1. Systemic Steroids in Otolaryngology: Uses or Abuses? Chia Haddad, PGY 3 Faculty Discussant: Dr Mirza Grand Rounds May 7, 2009

2. 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 Anaphylaxis Surgical edema Peri-extubation Infection Congenital malformations  Tonsillectomy Post operative pain/edema  Neuroprotection Acoustic Neuromas Parotid lesions

3. Where is the Evidence?

4. Steroids in Otolaryngology  Regulation/Synthesis of glucocorticoids/mineralocorticoids  Actions throughout body  Uses in otolaryngology  Clinical Examples/Evidence based  Side Effects  Clinical Conclusions  Treatment Guidelines

5. 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

6. 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

7. Glucocorticoids  Hypothalamus: Corticotropin Releasing Factor (CRF)  Pituitary: Adrencorticotropic Hormone (ACTH) Pulsatile, daily diurnal variation  Adrenal Cortex: Zona Fasiculata Cholesterol to cortisol  Bloodstream Circulates bound to corticosteroid binding globulin Only small fraction in biologically active free form

8. 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

9. 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

10. Glucocorticoids and Inflammation  Subcellular:

11. 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

12. 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

13. 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 Anaphylaxis Surgical edema Peri-extubation Infection  Tonsillectomy Pain and bleeding risk  Neuroprotection Acoustic Neuromas Parotid lesions

14. 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

15. 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. Complete paralysis 2. Prospective studies with controls 3. Idiopathic diagnosis only 4. Treatment started within 7 dy of diagnosis 5. Total prednisone dose of 400 mg or greater 6. No other interventions 7. Follow up for at least 4 mo 8. Unilateral disease

16. Bell’s Palsy  Corticosteroid Treatment of Idiopathic Facial Nerve Paralysis: A Meta- analysis (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)

17. 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 Scottish Anatomist/Surgeon/Artist: Sir Charles Bell Opisthotonus (Tetanus) (1809) The Maniac (1806)

18. 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 C 21 H 28 O 5 C 21 H 28 O 5

19. 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

20. 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

21. Idiopathic Sudden Sensorineural Hearing Loss  Relatively common disorder  65% will recover spontaneously  Oral steroids have been used for decades to treat this disease

22. 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.

23. 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

24. 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.

25. Idiopathic Sudden Sensorineural Hearing Loss  CONCLUSION: There is no level 1 evidence to support the use of steroids in SSNHL

26. 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

27. 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

28. 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”

29. Airway - Peri-extubation Adult  In favor of steroids : 12-h pretreatment with methylpred vs placebo for prevention of post- extubation 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, re- intubation 4% vs 8% placebo

30. 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) PopulationSample SizeInterventionEdema (steroid/placebo) Reintubation (steroid/placebo) Gaussorgues 1987 PNA, post-op, neuro 27640 mg IV + 40 mg IM methylpred 30 min prior 4/22/0 Darmon 1992 Hemo instab, neuro, post-op 7008mg IV dex 1 hr prior 11/172/5 Ho 1996 Hemo instab, neuro, post-op, trauma 77100 mg IV hydrocort 1 hr prior 7/100/1 Cheng 2006 Med + Surg37840 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 76120 mg methylpred 12 hr before then q4 x 2 11/761/14 Lee 2007 PNA, sepsis, CHF, ARDS, COPD 805 IV dex q6hr x 4, 24 hr prior 4/111/2

31. 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

32. Airway - Peri-extubation Adult  Meta-analysis - Conclusions 1. Despite various confounding variables, IV steroids do decrease incidence of laryngeal edema by 62% and re- intubation by 71% 2. Multiple dose steroids have a greater effect (edema 86%, re-intubation 71%) 3. When all steroid doses were converted to equivalent doses of methylprednisone, multidose administration with equiv total dose of 160mg did the best 4. No steroid-related adverse events were reported in any of the studies What is the ideal dosing regiment and time course of administration?

33. 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

34. 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%

35. What about the young ones?  CONCLUSIONS: There is insufficient evidence to conclude that prophylactic corticosteroids reduced incidence of re-intubation and post- extubation 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

36. Tonsillectomy  186,000 tonsillectomies performed each year  Common complications include nausea/vomiting, pain, and bleeding  Dexamethasone has known anti-emetic and anti- inflammatory properties

37. 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

38. 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!

39. Tonsillectomy  CONCLUSION: There is level 1 evidence that a single intra-operative dose will decrease post- operative pain and nausea, but will also increase post-operative bleeding risk

40. 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

41. 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

42. 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

43. Infection  Corticosteroids are known immunosuppressants  A large body of evidence exists to support a dose related increase in infection rate with corticosteroids 1.Steroids as anti-inflammatory agents in the context of infection 2. Steroids in the post-operative population with fresh wounds/anastamosis Low-dose pulse methylprednisolone for SLE flares is efficacious and has a decreased risk of infectious complications (Lupus 2002, 11: 508 – 513)

44. Wound healing  Glucocorticoids favor a catabolic state Table 2. Skin wound healing resistance (mean ± mean standard deviation) of mice at the seventh, 14th and 21st postoperative days GroupsHealing resistance (g/cm2) Initial7th day14th day21st day Group 11045.8 ± 55.2*––– Group 2–231.0 ± 9.5**461.0 ± 8.2745.5 ± 7.4 Group 3–141.2 ± 7.3457.3 ± 7.1726.3 ± 10.3 Group 4–138.6 ± 8.3453.8 ± 8.5720.4 ± 9.8 Group 5–147.5 ± 6.6448.5 ± 9.2735.3 ± 10.6 Group 1: control Group 2: surgery only Group 3: surgery + local saline injection Group 4: surgery + hydrocortisone injection Group 5: surgery + systemic hydrocortisone injection Effect of local or systemic hydrocotisone on skin wound healing resistance Einstein 2008; 6(3): 269-73.

45. Hypertension  Relative Mineralocorticoid effect Hypernatremia, hypokalemia, hypertension

46. 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

47. 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 !

48. Psychiatric  Profound emotional changes  Depression  Elation  Confusion  Frank Psychosis  Sleeplessness * No reliable method can predict a patient’s psychological reaction to steroids

49. Musculoskeletal  Osteoporosis – Guidelines American College of Rheumatology Prednisone ≥ 5mg/dy for ≥ 3mo  Calcium 1500mg/dy, Vitamin D 800U/dy, biphosphonates If long term obtain BMD (T-score <1 abnL), follow 1-2x/yr  Avascular Necrosis of Femoral Head 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

50. 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

51. 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

52. 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

53. Question the Evidence

54. References  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):269- 273.  Mechanisms of glucocorticoid induced hypertension. Whitworth, J. Kidney Int 1987;31:1213-1224.  Steroids ofr improving recovery following tonsillectomy in children. Welge et al. Cochranse database of Systematic Reviews 2003; CD003997.  Steroids for Post-Tonsillectomy Pain reduction: Meta-Analysis of Randomized Controlled Trials. Afman et al. Oto Head and Neck 2006;134(2):181- 186.  Dexamethasone and Risk of Nausea and Vomiting and Postopertive Bleeding After tonsillectomy in Children. Czarnetzki et al. JAMA 2008;300(22):2621-2630  Recommendations for the Prevention and Treatment of Glucocorticoid Induced Osteoporosis. Arthritis and Rheumatism 2001;44(7):1496-1503.  Steroids and the Surgical Patient. Jabbour, s. Med Clinic of Nor Amer 2001;85(5).

55. THANK YOU