Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Intensive Care Medicine
Published in: Intensive Care Medicine 12/2010

01-12-2010 | Review

Vascular hyporesponsiveness to vasopressors in septic shock: from bench to bedside

Authors: B. Levy, S. Collin, N. Sennoun, N. Ducrocq, A. Kimmoun, P. Asfar, P. Perez, F. Meziani

Published in: Intensive Care Medicine | Issue 12/2010

Login to get access

Abstract

Purpose

To delineate some of the characteristics of septic vascular hypotension, to assess the most commonly cited and reported underlying mechanisms of vascular hyporesponsiveness to vasoconstrictors in sepsis, and to briefly outline current therapeutic strategies and possible future approaches.

Methods

Source data were obtained from a PubMed search of the medical literature with the following MeSH terms: Muscle, smooth, vascular/physiopathology; hypotension/etiology; shock/physiopathology; vasodilation/physiology; shock/therapy; vasoconstrictor agents.

Results

Nitric oxide (NO) and peroxynitrite are crucial components implicated in vasoplegia and vascular hyporeactivity. Vascular ATP-sensitive and calcium-activated potassium channels are activated during shock and participate in hypotension. In addition, shock state is characterized by inappropriately low plasma glucocorticoid and vasopressin concentrations, a dysfunction and desensitization of alpha-receptors, and an inactivation of catecholamines by oxidation. Numerous other mechanisms have been individualized in animal models, the great majority of which involve NO: MEK1/2–ERK1/2 pathway, H2S, hyperglycemia, and cytoskeleton dysregulation associated with decreased actin expression.

Conclusions

Many therapeutic approaches have proven their efficiency in animal models, especially therapies directed against one particular compound, but have otherwise failed when used in human shock. Nevertheless, high doses of catecholamines, vasopressin and terlipressin, hydrocortisone, activated protein C, and non-specific shock treatment have demonstrated a partial efficiency in reversing sepsis-induced hypotension.
Literature
1.
Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR (2001) Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 29:1303–1310CrossRefPubMed
2.
3.
Matsuda N, Hattori Y (2007) Vascular biology in sepsis: pathophysiological and therapeutic significance of vascular dysfunction. J Smooth Muscle Res 43:117–137CrossRefPubMed
4.
Umans JG, Wylam ME, Samsel RW, Edwards J, Schumacker PT (1993) Effects of endotoxin in vivo on endothelial and smooth-muscle function in rabbit and rat aorta. Am Rev Respir Dis 148:1638–1645PubMed
5.
6.
Bernardin G, Pradier C, Tiger F, Deloffre P, Mattei M (1996) Blood pressure and arterial lactate level are early indicators of short-term survival in human septic shock. Intensive Care Med 22:17–25CrossRefPubMed
7.
Abid O, Akca S, Haji-Michael P, Vincent JL (2000) Strong vasopressor support may be futile in the intensive care unit patient with multiple organ failure. Crit Care Med 28:947–949CrossRefPubMed
8.
Lamia B, Chemla D, Richard C, Teboul JL (2005) Clinical review: interpretation of arterial pressure wave in shock states. Crit Care 9:601–606CrossRefPubMed
9.
Benchekroune S, Karpati PC, Berton C, Nathan C, Mateo J, Chaara M, Riche F, Laisne MJ, Payen D, Mebazaa A (2008) Diastolic arterial blood pressure: a reliable early predictor of survival in human septic shock. J Trauma 64:1188–1195CrossRefPubMed
10.
Benedict CR, Rose JA (1992) Arterial norepinephrine changes in patients with septic shock. Circ Shock 38:165–172PubMed
11.
12.
Alvarez S, Boveris A (2004) Mitochondrial nitric oxide metabolism in rat muscle during endotoxemia. Free Radic Biol Med 37:1472–1478CrossRefPubMed
13.
Lundberg JO, Weitzberg E (2005) NO generation from nitrite and its role in vascular control. Arterioscler Thromb Vasc Biol 25:915–922CrossRefPubMed
14.
Rees DD, Monkhouse JE, Cambridge D, Moncada S (1998) Nitric oxide and the haemodynamic profile of endotoxin shock in the conscious mouse. Br J Pharmacol 124:540–546CrossRefPubMed
15.
Julou-Schaeffer G, Gray GA, Fleming I, Schott C, Parratt JR, Stoclet JC (1990) Loss of vascular responsiveness induced by endotoxin involves l-arginine pathway. Am J Physiol 259:H1038–H1043PubMed
16.
Boyle WA 3rd, Parvathaneni LS, Bourlier V, Sauter C, Laubach VE, Cobb JP (2000) iNOS gene expression modulates microvascular responsiveness in endotoxin-challenged mice. Circ Res 87:E18–E24PubMed
17.
Walker TA, Curtis SE, King-VanVlack CE, Chapler CK, Vallet B, Cain SM (1995) Effects of nitric oxide synthase inhibition on regional hemodynamics and oxygen transport in endotoxic dogs. Shock 4:415–420PubMed
18.
Vincent JL, Zhang H, Szabo C, Preiser JC (2000) Effects of nitric oxide in septic shock. Am J Respir Crit Care Med 161:1781–1785PubMed
19.
Lopez A, Lorente JA, Steingrub J, Bakker J, McLuckie A, Willatts S, Brockway M, Anzueto A, Holzapfel L, Breen D, Silverman MS, Takala J, Donaldson J, Arneson C, Grove G, Grossman S, Grover R (2004) Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88: effect on survival in patients with septic shock. Crit Care Med 32:21–30CrossRefPubMed
20.
Levy B, Valtier M, de Chillou C, Bollaert PE, Cane D, Mallie JP (1999) Beneficial effects of l-canavanine, a selective inhibitor of inducible nitric oxide synthase, on lactate metabolism and muscle high energy phosphates during endotoxic shock in rats. Shock 11:98–103CrossRefPubMed
21.
22.
Cauwels A, Buys ES, Thoonen R, Geary L, Delanghe J, Shiva S, Brouckaert P (2009) Nitrite protects against morbidity and mortality associated with TNF- or LPS-induced shock in a soluble guanylate cyclase-dependent manner. J Exp Med 206:2915–2924CrossRefPubMed
23.
Wang P, Zhou M, Cioffi WG, Bland KI, Ba ZF, Chaudry IH (2000) Is prostacyclin responsible for producing the hyperdynamic response during early sepsis? Crit Care Med 28:1534–1539CrossRefPubMed
24.
Schildknecht S, Bachschmid M, Baumann A, Ullrich V (2004) COX-2 inhibitors selectively block prostacyclin synthesis in endotoxin-exposed vascular smooth muscle cells. FASEB J 18:757–759PubMed
25.
Höcherl K, Schmidt C, Kurt B, Bucher M (2008) Activation of the PGI(2)/IP system contributes to the development of circulatory failure in a rat model of endotoxic shock. Hypertension 52:330–335CrossRefPubMed
26.
Bernard GR, Wheeler AP, Russell JA, Schein R, Summer WR, Steinberg KP, Fulkerson WJ, Wright PE, Christman BW, Dupont WD, Higgins SB, Swindell BB (1997) The effects of ibuprofen on the physiology and survival of patients with sepsis. The Ibuprofen in Sepsis Study Group. N Engl J Med 336:912–918CrossRefPubMed
27.
Pacher P, Beckman JS, Liaudet L (2007) Nitric oxide and peroxynitrite in health and disease. Physiol Rev 87:315–424CrossRefPubMed
28.
Szabo C, Salzman AL, Ischiropoulos H (1995) Endotoxin triggers the expression of an inducible isoform of nitric oxide synthase and the formation of peroxynitrite in the rat aorta in vivo. FEBS Lett 363:235–238CrossRefPubMed
29.
Macarthur H, Westfall TC, Riley DP, Misko TP, Salvemini D (2000) Inactivation of catecholamines by superoxide gives new insights on the pathogenesis of septic shock. Proc Natl Acad Sci U S A 97:9753–9758CrossRefPubMed
30.
Salvemini D, Wang ZQ, Zweier JL, Samouilov A, Macarthur H, Misko TP, Currie MG, Cuzzocrea S, Sikorski JA, Riley DP (1999) A nonpeptidyl mimic of superoxide dismutase with therapeutic activity in rats. Science 286:304–306CrossRefPubMed
31.
Landry DW, Oliver JA (1992) The ATP-sensitive K+ channel mediates hypotension in endotoxemia and hypoxic lactic acidosis in dog. J Clin Invest 89:2071–2074CrossRefPubMed
32.
33.
Warrillow S, Egi M, Bellomo R (2006) Randomized, double-blind, placebo-controlled crossover pilot study of a potassium channel blocker in patients with septic shock. Crit Care Med 34:980–985CrossRefPubMed
34.
Morelli A, Lange M, Ertmer C, Broeking K, Van Aken H, Orecchioni A, Rocco M, Bachetoni A, Traber DL, Landoni G, Pietropaoli P, Westphal M (2007) Glibenclamide dose response in patients with septic shock: effects on norepinephrine requirements, cardiopulmonary performance, and global oxygen transport. Shock 28:530–535PubMed
35.
Cauwels A, Brouckaert P (2008) Critical role for small and large conductance calcium-dependent potassium channels in endotoxemia and TNF toxicity. Shock 29:577–582PubMed
36.
Pickkers P, Dorresteijn MJ, Bouw MP, van der Hoeven JG, Smits P (2006) In vivo evidence for nitric oxide-mediated calcium-activated potassium-channel activation during human endotoxemia. Circulation 114:414–421CrossRefPubMed
37.
Marik PE, Pastores SM, Annane D, Meduri GU, Sprung CL, Arlt W, Keh D, Briegel J, Beishuizen A, Dimopoulou I, Tsagarakis S, Singer M, Chrousos GP, Zaloga G, Bokhari F, Vogeser M (2008) Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine. Crit Care Med 36:1937–1949CrossRefPubMed
38.
Annane D, Maxime V, Ibrahim F, Alvarez JC, Abe E, Boudou P (2006) Diagnosis of adrenal insufficiency in severe sepsis and septic shock. Am J Respir Crit Care Med 174:1319–1326CrossRefPubMed
39.
Sprung CL, Annane D, Keh D, Moreno R, Singer M, Freivogel K, Weiss YG, Benbenishty J, Kalenka A, Forst H, Laterre PF, Reinhart K, Cuthbertson BH, Payen D, Briegel J (2008) Hydrocortisone therapy for patients with septic shock. N Engl J Med 358:111–124CrossRefPubMed
40.
Briegel J, Sprung CL, Annane D, Singer M, Keh D, Moreno R, Mohnle P, Weiss Y, Avidan A, Brunkhorst FM, Fiedler F, Vogeser M (2009) Multicenter comparison of cortisol as measured by different methods in samples of patients with septic shock. Intensive Care Med 35:2151–2156CrossRefPubMed
41.
Wu LL, Tang C, Liu MS (1997) Hyper- and hypocardiodynamic states are associated with externalization and internalization, respectively, of alpha-adrenergic receptors in rat heart during sepsis. Shock 7:318–323CrossRefPubMed
42.
McMillan M, Chernow B, Roth BL (1986) Hepatic alpha 1-adrenergic receptor alteration in a rat model of chronic sepsis. Circ Shock 19:185–193PubMed
43.
Hwang TL, Lau YT, Huang SF, Chen MF, Liu MS (1994) Changes of alpha 1-adrenergic receptors in human liver during intraabdominal sepsis. Hepatology 20:638–642CrossRefPubMed
44.
de Montmollin E, Aboab J, Mansart A, Annane D (2009) Bench-to-bedside review: β-adrenergic modulation in sepsis. Crit Care 13:230CrossRefPubMed
45.
Pacheco ME, Beltran A, Redondo J, Manso AM, Alonso MJ, Salaices M (2006) High glucose enhances inducible nitric oxide synthase expression. Role of protein kinase C-betaII. Eur J Pharmacol 538:115–123CrossRefPubMed
46.
Ellger B, Richir MC, van Leeuwen PA, Debaveye Y, Langouche L, Vanhorebeek I, Teerlink T, Van den Berghe G (2008) Glycemic control modulates arginine and asymmetrical-dimethylarginine levels during critical illness by preserving dimethylarginine-dimethylaminohydrolase activity. Endocrinology 149:3148–3157CrossRefPubMed
47.
Holger JS, Dries DJ, Barringer KW, Peake BJ, Flottemesch TJ, Marini JJ (2010) Cardiovascular and metabolic effects of high-dose insulin in a porcine septic shock model. Acad Emerg Med 17:429–435CrossRefPubMed
48.
Annane D, Cariou A, Maxime V, Azoulay E, D’Honneur G, Timsit JF, Cohen Y, Wolf M, Fartoukh M, Adrie C, Santre C, Bollaert PE, Mathonet A, Amathieu R, Tabah A, Clec’h C, Mayaux J, Lejeune J, Chevret S (2010) Corticosteroid treatment and intensive insulin therapy for septic shock in adults: a randomized controlled trial. JAMA 303:341–348CrossRefPubMed
49.
Mitchell JA, Kohlhaas KL, Sorrentino R, Warner TD, Murad F, Vane JR (1993) Induction by endotoxin of nitric oxide synthase in the rat mesentery: lack of effect on action of vasoconstrictors. Br J Pharmacol 109:265–270PubMed
50.
Stoclet JC, Martinez MC, Ohlmann P, Chasserot S, Schott C, Kleschyov AL, Schneider F, Andriantsitohaina R (1999) Induction of nitric oxide synthase and dual effects of nitric oxide and cyclooxygenase products in regulation of arterial contraction in human septic shock. Circulation 100:107–112PubMed
51.
Spronk PE, Ince C, Gardien MJ, Mathura KR, Oudemans-van Straaten HM, Zandstra DF (2002) Nitroglycerin in septic shock after intravascular volume resuscitation. Lancet 360:1395–1396CrossRefPubMed
52.
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 34:17–60CrossRefPubMed
53.
De Backer D, Biston P, Devriendt J, Madl C, Chochrad D, Aldecoa C, Brasseur A, Defrance P, Gottignies P, Vincent JL (2010) Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med 362:779–789CrossRefPubMed
54.
LeDoux D, Astiz ME, Carpati CM, Rackow EC (2000) Effects of perfusion pressure on tissue perfusion in septic shock. Crit Care Med 28:2729–2732CrossRefPubMed
55.
56.
Insel PA (1996) Seminars in medicine of the Beth Israel Hospital, Boston. Adrenergic receptors—evolving concepts and clinical implications. N Engl J Med 334:580–585CrossRefPubMed
57.
Katsaragakis S, Kapralou A, Theodorou D, Markogiannakis H, Larentzakis A, Stamou KM, Drimousis P, Bramis I (2006) Refractory septic shock: efficacy and safety of very high doses of norepinephrine. Methods Find Exp Clin Pharmacol 28:307–313CrossRefPubMed
58.
Lange M, Ertmer C, Westphal M (2008) Vasopressin vs. terlipressin in the treatment of cardiovascular failure in sepsis. Intensive Care Med 34:821–832CrossRefPubMed
59.
Kirov MY, Evgenov OV, Evgenov NV, Egorina EM, Sovershaev MA, Sveinbjornsson B, Nedashkovsky EV, Bjertnaes LJ (2001) Infusion of methylene blue in human septic shock: a pilot, randomized, controlled study. Crit Care Med 29:1860–1867CrossRefPubMed
60.
Honore PM, Matson JR (2002) Short-term high-volume hemofiltration in sepsis: perhaps the right way is to start with. Crit Care Med 30:1673–1674CrossRefPubMed
61.
Ataman K, Jehmlich M, Kock S, Neumann S, Leischik M, Filipovic Z, Hopf HB (2002) Short-term cardiovascular effects of plasmapheresis in norepinephrine-refractory septic shock. Intensive Care Med 28:1164–1167CrossRefPubMed
62.
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 95:1122–1125PubMed
63.
Sharshar T, Carlier R, Blanchard A, Feydy A, Gray F, Paillard M, Raphael JC, Gajdos P, Annane D (2002) Depletion of neurohypophyseal content of vasopressin in septic shock. Crit Care Med 30:497–500CrossRefPubMed
64.
Leone M, Boyle WA (2006) Decreased vasopressin responsiveness in vasodilatory septic shock-like conditions. Crit Care Med 34:1126–1130CrossRefPubMed
65.
Russell JA, Walley KR, Singer J, Gordon AC, Hebert PC, Cooper DJ, Holmes CL, Mehta S, Granton JT, Storms MM, Cook DJ, Presneill JJ, Ayers D (2008) Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 358:877–887CrossRefPubMed
66.
Westphal M, Traber DL (2005) Low-dose terlipressin for hemodynamic support in sepsis and systemic inflammatory response syndrome: art for (he)art’s sake or state of the art? Crit Care Med 33:455–457CrossRefPubMed
67.
Broking K, Lange M, Morelli A, Ertmer C, Aken HV, Luecke M, Rehberg S, Bowering N, Bone HG, Traber DL, Westphal M (2008) Employing dobutamine as a useful agent to reverse the terlipressin-linked impairments in cardiopulmonary hemodynamics and global oxygen transport in healthy and endotoxemic sheep. Shock 29:71–77PubMed
68.
Lange M, Morelli A, Ertmer C, Broking K, Rehberg S, Van Aken H, Traber DL, Westphal M (2007) Role of adenosine triphosphate-sensitive potassium channel inhibition in shock states: physiology and clinical implications. Shock 28:394–400CrossRefPubMed
69.
Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fisher CJ Jr (2001) Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 344:699–709CrossRefPubMed
70.
Mosnier LO, Zlokovic BV, Griffin JH (2007) The cytoprotective protein C pathway. Blood 109:3161–3172CrossRefPubMed
71.
72.
Joyce DE, Gelbert L, Ciaccia A, DeHoff B, Grinnell BW (2001) Gene expression profile of antithrombotic protein C defines new mechanisms modulating inflammation and apoptosis. J Biol Chem 276:11199–11203CrossRefPubMed
73.
Bilbault P, Lavaux T, Launoy A, Gaub MP, Meyer N, Oudet P, Pottecher T, Jaeger A, Schneider F (2007) Influence of drotrecogin alpha (activated) infusion on the variation of Bax/Bcl-2 and Bax/Bcl-xl ratios in circulating mononuclear cells: a cohort study in septic shock patients. Crit Care Med 35:69–75
74.
Nacira S, Meziani F, Dessebe O, Cattan V, Collin S, Montemont C, Gibot S, Asfar P, Ramaroson A, Regnault V, Slama M, Lecompte T, Lacolley P, Levy B (2009) Activated protein C improves lipopolysaccharide-induced cardiovascular dysfunction by decreasing tissular inflammation and oxidative stress. Crit Care Med 37:246–255CrossRefPubMed
75.
Favory R, Lancel S, Marechal X, Tissier S, Neviere R (2006) Cardiovascular protective role for activated protein C during endotoxemia in rats. Intensive Care Med 32:899–905CrossRefPubMed
76.
Monnet X, Lamia B, Anguel N, Richard C, Bonmarchand G, Teboul JL (2005) Rapid and beneficial hemodynamic effects of activated protein C in septic shock patients. Intensive Care Med 31:1573–1576CrossRefPubMed
77.
Annane D, Sebille V, Charpentier C, Bollaert PE, Francois B, Korach JM, Capellier G, Cohen Y, Azoulay E, Troche G, Chaumet-Riffaut P, Bellissant E (2002) Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 288:862–871CrossRefPubMed
78.
Prigent H, Maxime V, Annane D (2004) Clinical review: corticotherapy in sepsis. Crit Care 8:122–129CrossRefPubMed
79.
Kilger E, Weis F, Briegel J, Frey L, Goetz AE, Reuter D, Nagy A, Schuetz A, Lamm P, Knoll A, Peter K (2003) Stress doses of hydrocortisone reduce severe systemic inflammatory response syndrome and improve early outcome in a risk group of patients after cardiac surgery. Crit Care Med 31:1068–1074CrossRefPubMed
80.
Gibot S, Massin F, Alauzet C, Montemont C, Lozniewski A, Bollaert PE, Levy B (2008) Effects of the TREM-1 pathway modulation during mesenteric ischemia-reperfusion in rats. Crit Care Med 36:504–510CrossRefPubMed
81.
Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E, Tomlanovich M (2001) Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 345:1368–1377CrossRefPubMed
Metadata
Title
Vascular hyporesponsiveness to vasopressors in septic shock: from bench to bedside
Authors
B. Levy
S. Collin
N. Sennoun
N. Ducrocq
A. Kimmoun
P. Asfar
P. Perez
F. Meziani
Publication date
01-12-2010
Publisher
Springer-Verlag
Published in
Intensive Care Medicine / Issue 12/2010
Print ISSN: 0342-4642
Electronic ISSN: 1432-1238
DOI
https://doi.org/10.1007/s00134-010-2045-8

Other articles of this Issue 12/2010

Intensive Care Medicine 12/2010 Go to the issue

Correspondence

Use of ultrasonography in hemicraniectomized patients: a report of two cases

Experimental

Gas distribution in a two-compartment model ventilated in high-frequency percussive and pressure-controlled modes

End of Life: National Legislations

Compliance with DNR policy in a tertiary care center in Saudi Arabia

Correspondence

Accidental cut of peripherally inserted central venous catheter

Review

Propensity scores in intensive care and anaesthesiology literature: a systematic review

Pediatric Original

Noninvasive high frequency oscillatory ventilation through nasal prongs: bench evaluation of efficacy and mechanics