Nebulised N-Acetylcysteine (NAC)

Mucus typically consists of water (97%) and mucins (3%), such as MUC5AC and MUC5B, in addition to antimicrobial, immunomodulatory and protective molecules. Mucus prevents dehydration on the airway surface and aids in clearance of inhaled particles and inflammatory mediators [2]. Many chronic lung diseases are characterized by the hypersecretion of mucus which arises from hypertrophy and hyperplasia of the goblet and submucosal glands. This is usually accompanied by inadequate mucus clearance which further hinders the air passages. In these conditions, the administration of mucoactive agents is often indicated as adjuvant therapy.

NAC is also widely used by respiratory physicians as an oral mucolytic agent. The presence of the free sulfhydryl group enables it to cleave disulphide bonds in mucin (in addition to degrading fibrin, DNA and mucin polymers or F-actin) and reduce viscosity, thus causing mucus breakdown and enhancing mucocilliary clearance. It has both direct and indirect antioxidant activity, leading to oxygen radical scavenging, reduced inflammation and reduced mucus secretion. NAC is commonly used as an oral mucolytic in chronic respiratory disease, and is increasingly being considered as an adjunct in reducing frequency of COPD exacerbations due to the antioxidant activity.

It can be administered orally (300–1200 mg daily), nebulised (5 ml 10% solution six-hourly) or intravenously. Adverse side effects include nausea and vomiting, anaphylactoid reactions in 3% (urticarial rash, bronchoconstriction and hypotension) and confusion and electrolyte disturbance due to high osmolality.

Following failed conventional mucolysis therapy, nebulised N-acetylcysteine acted as a life-saving mucolytic, and prevented imminent cardiorespiratory arrest. Use of oral N-acetylcysteine as a mucolytic has been long established within respiratory medicine in managing chronic airway disease, but is rarely utilised in critically ill or mechanically ventilated patients due to the lack of comparative studies in literature. A Cochrane Database Systematic Review at 2013 concluded that they found no evidence to recommend the use of either nebulized or oral thiol derivatives in people with cystic fibrosis. There are very few good quality trials investigating the effect of these medications in cystic fibrosis, and further research is required to investigate the potential role of these medications in improving the outcomes of people with cystic fibrosis.

Methods of administration of nebulised N-Acetylcysteine (NAC) in literature:

Study	Method	Conclusion / Remark(s)
Gray et al. 2011: Injectable Drugs Guide.	1. Withdraw the required dose (and optional: dilute with NaCl 0.9% if required). 2. Give via a nebuliser using air (NOT oxygen).	• The adult dose is 3-5 mL acetylcysteine 20% injection, • Nebulised 3-4 times daily using air (avoid concentrated oxygen as it causes degradation of NAC). • Acetylcysteine may cause bronchospasm. This can be avoided either by: i.  Giving a lower dose – diluting 1 mL acetylcysteine 20% in 5 mL NaCl 0.9% and giving 3-4 mL, or; ii.  Pre-administering a nebulised bronchodilator
Brodier et al 2019	10 ml 2% N-acetylcysteine (NAC) was flushed via the bronchoscopic port	Nebulised NAC is an option when encountering airway obstruction due to refractory mucus plugging in critically ill patients.
Gallon AM 1996	4 ml nebulised NAC (for 10 mins; the nebulisers were driven by compressed air because oxygen inactivates acetylcysteine) + Deep breathing exercise + Assisted coughing Repeat after 4 hrs. Twice daily X 2 days	Following thoracotomy, nebulised acetylcysteine reduces sputum viscosity, making expectoration easier and improving oxygenation.
Masoompour et al. 2015	2 ml of NAC 20% with 8 ml normal saline ; 3 times a day for 1 day.	N-acetylcysteine via nebulization through endotracheal tubes in mechanically ventilated patients was not effective more than normal saline nebulization in reducing the density of mucous plugs

In Hospital Keningau:

Availability of N-Acetylcysteine (NAC) in Hospital Keningau : 5 g / 25 ml Inj  (20%)

KPK Application Form & Patient Off-label Treatment Consent Form are needed.

Case Report by Brodier et al 2019

The patient in this case report acutely deteriorated 48 h after admission becoming unresponsive and severely hypoxaemic. Intubation did not achieve ventilation, and subsequent direct bronchoscopy revealed a thick, solid, obstructing tracheal mucus plug, superior to the carina. It was resistant to aspiration despite the use of saline flushes, chest physiotherapy and bronchodilators and the bronchoscope could not pass it. 10 ml 2% N-acetylcysteine (NAC) was flushed via the bronchoscopic port, utilising ingenuitive clinical judgement in this critical situation.

This caused sufficient mucolysis to enable removal of the thick mucus cast, enabling ventilation and gas exchange. Such resistant mucus plugging is a rare cause of failed ventilation, with limited therapeutic options. Here, the unlicensed and rarely reported use of nebulised N-acetylcysteine was a life-saving mucolytic, allowing removal of the obstructing plug and re-establishing ventilation.

For this patient, mucolytic management continued with nebulised NAC, hypertonic saline flushes and bronchodilatory nebulisers.

Other Mucolytics

Expectorants increase airway water or the volume of airway secretions, thereby improving the ability to expectorate purulent secretions. Hypertonic saline is an example of an expectorant which has osmotic pressure greater than that of physiologic isotonic 0.9% NaCl. Hypertonic saline has been shown to significantly reduce the number of exacerbations in cystic fibrosis patients when compared to isotonic saline and has better mucociliary clearance.

Drug	Device	Indication	Proposed Mechanism of Action	Notes
Expectorants
Hypertonic saline 7%	Nebulizer	Cystic fibrosis, and bronchiectasis	Increases the amount of sodium and chloride in airway surface liquid, thereby increasing the osmotic gradient and rehydrating the mucus layer [5,7]	Improves lung function and quality of life in bronchiectasis [8]. Should not be given via a vibrating mesh nebulizer. Improves mucus clearance, airflow, and reduces rates of exacerbation among patients with cystic fibrosis [4,9].
Classical mucolytics
NAC (Mucomyst®)	Nebulizer	ABPA	Severs disulfide bonds that link mucin monomers to polymers, and solubilizes sputum antioxidant and anti-inflammatory	No evidence for use in any lung disease.
S-carboxymethylcysteine (carbocysteine)	Oral	COPD, and cystic fibrosis	Increases concentrations of sialomucins and reduces that of fucomucins, acts as a free radical scavenger [10], and has antioxidant and anti-inflammatory properties	Reduces measured sputum viscosity [11,12].
Dry powder mannitol (Bronchitol®)	Dry powder inhaler	Cystic fibrosis, bronchiectasis, and COPD	Increases mucus secretion	Nonabsorbable. Associated with bronchoconstriction and cough when used in children with cystic fibrosis.
Peptide mucolytics
Dornase alfa (Pulmozyme®)	Nebulizer	Cystic fibrosis	Hydrolyzes DNA polymer and reduces DNA length	Hydrolyzes DNA, improves lung function, and decreases the frequency of exacerbation [13,14].
Non-destructive mucolytics
Unfractionated heparin (UFH)	Nebulizer	COPD, and cystic fibrosis	Modifies ionic interactions and the intermolecular hydrogen bonds between mucin molecules, and untangles the charged oligosaccharide side chains of mucin	UFH reduces the elasticity and yield stress in the samples from cystic fibrosis patients [15].
Low molecular weight dextran (DCF 987)	Nebulizer	COPD	Disrupts the polyionic oligosaccharide mucin network and increases secretion hydration	Proven lung safety in animal studies [16,17].

·         ABPA = allergic bronchopulmonary aspergillosis;

·         COPD = chronic obstructive pulmonary disease;

·         NAC = N-acetylcysteine.

References:

1. Gray et al. Injectable Drugs Guide: Acetylcysteine. Pharmaceutical Press 2011.
2. Brodier et al. Use of nebulised N-acetylcysteine as a life-saving mucolytic in intensive care: A case report. Journal of the Intensive Care Society 2019, 0(0) 1–3. Accessed at: https://journals.sagepub.com/doi/full/10.1177/1751143719870089  [12 Mac 2020]
3. Out et al 2018. Nebulised N-Acetylcysteine for Unresponsive Bronchial Obstruction in Allergic Brochopulmonary Aspergillosis: A Case Series and Review of the Literature. J. Fungi 2018, 4(4), 117. Accessed at: https://www.mdpi.com/2309-608X/4/4/117/htm   [12 Mac 2020]
4. Masoompour et al. 2015. Evaluation of the Effect of Nebulized N-Acetylcysteine on Respiratory Secretions in Mechanically Ventilated Patients: Randomized Clinical Trial. Iran J Med Sci. 2015 Jul; 40(4): 309–315. Accessed at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4487455/   [12 Mac 2020]
5. Gallon AM 1996. Evaluation of nebulised acetylcysteine and normal saline in the treatment of sputum retention following thoracotomy. Thorax 1996;51:429-432. Accessed at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1090682/pdf/thorax00323-0097.pdf  [12 Mac 2020]
6. Tam et al. Nebulized and oral thiol derivatives for pulmonary disease in cystic fibrosis. Cochrane Database Syst Rev. 2013 Jul 12;(7):CD007168. Accessed at: https://www.ncbi.nlm.nih.gov/pubmed/23852992   [12 Mac 2020]

Further Reading:

For detailed explanation of pharmacology of N-Acetylcysteine in lung diseases, this is a good read:

Santus et al. Oxidative Stress and Respiratory System: Pharmacological and Clinical Reappraisal of N-Acetylcysteine. COPD. 2014 Dec; 11(6): 705–717.