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A STUDY TO EVALUATE THE INCIDENCE OF OCCULT
ADRENAL INSUFFICIENCY IN PATIENTS OF SEPTIC
SHOCK IN CARDIAC ICU
JEETENDRA SHARMA,S BEHRA,Y MEHTA, S KUMAR,N TREHAN
Dr Jeetendra Sharma
MD, IDCC, IFCC(Critical Care Medicine)
PGCC(Cardiology), PGCC(Diabetes)
Consultant Critical Care
Department of Critical Care Medicine
MeDanta The Medicity, Gurgaon
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Introduction
Severe illness and stress activates the
hypothalamic pituitary adrenal axis and release
of ACTH
This activation is essential component of
general adaptation to illness and stress
Even minor degrees of adrenal insufficiency
increase the mortality of critically ill
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Preserved adrenal function - Basal serum
cortisol level 20 g/dl and rise in concentration
of cortisol 9 g/dl after ACTH stimulation
Adrenal insufficiency - Basal serum cortisol
level < 20 g/dl
Functional hypoadrenalism - Basal serumcortisol level 20 g/dl and rise in concentration
of cortisol < 9 g/dl after ACTH stimulation
Introduction
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Objective To determine the incidence of
occult adrenal insufficiency in the patients of
septic shock in cardiac ICU
Design Prospective observational study
Setting Tertiary cardiac care centre
Subject - 25 cardiac ICU patients
Method
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INCLUSION CRITERIA
1. Age > 17 yrs
2. Patients fulfill criteria of sepsis
( According to American college of chest
physician / society of critical care medicine
consensus conference / report-1992)
3. Patients require inotropes to maintain perfusion
pressure
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EXCLUSION CRITERIA
1. Patients age 17 years
2. Preexisting adrenal disease
3. Adrenalectomy
4. Known malignancy
5. Tuberculosis (might have involved adrenal gland)
6. Burn
7. Hemorrhagic shock
8. Received steroids within 3 months before
admission
9. Acute MI
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Method
25 patients of septic shock (community/hospital
acquired)
Demographic and clinical data were collected
Basal corisol levels at admission (T0)were measured
using VIDAS KIT
An intravenous injection of 250g of ACTH
(Synacthen) was given and another sample for cortisol
estimation taken after 60 minutes of ACTH stimulation(T60)
After Second sample Hydrocortisone 50 mg Q6H was
started
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Results
All results have been reported as mean and the standard
deviation
Analysis of variance (ANOVA) have been used for
Tukeys method of multiple comparisons
The KruskalWallis test and the Wilcoxon
nonparametric test have been used to identify differencesin the rank of data between 3 groups.
Statistical significance was defined by p value < 0.05
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Total Patients = 25
1213
Male
Female
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Vital Signs
Adrenal Function Status n Temperature Heart
Rate
Blood Pressure
Systolic Diastolic MAP
Adrenal Insufficiency 3 98.71.2 8631 7315 4811 5812
Functional Hypoadrenalism 8 97.60.7 10121 8311 6010 6910
Preserved Adrenal Function 1499.72.3 10428 7915 5311 6211
p-Value 0.09 0.298 0.585 0.341 0.45
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Baseline Laboratory test
SN Laboratory Test Adrenal Function Status p - value
AI FH PAF
1 Sodium 132 3 132 11 136 7 0.432
2 Potassium 4.1 1.7 4.5 1.96 4.1 1.2 0.975
3 Glucose 136 64 151 91 157 113 0.929
4 BUN 70 57 78 45 102 103 0.636
5 Creatinine 2.6 1.8 1.9 1.3 3.3 3.8 0.6296 Hemoglobin 10.9 3.9 9.1 2.2 10.7 2.6 0.441
7 WBC Count 18.8 3.3 12.8 7.4 20.4 15 0.302
8 Polymorphs 92.3 75.8 20 78.9 13.4 0.078
9 Platelets 1.3 0.6 0.94 0.8 1.3 0.6 0.377
10 ESR 55 45 63 60 50 46 0.955
11 Total Bilirubin 1.8 2 2.6 2.9 1.3 1.1 0.89
12 SGOT 37.7 7.4 203 260 407 1176 0.053
13 SGPT 38 15.3 105.5 189 162 43.2 0.190
14 Prothrombin 17.4 4.1 18.8 5.2 18.5 5.2 0.964
15 INR 1.4 3 5 10 2.8 4.6 0.743
16 APTT 3.9 10.2 41.4 7 37.4 17.7 0.452
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Serum Cortisol Concentration and
ACTH stimulation Test
Serum Cortisol (g/dL) SDAdrenal Functional
Status
n (%) Baseline (T0) 60 min (T60) Delta
Adrenal
Insufficiency
3 (12%) 11.577.3 17.645.93 6.077.32
Functional
hypoadrenalism
8 (32%) 61.98 30.63 65.2528.28 3.262.65
Preserved adrenalfunction
14 (56%) 51.84 20.56 68.9423.82 17.112.5
p-Value ( FAH/PAF) 0.739 0.344 < 0.001
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Incidence of Adrenal Dysfunction
AI
12%
FHA
32%
PAF
56%
3
14 8
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Serum cortisol concentration and
ACTH stimulation test
11.57
17.64
6.07
61.98
65.25
3.26
51.84
68.94
17.1
0
10
20
30
40
50
60
70
AI FHA PAF
Baseline
60 min
delta
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Adrenaline dysfunction Vs Mortality
Adrenal Function Status n No. of Surviving to Discharge
Expired Discharge
Adrenal Insufficiency 3 3 (100%) 0 (0%)
Functional Hypoadrenalism 8 2 (25%) 6 (75%)
Preserved Adrenal Function 14 7 (50%) 7 (50%)
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Conclusion
In present study the incidence of adrenalinsufficiency was 44% (includes 32 % occult
adrenal insufficiency)
Mean serum cortisol values did not differ
significantly at baseline (p=0.739) and at 60
minutes (p=0.344). However delta maximumdiffered significantly (p
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Conclusion
Sepsis can cause occult adrenal insufficiency in thepresence of normal or even elevated serum cortisol
Overall mortality was 48 % in our study group and,
statistically there was no difference in mortality
among adrenal insufficiency, functional
hypoadrenalism and preserved adrenal function
group. However, the mortality was 100% in the
adrenal insufficiency group.
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References SCCM/ESICM/ACCP/ATS/SIS, International sepsis definition
conference. Critical care medicine 31;4:2003
Rivers et al: Early Goal directed therapy in the treatment of
severe sepsis and septic shock, NEJM 2001,345;19:1368-1377
Annane D, et al. Effect of treatment with low doses ofhydrocortisone and fludrocortisone on mortality in patients
with septic shock. JAMA 2002;288:862-71
Charles L. et al: Hydrocortisone Therapy for Patients with
Septic Shock-CORTICUS Study Group. N EJ M
2008;358:111-24.
Dellinger RP. Cardiovascular management of septic
shock. Crit Care Med 2003; 31:946-55.
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ResearchQuest for knowledge through
systematic and scientific wayon a specific topic, aimed at
discovery and interpretation ofnew knowledge
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RCT
Post marketing survey
Case Series
Expert Opinion
CME
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Study/Trial
1. Who wrote the paper?
2. Do they or the institution have a proven
academic record?
3. Is the paper interesting and relevant?
Title
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Crit Care Med 2009; 37:811818
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Study/Trial - Introduction
1. Did the study introduction address the
relevant points?
2. Was the study original?
3. Were the aims clearly stated?
Link Between Past & Present
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Hypothesis
.our hypothesis was that there is a
significant interaction of vasopressinand corticosteroid treatment in septic
shock
Crit Care Med
2009; 37:811
818
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Study/Trial - Methods
Was an appropriate group of subjects studies?
How were subjects recruited?
What were the inclusion criteria?
What were the exclusion criteria?
Was the sample size justified?
Was a power calculation performed?
Was the study design appropriate?
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Study Design
Post hoc substudy of a multicenter randomizedblinded controlled trial
Post hoc analysis of VAST
C h t St d
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Cohort Study
Large population of patients who have a specific condition or
receive a particular treatment over time Compared with another group that has not been affected
Observational
Not as reliable as RCTs, since the two groups may differ in ways
other than in the variable under study.
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Case Control Study
Patients who already have a specific condition are compared
with people who do not.
They often rely on medical records and patient recall
Statistical relationship does not mean than one factor
necessarily caused the other
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RCT
2 groups, one treatment group and one control group.
Patients are randomly assigned to all groups.
Assigning patients at random reduces the risk of bias
Helps creation of groups similar in their risk of the events
Balances the groups for prognostic factors
Increases the probability that differences between the groups is
due to the treatment
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Type of
QuestionSuggested best type of Study
Therapy RCT > cohort > case control > case series
Diagnosisprospective, blind comparison to a gold
standard
Etiology/Harm RCT > cohort > case control > case series
Prognosis cohort study > case control > case series
Prevention RCT > cohort study > case control > caseseries
Clinical Examprospective, blind comparison to gold
standard
Cost economic analysis
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Study/Trial - Methods
Drug treatment - randomised controlled trial
Prognosis - cohort study
Causation - case - control study
Were the study groups comparable?
Demographics, baseline criteria etc
Was the assignment of patients to treatments
randomised?
How was the randomisation performed
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Study/Trial - Methods
Were the groups treated equally other than for the
experimental intervention?
Were the outcome measures stated and relevant?
Were measurements valid and reliable?
Were patients and healthcare workers 'blinded' to the
treatment given?
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Errors
Sampling error
Measurement error
Chance error
Frame error
Non - Sampling error
Response error
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Surrogate End Point
Variable relatively easy, predicts rare/distant outcome Not itself a direct measure of harm/benefit
Reduce sample size, duration, cost
Used when primary outcome invasive/unethical
Example- con.-t curve, MIC, microalbuminuria
Ideal- reliable, re- producible, clinically available, easily
quantifiable, affordable, exhibit dose-response curve, true
predictor of dis., sensitivity, specificity, PPV, NPV
Drawback
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Study/Trial - Methods
Were all patients entered into the study properly
accounted for?
Is there any missing data?
Were side effects and adverse outcome documented?
Was the duration and completeness of follow up
appropriate?
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Intent To Treat Basis
All data on patients originally allocated to the
different arms of the study, including those
withdrew before the trial finished should be
analyzed in there respective groups
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Study/Trial - Statistics
1. Were the statistical methods described?
2. Does the tests chosen reflect the type of data
3. Parametric versus parametric tests
4. Were analyses performed on an intention to treat
basis?
5. Was systematic bias avoided or minimized?
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Errors - Outcome
Type I ()Rejecting the null hypothesis whenit is true
Type II ()Accepting the null hypothesiswhen it is false
Type III ()Correctly rejecting null hypothesisfor wrong reason
Type IVThe incorrect interpretation of
correctly rejected hypothesis
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Errors
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Example
Out of 10 smokers 9 have Ca lung
Out of 10 smokers 5 have Ca lung
Out of 10 smokers 1 has Ca lung
Avoid error; P value
Avoid error; Power
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Power
It is the probability that the test reject a false
null hypothesis (will not make type II error)
As power increases, chance of type II errordecreases
Power = 1-
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CORTICUS TRIAL
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Results
mortality at 28 days
Hydrocortisone group 86 of 251 (34.3%)
Placebo
78/248 (31.5%)
P = 0.51
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Study Population
Normal Distribution - Parametric
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Study Population
Non - normal Distribution (Skewed) -
Nonparametric
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Commonly used Statistic tests
Parametric Nonparametric Example
Unpaired t test Mann-Whitney U-test Girls Ht V/s Boys Ht
Paired t test Wilcoxon matched paired
test
Wt of infant before/after feed
F test Kruskall-Wallis test B sugar1,2or3 h after meal
- 2 test Acceptance in to medical
school more likely if born in
UK
Pearsons Correlation
coefficient (r)
Spearmans rank
correlation coefficient ()
HbA1C related to TG level in
DM
2 test For any association b/w 2 categorical variables ; NOTindicate what the association
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Results
1. How large was the treatment effect?
2. How precise was the estimate of the
treatment effect?
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