Treatment of Acute Asthma: Beyond BAgonists and Steroids

1
Treatment of Acute Asthma Beyond B-Agonists and
Steroids

• by
• Nicholas Kallay

2
ED Management of Asthma Exacerbation
Adapted from Expert Panel Report 2 Guidelines
for the Diagnosis and Management of Asthma. Fig
3-11
3
Potential Treatments for Acute Asthma

• B-agonists
• Corticosteroids
• Oxygen
• Intubation Mechanical Ventilation
• Methylxanthines
• Ipratropium Bromide
• BiPAP
• Heliox
• MgSO4 Infusion

• Mucolytics
• Chest Physical Therapy
• Aggressive Hydration
• Antibiotics
• Inhalational Anesthetics
• ECMO
• Inhalational Furosemide
• Inhalational MgSO4

4
Methylxanthines (Theophylline)

• Used for over 50 years to treat asthma
• Poorly understood mechanism of action
• Physiologic effects thought to include
  bronchodilation, stimulation of diaphragmatic
  contractility, mucocilliary clearance, and
  possibly some anti-inflammatory effect.
• Dose related toxicities include nausea, vomiting,
  headache, CNS stimulation, seizure, hematemasis,
  hyperglycemia, and hypokalemia

5
Rossing and Associates

• 48 patients randomized to 60 min of epinephrine
  SQ, isoproterenol neb, or aminophylline
• All groups showed improvement, but aminophylline
  significantly less
• strengths randomized, treatment groups similar
• weakness not blinded

Effect on FEV1
FEV1 (l)
Time (min)
Adapted from Amer Rev Respir Dis
1980. 122 365-371. Fig 2
6
Carlos and Gustavo Rodrigo

• 94 patients treated 2 hours with salbutamol MDI,
  hydrocortisone, and aminophylline or placebo
• No significant difference in PFTs, ED treatment
  times or rate of admission
• Increased incidence of side effects in
  aminophylline group
• Strengths randomized, double-blind, placebo
  controlled, adequate sample size

Side Effects Reported at End of Trial
of Patients
Adapted form Chest 1994. 106 1071-1076. Fig 2
7
Corroborating Studies and a Caveat

• Several other studies, including those by Fanta,
  Murphy, and Siegel have shown similar results
• Of note these studies were done at presentation
  in the ED
• Some studies, such as by Huang, suggest benefits
  of theophylline after admission

8
Bottom Line on Methylxanthines

• Guidelines published by the NIH report that in
  the ED, "theophylline/aminophylline is not
  recommended because it appears to provide no
  additional benefit to optimal inhaled B2-agonist
  therapy and may increase adverse effects.
• Use after admission remains controversial

9
Ipratropium Bromide

• A synthetic anticholinergic compound
• Anticholinergic compounds are known to cause
  bronchodilation
• Atropine has been used, but often limited due to
  side effects such as tachycardia, dry mouth,
  disturbances of visual accommodation, etc.
• Ipratropium thought to be relatively free of side
  effects, but with preservation of bronchodilatory
  properties

10
Bryant

• 28 patients with mild/mod asthma exacerbations
• Given two drugs at 0 and 90 minutes
• 1st treatment favored B-agonist only, but 2nd
  treatment and final result favored combination
• Strengths randomized, controlled, double-blind
• Weakness small study

Fenoterol vs. Ipratropium
FEV1 (liters)
Time (minutes)
Adapted from Chest 1985. 88 24-29
11
Ward

• 24 patients given hydrocortisone and salbutamol
  followed by salbutamol or ipratropium two hours
  later
• Combo group with significant improvement
• Strengths randomized, controlled, double-blind
• Weaknesses small study

Salbutamol vs. Ipratropium
PEFR (l/min)
Time (hour)
Adapted from Br J Dis Chest 1985. 79 374-378.
Fig 1
12
Karpel FitzGerald

• 384 patients
• Randomized, double-blind
• Albuterol or albuterol / ipratropium at 0 and 45
  minutes
• Significantly more responders in combo group at
  45 min, but no significant difference after, or
  in other categories

• 342 patients
• Randomized, double-blind
• Salbutamol or salbutamol / ipratropium at 0 and
  45 minutes
• All patients given O2 and methylprednisolone
• No significant differences found between groups

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Ipratropium Bromide Bottom Line

• Small, early studies tend to favor its use
• More recent, larger studies fail to find benefit
• NIH Guidelines state ipratropium may be
  considered
• Given ipratropiums relative lack of toxicity, I
  will probably generally use it by shouldnt
  hurt, might help reasoning

14
Noninvasive Positive-Pressure Ventilation (BiPAP)

• Literature is extensive in treatment of COPD, but
  sparse in treatment of acute asthma
• Studies using CPAP in asthma have shown it to
  improve symptoms, but not gas exchange

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BiPAP

• BiPAP theoretical benefits
• Decreased work of breathing (and CO2 production)
• Ameliorating large negative intrapleural
  pressures and accompanying potential for
  hemodynamic compromise
• Bronchodilation with decreased airway resistance
  (due to splinting airways open with air
  pressure)
• Improved delivery of inhalational medication
• Problems include
• Discomfort with facemask and pressure apparatus
• Requires very close observation by trained
  personnel

16
Meduri and Colleagues
Results on BiPAP

• 17 patients with severe asthma hypercarbia
  started on BiPAP (with corticosteroids and
  B-agonist by nebulizer
• Significant improvement in less than 2 hours
• Reported well tolerated
• Weakness uncontrolled case series

Time (hrs)
Adapted from Chest. 1996. 110 767-774. Figs 1
2
17
Pollack and Associates

• 100 asthmatics given 2 albuterol treatments by
  nebulizer or BiPAP 20 minutes apart
• Significantly improved PEFR in BiPAP group
• Strengths moderate sized trial, randomized,
  controlled
• Weaknesses not blinded, only followed patients
  for brief time

Modes of B-agonist Application
Mean PEFR (l/min)
Adapted from Ann Emerg Med 1995. 26 552-557.
Fig 1
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BiPAP Bottom Line

• Little evidence to guide us
• Existing evidence seems to support its use
• Given few known risks with an attempt, would
  consider BiPAP in patients refractory to
  conventional therapy (B-agonists and
  corticosteroids), or facing impending intubation

19
Magnesium Sulfate (Infused)

• Mechanism of action not well understood but may
  inhibit bronchial smooth muscle contraction by
  inhibiting intracellular influx of calcium
• Side effects are dose and rate related
• facial warmth, flushing, decrease in BP,
  sweating, nausea, emesis, CNS effects (including
  coma)

20
Green and Rothrock

• 120 patients received steroids, albuterol
  inhalation and MgSO4 2g iv over 20 minutes
• No difference in ED treatment time, admissions,
  PEFR, or relapse rates
• Strengths prospective, randomized, relatively
  large sample size
• Weaknesses not blinded, ? inclusion COPD, ?
  adequate levels serum Mg achieved

21
Skobeloff and Colleagues
Change In PEFR

• 38 patients with moderate/severe asthma who
  failed to improve significantly in 90 min
  following treatment with steroids, aminophylline,
  and metaproterenol neb (x2) were given MgSO4 1.2g
  iv over 20 min
• Modest but significant improvement in PEFR
• Strengths randomized, placebo controlled,
  double-blind
• Weaknesses small study, minimally aggressive
  with B-agonist

PEFR, L/min
Time, min
Adapted from JAMA 1989. 2621210-1213. Fig 1
22
Bloch and Associates

• 135 patients treated with albuterol, steroids,
  MgSO4 2g iv over 20 min
• MgSO4 only benefited severe subgroup
• Strength randomized, double-blind, placebo
  controlled
• Weakness subgroup needed for significance

FEV1 Change in Severe Asthma
Mg
FEV1 ( pred)
Time (minutes)
Adapted from Chest 1995. 107 1576-1581. Fig 1
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Is bronchodilation dose dependent?

• Okayama found benefit with 2.5g MgSO4 over 20
  minutes in smaller Asian patients
• At least 2 case series reporting benefit with
  higher doses MgSO4
• MgSO4 2g iv over 2 minutes
• some nausea/vomiting
• MgSO4 10-20g iv over 1 hour followed by 0.4 g/hr
• some patients did have mild/mod hypotention

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Bottom Line on MgSO4

• Lower doses (2g in 20 min) well tolerated but
  probably only helpful in severe asthma if at all
• Weak evidence that higher doses (2g in 2 min or
  10-20 g in 1 hour) more effective, but side
  effects may be more of a problem
• Doses on the order of 2g in 2 min shown to be
  safe in obstetrical literature

25
Heliox

• As described by Gluck Helium-oxygen mixtures
  improve ventilation by reducing the Reynolds
  number and reducing density dependent resistance.
  Heliums beneficial effects are due to its high
  kinematic viscosity, high binary diffusion
  coefficient for CO2, and high diffusivity.
• In English Helium flows through airways more
  easily that nitrogen, decreasing work of
  breathing
• Not thought to directly promote bronchodilation

26
Heliox an Ethereal Treatment

• Few clinical trials mostly consisting of case
  series, uncontrolled studies, and some pediatric
  literature
• No definitive study, but seems to be a
  consensus in the literature supporting its use in
  some cases - particularly severe asthma

27
Manthous and Associates

• 27 patients who presented to ED with acute asthma
  and did not significantly improve with 30 minutes
  treatment using B-agonists and steroids
• Patients randomized to heliox or room air
• PP, HR, RR, PEFR, and visual analog dyspnea
  scores measured at 30 min, 15 min into study gas,
  and 15 min after returning to room air
• Strengths controlled
• Weaknesses not randomized or blinded, small
  study, heliox group significantly greater
  baseline PP

28
Manthous and Associates
Asthmatic PEFR on Air Heliox
Asthmatic PP on Air Heliox
Pulsus Paradoxus (mmHg)
Peak Flow (lpm)
Time After B-agonist (min)
Time After B-agonist (min)
Adapted from Am J Respir Crit Care Med 1995.
151 310-314. Figs1 3
29
Heliox Bottom Line

• Little available evidence
• May be helpful (at least in very severe asthma)
  in buying time until other treatments become
  effective
• Use unlikely to cause harm unless it delays other
  necessary treatment such as B-agonists or
  necessary intubation

30
The Bottom, Bottom Line

• B-agonists and corticosteroids remain the
  mainstay treatments for asthma exacerbation
• Methylxanthines not helpful acutely, but may play
  a role subacutely and/or in chronic management
• Ipratropium Bromide not harmful, may help
• BiPAP and Heliox may spare a patient from more
  morbid treatments such as intubation
• MgSO4 is without good evidence of benefit, but
  high doses may be helpful in severe asthma