Systemic Steroids in
Otolaryngology: Uses or
Abuses?
Chia Haddad, PGY 3
Faculty Discussant: Dr Mirza
Grand Rounds May 7, 2009
Steroids in Otolaryngology

Otologic







Bell’s palsy
Meniere’s
SSHL
Vestibular Neuritis
Otitis Media with Effusion





Rhinologic



Allergic rhinitis
Acute/Chronic
rhinosinusitis
Nasal polyposis
Airway Management

Tonsillectomy


Anaphylaxis
Surgical edema
Peri-extubation
Infection
Congenital
malformations
Post operative
pain/edema
Neuroprotection


Acoustic Neuromas
Parotid lesions
Where is the Evidence?
Steroids in Otolaryngology







Regulation/Synthesis of glucocorticoids/mineralocorticoids
Actions throughout body
Uses in otolaryngology
Clinical Examples/Evidence based
Side Effects
Clinical Conclusions
Treatment Guidelines
Background

Edward Kendell, Tadeus Reichstein, and Philip Hench were awarded the 1950 Nobel
Prize for Physiology or Medicine the discovery of adrenal cortex hormones, their
structures, and functions
Background

Corticosteroids are a class of hormones
produced in the adrenal cortex

Glucocorticoids (cortisol):


metabolism of carbohydrate, fat,
and protein + anti-inflammatory effects
Mineralocorticoids (aldosterone):

control electrolyte and water balance
through renal sodium regulation
Glucocorticoids

Hypothalamus: Corticotropin
Releasing Factor (CRF)

Pituitary: Adrencorticotropic
Hormone (ACTH)


Adrenal Cortex: Zona Fasiculata


Pulsatile, daily diurnal variation
Cholesterol to cortisol
Bloodstream


Circulates bound to corticosteroid binding
globulin
Only small fraction in biologically active free
form
Downstream Effects

Cortisol is fat soluable, diffuses
through cell membrane to bind
receptors



Type I receptors bind glucocorticoids
and mineralocorticoids
Type II receptors bind glucocorticoids
only
Steroid-Receptor complex travels to
nucleus binding specific sites on
steroid regulated genes, modifying
mRNA levels and protein expression
Bert O'Malley, M.D., Baylor chair of molecular and cellular biology
Glucocorticoids and Metabolism

Raise serum glucose
levels


Suppress insulin secretion,
promote gluconeogenesis in
liver
Catabolic

Breakdown protein,
mobilize stores of amino
acids, enhance lipase,
inhibit nucleic acid
synthesis
Glucocorticoids and Inflammation

Subcellular:
Glucocorticoids and Inflammation

Cellular:

Block increased permeability of capillary endothelium
induced by acute inflammation

Prevent edema/vascular collapse

Suppress antigen phagocytosis

Stabilize lysozymal membranes


Inhibit hydrolysis, domino effect
Reduce quantities of inflammatory
cells
Synthetic Corticosteroids
• Do not compete for transcortin binding sites - biological affect earlier
• Metabolized more slowly in the liver
• Half Life determines level of hypothalamic pituitary adrenocortical suppression
Steroids in Otolaryngology

Otologic






Bell’s palsy
Meniere’s
SSHL
Vestibular Neuritis
Otitis Media with Effusion
Rhinologic



Allergic rhinitis
Acute/Chronic
rhinosinusitis
Nasal polyposis

Airway Management





Tonsillectomy


Anaphylaxis
Surgical edema
Peri-extubation
Infection
Pain and bleeding risk
Neuroprotection


Acoustic Neuromas
Parotid lesions
Bell’s Palsy

Idiopathic facial nerve paralysis
Most common cause of FN paralysis

Incidence: 20-30 cases per 100,000

Incomplete = good prognosis
Complete = poor prognosis



70-80% complete recovery
without treatment
Bell’s Palsy

Corticosteroid Treatment of Idiopathic Facial Nerve Paralysis: A
Meta-analysis
(Ramsey et al. Laryngoscope 2000; 110:335-341)
- Literature Review 1966 - 1998
- 47 trials identified, only 3 met inclusion criteria
1.
2.
3.
4.
5.
6.
7.
8.
Complete paralysis
Prospective studies with controls
Idiopathic diagnosis only
Treatment started within 7 dy of diagnosis
Total prednisone dose of 400 mg or greater
No other interventions
Follow up for at least 4 mo
Unilateral disease
Bell’s Palsy

Corticosteroid Treatment of Idiopathic Facial Nerve Paralysis: A Metaanalysis
(Ramsey et al. Laryngoscope 2000; 110:335-341)
CONCLUSION: Patients with IFNP treated with corticosteroids had
complete recovery 17% more on average than patients who
received placebo or no treatment (CI 99%, P = .005)
Bell’s Palsy

In 2007 a Cochrane Review was conducted of 4 randomized
controlled trials

They concluded that corticosteroids did NOT confer benefit
in patients with Bell’s Palsy - This review was withdrawn in
Issue 2 2009
Opisthotonus (Tetanus) (1809)
Scottish Anatomist/Surgeon/Artist: Sir Charles Bell
The Maniac (1806)
Bell’s Palsy

Early Treatment with Prednisolone or Acyclovir in Bell’s
Palsy
(Sullivan et al. NEJM 2007; 357: 1598 - 1607)
- DB, placebo-controlled, randomized trial
- 496 patients: within 72 hr of diagnosis, 10 dy of tx
1. Prednisolone 25mg bid
2. Acyclovir 400mg 5x/dy
3. Both agents
4. Placebo
-Evaluated at 3mo and 9mo according to HB scale
C21H28O5
Bell’s Palsy

Early Treatment with Prednisolone or Acyclovir in Bell’s
Palsy
(Sullivan et al. NEJM 2007; 357: 1598 - 1607)
CONCLUSIONS: In patients with Bell’s, early treatment with
prednisolone significantly improved the chances of
complete recovery at 3 and 9 mo. There is no evidence of a
benefit of acyclovir alone or with prednisolone
Bell’s Palsy

CONCLUSIONS:
There is good Level 1 evidence to treat Bell’s
Palsy with steroids
1. Initiate treatment within 72 hr of
diagnosis
2. Prednisolone 25 mg bid x 10dy OR
Prednisone total dose of 400 mg
There is no added benefit with acyclovir
Idiopathic Sudden Sensorineural
Hearing Loss
Relatively common disorder
 65% will recover spontaneously
 Oral steroids have been used for decades
to treat this disease

Idiopathic Sudden Sensorineural
Hearing Loss

The Efficacy of Steroids in the Treatment of Idiopathic SSNHL
(Wilson et al. Arch Otolaryngol 1980; 106: 772 - 776)
-
DB, placebo-controlled, randomized trial
67 patients: within 72 hr of diagnosis,
>30dB HL
1. Kaiser-Permanente: 0.75 - 4.5 mg bid dexamethasone
2. Mass Eye and Ear: 4mg qd - 16mg tid medrol
CONCLUSIONS: Overall recovery rate in the steroid group of 78% vs placebo
38%. Steroids had a statistically significant effect on the recovery of
hearing in patients with moderate hearing loss.
Idiopathic Sudden Sensorineural
Hearing Loss

Steroids, carbogen or placebo for sudden hearing loss: a
prospective double-blind study
(Cinamon et al. Eur Arch Otolaryngol 2001; 258: 477 - 480)
-
DB, placebo-controlled, randomized trial
41 patients: within 2wk of diagnosis,
>30dB HL
Prednisone 1mg/kg qd x 5dy
CONCLUSIONS: Overall recovery rate in the steroid group of
60% vs placebo 63%. Steroids had NO significant effect on
the recovery of patients with SSNHL
Idiopathic Sudden Sensorineural
Hearing Loss

Steroids for Idiopathic SSNHL
(Wei et al. Cochrane Data Syst Rev 2006; CD003998)
- Review of all RCT
- Only 2 of 516 studies met inclusion criteria
- Different treatment regiments
CONCLUSION: The value of steroids in the treatment of idiopathic
SSNHL remains unclear!

Treatment of Sudden Sensorineural HL
(Conlin et al. Arch Oto Head Neck Surg 2007; 133: 582-586)
- Meta-Analysis of all RCT
- 5 of 20 studies met inclusion criteria
- Different treatment regiments
CONCLUSION: Despite the traditional practice of treating SSHL
with systemic steroids, there is no evidence of benefit of steroids
over placebo. There was also no difference in the addition of
antivirals to steroids.
Idiopathic Sudden Sensorineural
Hearing Loss

CONCLUSION:
There is no level 1 evidence to support the
use of steroids in SSNHL
Airway Management

Parenteral Steroids are commonly used to
prevent and/or treat airway edema







Croup/Stridor
Congentital airway lesions/stenosis
Anaphylaxis
Infant/Adult peri-extubation
Head and Neck cancer
Trauma
Peritonsillar/Parapharyngeal infections
Airway - Peri-extubation Adult

Extubation Failure: increased mortality, ICU stay, need for
trach/long term acute care, hospital costs

Upper Airway Obstruction (UAO) is a common cause of
extubation failure

Intubation related laryngotracheal injury



Ulceration, edema, granulation, glottic/subglottic stenosis
Risk Factors: female, trauma, >80yo, large ETT, duration of intubation,
absence of cough, low Glasgow scale score
Quantitative Leak Test
Airway - Peri-extubation Adult

Against steroids:

Trials of Corticosteroids to Prevent Postextubation Airway
Complications (Meade et al. Chest 2001; 120: 464-468)



Reviewed 4RCT, over 1000 patients total, different diagnosis, different
steroids (methylprednisone, dexamethsone, hydrocortisone)
Infrequent need for re-intubation, wide CI, no significant effect
Concluded that tens of thousands of patients would be needed in order
to detect absolute differences “almost certainly not worth the resources
required”
Airway - Peri-extubation Adult

In favor of steroids:

12-h pretreatment with methylpred vs placebo for prevention of postextubation laryngeal edema
(Francois et al. Lancet 2007; 369: 1083-1089)
•Randomized DB trial,
698 patients
•20 mg
methylprednisolone IV
12hr prior to extubation
q4hr, endpoint within
24hr
•Laryngeal edema 3%
vs 22% placebo, reintubation 4% vs 8%
placebo
Airway - Peri-extubation Adult

Prophylactic administration of IV steroids for preventing airway
complications after extubation in adults
(Fan et al. BMJ 2008; Oct 20 337)
Population
Sample Size
Intervention
Edema
(steroid/placebo)
Reintubation
(steroid/placebo)
Gaussorgues
1987
PNA, post-op,
neuro
276
40 mg IV + 40
mg IM
methylpred 30
min prior
4/2
2/0
Darmon
1992
Hemo instab,
neuro, post-op
700
8mg IV dex 1 hr
prior
11/17
2/5
Ho 1996
Hemo instab,
neuro, post-op,
trauma
77
100 mg IV
hydrocort 1 hr
prior
7/10
0/1
Cheng 2006
Med + Surg
378
40 mg Iv
methylpred q6
x 4 or x 1
5: 1 dose
3: 4 dose
2: 1 dose
3: 4 dose
Francois
2007
Med, Surg,
Trauma
761
20 mg
methylpred 12 hr
before then q4 x
2
11/76
1/14
Lee 2007
PNA, sepsis,
CHF, ARDS,
COPD
80
5 IV dex q6hr x
4, 24 hr prior
4/11
1/2
Airway - Peri-extubation Adult

Prophylactic administration of IV steroids for preventing airway
complications after extubation in adults
(Fan et al. BMJ 2008; Oct 20 337)

Meta-analysis 6 RCTs, 1923 patients
Airway - Peri-extubation Adult

Meta-analysis - Conclusions
1.
2.
3.
4.
Despite various confounding variables, IV steroids do
decrease incidence of laryngeal edema by 62% and reintubation by 71%
Multiple dose steroids have a greater effect (edema
86%, re-intubation 71%)
When all steroid doses were converted to equivalent
doses of methylprednisone, multidose administration
with equiv total dose of 160mg did the best
No steroid-related adverse events were reported in any
of the studies
What is the ideal dosing regiment
and time course of administration?
What about the young ones?

Corticosteroids for the prevention and treatment of reintubation and
postextubation stridor in neonates children, and adults
(Markovitz et al. Cochrane Data Syst Rev 2008; 1 (2):CD001000)
NEONATES
1. Ferrara 1989: 59 neonates, >48hr intubation, excluded >1intubation
0.25 mg/kg IV dexamethasone 30 min prior to extubation
2. Couser 1992: 50 neonates, “high risk”: intubated >14dy, traumatic or multiple intubations
0.25 mg.kg IV dexamethasone 4hr prior to extubate, q8hr x 2 after extubation
CONLCUSIONS
-Overall trend toward decreased rate of intubation and post-extubation stridor
-Benefit appeared to be confined to the high risk group with multiple steroid doses
What about the young ones?

Corticosteroids for the prevention and treatment of reintubation and
postextubation stridor in neonates children, and adults
(Markovitz et al. Cochrane Data Syst Rev 2008; 1 (2):CD001000)
PEDIATRICS
1. Anene 1996: 63 patients, >48hr intubation, included airway abnormalities
0.5 mg/kg IV dexamethasone 6-12 hr prior to extubation then q6, 6 total doses
2. Tellez 1991: 153 patients, excluded upper airway infection/surgical trauma
0.5 mg/kg IV dexamethasone 6-12 hr prior to extubation then q6, 6 total doses
3. Harel 1997: 26 pt, effect of dex on re-intubation after initial failed extubation
0.5 mg/kg IV dexamethasone 6 hr prior to extubation then 6-12 hr after
CONLCUSIONS
-Overall trend toward decreased rate of intubation in study including underlying
airway abnormalities, higher reintubation rate when these patients were excluded
-Trend towards reduction in post-extubation stridor
-Nonsignificant reduced risk of reintubation after prior failed extubation of 45%
What about the young ones?

CONCLUSIONS:

There is insufficient evidence to conclude that prophylactic
corticosteroids reduced incidence of re-intubation and postextubation stridor

Trend toward benefit especially in “high risk” patients, multiple
doses of corticosteroids.

Future studies should separate high risk patients and included
large numbers to achieve statistical significance.

More adverse reactions were described in the pediatric trials: 7
cases glucosuria, 1 case GI bleeding
Tonsillectomy

186,000 tonsillectomies performed each year

Common complications include nausea/vomiting, pain, and
bleeding

Dexamethasone has known anti-emetic and antiinflammatory properties
Tonsillectomy

Steroids for improving recovery following tonsillectomy in children
(Steward et al. Cochrane Database 2003: CD003997)
-

Reviewed 9 studies, single intra-op dose 0.15 - 1.0 mg/kg of dex
With steroids 2x less likely to vomit, more likely to advance diet on POD1
NNT of 4 for both endpoints
No adverse events attributable to dexamethasone were reported
Steroids for Post-Tonsillectomy Pain reduction: Meta-Analysis of RCTs
(Afman et al. Otolaryng Head and Neck 2006; 134: 181-186)
-
Reviewed 8 RCTs, single intra-op dose 0.4 - 1.0 mg/kg dex
Rated pain scores using Visual Analog Scale in first 24 hr post-op
Found significant reduction of pain on POD1, 1 point less on VAS
No adverse events with single dose
Cost effective intervention
Tonsillectomy

Dexamethasone and Risk of Nausea and Vomiting and Postoperative
Bleeding After Tonsillectomy in Children
(Czarnetzki et al. JAMA 2008; 300; 2621 - 2629)
- DB, placebo-controlled, randomized trial
- 215 children - various surgical techniques
- Dexamethasone 0.05, 0.15, or 0.5 mg/kg x 1
CONCLUSIONS: Dexamethasone decreased risk of post-operative
nausea and vomiting in dose dependent manner, but also
demonstrated an increased bleeding risk. (2/53 vs 20/153)
THIS TRIAL WAS STOPPED EARLY FOR SAFETY REASONS!
Tonsillectomy

CONCLUSION:
There is level 1 evidence that a single
intra-operative dose will decrease postoperative pain and nausea, but will also
increase post-operative bleeding risk
In the context of infection?

Use of steroids in the treatment of peritonsillar abscess
(Ozbek et al. Journal of Laryngolog and Otology 2004; 118:439 - 442)
- 62 patients, 16-65 yo
1. Needle aspiration + IV abx + placebo
2. Needle aspiration + IV abx + 6-methyl-prednisolone 2-3mg/kg (max 250mg)
•There are no randomized
controlled trials to test whether
corticosteroids influence
peritonsillar abscess formation
Side Effects of Systemic Steroids

Short term








Infection Risk/Wound Healing
Hypertension
Hyperglycemia
Gastrointestinal
Psychiatric
Hypothalamic Pituitary-Adrenal
Suppression
Steroid induced myopathy
Long term





Avascular necrosis of femoral
head
Osteoporosis
Cushanoid Changes
Cataracts, glaucoma
Skin thinning, purpura
HPA Axis

Steroids suppress HPA axis

Cannot increase ACTH and cortisol during
stress → HYPOTENSIVE SHOCK

Doses ≤ 5mg Prednisone regardless of
duration, or any dose less than 3wk do not
suppress HPA axis
Doses ≥ 20mg Prednisone for more than 3
weeks, assume HPA suppression


After cessation of steroids, HPA axis can
take >12mo to recover

Minor surgery 100mg IV hydrocortisone,
maintain 20mg/dy
Major surgery 100mg IV hydrocortisone,
repeat Q8hr x 24hr, then maintenance

Infection


Corticosteroids are known immunosuppressants
A large body of evidence exists to support a dose related
increase in infection rate with corticosteroids
Low-dose pulse methylprednisolone for SLE flares is efficacious and has a decreased risk of infectious complications
(Lupus 2002, 11: 508 – 513)
1. Steroids as anti-inflammatory agents in the context of infection
2. Steroids in the post-operative population with fresh wounds/anastamosis
Wound healing

Glucocorticoids favor a catabolic state
Group 1
Table 2. Skin wound healing resistance (mean ± mean
standard deviation) of mice at the seventh, 14th and 21st
postoperative days
Healing resistance (g/cm2)
Initial
7th day
14th day
21st day
1045.8 ± 55.2*
–
–
–
Group
Group
Group
Group
–
–
–
–
Groups
Group
Group
Group
Group
Group
1:
2:
3:
4:
5:
control
surgery only
surgery + local saline injection
surgery + hydrocortisone injection
surgery +
systemic hydrocortisone injection
2
3
4
5
231.0
141.2
138.6
147.5
±
±
±
±
9.5**
7.3
8.3
6.6
461.0
457.3
453.8
448.5
Effect of local or systemic hydrocotisone on skin wound healing resistance
Einstein 2008; 6(3): 269-73.
±
±
±
±
8.2
7.1
8.5
9.2
745.5
726.3
720.4
735.3
±
±
±
±
7.4
10.3
9.8
10.6
Hypertension

Relative Mineralocorticoid
effect

Hypernatremia, hypokalemia,
hypertension
Hyperglycemia

Glucocorticoids increase
gluconeogenesis and induce
insulin resistance

Hyperglycemia increases morbidity
and mortality


Increase risk of MI/stroke, and
severity of each
Diabetes is an independent risk
factor for postoperative surgical
wound infection as well as
nosocomial infections
GI

Glucocorticoids increase the risk
of gastritis, peptic ulcer, and GI
bleeding

Steroids alone: risk of peptic ulcer
is 1.1 to 1.5 x nL

Steroids + NSAIDs: 15 x increase
in GI complications

GI prophylaxis !
Psychiatric






Profound emotional changes
Depression
Elation
Confusion
Frank Psychosis
Sleeplessness
* No reliable method can predict a patient’s psychological
reaction to steroids
Musculoskeletal

Osteoporosis – Guidelines American College of
Rheumatology

Prednisone ≥ 5mg/dy for ≥ 3mo



If long term obtain BMD (T-score <1 abnL), follow
1-2x/yr
Avascular Necrosis of Femoral Head




Calcium 1500mg/dy, Vitamin D 800U/dy, biphosphonates
1/3 cases caused by steroids,
transplant/neurosurg: 0.3% 60-150 mg dex cum
dose over 15-27dy
Hip> ankle/shoulder
Treatment is medullary decompression vs. total
joint replace
Steroid Induced Myopathy




Proximal muscle wasting and atrophy, diaphragm
Worse with fluorinated preparations: triamcinolone
and dexamethasone
Acute form: 5-7 dy after high dose (ie dex 40-80
mg/dy IV)
Chronic form: 40-60 mg prednisone/dy >3 mo
Clinical Conclusions

Bell’s Palsy: Prednisolone 25 mg bid x 10dy, within 72 hr of onset

SSNHL: No evidence steroids improve outcome

Airway:
 Adult peri-extubation: mutidose methylprednisone of 160 mg
?timing
 Neonate/Pediatric: utility in high risk?

Tonsillectomy: Intra-op dose 1.0 mg/kg
 Decrease N/V/pain, Increase bleeding risk, ?TORS

Peritonsillar/Parapharyngeal Abscess
 Steroids may speed recovery methylprednisolone 3mg/kg
 Unknown effect on abscess formation
Treatment Guidelines
•
Weigh risk/benefit carefully
•
HPA axis suppression can
be life threatening:
Prednisone >5mg/dy x 3 wk
•
•
•
Single morning dose
QOD dosing with intermediate
acting
Taper to prevent axis
suppression, 12mo to recover
Monitor and treat
hypertension
•
•
Minimize mineralocorticoid
effect
Treatment Guidelines
•Monitor
and treat
hyperglycemia
•Antibiotic
prophylaxis for
fresh wounds/anastamosis
•Leave
staples and sutures in
•GI
prophylaxis, Avoid
NSAIDS
•Protect
bones: prednisone
>5mg/dy for 3mo
•Calcium
1500, Vit D 800U,
biphos, bone scan
•Take musculoskeletal complaints
seriously
Question the Evidence
References
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The Use of Steroids in Otolaryngology. Nasal et al. Ear Nose Throat J 1996; 75(8).
Steroids in Otolaryngology. Cope et al. Laryngoscope 2008;118:1556-1560.
Prophylactic administration of parenteral steroids for preventing airway complications after extubation in adults: meta-analysis of randomised
placebo controlled trials. Fan et al. BMJ 2008;337.
Systemic Corticosteroids Thearpy: pharmacology and Endocrinologic Considerations. Melby et al. Ann of Int Med 1974;81:505-512.
Early Treatment with Prednisone or Acyclovir in Bell’s Plasy. Sullivan et al. NEJM 2007;357:1598-607.
Corticosteroid Treatment for Idiopathic Facial Nerve Paralysis: A Meta-analysis. Ramsey et al. Laryngoscope 2000;110:335-341.
Treatment of Sudden Senosrineural hearing Loss. Conlin et al. Arch Oto Head Neck Surg 2007;133:582-586.
The Efficacy of Steroids in the Treatment of Idiopathic Sudden Hearing Loss. Wilson et al. Arch Oto 1980;106:772-776.
Steroids, Carbogen, or placebo for sudden hearing loss: a prospective doublt-blind study. Cinamon et al. Eur Arch Oto 2001;258:477-480.
Steroids for Idiopathic Sudden Sensorineural hearing loss. Wei et al. Cochrane Database of Systematic Reviews 2006; CD003998.
Trials of Corticosteroids to Prevent Postextubation Airway Complications. Meade et al. Chest 2001;120:464-468.
12-h pretreatment with methylprednisolone vsersus placebo for prevention of postextubation laryngeal edema: a randomized double-blind trial.
Francois et al. 2007;369:1083-1089
Corticosteroids to prevent postextubation upper airway obstruction: the evidence mounts. Epstein, S. Critical Care 2007;11(4).
Corticosteroids for the Prevention of reintubation and postextubation stridor in the pediatric patients: A meta-analysis. Markovitz et al. Ped Crit Crae
Med 2002;3(3):223-226.
Corticosteroids for the prevention and treatment of post-extubation stridor in neonates, children, and adults. Markovitz et al. Cochrance Database of
Systematic Reviews 2008; CD001000
Corticosteroids and peritonsillar abscess formation in infectious mononucleosis. Hanna et al. J of Laryng and Oto 2004;118:459-461.
Use of steroids in the treatment of peritonsillar abscess. Ozbek et al. J of Laryng and Oto 2004;118:439-442.
Low-dose pulse methylprednisolone for SLE flares is efficacious and has a decreased risk of infectious complciations. Badsha et al. Lupus
2002;11:508-513.
Effects of local or systemic hydrocortisone on skin wound healing resistance, in different postoperative periods. Alberti et al. Einstein 2008;6(3):269273.
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