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

1. I’ve been at the gym,steroids help to make you big.Swollen to the max.

2. Steroids • Ste·roid, noun • A large class of organic compounds with a characteristic molecular structure. They include many hormones, alkaloids and vitamins. 1927

3. 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 andlanosterol • 1975, Vladimir Prelog – developed methods to determine the stereochemical course of cholesterol biosynthesis from mevalonic acid via squalene statins

4. Functions in Biological Systems • Frequentlyserve as signalingmolecules • 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

5. Ecosanoid Synthesis STEROIDS

6. Common Hospital Uses for Steroids • 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 • ErythemaMultiforme (SJS) • 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 • AnkylosingSpondylitis • Acute/Subacute Bursitis • Acute Tenosynovitis • Acute Gouty Arthritis • Osteoarthritis • Epicondylitis • Uveitis • Choroiditis • Sympathetic Ophthalmia • Allergic Conjunctivitis • Keratitis • Chorioretinitis • Optic Neuritis • Iritis • Iridocyclitis • Sarcoidosis • Decompensated Heart Failure • Bells Palsy JUST TO NAME A FEW

7. MAJOR ‘Before We Start’ Considerations • MAJOR Side Effects: • 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

8. MINOR ‘Before We Start’ Considerations • Nervousness • Acne • Steroid Rash • Appetite gain • Hyperactivity • Increased thirst • Frequent urination • Diarrhea • Reduced intestinal flora  Colitis • Leg pain/cramps/myalgia • Sensitive teeth

9. Topics We Will Focus On • COPD • Asthma • Acute spinal cord injury • CAP • HCAP • Sepsis

10. Asthma/COPD Algorithm MILD EXACERBATION MODERATE/SEVERE EXACERBATION

11. 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

12. 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

13. 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

14. EDAC – TBM – BO

15. EDAC – TBM – BO • Excessive Dynamic Airway Collapse • TracheoBronchoMalacia • BronchiolitisObliterans • In COPD/asthma patients that fail to respond to class I therapeutic recommendations for COPD/asthma exacerbation consider these

16. 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?

17. The Literature • EDAC, TM, BO are well represented in a variety of medical and scientific literature • Radiology • Neonatology • Pediatrics • Physical Therapy • Endocrinology • Pathology • Pulmonology • Dermatology • Immunology

18. 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 proteoglycanaggrecan • 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)

19. 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

20. We are not even going to touch on antibiotic therapy in COPD exacerbation

21. COPD/Asthma & Steroids Review AND GO P.O.! Think about EDAC – TBM – BO

22. Topics We Will Focus On • COPD • Asthma • Acute spinal cord injury • CAP • HCAP • Sepsis

23. Acute Spinal Cord Injury (SCI) • Motor vehicle accidents: 47% • Falls: 23% • Violence (esp. GSW): 14% • Sports accidents: 9% • Other: 7% • In this setting includes traumatic injury, not infarction

24. NASCIS II Trial – And I Quote • 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.

25. Let’s Look Closer at NASCIS II • 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 analysesAll 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

26. 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)!

27. 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-glucocorticoidtirilazad 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 • Significantlymoreglucocortioid-related immunosuppressive side effects were seen with more prolonged dosing • Severe sepsis and pneumonia • Tirilazadshowed no evidence of steroid-related side effects STILL CHARGING HARD IN NASCIS III

28. NASCAR…er…NASCIS III, 1997 • NASCIS III is being adopted worldwide: • 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 48-hour 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. BULLSHIT What do we know about positive results from post-hox subgroup analysis?

29. 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.

30. 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.

31. Topics We Will Focus On • COPD • Asthma • Acute spinal cord injury • CAP • HCAP • Sepsis

32. 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

33. 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

34. Topics We Will Focus On • COPD • Asthma • Acute spinal cord injury • CAP • HCAP • Sepsis

35. Sepsis SICK Vs. NOT SICK

36. 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

37. Severe Sepsis • Sepsis + organ dysfunction OR tissue hypoperfusion • HoTN, ↑ lactate or ↓ UOP • What defines sepsis again? • SIRS + Source of Infection • SIRS: • Temperature < 36ºC or > 38ºC • HR > 90/min • RR > 20/min OR PaCO2 < 32mmHg • WBC > 12k/mm3 OR < 4k/mm3 OR> 10% bands

38. Septic Shock • Severe sepsis + HoTN after fluid bolus • BONUS: Which fluid should you use? • What defines severesepsis again? • Sepsis + organ dysfunction OR tissue hypoperfusion • HoTN, ↑ lactate or ↓ UOP • What defines sepsis again? • SIRS + Source of Infection • SIRS: • Temperature < 36ºC or > 38ºC • HR > 90/min • RR > 20/min OR PaCO2 < 32mmHg • WBC > 12k/mm3 OR < 4k/mm3 OR> 10% bands

39. Early Goal Directed Therapy in Sepsis

40. 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?

41. 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

42. 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.

43. 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

44. Review of Steroids • 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!

45. Use It Or Lose It!