A Study to Evaluate the Incidence of Occult

8/22/2019 A Study to Evaluate the Incidence of Occult

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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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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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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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BIAS - ERROR


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Target population (Baseline Sate)

Allocation

Intervention group Control group

Exposed to

Intervention

Not Exposed to

Intervention

Follow up Follow up

Outcome Outcome

Selection Bias - Systematicdifferences in the comparison

group attributable to incomplete

randomization

Performance Bias- Systematicdifferences in the care provided

apart from the intervention group

Exclusion Bias - Systematicdifferences in withdrawals from trial

Detection Bias - Systematicdifferences in outcome assessment


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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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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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Errors

False Alarm

Missed


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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

S d P l i


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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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Confidence Intervals & Significance Testing

If the 95% CI for the (RR)does not

include 1, thenthe 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


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Expression of Result

Express the effect of intervention in terms of thelikely 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


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Expressing the results of validation study for

diagnostic or screening test

Result of gold standard test

Disease positive

a + c

Disease Negative

b + d

Result of

screening

test

Test positive

a + b

True positive

a

False positive

b

Test negativec + d

False negativec

True negatived


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Sensitivity - True Positive rate; a/a+c

SpecificityTrue Negative rate; d/b+d

Positive Predicted Value- Post test probability of positive test; a/a+b

Negative Predictive valueIndicates the post test probability of

negative test; d/c+d

Accuracy- What proportional of all tests have given the correctresult; 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, thecondition?; Sensitivity/(1- specificity)

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


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Discussion

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?


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Discussion

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?

DISCOVERY / RESEARCH


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DISCOVERY / RESEARCH


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