Patients with severe asthma exacerbations will get the proverbial “kitchen sink” thrown at them when it comes to treatment. First of all, that old idiomatic statement posits asthma treatment as a battle*, which it shouldn’t be. But you should be armed with a solid understanding of the evidence behind the treatments that we use when treating patients with this potentially fatal disease.

Short acting beta agonists

// Key Reference //
Cates et al. Holding chambers (spacers) versus nebulisers for beta‐agonist treatment of acute asthma. Cochrane Database of Systematic Reviews, 2013

Short-acting beta-2-selective adrenergic agonists (SABA) like albuterol treat asthma exacerbations by:

  • Relaxing bronchial smooth muscle
  • Decreasing mast cell mediator release
  • Inhibiting neutrophil, eosinophil, and lymphocyte functional responses
  • Increasing mucociliary transport
  • Affecting vascular tone and edema formation

The equivalent amount in “3 back-to-back treatments” can be given via neb or metered dose inhaler MDI (4-8 puffs). 4-6 puffs via MDI with spacer is equivalent to one neb in the cooperative patient. It is important to note that MDI with spacer can deliver a smaller particle size and thus reach the airways more effectively, whereas nebs are easier to deliver during a sicker or less cooperative patient’s tidal ventilation. In a 2013 Cochrane review of 39 RCTs in children an adults comparing nebs to inhaler the authors noted no difference in admission rates. There was a shorter length of stay in the ED for children with MDI + spacer (33 min shorter mean LOS – 95% CI -43 to -24 min). Finally, in children the pulse rate and risk of tremor was lower for MDI + spacer.

Continuous albuterol is when you fill a reservoir attached to a mask or other respiratory device to continually deliver albuterol to ill patients. If a patient is still working hard to breathe after the initial 3 back to back inhaled treatments you can elect to continue the albuterol in this manner. The usual “dose” for continuous albuterol in an adult sized patient is 10-15mg/hr. Albuterol 0.5 percent (5 mg/mL) comes in 20mL bottles and is diluted in saline to achieve a total volume of 4-5 mL for the nebulizer reservoir. You must reassess frequently, especially each hour to see if a patient can be taken off of continuous treatment.

Short acting anticholinergic agents

// Key Reference //
Griffiths B, et al. Combined inhaled anticholinergics and short‐acting beta2‐agonists for initial treatment of acute asthma in children. Cochrane Database of Systematic Reviews, 2013

Inhaled ipratropium is delivered concurrently with albuterol as a part of the well-loved “duoneb.” It also exists in inhaler form with a dose mirroring albuterol (4-8 puffs). Typically for severe asthma you give 3 back to back “duonebs” – at least every 20 minutes, but in general practice they re given right in a row. Short acting anticholinergics work synergistically with beta agonists to relieve bronchospasm. A Cochrane review of 23 child and adult trials showed decreased risk for hospitalization in severe exacerbations (RR 0.72, 95% CI 0.59 to 0.87) but not mild or moderate (test for difference between subgroups P = 0.02) when ipratropium was added to the three initial beta agonist treatments. SABA + SAAC also improve PEF more than albuterol alone. Furthermore there is a decreased ED return visits (RR 0.80, 95% CI 0.66 to 0.98) and finally, a slightly higher risk of adverse events (OR 2.03, 95% CI 1.28 to 3.20) (tremor, tachycardia) for SABA + SAAC.

Epinephrine

// Key Reference //
Baggott C, et al. Epinephrine (adrenaline) compared to selective beta- 2-agonist in adults or children with acute asthma: a systematic review and meta- analysis. Thorax, 2022

In children with markedly diminished aeration rapid delivery of beta agonists like epinephrine can supplement or augment SABA. IM Epi promotes bronchodilation and may decrease airway edema in addition to its circulatory effects. You can also use IM Epi in very anxious children, and in “anaphylasthma” – where you aren’t sure if it’s asthma, anaphylaxis or both. Here are two general scenarios in which IM Epi should be strongly considered:

  • The patient is in severe distress you cannot hear any air movement
  • You’ve given 3 SABA + SAAC treatments and the patient is no better or worse

IM Epi is better absorbed than subcutaneous Epi or terbutaline – so the best way to give it quickly is a shot.

Systemic glucocorticoids

// Key Reference //
Rowe BH, et al. Early emergency department treatment of acute asthma with systemic corticosteroids. Cochrane Database of Systematic Reviews, 2001

The moral of the story when it comes to steroids in severe asthma is the sooner the better. A 2001 Cochrane Systemic Review showed that early administration (≤1 hour from presentation) decreases admission rates (OR = 0.40, 95% CI: 0.21 to 0.78 & NNT = 8, 95% CI: 5 to 21). In general oral and IV forms are equally bioavailable. Dexamethasone is great for mild to moderate exacerbations, and even as the initial medication for severe. Oral prednisone/prednisolone requires a 5-day course whereas dex is given twice about 30 to 36 hours apart. IV glucocorticoids should be given to patients who present with impending or actual respiratory arrest, or are intolerant of oral glucocorticoids. The usual IV agent is methylprednisolone. If there is a document,ented IV dose by prehospital personnel then don’t repeat it – ours isn’t necessarily “better.” IM steroids are not the best idea, because systemic absorption can take up to 24 hours. That’s far too long when someone is sick.

Side Note: In the outpatient setting some are recommending quadrupling the dose of maintenance inhaled steroid for adolescents and adults with asthma as a potential alternative to oral steroids. This is not regular practice for children, but I figured I’d mention it here.

Intravenous magnesium

// Key Reference //
Griffiths B, et al. Intravenous magnesium sulfate for treating children with acute asthma in the emergency department. Cochrane Database of Systematic Reviews, 2016

IV magnesium is given as a rapid bolus (20 minutes) leads to bronchodilation due to inhibition of calcium influx into airway smooth muscle cells. You should administer to patients not responsive to SABA + SAAC and IV steroids. A 2014 Cochrane review of 14 RCTs in adults showed reduced hospital admissions vs placebo for severe exacerbations (OR=0.75, 95% CI 0.60 to 0.92). There were seven fewer hospital admissions for every 100 patients treated with IV Mag. In children the evidence is a little more limited, in yet another Cochrane Review, this time from 2016, a review of 3 RCTs showed that treatment with IV MgSO4 reduced the odds of admission to hospital by 68% (odds ratio (OR) 0.32, 95% confidence interval (CI) 0.14 to 0.74; children = 115; studies = 3; I2 = 63%). Finally, IV magnesium does have some side effects – but I have not seen clinically important hypotension from IV Mag, and you’ll be giving an isotonic fluid bolus anyway.

Non-invasive positive pressure ventilation

// Key Reference //
Beers SL, et al. Bilevel positive airway pressure in the treatment of status asthmaticus in pediatrics. Am J Emerg Med. 2007.

Non invasive positive pressure ventilation (NPPV) is a a therapy and temporizing measure while giving other concurrent treatments time to work. Bronchospasm and increased mucus production obstruct distal airways and increase airway resistance which leads to loooong expiratory times, air trapping, and dynamic hyperinflation (auto-PEEP). This means that patients need to generate even more negative inspiratory force which further tires them out. NPPV stents open collapsed and narrowed airways and allows for better exhalation which decreases the inspiratory work of breathing. Inspiratory positive airway pressure (IPAP) also unloads the respiratory muscles adding to the benefit.

The main indications for NPPV in severe asthma are:

  • Hypoxemia despite oxygen delivery – with or without HFNC
  • Documented hypercarbia (on a blood gas)
  • Progression towards respiratory muscle fatigue, and still awaiting maximal effect of glucocorticoids and bronchodilators

There are some limitations and important considerations. First, you must actually have equipment and Respiratory Therapist expertise. Second, the patient must cooperate. They may feel paradoxically more air hungry upon initiation – which dovetails into the feelings of claustrophobia. Patients also have impaired ability to clear secretions, NPPV is not definitive airway control, and it may cause gastric distention with increased risk of aspiration and vomiting. Despite these risks, the patient who can cooperate will benefit from NPPV – and the main modality I will discuss is BiPAP. Certainly CPAP, and to a degree high flow nasal cannula, also generate some degree of positive pressure ventilation – but BiPAP has definite advantages.

BiPAP, or Bi-level positive airway pressure features separate inspiratory (IPAP) and expiratory (EPAP) settings. It provides support and decreases the work of breathing in patients with significantly increased work of breathing and moderate or severe hypoxemia. A single center study showed reduction in PICU admission rate after initiation of BiPAP, and PICU RCTs have shown excellent safety and improved respiratory indicators with BiPAP + standard therapy.

In general you start low and increase for effectiveness and comfort. In kids, inspiratory pressure is 8 to 10 cm H2O & expiratory pressure at 5 cm H2O. You can increase inspiratory to 10 to 12 cm H2O, and the expiratory up to 7 to 8 cm H2O. There are many types of masks, and they have to be strapped to the patient’s face for a tight seal. This feeling of pressure, and the application of the mask are extra scary for a patient who is already highly anxious due to their difficulty breathing. Ketamine can be used for anxiolysis when initiating NIPPV. It is a great dissociative sedative and it is a bronchodilator. Bonus! The dosing is as follows:

  • 0.3 mg/kg (max 50 mg) IV bolus is a sub-dissociative dose
  • 4 mg/kg IM (max 100mg) – but you really should get an IV
  • IV infusion starts at 0.25 mg/kg/hr and titrates up by 0.5 mg/kg/hr increments up to a max of 2 mg/kg/hr

Other treatments

Terbutaline

“Terb” can be administered subcutaneously, intramuscularly, or via continuous intravenous infusion. It is a beta agonist that may help as an adjunctive infusion, though there are only a couple of well done RCTs. There is no role for its use as initial therapy in children and the Global Initiative for Asthma (GINA) does NOT recommend terbutaline in adults mostly due to the adverse effects including dysrhythmias, hypertension, and myocardial ischemia. In children who have received 3 dunes, steroids, IV mag, and continuous albuterol you can consider a Terbutaline infusion.

Magnesium infusion

This is an alternative to terbutaline infusion used in some settings. The evidence, especially in children is limited.

Inhaled magnesium

In short, it may reduce the risk of admission. But the evidence is low quality. This quote is directly from a 2017 Cochrane Review; “Treatment with nebulised MgSO₄ may result in modest additional benefits for lung function and hospital admission when added to inhaled β₂‐agonists and ipratropium bromide, but our confidence in the evidence is low and there remains substantial uncertainty. The recent large, well‐designed trials have generally not demonstrated clinically important benefits.” I haven’t personally used it.

Ketamine

I mentioned it. above in the NIPPV section, but ketamine has bronchodilator effects. It is useful in agitated patients being placed on BiPAP, and is an ideal sedative in RSI for asthma patients.

Intravenous fluids

Patients with asthma exacerbations may not be dehydrated, but they are tachycardic and have increased insensible losses. There is also decreased preload concurrent with pulmonary hyperinflation. Traditionally a 20ml/kg isotonic fluid bolus is given with IV Mag in severe acute status asthmaticus. After that let perfusion guide additional boluses versus a maintenance rate of fluids. And remember that “over-hydration” can lead to pulmonary edema that can complicate management in the PICU.

References

Baggott C, Hardy JK, Sparks J, et al. Epinephrine (adrenaline) compared to selective beta- 2-agonist in adults or children with acute asthma: a systematic review and meta- analysis. Thorax 2022; 77:563.

Basnet S , et al. Safety, efficacy, and tolerability of early initiation of noninvasive positive pressure ventilation in pediatric patients admitted with status asthmaticus: a pilot study. Pediatr Crit Care Med. 2012 Jul;13(4):393-8. 

Beers SL, et al. Bilevel positive airway pressure in the treatment of status asthmaticus in pediatrics. Am J Emerg Med. 2007;25(1):6. 

Bonini M, et al.. Beta₂-agonists for exercise-induced asthma. Cochrane Database Syst Rev. 2013 Oct 2;(10):CD003564. doi: 10.1002/14651858.CD003564.pub3. PMID: 24089311.

Cates CJ, Welsh EJ, Rowe BH. Holding chambers (spacers) versus nebulisers for beta‐agonist treatment of acute asthma. Cochrane Database of Systematic Reviews 2013, Issue 9. Art. No.: CD000052. DOI: 10.1002/14651858.CD000052.pub3. Accessed 19 August 2022.

D’Amato G, et al. Asthma-related deaths. MultidiscipRespir Med. 2016 Oct 12;11:37. doi: 10.1186/s40248-016-0073-0. PMID: 27752310; PMCID: PMC5059970.

Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and Prevention. www.ginasthma.org (Accessed on February 13, 2022).

Griffiths B, et al. Combined inhaled anticholinergics and short‐acting beta2‐agonists for initial treatment of acute asthma in children. Cochrane Database of Systematic Reviews 2013, Issue 8. Art. No.: CD000060. DOI: 10.1002/14651858.CD000060.pub2.

Griffiths B, Kew KM. Intravenous magnesium sulfate for treating children with acute asthma in the emergency department. Cochrane Database of Systematic Reviews 2016, Issue 4. Art. No.: CD011050. DOI: 10.1002/14651858.CD011050.pub2. Accessed 20 August 2022.

Kew KM, et al. Intravenous magnesium sulfate for treating adults with acute asthma in the emergency department. Cochrane Database Syst Rev. 2014.

Kirkland SW, Vandenberghe C, Voaklander B, Nikel T, Campbell S, Rowe BH. Combined inhaled beta‐agonist and anticholinergic agents for emergency management in adults with asthma. Cochrane Database of Systematic Reviews 2017, Issue 1. Art. No.: CD001284. DOI: 10.1002/14651858.CD001284.pub2. Accessed 19 August 2022.

Rowe BH, Spooner C, Ducharme F, Bretzlaff J, Bota G. Early emergency department treatment of acute asthma with systemic corticosteroids. Cochrane Database of Systematic Reviews 2001, Issue 1. Art. No.: CD002178. DOI: 10.1002/14651858.CD002178. Accessed 19 August 2022.

Travers AH, et al. Addition of intravenous beta(2)-agonists to inhaled beta(2)-agonists for acute asthma. Cochrane Database Syst Rev. 2012;12:CD010179. Epub 2012 Dec 12. 

*Everything but the kitchen sink” was a popular saying during the Second World War. The military would “throw everything but the kitchen sink” at enemies to force them to retreat or surrender.