Physiology and pathophysiology of mucus and mucolytic use in critically ill patients

Abstract

Airway mucus is a highly specialised secretory fluid which functions as a physical and immunological barrier to pathogens whilst lubricating the airways and humifying atmospheric air. Dysfunction is common during critical illness and is characterised by changes in production rate, chemical composition, physical properties, and inflammatory phenotype. Mucociliary clearance, which is determined in part by mucus characteristics and in part by ciliary function, is also dysfunctional in critical illness via disease related and iatrogenic mechanisms. The consequences of mucus dysfunction are potentially devastating, contributing to prolonged ventilator dependency, increased risk of secondary pneumonia, and worsened lung injury. Mucolytic therapies are designed to decrease viscosity, improve expectoration/suctioning, and thereby promote mucus removal. Mucolytics, including hypertonic saline, dornase alfa/rhDNase, nebulised heparin, carbocisteine/N-Acetyl cysteine, are commonly used in critically ill patients. This review summarises the physiology and pathophysiology of mucus and the existing evidence for the use of mucolytics in critically ill patients and speculates on journey to individualised mucolytic therapy.

Keywords: Critical care; Intensive care; Mechanical ventilation; Mucolytics.

Fig. 1

Mucus and tissue sampling with link to biochemical, microbiological, cytological, histological, rheological, genetic and proteomic analysis

Fig. 2

The direct and indirect actions of HTS. Direct: Deposition of itself onto the airway surface layer creating an osmotic effect leading to increased ASL height and reduced viscosity by disruption of ionic bonds in mucin-electrostatic interactions. Indirect: Repair of mucociliary mechanisms (secondary to reduced viscosity and increased water content of mucus), and dissociation of DNA from mucoproteins allowing for natural proteolytic enzymes to act

Fig. 3

Mechanism of action of N-acetylcysteine (NAC). Breakage of the disulphide bonds causes incomplete glycoprotein anchoring and reduction in mucus viscosity. NAC acts on ROS via glutathione and cysteine breakdown but also secondary to disulfide reduction. Together these reduce viscosity and elasticity of mucus

Fig. 4

Mechanism of action of heparin as a mucolytic is multimodal. Antimicrobial effects via competitive adhesion of viruses and bacteria to epithelial wall by attaching to GAG molecules on heparin molecule. The anti-inflammatory effects produced via inhibition of inflammatory cytokines and complement cascade, and subsequent neutrophil and macrophage inhibition. Heparin acts directly in the mucus by increasing the pH, and thereby reducing viscosity and mucin interactions. The antithrombotic mechanism of heparin acts in the local microvasculature, preventing coagulation and thrombosis

Fig. 5

Mechanism of action of Dornase Alfa. The enzyme cleaves extracellular DNA without any effect on intracellular DNA reducing viscosity of purulent sputum. Activity is altered by the presence of calcium and magnesium. Neutrophil activation and NETosis allows successful antimicrobial clearance, however, with prolonged exposure cellular apoptosis causes free long chain DNA to enter the mucus lining. This causes increased mucus viscosity and subsequent worsening of mucociliary clearance. Dornase alfa cleaves long chain DNA fragments, reducing this effect

Fig. 6

Mechanism of action of ambroxol. It possesses anti-inflammatory effects by reducing the production of pro-inflammatory cytokines. In addition, it acts as an antioxidant through reactive oxygen species scavenging and destruction. Antimicrobial effects via increased IgG and IgA secretion, and it increases stimulation of lamellar bodies within type II pneumocytes causing increased production of surfactant. Finally, ambroxol increases the ciliary beat frequency, improving mucociliary clearance

Fig. 7

Possible phenotypes of mucus composition analysis at the bedside, embedded with multi-omics data and known patient factors to facilitate mucolytic choice