vasopressors in septic shock - critical care canada...vasoactive therapy • use of vasoactive drugs...
TRANSCRIPT
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)