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Catecholamines: resuscitation or resurrection?
UNSW
John MyburghMBBCh PhD FCICM FAICD
The George Institute for Global Health St George Clinical School, University of New South Wales
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What is knowledge?
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Hein: Cell Tissue Research 2006
Neurohormonal vasoregulation
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Neurohormonal vasoregulation
Sadowska : J Physiol Pharm 2006
VP
NoradrenalineAdrenaline
Cortisol
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Mean arterial pressure
Cardiac output Right atrialpressure
Mean systemic pressure
Perfusion pressure
Unstressedvolume
Stressedvolume
Venous return
Arteriolar tone
Haemodynamics
15mmHg15mmHg
5mmHg
60mmHg
60mmHg
Guyton 1953
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Barcroft: Lancet 1949
n=7
Human studies
Goldenberg : Arch Int Med 1950
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Steele: Curr Opin Crit Care 2000
What the textbooks say …….
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What is “best” evidence?
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Synthetic catecholamines
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OH
CH2CH2NHCHCH2CH2
OH
CH3
OH . HCl
CHOHCH2 NHCH
OHOH
CH3
CH3
OH
CH2CH2NHCH2CH2CH2CH2CH2CH2NHCH2CH2
OH
. 2HCl
Isoprenaline
Dobutamine
Dopexamine
CH2CH2NH2
OHOH
HCOHCH2NHCH3
OHOH
Dopamine Adrenaline
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Cost
Dose Cost (AUD)
Adrenaline 6 mg 11 Noradrenaline 6mg 20
Dopamine 400mg 37
Dobutamine 500mg 119
Dopexamine 50mg 390
Isoprenaline 6mg 410
Milrinone 8mg 500
Levosimendan 12.5mg 1420
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Dobutamine and sepsis n Dose
(µg/kg/min)Endpoint Mortality Grade
Hayes 1994 100 5-200 DO2, VO2 34 v 54* III
Yu 1993 67 5-20 DO2, VO2 34 v 44 III
Tuschmidt 1992 51 5 + DO2, VO2 59 v 72% IV
Shoemaker 1986 10 5 – 10 + DO2, VO2 Not stated IV
Shoemaker 1989 25 2.5-10 DO2, VO2 Not stated IV
Shoemaker 1991 12 2.5- 10 DO2, VO2 Not stated IV
Tell 1987 6 2.5-20 SBP, UO 50% IV
Krachman 1994 12 5 + DO2, VO2 100% IV
Lejus 1991 10 5-15 PAOP, MAP 50% IV
Jardin 1981 19 3.6-28 DO2, VO2 Not stated IV
Vincent 1990 84 5 DO2, VO2 Not stated IV
(11) 396
Rudis CCM 1996
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Maximising DO2 : the evidence
Achieving “supranormal” DO2 and VO2 does not affect mortality
May benefit preoperatively
Responders ? index of reserve
-0.1
-1 1 10 100
Shoemaker 1988
Tuschmidt 1992
Yu 1993
Boyd 1993
Hayes 1994
Yu 1994
Gattinoni 1995
Combined Relative Risk 0.86 (0.62 - 1.2)
Heyland CCM 1996
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Catecholamines and septic shock
n Drug
Dose Endpoint Grade
Duranteau 1999 12 Adr ± Nor MAP >80 pHi III
Joly 1999 14 Dob 7.5 µg/kg/min pHi, CO IV
Levy 1999 24 Dob ± Dpx 5 / 1 µg/kg/min pHi, CO III
Reinelt 1999 6 Phenyleph MAP > 60 PHi IV
Martin 1999 26 Dob ± Nor MAP >75 CO, SVR, MAP III
Rhodes 1999 36 Dob 10 µg/kg/min Mortality pred IV
Creteur 1999 36 Dob 5 + 10 µg/kg/min pHi, CO III
Briegel 2000 40 Dob/Nor/Adr Shock resolution Requirement III
(8) 194
Steele: Curr Opin Crit Care 2000
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“Goal Directed Therapy”
Rivers: NEJM 2001
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Human trials
No conclusive evidenceDescriptive, observational, underpowered
Variable dose ranges, selection criteriaVariable endpointsVariable mortality
“Oxygen delivery” focusCommercial influence
Publication bias
Misapplication of biological principles
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Evidence-based guidelines
Dellinger: CCM 2004, 2008
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“Inotropes”
Dellinger: ICM 2008
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Biologically plausible, but unrelated to the evidence presented Publication bias
Intervention biasRegional bias
Adrenaline gets a “bad” wrapConcerns about dopamine.
“Vasopressors”
Dellinger: ICM 2008
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Noradrenaline + Dobutamine
Adrenaline
pHi
Hours
Adrenaline “toxicity”?
Splanchnic ischaemia
Levy: ICM 1997
n=23Malaria n=13Severe sepsis n=10
Cha
nge
in la
ctat
e (
mm
ol/L
)
Dopamine
Adrenaline
Lactic acidosis
Day: Lancet 1996
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What is “best” evidence?
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Mullner: Cochrane Collaboration 2007
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Systematic review: 2007
Intervention n RR 95%CI
ADR v NOR 0 0 0
NOR + DOB vs ADR 52 0.98 0.57 to 1.67
NOR vs DOP 62 0.88 0.57 to 1.36
Mullner: Cochrane Collaboration 2007
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What is “best” evidence?
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Myburgh: ICM 2008
Relative effectiveness blinded MC RCTn=280
Primary outcome: Clinician-prescribed target MAP > 24 hours
2004-2006
All patients
Severe Sepsis
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Myburgh: ICM 2008
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Annane: Lancet 2007
Blinded MC RCTn=330
Primary outcome: D28 mortality
1999-2004
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No difference in secondary outcome measures:Haemodynamic endpointsDose of drug(s)Organ failure resolutionICU LOS
Epinephrine associated with lactic acidosis
Annane: Lancet 2007
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De Backer: NEJM 2010
Blinded M RCTn=1679
Primary outcome: 28d mortality15% RRR from 40% mortality
2003-2007
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De Backer: NEJM 2010
Adverse events
A priori subgroups
Septic 62.1%Cardiogenic 16.7%
Hypovolaemic 15.6%
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Blinded MC RCTn=779
Primary outcome: 28d mortality10% ARR from 60% mortality
Vasopressin (max 0.03 u/min) vs noradrenaline (5-15µg/min)
Russell: NEJM 2008
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Russell: CCM 2009
Norepinephrine 131/293 (44.7%)Vasopressin 106/295 (35.9%)
P=0.03
Norepinephrine 19/89 (21.3%)Vasopressin 34/101 (33.7%)
P=0.06
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Systematic review: 2011
Havel: Cochrane Collaboration 2011
Additional 17 studies identified: total 23N=3212, 1629 mortality outcomes
Sensitivity analysis of 10 studies with low risk of bias
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On current high quality evidence:
Noradrenaline is the probably vasoactive drug of choice.Adrenaline is equieffective, with transient metabolic effects
Dopamine associated with adverse effects, particularly arrhythmia
Dobutamine has no demonstrable benefit
Vasopressin may have catecholamine-sparing effects, but no clinical benefit in septic shock
Hydrocortisone …… unproven
Dellinger: ICM 2012
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Non-catecholamine “inodilators”
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The SURVIVE Study
Mebazza: JAMA 2007
Blinded MC RCTn=1320
Primary outcome: 180d mortalitySecondary outcome: δBNP
Levosimendan (12µg/kg + 0.1 µg/kg/min) x 2 h vs dobutamine (5-40 µg/kg/min)
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Conclusions
An body of higher-quality, investigator-initiated trials of catecholamines on patient-centred outcomes in critically ill patients is finally emerging.
The is no evidence of superiority of any of the currently used catecholamines, used solely or in combination, over noradrenaline or adrenaline on resolution of shock, development or resolution of organ failure or mortality.
Catecholamine-sparing strategies with vasopressin and corticosteroids have an undefined, unproven role.
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Interpretation
The role of catecholamines for the treatment of shock is evolving from “rescue” therapy to “neurohormonal augmentation” therapy in vulnerable patients.
It is biologically implausible that synthetic catecholamine compounds will produce improvements in patient-centred outcomes.
Current evidence-based guidelines and bundles will need revision to accord with global considerations outside the imperative of industry.
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