I*ve been at the gym, steroids help to make you big. Swollen to the

I’ve been at the gym,
steroids help to make you big.
Swollen to the max.
Steroids
• Ste·roid, noun
• A large class of organic compounds with a
characteristic molecular structure. They
include many hormones, alkaloids and
vitamins.
1927
A Brief History
• 1927, Heinrich Otto Wieland - constitution of bile
acids, sterols and their connection with the vitamins
• 1939, Adolf Butenandt and Leopold Ruzicka – isolation and
structural studies of steroid sex hormones
• 1950, Edward Kendall, Tadeus Reichstein, Philip Hench structure and biological effects of adrenal hormones
• 1965, Robert Burns Woodward - synthesis of
cholesterol, cortisone and lanosterol
• 1975, Vladimir Prelog – developed methods to determine
the stereochemical course of cholesterol biosynthesis
from mevalonic acid via squalene  statins
Functions in Biological Systems
• Frequently serve as signaling molecules
• Steroids, along with phospholipids, function as
components of cell membranes
• All human cells are responsive to steroids
• Regulates DNA transcriptional activation
(SREBP), cellular metabolism, turnover and
growth
Ecosanoid Synthesis
STEROIDS
Common Hospital Uses for Steroids
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COPD
Asthma
Acute spinal cord injury
CAP
HCAP
Sepsis
Septic shock
Rheumatic disease
Allergies
UC/Chrons
Hypercalcemia of cancer
Thyroiditis
Laryngitis
Urticaria
Pericarditis
MS
Nephrotic Syndromes
Nephritic Syndromes
Lupus
Dermatomyositis
Bullous Dermatitis
Erythema Multiforme (SJS)
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Exfoliative Dermatitis
Mycosis Fungoides
Psorasis
Seborrheic Dermatitis
Myasthenia Gravis
Cluster headaches
Acute Lymphoblastic Leukemia
Non-Hodgkins Lymphomas
Hodgkin’s Lymphomas
Multiple Myeloma
Herxheimer Reactions
Duchenne Muscular Dystrophy
Psoriatic Arthritis
Ankylosing Spondylitis
Acute/Subacute Bursitis
Acute Tenosynovitis
Acute Gouty Arthritis
Osteoarthritis
Epicondylitis
Uveitis
Choroiditis
Sympathetic Ophthalmia
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Allergic Conjunctivitis
Keratitis
Chorioretinitis
Optic Neuritis
Iritis
Iridocyclitis
Sarcoidosis
Decompensated Heart Failure
Bells Palsy
JUST TO
NAME A
FEW
MAJOR ‘Before We Start’ Considerations
• MAJOR Side Effects:
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Hyperglycemia
Anisarca
Insomnia
Euphoria/Mania/Psychosis
Depression
Anxiety
Dehabilitating fatigue or
weakness
Blurred vision
Abdominal pain
Peptic ulcers Melena
Girdle Pain
– Steroid-induced
osteoporosis
– Stretch marks
– Osteonecrosis
– Avascular necrosis
– Arthralgia
– Cataracts or glaucoma
– Mucocutaneous erosion
&/or ulceration
– Hepatic steatosis
MINOR ‘Before We Start’ Considerations
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Nervousness
Acne
Steroid Rash
Appetite gain
Hyperactivity
Increased thirst
Frequent urination
Diarrhea
Reduced intestinal flora  Colitis
Leg pain/cramps/myalgia
Sensitive teeth
Topics We Will Focus On
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COPD
Asthma
Acute spinal cord injury
CAP
HCAP
Sepsis
Asthma/COPD Algorithm
MILD EXACERBATION
MODERATE/SEVERE EXACERBATION
This patient is REALLY sick
• On hospitalization, corticosteroids are generally administered IV
• Your resident/attending stops by to let you know that this patient
needs I.V. Steroids STAT
• Is the patient still conscious and breathing?
• Randomized to 60 mg IV vs. PO - Same dose?!
• NO DIFFERENCE in early treatment failure (death – the 1º
outcome), admission to the ICU, readmission to the ICU,
intensification of therapy during a 90 day follow-up or LOS
• Conclusion: PO preferable route of treatment in COPD exacerbation
• Cost of PO <<<<<<<<<< IV
Not only do they NOT need IV steroids…
• More than 90% of acutely ill people who are
hospitalized for COPD/asthma exacerbation
receive HIGH DOSE IV STEROIDS
• Same findings as the previous IV vs. PO study,
PLUS low-dose therapy has equivalent
outcomes as high-dose therapy
The Astute Observer
• You notice that we seem to treat a large
number of COPD exacerbations in the
hospital, yet 10-15% of them don’t seem to
improve with our standard, vanilla-blend
recipe
• You realize that something else has to be
going on in this patient population
EDAC – TBM – BO
EDAC – TBM – BO
• Excessive Dynamic Airway Collapse
• TracheoBronchoMalacia
• Bronchiolitis Obliterans
• In COPD/asthma patients that fail to respond
to class I therapeutic recommendations for
COPD/asthma exacerbation consider these
What It Is
• Patients often diagnosed with “difficult to
treat” or “refractory” asthma or COPD – ESP.
in the community setting and are often on
long-term, daily steroid therapy (inhaled or
systemic)
• EDAC, TBM and BO are on a SPECTRUM of
chronic, inflammatory airway diseases that
result in obstructive lung physiology
– EDAC  TBM  BO?
The Literature
• EDAC, TM, BO are well represented in a variety of
medical and scientific literature
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Radiology
Neonatology
Pediatrics
Physical Therapy
Endocrinology
Pathology
Pulmonology
Dermatology
Immunology
Steroid Use and Cartilage Ultra-Structure, 1950’s
• Temporary and permanent changes in soft tissue, bone and
cartilaginous structures occur with steroid use
– Inhibits pro-collagen II synthesis and increases release of
degradation products of the proteoglycan aggrecan
– Inhibition of chondroitin sulfate synthesis, the major
morphologic and functional component of hyaline cartilage
– Dose-dependent inhibition of sulfate fixation and decreased
glycine incorporation into cartilage matrices
– Ubiquitous decrease in elasticity (cartilage becomes
floppy), loss of protein polysaccharide in matrix (cartilage
becomes porous) , decreased chondrocytes (cartilage
cannot be maintained), collagen clumping (cartilage
becomes heterogenous) and breakdown in protein
synthesis (cartilage is destroyed)
EDAC – TBM – BO Radiographic Findings
• EDAC/TBM: Characterized by generalized or focal
airway wall weakness resulting in excessive
variation of the luminal diameter during the
respiratory cycle
• BO: Luminal narrowing as a result of submucosal
and peribronchiolar inflammation and fibrosis
without any intraluminal granulation tissue or
polyps / polyposis; absence of diffuse
parenchymal inflammation
We are not even going to touch on
antibiotic therapy in COPD exacerbation
COPD/Asthma & Steroids Review
AND GO P.O.!
Think about EDAC – TBM – BO
Topics We Will Focus On
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COPD
Asthma
Acute spinal cord injury
CAP
HCAP
Sepsis
Acute Spinal Cord Injury (SCI)
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Motor vehicle accidents: 47%
Falls: 23%
Violence (esp. GSW): 14%
Sports accidents: 9%
Other: 7%
In this setting includes traumatic injury, not
infarction
NASCIS II Trial – And I Quote
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In 1990 the National Acute Spinal Cord Injury Study II (NASCIS II) trial changed the way spinal
cord injuries (SCI) were treated.
Improved 6-month recovery of SCI patients, compared to placebo treated patients, when
administered in an intensive 24-hour intravenous methyprednisolone dosing regimen
beginning within 8 hours after injury.
The first randomized, double-blind, placebo-controlled trial that unequivocally demonstrated
that a pharmacologic agent can beneficially modify the course of events after severe CNS
injury.
Predictable side effects of steroid therapy were noted, including GI bleeding, wound
infections and delayed healing, although these were not statistically significant.
Most important, the fact that these studies accurately predicted the efficacy of MP gave
greater impetus to the pursuit of agents with greater antioxidant activity for acute
pharmacotherapy of CNS injury, in general.
Let’s Look Closer at NASCIS II
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Design: Multicentre, prospective, randomized, double-blind trial.
Patients: 487 patients with acute spinal cord injury. Follow-up of 427 patients (95%) at 1 year
(deaths excluded).
Exclusions: Injuries below L1, Children
Randomization:
Treatment 1: Methyprednisolone 30 mg/kg bolus, then 5.4 mg/kg/hr for 23 hours
Treatment 2: Naloxone 5.4 mg/kg bolus, then 4.5 mg/kg/hr for 23 hours
Treatment 3: Placebo
Neurologic outcome: Admission, 6 weeks, 6 months and 1 year. Motor strength. Pin prick & touch
sensation, both sides were examined.
There was no difference in motor score between treatment groups at any time point. There was a
statistically significant improvement in pinprick (3.4/58) and light touch (3.8/58) scores at 6 months
which was lost at 1 year.
Safety & Adverse events: Wound infection and pulmonary embolus were doubled in the steroid
group (non-significant, study not sufficiently powered).
Post-hoc analyses All the reported positive results from the NASCIS 2 trial are from post-hox
subgroup analysis.
When patients were stratified by time to treatment, patients receiving steroids within 8 hours had a
statistically significant improvement of 5 points on the motor score at 6 months and 1 year
(p=0.03). Patients treated with steroids more than 8 hours after injury had a worse neurological
outcome, but this did not achieve significance.
This means it was BULLSHIT
NASCIS II, 1990
• NASCIS 2 = negative study. The Level 1
evidence from this data is that there is no
difference between methylprednisolone and
placebo in the outcome of spinal cord injury.
Data from post-hoc analyses cannot be
classified as Level 1 or 2 evidence (or even
level 3)!
NASCIS III Trial – And I Quote
• Demonstrated efficacy of a 24-hour dosing regimen of MP in human SCI in
NASCIS II led to this
• Determine whether extension of the MP infusion from 24 to 48 hours
resulted in greater improvement in neurologic recovery
• Determine whether treatment initiation within 3 hours following injury
was more effective than therapy initiated from 3 to 8 hours post-SCI.
• AT COMPLETION: All treatment arms produced comparable degrees of
recovery when treatment was begun within the 3-hour window.
• Initiation of treatment within the first 3 hours is optimal
• Non-glucocorticoid tirilazad is as effective as 24-hour MP therapy
• If treatment is initiated more than 3 hours post-SCI, extension of the MP
dosing regimen is indicated, from 24 hours to 48 hours
• Significantly more glucocortioid-related immunosuppressive side effects
were seen with more prolonged dosing
STILL CHARGING
HARD
IN
NASCIS
III
– Severe sepsis and pneumonia
– Tirilazad showed no evidence of steroid-related side effects
NASCAR…er…NASCIS III, 1997
• NASCIS III is being adopted worldwide:
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Design: Multicentre, prospective, randomized, double-blind trial. No placebo arm.
Patients: 499 patients with acute spinal cord injury. Follow-up of 459 patients (92%) at 1 year (439 /
88% including deaths). Treatment initialized within 8 hours. All patients received a bolus of 20-40
mg/kg methylprednisolone.
Exclusions: Children
Randomization:
Treatment 1: Methyprednisolone 5.4 mg/kg/hr for 24 hours
Treatment 2: Methyprednisolone 5.4 mg/kg/hr for 48 hours
Treatment 3: Tirilizad 2.5 mg/kg every 6 hours for 48 hours
Neurologic outcome: At admission, 6 weeks, 6 months and 1 year. Motor strength. Pin prick &
touch sensation. Disability was scored using the Functional Independence Measure (FIM).
There was no significant difference in motor score between treatment groups at any time point.
Safety & Adverse events: Mortality due to respiratory complications was 6 times higher in the 48hour group (p=0.056). There was a 2x increase in the incidence of severe pneumonia and a 4x
increase in severe sepsis in the 48-hour group compared to the 24-hour group.
This was not statistically significant but the study was underpowered for this analysis.
Post-hoc analyses: All the reported positive results from the NASCIS 3 trial are from post-hox
subgroup analysis.
What do we know about positive results
from post-hox subgroup analysis?
NASCIS III, 1997
• NASCIS 3 was a negative study. As with NASCIS 2, no
difference between methylprednisolone and placebo in
the outcome of spinal cord injury. Data cannot be
classed as Level 1 or 2 evidence (or even level 3).
• Post-hoc analysis of subgroups is completely arbitrary.
Patients who received steroids early did not gain any
benefit from steroids (70% of the study population).
Ensuing statistically significant results are almost
certainly due to random events.
Acute SCI Treatment
• The use of methylprednisolone administration
in the treatment of acute SCI is not proven as
a standard of care, nor can it be considered a
recommended treatment.
• Take care of what you can and hope for the
best.
– Manage HoTN, pain, pressure sores, respiratory
complications, bowel and bladder complications,
temperature regulation.
Topics We Will Focus On
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COPD
Asthma
Acute spinal cord injury
CAP
HCAP
Sepsis
HCA/CA Pneumonia
• This is fairly straight forward…
• FACT: Steroids are immunosuppressive
• The American Thoracic Society (ATS) states that
corticosteroid therapy (> 10mg prednisone/day)
is an immunocomprimised risk equivalent
– Increased risk for atypicals, fungal, mould
– May require longer therapy (14d vs 7-10d)
• They DON’T (usually)
• Recommend AGAINST their use
Caveat
• If your patient ONLY has HCAP or CAP then DON’T use
an immunosuppressive agent along with your
antibiotics!
– Lots of randomized, double-blind placebo controlled trials
show no benefit in duration, LOS, time to stability,
defervescence, CRP, disease severity (CURB-65, PSI), etc
• If your patient has BOTH HCAP/CAP and a severe COPD
exacerbation (and MANY of them will), you must weigh
the clinical benefits of steroids with the
immunosuppressive effects on the treatment of the
pneumonia
– If you can get by with NSAIDS and albuterol nebulizers, DO
IT!
– If not, do what you have to do to keep them out of the ICU
Topics We Will Focus On
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COPD
Asthma
Acute spinal cord injury
CAP
HCAP
Sepsis
Sepsis
SICK Vs. NOT SICK
Sepsis Defined
• SIRS + Source of Infection
• What is SIRS?
• Systemic Inflammatory Response Syndrome:
– Temperature < 36ºC or > 38ºC
– HR > 90/min
– RR > 20/min OR PaCO2 < 32mmHg
– WBC > 12k/mm3 OR < 4k/mm3 OR > 10% bands
Severe Sepsis
• Sepsis + organ dysfunction OR tissue
hypoperfusion
– HoTN, ↑ lactate or ↓ UOP
• What defines sepsis again?
– SIRS + Source of Infection
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Temperature < 36ºC or > 38ºC
HR > 90/min
RR > 20/min OR PaCO2 < 32mmHg
WBC > 12k/mm3 OR < 4k/mm3 OR > 10% bands
Septic Shock
• Severe sepsis + HoTN after fluid bolus
– BONUS: Which fluid should you use?
• What defines severe sepsis again?
• Sepsis + organ dysfunction OR tissue
hypoperfusion
– HoTN, ↑ lactate or ↓ UOP
• What defines sepsis again?
– SIRS + Source of Infection
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Temperature < 36ºC or > 38ºC
HR > 90/min
RR > 20/min OR PaCO2 < 32mmHg
WBC > 12k/mm3 OR < 4k/mm3 OR > 10% bands
Early Goal Directed Therapy in Sepsis
Your REALLY sick patient comes in…
• First you need to decide what is important
– i.e., what is your primary endpoint?
– Here are some good thoughts:
• Death
• Time to cessation of vasopressor requirement
• Development of Multiple Organ Dysfunction Syndrome
(MODS)
• Should you use an immunosuppressive drug in
a patient with a MASSIVE systemic
inflammatory response?
Steroids in Sepsis
• Meta-analysis of 49 publications investigating
corticosteroid use in patients with sepsis and
septic shock
– 10 publications were prospective, randomized,
controlled trials with exact descriptions of dosage and
regimen
– No overall beneficial effect of corticosteroids in
patients with septic shock was observed; however,
there is some evidence for a positive effect in patients
with Gram negative septicemia.
Lefering, Critical Care Medicine, 1995; 23(7): 1294-1303
Steroids in Sepsis
• Stress Dose Hydrocortisone on the Duration of Vasopressor
Therapy in Human Septic Shock
• Prospective, randomized, double-blind trial
• 1º end point = time to cessation of vasopressor support
2º end points = evolution of hemodynamics and the
multiple organ dysfunction syndrome (MODS)
• Severity of illness graded with APACHE II, MODS evaluated
by SOFA
• SDS reduced the time to cessation of vasopressor therapy
and was associated with a trend to earlier resolution of
sepsis-induced organ dysfunctions. Overall shock reversal
and mortality were not significantly different between the
groups.
Steroids in Sepsis
• Benefits and risks of corticosteroid treatment in
severe sepsis and septic shock and the influence
of dose and duration
• Comprehensive meta-analysis of prospective,
randomized, double-blind placebo controlled
trials
• Corticosteroid therapy has been used in varied
doses for sepsis and related syndromes for more
than 50 years, with no clear benefit on mortality.
There is potentially benefit on short-term
mortality in subgroup analysis
Review of Steroids
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COPD
Asthma
Acute SCI
CAP
HCAP
Sepsis
In severe COPD/Asthma, YES. Remember,
go LOW and PO. If therapy isn’t working
think about EDAC/TBM/BO!
No, No, No!
In simple CAP/HCAP, NO. If also presenting
with severe COPD/Asthma, refrain from
steroids as medically tolerated.
No, No, No!
Use It Or Lose It!