure in critically ill patients: is plasma citrulline the right marker?. Intensive Care Med 37, 911–917 (2011). https://doi.org/10.1007/s00134-011-2172-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00134-011-2172-x

Keywords

Search

Navigation