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Three Part Question

In [patients with hyperkalemia] is [levalbuterol better than albuterol] at reducing [serum potassium]?

Clinical Scenario

A 67 year old man presents to the emergency department with chest pain and syncope. The electrocardiogram shows a wide QRS and peaked T-waves. Stat electrolytes show a potassium level of 7.3. While starting Ca gluconate, glucose/insulin, nebulized albuterol and kayexelate you wonder if substitution of levalbuterol for albuterol would have the same lowering effect on serum potassium and have fewer side effects.

Search Strategy

Medline 1966 - October 2004 using the OVID interface.
[levalbuterol.mp or exp Albuterol/ OR (albuterol or salbutamol).mp OR exp bronchodilator agents/ OR exp adrenergic beta-agonists/ OR beta-agonists.mp] AND [exp stereoisomerism/ OR enantiomers.mp OR racemic.mp] AND [hyperkalemia.mp. or exp hyperkalemia/ OR hyperkalaemia.mp OR exp potassium] LIMIT to human AND English language

Search Outcome

Seven papers were found of which 3 were irrelevant to the study question. The remaining four papers are shown in the table.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Pancu D et al, July 2003, USA	27 healthy adult volunteers. 9 nebulized normal saline, 9 albuterol (10mg), 9 levalbuterol (2.5mg)	Randomized, double blind, placebo-controlled trial.	Serum potassium values at baseline	No difference between any group - Albuterol 3.9 (0.3) mEq/L, Levalbuterol 4.1 (0.3) mEq/L, Placebo 4.1 (0.3) mEq/L	This study measured potassium changes in a small sample of healthy volunteers. The clinical significance of these small changes in potassium is uncertain and these changes may not be applicable to those patients presenting with pathological hyperkalaemia. Objective vital signs were only recorded in those patients reporting side effects.
			Serum potassium at 30 minutes	Albuterol reduced by 0.3mEq/L. Levalbuterol reduced by 0.3 mEq/L. Placebo increased by 0.1mEq/L. No significant difference between beta agonists. Both beta agonists better than placebo (p=0.005)
			Serum potassium at 60 minutes	Albuterol reduced by 0.3mEq/L. Levalbuterol reduced by 0.5 mEq/L. Placebo showed no change. No significant difference between beta agonists. Both beta agonists better than placebo (p=0.001)
			Side effects	Levalbuterol caused fewer reported side effects than albuterol. Levalbuterol vs albuterol: Total percent reporting symptoms, 22% vs 78%. Tremor, 22% vs 78%. Nervousness, 0% vs 56%. Palpitations, 0% vs 56%. Tachycardia, 0% vs 44%. No p-values provided
Lotvall J et al, 2001 Sweden	20 adult asthmatic patients were randomized into 4 study groups: nebulized R-albuterol (6.25-1600 ug), S-albuterol (6.25-1600 ug), RS-albuterol (12.5-3200 ug), or placebo	PCRT 4-way crossover	FEV1, heart rate, and plasma potassium levels before dosing	Differences/P-values not documented	Single K+ level was measured 20 min. after study drug. Small sample size The dose of albuterol required to reverse hyperkalemia is higher than standard bronchodilator doses used in this study
			FEV1, heart rate and plasma potassium levels 20 minutes after each dose	Rapid increase in plasma potassium level (0.3-0.4 mmol/L) after placebo administration (no p-value given)
			Side Effects	No serious adverse events and majority of adverse events were reported after treatment with R or RS albuterol. These included tremor, palpitations and tachyarrhythmias.
Lipworth BJ et al 1997 UK	12 volunteers were randomized into 4 study groups: nebulized R-albuterol (200-3200 ug), S-albuterol (200-3200 ug), RS-albuterol (400-6400 ug) or placebo	PCRT crossover	Pharmaco-dynamics at extra-pulmonary beta 2 receptors (tremor, plasma potassium, heart rate) measured at 0-100 minutes at 20 minute intervals	No significant differences were found in baseline plasma potassium values (no p-values provided)	Small doses of study drugs used in healthy volunteers Small sample size Mean age (20.6) may not be representative of majority of population presenting with hyperkalemia
Gumbhir-Shah et al 1999 USA	13 asthmatic subjects randomized to receive four cumulative doses of either nebulized 1.25 mg levalbuterol or 2.5 mg albuterol at 30 minute intervals	RCT crossover	FEV1, plasma potassium, plasma glucose, heart rate, QTc interval, and urine plasma drug concentration at 1, 2, 4, 6, 8 hours after final dose	No significant difference between R and RS albuterol in reduction of plasma potassium levels (AUC p=0.17)	Four consecutive small doses given at 30 minutes intervals may not be applicable to those patients presenting with pathological hyperkalaemia. Small sample size
			Side Effects	None severe. Included dizziness, tachycardia, nervousness (greater in R group), wheezing (greater in RS group). All events resolved spontaneously.

Comment(s)

Equipotent nebulized levalbuterol appears to be as effective as albuterol in lowering serum potassium in healthy adults. Studies comparing these two medications in hyperkalemic patients with co-morbidities and on various medications would be helpful in establishing their comparative efficacy in treating common presenters to the emergency department.

Editor Comment

Editors note: Albuterol is known as "Salbutamol" in the UK. Racemic albuterol contains 2 isomeric forms (R- and S-enantiomers). Levalbuterol was developed because the R-enantiomer was found to be the active component of the racemic form.

Clinical Bottom Line

Nebulized levalbuterol appears to be as effective as albuterol in lowering serum potassium in adults.

Level of Evidence

Level 2 - Studies considered were neither 1 or 3.

References

1. Pancu D, LaFlamme M, Evans E, et al. Levalbuterol is as effective as racemic albuterol in lowering serum potassium. J Emerg Med 2003;25(1):13-16.
2. Lotvall J, Palmqvist M, Arvidsson P et al. The therapeutic ratio of R-albuterol is comparable with that of RS-albuterol in asthmatic patients. J Allergy Clin Immunol 2001;108:726-731.
3. Lipworth BJ, Clark DJ, Koch P, et al. Pharmacokinetics and exrapulmonary B2-adrenoceptor activity of nebulized racemic salbutamol and its R and S isomers in healthy volunteers. Thorax 1997;53:849-8.
4. Gumbhir-Shah K, Kellerman DJ, DeGraw S, et al Pharmacokinetics and parmacodynamics of cumulative single doses of inhaled salbutamol enantiomers in asthmatic subjects. Pulm Pharmacol Ther 1999;12:353-362.