 
         
         
         ABSTRACT
         
         Sepsis accounts for more than 210,000 deaths per year. Despite adequate fluid resuscitation
            the associated maldistribution of blood flow may cause an imbalance between oxygen
            delivery and demand, leading to global tissue hypoxia, shock, and, if not reversed,
            death. Vasoactive therapies including catecholamine and noncatecholamine vasopressors,
            ionotropes, and vasodilating agents aimed at restoring perfusion and normalizing oxygen
            consumption have improved outcomes in patients with persistent shock despite crystalloid
            resuscitation. In this review we discuss the mechanisms, clinical use, and commonly
            observed pitfalls of the most common and a few uncommon vasodilator agents used in
            the management of sepsis and septic shock.
         
         
         
            
KEYWORDS
         
         
            Sepsis - vasodilators - shock
          
      
    
   
      
         REFERENCES
         
         
            - 1 
               Angus D C, Linde-Zwirble W T, Lidicker J, Carcillo J, Pinsky M R. 
               Epidemiology of severe sepsis in the United States: analysis of incidence, outcome
               and associated costs of care. 
               Crit Care Med. 
               2001; 
               29 
               1303-1310 
               
- 2 
               Bernard G R, Vincent J L, Laterre P F et al.. 
               Efficacy and safety of recombinant human activated protein C for severe sepsis. 
               N Engl J Med. 
               2001; 
               344 
               699-709 
               
- 3 
               Rivers E, Nguyen B, Havasted S et al.. 
               Early goal-directed therapy in the treatment of severe sepsis and septic shock. 
               N Engl J Med. 
               2001; 
               345 
               1368-1377 
               
- 4 
               Modlin R L, Brightbill H D, Godowski P J. 
               The toll of innate immunity on microbial pathogens. 
               N Engl J Med. 
               1999; 
               340 
               1834-1835 
               
- 5 
               Levy M M, Fink M P, Marshall J et al.. 
               SCCM/ESICM/ACCP/ATS/SIS international Sepsis Definitions Conference. 
               Crit Care Med. 
               2001; 
               31 
               1250-1256 
               
- 6 
               Hotchkiss R S, Tinsley K W, Swanson P E et al.. 
               Prevention of lymphocyte cell death in sepsis improves survival in mice. 
               Proc Natl Acad Sci USA. 
               1999; 
               96 
               12541-12546 
               
- 7 
               Oberholzer C, Oberholzer A, Clare-Salzer M, Moldawer L L. 
               Apoptosis in sepsis a new target for therapeutic exploration. 
               FASEB J. 
               2001; 
               15 
               879-892 
               
- 8 
               Hotchkiss R S, Karl I E. 
               The pathophysiology and treatment of sepsis. 
               N Engl J Med. 
               2003; 
               138-150 
               
- 9 
               Parrillo J E, Parker M M, Natanson C et al.. 
               Septic shock in humans: advances in the understanding of pathogenesis, cardiovascular
               dysfunction, and therapy. 
               Ann Intern Med. 
               1990; 
               113 
               227-242 
               
- 10 
               Fink M P. 
               Bench-to-bedside review: cytopathic hypoxia. 
               Crit Care. 
               2002; 
               6 
               491-499 
               
- 11 
               Martin C, Vivand X, Leone M, Thiron X. 
               Effect of norepinephrine on the outcome of septic shock. 
               Crit Care Med. 
               2000; 
               28 
               2758-2765 
               
- 12 
               Kirchheim H R, Ehmke H, Hackenthal E et al.. 
               Autoregulation of renal blood flow, glomerular filtration rate and renin release in
               conscious dogs. 
               Pflugers Arch. 
               1987; 
               410 
               441-449 
               
- 13 
               Manning R D, Guyton A C. 
               Dynamics of fluid distribution between the blood and interstitium during overhydration. 
               Am J Physiol. 
               1980; 
               238 
               H645-H651 
               
- 14 
               Kelleher S P, Robinette J B, Conger J D. 
               Sympathetic nervous system in the loss of autoregulation in acute renal failure. 
               Am J Physiol. 
               1984; 
               246 
               F379-F386 
               
- 15 
               Natanson C, Fink M P, Ballantyne H K, MacVittie T J, Conklin J J, Parrillo J E. 
               Gram-negative bacteremia produces both severe systolic and diastolic cardiac dysfunction
               in a canine model that simulates human septic shock. 
               J Clin Invest. 
               1986; 
               
- 16 
               Yu M, Levy M M, Smith P, Takiguchi S A, Miyaski A, Myers S A. 
               Effect of maximizing oxygen delivery on morbidity and mortality rates in critically
               ill patients: a prospective, randomized, controlled trial. 
               Crit Care Med. 
               1993; 
               21 
               830-838 
               
- 17 
               Hayes M A, Timmins A C, Yau E H, Palazzo M, Hinds C J, Watson D. 
               Elevation of systemic oxygen delivery in the treatment of critically ill patients. 
               N Engl J Med. 
               1994; 
               330 
               1717-1722 
               
- 18 
               Gattinoni L, Brazzi L, Pelosi P et al.. 
               A trial of goal-oriented hemodynamic therapy in critically ill patients. 
               N Engl J Med. 
               1995; 
               333 
               1025-1032 
               
- 19 
               Kobilka B. 
               Adrenergic receptors as models for G protein-coupled receptors. 
               Annu Rev Neurosci. 
               1992; 
               15 
               87-114 
               
- 20 
               Bohm M, Diet F, Feiler G, Kemkes B, Erdman E. 
               Alpha-adrenoreceptors and alpha-adrenoreceptor-mediated positive ionotropic effectsin
               failing human myocardium. 
               J Cardiovasc Pharmacol. 
               1988; 
               12 
               357-364 
               
- 21 
               Govier W C. 
               Myocardial alpha adrenergic receptors and their role in the production of a positive
               ionotropic effect by sympathomimetic agents. 
               J Pharmacol Exp. 
               1968; 
               159 
               82-90 
               
- 22 
               Kaufman A J, Hall J A, Murray K J, Wells F C, Brown M J. 
               A comparison of the effects of adrenaline and noradrenaline on the human heart: the
               role of beta-1 and beta-2 adrenoreceptors in the stimulation of adenylate cyclase
               and contractile force. 
               Eur Heart J. 
               1989; 
               10 (suppl/B) 
               29-37 
               
- 23 
               Levinson P D, Goldstein D S, Munson P J, Gill J R, Keiser H R. 
               Endocrine renal and hemodynamic responses to graded dopamine infusions in normal men. 
               J Clin Endocrinol Metab. 
               1985; 
               60 
               821-826 
               
- 24 
               Minniman K P. 
               Alpha1-adrenergic receptor subtypes, inositol phosphates, and sources of cell calcium. 
               Pharmacol Rev. 
               1988; 
               40 
               87-119 
               
- 25 
               Sibbald W J, Fox G, Martin C. 
               Abnormalities of vascular reactivity in the sepsis syndrome. 
               Chest. 
               1991; 
               100 
               155S-159S 
               
- 26 
               McKenna T M, Martin F M, Chernow B, Briglia F A. 
               Vascular endothelium contributes to decreased aortic contractility in experimental
               sepsis. 
               Circ Shock. 
               1986; 
               19 
               267-273 
               
- 27 
               Levy B, Bollaert P E, Charpentier C et al.. 
               Comparison of norepinephrine and dobutamine to epinephrine for hemodynamics, lactate
               metabolism, and gastric tonometric variables in septic shock: A prospective, randomized
               study. 
               Intensive Care Med. 
               1997; 
               23 
               282-287 
               
- 28 
               Desjars P, Pinaud M, Tasseau F et al.. 
               A reaapraisal of norepinephrine therapy in human septic shock. 
               Crit Care Med. 
               1987; 
               15 
               134-137 
               
- 29 
               Hesselvik J F, Brodin B. 
               Low-dose norepinephrine in patients with septic shock and oliguria. 
               Crit Care Med. 
               1989; 
               17 
               179-180 
               
- 30 
               Meadows D, Edwards J D, Wilkins R G et al.. 
               Reversal of intractable shock with norepinephrine therapy. 
               Crit Care Med. 
               1988; 
               16 
               663-667 
               
- 31 
               Martin C, Papaian L, Perrin G et al.. 
               Norepinephrine or dopamine for the treatement of hyperdynamic shock. 
               Chest. 
               1993; 
               103 
               1826-1831 
               
- 32 
               Redl-Wenzl E M, Armbruster C, Edelman G et al.. 
               The effects of norepinephrine on hemodynamics and renal function in severe septic
               shock states. 
               Intensive Care Med. 
               1993; 
               19 
               151-154 
               
- 33 
               Martin C, Eon B, Saux P et al.. 
               Renal effects of norepinephrine used to treat septic shock patients. 
               Crit Care Med. 
               1990; 
               18 
               282-285 
               
- 34 
               Conger J D, Robinette J B, Guggenheim S J. 
               Effect of acetylcholine on the early phase of reversible norepinephrine-induced actue
               renal failure. 
               Kidney Int. 
               1981; 
               19 
               399-409 
               
- 35 
               Ruokonen E, Takala J, Kari A et al.. 
               Regional blood flow and oxygen transport in septic shock. 
               Crit Care Med. 
               1993; 
               21 
               1296-1303 
               
- 36 
               Marik P E, Mohedin M . 
               The contrasting efects of dopamine and norepinephrine on systemic and splanchnic oxygenatio
               utilization in hyperdynamic sepsis. 
               JAMA. 
               1994; 
               271 
               1354-1357 
               
- 37 
               DeBacker D, Creteur J, Silva E, Vincent J L. 
               Effects of doapamine, norepinephrine and epinephrine on the splanchnic circulation
               in septic shock: which is best?. 
               Crit Care Med. 
               2003; 
               31 
               1659-1667 
               
- 38 
               Bellomo R, Chapman M, Finfer S, Hickling K, Myburgh J. 
               Low-dose dopamine in patients with early renal dysfunction: a placebo controlled randomised
               trial. Australian and New Aealand Intensive Care Society (ANZICS) Clinical Trials
               Group. 
               Lancet. 
               2000; 
               356 
               2139-2143 
               
- 39 
               Reginer B, Safran D, Carlet J et al.. 
               Comparative hemodynamic effects of dopamine and dobutamine in septic shock. 
               Intensive Care Med. 
               1979; 
               5 
               115-120 
               
- 40 
               Hannemann L, Reinhart K, Grenzer O et al.. 
               Comparison of dopamine to dobutamine and norepinephrine for oxygen delivery and uptake
               in septic shock. 
               Crit Care Med. 
               1995; 
               23 
               1962-1970 
               
- 41 
               Neviere R, Mathiew D, Chagnon J L et al.. 
               The contrasting effects of dobutamine and dopamine on mucosal perfusion in septic
               patients. 
               Am J Respir Crit Care Med. 
               1996; 
               154 
               1684-1688 
               
- 42 
               Meier-Hellmann A, Bredle D L, Specht M et al.. 
               The effects of low-dose dopamine and norepinephrine for oxygen delivery and uptake
               in septic shock. 
               Intensive Care Med. 
               1997; 
               23 
               31-37 
               
- 43 
               Schwartz D R, Malhotra A, Fink M P. 
               Cytopathic hypoxia in sepsis: an overview. 
               Sepsis. 
               1998; 
               2 
               279-289 
               
- 44 
               Gregory J S, Bonfiglio M F, Dasta J F, Reilly T E, Townsend M C, Flancbaum L. 
               Experience with phenylephrine as a component of a pharmacologic support of septic
               shock. 
               Crit Care Med. 
               1991; 
               19 
               1395-1400 
               
- 45 
               Flancbaum L, Dick M, Dasta J et al.. 
               A dose-response study of phenylephrine in critically ill septic surgical patients. 
               Eur J Clin Pharmacol. 
               1997; 
               51 
               461-465 
               
- 46 
               Yamazaki T, Shimada Y, Taenaka N. 
               Circulatory responses to afterloading wtih phenylephrine in hyperdynamic sepsis. 
               Crit Care Med. 
               1982; 
               10 
               432-435 
               
- 47 
               Duranteau J, Sitbon P, Teboul J L et al.. 
               Effects of epinephrine, norepinephrine, or the combination of norepinephrine on gastric
               mucosa in septic shock. 
               Crit Care Med. 
               1999; 
               27 
               893-900 
               
- 48 
               Cohen R I, Shapir Y, Davis A, Loona R, Scharf S M. 
               Comparison between selective and nonselective nitric oxide synthase inhibition and
               phenylephrine in normal and endotoxic swine. 
               Crit Care Med. 
               2000; 
               28 
               3257-3267 
               
- 49 
               Wilson W, Lipman J, Scribante J et al.. 
               Septic shock: does adrenaline have a role as a first-line inotropic agent?. 
               Anaesth Intensive Care. 
               1992; 
               20 
               470-474 
               
- 50 
               Mackenzie S J, Kapadia F , Nimmo G R. 
               Adrenaline in the treatment of septic shock: Effects on hemodynamics and oxygen transport. 
               Intensive Care Med. 
               1991; 
               17 
               36-39 
               
- 51 
               Day N P, Phu N H, Bethell D P et al.. 
               The effects of dopamine and adrenaline infusions on acid-base balance and systemic
               haemodynamics in severe infection. 
               Lancet. 
               1996; 
               348 
               219-223 
               
- 52 
               Meier-Hellmann A, Reinhart K, Bredle D L, Specht M , Spies C D, Hannemann L. 
               Epinephrine impairs splanchnic perfusion in septic shock. 
               Crit Care Med. 
               1997; 
               25 
               399-404 
               
- 53 
               Parker M M, Shelhamer J H, Natanson C, Alling D W, Parillo J E. 
               Serial cardiovascular variables in survivors and nonsurvivors of human septic shock:
               heart rate as an early predictor of prognosis. 
               Crit Care Med. 
               1987; 
               15 
               923-929 
               
- 54 
               Liu M, Wu L L. 
               Heart sarcolemmal calcium transport in endotoxic shock, II: Mechanism of inpairment
               in ATP-dependent calcium transport. 
               Mol Cell Biochem. 
               1992; 
               112 
               135-142 
               
- 55 
               Bensard D D, Banerjee A, McIntyre R C et al.. 
               Endotoxin disrupts beta-adrenergic signal transduction in the heart. 
               Arch Surg. 
               1994; 
               129 
               198-204 
               
- 56 
               Finkel M S, Oddis C V, Jacob T D, Watkins S C, Hattler B G, Simmons R L. 
               Negative ionotropic effects of cytokines on the heart mediated by nitric oxide. 
               Science. 
               1992; 
               257 
               387-389 
               
- 57 
               Jardin F, Sportiche M, Bazin M et al.. 
               Dobutamine: a hemodynamic evaluation in human septic shock. 
               Crit Care Med. 
               1981; 
               9 
               329-332 
               
- 58 
               De Backer D, Berre J, Zhange H. 
               Relationship between oxygen uptake and oxygen delivery in septic patients: effect
               of prostacyclin versus dobutamine. 
               Crit Care Med. 
               1993; 
               21 
               1658-1664 
               
- 59 
               Hannemann L, Reinhart K, Meier-Hellmann A et al.. 
               Dopexamine hydrochloride in septic shock. 
               Chest. 
               1996; 
               109 
               756-760 
               
- 60 
               Cain S M, Curtis S E. 
               Systemic and regional oxygen uptake and lactate flux in endotoxic dogs infused with
               dopexamine. 
               Crit Care Med. 
               1991; 
               19 
               1552-1560 
               
- 61 
               Vincent J L, Reuse C, Kahn R J. 
               Administration of dopexamine, a new adrenergic agent in cardiorespiratory failure. 
               Chest. 
               1989; 
               96 
               1233-1236 
               
- 62 
               Smithies M, Yee T H, Jackson L et al.. 
               Protecting the gut and liver in the critically ill: effects of dopexamine. 
               Crit Care Med. 
               1994; 
               22 
               789-795 
               
- 63 
               Spronk P E, Ince C, Gardien M J, Mathura K R, Oudemans-van Straaten H M, Zandstra D F.
               
               Nitroglycerin in septic shock after intravascular volume resuscitation. 
               Lancet. 
               2002; 
               360 
               1395-1396 
               
- 64 
               Preiser J, Sun Q, Hadj-Sadok D, Vincent J L. 
               Differential effects of a selective inhibitor of soluble guanylyl cyclase on global
               and regional hemodynamics during canine endotoxic shock. 
               Shock. 
               2003; 
               20 
               465-468 
               
- 65 
               Webb P J, Westwick J, Scully M F, Zahavi J, Kakkar V. 
               Do prostacyclin and thromboxane play a role in endotoxic shock?. 
               Br J Surg. 
               1981; 
               68 
               720-724 
               
- 66 
               Hannemann L, Reinhart K, Meier-Hellmann A, Bredle D L. 
               Prostacyclin in septic shock. 
               Chest. 
               1994; 
               105 
               1504-1510 
               
- 67 
               Radermacher P, Buhl R, Santak B et al.. 
               The effects of prostacyclin on gastric intramucosal pH in patients with septic shock. 
               Intensive Care Med. 
               1995; 
               21 
               414-421 
               
- 68 
               Daemen-Gubbels C RGH, Groeneveld P HP, Groeneveld A BJ, Van Kamp G J, Bronsveld W,
               Thijs L G. 
               Methylene blue increases myocardial function in septic shock. 
               Crit Care Med. 
               1995; 
               23 
               1363-1370 
               
- 69 
               Mayer B, Brunner F, Schnidt K. 
               Novel actions of methylene blue. 
               Eur Heart J. 
               1994; 
               14(suppl) 
               22-26 
               
- 70 
               Landry D W, Levin H R, Gallant E M et al.. 
               Vasopressin pressor hypersensitivity in vasodilatory septic shock. 
               Crit Care Med. 
               1997; 
               25 
               1279-1282 
               
- 71 
               Landry D W, Oliver J A. 
               The pathogenesis of vasodilatory shock. 
               N Engl J Med. 
               2001; 
               345 
               588-595 
               
- 72 
               Patel B M, Chittock D R, Russell J A, Walley K R. 
               Beneficial effects of short-term vasopressin infusion during severe septic shock. 
               Anesthesiology. 
               2002; 
               96 
               576-582 
               
- 73 
               Barton P, Garcia J, Kouatli A et al.. 
               Hemodynamic effects of milrinone lactate in pediatric patients with septic shock:
               a prospective, randomized, placebo-controlled interventional study. 
               Chest. 
               1996; 
               109 
               1302-1311 
               
Mitchell M LevyM.D. 
            Rhode Island Hospital, MICU
            
            7th floor Main Bldg., 753 Eddy St.
            
            Providence, RI 02903
            
            Email: Mitchell_Levy@Brown.edu