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Respiratory drugs 

Respiratory drugs
Chapter:
Respiratory drugs
Author(s):

Carl Waldmann

, Andrew Rhodes

, Neil Soni

, and Jonathan Handy

DOI:
10.1093/med/9780198723561.003.0011
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date: 22 April 2021

Chapter contents

Bronchodilators

Bronchodilators, as the name suggests, are used in airways disease, particularly in asthma and chronic obstructive pulmonary disease (COPD), to produce a reversal of airway obstruction. The three main categories are β‎2-adrenergic agonists, anticholinergic agents, and xanthine derivatives.

β‎2-Agonists

β‎2-Agonists give the greatest bronchodilation amongst the bronchodilators in asthma. They are classified by length of action:

  • Short–intermediate-acting: salbutamol, terbutaline, fenoterol.

  • Long-acting: formoterol, salmeterol.

Mode of action

β‎2-Agonists directly stimulate the β‎2-adrenergic receptor, which is found in virtually all types of cells. The receptors are subclassified as β‎1, β‎2, and β‎3. Although both β‎1 and β‎2 receptors are found in the lungs, bronchodilatory effects are predominantly a function of the β‎2-receptor. The receptor is a protein folded across the plasma membrane and is linked to the stimulatory guanine nucleotide-binding protein (Gs). Occupation of the receptor activates the enzyme adenylate cyclase via the Gs protein, and this converts adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP), which is responsible for the physiological response, in this case, relaxation of airway smooth muscle.

In addition, β‎2-agonists have non-direct bronchodilator actions, which may contribute to their therapeutic function:

  • Enhancement of mucociliary clearance.

  • Inhibition of cholinergic neurotransmission.

  • Inhibiting the release of bronchoconstrictor mediators (e.g. leukotrienes, histamine, prostaglandins) from inflammatory cells (e.g. mast cells).

  • Reducing microvascular leakage.

There is no evidence, however, that β‎2-agonists have a significant inhibitory effect on chronic inflammation in asthma, hence they must not be used as alternatives to inhaled steroids as anti-inflammatory therapy.

Therapeutic use

β‎2-Agonists are most commonly administered via the inhalation route; other routes include intravenous (IV), subcutaneous (SC), and oral. β‎2-Agonists may be inhaled in nebulized form, or as metered-dose inhalation (MDI) in the form of propellant-generated aerosol, or as a breath-propelled dry powder (e.g. Turbohaler®, Accuhaler®). Using the MDI optimally, ~12% of the drug is delivered to the respiratory airways; the remainder is deposited in the mouth, pharynx, and larynx. Nebulized doses need to be ~6–10 times those used in MDIs to produce the same level of bronchodilation.

  • Short-acting β‎2-agonists act rapidly and their duration of action lasts 3–4 h. In acute asthma, they are the bronchodilators of choice. In this setting, it is common practice to use nebulized β‎2-agonists, although studies have shown that supervised administration of β‎2-agonists by MDI with a spacer device in the emergency setting appears to be as effective as nebulizers in both adults and children. Short-acting β‎2-agonists are also useful in prevention of exercise-induced asthma or other triggers, including cold air and allergens.

  • In mild or stable asthma, short-acting β‎2-agonists should be used as required by symptoms, and not on a regular basis. Increased usage signals the need for step-up of anti-inflammatory therapy.

  • Long-acting β‎2-agonists (LABAs) were developed later and marked an important milestone in asthma management. The bronchodilator effect lasts >12 h. This is particularly important in addressing nocturnal asthma symptoms. LABAs are considered in Step 3 of the British Thoracic Society/Scottish Intercollegiate Guidelines Network (BTS/SIGN) chronic asthma guidelines. Formoterol is a full agonist compared with salmeterol, and has a more rapid onset of action. This may make formoterol suitable for symptom relief as well as symptom prevention in combination with an inhaled corticosteroid. LABAs have been shown to improve asthma symptoms and the need for additional bronchodilator therapy, peak expiratory flow, and asthma-specific measures of quality of life.

Side-effects

These are due to pharmacological actions on extrapulmonary β‎2-receptors. Side-effects are uncommon with inhalation therapy, and more significant in oral or IV therapy.

  • Muscle tremor—direct stimulation of skeletal muscle β‎2-receptors.

  • Tachycardia—direct effect on heart β‎2-receptors and reflex response to peripheral vasodilatation.

  • Metabolic—hypokalaemia, hypomagnesaemia, hyperglycaemia.

  • Transient decrease in arterial partial pressure of oxygen (PaO2)—increase of ventilation–perfusion mismatch by relaxation of compensatory vasoconstriction in underventilated areas of lung.

  • Tolerance/subsensitivity/desensitization—occurs with regular use of β‎2-agonists and is clearly demonstrated for the non-bronchodilatory responses (tremor, tachycardia, and metabolic effects). The mechanism is thought to be due to uncoupling, internalization, and/or downregulation of β‎2-receptors. Tolerance is not progressive and has not been shown to be of clinical importance.

Anticholinergic agents

Anticholinergics are one of the mainstays of treatment in COPD; they are also useful in the treatment of acute asthma exacerbation by nebulization but are less effective than β‎2-agonists.

Mode of action

Anticholinergics are antagonists of muscarinic receptors and inhibit cholinergic nerve reflexes, which give airway smooth muscle its tone. As the airways in COPD are structurally narrowed, the bronchodilator effects of anticholinergics are more significantly marked compared with normal airways.

Therapeutic use

Anticholinergics are most commonly administered in MDI. Short-acting agents (e.g. ipratropium bromide) have a maximum effect 30– 60min after use, and last from 4 to 6 h, hence they are prescribed four times daily. The newer long-acting anticholinergics (e.g. tiotropium bromide) last up to 24 h, and hence are used once a day. They have been shown to improve patient symptoms and spirometric parameters and to reduce the exacerbation rate in COPD.

Side-effects

Inhaled anticholinergics are minimally absorbed, so have relatively few side-effects. Nebulized anticholinergics may rarely precipitate glaucoma in elderly patients by a direct effect on the eyes, hence a mouthpiece should be used as an alternative to a mask. Other potential effects include dry mouth, blurred vision, and urinary retention.

Xanthine derivatives: theophylline

Theophylline has been used in asthma treatment for more than 60 years; it has seen its role change gradually with developments in other classes of bronchodilators and anti-inflammatory agents. Further developments included slow-release formulations that countered the rapid absorption and elimination of theophylline and rapid assays that made therapeutic drug monitoring readily possible.

Mode of action

Although theophylline has traditionally been classified as a bronchodilator, its therapeutic effect in controlling asthma has always been disproportionately greater than is explained by its relatively small degree of bronchodilator ability. There is recognition that theophylline has, in addition, anti-inflammatory, immunomodulatory, and bronchoprotective effects that may contribute to its efficacy as preventive treatment for chronic asthma:

  • Downregulation of the function of immune and inflammatory cells (e.g. T-lymphocytes, macrophages, mast cells).

  • Decrease of fatigue in diaphragmatic muscles.

  • Decrease of airway microvascular leakage.

  • Increasing mucociliary clearance.

  • Central action to block decrease in ventilation that occurs with sustained hypoxia.

These findings suggest, but do not establish, its non-bronchodilator efficacy, and some of these actions give a rationale for added therapy in acute asthma unresponsive to β‎2-agonists and systemic steroids, as well as its use in stable COPD.

On a molecular level, two modes of action are known to occur at clinically relevant drug concentrations:

  • Inhibition of phosphodiesterases—intracellular cAMP, essential for relaxation of airway smooth muscle, is hydrolysed by phosphodiesterase. Thus its inhibition by theophylline increases cAMP concentration, leading to bronchodilation. Anti-inflammatory effects may be due to action on the isoenzyme via cAMP in inflammatory cells.

  • Antagonism of adenosine receptors—this appears to be the mechanism by which theophylline stimulates ventilation in hypoxia, decreases fatigue in diaphragmatic muscles, and inhibits release of certain mediators from mast cells.

Therapeutic use

Theophylline is considered in Step 4 of the BTS/SIGN chronic asthma treatment guidelines if asthma is still uncontrolled with inhaled corticosteroids and LABAs. Theophylline can also be useful in stable COPD as an additional bronchodilator, improving dyspnoea and reducing hyperinflation. The drug is usually given in two divided doses at 12-h intervals. In acute asthma, evidence for the efficacy of IV theophylline is conflicting, hence it should only be considered for patients with severe acute symptoms unresponsive to other measures. Similarly, the benefits of adding theophylline in acute exacerbations of COPD remain unclear, with a few randomized controlled trials showing no benefit but with increased adverse effects. Doses giving peak serum concentrations between 10 and 20 µg/ml are most effective in symptom prevention and reducing the need for rescue therapy in chronic asthma.

Theophylline is predominantly eliminated by hepatic cytochrome P450 isoenzymes. Many factors affect plasma clearance and hence plasma concentration:

  • Increased plasma clearance—enzyme induction by drugs (e.g. rifampicin, antiepileptics); cigarette and cannabis smoking, even passive; high-protein, low-carbohydrate diet; in children.

  • Decreased plasma clearance—enzyme inhibition (e.g. ciprofloxacin, macrolides, methotrexate, allopurinol, cimetidine, alcohol); liver disease; cardiac decompensation; septic shock; prolonged pyrexia; in the elderly.

Side-effects

Efficacy and toxicity of theophylline are closely associated with serum drug concentration. Side-effects include nausea and vomiting, diarrhoea, headaches, irritability, and insomnia. Even higher serum concentrations can cause seizures, toxic encephalopathy, hyperthermia, cardiac arrhythmias, and death.

Nitric oxide

History

Nitric oxide (NO) was identified as an endogenous vasodilator (endothelial-derived relaxing factor) in 1987. It is now known to be a mediator of intracellular signalling and numerous physiological functions, including neurotransmission, inhibition of platelet and leukocyte adhesion, gastrointestinal motility, and host defence. The physiological role of endogenous NO was first demonstrated in healthy volunteers by evaluating the systemic and pulmonary pressor response to an infusion of an unselective inhibitor of NO synthase. It is a colourless, odourless gas, which is relatively insoluble in water. Environmental NO arises from fossil fuel combustion, cigarette smoke, and lightning. Atmospheric concentrations usually range between 10 and 500 parts per billion, but can be higher in heavy traffic.

Biochemistry

NO is synthesized from L-arginine by nitric oxide synthases (NOS). There are three isoforms: one is inducible (NOS II), and two are constitutively expressed, neuronal (NOS I) and endothelial (NOS III). The inducible form, NOS II, is expressed in response to various stimuli, including proinflammatory cytokines. Relatively large quantities of NO are produced continuously by inducible NOS II in blood vessel walls during an inflammatory response, suggesting that this pathway contributes to the vasculopathy of sepsis. Under physiological conditions, NO is produced in a highly regulated manner by NOS III and controls local vascular tone by diffusing from the vascular endothelium to act on smooth muscle cells. NO has a high affinity for iron-sulphur groups and haem, which accounts for its very short half-life in blood. In combination with oxyhaemoglobin, NO forms methaemoglobin and nitrate. Nitrate is excreted in urine, while most of the methaemoglobin is reduced to ferrous haemoglobin. NO also reacts very rapidly with superoxide species to produce peroxynitrite anions, which may form highly reactive and toxic hydroxyl radicals. These so called reactive nitrogen species are beneficial when used by leukocytes to kill microbes, but can also cause local tissue damage.

NOS inhibitors have been proposed as adjuncts to cardiovascular support in patients with septic shock. Despite reports of successful cases, larger trials demonstrated increased mortality in patients with sepsis associated with the use of non-selective NOS inhibitors and these agents are not currently used.

Clinical use of inhaled nitric oxide

Nitric oxide donors, including sodium nitroprusside and nitrates, have an established role in treating patients with hypertensive crises, angina, and acute heart failure. The objectives of using inhaled NO (iNO) are reducing pulmonary vascular resistance, reducing ventilation-perfusion mismatch, or replacing circulating NO stores. Endogenous NO activity is decreased after lung transplantation and in patients with sickle cell disease. iNO has been used effectively to support patients with primary graft dysfunction after lung transplantation. However, despite encouraging initial reports, its prophylactic use is of no benefit. High-dose iNO may be beneficial in treating sickle crises but has not been assessed in a randomized trial.

The commonest clinical scenarios in which iNO is used are acute respiratory distress syndrome (ARDS), right ventricular failure, and neonatal hypoxic respiratory failure.

ARDS

Severe hypoxaemia caused by extensive ventilation–perfusion mismatching is characteristic of ARDS. iNO augments hypoxic pulmonary vasoconstriction by selectively vasodilating vessels associated with ventilated alveoli; because the gas is delivered by inhalation the blood supply to unventilated lung units is unaffected. iNO improves indices of oxygenation in approximately two-thirds of patients with ARDS; however, there is no evidence from multiple randomized placebo-controlled trials that NO improves mortality or shortens the duration of mechanical ventilation. Therefore, the role of iNO is as a rescue treatment in cases where oxygenation is dangerously low despite optimal ventilation.

Right ventricular failure

The right ventricle is exquisitely sensitive to increased afterload. Therefore, iNO can markedly improve right ventricular function, cardiac output, and oxygen delivery by reducing pulmonary vascular resistance. The advantages of iNO over other vasodilators are that oxygenation tends to be improved and systemic pressures are maintained. However, in patients with left heart failure, iNO may increase pulmonary blood flow and left atrial pressure, causing an exacerbation of pulmonary oedema. Despite a lack of evidence from randomized trials, iNO is most commonly used in this context to support patients after cardiac surgery. There are also reports of haemodynamic benefit in cases of acute massive pulmonary embolism.

Neonatal hypoxic respiratory failure

In hypoxaemic infants born after 35 weeks of gestation, iNO reduced the need for extracorporeal membrane oxygenation, but mortality is not reduced. Oxygenation improves in approximately 50% of infants. Whether infants have evidence of persistent pulmonary hypertension of the newborn does not affect outcome.

Administration of inhaled nitric oxide

NO is most commonly administered to mechanically ventilated patients through an endotracheal tube, although it may also be given through a facemask or nasal cannulae. Intermittent flow, coincident with inspiration, reduces the production of nitrogen dioxide by minimizing the mixing time of oxygen and NO. iNO should be administered at the lowest effective dose for the shortest possible time because the toxic effects of iNO are largely unknown, the physiological benefit of continuous inhalation lasts no longer than 48 h, and it is very expensive. Dose-response studies in patients with ARDS have demonstrated that, over 1 day of continuous inhalation, the pulmonary vasculature becomes 10 times more sensitive to its effects. Before starting iNO, all other appropriate strategies to optimize pulmonary vascular resistance or oxygenation should have been deployed. The means of assessing effectiveness, such as PaO2 (partial arterial oxygen pressure), FiO2 (fractional inspired oxygen concentration) ratio (PaFi), or cardiac output monitoring should also be available before iNO is administered. Reasonable starting doses are 5 and 10 ppm to modify oxygenation and pulmonary haemodynamics, respectively. Gradual uptitration every 30 min to 20 ppm should be tried before concluding that there is no physiological response. Daily dose titration against the relevant physiological parameter should be performed with the expectation of a tenfold decrease in dose each day and withdrawal after 48 h or sooner if there is no longer physiological benefit.

If iNO has been administered for over 12 h, acute rebound pulmonary hypertension may develop on withdrawal, particularly in children. Incremental withdrawal with close haemodynamic monitoring is advised.

Adverse effects of inhaled nitric oxide

Most of the adverse effects of iNO can be predicted from the physiological effects and biochemical reactions of NO. There is a negligible risk of methaemoglobinaemia in adults receiving up to 40 ppm iNO, although administration is contraindicated by methaemoglobin reductase deficiency. Potentially damaging reactive nitrogen species are formed in patients with sepsis and ARDS, but the contribution of iNO to any pathological effects of these radicals is unknown. The effects of NO inhalation on bleeding time and other indices of platelet function in healthy volunteers and patients are variable. However, there is an increased risk of intraventricular haemorrhage in preterm infants. Analysis of data from studies in which iNO has been used for multiple indications suggests a dose-dependent increased risk of renal dysfunction of unknown cause.

Adjunctive therapies

Phosphodiesterase (PDE) hydrolyses cyclic guanosine monophosphate (cGMP), the secondary messenger of NO signalling in smooth muscle. Orally administered PDE 5 inhibitors are selective pulmonary vasodilators, partially because PDE 5 is highly expressed in the lung. For example, sildenafil augmented pulmonary vasodilation induced by iNO although the route of administration of these agents removes their beneficial effects on oxygenation, making them suitable only for the treatment of pulmonary hypertension and right ventricular failure.

Mucolytics

Introduction

The airway mucosa responds to infection and inflammation in a variety of ways, including surface mucous cell and submucosal gland hyperplasia and hypertrophy, with mucus hypersecretion. The viscosity of mucus secretions in the lungs depends on the concentrations of mucoprotein and the presence of disulfide bonds between these macromolecules and DNA.

Mucolytic drugs increase expectoration by reducing sputum viscosity and facilitating hypersecretion. This action often helps relieve respiratory difficulties in critically ill patients and respiratory diseases. These drugs can modify the production and secretion of mucus, as well as its nature and composition and its interaction with the mucociliary epithelium.

Other mucoactive drugs, such as expectorants and bronchodilators, may also increase mucus production or ciliary beat frequency, without altering the chemical properties of mucus.

Properties of mucus

The airways are lined by a layer of protective mucus gel that sits in a watery periciliary fluid. Mucus consists of an adhesive, viscoelastic gel resulting from the transudate and secretions from surface epithelial lining cells and submucosal glands. It comprises mainly water (95%), as well as glycoproteins, proteoglycans, lipids, proteins, and DNA. The composition changes in disease states, with a reduction in the water component.

Mucus helps to entrap and clear bacteria and inhibits bacterial growth and biofilm formation. It also protects the airway from inhaled irritants and from fluid loss.

Types of mucolytics

Naturally occurring mucolytics include mugwort, bromelain, papain, and clerodendrum. Pharmacological mucolytics are defined as classic, peptide, or non- destructive.

Classic mucolytics

Classic mucolytics depolymerize the mucin glycoprotein oligomers by hydrolysing the disulfide bonds that link the mucin monomers. The best known is acetylcysteine, an N-acetyl derivative of the amino acid L-cysteine and a precursor of the formation of the antioxidant glutathione inside the body. Acetylcysteine splits the sulfide bonds in the macromolecules, thereby decreasing viscosity and allowing removal via normal physiological clearance mechanisms. The action of acetylcysteine is pH-dependent, and the action of mucolytics in general is significant at pH values of 7–9. However, it has not been convincingly demonstrated that acetylcysteine improves the ability to expectorate mucus or decreases mucus viscosity in vivo. Its clinical effect on patients with chronic respiratory diseases is probably because of its antioxidant properties.

Peptide mucolytics

With airway inflammation and inflammatory cell necrosis, a secondary polymer network of DNA and F-actin develops in purulent secretions. Classic mucolytics may be unable to depolymerize them. Peptide mucolytics are designed to depolymerize the DNA polymer (e.g. dornase alfa) or the F-actin network (e.g. gelsolin). They are more effective when the sputum is rich in DNA pus.

Dornase alfa has been studied extensively in cystic fibrosis. It has been shown to reduce the viscosity and adhesiveness of infected sputum in some patients, achieving a modest improvement in pulmonary function. No conclusive positive results have been reported in patients with chronic bronchitis. F-actin depolymerizing agents used in conjunction with dornase alfa may reduce sputum viscoelasticity and cohesiveness.

Non-destructive mucolytics

It has been suggested that agents such as low-molecular weight dextran, heparin, and other sugars or glycoproteins may act on the oligosaccharide side-chains, although no conclusive clinical data are yet available.

Other mucoactive agents

Hypertonic (7%) saline increases expectoration when delivered as an aerosol, by increasing sodium chloride concentration in the airway. Water then flows from submucosal membrane by an osmotic gradient, improving mucociliary clearance and pulmonary function. However, it can induce bronchospasm. It may be particularly useful in cystic fibrosis and bronchiectasis, although the results so far are inconclusive. Tolerance may be improved by the association of hyaluronic acid.

Surfactant can reduce sputum adhesiveness and increase the cough transportability of secretions.

Clinical applications

Mucolytics may be indicated as adjuvant therapy in respiratory conditions with excessive or thick mucus production, such as COPD, bronchiectasis, and cystic fibrosis, as well as in some mechanically ventilated patients. They may also be used in other situations such as burn-associated inhalational injury or ARDS, although their effectiveness has not yet been convincingly demonstrated.

COPD

The volume of mucus secretion is greatly increased in COPD patients. Studies of several oral mucolytics suggest that oral mucolytic treatment may produce a slight reduction in acute exacerbations and has a small effect on overall quality of life.

Bronchiectasis and cystic fibrosis

Mucolytic agents such as acetylcysteine are considered as part of the management of patients with bronchiectasis, although there is not enough evidence to recommend routine use. No benefits have been reported with the use of recombinant DNase in non-cystic fibrosis bronchiectasis; in fact, it may have a negative effect on pulmonary function.

Recombinant DNase seems to be more effective when sputum is rich in DNA pus. It may slightly improve pulmonary function and may reduce hospitalizations in patients with cystic fibrosis.

Mechanically ventilated patients and ARDS

Few data are available on the use of acetylcysteine in ICU patients and clinicians should be aware of its potential deleterious effects. The administration of mucolytics in mechanically ventilated patients presents some limitations. The aerosol particles may deposit in the ventilator circuit and the endotracheal tube, and can inhibit ciliary function. Furthermore, acetylcysteine may induce bronchospasm and increase airway resistance, so the use of an associated bronchodilator should be considered. Gas exchange may worsen acutely after acetylcysteine administration, possibly because liquefied secretions gravitate into the smaller airways.

Case reports of the use of recombinant human DNase in status asthmaticus, ARDS, and mechanically ventilated paediatric patients have been published but no prospective efficacy studies are available to support its use in adult ICU patients.

Side-effects

Aerosol solutions can induce bronchospasms, nausea, and rashes. Oral mucolytics can cause nausea and diarrhoea.

Helium–oxygen gas mixtures

Nomenclature

Helium–oxygen mixtures are sometimes referred to as heliox, whilst nitrogen–oxygen mixtures are referred to as nitrox. However, heliox is sometimes used to refer specifically to helium 79%, oxygen 21%. In this chapter, heliox will refer to any mixture of helium and oxygen, whilst heliox21 refers to helium 79%, oxygen 21%.

Rationale

The efficiency of gas flow is dependent upon, amongst other things, the physical properties of the gas, specifically its density and viscosity. Reducing the density increases the efficiency of gas flow. Helium is a colourless, odourless gas, is chemically and biologically inert, and its density is seven times less than nitrogen and eight times less than oxygen, with a comparable viscosity. Thus, substituting helium for nitrogen in inspired gas mixtures increases the efficiency of convectional and diffusional gas transport.

Indications

Helium–oxygen mixtures should be considered as a rescue therapy in the immediate management of upper and/or lower airway obstruction due to such conditions as croup, epiglottitis, laryngitis, tracheitis, foreign body aspiration, postextubation or peribronchoscopy stridor, tumour (upper airway or proximal tracheobronchial tree), tracheomalacia, tracheal stenosis, acute severe asthma, and acute severe (hypercapnic) exacerbation of COPD.

Treatment with a helium–oxygen mixture should be initiated in a patient with any of these conditions who, despite first-line therapy, develops severe respiratory distress, specifically: reports severe dyspnoea, has a very high respiratory rate, is making excessive respiratory effort, is tiring, becomes drowsy or agitated, or is becoming hypoxic and/or hypercapnic. It may prevent the need to intubate or at least create a time window to allow this to be done urgently rather than as an emergency.

Expected effects

Administering helium–oxygen should improve the efficiency of ventilation and thereby reduce respiratory distress. However, it is only a temporizing intervention, i.e. it extends the period of time available for definitive treatment for the underlying condition to be delivered; it is not in itself therapeutic.

Presentation

Helium should only be available as heliox21 (79% helium, 21% oxygen). This is because you will never want to deliver a gas mixture with <21% oxygen.

Face mask administration

Helium–oxygen gas mixtures can be delivered through any tight-fitting mask. The mask should preferably have a reservoir bag into which the heliox is delivered, and one or more one-way expiratory valves. Every effort should be made to minimize air entrainment. Specialist masks and mixing/nebulizing circuits are available commercially. Supplemental oxygen can be provided either through a Y-piece mixing circuit or via nasal specs worn underneath the tight-fitting mask.

Nebulization

Generating a respirable aerosol using heliox21 through a standard, gas-driven, updraft nebulization chamber requires flow rates of ≥15 l/min as compared with air or oxygen, which run at 6–8 l/min. Thus, the efficiency and reliability of respirable particle generation using heliox21 are suboptimal. As a carrier gas for respirable particles, however, heliox21 demonstrates significantly higher delivery than more dense gas mixtures. Ideally, therefore, an alternative particle generation technique should be employed, such as ultrasound or vibrating mesh. Unfortunately, these techniques are not widely available. The choice in an individual circumstance will usually be decided by practicalities such as the need for supplemental oxygen or heliox21 availability. It may be difficult to run a reservoir bag and a nebulizer simultaneously off the same cylinder.

Caution: managing hypoxia

In hypoxic patients (peripheral capillary oxygen saturation [SpO2] <88%), a balance needs to be struck between improving ventilation (by minimizing gas density and hence minimizing the FiO2) and achieving adequate oxygenation (by diluting heliox21 with supplemental oxygen). As a starting guide, aim to achieve an SpO2 of 88–92%.

Patient monitoring during therapy

Routine respiratory monitoring is all that is required (airway patency, respiratory rate, clinical evaluation of the adequacy of ventilation, SpO2, and blood gas analysis). Continuous oxygen saturation monitoring should be used in all hypoxic patients. Always assess and optimize face mask position as any air entrainment will reduce the effectiveness of this intervention.

Safety

Standard safety precautions for compressed gases are all that is required. Helium is inert and insoluble in human tissues at atmospheric pressure. Helium does have a high thermal conductivity but does not cause significant airway or whole patient cooling, even in neonates.

Stopping helium–oxygen therapy

Helium–oxygen therapy can be withdrawn as soon as definitive therapy has taken sufficient effect to reduce respiratory distress. It may be useful as an intermittent therapy in such conditions as acute severe asthma where periodic reductions in the work of breathing can prevent decompensation and thereby prevent the need for intubation and mechanical ventilation.

Indications for helium–oxygen mask ventilation

Heliox may reduce the work of breathing to a similar extent to positive pressure mask ventilation (continuous positive airway pressure, bilevel positive airway pressure, pressure support ventilation. The effect of these two interventions is additive such that a patient failing one may benefit from the addition of the other). Delivering heliox mixtures through positive pressure mask ventilation devices is problematic, as none is currently designed for this. Some clinicians have tried entraining heliox21 at 15 l/min into the mask or as near to it in the circuit as practical. However, the efficacy of this technique, in particular, the actual gas mixture delivered to the patient, is uncertain.

Indications for helium–oxygen intermittent positive pressure ventilation via endotracheal or tracheostomy tube

Severe inspiratory and/or expiratory flow limitation necessitates the use of dangerously high airway pressures (≥35 cmH2O) and/or high levels of intrinsic positive end-expiratory pressure. The effectiveness of instituting helium–oxygen will be limited by the degree to which oxygen supplementation is required. A reversible pathology should have been identified and a treatment plan instituted. Patients may respond to relatively small reductions in gas density such that even an FiO2 of 0.7 should not necessarily preclude a therapeutic trial. It is sometimes possible to decrease the FiO2 gradually as ventilation improves, thus decreasing the gas density further.

Patient monitoring during intermittent positive pressure ventilation therapy

Routine respiratory/ventilator monitoring is all that is required. There are currently only two commercially available ventilators designed for use with heliox. Of note, both can be used to deliver mask ventilation. Some other ventilators can be connected to heliox in place of air. Heliox may interfere with both internal performance and patient monitoring. Extreme care needs to be employed to avoid the delivery of excessive or inadequate tidal volumes. Always use a pressure control mode and measure the FiO2. Switching gas mixtures between heliox and nitrox usually requires recalibration of the pneumotachograph, which in most ventilators cannot be performed whilst delivering ventilation to a patient. Capnography is also affected by substituting helium for nitrogen. The efficacy of heliox over nitrox should be evident almost immediately, with a maximal effect seen within 15 min.

Stopping helium–oxygen therapy

Assuming that helium–oxygen has proven to be efficacious and that a sufficient time interval has elapsed to allow definitive therapy to have taken effect, then institute a trial of switching the inspiratory gas mixture back to nitrogen–oxygen. If this results in a significant deterioration in respiratory mechanics, then reinstitute helium–oxygen and set a time interval at which a retrial of nitrogen–oxygen will be undertaken. Intermittent use of a helium–oxygen mixture may be considered as part of a weaning strategy.

Published trials

There are a significant number of published trials of heliox in a variety of settings. These have been extensively reviewed. However, there is currently insufficient evidence to justify its routine use.

Multiple choice questions and further reading

Respiratory drugs Interactive multiple choice questions to test your knowledge on this chapter and additional further reading can be found in Appendix Chapter 11 Multiple choice questions and further reading