therapies for severe asthma
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Therapies for Severe Asthma
Joan Roberts, M.D.
Assistant Professor
Pediatric Critical Care Medicine
University of Washington
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Asthma is More Prevalent
Asthma is the most common disease of childhood
Affects 9% of kids (groups 15-20%) 10 million missed days of school 3 million office visits (1995, < 15 year
olds) 570,000 ED visits (1995, < 15 year olds)
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Is Asthma More Severe? Hospitalization rates till mid 90’s Death- rates for all ages
– 2.1/1,000,000 kids < 5 years– 3.7/1,000,000 kids 5-14 years– 2/10,000 hospital kids (California)– 4/1000 PICU kids
Intubation rates in mid 80’s - 90’s (0.25 - 0.6 of hospital admits for
children with asthma– (large range) mean 16% of PICU admits
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Asthma Death
Half at home Some unpredictable Risk factors
– poor compliance, hx severe disease, poverty/Medicaid insurance
– twice as common in African Americans– psychological problems
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Established Therapies for Asthma Exacerbation Oxygen Steroids Beta agonists Anticholinergics
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Steroids for an “Inflammatory” Disease Systemic steroids for all hospitalized pts equally effective IV vs PO some effect in several hrs, peak 9-12
hrs recommended dose is 1 mg/kg per dose
q 4-6 hours of methylpred or prednisone
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Mechanism of Action Multiple effects: Am J Resp Crit Care 1996; 154: S21-
27, Barnes production of: interleukins, TNF alpha,
GMCSF, RANTES and others breakdown of IL-2 iNO synthase, cyclo-oxygenase,
phospholipase A2
protease inhibitors, β-2 receptors cellular immune function & mucus formation
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Steroid Therapy t1/2 of prednisone 2-4 hours regimens < 5 days - stop w/o taper inhaled fluticasone 2mg not adequate
for ED visits (N Engl J Med 2000; 343: 689 by Schuh et al)
inhaled budesonide (1600 μgm/day) for 21 days after admit relapse (JAMA 1999; 281: 2119-2126, by Rowe et al)
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Beta agonists
Most used and effective bronchodilators actives adenyl cyclase cAMP cAMP activates protein kinase leading
to smooth muscle relaxation available po, inhaled, sub Q and IV
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Inhaled β agonists
Greater bronchial dilatation systemic effects
All dosed to effect When to give continuous not crystal
clear Continuous cheaper, associated with
faster improvement & LOS
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Delivery of Inhaled Medication
Affected by particle size & shape, pt breathing factors and airway caliber
particle size (1-5 μm ideal) Jet nebulizers - (average particle 1.5-6
μm) (1-5% inhaled) MDI’s - powder and a liquid propellant
(15 m/sec) (7-14 % inhaled)
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MDI vs Nebs
ED & hospital asthma- MDI’s- cost and same to slightly LOS (Arch Dis Child 1999; 80: 421-423, Dewar et al)
MDI’s hard to give continuously If intubated MDI’s have better drug
delivery (3-4% with 6.5 ETT vs < 1% neb)
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Continuous Albuterol
Recommended doses 0.5 mg/kg/hr or 10-60 mg/hr
toxicity- hypokalemia, agitation, tremulousness, tachycardia, ventricular dysrhythmias, hypoxia- HPV
dosed to effect
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IV Terbutaline
No studies to support over inhaled tx Can ensure delivery if obstructed or
intubated Dose 10 μg/kg IV load over 5-10 min infusion 0.4-4 μg/kg/min Rebolus with increased doses 2-5
mcg/kg
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Terbutaline Toxicity
Dysrhythmias Increased myocardial O2 consumption Myocardial ischemia Hypokalemia Past history with isuprel Chiang et al. J Pediatrics 2000; 137: 73-7
(29 patients)
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Toxicity
28 children with severe asthma on continuous nebs
19 (66%) had possible ischemic changes on EKG before terbutaline
80% of children on terb had NSST changes
17/28 had CPK, 3/28 had CPK MB 0/28 had significantly troponin
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Terbutaline Dosing
No studies to guide us IV + inhaled? IV alone? If using ventilator- IV administration
reliable
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Anticholinergics
Ipatropium- quarternary amino acid blocks cholinergic bronchoconstriction
About 10% improvement in PEF over albuterol alone
Three repeat doses in ED- admission and PEF. Schuh et al (250 μgm/dose,J Pediatr 1995; 126: 639-45)
dosed q 6 hours after admission
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Other Non-Established Therapies
Theophylline Magnesium sulfate Heliox Volatile agents ECLS
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Theophylline
Still recommended as a second line agent for asthma
Mechanism of action: nonselective III and IV PDE inhibitor- cAMP & cGMP
immunomodulatory, anti-inflammatory and bronchoprotective effects
toxicity in overdose
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Theophylline for Status Asthmaticus No studies in US that suggest additional
benefit over inhaled β-agents + steroids Yung and South (Arch Dis Child 1998; 79: 405-
410) studies 163 kids 0/81 Aminophylline patients intubated
compared to 5/82 2/3’s had nausea and vomiting
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Magnesium Sulfate
Decreases free Ca++- smooth muscle relaxation, may stabilize Mast cells and histamine release
No definitive studies Bloch et al (Chest 1995; 107: 1576-81)
– 67 adults 2 gm MgSO4
– subset of severe FEV1 (< 25%) had admission rates
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Magnesium Sulfate
Pediatric dose 25-100 mg/kg over 20 minutes
Target serum level 3.5- 4.5 mg/dL Believers speculate a dose response
relationship is present May or may not work- but nontoxic
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Helium + Oxygen = Heliox
Helium- inert low MW gas, insoluble at 1 ATM
low density (0.179 μ poise) vs. air (1.293) and O2 (1.429)
density- turbulent flow increases laminar and turbulent
– P = k1 (laminar flow) + k2 (turbulent flow)2
– k2 α density
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Heliox
Discovered in 1895 1934 used for airway obstruction (Barach) Limited use if pt needs O2
Try to deliver at least 60% helium, ideally 80%
20/80 = 0.429, 40/60 = 0.678 & 80/20 = 1.178 μ poise
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Heliox
Established therapies Post extubation stridor RCT Kemper et
al (Crit Care Med 1991; 19: 356-9)
Heliox improves delivery of nebulized meds. Anderson et al (Am Rev Respir Dis 1993; 147: 524-528)
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Heliox Case series of severe asthmatics
– showed paCO2 and pH.
Pt served as control- pulsus paradoxus & FEV1
Non intubated patients- Randomized studies– studies 11-18 subjects each
– some show pulsus paradoxus & PEF or FEV1 and others did not.
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Heliox and Ventilation
Many ventilators not calibrated for Helium and underestimate TV.
Case series of Heliox via ventilator– heliox use- paO2, pH while paCO2 and
peak pressures on the ventilator
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Volatile Agents
Halogenated anesthetic gases relax smooth muscle & antagonize acetyl choline and histamine mediated constriction
Case reports for use in life-threatening status asthmatics
Problems with waste gas Can use Siemens 900 C ventilator
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Extracorporeal Life Support
Both VV and VA ECMO have been used for life threatening
ELSO registry in 1997 had 27 cases of asthma
88% survival
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Mechanical Ventilation
Indications - profound hypoxemia, life-threatening respiratory muscle fatigue or altered mental status
What does that mean? NIH recommends intubation for paCO2
over 42 torr
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Mechanical Ventilation
Historically associated with increased risk of death.
Problematic- patients have severe airway obstruction and develop air trapping, pneumothorax & bronchopleural fistula.
Limits delivery of inhaled meds.
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Mechanical Ventilation Strategy of permissive hypercapnia Prevent hypoxia Provide long E time Normal I time Infrequent breaths Limit airway pressure (small TV) Mortality Stein 1980’s (8% PICU now
0.4%)
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Controlled Ventilation
Use low respiratory rates to increase expiratory time - avoid air trapping.
Heavily sedated +/- muscle relaxed. Full ventilatory support.
Risk of steroid and NMBA myopathies
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Controlled Ventilation
Ventilate till anti-inflammatory and bronchodilators have decreased airway obstruction and airway pressures.
Extubate deeply sedated.
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Support Mode Ventilation
Wetzel (Crit Care Med 1996; 24: 1603-1605)
Use either PS or VS Patient determines respiratory rate,
inspiratory time and can increase tidal volume
Results in lower airway pressures, improved patient comfort
Avoids NMBD
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Support Ventilation
Only studied in case series paCO2 and pH Proposed mechanism: pt’s accessory
muscles augment exhalation
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Clinical PICU Practice
14 PICUs with 1631 asthmatics 16% received mechanical ventilation Centers use of ventilation varied from 0-
47% When grouped into 20% or > 20% use of
ventilation, Groups did not vary by PRISM III score, pH, paO2, paCO2 or respiratory rates.
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PICU Clinical Practice
Study limitations:– grouping arbitrary 2/3 vs 1/3, also done with
25% and 30% cuts- similar results– gases obtained on 40% of pts– no information on use of
• continuous neb /dose• IV terbutaline• heliox
• MgSO4
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NonVentilation among “High” & “Low” Use Centers “Low” N=1041 PRISM III 2.2 (3.2) paCO2 40 (17) days PICU 1 (1,2)* days hosp 3 (2,5)* aline 7%, CVC .3%* Worst gases
– 50-60 torr 8%– 60-80 torr 2%– > 80 torr 2%
“High” N=332 PRISM III 2.3 (2.8) paCO2 41 (9) days PICU 2 (1,2) Days in hosp 4 (3,6) aline 15%, CVC 3% Worst gases
– 50-60 torr 11%– 60-80 torr 4%– > 80 torr 0%
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Ventilation among “High” & “Low” Use Centers < “low” Pts N=133 PRISM III 6 (3,10) paCO2 67 (28)* a line 65%* CVC 25%* Days PICU 3 (1,6)* Days Vent 2 (1,5)* Days Hosp 6 (4,10)*
“high” Pts N=125 PRISM III 6 (3,9) paCO2 59 (21) a lines 79% CVC 68% Days PICU 4 (2,8) Days Vent 3 (2,6) Days Hosp 8(4.5,13)
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High vs Low Ventilation Centers
After adjustment for age, paCO2 and PRISM III scores: “high” use center - independent risk factor for PICU and Hospital LOS for ventilated & non ventilated asthmatics
Among ventilated pts - “high” use was an independent risk factor for length of ventilation
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Severity of Asthma Exacerbation
Mild Mod SevereBreathless w/ walking w/talking at rest
talks sentences phrases words
Accessorymuscles use
usually not commonly usually
Pulsusparadox
< 10 mm Hg 10-20 mm Hg > 20 mm Hg
PEF 80% 50-80% < 50%
Sat on RA
PaCO2
> 95%
< 42 torr
91-95%
< 42 torr
< 91%
> 42 torr
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Management Mild-Moderate Asthma Exacerbation PEF > 50% Oxygen sats > 90%, repeated inhaled -
2 agonist, systemic steroids Reassess PEF 50-80%, treat 1-3 hrs If PEF > 70% 1 hr after tx- Discharge
– with written plan
– course of steroids
– close medical follow
– education
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Management Moderate Asthma Exacerbation PEF < 50% Oxygen sats > 90%, repeated inhaled β-
2 agonist & anti-cholinergics, systemic steroids
Reassess PEF 50-70%, Admit ward Oxygen sats > 90%, repeated inhaled β-
2 agonist q 1-3 hours & inhaled anti-cholinergics, systemic steroids
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Management of Severe Asthma Exacerbation PEF < 50% Oxygen sats > 90%, repeated inhaled
ß-2 agonist & anti-cholinergics, systemic steroids
Reassess PEF < 50% admit PICU Oxygen sats > 90%, continuous inhaled
ß-2 agonist & inhaled anti- cholinergics, systemic steroids
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Near or Impending Respiratory Failure Oxygen > 90% (goal) IV steroids Continuous ß-2 agonist inhaled Repeated anti-cholinergics inhaled Move to ICU Monitor closely- intubation
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My Treatment for Severe Asthma
Systemic steroids (1-2mg/kg/dose q6) Albuterol (10mg) + ipatroprium X three Move to PICU if in extremus Continuous Albuterol escalating each
hour up to straight drug if not improving. If not improving, consider IV terbutaline
and or Heliox
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My Treatment for Severe Asthma
If still clinically in marked distress Blood gases worsening Try MgSO4
Escalate terbutaline and monitor to intubate if obtunded or hypoxemic
If intubating expect problems
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My Treatment for Severe Asthma
Intubate with ketamine, rocuronium, lidocaine
Sedative infusion Handbag pt to determine initial rate and
pressure limits Allow spontaneous ventilation Volume support or pressure support
mode
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My Treatment for Severe Asthma
Extubate when paCO2 normal on minimal vent setting VS 5 cc/kg or PS 10 and dyspnea only slight and off heliox.
Extubate to continuous nebs. Wean terbutaline Then nebs Consult pulmonary for better home
routine!
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Clinical Asthma Patterns
Infrequent Episodic Asthma (75%)- wheezes < 1/4-6 wks, minor wheezing - heavy exertion, no interval symptoms, nl lung function
Frequent Episodic Asthma (20%)- wheezes <1/wk, wheezes - moderate exercise but prevented
with β-2 agonist. Prophylactic tx usually needed
Persistent Asthma (5%) need β-2 agonist > 3/wk, frequent night awakening, chest tightness wheezes with minor exercise. Prophylactic tx mandatory