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