This review underscores the paucity of published clinical data to inform practice regarding vasopressor dosing. The strength of this work lies in the application of rigorous systematic review methodology to a clinically important but overlooked research question. Systematic reviews finding insufficient data to guide clinical practice underscore the uncertain effects of variation in usual practices. Nevertheless, our study has limitations. First, we focused on comparisons between blood pressure targets. Although some clinicians may titrate vasopressors to other physiologic end points, these alternative practices are less common and not incorporated in clinical practice guidelines. Second, the association between higher blood pressure targets and cardiac index varies considerably across crossover trials, suggesting that it may depend on specific study characteristics. Unfortunately, many potential explanatory variables were not measured in included studies. Post hoc subgroup analyses should be considered hypothesis generating. At this time, we cannot identify with certainty under what conditions this association exists. Third, although our search strategy for published studies was comprehensive, we cannot rule out publication bias. Funnel plots analysis suggests that the risk of publication bias is more likely to affect the positive association between blood pressure targets and heart rate. Fourth, we found no observational study directly addressing our research question, which highlights the paucity of the evidence informing vasopressor use. Cohort studies reporting associations between vasopressor doses or observed blood pressure values and clinical outcomes are subject to residual confounding and are not suitable to provide guidance for titration of vasopressors. Finally, given the limited experimental evidence in humans, a summary of preclinical data may be of interest. We opted to focus on clinical studies because the limited clinical relevance of animal experiments precludes any inference to clinical practice even when the results are compelling (43, 44).
Increasing research activity in this field reflects a growing interest in the question of optimal vasopressor dosing and provides context to our work. Our findings point to a paradox of contemporary critical care: fewer than 850 patients have been enrolled in clinical trials of blood pressure targets for septic shock, yet administration of vasopressors to the sickest patients in our hospitals occurs daily. Because strong recommendations for clinical care require concordant results from a number of clinical trials (10, 20), further research comparing the target recommended by the Surviving Sepsis Campaign with alternative dosing regimens is needed.
The authors thank Neera Bhatnagar, Claudio Martin, Lauralyn McIntyre, and Robert Green for their critical review of the manuscript and Nicolay Ferrari for his administrative support. This work was conducted without designated funding.
1. Jones AE, Aborn LS, Kline JA: Severity of emergency department hypotension predicts adverse hospital outcome. Shock
22 (5): 410–414, 2004.
2. Hollenberg SM: Vasopressor support in septic shock
132 (5): 1678–1687, 2007.
3. Hollenberg SM: Vasoactive drugs in circulatory shock. Am J Respir Crit Care Med
183 (7): 847–855, 2011.
4. Buckberg G, Cohn J, Darling C: Escherichia coli
bacteremic shock in conscious baboons. Ann Surg
173 (1): 122–130, 1971.
5. Hollenberg SM, Ahrens TS, Annane D, Astiz ME, Chalfin DB, Dasta JF, Heard SO, Martin C, Napolitano LM, Susla GM, et al.: Practice parameters for hemodynamic support of sepsis in adult patients: 2004 update. Crit Care Med
32 (9): 1928–1948, 2004.
6. Kirchheim HR, Ehmke H, Hackenthal E, Löwe W, Persson P: Autoregulation of renal blood flow, glomerular filtration rate and renin release in conscious dogs. Pflugers Arch
410 (4–5): 441–449, 1987.
7. Thuijls G, Derikx JP, de Kruijf M, van Waardenburg DA, van Bijnen AA, Ambergen T, van Rhijn LW, Willigers HM, Buurman WA: Preventing enterocyte damage by maintenance of mean arterial pressure during major nonabdominal surgery in children. Shock
37 (1): 22–27, 2012.
8. Dries DJ: Vasoactive drug support in septic shock
26 (5): 529–530, 2006.
9. da Silva Ramos FJ, Azevedo LC: Hemodynamic and perfusion end points for volemic resuscitation in sepsis. Shock
34 (Suppl 1): 34–39, 2010.
10. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, et al.: Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock
: 2012. Crit Care Med
41 (2): 580–637, 2013.
11. Bulkley GB, Womack WA, Downey JM, Kvietys PR, Granger DN: Collateral blood flow in segmental intestinal ischemia: effects of vasoactive agents. Surgery
100 (2): 157–166, 1986.
12. Pawlik W, Shepherd AP, Jacobson ED: Effect of vasoactive agents on intestinal oxygen consumption and blood flow in dogs. J Clin Invest
56 (2): 484–490, 1975.
13. Sterling SA, Puskarich MA, Shapiro NI, Trzeciak S, Kline JA, Summers RL, Jones AE; Emergency Medicine Shock
Research Network (EMSHOCKNET): Characteristics and outcomes of patients with vasoplegic versus tissue dysoxic septic shock
40 (1): 11–14, 2013.
14. Lamontagne F, Cook DJ, Adhikari NK, Briel M, Duffett M, Kho ME, Burns KE, Guyatt G, Turgeon AF, Zhou Q, et al.: Vasopressor administration and sepsis: a survey of Canadian intensivists. J Crit Care
26 (5): 532 e1–e7, 2011.
15. Mulrow CD: Rationale for systematic reviews. BMJ
309 (6954): 597–599, 1994.
16. Antman EM, Lau J, Kupelnick B, Mosteller F, Chalmers TC: A comparison of results of meta-analyses of randomized control trials and recommendations of clinical experts. Treatments for myocardial infarction. JAMA
268 (2): 240–248, 1992.
17. Bourgoin A, Leone M, Delmas A, Garnier F, Albanèse J, Martin C: Increasing mean arterial pressure in patients with septic shock
: effects on oxygen variables and renal function. Crit Care Med
33 (4): 780–786, 2005.
18. Higgins J, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions Version 510 (updated March 2011).
20. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, Schünemann HJ; GRADE Working Group: GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ
336 (7650): 924–926, 2008.
21. Suk P, Hruda J, Leverve X, Sramek V: Early resuscitation of septic shock
to different levels of arterial blood pressure [In Czech]. Anesteziologie a Intenzivni Medicina
18 (3): 150–156, 2007.
22. Asfar P, Meziani F, Hamel JF, Grelon F, Megarbane B, Anguel N, Mira JP, Dequin PF, Gergaud S, Weiss N, et al.: High versus low blood-pressure target in patients with septic shock
. N Engl J Med
370 (17): 1583–1593, 2014.
23. Dünser MW, Ruokonen E, Pettilä V, Ulmer H, Torgersen C, Schmittinger CA, Jakob S, Takala J: Association of arterial blood pressure and vasopressor load with septic shock
mortality: a post hoc
analysis of a multicenter trial. Crit Care
13 (6): R181, 2009.
24. Janssen van Doorn K, Verbrugghe W, Wouters K, Jansens H, Jorens PG: The duration of hypotension determines the evolution of bacteremia-induced acute kidney injury in the intensive care unit. PLoS One
9 (12): e114312, 2014.
25. Subramanian S, Yilmaz M, Rehman A, Hubmayr RD, Afessa B, Gajic O: Liberal vs. conservative vasopressor use to maintain mean arterial blood pressure during resuscitation of septic shock
: an observational study. Intensive Care Med
34 (1): 157–162, 2008.
26. Loeb HS, Winslow EB, Rahimtoola SH, Rosen KM, Gunnar RM: Acute hemodynamic effects of dopamine in patients with shock. Circulation
44 (2): 163–173, 1971.
27. Nouira S, Dhainaut JF, Brunet F, Armaganidis A, Giraud T, Garrauste MT, Corsia G, Schremmer B, Monsallier JF: [Septic shock
: hemodynamic effects of noradrenaline and a noradrenaline-dopexamine combination]. Annales francaises d’anesthesie et de reanimation
8 (Suppl): R234, 1989.
28. Redl-Wenzl EM, Armbruster C, Edelmann G, Fischl E, Kolacny M, Wechsler-Fordos A, Sporn P: The effects of norepinephrine on hemodynamics and renal function in severe septic shock
states. Intensive Care Med
19 (3): 151–154, 1993.
29. Winslow EJ, Loeb HS, Rahimtoola SH, Kamath S, Gunnar RM: Hemodynamic studies and results of therapy in 50 patients with bacteremic shock. Am J Med
54 (4): 421–432, 1973.
30. Day NP, Phu NH, Bethell DP, Mai NT, Chau TT, Hien TT, White NJ: The effects of dopamine and adrenaline infusions on acid–base balance and systemic haemodynamics in severe infection. Lancet
348 (9022): 219–223, 1996.
31. Hall LG, Oyen LJ, Taner CB, Cullinane DC, Baird TK, Cha SS, Sawyer MD, et al.: Fixed-dose vasopressin compared with titrated dopamine and norepinephrine as initial vasopressor therapy for septic shock
24 (8): 1002–1012, 2004.
32. Mayeur N, Vallée F, De Soyres O, Mebazaa A, Salem R, Fourcade O, Minville V, Genestal M: Dopexamine Test in septic shock
with hyperlactatemia. Annales francaises d’anesthesie et de reanimation
29 (11): 759–764, 2010.
33. Meier-Hellmann A, Bredle DL, Specht M, Hannemann L, Reinhart K: Dopexamine increases splanchnic blood flow but decreases gastric mucosal pH in severe septic patients treated with dobutamine. Crit Care Med
27 (10): 2166–2171, 1999.
34. Meier-Hellmann A, Bredle DL, Specht M, Spies C, Hannemann L, Reinhart K: The effects of low-dose dopamine on splanchnic blood flow and oxygen uptake in patients with septic shock
. Intensive Care Med
23 (1): 31–37, 1997.
35. Moran JL, O’Fathartaigh MS, Peisach AR, Chapman MJ, Leppard P: Epinephrine as an inotropic agent in septic shock
: a dose-profile analysis. Crit Care Med
21 (1): 70–77, 1993.
36. Obritsch MD, Jung R, Fish DN, MacLaren R: Effects of continuous vasopressin infusion in patients with septic shock
. Ann Pharmacother
38 (7–8): 1117–1122, 2004.
37. Persichini R, Silva S, Teboul JL, Jozwiak M, Chemla D, Richard C, Monnet X: Effects of norepinephrine on mean systemic pressure and venous return in human septic shock
. Crit Care Med
40 (12): 3146–3153, 2012.
38. Fukuoka T, Nishimura M, Imanaka H, Taenaka N, Yoshiya I, Takezawa J: Effects of norepinephrine on renal function in septic patients with normal and elevated serum lactate levels. Crit Care Med
17 (11): 1104–1107, 1989.
39. Loeb HS, Cruz A, Teng CY, Boswell J, Tobin JR Jr, Gunmar RM: Haemodynamic studies in shock associated with infection. Br Heart J
29 (6): 883–894, 1967.
40. St-Arnaud C, Éthier J, Leclair M, Lamontagne F: Prescribed targets for vasopressor titration in septic shock
: a retrospective cohort study. Intensive Care Med
37 (Suppl 1): 231, 2011.
41. Naumann CP, Ruetsch YA, Fleckenstein W, Fennema M, Erdmann W, Zäch GA: pO2-profiles in human muscle tissue as indicator of therapeutical effect in septic shock
patients. Adv Exp Med Biol
317: 869–877, 1992.
42. Xu YJ, Yang Y, Qiu BH: Titrating mean arterial pressure in consideration of interindividual effect improves microcirculation in patients with septic shock
. Intensive Care Med
38 (Suppl 1): S87, 2012.
43. Lamontagne F, Briel M, Duffett M, Fox-Robichaud A, Cook DJ, Guyatt G, Lesur O, Meade MO: Systematic review
of reviews including animal studies addressing therapeutic interventions for sepsis. Crit Care Med
38 (12): 2401–2408, 2010.
44. Lamontagne F, Meade M, Ondiveeran HK, Lesur O, Fox-Robichaud AE: Nitric oxide donors in sepsis: a systematic review
of clinical and in vivo preclinical data. Shock
30 (6): 653–659, 2008.
45. Bauman ZM, Killu KF, Rech MA, Bernabei-Combs JL, Gassner MY, Coba VE, Tovbin A, Kunkel PL, Mlynarek ME: Racial differences in vasopressor requirements for septic shock
41 (3): 188–192, 2014.
46. De Backer D, Aldecoa C, Njimi H, Vincent JL: Dopamine versus norepinephrine in the treatment of septic shock
: a meta-analysis. Crit Care Med
40 (3): 725–730, 2012.
47. Guérin JP, Levraut J, Samat-Long C, Leverve X, Grimaud D, Ichai C: Effects of dopamine and norepinephrine on systemic and hepatosplanchnic hemodynamics, oxygen exchange, and energy balance in vasoplegic septic patients. Shock
23 (1): 18–24, 2005.
48. Patel GP, Grahe JS, Sperry M, Singla S, Elpern E, Lateef O, Balk RA: Efficacy and safety of dopamine versus norepinephrine in the management of septic shock
33 (4): 375–380, 2010.
49. Leone M, Albanèse J, Delmas A, Chaabane W, Garnier F, Martin C: Terlipressin in catecholamine-resistant septic shock
22 (4): 314–319, 2004.
50. Matok I, Vard A, Efrati O, Rubinshtein M, Vishne T, Leibovitch L, Adam M, Barzilay Z, Paret G: Terlipressin as rescue therapy for intractable hypotension due to septic shock
in children. Shock
23 (4): 305–310, 2005.
51. Russell JA, Walley KR, Singer J, Gordon AC, Hébert PC, Cooper DJ, Holmes CL, Mehta S, Granton JT, Storms MM, et al.: Vasopressin versus norepinephrine infusion in patients with septic shock
. N Engl J Med
358 (9): 877–887, 2008.
52. Kim WY, Jun JH, Huh JW, Hong SB, Lim CM, Koh Y: Radial to femoral arterial blood pressure differences in septic shock
patients receiving high-dose norepinephrine therapy. Shock
40 (6): 527–531, 2013.
53. Dettmer M, Holthaus CV, Fuller BM: The impact of serial lactate monitoring on emergency department resuscitation interventions and clinical outcomes in severe sepsis and septic shock
: an observational cohort study. Shock
43 (1): 55–61, 2015.
54. Wacharasint P, Nakada TA, Boyd JH, Russell JA, Walley KR: Normal-range blood lactate concentration in septic shock
is prognostic and predictive. Shock
38 (1): 4–10, 2012.
55. Noritomi DT, Vieira ML, Mohovic T, Bastos JF, Cordioli RL, Akamine N, Fischer CH: Echocardiography for hemodynamic evaluation in the intensive care unit. Shock
34 (Suppl 1): 59–62, 2010.
56. Skarda DE, Mulier KE, Myers DE, Taylor JH, Beilman GJ: Dynamic near-infrared spectroscopy measurements in patients with severe sepsis. Shock
27 (4): 348–353, 2007.
57. Dahlqvist M, Hasibeder WR, Dünser MW: Hemodynamic and perfusion end points for volemic resuscitation in sepsis. Shock
35 (4): 434, 2011.