FA 7121 Potential Harms from Bronchodilator Administration: FA ScR

Conflict of Interest Declaration

The ILCOR Continuous Evidence Evaluation process is guided by a rigorous ILCOR Conflict of Interest policy. The Task Force members report no conflicts of interest.

Task Force Synthesis Citation

Charlton NP, Berry D, Djärv T, Carlson J on behalf of the International Liaison Committee on Resuscitation First Aid Task Force. Potential Harm from Bronchodilators for Respiratory Concerns First Aid Task Force Synthesis of a Scoping Review Brussels, Belgium: International Liaison Committee on Resuscitation (ILCOR) First Aid Task Force, November 24, 2022. Available from: http://ilcor.org

Methodological Preamble and Link to Published Scoping Review

The continuous evidence evaluation process started with a scoping review of possible harms from bronchodilator administration conducted by the ILCOR First Aid Task Force Scoping Review team. Evidence for adult and pediatric literature was sought and considered by the First Aid Task Force.

Scoping Review

Webmaster to insert the Scoping Review citation and link to Pubmed using this format when/if it is available.

PICOST

The PICOST (Population, Intervention, Comparator, Outcome, Study Designs and Timeframe)

Population: Among adults and children in any setting with acute undifferentiated respiratory problems

Intervention: Does administration of an inhaled bronchodilator

Comparators: No administration of an inhaled bronchodilator

Outcomes: Result in adverse events including survival, dysrhythmia, cardiac ischemia, hypokalemia, need for emergency department treatment, need for hospitalization or time to treatment.

Study Designs: Randomized controlled trials (RCTs) and non-randomized studies (non-randomized controlled trials, interrupted time series, controlled before-and-after studies, cohort studies) were eligible for inclusion. It was anticipated that there would be insufficient studies from which to draw a conclusion, therefore case series were included. Only English language studies were included.

Timeframe: All years to November 2, 2022

Search Strategies

Pubmed/MEDLINE, Web of Science, and CINAHL were searched from database inception to November 2, 2022, using the following search and the English Language filter.

((((("Bronchodilator Agents"[Mesh] OR LABA[tiab] OR LAMA[tiab] OR "Bronchodilator Agents" [Pharmacological Action]) OR ("inhaled bronchodilator*"[tw] OR "beta 2-agonist*"[tiab] OR anticholinergics[tiab] OR theophylline[tiab] OR albuterol[tiab] OR Ventolin[tiab] OR levalbuterol[tiab] OR "Xopenex"[tiab] OR "ipratropium bromide"[tiab] OR "DuoNeb"[tiab])) AND ((("Patient Harm"[Mesh]) OR ( "adverse effects" [Subheading] OR "Long Term Adverse Effects"[Mesh] )) OR (harm*[tiab] OR "side effect*"[tiab] OR "adverse effect*"[tiab] OR safety[tiab] OR safe[tiab] OR toxic[tiab]))) AND ("chest tightness" OR Dyspnea OR Palpitation* OR respiratory OR painful breathing OR exercise intolerance OR "Faintness" OR noisy breathing OR grunting OR wheezing OR stridor OR Bradypnea OR Tachypnea OR Cyanosis OR "nasal flaring" OR Retraction)) AND ((cohort studies[mesh:noexp] OR longitudinal studies[mesh:noexp] OR follow-up studies[mesh:noexp] OR prospective studies[mesh:noexp] OR retrospective studies[mesh:noexp] OR cohort[TIAB] OR longitudinal[TIAB] OR prospective[TIAB] OR retrospective[TIAB]) OR "Case-Control Studies"[Mesh:noexp] OR "retrospective studies"[mesh:noexp] OR ("Control Groups"[Mesh:noexp] OR (case[TIAB] AND control[TIAB]) OR (cases[TIAB] AND controls[TIAB]) OR (cases[TIAB] AND controlled[TIAB]) OR (case[TIAB] AND comparison*[TIAB]) OR (cases[TIAB] AND comparison*[TIAB]) OR "control group"[TIAB] OR "control groups"[TIAB]) OR ("Clinical Trial" [PT:NoExp] OR "clinical trial, phase i"[pt] OR "clinical trial, phase ii"[pt] OR "clinical trial, phase iii"[pt] OR "clinical trial, phase iv"[pt] OR "controlled clinical trial"[pt] OR "multicenter study"[pt] OR "randomized controlled trial"[pt] OR "Clinical Trials as Topic"[mesh:noexp] OR "clinical trials, phase i as topic"[MeSH Terms:noexp] OR "clinical trials, phase ii as topic"[MeSH Terms:noexp] OR "clinical trials, phase iii as topic"[MeSH Terms:noexp] OR "clinical trials, phase iv as topic"[MeSH Terms:noexp] OR "controlled clinical trials as topic"[MeSH Terms:noexp] OR "randomized controlled trials as topic"[MeSH Terms:noexp] OR "early termination of clinical trials"[MeSH Terms:noexp] OR "multicenter studies as topic"[MeSH Terms:noexp] OR "Double-Blind Method"[Mesh] OR ((randomised[TIAB] OR randomized[TIAB]) AND (trial[TIAB] OR trials[tiab])) OR ((single[TIAB] OR double[TIAB] OR doubled[TIAB] OR triple[TIAB] OR tripled[TIAB] OR treble[TIAB] OR treble[TIAB]) AND (blind*[TIAB] OR mask*[TIAB])) OR ("4 arm"[tiab] OR "four arm"[tiab]))) AND (english[Filter])) AND ((("Emergency Treatment"[Mesh]) OR ( "Emergencies"[Mesh] OR "Emergency Service, Hospital"[Mesh] OR "Emergency Medicine"[Mesh] OR "Emergency Medical Dispatch"[Mesh] OR "Ambulances"[Mesh] )) OR ("first aid"[tiab] OR emergen*[tiab])) NOT "asthma"[TI] 

403 unique citations were identified following deduplication and screened for inclusion by title and abstract. Fifteen articles were identified for full text review. No articles were identified that directly pertained to the PICOST, however, we included 13 articles that were conducted in persons with known reactive airway disease in this scoping review as they discussed adverse events associated with inhaled short-acting bronchodilators.

Inclusion and Exclusion criteria

Inclusion criteria

All ages with no known history of reactive respiratory disease that developed difficulty breathing or symptoms that may be perceived as respiratory in nature and were administered a short acting inhaled bronchodilator.

Exclusion criteria

Original exclusion criteria:

• Known asthma or chronic respiratory disease known to respond to inhaled bronchodilators. Known asthma studies later included because no studies directly addressing PICOST were found, and these studies included evidence of harm.
• Bronchodilators that are not available in a first aid setting (e.g., nitrous oxide, inhaled anesthetics).
• Long-acting inhaled bronchodilators including long-acting beta agonists and inhaled steroids.

Attachment: Data tables

FA 7121 Data tables

Task Force Insights

1. Why this topic was reviewed.

• A prior ILCOR review, FA 534, evaluated the benefits of bronchodilators in persons experiencing an asthma exacerbation or suspected asthma exacerbation, but it is unknown whether first aid providers can appropriately identify a person with an asthma exacerbation.
• In addition, while bronchodilators show benefit in persons with asthma, in those with undifferentiated respiratory symptoms it is unknown whether or not indiscriminant use of a bronchodilator could result in harm.
• Potential adverse effects associated with inhaled beta-2 agonist bronchodilators include tachycardia, arrhythmias, cardiomyopathy, and myocardial ischemia {Salpeter 2004 2309}.
• If no harm is found with the use of bronchodilators for persons with undifferentiated respiratory difficulty, guidelines writers could feel more comfortable advocating for their use in a wider population.
• Conversely, if there is harm associated with a broader use then recommendations for the use of bronchodilators may need to be recommended more specifically for a certain population.

2. Narrative summary of evidence identified

• This scoping review did not identify any articles directly addressing the PICOST.
• Thirteen articles were identified that reported adverse effects of short acting inhaled bronchodilators that could be available to first aid providers in patients with reactive airway disease. (See Data Table for summary of findings).
• We identified one systematic review with meta-analysis {Payares-Salamanca 2020 3268}, three randomized controlled trials {Duarte 2020 209, Muchão 2016 1122, Newhouse 1996 595}, five observations studies {DaCruz 1989 22, Hung 1999 1099, Jerrard 1995 392, Kenyon 2014 e976, Newhouse1993 131}, and four case reports {Kokulu 2019 1217, McGonigle 2011 248, Patel 2014 221, Spooner 2005 1924}.
• A systematic review with meta-analysis reported an increase in heart rate with both albuterol metered dose inhaler (MDI) and nebulizer. There was less of an increase in heart rate when albuterol was delivered through MDI compared to when it was delivered through nebulizer (MD, −6.47; 95% CI, −11.69 to −1.25; p = .02). There was no difference in hospital admission rate between the two groups (RR, 0.89; 95% CI, 0.55–1.46; p = .65). {Payares-Salamanca 2020 3268}
• In one RCT side effects were reported in 17.2% of the nebulizer group and in 4.1% of the MDI group (p = 0.003). These side effects included generalized muscle tremors, pallor, hand tremors, headache, palpitation, vomiting, dizziness and extrasystoles on cardiac auscultation. There was in increase in heart rate in both groups. {Duarte 2002 909}
• A second RCT reported a drop in serum potassium concentrations drop in both the high dose (4.42±0.59 initial, 4.03±0.64 final) and low dose (4.60±0.61 initial 4.01±0.50 final) albuterol treatment groups (p <0.001). Glucose concentrations elevated in both high dose (91.55±18.24 initial, 126.27±45.80 final) and low dose (92.53±13.42 initial 115.43±29.24 final) groups (p<0.001). In addition, bicarbonate concentrations dropped in both the high dose (22.76±2.21 initial, 21.01±2.30 final) and low dose (23.02±2.35 initial, 21.57±1.97 final) groups (p<0.001). This study also found no difference in hospital admission rates between the two groups (p = 0.48). {Muchão 2016 1122}
• In the third RCT, 32 patients (14 fenoterol, 18 albuterol) had premature ventricular contractions and 34 patients (17 fenoterol, 17 albuterol) had premature supraventricular contractions. There was a decrease in serum potassium concentrations that was significantly greater in the fenoterol (0.23±0.04 mmol/L) than in the salbutamol (0.06±0.03 mmol/L) group (p=0.0002). There was also a greater increase in the Q-Tc interval in the fenoterol group, 0.011±0.003 s compared with 0.003±0.003 s in the albuterol group (p<0.05). This study did not show an increased risk of serious cardiac disturbances. {Newhouse 1996 595}.
• Multiple studies {DaCruz 1989 22, Kenyon 2014 e976, Newhouse 1996 595} document a decrease in serum potassium concentration following use of short acting beta agonists.
• In one study the greatest drop was 1 mmol/L with a mean on 0.54 mmol/L. {DaCruz D 1989 22} A second study reported a mean difference of −0.52 mmol/L; p < 0.001 before and after short acting beta against nebulization. {Hung 1999 27}
• An increase in heart rate was also documented in one study with a baseline heart rate of 96.4 ± 2.6 beats/min to 109.62 ± 2.9 beats/min at the conclusion of three nebulizations (95% CI 8.1 - 18.3). In this study one patient experienced a two-minute run of supraventricular tachycardia at a rate of 200 beats/rain, which spontaneously converted to a sinus tachycardia of 115 beats/min. {Jerrard 1995 392}
• A separate study reported that two patients (2.6%) felt flushed, 3 patients (4%) felt tremulous, and 1 patient (1.3%) had the feeling of palpitations. {Olshaker 1993 131}
• Case reports describe multiple side effects in patients exposed to short acting bronchodilators.
• A case of unilateral mydriasis developed after exposure to ipratropium bromide. This resulted in the person receiving a CT scan of the brain to evaluate for intracranial abnormalities. {Kokulu 2019 e3-1217}
• Severe bronchospasm occurred after exposure to an albuterol inhaler and nebulizer treatment. {Spooner 2005 1924}
• One patient experience hypokalemia and lactic acidosis after multiple uses of an albuterol inhaler and nebulizer treatment. {McGonigle R 2011 284}
• Finally, one patient developed Takotsubo cardiomyopathy, which was confirmed with angiography, that was associated with repetitive use of an albuterol inhaler. {Patel 2014 221}

3. Narrative Reporting of the task force discussions

• The task force discussed that the majority of studies on inhaled bronchodilators are conducted in a patient population with reactive airway disease including asthma and chronic obstructive pulmonary disease.
• The absence of documented harm in the pre-hospital setting does not necessary mean that harm does not occur.
• It is still not known if a first aid provider can recognize symptoms of asthma in patients with known asthma or without a formal diagnosis.
• Hypokalemia, tachycardia and tremor are described side effects in the available studies in those patients with reactive airway disease treated with short active bronchodilators.
• One systematic review and one RCT found no difference in hospital admission rates between the use of nebulized albuterol compared with MDI albuterol or high dose albuterol MDI compared with low dose albuterol MDI, respectively. {Payares-Salamanca 2020 3268, Muchão 2016 1122}
• Tachycardia, with an average increase of 13 beats per minute in one study, could potentially cause demand ischemia in a patient with cardiac disease or cause or worsen supraventricular tachycardia (SVT) in a patient with SVT. {Jerrard 1995 392}
• Hypokalemia, typically < 1mmol/L, with an average drop or 0.54 mmol/L in one study and 0.52 mmol/L in another, is described following inhaled bronchodilator treatment for the in-hospital setting. {DaCruz 1989 22, Hung 1999 27}
• It is not known if the risk of hypokalemia or tachycardia is outweighed by the potential benefits of bronchodilators.
• There is inadequate evidence to pursue a systematic review on this topic currently.

Knowledge Gaps

• No studies were identified that directly evaluated the PICOST in the first aid setting.
• In addition, no studies in the out-of-hospital setting were identified.
• In the first aid context, it is still unknown whether or not administration of a bronchodilator to a person without a diagnosis of reactive respiratory disease who is having symptoms that are potentially respiratory in nature could cause harm, particularly in those with heart disease.

References

DaCruz D, Holburn C. Serum potassium responses to nebulized salbutamol administered during an acute asthmatic attack. Arch Emerg Med. 1989 Mar;6(1):22-6. doi: 10.1136/emj.6.1.22. PMID: 2712984; PMCID: PMC1285553.

Duarte M, Camargos P. Efficacy and safety of a home-made non-valved spacer for bronchodilator therapy in acute asthma. Acta Paediatr. 2002;91(9):909-13. doi: 10.1080/080352502760272579. PMID: 12412864.

Hung CH, Chu DM, Wang CL, Yang KD. Hypokalemia and salbutamol therapy in asthma. Pediatr Pulmonol. 1999 Jan;27(1):27-31. doi: 10.1002/(sici)1099-0496(199901)27:1<27::aid-ppul6>3.0.co;2-p. PMID: 10023788.

Jerrard DA, Olshaker J, Welebob E, Caraballo V, Hooper F. Efficacy and safety of a rapid-sequence metaproterenol protocol in the treatment of acute adult asthma. Am J Emerg Med. 1995 Jul;13(4):392-5. doi: 10.1016/0735-6757(95)90121-3. PMID: 7605520.

Kenyon CC, Fieldston ES, Luan X, Keren R, Zorc JJ. Safety and effectiveness of continuous aerosolized albuterol in the non-intensive care setting. Pediatrics. 2014 Oct;134(4):e976-82. doi: 10.1542/peds.2014-0907. PMID: 25266428.

Kokulu K, Öner H, Özen C, Eroğlu SE, Altunok İ, Akça HŞ. Pharmacologic anisocoria due to nebulized ipratropium bromide: A diagnostic challenge. Am J Emerg Med. 2019 Jun;37(6):1217.e3-1217.e4. doi: 10.1016/j.ajem.2019.03.047. Epub 2019 Mar 28. PMID: 30948255.

McGonigle R, Woods RA. Take my breath away: a case of lactic acidosis in an asthma exacerbation. CJEM. 2011 Jul;13(4):284-8. doi: 10.2310/8000.2011.110236. PMID: 21722560.

Muchão FP, Souza JM, Torres HC, De Lalibera IB, de Souza AV, Rodrigues JC, Schvartsman C, da Silva Filho LV. Albuterol via metered-dose inhaler in children: Lower doses are effective, and higher doses are safe. Pediatr Pulmonol. 2016 Nov;51(11):1122-1130. doi: 10.1002/ppul.23469. Epub 2016 May 12. PMID: 27171324.

Newhouse MT, Chapman KR, McCallum AL, Abboud RT, Bowie DM, Hodder RV, Paré PD, Mesic-Fuchs H, Molfino NA. Cardiovascular safety of high doses of inhaled fenoterol and albuterol in acute severe asthma. Chest. 1996 Sep;110(3):595-603. doi: 10.1378/chest.110.3.595. PMID: 8797398.

Olshaker J, Jerrard D, Barish RA, Brandt G, Hooper F. The efficacy and safety of a continuous albuterol protocol for the treatment of acute adult asthma attacks. Am J Emerg Med. 1993 Mar;11(2):131-3. doi: 10.1016/0735-6757(93)90105-k. PMID: 8476452.

Patel B, Assad D, Wiemann C, Zughaib M. Repeated use of albuterol inhaler as a potential cause of Takotsubo cardiomyopathy. Am J Case Rep. 2014 May 19;15:221-5. doi: 10.12659/AJCR.890388. PMID: 24855502; PMCID: PMC4029766.

Payares-Salamanca L, Contreras-Arrieta S, Florez-García V, Barrios-Sanjuanelo A, Stand-Niño I, Rodriguez-Martinez CE. Metered-dose inhalers versus nebulization for the delivery of albuterol for acute exacerbations of wheezing or asthma in children: A systematic review with meta-analysis. Pediatr Pulmonol. 2020 Dec;55(12):3268-3278. doi: 10.1002/ppul.25077. Epub 2020 Sep 25. PMID: 32940961.

Salpeter SR, Ormiston TM, Salpeter EE. Cardiovascular effects of beta-agonists in patients with asthma and COPD: a meta-analysis. Chest. 2004 Jun;125(6):2309-21. doi: 10.1378/chest.125.6.2309. PMID: 15189956.

Spooner LM, Olin JL. Paradoxical bronchoconstriction with albuterol administered by metered-dose inhaler and nebulizer solution. Ann Pharmacother. 2005 Nov;39(11):1924-7. doi: 10.1345/aph.1G248. Epub 2005 Sep 20. PMID: 16174783.