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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

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

Preserved adrenal function - Basal serum

cortisol level 20 g/dl and rise in concentration

of cortisol 9 g/dl after ACTH stimulation Adrenal insufficiency level < 20 g/dl Functional hypoadrenalism Basal serum Basal serum cortisol

cortisol level 20 g/dl and rise in concentration

of cortisol < 9 g/dl after ACTH stimulation

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

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

Patients age 17 years Pre existing adrenal disease Adrenalectomy Known malignancy Tuberculosis (might have involved adrenal gland) Burn Hemorrhagic shock Received steroids within 3 months before admission 9. Acute MI 1. 2. 3. 4. 5. 6. 7. 8.

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

All results have been reported as mean and the standard

Analysis of variance (ANOVA) have been used for Tukeys method of multiple comparisons The Kruskal Wallis test and the Wilcoxon nonparametric test have been used to identify differences

in the rank of data between 3 groups.

Statistical significance was defined by p value < 0.05

Total Patients = 25



Male Female

Vital Signs
Adrenal Function Status n Temperature Heart Rate Blood Pressure
Systolic Diastolic MAP

Adrenal Insufficiency Functional Hypoadrenalism Preserved Adrenal Function p-Value

3 8 14

98.71.2 97.60.7 99.72.3


8631 10121 10428


7315 8311 7915


4811 6010 5311


5812 6910 6211


Baseline Laboratory test

1 2 3 4 5 6 7 8 9

Laboratory Test
AI Sodium Potassium Glucose BUN Creatinine Hemoglobin WBC Count Polymorphs Platelets

Adrenal Function Status

FH 132 11 4.5 1.96 151 91 78 45 1.9 1.3 9.1 2.2 12.8 7.4 75.8 20 0.94 0.8 PAF 136 7 4.1 1.2 157 113 102 103 3.3 3.8 10.7 2.6 20.4 15 78.9 13.4 1.3 0.6 132 3 4.1 1.7 136 64 70 57 2.6 1.8 10.9 3.9 18.8 3.3 92.3 1.3 0.6

p - value

0.432 0.975 0.929 0.636 0.629 0.441 0.302 0.078 0.377

11 12

Total Bilirubin SGOT

55 45
1.8 2 37.7 7.4

63 60
2.6 2.9 203 260

50 46
1.3 1.1 407 1176

0.89 0.053

14 15 16

Prothrombin INR APTT

38 15.3
17.4 4.1 1.4 3 3.9 10.2

105.5 189
18.8 5.2 5 10 41.4 7

162 43.2
18.5 5.2 2.8 4.6 37.4 17.7

0.964 0.743 0.452

Serum Cortisol Concentration and ACTH stimulation Test

Serum Cortisol (g/dL) SD
Adrenal Functional Status Adrenal Insufficiency n (%) 3 (12%) Baseline (T0) 11.577.3 60 min (T60) Delta 17.645.93 6.077.32

Functional hypoadrenalism
Preserved adrenal function p-Value ( FAH/PAF)

8 (32%)
14 (56%)

61.98 30.63
51.84 20.56 0.739

65.2528.28 3.262.65
68.9423.82 17.112.5 0.344 < 0.001

Incidence of Adrenal Dysfunction

AI 12%

PAF 56%


FHA 32%

Serum cortisol concentration and ACTH stimulation test

61.98 68.94 65.25


50 40 30 20
11.57 17.64

Baseline 60 min delta

17.1 6.07

10 0 AI




Adrenaline dysfunction Vs Mortality

Adrenal Function Status

No. of Surviving to Discharge Expired Discharge 0 (0%)

Adrenal Insufficiency

3 (100%)

Functional Hypoadrenalism


2 (25%)
7 (50%)

6 (75%)
7 (50%)

Preserved Adrenal Function

In present study the incidence of adrenal

insufficiency 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 maximum

differed significantly (p<0.001) across the different

categories of adrenal functional status.

Sepsis can cause occult adrenal insufficiency in the presence 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.

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 of hydrocortisone 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.

Quest for knowledge through systematic and scientific way on a specific topic, aimed at discovery and interpretation of new knowledge


Case Series
Post marketing survey


Expert Opinion

1. Who wrote the paper?
2. Do they or the institution have a proven

academic record?
3. Is the paper interesting and relevant?


Crit Care Med 2009; 37:811818

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

.our hypothesis was that there is a significant interaction of vasopressin and corticosteroid treatment in septic shock
Crit Care Med 2009; 37:811 818

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?

Study Design
Post hoc substudy of a multicenter randomized blinded controlled trial
Post hoc analysis of VAST

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.

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


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

Type of Question Therapy Diagnosis Etiology/Harm Prognosis Prevention Clinical Exam

Suggested best type of Study RCT > cohort > case control > case series prospective, blind comparison to a gold standard RCT > cohort > case control > case series cohort study > case control > case series RCT > cohort study > case control > case series prospective, blind comparison to gold standard


economic analysis

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

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?


Target population (Baseline Sate)

Selection Bias - Systematic
differences in the comparison group attributable to incomplete randomization

Intervention group

Control group

Performance Bias - Systematic

differences in the care provided apart from the intervention group

Exposed to Intervention

Not Exposed to Intervention


Systematic differences in withdrawals from trial


Follow up Outcome

Follow up

Detection Bias -

Systematic differences in outcome assessment


Frame error

Sampling error
Chance error

Response error

Non - Sampling error

Measurement error

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


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?

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

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?

Errors - Outcome
Type I () Rejecting the null hypothesis when it is true Type II () Accepting the null hypothesis when it is false Type III () Correctly rejecting null hypothesis for wrong reason

Type IV The incorrect interpretation of correctly rejected hypothesis


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; Power Avoid error; P value



False Alarm

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 error decreases Power = 1-


mortality at 28 days
Hydrocortisone group
86 of 251 (34.3%)

78/248 (31.5%)

P = 0.51

Study Population

Normal Distribution - Parametric

Study Population

Non - normal Distribution (Skewed) Nonparametric

Commonly used Statistic tests

Unpaired t test Paired t test F test -

Mann-Whitney U-test Wilcoxon matched paired test Kruskall-Wallis test 2 test

Girls Ht V/s Boys Ht Wt of infant before/after feed B sugar1,2or3 h after meal Acceptance in to medical school more likely if born in UK HbA1C related to TG level in DM

Pearsons Correlation coefficient (r)

Spearmans rank correlation coefficient ()

2 test For any association b/w 2 categorical variables ; NOT indicate what the association

1. How large was the treatment effect?
2. How precise was the estimate of the treatment effect?

Confidence Intervals & Significance Testing

If the 95% CI for the (RR) does not include 1, then the result is significant
Correspond to p < 0.05

If the 95% CI for the RR includes 1, then the result

is not significant
Correspond to p > 0.05

Wide CI imply less reliable result; narrow CI imply a more reliable study

Expression of Result
Express the effect of intervention in terms of the likely benefit or harm which an individual pt can expect
Relative Risk (RR) = y/x

Relative Risk Reduction (RRR) = 1 y/x

Absolute Risk Reduction (ARR) = x y

Number Needed to Treat (NNT) = 1/ARR

Odds Ratio =odds of control/ odds of intervention

Expressing the results of validation study for diagnostic or screening test

Result of gold standard test
Disease positive a+c Disease Negative b+d False positive b True negative d

Result of screening test

Test positive a+b Test negative c+d

True positive a False negative c

Sensitivity - True Positive rate; a/a+c Specificity True Negative rate; d/b+d Positive Predicted Value- Post test probability of positive test; a/a+b

Negative Predictive value Indicates the post test probability of

negative test; d/c+d Accuracy- What proportional of all tests have given the correct

result; a+d/a+b+c+d
Likelihood ratio of a positive test- How much more likely is positive test to be found in a person with, as opposed to without, the

condition?; Sensitivity/(1- specificity)

Likelihood ratio of a negative test; (1- Sensitivity)/ specificity

1. Were the aims of the study fulfilled?
2. Were the sources of error discussed?

3. Are the relevant findings justified?

4. Are the conclusions of the paper justified?

5. Are likely treatment benefits worth the potential harm or costs? 6. What is the impact of the paper? 7. Can the results be generalised to other populations? 8. What do you think of the paper?