Timing of Vasopressors in Septic Shock: How Soon is Too Soon?

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1 Timing of Vasopressors in Septic Shock: How Soon is Too Soon? Anand Kumar, MD Sections of Critical Care Medicine and Infectious Diseases Professor of Medicine, Medical Microbiology and Pharmacology University of Manitoba, Winnipeg, Canada

2 An Injury Paradigm of Septic Shock: The Golden Hours A Kumar, Virulence 214;5:8 97 DEATH Cellular dysfunction/tissue injury Inflammatory response Toxic burden Shock Threshold Microbial load TIME 2

3 An Injury Paradigm of Sepsis and Antimicrobial therapy Septic Shock Cellular dysfunction/tissue injury Inflammatory response Shock Threshold Toxic burden Microbial load A Kumar, Virulence 214;5:8 97 TIME 3

4 An Injury Paradigm of Sepsis and Septic Shock earlier antimicrobial therapy Cellular dysfunction/tissue injury Shock Threshold Microbial load Inflammatory response Toxic burden A Kumar, Virulence 214;5:8 97 TIME 4

5 An Injury Paradigm of Sepsis and Antimicrobial therapy Septic Shock Cellular dysfunction/tissue injury Inflammatory response Shock Threshold Toxic burden Fluid resuscitation Microbial load A Kumar, Virulence 214;5:8 97 TIME 5

6 Fluids in Septic Shock most published studies on resuscitation in septic shock addressed the timing, volume, and composition of administered fluids compared early versus late fluids,high versus low volume fluid administration, and resuscitation protocols versus no protocol

7 Fluid Resuscitation in Septic Shock (n=399) fluid volume (L) crystalloid colloid total fluid volume crystalloid-equivalent volume (corrected) <1 <6 <24 time interval (hrs)

8 Cumulative volume (liters) Fluid Requirements in Sepsis 1 8 Isotonic saline Hydroxyethyl starch 5% Albumin Time (in hours) Rackow EC, et al. Crit Care Med 1983;11:839-5.

9 The effect of increasing fluid balance Retrospective cohort study, n= Mixed ICUs. on mortality Sadaka et al. ICM 213

10 Saline vs Albumin Finfer S and the SAFE Study Group, NEJM 24

11 Commonly Used Vasopressor Agents (Relative Potency) Cardiac Peripheral Vasculature Agent Dose Heart Rate Contractility Vasoconstriction Vasodilation Dopami- nergic Dopamine Norepinephrine Dobutamine Isoproterenol Epinepherine Phenylepherine 1-4 g/kg/min 4-2 g/kg/min 2-4 g/min 2-2 g/kg/min 1-4 g/min 1-2 g/min 2-2 g/min Adapted from Kumar A, Parrillo JE: Shock: Classification, pathophysiology, and approach to management. In Textbook of Critical Care Medicine. 2nd Edition. Editors: Joseph E. Parrillo, MD and R. Phillip Dellinger, MD. Mosby Publications 21.

12 Surviving Sepsis Guidelines 1 = strong recommendation 2 = weak recommendation or suggestion A = good evidence from randomized trials B = moderate strength evidence from small randomized trial(s) or upgraded observational trials C = low strength evidence, well-done observational trials with control randomized controlled trials D = very low strength evidence, downgraded controlled studies or expert opinion.

13 Surviving Sepsis Guidelines Vasopressors should be begun initially to target a mean arterial pressure of 65 mm Hg (Grade 1C)

14 MAP 65-7 vs 8-85 mm Hg? Asfar et al, NEJM 213;37: P=.2 ANOVA

15 MAP 65-7 vs 8-85 mm Hg? Asfar et al, NEJM 213;37:

16 Surviving Sepsis Guidelines Norepinephrine (Levophed) should be provided as the first-line vasopressor (Grade 1B)

17 Surviving Sepsis Guidelines Dopamine is suggested to not be used as an alternative to norepinephrine in septic shock, except in highly selected patients such as those with inappropriately low heart rates (absolute or relative bradycardia) who are at low risk for tachyarrhythmias (Grade 2C)

18 NE vs dopamine in shock De Backer et al, NEJM 21;362:779-89

19 NE vs dopamine? De Backer et al, CCM 212;725-73

20 Vasopressors Short term macrovascular benefit -increased MAP (supports autoregulation) Long term microvascular/cellular injury? -myocardial injury -decreased bioenergetic efficiency -metabolic modulation -thrombogenic -immunosuppression/bacterial stimulation Obvious clinical side effects: tachyarrythmia, macrovascular ischemia, increased cardiac work Singer et al, Lancet 27

21 An Injury Paradigm of Sepsis Antimicrobial therapy and Septic Shock Cellular dysfunction/tissue injury Inflammatory response Pressors Shock Threshold Toxic burden Microbial load TIME 21

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26 Vasopressor Figure 2 Delay in Septic Shock n = 864 Mortality Odds Ratio aor 1.2/hr CI 1.1 to 1.3 p < > Pressor Delay Decile Range (hrs) Beck and CATSS. Critical Care 214, 18:R97

27 Fluid/Pressor Interactions in Septic Shock (n=2849) Overall: p<.1 Non-linearity: p<.1 Waechter and CATSS, Crit Care Med 214;42:

28 Results Fluids and vasoactive agents had strong, interacting associations with mortality, which ranged 25-71% (p<.1) Mortality lowest when vasoactive agents were begun 1-6 hours after onset, with >1 L of fluids in the initial hour after shock onset, >2.4 L from hours 1-6, and L from 6-24 hours Volume administered during the 1-6 hour period was the largest independent influence Initiating vasoactive drugs during the first hour was associated with administration of lower fluid volumes

29 Conclusion Potentially detrimental to start vasoactive agents within the first hour after onset of septic shock Aggressive fluid resuscitation should be the focus during the first hour, thereafter starting vasoactive drugs and continuing aggressive fluid resuscitation A possible mechanism for the detrimental influence of very early use of vasoactive agents may be that higher MAP produced with such agents leads clinicians to provide less early fluids