Use of nebulised N-acetylcysteine as a life-saving mucolytic in intensive care: A case report

Abstract

We present a case of critical airway obstruction secondary to a solid tracheal mucus plug in a patient with pneumonia. 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 28-year-old female presented to the emergency department with shortness of breath and a productive cough. She was six weeks post-partum with no past medical history. Initial management for a community acquired pneumonia with type 1 respiratory failure included intensive care admission, antibiotics, fluid therapy and bronchodilators. The patient 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. N-acetylcysteine, administered via the bronchoscopic port, 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.

Case presentation

A 28-year-old female presented to the emergency department with a two-day history of shortness of breath and a productive cough. She was an ex-smoker, six weeks post-partum with no medical history. Clinical examination noted tachypnoea (24 breaths/min), bilateral mild wheeze, reduced breath sounds in the right lower zone and apyrexia. Blood tests results included: white cell count 13.2 × 10⁹/L, neutrophils 9.5 × 10⁹/L, CRP 1 mg/L, and no evidence of other organ impairment. Further investigations included an unremarkable chest X-ray, normal cardiac function on echocardiogram and a computed tomography pulmonary angiogram (CTPA) excluded pulmonary emboli but showed mild bibasal interstitial thickening suggestive of bronchiolitis. Results of influenza swabs, sputum culture and virology and atypical screening were negative. She was managed for a community acquired pneumonia with intravenous benzylpenicillin, clarithromycin, fluid resuscitation and nebulisers (salbutamol and ipratropium).

Four hours following admission, the patient decompensated with a heart rate of 135 beats/min, respiratory rate of 30 breaths/min and hypoxaemia (pO₂ 12 kPa on 15 L/min oxygen via a non-rebreathe mask). She was admitted to the intensive care unit (ICU) for the management of type one respiratory failure. Over the subsequent 24 h the patient remained alert, with a sustained sinus tachycardia (110–130 beats/min) and oxygen requirements fluctuating between periods of nasal cannulae and high flow nasal oxygen (FiO₂ 0.6). She had a strong cough with an occasional mild wheeze. Treatment continued with intravenous antibiotics, bronchodilatory and saline nebulisers and chest physiotherapy.

Forty-eight hours after ICU admission, the patient acutely deteriorated; her Glasgow coma scale score reduced to 3/15 (E1 V1 M1) and she developed sudden hypoxaemia and failure to ventilate (pH 6.94, pCO₂ 19.4 kPa, pO₂ 7.1 kPa, lactate 1.2 mmol/L). Minimal air entry was possible using a bag-valve mask, with a quiet inspiratory wheeze present on examination. Intubation proceeded using ketamine, propofol and rocuronium, with a Grade 1 McCormack view. However, ventilation with a Waters circuit failed and oesophageal intubation was suspected. Intubation was repeated with a similarly adequate view at laryngoscopy, but there was still difficulty ventilating post-intubation. Oxygenation was maintained with saturations of 90%. Additional bronchospasm management was initiated with intravenous magnesium, aminophylline, hydrocortisone and a ketamine infusion.

Immediate bronchoscopy revealed a thick and solid mucus plug completely obstructing the trachea, above the carina. The mass was not amenable to aspiration utilising saline flushes, chest physiotherapy, repositioning and suction. Disruption by the mechanical force of the bronchoscope was unsuccessful, and gas exchange worsened threatening imminent cardiorespiratory collapse (pH 6.73, pCO₂ 32.9 kPa, pO₂ 21.5 kPa, lactate 0.5 mmol/L). On consultation with a second intensivist, 10 ml 2% N-acetylcysteine (NAC) was flushed via the bronchoscopic port, utilising ingenuitive clinical judgement in this critical situation. This achieved sufficient lysis of the mass to enable suction and removal of a thick mucus cast, outlining the proximal bronchial tree (see Figure 1). Ventilation was restored, and gas exchange began to normalise with a pCO₂ 12 kPa within 1 h.

Figure 1.

Mucus cast suctioned from the trachea via bronchoscopy, with the aid of NAC.

Over the following 48 h, the patient had further episodes of sudden hypoxaemia and worsening ventilation secondary to bronchospasm and repeated mucus plugging. Mucolytic management continued with nebulised NAC, hypertonic saline flushes and bronchodilatory nebulisers. With worsening gas exchange, the patient was paralysed and ventilated with volatile agents to assist bronchodilation. Discussion with the local extracorporeal membrane oxygenation (ECMO) centre led to transfer for ongoing management.

Discussion

NAC is a thiol derivative that metabolises to L-cysteine, a precursor of reduced glutathione (GSH), which acts as a free oxygen radical scavenger. Intracellular glutathione is commonly depleted in oxidative stress and inflammation. Within intensive care, NAC is most commonly known for its therapeutic indication in acetaminophen overdose to replenish glutathione levels and enable paracetamol metabolism.¹ Due to the anti-oxidant properties, it is used despite limited data to prevent contrast-induced nephropathy^2,3 and has been considered in treatment of infertility, ulcerative colitis, myocardial infarction, sepsis, acute lung injury and human immunodeficiency virus.^1,4

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 and reduce viscosity, thus causing mucus breakdown and enhancing mucocilliary clearance.⁵ It has both direct and indirect antioxidant activity, leading to oxygen radical scavenging, reduced inflammation and reduced mucus secretion.⁴ NAC is commonly used as an oral mucolytic in chronic respiratory disease,⁶ and is increasingly being considered as an adjunct in reducing frequency of COPD exacerbations due to the antioxidant activity.^5,7,8

It can be administered orally (300–1200 mg daily), nebulised (5 ml 10% solution six-hourly) or intravenously.¹ 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.¹

Beyond small studies suggesting some benefit,⁹ there is limited high-quality literature assessing the efficacy of mucolytic agents in critically ill patients.¹⁰ Most literature focuses on oral preparations, used in the outpatient clinical setting. Nebulised NAC in mechanically ventilated patients has not yet been demonstrated as an effective mucolytic¹¹ with very few reports of its use acutely in airway obstruction. Consequently, NAC is rarely integrated into mucolytic protocols in these patient cohorts. Knowledge of the properties and mechanism of action of the drug led to its unconventional use and success in this scenario.

Conclusion

When presented with acute, life-threatening clinical situations, it may be appropriate to consider unlicensed treatment following failure of protocols. In this case, NAC was successful in degrading the obstructing mucus plug, and achieving life-saving ventilation. Other conventional mucolytic and bronchospastic treatment had been attempted without success. In this circumstance, the patient was peri-arrest with a severe respiratory acidosis. There was no clinical experience in the use of nebulised NAC as a mucolytic, but it radically altered the patient's prognosis. We present this case to highlight nebulised NAC as an option when encountering airway obstruction due to refractory mucus plugging in critically ill patients.