We all are all too aware of the potential morbidity and mortality associated with Asthma in children. While we agree what the 1st line strategies are to treat an asthma exacerbation (Steroids and Inhaled beta-agonists), there is often disagreement about what should be included in the 2nd and 3rd and 4th lines. Variability between not only individual providers but also regions of the country exists. This can create frustration for all of us, especially our students and residents. “Should I use Magnesium or not?” “Should I use IV beta-agonists or not?” Recently one of my illustrious Pediatric EM Fellows, Dr. Nikki Richardson, in an attempt to avoid intubating a patient with status asthmatics, used a therapy that I had long given up on – Aminophylline. I haven’t even considered Aminophylline in numerous years, but perhaps I need to put it back in the “Kitchen Sink.” Let us review one recent paper that discusses the potential benefit of Aminophylline for Status Asthmaticus:

Aminophylline: Basics

Aminophylline is actually a combination of two medications: [Zafar, 2022]
- Theophylline
- Ethylenediamine
- 2:1 ratio of Theophylline : Ethylenediamine

Mechanism is still not fully defined. [Zafar, 2022]
- Phosphodiesterase Inhibitor
  - Leads to smooth muscle relaxation in lungs and pulmonary vessesl.
  - Also leads to diuresis as well as CNS and Cardiac stimulation.
- Adenosine Receptor Antagonist
  - Inhibits release of histamine and leukotrienes.
  - Prevents bronchoconstriction.
- Histone Deacetylase Activator
  - Helps to reduce inflammatory mediators.

Adverse Reactions [Zafar, 2022]
- Theophylline has a NARROW THERAPEUTIC WINDOW (which is never good).
  - In children, goal serum concentration is 5 to 15 mcg/mL.
  - In adults, goal serum concentration can increase to 10 to 20 mcg/mL.
- Peak serum concentrations UNDER 20 mcg/mL:
  - Most side-effects are similar to caffeine (personally, I wasn’t aware caffeine had any negative effects…).
  - Restlessness, Increased diuresis, Shakiness, Increased gastric secretions, Increased GER, Irritability, Insomnia, Headache…
- Peak serum concentrations ABOVE 20 mcg/mL:
  - Cardiac arrhythmias (too fast, too slow, or irregular all seen; avoid if known cardiac disorder)
  - Intractable seizures (avoid in patients with seizure disorders)
  - CNS depression
  - Elevated liver enzymes (avoid in patients with hepatic dysfunction)
  - Allergic skin reactions

Aminophylline in the Kitchen Sink

The Kitchen Sink – Not First Line, but Hoping to Avoid the Last Line!

To be clear, we are now considering the severe presentation of status asthmaticus; the patient in whom intubation is a very real consideration. Knowing that intubating the pediatric patient in severe respiratory distress due to asthma often creates more problems (quite literally a Rock and a Hard Place), it is critically important to have many strategies that “throw” at the problem. (Some may say “throw everything BUT the kitchen sink,” but I think, “why stop at the kitchen sink… use it all!”)

MORE Beta Agonists (naturally)
Inhaled anticholingerics (useful in that first hour of therapy).
IV steroids (because it is hard to take PO meds when you are struggling to breath)
Magnesium
Heliox
NonInvasive Ventilation
Strategic Anxiety Management (Dexmedetomidine, Ketamine)
Terbutaline
Aminophylline (?)

Should Aminophylline be included in the Kitchen Sink?

Arguments Against: [Mittal, 2020]
- We have “better” medication options now.
- Has many problematic side-effects and a narrow therapeutic window.
- For severe asthma no substantial difference of efficacy comparing IV salbutamol with IV aminophylline.
- IV magnesium sulphate is more useful and safer than IV aminophylline or terbutaline. [Singhi, 2014] (interesting, since we still use terbutaline)
- International guidelines do not recommend its routine use.

Argument For:
- There is limited literature comparing 2nd line medications head to head. [Stulce, 2020]
  - Much of the literature exclude the critically ill patients!
  - It can be argued that the guidelines do not apply to the most critically ill patients.
- In patient who has had minimal response to beta-agonists, using a medication that attacks the problem via different pathophysiology may be helpful (instead of just using more beta-agonist).
- Aminophylline is associated with lower odds of intubation in African American patients compared to terbutaline. [Stulce, 2020]
  - NOTE TO THE WISE:
  - The decreased mortality from theophylline-receiving-patients could be from many reasons – know that race is a poor proxy for genetics and more of a social construct.
  - There needs to be more research to learn more about the difference before this affects practice.

Aminophylline vs Terbutaline as 2nd line Rx

We don’t typical discuss just one article (as this is not Journal Club… although a Journal Club Sandwich could be a delicious Morsel), but this one I do think deserves some consideration:

Stulce C, Gouda S, Said SJ, Kane JM. Terbutaline and aminophylline as second-line therapies for status asthmaticus in the pediatric intensive care unit. Pediatr Pulmonol. 2020 Jul;55(7):1624-1630. PMID: 32426910.

Large Retrospective Cohort Study
- Used Pediatric Health Information System Database.
- Included 53 tertiary children’s hospitals.

Results
- Included 11,133 pediatric patients treated for status asthmaticus
- 1,1144 (10.3%) received either terbutaline or aminophylline
  - Preadmission asthma severity scores were similar amongst both groups.
- Use of aminophylline varies by geographical region (the South used it the least – 7.4% vs 52.8%)
- Primary Outcome of intubation and mechanical ventilation were NOT different between the two groups.
- Sub-population of African American children, also with similar asthma severity scores, did show difference in the primary outcomes.
  - Significantly lower frequency of PICU intubation and mechanical ventilation in patients who were given aminophylline compared to terbutaline.
    - 0.68% vs 4.77%
  - African American patients who received terbutaline had significantly higher odds of being intubated during their PICU stay (OR = 12.41).

Weakness
- Retrospective study based on database – so has data input issues.
- Database is of tertiary, pediatric hospitals – so does not generalize to all hospitals.
- The decreased mortality from theophylline-receiving-patients could be from many reasons – know that race is a poor proxy for genetics and more of a social construct.
- There needs to be more research to learn more about the difference before this affects practice.

Possible Explanation
- Some people have genetic polymorphisms in their Beta-2 Receptors that limit the efficacy of Beta agonists.
- Specific genotype may be more important than phenotype.

Moral of the Morsel

Kitchen Sinks should be Full… of Options. Intubation does not make the scenario easier.. so don’t be coy with your options to prevent it.
Literature continues to evolve… because it is science. Don’t be stagnant, because that stinks.
Aminophylline is not a 1st line med… and it may not be 2nd line for everyone. There may, however, be cases where it will be more beneficial to use instead of terbutaline.
Don’t be too nostalgic… the Future offers the opportunities. One day, management may be based on genotype, not just phenotype.