Corticosteroids in critical conditions

Table of Contents
Respiratory Conditions
01
Acute Severe Asthma
Acute Exacerbation of COPD
Acute Respiratory Distress Syndrome
Septic Shock
02
Comparison of Corticosteroids
03

Definition of Asthma
Asthma is a disease characterized by recurrent attacks of breathlessness and
wheezing, which vary in severity and frequency from person to person.
This condition is due to inflammation of the air passages in lungs affecting sensitivity
of the nerve endings in airways, hence they become easily irritated. In an attack, the
lining of the passages swell causing the airways to narrow and reducing the flow of
air in and out of the lungs1
Asthma is a heterogeneous disease, usually characterized by chronic airway
inflammation. It is defined by the history of respiratory symptoms such as wheeze,
shortness of breath, chest tightness and cough that vary over time and in intensity,
together with variable expiratory airflow limitation2
1. WHO | Asthma: Definition [Internet]. Who.int. 2018 [cited 14 October 2019]. Available from: http://www.who.int/respiratory/asthma/definition/en/
2. (*NEW) 2018 GINA Report: Global Strategy for Asthma Management and Prevention - Global Initiative for Asthma - GINA [Internet]. Global Initiative for Asthma - GINA. 2018 Accessed
on 18th June 2020. Available from: https://ginasthma.org/2018-gina-report-global-strategy-for-asthma-management-and-prevention/

• Over 300 million individuals people suffer from asthma worldwide
• Asthma is the most chronic disorder among children
• An Indian Study on Epidemiology of Asthma, Respiratory Symptoms and Chronic
Bronchitis (INSEARCH) conducted in 85,105 men and 84,470 women from 12 urban
and 11 rural Indian sites estimated the prevalence of asthma to be 2.05% among
individuals aged >15 years
Prevalence of Asthma
Koul PA, Patel D. Indian guidelines for asthma: Adherence is the key. Lung India: official organ of Indian Chest Society. 2015 Apr;32(Suppl 1):S1.
≈ One tenth of them live in
India
3 to 38% in children
2-12% in adults
18 million
asthmatics

Allergens
Air Pollutants
Respiratory infections
Exercise
Hyper-ventilation
Factors that exacerbate asthma1
Complete control of
Asthma2
 No daytime symptoms
 No night-time awakening due to
asthma
 No need for rescue medication
 No asthma attacks
 No limitations on activity including
exercise
 Normal lung function (in practical
terms FEV1 and/or PEF>80%
predicted or best)
 Minimal side effects from medication
1. Rodrigo GJ, Rodrigo C, Hall JB. Acute asthma in adults: a review. Chest. 2004 Mar 1;125(3):1081-102..
2. British guideline on the management of asthma [Internet]. Brit-thoracic.org.uk. 2014 Accessed on 18th June 2020. Available from: https://www.brit-thoracic.org.uk/document-library/clinical-
information/asthma/btssign-asthma-guideline-2014/

Step-wise Approach to Asthma Treatment: GINA
*Not for children <12 years
**For children 6-11 years, the
preferred Step 3 treatment is
medium dose ICS
#For patients prescribed
BDP/formoterol or BUD/
formoterol maintenance and
reliever therapy
 Tiotropium by mist inhaler is
an add-on treatment for patients
≥12 years with a history of
exacerbations
Diagnosis
Symptom control & risk factors
(including lung function)
Inhaler technique & adherence
Patient preference
Asthma medications
Non-pharmacological strategies
Treatment of t modifiable risk factors
Symptoms
Exacerbations
Side-effects
Patient satisfaction
Lung function
Other
controller
options
RELIEVER
STEP 1 STEP 2
STEP 3
STEP 4
STEP 5
Low dose ICS
Consider low
dose ICS
Leukotriene receptor antagonists (LTRA)
Low dose theophylline*
Med/high dose ICS
Low dose ICS + LTRA
(or + theoph*)
As-needed short-acting beta2-agonist (SABA) As-needed SABA or
low dose ICS/formoterol#
Low dose
ICS/LABA**
Med/high
ICS/LABA
PREFERRED
CONTROLLER
CHOICE
Add tiotropium*
Med/high dose
ICS + LTRA
(or + theoph*)
Add low
dose OCS
Refer for
add-on
treatment
e.g.
tiotropium,*
anti-IgE,
anti-IL5*
Image extract from (*NEW) 2018 GINA Report: Global Strategy for Asthma Management and Prevention - Global Initiative for Asthma - GINA [Internet]. Global
Initiative for Asthma - GINA. 2018 Accessed on 18th June 2020. Available from: https://ginasthma.org/2018-gina-report-global-strategy-for-asthma-management-and-
prevention/

9
© Global Initiative for Asthma, www.ginasthma.org
ICS-formoterol is the
preferred reliever for
patients prescribed
maintenance and reliever
therapy. For other
ICS-LABAs, the reliever
is SABA
GINA 2020, Box 3-5A

10
© Global Initiative for Asthma, www.ginasthma.org
A reminder – the key change in GINA 2019

GINA Recommendations for Corticosteroid Use
• Oral Corticosteroids (preferable morning dosing)
• Adults – prednisolone 1 mg/kg/day up to 50 mg, usually for 5-7 days
• Children – 1-2 mg/kg/day up to 40 mg, usually for 3-5 days
• Tapering not needed if treatment has been given less than 2 weeks
• Managing Exacerbations in primary or acute care
• Arrange immediate transfer to an acute care facility if there are signs of
severe exacerbation, or to intensive care if the patient is drowsy, confused, or
has a silent chest
• For these patients, immediately give inhaled SABA, inhaled ipratropium
bromide, oxygen and systemic corticosteroids
GINA. Pocket Guide for Asthma Prevention and Management [Internet]. Ginasthma.org. 2018 Accessed on 18th June 2020. Available from: https://ginasthma.org/wp-content/uploads/2018/03/wms-GINA-main-
pocket-guide_2018-v1.0.pdf

GINA Guidelines: Controller Medications
Medication
• Inhaled
corticosteroids (ICS)
(pMDIs or DPIs)
• e.g. beclometasone,
budesonide,
ciclesonide,
fluticasone
propionate,
fluticasone furoate,
mometasone,
triamcinolone
Action and use
• The most effective
anti-inflammatory
medications for
persistent asthma.
ICS reduce
symptoms, increase
lung function,
improve quality of
life, and reduce risk
of exacerbations
and asthma-related
hospitalizations or
death
• ICS differ in their
potency and
bioavailability, but
most of the benefit is
seen at low doses
Adverse effects
• Most patients using
ICS do not
experience side
effects
• Local side effects
include
oropharyngeal
candidiasis and
dysphonia
• Use of spacer with
pMDI, and rinsing
with water and
spitting out after
inhalation, reduce
local side effects
• High doses increase
the risk of systemic
side effects

GINA Guidelines: Add-on Controller Medications
Medication
• Systemic corticosteroids
(tablets, suspension, or
intramuscular (IM) or
intravenous (IV) injection)
• e.g. prednisone,
prednisolone,
methylprednisolone,
hydrocortisone
Action and use
• Short-term treatment
(usually 5-7 days in adults)
is important in the
treatment of severe acute
exacerbations, with main
effects seen after 4-6
hours
• Oral corticosteroid (OCS)
therapy is preferred and is
as effective as IM or IV
therapy in preventing
relapse
• Tapering is required if
treatment given for more
than 2 weeks
• Long-term treatment with
OCS may be required for
some patients with severe
asthma, but side effects
must be taken into account
Adverse effects
• Short-term use: some
adverse effects e.g. sleep
disturbance, reflux,
appetite increase,
hyperglycemia, mood
changes
• Long-term use: limited by
the risk of significant
systemic adverse effects
e.g. cataract, glaucoma,
osteoporosis, adrenal
suppression
• Patients should be
assessed for osteoporosis
risk and treated
appropriately

Study: Comparing the efficacy and safety of two regimens of sequential
systemic corticosteroids in the treatment of acute exacerbation of bronchial
asthma
• Group A: Hydrocortisone 200 mg IV 6-hourly until discharge from the ED,
followed by oral prednisolone 0.75 mg/kg daily for 2 weeks
• Group B: Methylprednisolone 125 mg IV bolus, followed by 40 mg MP IV
6-hourly until discharge, and then oral MP 0.6 mg/kg daily for 2 weeks
• At 2 weeks of follow-up, Group B (Methylprednisolone) showed
significant improvement over Group A (Hydrocortisone) in
-PEF (P < 0.0001),
-FEV(1) (P < 0.0001) and
-Asthma score (P = 0.034)
Aggarwal P, Bhoi S. Comparing the efficacy and safety of two regimens of sequential systemic corticosteroids in the treatment of acute
exacerbation of bronchial asthma. Journal of emergencies, trauma, and shock. 2010;3(3):231.

Study Conclusion
• This study has shown a higher efficacy and safety of IV Methyl
Prednisolone (MP) followed by oral MP as compared to IV
Hydrocortisone (HC) followed by oral prednisolone in acute asthma
patients
• Based on the results of this study, IV MP followed by oral MP, may form
the treatment of choice among the two regimens for acute bronchial
asthma
Aggarwal P, Bhoi S. Comparing the efficacy and safety of two regimens of sequential systemic corticosteroids in the treatment of acute
exacerbation of bronchial asthma. Journal of emergencies, trauma, and shock. 2010;3(3):231.

Acute Exacerbation of COPD Definition and Incidence
• The American Thoracic Society (ATS) and European Respiratory Society
(ERS) define an exacerbation as an acute change in a patient's baseline
dyspnea, cough, or sputum that is beyond normal variability, and that is
sufficient to warrant a change in therapy1
• In patients with known chronic obstructive pulmonary disease (COPD),
exacerbations occur an average of 1.3 times per year1
• In the Indian subgroup of Asia-Pacific Burden of Respiratory Diseases
study, it was found that asthma was the most frequent primary diagnosis
among four common respiratory diseases including COPD2
1. Evensen AE. Management of COPD exacerbations. American family physician. 2010 Mar;81(5):607-13.
2. Singh V, Sharma BB. Respiratory disease burden in India: Indian chest society SWORD survey. Lung India: official organ of Indian Chest Society. 2018 Nov;35(6):459.

Prevalence in India
• India contributes very significantly to mortality from COPD
102.3/100,000 and 6,740,000 DALYs out of world total of 27,756,000
DALYs; thus significantly affecting health related Quality of Life in the
country1
• COPD prevalence varies from 3% to 8% amongst Indian males and
approximately 2.5% to 4.5% among Indian females1
• In a study by Chandra and Guleria from Delhi, it was found that there
was an increase in the frequency of admissions due to acute
exacerbation of COPD starting in November and peaking in February of
the subsequent year without any clear-cut tendency toward seasonality2
1. Bhome A. B. (2012). COPD in India: Iceberg or volcano?. Journal of thoracic disease, 4(3), 298–309. doi:10.3978/j.issn.2072-1439.2012.03.15
2. Singh V, Sharma BB. Respiratory disease burden in India: Indian chest society SWORD survey. Lung India: official organ of Indian Chest Society. 2018 Nov;35(6):459.

Classification of COPD Exacerbations by Severity
Adapted from Evensen AE. Management of COPD exacerbations. American family physician. 2010 Mar;81(5):607-13.
• Can be controlled with an increase in
dosage of regular medications
Mild
• Requires treatment with systemic
corticosteroids or antibiotics
Moderate
• Requires hospitalization or
evaluation in the emergency
department
Severe

Symptoms of COPD Exacerbation
Body System Symptoms
Cardiac Chest tightness
tachycardia
Musculoskeletal Decreased exercise tolerance
Psychiatric Confusion
Depression
Insomnia
Sleepiness
Pulmonary Change in volume, color, or tenacity of sputum
Cough
Dyspnea
Tachypnea
Wheezing
Systemic Fatigue
Fever
Malaise

Factors that Increase the Risk of Severe COPD Exacerbations
Altered mental status
At least three exacerbations in the previous 12 months
Body mass index of 20 kg per m2 or less
Marked increase in symptoms or change in vital signs
Medical comorbidities (especially cardiac ischemia, congestive heart failure, pneumonia, diabetes mellitus,
or renal or hepatic failure)
Poor physical activity levels
Poor social support
Severe baseline COPD (FEV1/FVC ratio less than 0.70 and FEV1 less than 50 percent of predicted)
Underutilization of home oxygen therapy

AAFP Recommendation on Treatment of Acute COPD
Exacerbations: Corticosteroids
Evensen AE. Management of COPD exacerbations. American family physician. 2010 Mar;81(5):607-13.
Outpatient
management
• Consider using oral
corticosteroids in
moderately ill
patients, especially
those with purulent
sputum
Inpatient
management
• Use oral
corticosteroids if
patient can tolerate;
if not suitable for
oral therapy,
administer
intravenously
Benefits
• Decreases risk of
subsequent
exacerbation, rate of
treatment failures,
and length of
hospital stay
• Improves FEV1 and
hypoxemia
Typical Dosage
• Oral prednisone: 30
to 60 mg once daily
• Intravenous
methylprednisolone
: 60 to 125 mg 2
times daily
Common Adverse Effects: Gastrointestinal bleeding, heartburn, hyperglycemia,
infection, psychomotor disturbance, steroid myopathy
• Short courses of systemic corticosteroids in patients with COPD increase the time to
subsequent exacerbation, decrease the rate of treatment failure, shorten hospital stays,
and improve FEV1 and hypoxemia
• Low-dosage corticosteroid regimens are not inferior to high-dosage regimens in
decreasing the risk of treatment failure in patients with COPD
• Oral prednisolone is equivalent to intravenous prednisolone in decreasing the risk of
treatment failure in patients with COPD

GOLD Guidelines 2019: Use of Corticosteroids (ICS)
• An ICS combined with LABA is more effective than the individual
components in improving lung function and health status and reducing
exacerbations in patients with exacerbations and moderate to very
severe COPD
• Regular treatment with ICS increases the risk of pneumonia especially in
those with severe disease
• Triple inhaled therapy of ICS/LAMA/LABA improves lung function,
symptoms and health status and reduces exacerbations compared to
ICS/LABA, LABA/LAMA or LAMA monotherapy
• Systemic corticosteroids can improve lung function (FEV1), oxygenation
and shorten recovery time and hospitalization duration
• Duration of therapy should not be more than 5-7 days
GOLD Guidelines. Pocket Guide to COPD Diagnosis, Management and Prevention [Internet]. Goldcopd.org. 2019 Accessed on 18th June 2020. Available from: https://goldcopd.org/wp-
content/uploads/2018/11/GOLD-2019-POCKET-GUIDE-DRAFT-v1.7-14Nov2018-WMS.pdf

Meduri GU et al.
• Effect of prolonged methylprednisolone therapy in unresolving acute
respiratory distress syndrome: a randomized controlled trial. JAMA.
1998 Jul 8;280(2):159-65.
• RCT
• double blind (placebo controlled)
• n = 24
• inclusion criteria: severe ARDS who failed to improve by day 7 of
respiratory failure
• methylpredisolone VS placebo
-> reduction in ICU mortality
-> reduced oxygenation requirement
-> reduction in MODS score
– criticisms: small numbers, differences in baseline characteristics
between groups

National Heart, Lung, and Blood Institute Acute Respiratory
Distress Syndrome (ARDS) Clinical Trials Network.
• Efficacy and safety of corticosteroids for persistent acute respiratory
distress syndrome. N Engl J Med. 2006 Apr 20;354(16):1671-84.
• RCT
• n = 180
• randomised after 7-28 days
• placebo VS methylprednisolone
-> no difference in 60 day mortality
-> increased death rate in those commenced on steroids after 2 weeks
-> no increase in nosocomial infections
-> trend towards increased neuromyopathy
-> increase in number of ventilator-free, ICU free days in the first 28
days after treatment

Summary
• exact place of steroids in ARDS is unknown
• further investigation required

Design
• Multi centered, randomized, controlled trial
• N=277
• Dexamethasone (n=139)
• Control (n=138)
• Setting: 17 ICUs in Spain
• Enrollment: 28 March 2013, to 31 Dec 2018
• Analysis: Intention-to-treat
• Primary Outcome: ventilator free days at 28 days after randomization

Inclusion Criteria
• mechanically ventilated
• acute onset of ARDS
• defined by the American-European Consensus Conference criteria for ARDS
• the Berlin criteria as moderate-to-severe ARDS

Dexamethasone Group displayed
• Demographics: mean age 56 years,
• Grouping: mean SOFA score8.7, mean days from intubation to
randomization 2.1, mean days from ARDS to randomization 1, 85%
Moderate ARDS (100 <PaO2/FiO2 ≤200), 15% Severe ARDS
(PaO2/FiO2 ≤100)
• Physiologic parameters: mean PaO2/FiO2 142.4 mm Hg, mean Tidal
volume 6.9 mL per predicted bodyweight, mean respirator rate 23 breath
per minute, FiO2 64%, Positive end-expiratory pressure 12.6 cm H2O,
Inspiratory plateau pressure 26.4 cm H2O, PaCO2 47.9 mm Hg, Arterial
pH 7.34
• Cause of ARDS: 54% Pneumonia, 24% Sepsis, 10.3% Aspiration, 8%
Trauma, 1% other

Interventions
• Dexamethasone 20mg IV daily for Days 1-5, then 10mg from days 6-10,
drug discontinued upon extubation
• Standard of care

Primary Outcomes
• Ventilator-free days at 28 days after randomization 12.3 vs. 7.5, ARR
4.8 (95% CI 2.57 to 7.03) P < 0.0001
Secondary Outcomes
• All-cause mortality at day 60 21% vs. 36%, Difference –15.3% (95% CI
–25.9 to –4.9) P = 0.0047; NNT 7
• ICU mortality 19% vs. 31%, Difference –12.5% (95% CI –22.4 to –2.3) P
= 0.0166; NNT 8
• Hospital mortality 24% vs. 36%, Difference –12.5% (95% CI –22.9 to –
1.7) P = 0.0235; NNT 8
• Actual duration of mechanical ventilation in ICU survivors, days 14.2
days vs. 19.5 days, Difference –5.3 (95% CI –8.4 to –2.2) P = 0.0009
• Actual duration of mechanical ventilation in survivors at day 60,
days14.3 days vs. 20.2 days, Difference –5.9 (95% CI –9.1 to –2.7) P =
0.0004

Adverse Events
• Hyperglycaemia in ICU 76% vs. 70%, difference 5.2% (95% CI –5.2 to
15.6) P = 0.33
• New infections in ICU 24% vs. 25%, difference 1.6% (95% CI –8.5 to
11.7) P = 0.75
• Barotrauma10% vs. 7%, difference 2.8% (95% CI –4.0 to 9.8) P = 0.41

RECOVERY
(Randomised Evaluation of COVid-19 thERapY) trial
• Corticosteroid - dexamethasone administered as an oral (liquid or
tablets) or intravenous preparation 6 mg once daily for 10 days.
• In pregnancy or breastfeeding women, prednisolone 40 mg administered
by mouth (or intravenous hydrocortisone 80 mg twice daily) administered
instead of dexamethasone
• Unblinded adaptive randomised control trial
• Multi-centre: 176 NHS hospitals in the UK
• Inclusion:
• clinically suspected or proven SARS-CoV-2 infection
• age >18 years (but after May 9 no age limit)
• patients were permitted to be included if pregnant or breast-feeding
• Primary outcome: 28-Day mortality (dexamethasone vs usual care) –
significantly reduced in dexamethasone group

Secondary outcome: (dexamethasone vs usual care)
• Mechanically ventilated: 28-day mortality – significantly reduced in
dexamethasone group
• Patients receiving O2: 28-day mortality – significantly reduced in
dexamethasone group
• 21.5% vs 25% [Rate Ratio 0.80; 95% CI 0.70-0.92, p = 0.002]
• Patients not receiving respiratory support: no significant difference
• 17% vs 13.2% [Rate Ratio 1.22; 95% CI 0.93-1.61 p=0.14]
Dexamethasone was associated with a reduction in 28-day mortality among
those symptoms for >7 days but not among those with symptoms for <7 days
(test for trend p<0.001)
• Length of hospital stay – significantly reduced in dexamethasone group
Composite secondary outcome of invasive mechanical ventilation and
death – significantly reduced in dexamethasone group
• Rate Ratio 0.91; 95% CI 0.82-1.00, p=0.049
• Use of ventilation – significantly reduced in dexamethasone group
• Rate Ratio 0.76; 95% CI 0.61-0.96, p=0.021

Gotts J, Matthay M. Sepsis: pathophysiology and clinical management. BMJ. 2016;353:i1585.
Revised definitions
Sepsis
• Life threatening organ dysfunction* caused by a dysregulated host
response to infection
Septic
shock
• Sepsis and vasopressor therapy needed to increase mean arterial
pressure to 65 mm Hg and lactate to >2 mmol/L despite adequate
ﬂuid resuscitation
Category
Definition
Category
Definition
*As assessed by an acute change of ≥2 points in the sequential organ failure assessment score
(components: partial pressure of oxygen in arterial blood/fractional inspired oxygen (PaO 2 /FIO 2
) ratio, Glasgow coma scale, mean arterial pressure, vasopressor use, serum creatinine or urine
output, bilirubin, and platelet count).
Sepsis: New Definition 2016

Epidemiology of Severe Sepsis in India
16.45
59.26
65.2 64.6
57.45
72.45
13.13
%
• Duration: June 2006 to June 2009
• Multicenter, prospective, observational study in 4 ITUs across India
• Total No. of ITU admissions: 5,478
Todi S, Chatterjee S, Sahu S, Bhattacharyya M. Epidemiology of severe sepsis in India: an update. Critical care. 2010;14(Suppl 1):P382-P.

Causes
• Infection caused in any part of the
body, mainly skin, lungs, urinary tract,
abdomen that can result in
bloodstream access to Gram positive
or Gram negative bacteria
• In hospitals: IV lines, surgical wounds,
surgical drains and sites of skin
breakdown (bedsores or pressure
ulcers)
Places
of
Infection
Origin
Bloodstream
Bones (common in children)
Bowel (peritonitis)
Kidneys (pyelonephritis)
Lining of brain (meningitis)
Liver or gallbladder
Lungs (bacterial pneumonia)
Skin (cellulitis)
Jatin M. Vyas, a. (2016) Sepsis: MedlinePlus Medical Encyclopedia. [online] Nlm.nih.gov. Available at: https://www.nlm.nih.gov/medlineplus/ency/article/000666.htm Accessed on 18th June 2020

Diagnostic Criteria
Adapted from Dellinger RP, et al. Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup. Surviving sepsis campaign: international guidelines for management of severe
sepsis and septic shock: 2012. Crit Care Med. 2013 Feb;41:580-637.
Organ dysfunction variables
Arterial hypoxemia (PaO2 /FiO2 <300)
LOW GCS
Hyperbilirubinemia (plasma total
bilirubin >4 mg/dL or 70 µmol/L)
Tissue perfusion variables
Hyperlactatemia (>1
mmol/L)
Decreased capillary reﬁll or
mottling
Acute oliguria (urine output <0.5
mL/kg/h for at least 2h despite
adequate ﬂuid resuscitation)
Creatinine increase >0.5 mg/dL or
44.2 µmol/L
CVS abnormalities (MAP <65mmHg)
Thrombocytopenia (platelet count
<100,000/µL)

Surviving Sepsis Guideline 2016 Highlights
• Vasopressors: Target MAP of 65 mmHg
• Norepinephrine
• Epinephrine if not at target MAP or vasopressin to reduce norepinephrine requirement
• Avoid dopamine in most patients
• Steroids:
• Only indicated for patients with septic shock refractory to adequate fluids and vasopressors
• Antibiotics:
• Initial broad spectrum antibiotics (ex: vancomycin + piperacillin-tazobactam)
• Against combine therapy (i.e. do not double cover pseudomonas)
• May use procalcitonin to guide de-escalation
• Source control: Achieve as soon as medically and logically feasible
• Ventilator:
• 6 cc/kg tidal volume
• Prone patients with severe ARDS (P/F <150 in 2017 guidelines)
• Against high frequency oscillatory ventilation (HFOV)
• Unable to make recommendation on noninvasive ventilation
Rhodes A, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017;43:304-77.
Suggest against using IV hydrocortisone to treat septic shock patients if
adequate fluid resuscitation and vasopressor therapy are able to restore
hemodynamic stability. If this is not achievable, we suggest IV
hydrocortisone at a dose of 200 mg per day

SSC Recommendations: Hemodynamic Support and
Adjunctive Therapy: Corticosteroids
Dellinger RP et al. Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup.. Surviving sepsis campaign: international guidelines for management of severe sepsis and
septic shock: 2012. Crit Care Med. 2013 Feb;41(2):580-637.
• Not using the ACTH stimulation test to identify adults with septic
shock who should receive hydrocortisone
Grade
2B
• Intravenous hydrocortisone alone at a dose of 200 mg per day to
treat adult septic shock patients, if vasopressor therapy and
adequate fluid resuscitation does not restore hemodynamic stability
Grade
2C
• Corticosteroids not be administered for the treatment of sepsis in the
absence of shock
Grade
1D
• In treated patients hydrocortisone tapered when vasopressors are
no longer required
• When hydrocortisone is given, use continuous flow
Grade
2D

ADRENAL trial (2018)
• Multicenter international double-blind randomised placebo-controlled
trial
• 69 ICUs, mostly in Australia
• n= 3658 adult patients with septic shock requiring vasopressors and
mechanical ventilation
• intervention: IV hydrocortisone 200mg/day, given as continuous infusion
for 7 days or until ICU discharge
• comparison: placebo + standard therapy

Outcomes
• No difference in the primary outcome of 90-day mortality
• 511 of 1832 patients (27.9%) in the hydrocortisone group died vs 526 of 1826
(28.8%) in the placebo group
• Odds ratio (OR), 0.95; 95% confidence interval [CI], 0.82 to 1.10; P=0.50
• Absolute risk reduction (ARR) 0.91%; 95% CI -2.01% to 3.83%; P=0.56 (Fisher’s
exact)
• Multiple secondary outcomes were assessed, those that were significant
were:
• Median days to resolution of shock
• 3 vs 4 days (Hazard ratio [HR] 1.32; 95% C.I. 1.23-1.41, P=<0.001)
• Median time to cessation of initial mechanical ventilation
• 6 vs. 7 days (HR 1.13; 95% C.I. 1.05-1.22, P=<0.001)
• Median time to discharge from the ICU
• 10 vs. 12 days (HR 1.14, 95% C.I. 1.06-1.23, P=<0.001)
• Use of blood transfusion
• 37.0% vs. 41.7% (OR 0.82; 95% C.I. 0.72-0.94, P=0.004)
• Number of patients with adverse events were significantly greater in hydrocortisone
group
• 21 (1.1%) vs. 6 (0.3%), p=0.009
• e.g. hyperglycaemia, hypernatraemia, encephalopathy

49
COMPARISON OF
CORTICOSTEROIDS

Classification
• Ratio of glucocorticoid to mineralocorticoid potency acts as an important criteria
to classify corticosteroids
• Higher the ratio, greater is the anti-inflammatory action and lesser the
mineralocorticoid side effects
• Methylprednisolone (10) > Prednisolone (5) > hydrocortisone (1)
Gupta P, Bhatia V. Corticosteroid physiology and principles of therapy. Indian J Pediatr. 2008;75(10):1039-1044.
CS
Relative GC
potency
Relative MS
potency
GC:MS ratio
Hydrocortisone 1 1 1
Prednisolone 4 0.8 5
Methylprednisolone 5 0.5 10
Dexamethasone 25 0 25
GC-Gas chromatography, MS- mass spectrometry

Pharmacologic advantages of methylprednisolone over other corticosteroids:
• Greater anti-inflammatory efficacy compared with prednisone and
prednisolone with minimal less mineralocorticoid effects (and hence
adverse effects) and more glucocorticoid potency
1. Peter Barnes. Chapter 40. The pharmacological basis of therapeutics. Goodman and Gilman's Mc Graw-Hill. 2006.
2. Fiel SB, Vincken W. Systemic corticosteroid therapy for acute asthma exacerbations. Journal of Asthma. 2006;43(5):321-31.
Less tendency to cause sodium and water retention
 Hypertension, edema, cardiac failure are not a concern during
treatment with methylprednisolone
Less tendency to cause potassium loss
 Muscle wasting, muscle weakness, metabolic alkalosis are not a
concern during treatment with methylprednisolone
Advantages of Methylprednisolone over other Corticosteroids

10-fold greater potency in inhibiting T-cell blastogenesis compared with
prednisolone (P<.01)1
• Penetration of lung tissue is greater with methylprednisolone than
with prednisone2
• Methylprednisolone resistance significantly less likely to develop than
prednisolone resistance (P<.05)1
1. Hirano T, Homma M, Oka K, Tsushima H, Niitsuma T, Hayashi T. Individual variations in lymphocyte-responses to glucocorticoids in patients with bronchial
asthma: comparison of potencies for five glucocorticoids. Immunopharmacology. 1998;40(1):57-66.
2. Braude A, Rebuck A. Prednisone and methylprednisolone disposition in the lung. The Lancet. 1983;322(8357):995-7.
Advantages of Methylprednisolone over other Corticosteroids

ACUTE SPINAL CORD INJURY
• Bracken MB, Shepard MJ, Collins WF, et al: A randomized, controlled
trial of methylprednisolone or naloxone in the treatment of acute spinal-
cord injury. Results of the Second National Acute Spinal Cord Injury
Study. N Engl J Med 1990; 322:1405-1411.
• high dose methylprednisolone within 8 hours in injury
-> supported use

TRAUMATIC BRAIN INJURY
• Roberts I, Yates D, Sandercock P, et al: CRASH trial collaborators:
Effect of intravenous corticosteroids on death within 14 days in 10,008
adults with clinically significant head injury (MRC CRASH trial):
Randomised placebo-controlled trial. Lancet 2004; 364:1321-1328.
• Edwards P, Arango M, Balica L, et al: CRASH trial collaborators: Final
results of MRC CRASH, a randomised placebo-controlled trial of
intravenous corticosteroid in adults with head injury-outcomes at 6
months. Lancet 2005; 365:1957-1959.
• 48 hours of IV steroids vs placebo
-> increased mortality within 14 days
-> increases mortality @ 6 months
-> increased risk of severe disability

SUMMARY OF PROVEN ROLES FOR STEROIDS
Airway
• croup
• decreased post-extubation stridor in those at risk
Breathing
• anaphylaxis
• asthma
• COPD
• Severe PJP pneumonia
Nervous
• bacterial meningitis
• myasthenic crises
• myxoedema coma
• decreases cerebral oedema associated with brain tumour

Endocrine
• Addison’s
• hypercalcaemia
• myxoedema coma
• hypothalamic-pituitary-adrenal insufficiency
• previous steroid use
• Other
• purpura fulminans
• vasculitidies (e.g. GCA)
• organ transplantation
• various malignancy (lymphoma)
• anti-emetic
• palliative care

• ACCEPTED BUT CONTROVERSIAL USES OF STEROIDS
• – severe sepsis with resistant shock
– spinal injury
– early ARDS
• CONTRAINDICATIONS TO USE OF STEROIDS
• – Cushing disease
– traumatic brain injury
– late ARDS (after 2 weeks)

Corticosteroids in critical conditions

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