Vasopressors in Septic Shock Keith R. Walley, MD St. Paul s Hospital University of British Columbia Vancouver, Canada
Echocardiogram: EF=25% 57 y.o. female, pneumonia, shock
Echocardiogram: EF=25% 57 y.o. female, pneumonia, shock
Echocardiogram: EF=25% 57 y.o. female, pneumonia, shock
Early Goal- Directed Therapy Rivers E et al N Engl J Med 345:1368-77, 2001
Vasoactive Therapy Use of vasoactive drugs has been ad hoc Recent RCTs of vasopressor drugs in shock / sepsis Vasopressin Low severity of illness Renal Risk category Corticosteroids Assessing vasoactive therapy clinically
Which Vasopressor? Recent RCTs Norepinephrine vs. Epinephrine (2007,08) Norepinephrine vs. Dopamine (2010) Norepinephrine vs. Vasopressin (2008)
Norepinephrine vs. Epinephrine Annane. CATS Lancet. 2007 Myburgh. CAT. ICM. 2008 (n=280) Mortality NE Epi 28 d 26.1% 22.5% p=0.48 90 d 34.3% 30.4% p=0.49
Norepinephrine vs. Dopamine De Backer. NEJM. 2010.
Norepinephrine vs. Dopamine De Backer. NEJM. 2010. p<0.001 Dopamine Norepi All 24.1% 12.4% A fib 20.5 11.0 V tach 2.4 1.0 V fib 1.2 0.5
Norepinephrine vs. Vasopressin (+ open label NE) Russell. VASST. NEJM. 2010
Recent RCTs Norepinephrine / Epinephrine: p=ns Annane et al. Lancet 370:676, 2007 (CATS, n=330, SS) NE+d better Myburgh et al. Intens Care Med. 34:2226, 2008 (CAT, n=280, S) NE worse Norepinephrine / Dopamine: p=ns Dopamine more tachydysrhythmias De Backer et al. NEJM, 362:779-789, 2010 (SOAP II, n=1679, S) Norepinephrine / Vasopressin: p = NS Benefit in lower severity of illness stratum Russell et al, NEJM, 358:877-887, 2008. (VASST, n=778, SS)
Low severity of shock stratum 5 µg/min < NE < 15 µg/min Log-rank statistic p = 0.05 day 28 p = 0.03 day 90
High severity of shock stratum NE > 15 µg/min Log-rank statistic p = 0.77 day 28 p = 0.92 day 90
Plasma vasopressin levels (n = 107) Vasopressin Off Vasopressin Norepinephrine
Norepinephrine-sparing effect of low-dose vasopressin (0.03 U/min) Norepinephrine µg/min Norepinephrine Vasopressin+NE Days
Heart rate: norepinephrine-sparing versus direct vasopressin effect Heart Rate Norepinephrine Vasopressin+NE Days
Serious adverse events Norepinephrine Vasopressin p (n=382) (n=397) Myocardial infarction / 7 (1.8) 8 (2.0) ischemia 1.00 Cardiac arrest 8 (2.1) 3 (0.8) 0.14 Tachyarrythmia 3 (0.8) 4 (1.0) 1.00 Bradyarrythmia 3 (0.8) 4 (1.0) 1.00 Mesenteric ischemia 13 (3.4) 9 (2.3) 0.39 Digital ischemia 2 (0.5) 8 (2.0) 0.11 Cerebrovascular accident 1 (0.3) 1 (0.3) 1.00 Hyponatremia 1 (0.3) 1 (0.3) 1.00 Other 2 (0.5) 5 (1.3) 0.45 Total 40 (10.5) 41 (10.3) 1.00
Relationship to renal function RIFLE Risk Category (Cr 1.5X) Vasopressin Norepinephrine P=0.009 Gordon AC et al. Intensive Care Med. 36:83-91, 2010.
Relationship to renal function RIFLE Risk Category (Cr 1.5X) Post-hoc Vasopressin Norepinephrine P=0.009 Gordon AC et al. Intensive Care Med. 36:83-91, 2010.
Vasopressin effect in renal Risk Category Decreased progression to renal failure or loss Vasopressin 21.1% Norepinephrine 41.2% (p=0.03) Decreased use of Renal Replacement Therapy Vasopressin 17.0% Norepinephrine 37.7% (p=0.02)
Microvascular renal effects Constriction of afferent arteriole: Edwards RM et al. Am J Physiol. 26: F274-F278, 1989
Microvascular renal effects Constriction of efferent arteriole: Vasopressin > Norepinephrine
Corticosteroids Annane Inclusion: refractory septic shock! 50 mg hydrocortisone q6h Surviving Sepsis Campaign Guidelines CORTICUS Non overall benefit Potentiation of adrenergic signalling Vasopressin x corticosteroid interaction
Vasopressin x Steroid Interaction Septic shock survival vasopressin plus steroids 80.9% vs vasopressin without steroids 47.6%, P = 0.02. Retrospective Baseline differences Controls 4 years older Steroids more CRRT Bauer SR et al. J Crit Care. 23:500-506, 2008
Vasopressin X Steroid Interaction Survival Vasopressin Norepinephrine Norepinephrine Russell JA, Walley KR, et al. Crit Care Med. 37:811-8, 2009. Survival Interaction P=0.008 Days Vasopressin
Vasopressin levels steroid interaction Corticosteroids Vasopressin No corticosteroids Norepinephrine Russell et al. Critical Care Medicine. 37:811-818, 2009.
Assessing vasoactive therapy Volemia: CVP, PPV, Echo Mean Arterial Pressure: sufficient to allow flow redistribution Adequacy of oxygen delivery: S CV o 2 Lactate Cardiac output (PAC, dye dilution, Doppler)
Potential problem with too much fluid Boyd JH; Forbes J; Nakada TA; Walley KR; Russell JA. Critical Care Medicine. 39(2):259-65, 2011 Feb. 2
Vasoactive Therapy Beta-adrenergic agonists increase heart rate and incidence of arrhythmias NE versus Epi NE versus Dopamine Vasopressin versus NE Consider adding vasopressin NE dose is low creatinine is slightly elevated with steroids?
Co-investigators Jim Russell John Boyd Databases VASST Investigators and coordinators Funding Heart & Stroke Foundation CIHR Michael Smith Foundation
Table 4. Fluid resuscitation in septic shock: a positive fluid balance and elevated central venous pressure are associated with increased mortality. Boyd JH; Forbes J; Nakada TA; Walley KR; Russell JA Critical Care Medicine. 39(2):259-65, 2011 Feb. Table 4. 12-hr fluid balance: Survivors vs. nonsurvivors within CVP groups 2011 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins. 2
Figure 1. Fluid resuscitation in septic shock: a positive fluid balance and elevated central venous pressure are associated with increased mortality. Boyd JH; Forbes J; Nakada TA; Walley KR; Russell JA Critical Care Medicine. 39(2):259-65, 2011 Feb. Figure 1. A, Daily fluid intake, urine output and fluid balance at 12 hrs and days 1-4. B, Cumulative daily fluid intake, urine output and fluid balance at 12 hrs and days 1-4. 2
Annane. CATS. Lancet. 2007 Myburgh. CAT. ICM. 2008 (n=280) NE Epi 28 d 26.1% 22.5% p=0.48 90 d 34.3% 30.4% p=0.49 De Backer. NEJM. 2010 Russell. VASST. NEJM. 2010
For vasopressin tx: Steroids good for low severity, lack of steroids bad for high severity Less Severe More Severe Received 257/378 331/400 Steroids 68.0% 82.8% Mortality VP NE P-value VP NE P-value All 52/196 65/182 88/200 85/200 26.5% 35.7% 0.05 44.0% 42.5% 0.77 No steroids 15/65 9/56 19/36 10/33 23.1% 16.1% 0.46 52.8% 30.3% 0.10 Steroids 37/131 56/126 69/164 75/167 28.2% 44.4% 0.01 42.1% 44.9% 0.68 Interaction p-value = 0.002
Relationship to renal function RIFLE Criteria GFR criteria Urine output criteria Risk Injury Loss Increased serum creatinine x1.5 or Decreased GFR >25% Increased serum creatinine x2 or Decreased GFR >50% Increased serum creatinine x3 or Decreased GFR >75% or Increased serum creatinine 44µmol/l if baseline 350µmol/l < 0.5ml/kg/h x6 hours < 0.5ml/kg/h x12 hours < 0.3ml/kg/h x24 hours or Anuria x12 hours Failure Persistent acute renal failure = complete loss of renal function for > 4 weeks End stage End-Stage Kidney Disease (>3 months)
Baseline demographics Norepinephrine (n=382) Vasopressin (n=396) Age, years 61.8 ±16 59.3 ±16.4 Male sex 229 (59.9) 246 (62.0) Caucasian 320 (83.8) 336 (84.6) Co-morbidities Ischemic heart disease 65 (17.0) 68 (17.1) COPD 72 (18.8) 55 (13.9) Chronic renal failure 48 (12.6) 40 (10.1) Cancer 104 (27.2) 85 (21.4) Pre-existing steroid use 86 (22.5) 82 (20.7) Recent surgery 132 (34.6) 151 (38.0) Time from eligibility to infusion, hrs 11.5 ± 9.4 11.9 ± 8.9 Values are n (%) or mean ± SD, as appropriate
Baseline severity of illness Norepinephrine (n=382) Vasopressin (n=396) APACHE II 27.1 ± 6.9 27.0 ± 7.7 New organ dysfunction Cardiovascular 382 (100) 397 (100) Respiratory 341 (89.3) 342 (86.1) Renal 258 (67.5) 264 (66.5) Coagulation 84 (22.0) 118 (29.7) Neurologic 89 (23.3) 101 (25.4) Number of new organ dysfunctions 2.5 ± 1.1 2.6 ± 1.1 Lactate, mmol/l 3.5 ± 3.0 3.5 ± 3.2 Mean arterial pressure, mmhg 73.2 ± 9.9 72.3 ± 9.1 Norepinephrine, µg/min 20.7 ± 18.1 20.7 ± 22.1 (n=329) (n=344) Values are n (%) or mean ± SD, as appropriate
Rates and risks of death at day 28 Norepinephrine Vasopressin p Absolute risk reduction % (95% CI) Relative risk of death (95% CI) All 150/382 39.3% 140/396 35.4% 0.26 3.91 (-2.88 to 10.71) 0.90 (0.75 to 1.08) More severe subgroup 85/200 42.5% 88/200 44.0% 0.76-1.50 (-11.21 to 8.21) 1.04 (0.83 to 1.3) Less severe subgroup 65/182 35.7% 52/196 26.5% 0.05 9.18 (-0.13 to 18.49) 0.74 (0.55 to 1.01)