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)