Advertisement

Metabolic Brain Disease

, Volume 22, Issue 3–4, pp 353–373 | Cite as

Caecal ligation and puncture in the rat mimics the pathophysiological changes in human sepsis and causes multi-organ dysfunction

  • H. F. Brooks
  • C. K. Osabutey
  • R. F. Moss
  • P. L. R. Andrews
  • D. C. Davies
ORIGINAL PAPER

Abstract

Sepsis is a major clinical challenge that is associated with encephalopathy and multi-organ dysfunction. Current therapeutic interventions are relatively ineffective and the development of novel treatments is hampered by the lack of a well-characterised animal model. Therefore, the behavioural, metabolic, physiological and histological changes resulting from 'through and through' caecal ligation and puncture (CLP) in the rat were investigated to determine its suitability as an animal model of human sepsis. CLP resulted in bacteraemia, characterised by the presence of multiple enteric species within 18–20 h. Locomotor activity was reduced within 4 h of CLP and this reduction increased with time. Pyrexia was evident 4–5 h after CLP and was followed by hypothermia beginning 17 h after intervention. CLP resulted in reduced white blood cell and platelet counts and an increased neutrophil: lymphocyte ratio within 18–20 h. It also resulted in decreased blood glucose, but not lactate levels. CLP caused histopathological changes in the cerebral cortex, liver, lungs and vascular system indicative of multi-organ dysfunction. Therefore, CLP in the rat mimics the cardinal clinical features of human sepsis and the subsequent development of multi-organ dysfunction. It appears to be the best available animal model currently available, in which to investigate the underlying pathophysiology of sepsis and identify therapeutic targets.

Keywords

Sepsis Animal model Caecal ligation and puncture Encephalopathy Multi-organ dysfunction 

Notes

Acknowledgements

The authors thank Y-L Liu, Division of Basic Medical Sciences, St George's University of London for help during the activity data collection and M. Bushnell, Department of Diagnostic Bacteriology, Royal Veterinary College, London for the blood bacteriology.

References

  1. Aird WC (2003) The haematological system as a marker of organ dysfunction in sepsis. Mayo Clin Proc 78:869–881PubMedCrossRefGoogle Scholar
  2. Agrawal S, Sachdev A, Gupta D, Chugh K (2004) Role of lactate in critically ill children. Indian J Crit Care Med 8:173–181Google Scholar
  3. Angus DC, Wax RS (2001) Epidemiology of sepsis: an update. Crit Care Med 29:S109–S116PubMedCrossRefGoogle Scholar
  4. Ari I, Kafa IM, Kurt MA (2006) Perimicrovascular edema in the frontal cortex in a rat model of intraperitoneal sepsis. Exp Neurol 198:242–249PubMedCrossRefGoogle Scholar
  5. Barrow GI, Feltham RK (1993) Cowan and Steel’s manual for identification of medical bacteria, 3rd edn. Cambridge University Press, UK, pp 21–49Google Scholar
  6. Baskurt OK, Gelmont D, Meiselman HJ (1998) Red blood cell deformability in sepsis. Am J Respir Crit Care Med 157:421–427PubMedGoogle Scholar
  7. Bedard S, Marcotte B, Marette A (1997) Cytokines modulate glucose transport in skeletal muscle by inducing the expression of inducible nitric oxide synthase. Biochem J 325:487–493PubMedGoogle Scholar
  8. Bleck TP, Smith MC, Pierre-Louis SJ, Jares JJ, Murray J, Hansen CA (1993) Neurologic complictions of critical medical illnesses. Crit Care Med 21:98–103PubMedCrossRefGoogle Scholar
  9. Bluthe RM, Laye S, Michaud B, Combe C, Dantzer R, Parnet P (2000) Role of interleukin-1 beta and tumour necrosis factor-alpha in lipopolysaccharide-induced sickness behaviour: a study with interleukin-1 type 1 receptor deficient mice. Eur J Neurosci 12:446–456CrossRefGoogle Scholar
  10. Bone RC (1997) Important new findings in sepsis. JAMA 278:249PubMedCrossRefGoogle Scholar
  11. Brun-Buisson C, Doyon F, Carlet J, Dellamonica P, Gouin F, Lepoutre A, Mercier JC, Offenstadt G, Regnier B (1995) Incidence, risk factors, and outcome of severe sepsis and septic shock in adults. A multicenter prospective study in intensive care units. French ICU Group for Severe Sepsis. JAMA 274:968–974PubMedCrossRefGoogle Scholar
  12. Centers for Disease Control (1990) Increase in national hospital discharge survey rates for septicemia—United States, 1979–1987. JAMA 263:937–938CrossRefGoogle Scholar
  13. Chang L, Du J-B, Gao L-R, Pang Y-Z, Tang C-S (2003) Effect of ghrelin on septic shock in rats. Acta Pharmacol Sin 24:45–49PubMedGoogle Scholar
  14. Chinnaiyan A, Huber-Lang M, Kumar-Sinha C, Barette T, Shankar-Sinha S, Sarma VJ, Padgaonkar V, Ward P (2001) Molecular signatures of sepsis. Am J Pathol 159:1199–1209PubMedGoogle Scholar
  15. Daley C, Lim I, Modra J, Wilkinson I (1990) Comparative evaluation of nonradiometric BACTEC and improved oxoid signal blood culture system in a clinical laboratory. J Clin Microbiol 28:1586–1590PubMedGoogle Scholar
  16. Das UN (2000) Critical advances in septicemia and septic shock. Crit Care 4:290–296PubMedCrossRefGoogle Scholar
  17. Deitch EA, Rutan R, Waymack JP (1996) Trauma, shock, and gut translocation. New Horizons 4:289–299PubMedGoogle Scholar
  18. Deutschman CS, Andrejko KM, Haber BA, Bellin L (1997) Sepsis-induced depression of rat glucose-6-phosphatase gene expression and activity. Am J Physiol 273:R1709–R1718PubMedGoogle Scholar
  19. Duke T, Butt W, South M (1997) Predictors of mortality and multiple organ failure in children with sepsis. Intensive Care Med 23:684–692PubMedCrossRefGoogle Scholar
  20. Eggers V, Schilling A, Kox WJ, Spies C (2003) Septic encephalopathy. Diagnosis and therapy. Anaesthesist 52:294–303PubMedCrossRefGoogle Scholar
  21. Eidelman LA, Putterman D, Putterman C, Sprung CL (1996) The spectrum of septic encephalopathy. Definition, etiologies, and mortalities. JAMA 275:470–473PubMedCrossRefGoogle Scholar
  22. Fakeye TO, Oladipupo T, Showande O, Ogunremi Y (2007) Effect of Carica papaya linn (family Cariaceae) on activity of two oral hypoglycaemic agents. Tropic J Pharm Res 6:671–678Google Scholar
  23. Friedman G, Berlot G, Kahn RJ, Vincent J-L (1995) Combined measurements of blood lactate concentrations and gastric intramucosal pH in patients with severe sepsis. Crit Care Med 23:1184–1193PubMedCrossRefGoogle Scholar
  24. Friedman JM, Halaas JL (1998) Leptin and the regulation of body weight in mammals. Nature 395:763–770PubMedCrossRefGoogle Scholar
  25. Funke A, Berner R, Traichel B, Schmeisser D, Leititis UJ, Niemeyer CM (2000) Frequency, natural course, and outcome of neonatal neutropenia. Pediatrics 106:45–51PubMedCrossRefGoogle Scholar
  26. Gabay C, Kushner I (1999) Acute-phase proteins and other systemic responses to inflammation. N Engl J Med 340:448–454PubMedCrossRefGoogle Scholar
  27. Galley HF, Webster NR (1996) The immuno-inflammatory cascade. Brit J Anaesth 77:11–16PubMedGoogle Scholar
  28. Gibot S, Buonsanti C, Massin F, Romano M, Kolopp-Sarda M-N, Benigni F, Faure GC, Béné M-C, Panina-Bordignon P, Passini N, Lévy B (2006) Modulation of the triggering receptor expressed on the myeloid cell type 1 pathway in murine septic shock. Infect Immun 74:2823–2830PubMedCrossRefGoogle Scholar
  29. Gobatto CA, de Mello MA, Sibuya CY, de Azevedo JR, dos Santos LA, Kokubun E (2001) Maximal lactate steady state in rats submitted to swimming exercise. Comp BiochemPhysiol A Mol Integr Physiol 130:21–27CrossRefGoogle Scholar
  30. Grunfeld C, Zhao C, Fuller J, Pollack A, Moser A, Friedman J, Feingold KR (1996) Endotoxin and cytokines induce expression of leptin, the ob gene product, in hamsters. J Clin Invest 97:2152–2157PubMedCrossRefGoogle Scholar
  31. Harkness JE, Wagner JE (1989) The biology and medicine of rabbits and rodents, 3rd edn. Lea and Febiger, Philadelphia, p 49Google Scholar
  32. Harrison DA, Welch CA, Eddleston JM (2006) The epidemiology of severe sepsis in England, Wales and Northern Ireland, 1996 to 2004: secondary analysis of a high quality clinical database, the ICNARC Case Mix Programme Database. Crit Care 10:R42PubMedCrossRefGoogle Scholar
  33. Heuer JG, Bailey DL, Sharma GR, Zhang T, Ding C, Ford A, Stephens EJ, Holmes KC, Grubbs RL, Fynboe KA, Chen YF, Jakubowski JA (2004) Cecal ligation and puncture with total parenteral nutrition: a clinically relevant model of the metabolic, hormonal, and inflammatory dysfunction associated with critical illness. J Surg Res 121:178–186PubMedCrossRefGoogle Scholar
  34. Horn KD (1998) Evolving strategies in the treatment of sepsis and systemic inflammatory response syndrome (SIRS). Q J Med 91:265–277Google Scholar
  35. Inui A, Asakawa A, Bowers CY, Mantovani G, Laviano A, Meguid MM, Fujimiya M (2004) Ghrelin, appetite, and gastric motility: the emerging role of the stomach as an endocrine organ. FASEB J 18:439–456PubMedCrossRefGoogle Scholar
  36. Jones GR (1998) Assessment criteria in identifying the sick sepsis patient. J Infect 37(Suppl 1):24–29PubMedCrossRefGoogle Scholar
  37. Katayama T, Ikeda Y, Handa M, Tamatani T, Sakamoto S, Ito M, Ishimura Y, Suematsu M (2000) Immunoneutralization of glycoprotein Ib alpha attenuates endotoxin-induced interactions of platelets and leukocytes with rat venular endothelium in vivo. Circ Res 86:1031–1037PubMedGoogle Scholar
  38. Konsman JP, Parnet P, Dantzer R (2002) Cytokine–induced sickness behaviour: mechanisms and implications. Trends Neurosci 25:154–159PubMedCrossRefGoogle Scholar
  39. Krinke GJ (2000) The laboratory rat. Academic, London, p 442Google Scholar
  40. Lewis S, Brain B, Bates I (2001) Dacies and Lewis practical haematology, 9th edn. Churchill Livingstone, UK, pp 595–598Google Scholar
  41. Luft FC (2001) Lactic acidosis update for critical care clinicians. J Am Soc Nephrol 12(suppl 17):S15–S19PubMedGoogle Scholar
  42. Maier SF, Watkins LR (1998) Cytokines for psychologists: implications of bidirectional immune-to-brain communication for understanding behavior, mood, and cognition. Psychol Rev 105:83–107PubMedCrossRefGoogle Scholar
  43. Maitra SR, Wojnar MM, Lang CH (2000) Alterations in tissue glucose uptake during the hyperglycemic and hypoglycemic phases of sepsis. Shock 13:379–385PubMedGoogle Scholar
  44. Malik NM, Moore GBT, Smith G, Liu Y-L, Sanger GJ, Andrews PLR (2006) Behavioural and hypothalamic molecular effects of the anti-cancer agent cisplatin in the rat: a model of chemotherapy-related malaise? Pharmacol Biochem and Behav 83:9–20CrossRefGoogle Scholar
  45. Martin GS, Mannino DM, Moss M (2006) The effect of age on the development and outcome of adult sepsis. Crit Care Med 34:15–21PubMedCrossRefGoogle Scholar
  46. Mavrommatis AC, Theodoridis T, Orfanidou A, Roussos C, Christopoulou-Kokkinou V, Zakynthinos S (2000) Coagulation system and platelets are fully activated in uncomplicated sepsis. Crit Care Med 28:451–457PubMedCrossRefGoogle Scholar
  47. McCarthy DO (2000) Cytokines and the anorexia of infection: potential mechanisms and treaments. Biol Res Nurs 1:287–298PubMedCrossRefGoogle Scholar
  48. Mizock BA, Falk JL (1992) Lactic acidosis in critical illness. Crit Care Med 20:80–93PubMedCrossRefGoogle Scholar
  49. Mori M, Kudo H, Yoshitake S, Ito K, Shinguu C, Noguchi T (2000) Transient EDTA-dependent pseudothrombocytopenia in a patient with sepsis. Intensive Care Med 26:218–220PubMedCrossRefGoogle Scholar
  50. Morton DB, Griffiths PH (1985) Guidelines on the recognition of pain, distress and discomfort in experimental animals and an hypothesis for assessment. Vet Rec 116:431–436PubMedGoogle Scholar
  51. Otto B, Cuntz U, Fruehauf E, Wawarta R, Folwaczny C, Riepl RL, Heiman ML, Lehnert P, Fichter M, Tschop M (2001) Weight gain decreases elevated plasma ghrelin concentrations of patients with anorexia nervosa. Eur J Endocrin 145:669–673CrossRefGoogle Scholar
  52. Papadopoulos MC, Lamb FJ, Moss RF, Davies DC, Tighe D, Bennett ED (1999) Faecal peritonitis causes oedema and neuronal injury in pig cerebral cortex. Clin Sci 96:461–466PubMedCrossRefGoogle Scholar
  53. Parrillo JE, Parker MM, Natanson C, Suffredini AF, Danner RL, Cunnion RE, Ognibene FP (1990) Septic shock in humans. Advances in the understanding of pathogenesis, cardiovascular dysfunction, and therapy. Ann Intern Med 113:227–242PubMedGoogle Scholar
  54. Quezado Z, Parent C, Karzai W, Depietro M, Natanson C, Hammond W, Danner RL, Cui X, Fitz Y, Banks SM, Gerstenberger E, Eichacker PQ (2001) Acute G-CSF therapy is not protective during lethal E. coli sepsis. Am J Physiol Regul Integr Comp Physiol 281:R1177–R1185PubMedGoogle Scholar
  55. Reimer LG, Wilson ML, Weinstein MP (1997) Update on detection of bacteremia and fungemia. Clin Microbiol Rev 10:444–465PubMedGoogle Scholar
  56. Remick DG, Newcomb DE, Bolgos GL, Call DR (2000) Comparison of the mortality and inflammatory response of two models of sepsis: lipopolysaccharide vs. cecal ligation and puncture. Shock 13:110–116PubMedGoogle Scholar
  57. Remick DG, Bolgos G, Copeland S, Siddiqui J (2005) Role of interleukin-6 in mortality from and physiologic response to sepsis. Infect Immun 73:2751–2757PubMedCrossRefGoogle Scholar
  58. Revelly J-P, Tappy L, Martinez A, Bollmann M, Cayeux M-C, Berger MM, Chiolero RL (2005) Lactate and glucose metabolism in severe sepsis and cardiogenic shock. Crit Care Med 33:2235–2240PubMedCrossRefGoogle Scholar
  59. Riedemann NC, Guo R-F, Ward PA (2003) The enigma of sepsis. J Clin Invest 112:460–467PubMedCrossRefGoogle Scholar
  60. Riquelme R, Torres A, el-Ebiary M, Mensa J, Estruch R, Riuz M, Angrill J, Soler N (1997) Community-acquired pneumonia in the elderly: clinical and nutritional aspects. Am J Respir Crit Care Med 156:1908–1914PubMedGoogle Scholar
  61. Rivier C (1993) Effect of peripheral and central cytokines on the hypothalamic-pituitary-adrenal axis of the rat. Ann N Y Acad Sci 697:97–105PubMedCrossRefGoogle Scholar
  62. Rusavy Z, Sramek V, Lacigova S, Novak I, Tesinsky P, Macdonald IA (2004) Influence of insulin on glucose metabolism and energy expenditure in septic patients. Crit Care 8:R213–R220PubMedCrossRefGoogle Scholar
  63. Russell JA, Singer J, Bernard GR, Wheeler A, Fulkerson W, Hudson L, Schein R, Summer W, Wright P, Walley KR (2000) Changing pattern of organ dysfunction in early human sepsis is related to mortality. Crit Care Med 28:3405–3411PubMedCrossRefGoogle Scholar
  64. Sachot C, Poole S, Luheshi GN (2004) Circulating leptin mediates lipopolysaccharide–induced anorexia and fever in rats. J Physiol 561:263–272PubMedCrossRefGoogle Scholar
  65. Shibazaki M, Kawabata Y, Yokochi T, Nishida A, Takada H, Endo Y (1999) Complement-dependent accumulation and degradation of platelets in the lung and liver induced by injection of lipopolysaccharides. Infect Immun 67:5186–5191PubMedGoogle Scholar
  66. Stephan F, Cheffi MA, Kaplan C, Maillet J, Novara A, Fagon J, Bonnet F (2000) Autoantibodies against platelet glycoproteins in critically ill patients with thrombocytopenia. Am J Med 108:554–560PubMedCrossRefGoogle Scholar
  67. Tsiotou AG, Sakorafas GH, Anagnostopoulos G, Bramis J (2005) Septic shock; current pathogenetic concepts from a clinical persective. Med Sci Monit 11:RA76–RA85PubMedGoogle Scholar
  68. Van der Poll T, van Deventer JH (1999) Cytokines and anticytokines in the pathogenesis of sepsis. Infect Dis Clin North Am 13:413–426PubMedCrossRefGoogle Scholar
  69. Wheeler AP, Bernard GR (1999) Treating patients with severe sepsis. N Engl J Med 340:207–214PubMedCrossRefGoogle Scholar
  70. Wichterman K, Baue A, Chaudry I (1980) Sepsis and septic shock: a review of laboratory models and a proposal. J Surg Res 29:189–201PubMedCrossRefGoogle Scholar
  71. Wyllie DH, Bowler IC, Peto TE (2004) Relation between lymphopenia and bacteraemia in UK adults with medical emergencies. J Clin Pathol 57:950–955PubMedCrossRefGoogle Scholar
  72. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372:425–432PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • H. F. Brooks
    • 1
  • C. K. Osabutey
    • 1
  • R. F. Moss
    • 1
  • P. L. R. Andrews
    • 1
  • D. C. Davies
    • 1
  1. 1.Division of Basic Medical Sciences and Image Resource FacilitySt George’s University of LondonLondonUK

Personalised recommendations