Therapies For Severe Asthma

Therapies for Severe Asthma

Joan Roberts, M.D.

Assistant Professor

Pediatric Critical Care Medicine

University of Washington

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)

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

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

Established Therapies for Asthma Exacerbation Oxygen Steroids Beta agonists Anticholinergics

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

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

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)

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

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

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)

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)

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

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

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)

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

Terbutaline Dosing

No studies to guide us IV + inhaled? IV alone? If using ventilator- IV administration

reliable

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

Other Non-Established Therapies

Theophylline Magnesium sulfate Heliox Volatile agents ECLS

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

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

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

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

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

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

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)

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.

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

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

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

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

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.

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%)

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

Controlled Ventilation

Ventilate till anti-inflammatory and bronchodilators have decreased airway obstruction and airway pressures.

Extubate deeply sedated.

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

Support Ventilation

Only studied in case series paCO2 and pH Proposed mechanism: pt’s accessory

muscles augment exhalation

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.

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

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%

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)

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

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

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

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

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

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

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


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


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


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!

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

Health & Medicine

Therapies For Severe Asthma