Keith R. Walley, MD St. Paul’s Hospital University of British Columbia Vancouver, Canada Vasopressors in Septic Shock
Keith R. Walley, MDSt. Paul’s Hospital
University of British ColumbiaVancouver, Canada
Vasopressors in Septic Shock
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-DirectedTherapy
Rivers E et alN Engl J Med345:1368-77, 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)
Mortality NE Epi 28 d 26.1% 22.5% p=0.48 90 d 34.3% 30.4% p=0.49
Annane.CATSLancet. 2007
Myburgh. CAT.ICM. 2008(n=280)
Norepinephrine vs. Epinephrine
Norepinephrine vs. Dopamine De Backer. NEJM. 2010.
Norepinephrine vs. DopamineDe 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
Russell. VASST. NEJM. 2010
Norepinephrine vs.Vasopressin (+ open label NE)
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 stratum5 µg/min < NE < 15 µg/min
Log-rank statistic
p = 0.05 day 28
p = 0.03 day 90
Log-rank statistic
p = 0.77 day 28
p = 0.92 day 90
High severity of shock stratumNE > 15 µg/min
Plasma vasopressin levels(n = 107)
Vasopressin
Norepinephrine
Off Vasopressin
Norepinephrine-sparing effect oflow-dose vasopressin (0.03 U/min)
Norepinephrine
Vasopressin+NE
Days
Nor
epin
ephr
ine µg
/min
Heart rate: norepinephrine-sparing versus direct vasopressin effect
Norepinephrine
Vasopressin+NE
Days
Hea
rt R
ate
Serious adverse eventsNorepinephrine
(n=382)Vasopressin
(n=397)p
Myocardial infarction / ischemia
7 (1.8) 8 (2.0) 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
Vasopressin
Norepinephrine
P=0.009
Relationship to renal function – RIFLE Risk Category (Cr 1.5X)
Gordon AC et al. Intensive Care Med. 36:83-91, 2010.
Vasopressin
Norepinephrine
P=0.009
Relationship to renal function – RIFLE Risk Category (Cr 1.5X)
Gordon AC et al. Intensive Care Med. 36:83-91, 2010.
Post-hoc
• 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)
Vasopressin effect in renal“Risk” Category
Microvascular renal effectsConstriction of afferent arteriole:
Edwards RM et al. Am J Physiol. 26: F274-F278, 1989
Microvascular renal effectsConstriction 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 InteractionSeptic shock survival vasopressin plus steroids 80.9% vs vasopressin without steroids 47.6%, P = 0.02.
Bauer SR et al. J Crit Care. 23:500-506, 2008
Retrospective
Baseline differencesControls 4 years olderSteroids more CRRT
Sur
viva
lS
urvi
val
Days
InteractionP=0.008
Vasopressin
Norepinephrine
Norepinephrine
Vasopressin
VasopressinX
SteroidInteraction
Russell JA, Walley KR, et al. Crit Care Med. 37:811-8, 2009.
Vasopressin levels – steroid interaction
Corticosteroids
No corticosteroids
Vasopressin
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:– SCVo2
– Lactate– Cardiac output (PAC, dye dilution, Doppler)
2
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.
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-investigatorsJim RussellJohn Boyd
DatabasesVASST Investigators and coordinators
FundingHeart & Stroke FoundationCIHRMichael Smith Foundation
© 2011 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins. 2
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
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.
Myburgh. CAT. ICM. 2008 (n=280)
NE Epi28 d 26.1% 22.5% p=0.4890 d 34.3% 30.4% p=0.49
De Backer. NEJM. 2010
Annane. CATS. Lancet. 2007
Russell. VASST. NEJM. 2010
For vasopressin tx: Steroids good for low severity, lack of steroids bad for high severity
Less Severe More SevereReceived 257/378 331/400
Steroids 68.0% 82.8%
MortalityVP 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% 0.10Steroids 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
GFR criteria Urine output criteria
Risk Increased serum creatinine x1.5 orDecreased GFR >25%
< 0.5ml/kg/h x6 hours
Injury Increased serum creatinine x2 orDecreased GFR >50%
< 0.5ml/kg/h x12 hours
Loss Increased serum creatinine x3 orDecreased GFR >75% orIncreased serum creatinine ≥44µmol/l if baseline ≥350µmol/l
< 0.3ml/kg/h x24 hours orAnuria x12 hours
Failure Persistent acute renal failure = complete loss of renal function for > 4 weeks
End stage End-Stage Kidney Disease (>3 months)
Relationship to renal function – RIFLE Criteria
Baseline demographicsNorepinephrine
(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-morbiditiesIschemic 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 ± 8.9Values are n (%) or mean ± SD, as appropriate
Baseline severity of illnessNorepinephrine
(n=382)Vasopressin
(n=396)
APACHE II 27.1 ± 6.9 27.0 ± 7.7
New organ dysfunctionCardiovascular 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(n=329)
20.7 ± 22.1(n=344)Values are n (%) or mean ± SD, as appropriate
Rates and risks of death at day 28
Norepinephrine Vasopressin pAbsolute risk
reduction% (95% CI)
Relative risk of death(95% CI)
All150/382 39.3%
140/39635.4%
0.26 3.91 (-2.88 to 10.71)
0.90(0.75 to 1.08)
More severe
subgroup
85/20042.5%
88/20044.0%
0.76 -1.50(-11.21 to 8.21)
1.04(0.83 to 1.3)
Less severe
subgroup
65/18235.7%
52/19626.5%
0.05 9.18(-0.13 to 18.49)
0.74(0.55 to 1.01)