Therapies For Severe Asthma

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Therapies For Severe Asthma

  1. 1. Therapies for Severe Asthma Joan Roberts, M.D. Assistant Professor Pediatric Critical Care Medicine University of Washington
  2. 2. Asthma is More Prevalent <ul><li>Asthma is the most common disease of childhood </li></ul><ul><li>Affects 9% of kids (groups 15-20%) </li></ul><ul><li>10 million missed days of school </li></ul><ul><li>3 million office visits (1995, < 15 year olds) </li></ul><ul><li>570,000 ED visits (1995, < 15 year olds) </li></ul>
  3. 3. Is Asthma More Severe? <ul><li>Hospitalization rates  till mid 90’s </li></ul><ul><li>Death- rates for all ages </li></ul><ul><ul><li>2.1/1,000,000 kids < 5 years </li></ul></ul><ul><ul><li>3.7/1,000,000 kids 5-14 years </li></ul></ul><ul><ul><li>2/10,000 hospital kids (California) </li></ul></ul><ul><ul><li>4/1000 PICU kids </li></ul></ul><ul><li>Intubation rates </li></ul><ul><ul><li> in mid 80’s - 90’s (0.25 - 0.6 of hospital admits for children with asthma </li></ul></ul><ul><ul><li>(large range) mean 16% of PICU admits </li></ul></ul>
  4. 4. Asthma Death <ul><li>Half at home </li></ul><ul><li>Some unpredictable </li></ul><ul><li>Risk factors </li></ul><ul><ul><li>poor compliance, hx severe disease, poverty/Medicaid insurance </li></ul></ul><ul><ul><li>twice as common in African Americans </li></ul></ul><ul><ul><li>psychological problems </li></ul></ul>
  5. 5. Established Therapies for Asthma Exacerbation <ul><li>Oxygen </li></ul><ul><li>Steroids </li></ul><ul><li>Beta agonists </li></ul><ul><li>Anticholinergics </li></ul>
  6. 6. Steroids for an “Inflammatory” Disease <ul><li>Systemic steroids for all hospitalized pts </li></ul><ul><li>equally effective IV vs PO </li></ul><ul><li>some effect in several hrs, peak 9-12 hrs </li></ul><ul><li>recommended dose is 1 mg/kg per dose q 4-6 hours of methylpred or prednisone </li></ul>
  7. 7. Mechanism of Action <ul><li>Multiple effects: Am J Resp Crit Care 1996; 154: S21-27, Barnes </li></ul><ul><li> production of: interleukins, TNF alpha, GMCSF, RANTES and others </li></ul><ul><li> breakdown of IL-2 </li></ul><ul><li> iNO synthase, cyclo-oxygenase, phospholipase A 2 </li></ul><ul><li> protease inhibitors, β -2 receptors </li></ul><ul><li> cellular immune function & mucus formation </li></ul>
  8. 8. Steroid Therapy <ul><li>t 1/2 of prednisone 2-4 hours </li></ul><ul><li>regimens < 5 days - stop w/o taper </li></ul><ul><li>inhaled fluticasone 2mg not adequate for ED visits ( N Engl J Med 2000; 343: 689 by Schuh et al ) </li></ul><ul><li>inhaled budesonide (1600 μgm/day) for 21 days after admit  relapse ( JAMA 1999; 281: 2119-2126, by Rowe et al) </li></ul>
  9. 9. Beta agonists <ul><li>Most used and effective bronchodilators </li></ul><ul><li>actives adenyl cyclase  cAMP </li></ul><ul><li>cAMP activates protein kinase leading to smooth muscle relaxation </li></ul><ul><li>available po, inhaled, sub Q and IV </li></ul>
  10. 10. Inhaled β agonists <ul><li>Greater bronchial dilatation  systemic effects </li></ul><ul><li>All dosed to effect </li></ul><ul><li>When to give continuous not crystal clear </li></ul><ul><li>Continuous cheaper, associated with faster improvement &  LOS </li></ul>
  11. 11. Delivery of Inhaled Medication <ul><li>Affected by particle size & shape, pt breathing factors and airway caliber </li></ul><ul><li>particle size (1-5 μm ideal) </li></ul><ul><li>Jet nebulizers - (average particle 1.5-6 μm) (1-5% inhaled) </li></ul><ul><li>MDI’s - powder and a liquid propellant (15 m/sec) (7-14 % inhaled) </li></ul>
  12. 12. MDI vs Nebs <ul><li>ED & hospital asthma- MDI’s-  cost and same to slightly  LOS ( Arch Dis Child 1999; 80: 421-423, Dewar et al ) </li></ul><ul><li>MDI’s hard to give continuously </li></ul><ul><li>If intubated MDI’s have better drug delivery (3-4% with 6.5 ETT vs < 1% neb) </li></ul>
  13. 13. Continuous Albuterol <ul><li>Recommended doses 0.5 mg/kg/hr or 10-60 mg/hr </li></ul><ul><li>toxicity- hypokalemia, agitation, tremulousness, tachycardia, ventricular dysrhythmias, hypoxia-  HPV </li></ul><ul><li>dosed to effect </li></ul>
  14. 14. IV Terbutaline <ul><li>No studies to support over inhaled tx </li></ul><ul><li>Can ensure delivery if obstructed or intubated </li></ul><ul><li>Dose 10 μg/kg IV load over 5-10 min </li></ul><ul><li>infusion 0.4-4 μg/kg/min </li></ul><ul><li>Rebolus with increased doses 2-5 mcg/kg </li></ul>
  15. 15. Terbutaline Toxicity <ul><li>Dysrhythmias </li></ul><ul><li>Increased myocardial O 2 consumption </li></ul><ul><li>Myocardial ischemia </li></ul><ul><li>Hypokalemia </li></ul><ul><li>Past history with isuprel </li></ul><ul><li>Chiang et al . J Pediatrics 2000; 137: 73-7 (29 patients) </li></ul>
  16. 16. Toxicity <ul><li>28 children with severe asthma on continuous nebs </li></ul><ul><li>19 (66%) had possible ischemic changes on EKG before terbutaline </li></ul><ul><li>80% of children on terb had NSST changes </li></ul><ul><li>17/28 had  CPK, 3/28 had  CPK MB </li></ul><ul><li>0/28 had significantly  troponin </li></ul>
  17. 17. Terbutaline Dosing <ul><li>No studies to guide us </li></ul><ul><li>IV + inhaled? </li></ul><ul><li>IV alone? </li></ul><ul><li>If using ventilator- IV administration reliable </li></ul>
  18. 18. Anticholinergics <ul><li>Ipatropium- quarternary amino acid blocks cholinergic bronchoconstriction </li></ul><ul><li>About 10% improvement in PEF over albuterol alone </li></ul><ul><li>Three repeat doses in ED-  admission and  PEF. Schuh et al (250 μgm/dose, J Pediatr 1995; 126: 639-45) </li></ul><ul><li>dosed q 6 hours after admission </li></ul>
  19. 19. Other Non-Established Therapies <ul><li>Theophylline </li></ul><ul><li>Magnesium sulfate </li></ul><ul><li>Heliox </li></ul><ul><li>Volatile agents </li></ul><ul><li>ECLS </li></ul>
  20. 20. Theophylline <ul><li>Still recommended as a second line agent for asthma </li></ul><ul><li>Mechanism of action: nonselective III and IV PDE inhibitor-  cAMP & cGMP </li></ul><ul><li>immunomodulatory, anti-inflammatory and bronchoprotective effects </li></ul><ul><li>toxicity in overdose </li></ul>
  21. 21. Theophylline for Status Asthmaticus <ul><li>No studies in US that suggest additional benefit over inhaled β -agents + steroids </li></ul><ul><li>Yung and South (Arch Dis Child 1998; 79: 405-410) studies 163 kids </li></ul><ul><li>0/81 Aminophylline patients intubated compared to 5/82 </li></ul><ul><li>2/3’s had nausea and vomiting </li></ul>
  22. 22. Magnesium Sulfate <ul><li>Decreases free Ca ++ - smooth muscle relaxation, may stabilize Mast cells and  histamine release </li></ul><ul><li>No definitive studies </li></ul><ul><li>Bloch et al (Chest 1995; 107: 1576-81) </li></ul><ul><ul><li>67 adults 2 gm MgSO 4 </li></ul></ul><ul><ul><li>subset of severe  FEV 1 (< 25%) had  admission rates </li></ul></ul>
  23. 23. Magnesium Sulfate <ul><li>Pediatric dose 25-100 mg/kg over 20 minutes </li></ul><ul><li>Target serum level 3.5- 4.5 mg/dL </li></ul><ul><li>Believers speculate a dose response relationship is present </li></ul><ul><li>May or may not work- but nontoxic </li></ul>
  24. 24. Helium + Oxygen = Heliox <ul><li>Helium- inert low MW gas, insoluble at 1 ATM </li></ul><ul><li>low density (0.179 μ poise) vs . air (1.293) and O 2 (1.429) </li></ul><ul><li> density-  turbulent flow </li></ul><ul><li>increases laminar and turbulent </li></ul><ul><ul><li>P = k 1 (laminar flow) + k 2 (turbulent flow) 2 </li></ul></ul><ul><ul><li>k 2 α density </li></ul></ul>
  25. 25. Heliox <ul><li>Discovered in 1895 </li></ul><ul><li>1934 used for airway obstruction (Barach) </li></ul><ul><li>Limited use if pt needs  O 2 </li></ul><ul><li>Try to deliver at least 60% helium, ideally 80% </li></ul><ul><li>20/80 = 0.429, 40/60 = 0.678 & 80/20 = 1.178 μ poise </li></ul>
  26. 26. Heliox <ul><li>Established therapies </li></ul><ul><li>Post extubation stridor RCT Kemper et al (Crit Care Med 1991; 19: 356-9) </li></ul><ul><li>Heliox improves delivery of nebulized meds. Anderson et al (Am Rev Respir Dis 1993; 147: 524-528) </li></ul>
  27. 27. Heliox <ul><li>Case series of severe asthmatics </li></ul><ul><ul><li>showed  paCO 2 and  pH. </li></ul></ul><ul><li>Pt served as control-  pulsus paradoxus &  FEV 1 </li></ul><ul><li>Non intubated patients- Randomized studies </li></ul><ul><ul><li>studies 11-18 subjects each </li></ul></ul><ul><ul><li>some show  pulsus paradoxus &  PEF or FEV 1 and others did not. </li></ul></ul>
  28. 28. Heliox and Ventilation <ul><li>Many ventilators not calibrated for Helium and underestimate TV. </li></ul><ul><li>Case series of Heliox via ventilator </li></ul><ul><ul><li>heliox use-  paO 2 , pH while  paCO 2 and peak pressures on the ventilator </li></ul></ul>
  29. 29. Volatile Agents <ul><li>Halogenated anesthetic gases relax smooth muscle & antagonize acetyl choline and histamine mediated constriction </li></ul><ul><li>Case reports for use in life-threatening status asthmatics </li></ul><ul><li>Problems with waste gas </li></ul><ul><li>Can use Siemens 900 C ventilator </li></ul>
  30. 30. Extracorporeal Life Support <ul><li>Both VV and VA ECMO have been used for life threatening </li></ul><ul><li>ELSO registry in 1997 had 27 cases of asthma </li></ul><ul><li>88% survival </li></ul>
  31. 31. Mechanical Ventilation <ul><li>Indications - profound hypoxemia, life-threatening respiratory muscle fatigue or altered mental status </li></ul><ul><li>What does that mean? </li></ul><ul><li>NIH recommends intubation for paCO 2 over 42 torr </li></ul>
  32. 32. Mechanical Ventilation <ul><li>Historically associated with increased risk of death. </li></ul><ul><li>Problematic- patients have severe airway obstruction and develop air trapping, pneumothorax & bronchopleural fistula. </li></ul><ul><li>Limits delivery of inhaled meds. </li></ul>
  33. 33. Mechanical Ventilation <ul><li>Strategy of permissive hypercapnia </li></ul><ul><li>Prevent hypoxia </li></ul><ul><li>Provide long E time </li></ul><ul><li>Normal I time </li></ul><ul><li>Infrequent breaths </li></ul><ul><li>Limit airway pressure (small TV) </li></ul><ul><li>Mortality  Stein 1980’s (8% PICU now 0.4%) </li></ul>
  34. 34. Controlled Ventilation <ul><li>Use low respiratory rates to increase expiratory time - avoid air trapping. </li></ul><ul><li>Heavily sedated +/- muscle relaxed. Full ventilatory support. </li></ul><ul><li>Risk of steroid and NMBA myopathies </li></ul>
  35. 35. Controlled Ventilation <ul><li>Ventilate till anti-inflammatory and bronchodilators have decreased airway obstruction and airway pressures. </li></ul><ul><li>Extubate deeply sedated. </li></ul>
  36. 36. Support Mode Ventilation <ul><li>Wetzel (Crit Care Med 1996; 24: 1603-1605) </li></ul><ul><li>Use either PS or VS </li></ul><ul><li>Patient determines respiratory rate, inspiratory time and can increase tidal volume </li></ul><ul><li>Results in lower airway pressures, improved patient comfort </li></ul><ul><li>Avoids NMBD </li></ul>
  37. 37. Support Ventilation <ul><li>Only studied in case series </li></ul><ul><li> paCO 2 and  pH </li></ul><ul><li>Proposed mechanism: pt’s accessory muscles augment exhalation </li></ul>
  38. 38. Clinical PICU Practice <ul><li>14 PICUs with 1631 asthmatics </li></ul><ul><li>16% received mechanical ventilation </li></ul><ul><li>Centers use of ventilation varied from 0-47% </li></ul><ul><li>When grouped into 20% or > 20% use of ventilation, Groups did not vary by PRISM III score, pH, paO 2 , paCO 2 or respiratory rates. </li></ul>
  39. 39. PICU Clinical Practice <ul><li>Study limitations: </li></ul><ul><ul><li>grouping arbitrary 2/3 vs 1/3, also done with 25% and 30% cuts- similar results </li></ul></ul><ul><ul><li>gases obtained on 40% of pts </li></ul></ul><ul><ul><li>no information on use of </li></ul></ul><ul><ul><ul><li>continuous neb /dose </li></ul></ul></ul><ul><ul><ul><li>IV terbutaline </li></ul></ul></ul><ul><ul><ul><li>heliox </li></ul></ul></ul><ul><ul><ul><li>MgSO 4 </li></ul></ul></ul>
  40. 40. NonVentilation among “High” & “Low” Use Centers <ul><li>“ Low” N=1041 </li></ul><ul><li>PRISM III 2.2 (3.2) </li></ul><ul><li>paCO 2 40 (17) </li></ul><ul><li>days PICU 1 (1,2)* </li></ul><ul><li>days hosp 3 (2,5)* </li></ul><ul><li>aline 7%, CVC .3%* </li></ul><ul><li>Worst gases </li></ul><ul><ul><li>50-60 torr 8% </li></ul></ul><ul><ul><li>60-80 torr 2% </li></ul></ul><ul><ul><li>> 80 torr 2% </li></ul></ul><ul><li>“ High” N=332 </li></ul><ul><li>PRISM III 2.3 (2.8) </li></ul><ul><li>paCO 2 41 (9) </li></ul><ul><li>days PICU 2 (1,2) </li></ul><ul><li>Days in hosp 4 (3,6) </li></ul><ul><li>aline 15%, CVC 3% </li></ul><ul><li>Worst gases </li></ul><ul><ul><li>50-60 torr 11% </li></ul></ul><ul><ul><li>60-80 torr 4% </li></ul></ul><ul><ul><li>> 80 torr 0% </li></ul></ul>
  41. 41. Ventilation among “High” & “Low” Use Centers <ul><li>< “low” Pts N=133 </li></ul><ul><li>PRISM III 6 (3,10) </li></ul><ul><li>paCO 2 67 (28)* </li></ul><ul><li>a line 65%* </li></ul><ul><li>CVC 25%* </li></ul><ul><li>Days PICU 3 (1,6)* </li></ul><ul><li>Days Vent 2 (1,5)* </li></ul><ul><li>Days Hosp 6 (4,10)* </li></ul><ul><li>“ high” Pts N=125 </li></ul><ul><li>PRISM III 6 (3,9) </li></ul><ul><li>paCO 2 59 (21) </li></ul><ul><li>a lines 79% </li></ul><ul><li>CVC 68% </li></ul><ul><li>Days PICU 4 (2,8) </li></ul><ul><li>Days Vent 3 (2,6) </li></ul><ul><li>Days Hosp 8(4.5,13) </li></ul>
  42. 42. High vs Low Ventilation Centers <ul><li>After adjustment for age, paCO 2 and PRISM III scores: “high” use center - independent risk factor for PICU and Hospital LOS for ventilated & non ventilated asthmatics </li></ul><ul><li>Among ventilated pts - “high” use was an independent risk factor for length of ventilation </li></ul>
  43. 43. Severity of Asthma Exacerbation
  44. 44. Management Mild-Moderate Asthma Exacerbation <ul><li>PEF > 50% </li></ul><ul><li>Oxygen sats > 90%, repeated inhaled  -2 agonist, systemic steroids </li></ul><ul><li>Reassess PEF 50-80%, treat 1-3 hrs </li></ul><ul><li>If PEF > 70% 1 hr after tx- Discharge </li></ul><ul><ul><li>with written plan </li></ul></ul><ul><ul><li>course of steroids </li></ul></ul><ul><ul><li>close medical follow </li></ul></ul><ul><ul><li>education </li></ul></ul>
  45. 45. Management Moderate Asthma Exacerbation <ul><li>PEF < 50% </li></ul><ul><li>Oxygen sats > 90%, repeated inhaled β - 2 agonist & anti-cholinergics, systemic steroids </li></ul><ul><li>Reassess PEF 50-70%, Admit ward </li></ul><ul><li>Oxygen sats > 90%, repeated inhaled β - 2 agonist q 1-3 hours & inhaled anti-cholinergics, systemic steroids </li></ul>
  46. 46. Management of Severe Asthma Exacerbation <ul><li>PEF < 50% </li></ul><ul><li>Oxygen sats > 90%, repeated inhaled  ß-2 agonist & anti-cholinergics, systemic steroids </li></ul><ul><li>Reassess PEF < 50% admit PICU </li></ul><ul><li>Oxygen sats > 90%, continuous inhaled  ß-2 agonist & inhaled anti- cholinergics, systemic steroids </li></ul>
  47. 47. Near or Impending Respiratory Failure <ul><li>Oxygen > 90% (goal) </li></ul><ul><li>IV steroids </li></ul><ul><li>Continuous ß-2 agonist inhaled </li></ul><ul><li>Repeated anti-cholinergics inhaled </li></ul><ul><li>Move to ICU </li></ul><ul><li>Monitor closely- intubation </li></ul>
  48. 48. My Treatment for Severe Asthma <ul><li>Systemic steroids (1-2mg/kg/dose q6) </li></ul><ul><li>Albuterol (10mg) + ipatroprium X three </li></ul><ul><li>Move to PICU if in extremus </li></ul><ul><li>Continuous Albuterol escalating each hour up to straight drug if not improving. </li></ul><ul><li>If not improving, consider IV terbutaline and or Heliox </li></ul>
  49. 49. My Treatment for Severe Asthma <ul><li>If still clinically in marked distress </li></ul><ul><li>Blood gases worsening </li></ul><ul><li>Try MgSO 4 </li></ul><ul><li>Escalate terbutaline and monitor to intubate if obtunded or hypoxemic </li></ul><ul><li>If intubating expect problems </li></ul>
  50. 50. My Treatment for Severe Asthma <ul><li>Intubate with ketamine, rocuronium, lidocaine </li></ul><ul><li>Sedative infusion </li></ul><ul><li>Handbag pt to determine initial rate and pressure limits </li></ul><ul><li>Allow spontaneous ventilation </li></ul><ul><li>Volume support or pressure support mode </li></ul>
  51. 51. My Treatment for Severe Asthma <ul><li>Extubate when paCO 2 normal on minimal vent setting VS 5 cc/kg or PS 10 and dyspnea only slight and off heliox. </li></ul><ul><li>Extubate to continuous nebs. </li></ul><ul><li>Wean terbutaline </li></ul><ul><li>Then nebs </li></ul><ul><li>Consult pulmonary for better home routine! </li></ul>
  52. 52. Clinical Asthma Patterns <ul><li>Infrequent Episodic Asthma (75%)- wheezes < 1/4-6 wks, minor wheezing - heavy exertion, no interval symptoms, nl lung function </li></ul><ul><li>Frequent Episodic Asthma (20%)- wheezes <1/wk, wheezes - moderate exercise but prevented with  β - 2 agonist. Prophylactic tx usually needed </li></ul><ul><li>Persistent Asthma (5%) need  β - 2 agonist > 3/wk, frequent night awakening, chest tightness wheezes with minor exercise. Prophylactic tx mandatory </li></ul>

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