Journal presentation Dr Kiung Supervisor: Dr Shanti, Dr Tai

INTRO
Etomidate- excellent hemodynamic profile, first line induction agent in RSI for hemodynamically unstable patient  single dose blocks cortisol synthesis lasting for 48 hrs post induction dose  Higher rates of mortality and morbidity in ICU in patients admitted for trauma or septic shock

INTRO
 Moderate

dose hydrocortisone ( 200300mg/day) -overcome critical illness-related adrenal insufficiency, particularly in septic patients responding poorly to fluid resuscitation and vasopressor agents - reduces noradenaline requirement in brain dead patients

AIM
 To

investigate the effectiveness of supplementation at decreasing the proportion of vasopressordependent patients without septic shock after single dose etomidate.

METHODS
Prospective randomised controlled double blind trial July 2008- July 2010, in university hospital included 3 ICUs  Informed written consent – patient, relatives, legally authorised representatives  Patient selections: - Adult patients requiring sedation for RSI in ER or in the field (etomidate and suxamethonium) - Sedations – midazolam, propofol, sufentanyl and fentanyl

METHODS

- Excluded – - septic shock + steroid - chronic adrenal insufficiency, - pituitary dysfunction, - HIV infection, - ketoconazole or fluconazole, - previous corticotrophin stimulation test, -survival<48hrs, -5hrs post induction, -sedation with etomidate> 24hrs

- Approved by local ethics comittee

STUDY PROTOCOL
Induction time H0  Usage of etomidate is left to the discretion of physician incharge  Patients were randomly assigned in a 1:1 ratio to receive either hydrocortisone or saline from H6 to H48  Computerised randomisation, handled by statistician not involved  ICU physicians and nurses blinded

STUDY PROTOCOL
After 6 hours of induction ( completion of blood sampling for the corticotrophin test) - control group- 50mls of NS - HC group- 200mg HC diluted in 50mls saline  A bolus of 12.5 mL of the solution, containing 50 mg HC was initially injected over 30 mins at a rate of 25 mL/hr.  The solution was then continuously infused at a rate of 2.1 mL/hr until H48, unless the patient was discharged beforehand.  In total HC 200mg/day

STUDY PROTOCOL
Variables were collected on admission and at 6, 12, 24, and 48 hrs especially the cardiovascular Sequential Organ Failure Assessment (SOFA) score  MAP 65-90 by noradrenaline if required and TBI- MAP 80-90  Insulin administered to maintain glucose <10mmol/l

HORMONAL ASSAY
Adrenal function assessed using high dose corticotrophin stimulation test  Serum total cortisol and concomitant 11Bdeoxycortisol concentrations were determined at H5 and 60 mins after the IV administration of 250 mg of synthetic 1-24 adrenocorticotropic hormone  Subsequent measurements of serum total cortisol and 11B-deoxycortisol concentrations were performed at H12, H24, and H48

HORMONAL ASSAY

Etomidate-related adrenal insufficiency was defined as change in serum cortisol concentrations <250 nmol/L (9 mcg/dL) after CST associated with serum 11Bdeoxycortisol concentrations >8 nmol/L (0.28 mcg/dL)

PRIMARY OUTCOME

The primary study outcome was the course of patients with a cardiovascular SOFA score of 3 or 4, i.e., requirement of norepinephrine to treat moderate-to-severe cardiovascular failure at H6, H12, H24, and H48

SECONDARY OUTCOME
       

course of norepinephrine dose maximum serum glucose, the number of patients treated by insulin, maximum cardiovascular SOFA score during the study period. 28-day all-cause mortality, the duration of mechanical ventilation number of ICU days with norepinephrine support.

STATISTICAL ANALYSIS
Statistical analysis was performed using Stata version 11.0 (Stata Corp,College Station, TX).  Statistical significance was declared when p < .05., power 0.8  Chi sq(non parametric) and MannWhitney tests (categorical/continuous)  Patients with premature ending of the HC infusion were considered in the analysis

RESULTS

RESULTS

Higher serum cortisol concentrations at H12, H24, and H48 in the HC group compared with the control group
The accumulation of serum 11B-deoxycortisol progressively declined over time (p <.01) with no difference between the two groups Serum albumin changes similar between both groups ( p<0.01)

SOFA score
All of these patients received norepinephrine, and dobutamine was additionally administered at similar frequencies in the HC and control groups  In the HC and control groups, the proportion of patients with cardiovascular SOFA scores of 3 or 4 declined comparably over time between H6 and H48 (p <.01)

Mean Arterial Pressures

MAP comparable between both groups, with higher readings at H48 vs H6

Noradrenaline doses
Time related evolution of dose and group (p<0.01)  Lower doses required at H24 and H48 vs H6 in the HC group (p<0.01)  No differences existed regarding the doses of dobutamine between the two groups.

Secondary outcomes

No significant difference except higher maximum glucose level in HC group

DISCUSSIONS

In this study…

Concomittent assessment of levels of serum cortisol and 11B-deoxycortisol in the search for etomidate-related adrenal insufficiency. (numerous causes of arenal insufficiency in ill patients) The progressive decline in serum 11Bdeoxycortisol by 48 hrs confirms the transient blockade of cortisol synthesis post etomidate

Moderate dose Hc does not change the primary outcome Suggests that etomidate and its resulting transient adrenal derangement play no major role in the evolution of cardiovascular status.

But most patients had stabilised hemodynamics before recruitment, most brain injury- prevention of arterial hypotension prevent one major predictor of poor outcome

HC administration for < 48hrs enhances catecholamine sensitivity , therefore MAP stable independent of etomidate related adrenocortical insufficiency Explains the significant decrease in required levels of noradrenaline at H24 vs H48hrs

LIMITATIONS
Decision for etomidate use is at dicretion of ER physician, not involved in subsequent care  No ICU intubations, therefore not representative of all clinical situations req etomidate for intubations esp septic shock req vasopressors  HC given at H6 not H0 ( on induction) effect warrants further IX

A progressive inhibition of the adrenocorticotropic hormone synthesis secondary to HC infusion might be possible, explaining a decreasein serum cortisol level

CONCLUSION

Critically ill patients without septic shock did not benefit from HC administered to overcome etomidate-related adrenal insufficiency.

CONCLUSION
No major effects on hemodynamic status were found in the treated group.  These findings suggest that single- dose etomidate could be considered in critically ill patients undergoing RSI in the field or in the emergency room without major concerns about its drug induced hormonal derangement.

APPRAISAL
Was the assignment of patients to treatments randomised? Randomization was assured using a computerized random-number generator list  Were the groups similar at the start of the trial? Yes, comparable baseline characteristics 88% showed etomidate related adrenal insufficiency

Were all patients who entered the trial accounted for? – and were they analysed in the groups to which they were randomised? YES , all patients followed up till 48hrs for primary outcome. Premature ending of HC infusions – analysed (intention to treat)

Were measures objective or were the patients and clinicians kept “blind” to which treatment was being received? Yes, investigators and nurses kept blinded
 

How precise was the estimate of the treatment effect?

Applicability
Etomidate can be used in brain injury patients as the risk of arterial hypotension outweighs the benefit of not using

Adrenal suppression not as severe , HC supplementation does not alter the course of the illness

Thank you

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