Intensive Care Medicine

, Volume 35, Issue 7, pp 1286–1296 | Cite as

Role of arginine vasopressin and terlipressin as first-line vasopressor agents in fulminant ovine septic shock

  • Sebastian Rehberg
  • Christian Ertmer
  • Gabriele Köhler
  • Hans-Ulrich Spiegel
  • Andrea Morelli
  • Matthias Lange
  • Katharina Moll
  • Katrin Schlack
  • Hugo Van Aken
  • Fuhong Su
  • Jean-Louis Vincent
  • Martin Westphal



To compare the effects of first-line therapy with low-dose arginine vasopressin (AVP) or terlipressin (TP) on mesenteric blood flow, plasma AVP levels, organ function and mortality in ovine septic shock.


Twenty-four adult ewes were anesthetized and instrumented for chronic hemodynamic monitoring. A flow-probe was placed around the superior mesenteric artery, and feces were extracted from the cecum. Following baseline measurements, feces were injected into the peritoneal cavity. When mean arterial pressure (MAP) decreased to less than 60 mmHg, animals were randomly assigned to receive AVP (0.5 mU kg−1 min−1), TP (1 μg kg−1 h−1) or saline (n = 8 each). A norepinephrine infusion was titrated to maintain MAP at 70 ± 5 mmHg in all groups.


Cardiovascular pressures, cardiac output, mesenteric blood flow, and lung tissue concentrations of 3-nitrotyrosine and hemoxygenase-1 were similar among groups throughout the study period. TP infusion resulted in lower plasma AVP concentrations, reduced positive net fluid balance, increased central venous oxygen saturation and slightly prolonged survival compared to control and AVP-treated animals. However, TP treatment was associated with higher liver transaminases and lactate dehydrogenase versus control animals after 12 h.


This study provides evidence that the effects of low-dose TP differ from those of AVP, not only as TP has a longer half life, but also because of different mechanisms of action. Although low-dose TP infusion may be superior to sole norepinephrine or AVP therapy in septic shock, the safety of this therapeutic approach should be determined in more detail.


Sepsis Septic shock Arginine vasopressin Terlipressin First-line therapy Mesenteric blood flow 



The authors thank Dr. med. Michael Erren (Department for Laboratory Medicine, University of Muenster, Muenster, Germany) for the analyses of the plasma samples and Christina Großerichter as well as Jennifer Seisel (Department of Anesthesiology and Intensive Care, University of Muenster, Muenster, Germany) for expert technical assistance during the experiment. This study was supported by intramural funding. Haemopressin® was provided as a gift from Prof. Dr. Klaus Doehler, Curatis Pharma, Hanover, Germany.

Conflicts of interest

The authors have no conflicts of interest to disclose.

Supplementary material

134_2009_1470_MOESM1_ESM.doc (20 kb)
Supplementary material (DOC 20 kb)


  1. 1.
    Engel C, Brunkhorst FM, Bone HG, Brunkhorst R, Gerlach H, Grond S, Gruendling M, Huhle G, Jaschinski U, John S, Mayer K, Oppert M, Olthoff D, Quintel M, Ragaller M, Rossaint R, Stuber F, Weiler N, Welte T, Bogatsch H, Hartog C, Loeffler M, Reinhart K (2007) Epidemiology of sepsis in Germany: results from a national prospective multicenter study. Intensive Care Med 33:606–618PubMedCrossRefGoogle Scholar
  2. 2.
    Friedman G, Silva E, Vincent JL (1998) Has the mortality of septic shock changed with time. Crit Care Med 26:2078–2086PubMedCrossRefGoogle Scholar
  3. 3.
    Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, Calandra T, Dhainaut JF, Gerlach H, Harvey M, Marini JJ, Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson BT, Townsend S, Vender JS, Zimmerman JL, Vincent JL (2008) Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2008. Intensive Care Med 34:17–60PubMedCrossRefGoogle Scholar
  4. 4.
    Russell JA (2007) Vasopressin in vasodilatory and septic shock. Curr Opin Crit Care 13:383–391PubMedCrossRefGoogle Scholar
  5. 5.
    Duranteau J, Sitbon P, Teboul JL, Vicaut E, Anguel N, Richard C, Samii K (1999) Effects of epinephrine, norepinephrine, or the combination of norepinephrine and dobutamine on gastric mucosa in septic shock. Crit Care Med 27:893–900PubMedCrossRefGoogle Scholar
  6. 6.
    Sun Q, Dimopoulos G, Nguyen DN, Tu Z, Nagy N, Hoang AD, Rogiers P, De Backer D, Vincent JL (2003) Low-dose vasopressin in the treatment of septic shock in sheep. Am J Respir Crit Care Med 168:481–486PubMedCrossRefGoogle Scholar
  7. 7.
    Russell J, Walley K, Singer J, Gordon A, Hébert P, Cooper D, Holmes C, Mehta S, Granton J, Storms M, Cook D, Presneill J, Ayers D (2008) Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 358:877–887PubMedCrossRefGoogle Scholar
  8. 8.
    Pesaturo AB, Jennings HR, Voils SA (2006) Terlipressin: vasopressin analog and novel drug for septic shock. Ann Pharmacother 40:2170–2177PubMedCrossRefGoogle Scholar
  9. 9.
    Leone M, Martin C (2006) Rescue therapy in septic shock—is terlipressin the last frontier? Crit Care 10:131PubMedCrossRefGoogle Scholar
  10. 10.
    Michel F, Thomachot L, David M, Nicaise C, Vialet R, Di Marco JN, Lagier P, Martin C (2007) Continuous low-dose infusion of terlipressin as a rescue therapy in meningococcal septic shock. Am J Emerg Med 25:863 e861–862PubMedCrossRefGoogle Scholar
  11. 11.
    Lange M, Morelli A, Ertmer C, Koehler G, Broking K, Hucklenbruch C, Bone HG, Van Aken H, Traber DL, Westphal M (2007) Continuous versus bolus infusion of terlipressin in ovine endotoxemia. Shock 28:623–629PubMedCrossRefGoogle Scholar
  12. 12.
    Bernadich C, Bandi JC, Melin P, Bosch J (1998) Effects of F-180, a new selective vasoconstrictor peptide, compared with terlipressin and vasopressin on systemic and splanchnic hemodynamics in a rat model of portal hypertension. Hepatology 27:351–356PubMedCrossRefGoogle Scholar
  13. 13.
    Rehberg S, Ertmer C, Lange M, Pinto B, Morelli A, Van Aken H, Su F, Vincent J, Westphal M (2008) Vasopressin and terlipressin as first-line therapy in fulminant ovine septic shock. Crit Care 12:P405CrossRefGoogle Scholar
  14. 14.
    Su F, Nguyen ND, Creteur J, Cai Y, Nagy N, Anh-Dung H, Amaral A, Bruzzi de Carvalho F, Chochrad D, Vincent JL (2004) Use of low tidal volume in septic shock may decrease severity of subsequent acute lung injury. Shock 22:145–150PubMedCrossRefGoogle Scholar
  15. 15.
    Wang Z, Su F, Rogiers P, Vincent JL (2007) Beneficial effects of recombinant human activated protein C in a ewe model of septic shock. Crit Care Med 35:2594–2600PubMedCrossRefGoogle Scholar
  16. 16.
    Su F, Wang Z, Cai Y, Rogiers P, Vincent JL (2007) Fluid resuscitation in severe sepsis and septic shock: albumin, hydroxyethyl starch, gelatin or ringer’s lactate-does it really make a difference? Shock 27:520–526PubMedCrossRefGoogle Scholar
  17. 17.
    Su F, Wang Z, Cai Y, Remmelink M, Vincent JL (2007) Beneficial effects of ethyl pyruvate in septic shock from peritonitis. Arch Surg 142:166–171PubMedCrossRefGoogle Scholar
  18. 18.
    Cox RA, Burke AS, Soejima K, Murakami K, Katahira J, Traber LD, Herndon DN, Schmalstieg FC, Traber DL, Hawkins HK (2003) Airway obstruction in sheep with burn and smoke inhalation injuries. Am J Respir Cell Mol Biol 29:295–302PubMedCrossRefGoogle Scholar
  19. 19.
    Westphal M, Cox RA, Traber LD, Morita N, Enkhbaatar P, Schmalstieg FC, Hawkins HK, Maybauer DM, Maybauer MO, Murakami K, Burke AS, Westphal-Varghese BB, Rudloff HE, Salsbury JR, Jodoin JM, Lee S, Traber DL (2006) Combined burn and smoke inhalation injury impairs ovine hypoxic pulmonary vasoconstriction. Crit Care Med 34:1428–1436PubMedCrossRefGoogle Scholar
  20. 20.
    Westphal M, Enkhbaatar P, Schmalstieg FC, Kulp GA, Traber LD, Morita N, Cox RA, Hawkins HK, Westphal-Varghese BB, Rudloff HE, Maybauer DM, Maybauer MO, Burke AS, Murakami K, Saunders F, Horvath EM, Szabo C, Traber DL (2008) Neuronal nitric oxide synthase inhibition attenuates cardiopulmonary dysfunctions after combined burn and smoke inhalation injury in sheep. Crit Care Med 36:1196–1204PubMedCrossRefGoogle Scholar
  21. 21.
    Laird NM, Ware JH (1982) Random-effects models for longitudinal data. Biometrics 38:963–974PubMedCrossRefGoogle Scholar
  22. 22.
    Parrillo JE (1993) Pathogenetic mechanisms of septic shock. N Engl J Med 328:1471–1477PubMedCrossRefGoogle Scholar
  23. 23.
    Galeotti L, Adrian K, Berg S, Tarkowski A, Bokarewa M (2008) Circulating survivin indicates severe course of juvenile idiopathic arthritis. Clin Exp Rheumatol 26:373–378PubMedGoogle Scholar
  24. 24.
    Marx G, Pedder S, Smith L, Swaraj S, Grime S, Stockdale H, Leuwer M (2006) Attenuation of capillary leakage by hydroxyethyl starch (130/0.42) in a porcine model of septic shock. Crit Care Med 34:3005–3010PubMedGoogle Scholar
  25. 25.
    Czabanka M, Peter C, Martin E, Walther A (2007) Microcirculatory endothelial dysfunction during endotoxemia—insights into pathophysiology, pathologic mechanisms and clinical relevance. Curr Vasc Pharmacol 5:266–275PubMedCrossRefGoogle Scholar
  26. 26.
    Traber D (2007) Selective V1a receptor agonists in experimental septic shock [Abstract]. Crit Care 11:P51CrossRefGoogle Scholar
  27. 27.
    Laporte R, Wisniewska H, Callejas L, Russell J, Landry D, Rivière P (2008) The selective V1a receptor agonist FE 202158 reverses platelet activating factor (PAF)-induced hypotension, vascular leak, impaired tissue perfusion, and mortality in rats. Shock Suppl 1, P21Google Scholar
  28. 28.
    O’Brien A, Clapp L, Singer M (2002) Terlipressin for norepinephrine-resistant septic shock. Lancet 359:1209–1210PubMedCrossRefGoogle Scholar
  29. 29.
    Dunser MW, Mayr AJ, Ulmer H, Knotzer H, Sumann G, Pajk W, Friesenecker B, Hasibeder WR (2003) Arginine vasopressin in advanced vasodilatory shock: a prospective, randomized, controlled study. Circulation 107:2313–2319PubMedCrossRefGoogle Scholar
  30. 30.
    Patel BM, Chittock DR, Russell JA, Walley KR (2002) Beneficial effects of short-term vasopressin infusion during severe septic shock. Anesthesiology 96:576–582PubMedCrossRefGoogle Scholar
  31. 31.
    Luckner G, Dunser MW, Jochberger S, Mayr VD, Wenzel V, Ulmer H, Schmid S, Knotzer H, Pajk W, Hasibeder W, Mayr AJ, Friesenecker B (2005) Arginine vasopressin in 316 patients with advanced vasodilatory shock. Crit Care Med 33:2659–2666PubMedCrossRefGoogle Scholar
  32. 32.
    Landry DW, Oliver JA (2001) The pathogenesis of vasodilatory shock. N Engl J Med 345:588–595PubMedCrossRefGoogle Scholar
  33. 33.
    Malay MB, Ashton RC Jr, Landry DW, Townsend RN (1999) Low-dose vasopressin in the treatment of vasodilatory septic shock. J Trauma 47:699–703 discussion 703–695PubMedCrossRefGoogle Scholar
  34. 34.
    Morelli A, Rocco M, Conti G, Orecchioni A, De Gaetano A, Cortese G, Coluzzi F, Vernaglione E, Pelaia P, Pietropaoli P (2004) Effects of terlipressin on systemic and regional haemodynamics in catecholamine-treated hyperkinetic septic shock. Intensive Care Med 30:597–604PubMedCrossRefGoogle Scholar
  35. 35.
    Albanese J, Leone M, Delmas A, Martin C (2005) Terlipressin or norepinephrine in hyperdynamic septic shock: a prospective, randomized study. Crit Care Med 33:1897–1902PubMedCrossRefGoogle Scholar
  36. 36.
    Leone M, Albanese J, Delmas A, Chaabane W, Garnier F, Martin C (2004) Terlipressin in catecholamine-resistant septic shock patients. Shock 22:314–319PubMedCrossRefGoogle Scholar
  37. 37.
    Booke M, Hinder F, McGuire R, Traber LD, Traber DL (1996) Nitric oxide synthase inhibition versus norepinephrine in ovine sepsis: effects on regional blood flow. Shock 5:362–370PubMedCrossRefGoogle Scholar
  38. 38.
    Lange M, Broking K, Hucklenbruch C, Ertmer C, Van Aken H, Lucke M, Bone HG, Westphal M (2007) Hemodynamic effects of titrated norepinephrine in healthy versus endotoxemic sheep. J Endotoxin Res 13:53–57PubMedCrossRefGoogle Scholar
  39. 39.
    Dunser MW, Mayr AJ, Tur A, Pajk W, Barbara F, Knotzer H, Ulmer H, Hasibeder WR (2003) Ischemic skin lesions as a complication of continuous vasopressin infusion in catecholamine-resistant vasodilatory shock: incidence and risk factors. Crit Care Med 31:1394–1398PubMedCrossRefGoogle Scholar
  40. 40.
    Martikainen TJ, Tenhunen JJ, Uusaro A, Ruokonen E (2003) The effects of vasopressin on systemic and splanchnic hemodynamics and metabolism in endotoxin shock. Anesth Analg 97:1756–1763PubMedCrossRefGoogle Scholar
  41. 41.
    Klinzing S, Simon M, Reinhart K, Bredle DL, Meier-Hellmann A (2003) High-dose vasopressin is not superior to norepinephrine in septic shock. Crit Care Med 31:2646–2650PubMedCrossRefGoogle Scholar
  42. 42.
    Scharte M, Meyer J, Van Aken H, Bone HG (2001) Hemodynamic effects of terlipressin (a synthetic analog of vasopressin) in healthy and endotoxemic sheep. Crit Care Med 29:1756–1760PubMedCrossRefGoogle Scholar
  43. 43.
    Holmes CL, Walley KR, Chittock DR, Lehman T, Russell JA (2001) The effects of vasopressin on hemodynamics and renal function in severe septic shock: a case series. Intensive Care Med 27:1416–1421PubMedCrossRefGoogle Scholar
  44. 44.
    Landry DW, Levin HR, Gallant EM, Seo S, D’Alessandro D, Oz MC, Oliver JA (1997) Vasopressin pressor hypersensitivity in vasodilatory septic shock. Crit Care Med 25:1279–1282PubMedCrossRefGoogle Scholar
  45. 45.
    Asfar P, Hauser B, Ivanyi Z, Ehrmann U, Kick J, Albicini M, Vogt J, Wachter U, Bruckner UB, Radermacher P, Bracht H (2005) Low-dose terlipressin during long-term hyperdynamic porcine endotoxemia: effects on hepatosplanchnic perfusion, oxygen exchange, and metabolism. Crit Care Med 33:373–380PubMedCrossRefGoogle Scholar
  46. 46.
    Asfar P, Pierrot M, Veal N, Moal F, Oberti F, Croquet V, Douay O, Gallois Y, Saumet JL, Alquier P, Cales P (2003) Low-dose terlipressin improves systemic and splanchnic hemodynamics in fluid-challenged endotoxic rats. Crit Care Med 31:215–220PubMedCrossRefGoogle Scholar
  47. 47.
    Zeballos G, Lopez-Herce J, Fernandez C, Brandstrup KB, Rodriguez-Nunez A (2006) Rescue therapy with terlipressin by continuous infusion in a child with catecholamine-resistant septic shock. Resuscitation 68:151–153PubMedCrossRefGoogle Scholar
  48. 48.
    Rodriguez-Nunez A, Lopez-Herce J, Gil-Anton J, Hernandez A, Rey C (2006) Rescue treatment with terlipressin in children with refractory septic shock: a clinical study. Crit Care 10:R20PubMedCrossRefGoogle Scholar
  49. 49.
    Landry DW, Levin HR, Gallant EM, Ashton RC Jr, Seo S, D’Alessandro D, Oz MC, Oliver JA (1997) Vasopressin deficiency contributes to the vasodilation of septic shock. Circulation 95:1122–1125PubMedGoogle Scholar
  50. 50.
    Sharshar T, Blanchard A, Paillard M, Raphael JC, Gajdos P, Annane D (2003) Circulating vasopressin levels in septic shock. Crit Care Med 31:1752–1758PubMedCrossRefGoogle Scholar
  51. 51.
    Westphal M, Freise H, Kehrel BE, Bone HG, Van Aken H, Sielenkamper AW (2004) Arginine vasopressin compromises gut mucosal microcirculation in septic rats. Crit Care Med 32:194–200PubMedCrossRefGoogle Scholar
  52. 52.
    Vincent JL (2002) Endocrine support in the critically ill. Crit Care Med 30:702–703PubMedCrossRefGoogle Scholar
  53. 53.
    Tsuneyoshi I, Yamada H, Kakihana Y, Nakamura M, Nakano Y, Boyle WA 3rd (2001) Hemodynamic and metabolic effects of low-dose vasopressin infusions in vasodilatory septic shock. Crit Care Med 29:487–493PubMedCrossRefGoogle Scholar
  54. 54.
    Van Tol HH, Kiss JZ, Burbach JP (1989) Differential responses in vasopressin and oxytocin gene expression in distinct hypothalamic nuclei after hypothalamoneurohypophyseal disconnection and vasopressin substitution. Neuroendocrinology 49:337–343PubMedCrossRefGoogle Scholar
  55. 55.
    Naylor AM, Cooper KE, Veale WL (1987) Vasopressin and fever: evidence supporting the existence of an endogenous antipyretic system in the brain. Can J Physiol Pharmacol 65:1333–1338PubMedGoogle Scholar
  56. 56.
    Zhao L, Brinton RD (2004) Suppression of proinflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha in astrocytes by a V1 vasopressin receptor agonist: a cAMP response element-binding protein-dependent mechanism. J Neurosci 24:2226–2235PubMedCrossRefGoogle Scholar
  57. 57.
    Radi R (2004) Nitric oxide, oxidants, and protein tyrosine nitration. Proc Natl Acad Sci USA 101:4003–4008PubMedCrossRefGoogle Scholar
  58. 58.
    Chung SW, Liu X, Macias AA, Baron RM, Perrella MA (2008) Heme oxygenase-1-derived carbon monoxide enhances the host defense response to microbial sepsis in mice. J Clin Invest 118:239–247PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Sebastian Rehberg
    • 1
  • Christian Ertmer
    • 1
  • Gabriele Köhler
    • 2
  • Hans-Ulrich Spiegel
    • 3
  • Andrea Morelli
    • 4
  • Matthias Lange
    • 1
  • Katharina Moll
    • 1
  • Katrin Schlack
    • 1
  • Hugo Van Aken
    • 1
  • Fuhong Su
    • 5
  • Jean-Louis Vincent
    • 5
  • Martin Westphal
    • 1
  1. 1.Department of Anesthesiology and Intensive CareUniversity Hospital of MuensterMuensterGermany
  2. 2.Department of PathologyUniversity of MuensterMuensterGermany
  3. 3.Department of SurgeryUniversity of MuensterMuensterGermany
  4. 4.Department of Anesthesiology and Intensive CareUniversity of Rome, “La Sapienza”RomeItaly
  5. 5.Department of Intensive Care, Erasme HospitalUniversité Libre de BruxellesBrusselsBelgium

Personalised recommendations