April 2019 FAQs

Is there a role for newer cation exchange resins (ie, patiromer and sodium zirconium cyclosilicate) in the emergency management of hyperkalemia?

Background

Of all the electrolyte emergencies, hyperkalemia has the greatest possibility to lead to cardiac arrest.¹Clinical signs and symptoms of hyperkalemia depend on the severity of potassium (K+) depletion, but may include weakness, ascending paralysis, and respiratory failure.² Hyperkalemia also depolarizes the myocardial cell membrane, therefore, changes on the electrocardiogram (ECG) are common.

Standardized criteria for identifying patients who require emergency management of hyperkalemia (ie, those presenting with hyperkalemic emergencies) are not available.³ In general, patients with severe hyperkalemia (serum K+ ≥6 or 6.5 mEq/L) or ECG abnormalities require rapid reduction of serum K+.

Treatment of hyperkalemic emergencies

Severe hyperkalemia can lead to fatal arrhythmias if not quickly recognized and treated.³ For patients who require rapid reductions in serum K+, treatment modalities are largely based on anecdotal evidence and generally driven by institutional protocols. As with other electrolyte disorders, clinicians should be mindful of identifying and treating the underlying cause of the disorder.⁴ Nonetheless, the initial treatment of severe hyperkalemia is independent of the cause of the disturbance.^3,4 In chronological order, the physiological goals and recommended therapies for patients who require rapid reduction in serum K+ are as follows:^2,3,4

1. Stabilization of the myocardial membrane: intravenous (IV) calcium
2. Redistribution of extracellular K+ back into the cells: regular IV insulin and glucose, IV sodium bicarbonate, inhaled beta-2 agonists (ie, albuterol)
3. Removal of excess K+ from the body: loop or thiazide diuretics, cation exchange resins, hemodialysis

Removal of excess K+ from the body is an important step in the acute management of hyperkalemia.³Loop diuretics can help achieve this goal and have a relatively quick onset of action (~15 minutes) and modest duration of effect (~2 to 3 hours).^3,5 However, these agents can only be used in patients with functioning kidneys. Cation exchange resins are another non-invasive strategy to bind and remove K+ from the lumen of the gastrointestinal tract.³ Sodium polystyrene sulfonate (SPS), an older cation exchange resin, has been used for the acute treatment of hyperkalemia. However, the onset of action and reduction of serum K+ with this agent are unpredictable. More importantly, severe complications such as colonic necrosis have been linked to SPS. For these reasons, experts do not recommend SPS for acute therapy.

Patiromer (Veltassa^®) and sodium zirconium cyclosilicate (Lokelma™) are newer cation exchange resins indicated for the treatment of hyperkalemia.² A comparison of key pharmacological and pharmacokinetic properties of these agents is provided in Table 1.^2,5-7 Both patiromer and sodium zirconium cyclosilicate are available as an oral powder for suspension and provide significant tolerability advantages when compared to SPS.^6,7 The remainder of this review will focus on the role of these agents for the emergency management of hyperkalemia.

Table 1. Pharmacological and pharmacokinetic properties of newer cation exchange resins.^2,5-7  

The role of newer cation exchange resins

According to a 2016 treatment algorithm for hyperkalemic emergencies from the Investigator Network Initiative Cardiovascular and Renal Clinical Trialists (INI-CRCT), newer cation exchange resins may have a future role in the emergency management of severe hyperkalemia; albeit, studies to date in this population are limited.³ Currently, potassium-binding agents can be considered along with standard care therapies, including IV calcium, sodium bicarbonate, and loop diuretics for the acute management of hyperkalemia. Similar guidance is provided in a 2017 expert consensus from the Academy of Managed Care Pharmacy and a 2018 review article by Long et al.^2,4

Pivotal phase 3 trials of newer cation exchange resins have generally excluded patients presenting with hyperkalemic emergencies, specifically those with clinically significant arrhythmias that require immediate treatment.^8-10 As such, the manufacturers of patiromer and sodium zirconium cyclosilicate warn against the use of these agents for emergency treatment of  life-threatening hyperkalemia.^6,7However, the efficacy of these agents for acute lowering of serum K+ appears feasible based on data from a few trials and post-hoc analyses.^9-13

Patiromer

In 2018, a randomized, open-label pilot study investigated the efficacy of patiromer 25.2 grams plus standard care therapy versus standard care therapy alone in 30 patients with acute hyperkalemia (serum K+ ≥ 6 mEq/L) in the emergency department.¹¹ Standard care therapy was chosen by the treating physician, and patients who had a clinically significant arrhythmia were excluded from this trial.

At baseline, patients in the standard care therapy group had a significantly higher serum K+ (6.7 mEq/L; 95% CI, 6.2 to 6.7) versus those in the standard care therapy plus patiromer group (6.4 mEq/L; 95% CI, 6.5 to 6.9; p<0.05), but the clinical significance of this difference is questionable.¹¹ The change in serum K+ after 4 and 6 hours are presented in Table 2. Changes in serum K+ were not significant in either group at either time point. However, significantly fewer adjunct potassium-lowering interventions were needed by patients who received patiromer versus standard care therapy alone (p<0.05).

Table 2: Change in K+ (mEq/L) after administration of patiromer 25.2 grams.¹¹

Another study evaluated the K+ lowering effects of patiromer in 25 patients with chronic kidney disease (CKD) on ≥1 renin-angiotensin-aldosterone system inhibitor.¹² This was a phase 1, open-label, single arm trial. During a 3-day run-in period, patients were stabilized on a controlled metabolic diet (K+ 60 mEq/day and Na+ 100 mEq/day), which continued throughout a 6-day inpatient stay. After the run-in period, patients whose serum K+ was 5.5 to <6.5 mEq/L, started taking patiromer 8.4 grams twice daily with meals for 2 days (4 doses total).

At baseline, the mean (± standard deviation [SD]) estimated glomerular filtration (eGFR) rate was 34.8 mL/min/1.73m² (20.7), and the majority of patients had stage 3 or 4 CKD (ie, eGFR between 15 and 59 mL/min/1.73m²).¹² The mean (±SD) serum K+ was 5.93 (0.18) mEq/L and 8 patients had a serum K+ >6 mEq/L. Overall, significant reductions in serum K+ occurred at all measured timepoints between 7 and 48 hours. Seven hours after the first dose, the mean change from baseline in serum K+ was -0.21 mEq/L (95% CI, -0.35 to -0.07; p=0.004). In a post hoc analysis, the median time to achieve first serum K+ ≤5.5 mEq/L was 12.7 hours (95% CI, 11.0 to 22.6).

Zirconium cyclosilicate

During an open-label phase of a large, phase 3, randomized, double-blind, placebo-controlled trial by Kosiborod et al (HARMONIZE), outpatients with a serum K+ ≥5.1 mEq/L were treated with sodium zirconium cyclosilicate 3 times daily for 2 days.¹⁰ The average serum K+ at baseline was 5.6 mEq/L. Also at baseline, 39% of patients had a serum K+ between 5.5 to <6.0 mEq/L and 15% had K+ ≥6.0 mEq/L. The reduction in serum K+ at 1, 2, and 4 hours after the first 10-gram dose of sodium zirconium cyclosilicate is provided in Table 3. Sodium zirconium cyclosilicate demonstrated significant reductions in serum K+ at all measured timepoints (p<0.001 for all timepoints vs baseline). The median time to normalization of serum K+ was 2.2 hours, however, the range was wide (1 to 22.3 hours).

Table 3. Reduction in K+ (mEq/L) after 10 grams of sodium zirconium cyclosilicate.¹⁰

A significant reduction in serum K+ as soon as 1 hour post-dose of sodium zirconium cyclosilicate was also seen in the initial phase of another large, phase 3, randomized, double-blind, placebo-controlled trial by Packham et al of outpatients with a serum K+ between 5 and 6.5 mEq/L.⁹ The majority of patients in this trial had a baseline serum K+ between 5 and 5.3 mEq/L (~66%); 19% of patients had a serum K+ between 5.4 and 5.5 mEq/L, and 15% had a serum K+ between 5.6 and 6.5 mEq/L. The mean reduction in serum K+ from baseline 1 hour after sodium zirconium cyclosilicate was administered was 0.11 mEq/L (95% CI, −0.17 to −0.05), as compared with an increase of 0.01 mEq/L in the placebo group (95% CI, −0.05 to 0.07; p=0.009).

In 2015, Kosiborod and colleagues published a letter to the editor which describes the outcomes of 45 patients with severe hyperkalemia (serum K+ ≥6 mEq/L [range 6.1 to 7.2]) treated with sodium zirconium cyclosilicate who were enrolled in the phase 3 trials mentioned above.¹³ Again, patients in these trials were given a 10-gram dose of sodium zirconium cyclosilicate and serum K+ levels were tracked for 4 hours post-dose. Among this cohort of patients with severe hyperkalemia, the baseline serum K+ level was 6.3 mEq/L, and the reduction in serum K+ at 1, 2, and 4 hours post-dose is presented in Table 4. The median time to a serum K+ <6 mEq/L was approximately 64 minutes and the median time to a level ≤5.5 mEq/L was <4 hours. The majority of patients (80%) had a serum K+ <6 mEq/L 4 hours after the first dose, and more than half had a serum K+ that was ≤5.5 mEq/L (52%).

Table 4. Reduction in K+ (mEq/L) after 10 grams of sodium zirconium cyclosilicate.¹³

Results of a completed phase 2, randomized, double-blind trial (ENERGIZE) in acutely hyperkalemic patients that has evaluated the efficacy of standard care therapy (insulin and glucose) with or without sodium zirconium cyclosilicate are pending.¹⁴

Discussion

All trials in this review excluded patients with clinically significant arrhythmias that required emergent treatment.^9-13 The trial by Packham et al, which evaluated sodium zirconium cyclosilicate, also excluded patients with serum K+ ≥6.5 mEq/L.⁹ However, the relatively rapid onset of action with sodium zirconium cyclosilicate (~1 hour) has promoted interest in the feasibility of using this agent in patients with severe hyperkalemia, as seen by the 2015 publication by Kosiborod et al.¹³ Results of the ENERGIZE trial will also provide further data on the risks and benefits of using this agent with more immediate acting therapies such as insulin and glucose.¹⁴

Unlike sodium zirconium cyclosilicate, patiromer has actually been studied in patients with acute hyperkalemia who are also receiving other physician-directed emergency therapies.¹¹ In this setting, a decrease in K+ with patiromer versus standard care therapy alone was not significantly different. However, significantly fewer adjunct potassium-lowering interventions were required by patients who received patiromer.

For both patiromer and sodium zirconium cyclosilicate, the magnitude of change in serum K+ appeared greater for patients with higher baseline levels.^10,12

Recommendation

Available guidelines, consensus documents, and other literature suggest that patiromer and sodium zirconium cyclosilicate are viable adjunct therapies to standard care treatments used in the acute management of hyperkalemia. The doses studied in this setting include patiromer 25.2 grams and sodium zirconium cyclosilicate 10 grams.

References

1. Helman, A, Baimel, M, Etchells, E. Emergency management of hyperkalemia. Emergency Medicine Cases website. https://emergencymedicinecases.com/emergency-management-hyperkalemia/. September 27, 2016. Accessed March 23, 2019.
2. Long B, Warix JR, Koyfman A. Controversies in management of hyperkalemia. J Emerg Med. 2018;55(2):192-205.
3. Rossignol P, Legrand M, Kosiborod M, et al. Emergency management of severe hyperkalemia: guideline for best practice and opportunities for the future. Pharmacol Res. 2016;113(Part A):585-591.
4. Alvarez P, Brenner M, Butler J, et al. Focus on hyperkalemia management: expert consensus and economic impacts. J Manag Care Spec Pharm. 2017; 23(4-a Suppl):S2-S20.
5. Lexicomp [database online]. Hudson, OH: Wolters Kluwer Health, Inc; 2019. http://www.lexicomp.com. Accessed March 23, 2019.
6. Veltassa  [package insert]. Redwood City, CA: Relypsa, Inc. May 2018.
7. Lokelma [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP. July 2018.
8. Weir MR, Bakris GL, Bushinsky DA, et al. Patiromer in patients with kidney disease and hyperkalemia receiving RAAS inhibitors. N Engl J Med. 2015;372(3):211–222
9. Packham DK, Rasmussen HS, Lavin P, et al. Sodium zirconium cyclosilicate in hyperkalemia. N Engl J Med. 2015;372(3):222-231.
10. Kosiborod M, Rasmussen HS, Lavin P, et al. Effect of sodium zirconium cyclosilicate on potassium lowering for 28 days among outpatients with hyperkalemia: the HARMONIZE randomized clinical trial. JAMA. 2014;312(21):2223-2233.
11. Liu M, Rafique Z, Peacock WF. Patiromer for treatment of hyperkalemia in the emergency department: a pilot study. Presented at: Society for Academic Emergency Medicine annual meeting; May 15 to May 18, 2018; Indianapolis, IN. Abstract no. 408.
12. Bushinsky DA, Williams GH, Pitt B, et al. Patiromer induced rapid and sustained potassium lowering in patients with chronic kidney disease and hyperkalemia. Kidney Int. 2015;88(6):1427-1433.
13. Kosiborod M, Peacock WF, Packham DK. Sodium zirconium cyclosilicate for urgent therapy of severe hyperkalemia. N Engl J Med. 2015;372(16):1577-1578.
14. Open-label safety and efficacy of sodium zirconium cyclosilicate for up to 12 months (ENERGIZE). Clinicaltrials.gov website. https://www.clinicaltrials.gov/ct2/show/NCT02163499. Accessed March 23, 2019.

Prepared by:
Katherine Sarna, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

April 2019

The information presented is current as March 1, 2019. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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Update: What data are available to direct dosing of intravenous immunoglobulin G based on total versus ideal or adjusted body weight?

Introduction

Previously, the Drug Information Group reviewed clinical and pharmacokinetic data, guideline recommendations, practice patterns, and practical considerations for weight-based dosing of intravenous immunoglobulin (IVIG), which can be accessed here.¹ At the time of the previous frequently asked question (FAQ), there were limited data on the impact of weight-based dosing on clinical outcomes, and no clear consensus on whether actual, ideal, or adjusted body weight is optimal. Since 2013, additional data have been published to help further elucidate appropriate weight-based dosing of IVIG. This article will serve to update the previous FAQ with new clinical and pharmacokinetic data, which is particularly relevant in light of the current IVIG shortage.²

Literature review

Several retrospective evaluations are available examining the impact of using dosing weights other than actual body weight (Table 1).^3-6 The most robust of these is a 2017 review of patients with hematologic malignancies who received IVIG to prevent infections due to secondary hypogammaglobulinemia at a single center. The institution evaluated the impact of a revised IVIG guideline that recommended use of precision-dosing (using ideal or adjusted body weight) by comparing outcomes to patients who received IVIG dosed by actual body weight (traditional-dosing) in the pre-implementation period.³ The study found no differences in the infection rate within 30 and 60 days of IVIG administration between the precision- and traditional-dosing groups. The evaluation was limited by a protocol adherence rate of 55%, but, despite that, the authors did report significant cost savings. A smaller single-center evaluation of adult patients who received IVIG for immune thrombocytopenia, myasthenia gravis, or Guillian-Barre syndrome also found that use of ideal body weight dosing had comparable clinical outcomes to actual body weight dosing.⁴ While finding no difference between dosing weight strategies in these studies does not imply that the dosing approaches are equivalent, they did show that some institutions have had success in transitioning to ideal and adjusted body weight dosing. Another evaluation of 2 hospitals using different dosing weight strategies for IVIG compared the impact on the incidence of adverse events.⁵ The authors found that obese/overweight patients had a higher incidence of adverse events as compared to normal/underweight patients at the institution using adjusted body weight for patients whose actual weight exceeded their ideal body weight by 25%. However, these data are only available in abstract form and underlying baseline characteristics of the patients are not known. Further, in general, obese patients are at a higher risk for serious adverse events independent of dose.⁷

The previous FAQ summarized a 2011 study that evaluated the correlation between IVIG doses and trough levels of immunoglobulin G (IgG) and found that trough IgG levels were not correlated with the dose of IVIG when adjusted for patient weight or body mass index.^1,8 That study concluded that IVIG dosing based on ideal or adjusted body weight can yield appropriate IgG trough levels. A more recent study examined the correlation between IVIG dosing weights and serum IgG levels.⁶ Anderson and colleagues found that IVIG dosing based on ideal body weight demonstrated the strongest correlation with resulting serum IgG concentrations after administration; however, a statistically significant difference between ideal body weight dosing and adjusted or actual body weight was not observed.

Lastly, one recent case report was identified that described the experience of a patient who was receiving IVIG, and later subcutaneous immunoglobulin (SCIG), for a primary immunodeficiency disorder (PID).⁹ The patient underwent bariatric surgery and her actual weight decreased by 50%; this was correlated with an IgG trough level that increased from 7 g/L prior to surgery to 11.7 g/L after surgery. Due to the increase in IgG trough level, the dose of SCIG was reduced by about 20%. The authors concluded that this observation helps support that adjusted body weight is appropriate to use to calculate loading doses in patients with PID.

Some limitations of the current data includes its retrospective nature and small sample sizes, potentially leading to the inability to detect differences in dosing strategies. Additionally, some data are only available as meeting abstracts, which limits the ability to interpret these data without additional details.

Table 1. Evaluation of clinical or safety responses with actual, adjusted, or ideal IVIG dosing weights

In addition to published data on dosing weights used for IVIG, there are also data available on stewardship programs and the financial impact of using ideal or adjusted body weight dosing practices.^10-14 Brigham and Women’s Hospital have reported on the impact of an extensive inpatient prescribing guideline for IVIG, which utilizes pharmacy driven stewardship to improve adherence to their IVIG guideline recommendations.¹⁰ The institutional IVIG guideline provided appropriateness criteria for indications, dose, dosing weight, and frequency. Ideal body weight was used for all inpatient orders. The stewardship program resulted in compliance with dosing weight in 99.3% of the 406 IVIG administration cases evaluated. It was estimated that 6088 g of IVIG was saved between January 2013 and December 2014 by using ideal body weight as opposed to actual body weight. Other published experiences with institutional protocols or algorithms specifying dosing weight and dosing rounding are available (Table 2).^11-14 All describe financial savings with using ideal body weight dosing, but only consider drug costs.

Table 2. Financial impact of using ideal body weight and IVIG algorithms to guide IVIG dosing

Practice patterns

A cross-sectional survey in 2012-2013 aimed to evaluated the prevalence of various dosing and dose rounding strategies used in academic medical centers in the United States.¹⁵ A total of 57 institutions were surveyed and 38.6% reported using actual body weight, 14% used ideal body weight, and another 14% used ideal or adjusted body weight. For institutions using ideal or adjusted body weight, adjusted body weight was used in patients considered obese. However, the definition of obesity varied among the institutions, with >30% of the ideal body weight as the most common defintion (33.3% of respondents). Additionally, the survey showed that most institutions did have a dose rounding strategy (6 of 57 either did not round or did not respond to the question). The most common rounding strategy was to the nearest vial size. Overall, this survey highlighted the lack of consensus among IVIG dosing strategies.

Recommendations

As discussed in the previous FAQ, available data suggest that use of ideal or adjusted body weight for IVIG may be appropriate. Single-center retrospective evaluations have not observed clinical differences between use of ideal or adjusted body weight dosing as compared to actual body weight dosing, though these studies may be underpowered.^3,4 Available pharmacokinetic data are supportive of using these alternative dosing strategies. It has been previously observed that obese patients do tend to achieve higher IgG trough levels as compared to leaner patients when actual body weight is used, so reduced doses may be necessary.⁷ Further, a recent evaluation by Anderson demonstrated a strong correlation between ideal body weight dosing and resulting serum IgG changes.⁶

Overall, there is no consensus on the optimal dosing weight to use for obese patients. Due to this lack of data, some clinicans advocate for a individualized approach, rather than implementation of a “one size fits all” approach.¹⁶  Conversely, others advise that a change to ideal or adjusted body weight dosing is appropriate based on available data, particularly for indications where IVIG is used in higher doses such as those used in replacement.¹⁷ Overall, stewardship of IVIG does move beyond using a particular dosing weight as indications and doses used should also be evaluated. In particular, the report by Rocchio et al demonstrated that a pharmacy-led conservation program has been successful in promoting more optimal use of IVIG and resulted in cost savings.¹⁰

References

1. Reddy A. What data are available to direct dosing of intravenous immunoglobulin G based on total versus ideal or adjusted body weight? UIC Drug Information Group website. https://pharmacy.uic.edu/departments/pharmacy-practice//centers-and-sections/drug-information-group/2014/2013/november-2013-faqs. Published November 2013. Accessed March 25, 2019.
2. Current drug shortages – Immune Globulin, Intravenous or Subcutaneous (Human). American Society of Health-System Pharmacists website. https://www.ashp.org/Drug-Shortages/Current-Shortages/Drug-Shortage-Detail.aspx?id=407. Last updated March 8, 2019. Accessed March 25, 2019.
3. Stump SE, Schepers AJ, Jones AR, Alexander MD, Auten JJ. Comparison of weight-based dosing strategies for intravenous immunoglobulin in patients with hematologic malignancies. Pharmacotherapy. 2017;37(12):1530-1536.
4. Sulyk N, Lin A, Demekhin V. Evaluation of the clinical and economic impact of ideal body weight dosing for intravenous immune globulin (IVIG) [abstract]. Journal of Pharmacy Practice. 2016: 29(4):438-448.
5. Na SS, Rusay M, Bridgeman M, Kagan L, Brunetti L. Intravenous immunoglobulin dosing protocols in obese patients with acute versus chronic indications [abstract 294]. J Am Coll Clin Pharm. 2018; 1(2):122-353.
6. Anderson CR, Olson JA. Correlation of weight-based i.v. immune globulin doses with changes in serum immunoglobulin G levels. Am J Health Syst Pharm. 2015;72(4):285-289.
7. Hodkinson JP, Lucas M, Lee M, Harrison M, Lunn MP, Chapel H. Therapeutic immunoglobulin should be dosed by clinical outcome rather than by body weight in obese patients. Clin Exp Immunol. 2015;181(1):179–187.
8. Khan S, Grimbacher B, Boecking C, et al. Serum trough IgG level and annual intravenous immunoglobulin dose are not related to body size in patients on regular replacement therapy. Drug Metabolism Letters. 2011;5(2):132-136.
9. Ameratunga R. Initial intravenous immunoglobulin doses should be based on adjusted body weight in obese patients with primary immunodeficiency disorders. Allergy Asthma Clin Immunol. 2017;13:47.
10. Rocchio MA, Schurr JW, Hussey AP, Szumita PM. Intravenous immune globulin stewardship program at a tertiary academic medical center. Ann Pharmacother. 2017;51(2):135-139.
11. Rocchio MA, Hussey AP, Southard RA, Szumita PM. Impact of ideal body weight dosing for all inpatient i.v. immune globulin indications. Am J Health Syst Pharm. 2013;70(9):751-752.
12. Mychajlonka C, Cherrier L. Retrospective financial evaluation of an adult intravenous immunoglobulin (IVIG) dosing protocol based on ideal body weight (IBW) at a large academic medical center [abstract 18]. Pharmacotherapy. 2017;37(12):e124-e238.
13. Davies J, Ferguson B, Piper J, Kerr P. Experience of using ideal body weight dosing for intravenous immunoglobulin [abstract S107]. Transfus Med. 2016;26(S2):3-24.
14. Ice C, Oyen L. Evaluation of intravenous immune globulin prescribing patterns prior to and following a standardized prescribing algorithm at a tertiary care center [abstract 123]. Pharmacotherapy. 2015;35(11):e175-e325.
15. Lagasse C, Hatton RC, Pyles E. A survey of intravenous immune globulin (IVIG) dosing strategies. Ann Pharmacother. 2015;49(2):254-257.
16. Hodkinson JP. Considerations for dosing immunoglobulin in obese patients. Clin Exp Immunol. 2017;188(3):353-362.
17. Kerr J, Quinti I, Eibl M, et al. Is dosing of therapeutic immunoglobulins optimal? A review of a three-decade long debate in Europe. Front Immunol. 2014;5:629.

Prepared by:
Samantha Spencer, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

April 2019

The information presented is current as March 25, 2019. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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What evidence exists to support the use of nebulized sodium bicarbonate as a mucolytic in hospitalized patients?

Background

Mucus is an important component of the airways, and serves as a barrier to protect the lungs from toxins, pathogens, and other inhaled contaminants.¹ Mucus is regularly cleared by cilia in the airways in healthy patients; however, when infection or inflammation exist within the lungs due to various conditions, the production of mucus may increase, cilia function may be compromised, and the sputum may become more viscous.² The most common symptoms associated with improper functioning of the mucociliary system are cough and dyspnea.¹ Hypersecretion of mucus can be especially harmful in patients with severe lung disease or in those with impaired coughing mechanisms, and has been associated with decreased respiratory function and quality of life, increased coughing and discomfort, and worsening of respiratory conditions such as chronic obstructive pulmonary disease (COPD).²

Mucoactive drugs include a variety of agents that have the ability to modify mucus production or secretion, alter the nature and composition of mucus, or interact with the mucociliary epithelium.³This broad category of medications includes expectorants, mucolytics, mucoregulators, and mucokinetic agents, which work by increasing the secretion of mucus or the amount of water in the airway to facilitate mucus expulsion, reducing mucus viscosity, or improving clearance via ciliary mechanisms.⁴ Since mucoactive drugs have an indirect effect on pulmonary function, the rate of mucus clearance (rather than measurement of direct pulmonary function) may be the most appropriate measure to evaluate when determining clinical efficacy.³ Some examples of agents that have been considered as potentially mucoactive include dornase alfa, sodium bicarbonate, guaifenesin, hypertonic saline, and N-acetylcysteine, among others.

Guidelines recommendations related to mucoactive agents

Most of the guidelines for common respiratory diseases that are associated with hypersecretion of mucus, including asthma and COPD, do not discuss use of mucoactive agents. Of the guidelines that specifically mention mucolytic agents, a 2009 guideline from the American Academy of Allergy, Asthma, and Immunology (AAAAI), the American Academy of Emergency Medicine (AAEM), and the American Thoracic Society (ATS) on management of asthma exacerbations simply states that the panel does not recommend the use of mucolytics.⁵ The 2019 Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines for management of COPD state that regular treatment with mucolytics may moderately improve health status in COPD patients that are not receiving corticosteroids.⁶ Specific agents that are cited for this recommendation based on existing data include erdosteine, carbocysteine, and N‑acetylcysteine; however, the authors state that it is difficult to determine the appropriate target population and dosing of mucolytic agents due to heterogeneity within the literature.

The American Association for Respiratory Care published guidelines in 2015 that specifically discuss pharmacologic treatment strategies for airway clearance in hospitalized patients.⁷ The recommendations in the guideline are based on the findings from a systematic review that was performed to evaluate the existing literature for various mucoactive agents.² The guideline makes recommendations related to airway clearance therapies for several different patient populations, including: hospitalized patients (both pediatric and adult) without cystic fibrosis, those with neuromuscular disease, respiratory muscle weakness, or impaired cough, and in the post‑operative setting.⁷ For all of the patient populations discussed, the authors do not recommend use of airway clearing drugs, largely due to the overall lack of evidence. Although sodium bicarbonate is listed as a mucoactive agent within this guideline, it is not discussed individually, and was not included in the systematic review of the literature. The purpose of this FAQ is to review relevant literature on the use of sodium bicarbonate as a mucolytic agent.

Sodium bicarbonate as a mucoactive agent

Use of sodium bicarbonate as a mucoactive agent, either as an aerosol or by direct tracheal irrigation, has been suggested.^8,9  The basic pH of sodium bicarbonate is thought to alter the pH within the lungs, resulting in weakened bonding of the mucus side chains and an ultimate decrease in the viscosity and elasticity of mucus. Although use of sodium bicarbonate for this purpose is not widely reported, a 1995 review article suggests that a common preparation is a 2% sodium bicarbonate solution, either aerosolized or given via direct instillation into the trachea in increments of 2 to 5 milliliters.⁹

A search of the literature identified a review article from 2017 that discusses the use of mucoactive agents for mucus clearance in mechanically ventilated patients, and specifically describes the use of sodium bicarbonate within the literature.¹⁰ One of the articles referenced in  is an earlier review that suggests that sodium bicarbonate is irritating to the airways, and is not effective at breaking down or enhancing clearance of secretions; however, specific statements within the article are not referenced, and appear to be the opinion of the author.¹¹  The authors of the 2017 review were unable to find any clinical trials that evaluated the use of sodium bicarbonate as a mucoactive agent, but describe 3 in vitrostudies that have been conducted to better characterize the effect that sodium bicarbonate has on mucus.^12-14

Two of the in vitro studies evaluated the effect of bicarbonate on porcine mucus samples.^12,13 The first found bicarbonate to reduce mucus aggregates and remove/chelate calcium ions, thus leading to expansion and diffusion of the mucin matrix, resulting in a reduction in mucus viscosity.¹² A second study evaluated the effects of bicarbonate within porcine tracheas, and found that addition of bicarbonate led to a significant increase in acetylcholine-mediated mucociliary transport.¹³ The final study discussed performed studies to evaluate the viscosity of mucus samples from patients with cystic fibrosis after exposure to a sodium bicarbonate solution, and found a reduction in complex viscosity associated with the addition of sodium bicarbonate.¹⁴

Conclusion

Overall, there is a paucity of evidence to support the use of sodium bicarbonate as a mucolytic in hospitalized patients. A small number of in vitro studies have shown the potential for sodium bicarbonate to reduce the viscosity of mucus and to enhance mucociliary transport; however, these findings have not been tested in clinical trials. Future studies will be necessary in order to determine the true efficacy of sodium bicarbonate for this purpose.

References

1. Dickey BF, Knowles MR, Boucher RC. Mucociliary clearance. In: Fishman’s Pulmonary Diseases and Disorders. 5th ed. New York, NY: McGraw-Hill Education; 2015.
2. Sathe NA, Krishnaswami S, Andrews J, Ficzere C, McPheeters ML. Pharmacologic agents that promote airway clearance in hospitalized subjects: A systematic review. Respir Care. 2015;60(7):1061-1070.
3. Task Group on Mucoactive Drugs. Recommendations for guidelines on clinical trials of mucoactive drugs in chronic bronchitis and chronic obstructive pulmonary disease. Chest. 1994;106(5):1532-1537.
4. Tietze KJ, Manaker S. Pulmonary pharmacotherapy. In: Fishman’s Pulmonary Diseases and Disorders.5th ed. New York, NY: McGraw-Hill Education; 2015.
5. Schatz M, Kazzi AA, Brenner B, et al. Joint task force report: Supplemental recommendations for the management and follow-up of asthma exacerbations. Introduction. J Allergy Clin Immunol. 2009;124(2 Suppl):S1-S4.
6. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. http://goldcopd.org/gold-reports/. 2019 update. Accessed March 20, 2019.
7. Strickland SL, Rubin BK, Haas CF, Volsko TA, Drescher GS, O’Malley CA. AARC clinical practice guideline: effectiveness of pharmacologic airway clearance therapies in hospitalized patients. Respir Care. 2015;60(7):1071-1077.
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Prepared by:
Jessica Zacher, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

April 2019

The information presented is current as of March 20, 2019. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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