VASOPRESSOR AGENTS IN SEPTIC SHOCK

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1 VASOPRESSOR AGENTS IN SEPTIC SHOCK Daniel De Backer Head Dept Intensive Care, CHIREC hospitals, Belgium Professor of Intensive Care, Université Libre de Bruxelles President European Society of Intensive Care Medicine

2 Even non sustained (<60min) hypotension is associated with a poor outcome and should not be neglected Marchick et al ICM 35:1261; pts with sepsis at ED OR 2.7 ( )

3 Time spent with hypotension is associated with a poor outcome Dunser M et al ICM 35:1225; pts with sepsis in ICU

4 High doses of vasopressors used to reach a given pressure levels are deleterious Dunser et al Crit Care 13:R181;2009 MAP quartiles: I II III IV pts with septic shock VP for MAP>70 mmhg

5 Both severity and duration of hypotension are associated with poor outcome. It sounds thus reasonable to try to correct hypotension without delay. Which blood pressure target? Which agent should be used?

6 Does correction of hypotension with vasopressors affect tissue perfusion? DDB USI

7 Correction of hypotension improves urine output and renal function in septic patients Albanese et al Chest 126:534;2004 MAP 50 => 78 mmhg Patients with septic shock (n=14) DDB USI

8 MAP 54 => 77 mmhg Correction of hypotension improves microvascular reactivity (NIRS) Georger et al ICM 36:1882;2010

9 Which blood pressure target? DDB USI

10 PRESSURE GOAL? LeDoux et al CCM 28:2729;2000

11 High vs Low MAP? VS mmhg Asfar P et al NEJM 2014 But lower incidence of AKI with high MAP in previously hypertensive patients Higher rate of arrhythmias and AMI in high MAP 798 pts septic shock

12 High vs Low MAP? VS mmhg Asfar P et al NEJM 2014 Target pts septic shock

13 High variablity in response to increase in MAP Renal Doppler Deruddre et al ICM 33:1557; pts septic shock

14 Impact of MAP/NE on microvascular perfusion Dubin et al Crit Care 2009

15 VASOPRESSOR SUPPORT Adrenergic agents: Dopamine Norepinephrine Epinephrine Phenylephrine

16 ADRENERGIC AGENTS ALPHA BETA DOPA DOPAMINE ++ +(+) + NOREPINPHRINE EPINEPHRINE PHENYLEPHRINE

17 ADRENERGIC AGENTS Alpha + vasopressor effect - increase in afterload, decrease in regional blood flows Beta + inotropic effect, increase in regional blood flows - arrhythmias, immunodepression, metabolic effects Dopa + increase in renal and splanchnic blood flow (?) - alteration hypothalamo-pituitary axis

18 Hemodynamic effects of vasopressors CO EPINEPHRINE DOPA NOREPINEPHRINE PHENYLEPHRINE MAP

19 Rats CLP Ducrocq N et al Anesthesiology 116:1083;2012

20 Change in CI (%) Schreuder et al Chest 95:1282;1989 DOPA NOREPI

21 De Backer et al CCM 31:1659;2003 CARDIAC INDEX L/min.M² 7 6 **$$ DOPA NOREPI EPI MAP constant

22 DOPAMINE vs NOREPINEPHRINE Effects on regional blood flow?

23 Correction of hypotension improves urine output and renal function in septic patients Albanese et al Chest 126:534;2004 MAP 50 => 78 mmhg Patients with septic shock (n=14) DDB USI

24 Effects of dopamine, norepnephrine and epinephrine in patients with septic shock De Backer et al CCM 31:1659;2003

25 Beck et al Crit Care 4:485;2004 But these agents are not only correcting blood pressure..

26 NOREPINEPHRINE vs EPINEPHRINE Background

27 Dose dependent stimulation of beta adrenergic receptor with EPI VO2 CO Dose

28 Lactate mm/l 6 5 Metabolic effects of epinephrine Levy B, Intensive Care Med 1997, 23; * * Epinephrine Norepinephrine + dobutamine Hours DDB USI

29 280 pts Myburgh et al ICM 34:2226;2008

30 Annane et al Lancet 370:676;2007 MAP 330 pts septic shock ph Lactate

31 Myburgh et al ICM 34:2226; pts

32 Levy B et al CCM pts cardiogenic shock Norepi + dobu VS Epi

33 EPI vs NOREPI (+-DOBU) Annane et al Lancet 370:676; pts septic shock

34 DOPAMINE vs NOREPINEPHRINE

35 SOAP study DOPAMINE vs NOREPINEPHRINE 1058 pts in shock (any cause) Sakr et al CCM 34:589;2006 No dopamine n=683 Dopamine n=375 Log Rank = 4.6; p = 0.032

36 SOAP study DOPAMINE vs NOREPINEPHRINE 1058 pts in shock Multivariate logitstic regression Sakr et al CCM 34:589;2006 Coefficient Mean, SE Odds ratio (95 % CI) p value Mean SOFA score ( ) <0.001 Mean fluid balance ( ) <0.001 Medical admission ( ) <0.001 Age ( ) Dopamine administration ( ) Cancer ( ) 0.003

37 SACiUCI study DOPAMINE vs NOREPINEPHRINE Povoa et al CCM 37:410;2009 Dopamine Norepi 458 patients septic shock

38 Prospective Randomized Double blind Multicenter

39 Administration of vasoactive drugs: Open label NE Study drug (DOPA vs NE) Dose increments (study drug)*: 2 mcg/kg.min for DOPA 0.04 mcg/kg.min for NE Maximal dose (study drug)*: 20 mcg/kg.min for DOPA 0.19 mcg/kg.min for NE * Calculated after Marik et al JAMA 272:1354;1994 De Backer et al CCM 31:1659;2003

40 De Backer et al NEJM 362: 779; 2010

41 Comparison of dopamine and norepinephrine as the first vasoactive agent in the management of shock De Backer et al NEJM 362: 779; 2010 Type of shock DOPA NOREPI Septic 542 (63) 502 (61) Cardiogenic 135 (16) 145 (18) Hypovolemic 138 (16) 125 (15) other 48 (6) 44 (5) p = 0.707

42 Norepinephrine vs Dopamine in shock (SOAP investigators) De Backer et al NEJM 362: 779; 2010 N = 1679 * p<0.05

43 Comparison of dopamine and norepinephrine as the first vasoactive agent in the management of shock De Backer et al NEJM 362: 779; 2010 * p<0.05

44 Cardiac index De Backer et al NEJM 362: 779; 2010

45 Lactate De Backer et al NEJM 362: 779; 2010

46 Norepinephrine vs Dopamine in shock (SOAP investigators) De Backer et al NEJM 362: 779; 2010

47 Comparison of dopamine and norepinephrine as the first vasoactive agent in the management of shock De Backer et al NEJM 362: 779; 2010 Septic (1044) / Cardiogenic (280) / hypovolemic (263)

48 Comparison of dopamine and norepinephrine as the first vasoactive agent in the management of shock Arrhythmias N= P < De Backer et al NEJM 362: 779; DOPA NOREPI 50 0 Atr fib Ventr tachyc Ventr fib

49 Other trials??

50 Septic shock n=252 / Single centre Patel et al Shock 33: 375; 2010

51 Arrhythmias N= P < Patel et al Shock 33: 375; DOPA NOREPI 10 0 Atr tachyc Atr fib Septic shock n=252 / Single centre Ventr tachyc

52 Dopamine vs norepinephrine in septic shock A meta-analysis De Backer et al CCM 40:725:2012 Norepi better

53 VASOPRESSOR SUPPORT Adrenergic agents: Dopamine Norepinephrine Epinephrine Non-Adrenergic agents: Vasopressin (NO inhibition)

54 VASOPRESSIN Vasopressin deficiency in septic shock Landry et al Circ 95:1122;1997 DDB USI

55 VASOPRESSIN IN PATIENTS WITH SEPTIC SHOCK Vasopressin u/min in 5 patients with septic shock Landry et al CCM 25:1279;1997 Mean arterial Pressure mmhg BASE AVP P<0.01 PAT 1 PAT 2 PAT 3 PAT 4 PAT 5 DDB USI

56 The pro side increases blood pressure spares vasopressors improves renal function (?) less arrhythmias The con side high doses are detrimental decreases cardiac output promotes gut ischemia? impairs liver function? Impact on platelets?

57 VASST Russell et al NEJM 358:877; septic shock pts

58 VASST Russell et al NEJM 358:877;2008 Mortality (%) according to severity at baseline day 90 day NOREPI VP p< day 90 day p<0.05 More severe n= 400 (NE > 15 mcg/min) Less severe n= 378 (NE < 15 mcg/min)

59 Vasopressin vs Noradrenaline as Initial therapy in Septic Shock (VANISH): a randomised controlled trial. Gordon A et al A double-blind parallel group factorial (2x2) randomised controlled trial of vasopressin (up to 0.06 u/min) vs noradrenaline, and hydrocortisone vs placebo in septic shock. 400 pts To be presented at ESICM LIVES 2015

60 LNNMA IN PATIENTS WITH SEPTIC SHOCK Lopez et al CCM 32:21;2004 Placebo LNNMA DDB USI

61 VASOPRESSOR SUPPORT IN SHOCK Correction of hypotension (MAP ~65 mmhg) MAP higher than mmhg do not seem to further improve tissue perfusion Adrenergic agents as first line agent, with norepinephrine as the 1st choice agent Vasopressin appears to be promising in septic shock DDB USI

62 Thank you

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