the acutely ill - ubc critical care medicine
TRANSCRIPT
Adrenals, antifreeze and the acutely ill
Dr David RayConsultant in Anaesthesia & Critical Care
Royal InfirmaryEdinburgh
… the etomidate debate …
“… safest induction agent for use in the critically ill …”
“… safest induction agent for use in the critically ill …”
“… useful agent with known complication which can be dealt with …”
“… safest induction agent for use in the critically ill …”
“… useful agent with known complication which can be dealt with …”
“… etomidate is antifreeze which belongs in cars and not patients …”
Objectives
• Discuss the pros and cons of etomidate• Examine the evidence• Review the experience from our ICU
Etomidate pros & cons
Pros
• CVS stability• Prolongs fit duration
in ECT
Cons
• Nausea & vomiting• Pain on injection• Adrenal suppression
Etomidate and BPDose Mean % decrease
in systolic BPEtomidate 0.3 mg/kg 5
Thiopental 5 mg/kg 10
Propofol 2.5 mg/kg 17
McCollum & Dundee Br J Anaesth 1986
Effect of induction agents on BP(ASA 3+ patients)
75
80
85
90
95
100
105
Pre 5 min 10 min 15 min
Time
MA
P (m
mH
g)
EtomidateThiopentalPropofol
Benson et al J Clin Monit 2000; 16: 183-190
Adrenal suppression
Adrenal suppression
Etomidate
Adrenal suppression
Etomidate
How did it all start?
ICU mortality; 1969 - 1980 19 - 29%1981 - 82 47%
Only change was introduction of etomidateinfusion for sedation
ICU mortality; 1969 - 1980 19 - 29%1981 - 82 47%
Only change was introduction of etomidateinfusion for sedation
n Mortality
Morphine +/or benzodiazepine 50 28 %
Morphine + etomidate 27 77 %
ICU mortality; 1969 - 1980 19 - 29%1981 - 82 47%
Only change was introduction of etomidateinfusion for sedation
n Mortality
Morphine +/or benzodiazepine 50 28 %
Morphine + etomidate 27 77 %
Morphine +/or benzodiazepine 12 25 %
Identifying adrenal insufficiency
• Basal cortisol <200 nmol/l• Short synacthen test (250µg vs 1 µg
ACTH)• Peak cortisol level or ! max at 30/60
min• Relative adrenal insufficiency exists if:
– Basal cortisol <400 nmol/l– ! max cortisol <250nmol/l
Etomidate-induced adrenal suppressionResults with:• Continuous infusion 33 mg/h• Induction dose 0.3 mg/kg• Subanaesthetic dose 0.04 mg/kg
Duration:• Varies from 12 – 72 h
ICU physicians should abandon the use of etomidate!
BJA 2006; 97: 116-7
Intensive Care Medicine 2005; 31: 325-6
Anaesthesia 2005; 60: 737-40
ED etomidate use
31 4356 71
88 119
7511
129125
115 12996 121
15842
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
1999 2000 2001 2002 2003 2004 2005 2006
Year
Not Etomidate
Etomidate
Dunn et al 2006
Where’s the evidence?
Effect of Treatment With Low Doses of Hydrocortisone and Fludrocortisone on Mortality in Patients With Septic ShockAnnane, Djillali MD, PhD: Sébille, Veronique PhD; Charpentier, Claire MD; Bollaert, Pierre-EdouardMD, PhD; François, Bruno MD; Korach, Jean-Michel MD; Capellier, Gilles MD, PhD; Cohen, Yves MD PhD; Azoulay, Elie MD; Troché, Gilles MD; Chaumet-Riffaut, Philippe MD; Bellissant, Eric Md, PhD
Effect of Treatment With Low Doses of Hydrocortisone and Fludrocortisone on Mortality in Patients With Septic ShockAnnane, Djillali MD, PhD: Sébille, Veronique PhD; Charpentier, Claire MD; Bollaert, Pierre-EdouardMD, PhD; François, Bruno MD; Korach, Jean-Michel MD; Capellier, Gilles MD, PhD; Cohen, Yves MD PhD; Azoulay, Elie MD; Troché, Gilles MD; Chaumet-Riffaut, Philippe MD; Bellissant, Eric Md, PhD
• 77 patients received etomidate• 94% did not respond to short synacthen
test• blockade of steroid synthesis lasted 72hr• greater fluid & vasopressor requirement
in 24 h after induction• 28-day mortality was 76%, reduced to
56% if steroid supplementation given
But…..
• 70% of 177 etomidate-free patients were non-responders
• 77% of all 299 patients were non-responders• fluid difference was 2.5 v 1.9 litre (P=0.049)• vasopressor was dopamine in >90% of
patients (mean dose 11µg/kg/min)• protocol was altered during study to exclude
patients given etomidate• authors acknowledged many other causes of
adrenal suppression during sepsis
• 62 patients, ventilated >24 h• ACTH test 24 h after tracheal intubation
• Etomidate a risk factor for blunted response to ACTH (OR 12.2; 95% CI 2.99 – 49.74)
Responders n=35 Non-responders n=27Etomidate (n) 9 19Mortality (%) 31 70
But …….
• only 21% received hydrocortisone (nonresponders 33%)
• non-responders were sicker at entry SAPS II score 60 vs 49
• decision to use etomidate was based on CVS instability
• 477 patients with severe sepsis and ACTH test• 237 were given etomidate
Etomidate use predicted death• univariate OR 1.53 (95% CI 1.06 - 2.26)• multivariate OR 1.82 (95% CI 0.52 - 6.36)
Critical Care Medicine 2007; 35: 1012-8
But….
• 77% of patients came from databases of previously published studies
• no details about whether patients given etomidatewere sicker
• no details about incidence of adrenal suppression with etomidate
• increased risk of death with etomidate OR only just significant
OR for vasopressor 38.52 (95% CI 20.69-71.73)
• reference used to support increased mortality with etomidate was for etomidate by infusion
Evidence supporting etomidate
Evidence supporting etomidate
• Mullen M, Ellis T, Marcelin J et alAcad Emerg Med 2007; 14: S187
• Dmello D, Taylor S, O’Brien J, Veremakis CCrit Care Med 2006; 34: A110
• Young SP, Newman LAnaesthesia on-line correspondence 12 Aug 2005
Mullen M et alAcad Emerg Med 2007• 35 intubated patients with severe sepsis• 25 received etomidate
Etomidate Non etomidate
P value
Adrenal insufficiency
40 % 20 % 0.62
Vasopressorduration (h)
67 37 0.33
Ventilator days
14.6 8.0 0.21
Mortality (%) 36 70 0.13
Dmello D et alCritical Care Medicine 2006• 224 patients with severe sepsis / septic
shock• 113 received etomidate• No difference in mortality
RR 0.88 (95% CI 0.64-1.21; P=0.43)• No increase in vasopressor use in
etomidate group RR 1.18 (95% CI 0.9-1.54; P=0.23)
Young SP, McAuley DFAnaesthesia 200559 patients with septic shock; all had
ACTH testEtomidate
n=45Propofol
n=14Basal cortisol 414 405
! max cortisol 45 116
ICU mortality 36 % 36 %
Summary of evidence
• Potent inhibitor of adrenal steroidogenesis via 11 ß-hydroxylase
• Increased mortality in ICU when given by infusion for sedation
• More recent suggestions that single bolus dose may be harmful
• Evidence of detrimental clinical effect is not strong
Primary objective
Is there a relationship between induction agent used, the need for vasopressor support, steroid administration and outcome?
Methods
• All patients admitted to ICU 1.4.2003 – 31.8.2006
• Wardwatcher™ details septic shock (any diagnosis)
• Retrospective case note review• Protocol administered IV hydrocortisone
for vasopressor-dependent shock
Measurements
• Demographic data• Apache II, modified SOFA scores• Induction agent used• Vasopressor support• Steroid supplementation• ICU & hospital outcome • Any cardiovascular deterioration at induction
3554 patients admitted to ICU
242 patients with septic shock
208 patients intubated
192 records reviewed
159 records analysed
16 records missing
10 intubated in other hospital
13 intubation data incomplete
10 did not receive vasopressor
Patient detailsMale:female 90:69Age (yr) 65 (14)Apache II score 27 (11 - 53)Predicted mortality 67% (11 - 99)ICU mortality 60%Hospital mortality 65%Source of sepsis
Pulmonary 51 (32%)Gastrointestinal 63 (40%)Renal 5 (3%)Unspecified 40 (25%)
Which induction agent?Agent Number
Etomidate 74
Propofol 25
Thiopental 26
Midazolam 14
Ketamine 1
Fentanyl 1
Inhalational 2
Nil 16
Severity of illness & outcomeAge (yr)
Apache II score
SOFA score
Predicted mortality
(%)
Hospital mortality
(%)
Crude SMR
Etomidate 65 28 10 69 69 1.0
Propofol 63 24 10 57 56 0.98
Thiopental 66 24 8 52 46 0.88
Other 66 29 11 71 67 0.94
No agent 66 30 10 75 81 1.08
Effect on mortality
Effect on vasopressor therapy
Effect on steroid therapy
% patients 53 56 65 67 56
given steroids
Steroid supplementation
ICU mortality (%)
No steroid 58
Steroid 74
74 patients received etomidate
43 received steroid
Steroid supplementation
ICU mortality (%)
Annanemortality (%)
No steroid 58 76
Steroid 74 56
74 patients received etomidate
43 received steroid
Summary from our study
Etomidate appears to:• have no effect on outcome• have no effect on vasopressor therapy• have no effect on steroid therapy• cause less cardiovascular depression at
inductionRay DC, McKeown DW Critical Care 2007; 11: R56
Overall conclusions
• etomidate causes less cardiovascular depression
• etomidate causes adrenal suppression• no clear evidence for this causing
deleterious clinical effect• benefit of steroid replacement unclear