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					Treating Life Threatening Asthma

Toni Petrillo-Albarano, MD
Division of Pediatric Critical Care
Children’s Healthcare of Atlanta
Asthma: Increased Severity
Hospitalization Increased 28%

                   -MMWR, CDC
 Asthma: Increased Severity
Death Rate Increased 118% (1980 -

                        -MMWR, CDC
     The Cost of Asthma

Asthma related costs
 $6.2 billion
 Direct 3.6 billion
 Indirect $2.6 billion
 Pediatric $465 million
  Children Who Die from Asthma

Risk Factors:
   Severe disease - history of intubation,
    seizures, rapid progress
   Lack of adequate support systems
   Psychologic disease
  Children Who Die from Asthma

Risk Factors:
   Lack of perception of severity; self-
   Males
   Exclusive reliance on b agonists
50% of deaths prior to hospital
          Mechanisms of Status
  Hypersecretion                               Mucosal

                Increased resistance to air

Atelectasis    Uneven              Hyperinflation
                                deadspace compliance
   pCO2         V/Q
    pO2                         alveolar
                             hypoventilation    WOB
         Status Asthmaticus

Relative hypoxemia:
   V/Q mismatch
   hypoventilation
Hypoxemia            bronchoconstriction
    agonists impair hypoxic pulmonary
   vasoconstriction       shunt
Oxygen to keep pulse ox > 92%
           Status Asthmaticus
           Beta2 Agonist Therapy

Mainstay of therapy   Mode of delivery:
Rapid onset              Inhaled vs Systemic
                          Intermittent vs
Selective  2:
   Metaproterenol
                          Nonintubated vs
   Terbutaline            Intubated
   Albuterol
      Intravenous  Agonists

Most studies:
   inhaled therapy > to IV  agonist
Greater side effects with IV
Potential benefit    severe bronchospasm
Experience anecdotal with severe SA
IV Terbutaline:
   bolus    10 mcq/kg
   infusion   0.1-4.0 mcq/kg/min
         Status Asthmaticus
         Isoproterenol (Isuprel)

Almost pure  effects
Potent vasodilator
   pulmonary
   bronchial
Increased cardiac output
Widened pulse pressure
Increases flow to non-critical tissue
 beds (skeletal muscle)
        Status Asthmaticus
         Isoproterenol (Isuprel)

Peripheral vasodilation
Increased myocardial O2 consumption
Decreased coronary O2 delivery
“Splanchnic steal” by skeletal muscle
              Severe Asthma
         Intravenous Isoproterenol

Equivocal results
high incidence of dysrhythmias
 report of fatal myocardial ischemia
“DO not use IV Isuprel in the treatment
 of asthma ...”

         Status Asthmaticus
       Subcutaneous  Agonists

No advantage over inhaled  agonists
Increased side effects
   inability to cooperate with inhalation therapy
   rapidly decompensating patient
   failure to respond to inhaled beta-agonists
     Status Asthmaticus

  agonist

             Status Asthmaticus
        Inhaled Ipratropium + Albuterol

120 children - severe acute asthma:
   FEV1 < 50%
Albuterol (0.15 mg/kg) x 3 within 60
 minutes                     PLUS
   control saline
   ipratropium 250 mcq x 1
   ipratropium 250 mcg x 3
                              -Schuh, J Peds,
           Status Asthmaticus
       Effect of Inhaled Ipratropium

                       *   *   *
                *                       *

-Schuh, J Peds, 1995               * p < .05
              Effect with FEV1 < 30%

                             *   *     *
                        *              *

-Schuh, J Peds,
                                           * p < .05
       Status Asthmaticus
      IV or oral Corticosteroids

Mechanism of Effect:
interferes with leukotriene,
 prostaglandins synthesis
prevent cell migration
up-regulate airway  receptors
          Status Asthmaticus
        IV or oral Corticosteroids

Proven effective in 3 level I trials, meta-
Decreased hospital admission if given
 within 30 minutes
Equally effective oral or IV
IV dose effect in 1-6 hours by reversing
 2 receptor down-regulation
    Status Asthmaticus
   IV or oral Corticosteroids

Recommended dose
  Prednisone or methylprednisolone
    suggested initial dose 2 mg/kg
    1 mg/kg IV q 6 hours (max 60 mg) x 48
    then 1mg/kg q 12 hours for 3-5 days

                       -NHLBI Expert
          Status Asthmaticus
         Inhaled Corticosteroids

SI asthma has several characteristic features
   severe asthma with persistent respiratory symptoms
   frequent nighttime symptoms
   chronic airflow obstruction (FEV1 <70% of predicted)
   tend to have required systemic GC therapy at a
    younger age
   require higher daily maintenance doses of oral GCs
   are often African American.
         Status Asthmaticus
        Inhaled Corticosteroids
            Acute Asthma
ICS have been considered ineffective in
 treatment of acute exacerbations
Nevertheless, many studies published in the
 last 15 years have showed therapeutic early
 effects (after minutes of its administration)
 suggesting a different mechanism of action
 of topical character
         Status Asthmaticus
         Inhaled Corticosteroids
             Acute Asthma
These rapid effects are initiated by specific
 interactions with membrane-bound or
 cytoplasmic CS receptors, or nonspecific
 interactions with the cell membrane
asthmatic patients present a significant
 increase in airway mucosal blood flow
         Status Asthmaticus
         Inhaled Corticosteroids
             Acute Asthma
ICS would decrease blood flow by
 modulating sympathetic control of vascular
   This nongenomic action might reduce the airway
    obstruction, improving clinical and spirometric
Furthermore, the decrease of airway blood
 flow is likely to enhance the action of inhaled
 bronchodilators by diminishing their
 clearance from the airway
         Status Asthmaticus
   Long term inhaled corticosteroid

Most studies done on moderate to severe
 persistent asthma (beneficial)
Data on mild or moderate and intermittent
 not well studied
Studies by O‘Byrne et al and Lange et al
 reinforce current practice of preventing
 asthma events with the regular use of ICS in
 patients who have symptoms on most days
      Status Asthmaticus
          IV Theophylline

Phosphodiesterase inhibitor
Randomized trials (x2) - no benefit
 over standard 2agonists and/or
Uncertain benefit in episodes
 unresponsive to all other therapy
        Status Asthmaticus
            IV Theophylline

21 hospitalized children
Standard nebulized albuterol, steroids
     IV Aminophylline load/infusion
             Saline placebo

                              -Carter, J Peds,
             Status Asthmaticus
                  IV Theophylline

•No difference in hospital days
                                    - Carter, J Peds,
•Confirmed by another study
IV Theophylline in Severe Pediatric

                         -Carter, J Peds,
“Methylxanthines are NOT generally

                       -Expert Panel,
      Status Asthmaticus

Dissociative anesthetic
Direct bronchodilator
Potentiates catecholamines
Other side effects:
   tachycardia
      BP
        Status Asthmaticus

Adult studies
Case reports:
   benefit in avoiding intubation
Randomized trials:
   no added benefit
   required lower dose due to dysphoria
Children might respond better, less
          Status Asthmaticus
           Ketamine in Pediatrics

8 case reports:
   12 patients - not controlled
8 months - 14 years
Positive affect in all
9/12 intubated
Bolus/Infusion 0.2 - 2.5 mg/kg/hr
         Status Asthmaticus
          Ketamine in Pediatrics

One small pediatric study in non-
 intubated patients
   10 patients
   ketamine bolus plus 1 hr infusion in addition
    to standard therapy
   Improved CAS
   improved indicators of distress
       Status Asthmaticus
         Magnesium Sulfate

   inhibits cellular Ca++ uptake/release
   stabilizes most cell membranes
Clinical effect:
   10/13 studies showed improved PEFR in
    adults, children
2 adult studies no outcome benefit
      Status Asthmaticus
        Magnesium Sulfate

31 children (6-18 yrs) in ER
Asthma exacerbation:
   PEFR < 60% after albuterol
     MgSO4 25 mg/kg
                     -Ciarallo, J Peds, 1996
           Status Asthmaticus
              Magnesium Sulfate

                      *      *

                                  * p < .05
-Ciarallo, J Peds,
             Status Asthmaticus
                Magnesium Sulfate

                                        * p < .05

-Ciarallo, J Peds,
         Status Asthmaticus
           Magnesium Sulfate

ER discharge home:
   27% vs 0% control (p = .03)
No difference in hospital stay
No significant side effects

                            -Ciarallo, J Peds,
        Status Asthmaticus
       Leukotriene Antagonist

Mostly used as controller med
Some newer small studies to suggest
 possible benefit in acute setting
   Rapid improvement in FEv1 with single IV
    monoleukast dose (Thorax 2000; 55:260-5)
   160 mg Po Zafirlukast improved ER
    outcomes ( Ann Emerg Med 2000; 35:S10
           Status Asthmaticus
       Helium - Oxygen (HELIOX)

Blend of 80:20 helium:oxygen
Biologically inert
Insoluble in human tissue
No deleterious effects
Low density gas
   Air: 1.29 g/l
   O2: 1.43 g/l
   Helium: 0.17 g/l
       Status Asthmaticus
     Helium - Oxygen (HELIOX)

 Major effects to reduce resistance:
   Reduces turbulence
Used in upper airway obstruction
Improved pulsus paradoxus, PEFR in
 adult asthmatics
         Status Asthmaticus
       Helium - Oxygen (HELIOX)

Most recent case reports and clinical studies
 have found mixed results in the role of heliox
 for use in asthma
           Status Asthmaticus
         Helium - Oxygen (HELIOX)
 Kudukis et al showed that heliox therapy resulted in
  a significant decrease in pulsus paradoxus, a
  decrease in a modified dyspnea index, and an
  increase in peak flow
 Manthous et al reported similar findings in dyspnea
  index and pulsus paradoxus accompanied by an
  increase in peak expiratory flow.
 Rivera et al the heliox group had a lower admission
  rate compared with the placebo group (60% vs 81%).
 Other studies have shown a decrease in carbon
  dioxide, reversal of acidosis, and an increase in peak
  expiratory flow rate
          Status Asthmaticus
        Helium - Oxygen (HELIOX)
Carter et al found that short-term inhalation of
 heliox offered no benefit in hospitalized children
 with severe asthma.
Henderson et al found that 3 treatments of
 albuterol nebulized in heliox over 45 minutes
 offered no additional benefit in the ED
 management of mild to moderate asthma
Rose et al found that heliox-driven continuous
 albuterol in the ED management no difference in
 peak expiratory flow rate, respiratory rate, or
 oxygen saturation
      Status Asthmaticus
        Inhaled Anesthetics

Halothane, enflurane, isoflurane
  2 agonist effect
   vagolytic
   direct airway relaxation
No randomized (level I) trials
         Status Asthmaticus
           Inhaled Anesthetics

8 pediatric case reports:
   effect in 7/8
   isoflurane 5/8
Duration 1-34 hrs;
   Time interval for changes: 1-2 hrs
   hypotension,
   pneumothorax
Response to Inhaled Anesthetics

         Status Asthmaticus
         “Mechanical” Support

Intubation/Mechanical Ventilation
Extracorporeal Life Support
         Status Asthmaticus
        Non invasive Ventilation

Positive-pressure by nasal mask (BiPAP)
Potential benefits:
   airway stenting
   improve V/Q match
CPAP improved hypoxemia in 8 asthmatic
       Status Asthmaticus
      Non invasive Ventilation

26 children (+ 7.2 years) in PICU
19/26 managed without intubation:
     RR,    HR, SaO2
7/26 intubated
11/26 BiPAP held
Efficacy remains uncertain
               -Teague, Lang, et al, ATS,
        Status Asthmaticus
       Non invasive Ventilation

Beers et al immediate improvement in
 subjects' clinical status upon initiation of
 BiPAP, with 77% showing a decrease in
 respiratory rate, averaging 23.6% (range,
 4%-50%), and 88% showing an improved
 oxygen saturation, averaging 6.6 percentage
 points (1-28 percentage points). There were
 no adverse events due to the use of BiPAP.
          Status Asthmaticus
                Nitric Oxide

Smith et al showed that FENO measurements
 provide a useful guide about whether benefits will
 be obtained from a trial of ICS treatment.
the response to inhaled fluticasone for 4 weeks
 was significantly greater than placebo and
 occurred predominantly in the ⅓ of subjects
 whose FENO was greater than 47 ppb
In the absence of high FENO levels, a response to
 steroid was much less likely
         Status Asthmaticus
               Nitric Oxide

Exhaled nitric oxide (FENO) surrogate marker for
 eosinophilic airway inflammation.
FENO may be used to guide steroid requirements
High FENO levels may be used to predict likely
 benefits with inhaled corticosteroid (ICS)
repeated FENO measurements improve the cost-
 effectiveness of ICS therapy when used to guide
 dose requirements
         Status Asthmaticus

Usually last resort
Potential M&M
Mortality rate
   in adults 0 - 40%
   in children 0 - 5%
24-33% of PICU admissions required
 mechanical ventilation (very high?)
 Status Asthmaticus

Wear Depends !
Intubation by MD with experience
Have volume ready: hypotension
 due to ed intrathoracic pressure
           Status Asthmaticus

Best done semi-electively
   earlier rather than later
Drugs of choice:
   Atropine
   Ketamine/Midazolam
   Succinylcholine
        Status Asthmaticus
       Mechanical Ventilation

  Rest inspiratory muscles
  Protect airway
  Provide adequate gas exchange NOT
   normal exchange
  Avoid barotrauma, catastrophe
            Status Asthmaticus
     Mechanical Ventilation Indications

          Respiratory or cardiac arrest

          Cyanosis and hypoxemia on O2
          PaCO2 greater than 50 and rising >
Relative:   5mmHg/hr
          Deteriorating mental status
          Minimal chest movement/air exchange
        Status Asthmaticus
        Mechanical Ventilation

Key approach: permissive hypercapnia
    (“controlled hypoventilation”)
tolerate pCO2 to keep pH > 7.20 - 7.25
prolonged expiratory time
 rate, inspiratory time
 tidal volume
 PEEP: auto-PEEP
         Status Asthmaticus
Extracorporeal Membrane Oxygenation

Veno-venous bypass for life support in
 asthma unresponsive to all other
Membrane lung extremely efficient at
 CO2 clearance, low-flow
Allows for bronchoscopy
       Status Asthmaticus
Extracorporeal Membrane Oxygenation

 60 pediatric patients
 pCO2 at cannulation: 37-284 mmHg
 Maximal therapy
 83% survival
 7 here who all survived without
     Therapies NOT Recommended

Empiric, aggressive hydration
Chest PT
      Evidence-Based Guidelines:
               Report Card

 A: GOOD evidence to recommend for USE of
B: FAIR evidence to recommend for USE
 C: POOR evidence to support
    recommendation, but USE recommended
    on other grounds
 D : FAIR evidence to recommend EXCLUSION
F : GOOD evidence to recommend
                              -CMAJ, 1993
 Report Card: Status
 Asthmaticus Therapy

Oxygen                 C
 Agonists
  Inhaled              A+
  IV                   B
Ipratropium            A
Corticosteroids        A
Methylxanthines        D
Report Card: Status Asthmaticus Therapy

Magnesium                      B+
Ketamine                       C
HELIOX                         B-
Inhaled Anesthesia             C+
BiPAP                          C+

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