Drugs Acting on the Respiratory System

Published on 27/02/2015 by admin

Filed under Anesthesiology

Last modified 22/04/2025

Print this page

rate 1 star rate 2 star rate 3 star rate 4 star rate 5 star
Your rating: none, Average: 4.5 (2 votes)

This article have been viewed 3045 times

Drugs Acting on the Respiratory System

An understanding of how drugs interact with the respiratory system is vital for anaesthetists and those working in critical care. Knowledge of the drugs discussed in this chapter will facilitate effective management of common, potentially life-threatening medical emergencies. An appreciation of the steps in the British Thoracic Society guidelines on asthma management may help risk-stratify and optimize asthmatic patients in the perioperative period. Oxygen is increasingly being considered as a therapeutic agent or drug requiring a written prescription. Nearly 300 serious incidents associated with oxygen misuse, including nine deaths, were reported to the National Patient Safety Agency (NPSA) over a 5-year period. Anaesthetists are well placed to lead implementation of the NPSA’s recent guidance and assist in the education of other healthcare staff regarding the safe use of oxygen.

DRUGS AFFECTING AIRWAY CALIBRE

Airway smooth muscle tone results from a balance between opposing sympathetic and parasympathetic influences (Fig. 9.1). Sympathetic activity causes bronchodilatation while cholinergic parasympathetic activity from the vagus nerve causes bronchoconstriction. Drugs which increase sympathetic influence or decrease cholinergic parasympathetic activity generally cause bronchodilatation by relaxation of airway smooth muscle, and so may be used in the management of asthma and chronic obstructive pulmonary disease (COPD). Sympathetic control is mediated at a cellular level by β2-receptors. Agonists such as adrenaline that bind to these G-protein coupled receptors (Gs) stimulate adenylate cyclase. This enzyme catalyses the conversion, within the cell, of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP). Through kinase enzyme systems, cAMP relaxes airway smooth muscle. Cyclic AMP is degraded to inactive 5′-AMP by the enzyme phosphodiesterase. Drugs that increase the concentration of cAMP within the cell relax airway smooth muscle (e.g. β2-agonists, phosphodiesterase inhibitors). Conversely, drugs which reduce the level of cAMP (e.g. β2-antagonists) may cause bronchoconstriction.

The cholinergic parasympathetic system is mediated through several subtypes of muscarinic receptor. The most common subtype found in pulmonary tissue is the M3 receptor. This is also a G-protein coupled receptor (Gq) but one which, when activated, stimulates phospholipase C to produce inositol triphosphate, which then binds to sarcoplasmic reticulum receptors causing release of calcium from intracellular stores, and so results in smooth muscle contraction and bronchoconstriction. Therefore muscarinic agonists cause bronchoconstriction and anticholinergic drugs cause bronchodilatation.

A third, minor, neural pathway also exists, referred to as the non-cholinergic parasympathetic system. This is a bronchodilator pathway which has vasoactive intestinal peptide (VIP) as its neurotransmitter and nitric oxide (NO) as the second messenger. The physiological significance of this in humans is unknown.

Histamine and other mediators also play an important role in promoting bronchial constriction via H1-receptors, especially during anaphylaxis, drug reactions, allergy, asthma and respiratory infections. Anti-inflammatory agents (e.g. steroids) and membrane stabilizers (e.g. sodium cromoglicate) may reduce or prevent bronchoconstriction in these conditions.

Bronchodilators

Bronchodilators are used commonly in the management of acute asthma or an exacerbation of COPD with the aim of reversing the abnormal bronchospasm that occurs in these potentially life-threatening conditions. All doctors working in acute specialties need to be familiar with their use. Anaesthetists, by ensuring optimal bronchodilator therapy, may avoid the need for invasive ventilation in some patients. In addition to alleviating the symptoms of wheeze and dyspnoea, bronchodilators improve the adequacy of ventilation and decrease the work of breathing.

β-Adrenergic Agonists

β-Adrenergic agonists are usually the first-line treatment for relieving bronchospasm in asthma and COPD. These drugs have additional beneficial effects in the management of asthma (Table 9.1). There are at least three subtypes of β-receptor in the body: β1 is found in cardiac tissue, β2 in pulmonary tissue and peripheral vasculature and β3 in adipose tissue. Although non- selective β-agonists such as adrenaline and ephedrine can be used as bronchodilators, their unwanted β1 action (e.g. tachycardia) has meant that β2-specific agonists are preferred. Salbutamol, a synthetic sympathomimetic amine, is the most commonly used selective β2-agonist. Although developed as a selective β2-agonist, salbutamol may have β1 side-effects in high doses or in the presence of hypoxaemia or hypercapnia. Salbutamol is a short-acting bronchodilator with a fast onset of action used for the relief of acute symptoms.

TABLE 9.1

Effects of β-Agonist Drugs on the Airways

Specific
Increase in intracellular cAMP and bronchodilatation

Non-Specific but Complementary
Inhibition of mast cell mediator release
Inhibition of plasma exudation and microvascular leakage
Prevention of airway oedema
Increased mucous secretion
Increased mucociliary clearance
Prevention of tissue damage mediated by oxygen free radicals
Decreased acetylcholine release in cholinergic nerves by an action on prejunctional β2-receptors

Route of Administration and Dose: Inhalation is usually the most appropriate route of administration of β2-agonists in order to minimize systemic side-effects. An inhaled drug may also be more effective, because it easily reaches the mast and epithelial cells of the airway which are relatively inaccessible to a drug administered systemically. Salbutamol is administered from a pressurized aerosol (100 μg per puff; 1 or 2 puffs four times daily). The effect lasts for 4–6 h. The drug may also be nebulized in inspired gases and inhaled via a face mask or added to the breathing system in patients undergoing artificial ventilation. For this purpose, a dose of 2.5–5 mg up to four times daily is used. In severe bronchospasm, up to 5 mg may be given as frequently as every 30 min initially. Side-effects are more likely when these drugs are nebulized as they deliver a larger dose of which a significant proportion is absorbed systemically.

Oral administration has no advantage over the inhalational route and is associated with a greater incidence of adverse-effects. Intravenous administration is used occasionally, as a last resort, when bronchospasm is so severe that an aerosol or nebulizer is unlikely to deliver the drug to the narrowed airways or when inhalational therapy has failed. Intravenous administration is associated with more frequent systemic side-effects and should be used only when the patient is appropriately monitored.

Salmeterol is a more potent, longer acting β2-agonist than salbutamol. Its effects last up to 12 h, allowing twice daily administration for the prevention of asthma attacks. It is available as an aerosol inhaler (dose: 50–100 μg twice daily).

Adverse Effects: Adverse effects of β-agonists include the following:

Bronchodilatation may lead to transient hypoxaemia due to increased image mismatch and inhibition of the normal hypoxic pulmonary vasoconstriction mechanism. This may be overcome easily by supplying supplementary oxygen. β2-agonists also cause relaxation of the gravid uterus and may be used in the management of pre-term labour.

Anticholinergic Drugs

The use of anticholinergic agents for their bronchodilator properties dates back two centuries when Datura plants were smoked for the relief of asthma. As an anticholinergic, atropine does cause bronchodilatation but side-effects such as tachycardia and dry mucous membranes limit its usefulness. Anticholinergic drugs are usually used as second-line agents in the management of acute bronchospasm and are very effective in reducing the frequency of acute exacerbations of COPD when taken regularly. One of the most commonly used drugs is ipratropium bromide. It is a synthetic quaternary ammonium compound derived from atropine. Ipratropium is active topically and there is little systemic absorption from the respiratory tract. Mast cell stabilization has also been proposed as a complementary mechanism of action. Maximum effect occurs 30–60 min after inhalation and may continue for up to 8 h. Tiotropium is a more recently introduced antimuscarinic bronchodilator with a longer duration of action that allows once daily administration.

Methylxanthines

The bronchodilator effect of strong coffee was first described in the 19th century. Methylxanthines, which are chemically related to caffeine, have been used to manage obstructive airways disease since the 1930s. Theophylline is the most commonly used methylxanthine and is available as an oral modified-release preparation. Aminophylline is a water-soluble salt which is used as an injectable form of theophylline. Methylxanthines have widespread effects involving multiple organ systems. With regard to their bronchodilator effects, the following mechanisms have been proposed:

Methylxanthines also increase cardiac output and the efficiency of the respiratory muscles, including improved diaphragmatic contractility. Aminophylline has been used occasionally in the management of heart failure and is known to reduce the frequency of apnoea in the premature neonate.

Route of Administration and Dose: Theophylline may be used as a sustained release oral preparation for the prevention of acute exacerbations of COPD. The dose depends on the preparation being used and is given twice daily. Aminophylline is an intravenous preparation used for the relief of acute episodes of bronchospasm. It is a strong alkaline solution and should not be given intramuscularly or subcutaneously. A loading dose of 5 mg kg–1 should be given slowly over 20 min followed by an infusion of 0.5-0.7 mg kg–1 h–1. If the patient is already taking an oral theophylline, then the loading dose should be omitted.

There is a close relationship between the degree of bronchial dilatation and the plasma concentration of theophylline. A concentration of < 10 mg L–1 is associated with a mild effect and a concentration of > 25 mg L–1 with frequent side-effects. Consequently, the therapeutic window is narrow and the plasma concentration should be maintained within the range 10–20 mg L–1 (55–110 μmol L–1). Plasma assays should be performed 6 h after commencing an infusion or following a rate change and then every 24 h. Approximately 40% of the drug is protein-bound. Theophylline is metabolized mainly in the liver by cytochrome P450 microenzymes; 10% is excreted unchanged in urine. Factors which affect the activity of hepatic enzymes and thus the clearance of the drug are summarized in Table 9.2. The infusion rate of aminophylline should be adjusted accordingly (e.g. 1.6 times for smokers, 0.5 times for patients receiving erythromycin). The dose for obese patients should be based on ideal body weight and frequent estimation of plasma concentration is required to prevent ineffective therapy or toxicity.

TABLE 9.2

Factors Affecting the Plasma Concentration of Methylxanthines for a Given Dose

Factors Which Lower the Plasma Concentration:
Children
Smoking
Enzyme induction – rifampicin, chronic ethanol use, phenytoin, carbamazepine, barbiturates
High protein diet
Low carbohydrate diet

Factors Which Increase the Plasma Concentration:
Old age
Congestive heart failure
Enzyme inhibition – erythromycin, omeprazole, valproate, isoniazid, ciprofloxacin
High carbohydrate diet

Adverse Effects: Adverse effects of methylxanthines may be severe and are more likely to occur in patients also receiving a β-agonist bronchodilator or other sympathomimetic drugs.

Extreme care should be exercised when administering aminophylline in the presence of hypoxaemia, hypercapnia, dehydration, hypokalaemia or cardiac arrhythmias. Patients must be monitored closely. Deaths caused by gross hypokalaemia and cardiac arrhythmias have been reported. If toxic symptoms develop, administration of the drug should be discontinued and symptomatic treatment provided. Serum potassium concentration should be measured and corrected if necessary. In extreme cases, haemodialysis may be required to hasten elimination of the drug.

Anti-Inflammatory Agents

Steroids

Steroids are used commonly as anti-inflammatory agents. Synthetic glucocorticoids have metabolic, anti-inflammatory and immunosuppressive effects (Table 9.3). They are able to penetrate the cell membrane and interact with intracellular steroid receptors, influencing transcription of genes and protein synthesis. Steroid administration leads to reduced numbers of lymphocytes and eosinophils, reduced secretion of prostaglandins from macrophages and a reduction in endothelial permeability. Steroids also increase the sensitivity of β2-adrenoceptors to both endogenous and inhaled agonists and help prevent tachyphylaxis to adrenoceptor agonists such as salbutamol. There is some evidence that high-dose inhaled steroids help to slow the airway remodelling that results from chronic inflammation in asthma. Remodelling consists of airway smooth muscle hypertrophy, excess mucous glands and thickening of the basement membrane. It is thought to be one cause for the airway hyper-responsiveness that is characteristic of asthma.

TABLE 9.3

Sites of Action for the Anti-Inflammatory Effects of Steroids

Site of Action Mechanism
Intracellular steroid receptors Steroid–receptor complex alters the transcription of genes leading to altered protein synthesis
Lipocortin Increased lipocortin production inhibits release of arachidonic acid metabolites and platelet-activating factor from lung and macrophages
Eosinophils Decrease in the number of eosinophils and inhibition of degranulation
T lymphocytes Reduction in the number of T lymphocytes and the production of cytokines
Macrophages Reduced secretion of leukotrienes and prostaglandin
Endothelial cells Reduction of the leak between cells
Airway smooth muscle
β2-adrenoceptors		 Increased agonist sensitivity, augmenting the effect of agonists; increase in receptor density and prevention of tachyphylaxis
Mucous glands Reduced mucous secretion

Indications: Inhaled steroids are used commonly in the management of chronic asthma to reduce the frequency of attacks. They are usually considered when patients require a β2-agonist more than twice a week, if symptoms disturb sleep more than once a week or if the patient has suffered exacerbations in the last 2 years which required a systemic corticosteroid. The addition of an inhaled steroid constitutes ‘Step 2’ of the British Thoracic Society (BTS) guidelines for the management of asthma (Fig. 9.2). Some patients with COPD may have steroid-responsive disease. Inhaled steroids are unlicensed for COPD but may be considered in patients with an FEV1 < 50% of predicted, or for patients having more than two acute exacerbations requiring oral steroids per year. Oral and intravenous steroids are useful in the management of acute asthma or COPD. They may also have a role in the treatment of sarcoidosis, interstitial lung disease and pulmonary eosinophilia.

Route of Administration and Dose: The three most commonly used inhaled steroids are shown in Table 9.4. Standard doses are those used in Step 2 of the BTS guidelines. If symptom control is still poor on Step 3 of the protocol (steroid + long acting β2-receptor agonist) then high-dose inhaled steroid constitutes Step 4.

TABLE 9.4

Doses of Inhaled Steroids. Step 2 and Step 4 Refer to British Thoracic Society Asthma Guidelines (Fig. 9.2)

Steroid Standard (Step 2) Dose High (Step 4) Dose
Beclometasone dipropionate 100–400 μg twice daily 0.4–1.0 mg twice daily
Fluticasone dipropionate 50–200 μg twice daily 200–500 μg twice daily
Mometasone furoate 200 μg twice daily 400 μg twice daily

Systemic steroids are part of the standard treatment for acute asthma or COPD. In moderate acute attacks, prednisolone 40–50 mg per day may be given orally. In acute severe or acute life-threatening asthma, intravenous hydrocortisone 100 mg every 6 h may be required until oral prednisolone can be taken. Therapy is usually continued for 5–7 days. Long-term or high doses of steroids may cause adrenal suppression and if stopped abruptly may precipitate an Addisonian crisis. Courses of steroids lasting less than 3 weeks may usually be stopped abruptly without the risk of precipitating a crisis. Caution should be exercised in patients who have received repeated short courses, recently stopped long-term steroid therapy, those receiving evening doses, or patients receiving > 40 mg (or equivalent) of prednisolone per day.

Adverse Effects: Steroids have many local and systemic side-effects which commonly limit their use. Inhaled drugs are less likely than oral or intravenous steroids to cause systemic side-effects but may cause local irritation and predisposition to oral candidiasis. Some of the recognized side-effects of steroids are listed in Table 9.5.

TABLE 9.5

Common Adverse Effects of Steroids

Local Effects (Inhaled Steroids)
Hoarse voice
Oral/pharyngeal candidiasis
Throat irritation and cough

Systemic Effects (from Inhaled or Systemic Steroids)
Adrenergic suppression
Fluid retention
Hypertension
Peptic ulceration
Diabetes mellitus
Increased appetite
Weight gain
Bruising and skin thinning
Osteoporosis
Cataracts
Psychosis

Other Drugs

Sodium Cromoglicate

This is a derivative of khellin, an Egyptian herbal remedy which was found to protect bronchi against allergens. The mechanism of action is not fully understood but is thought to involve the stabilization of mast cell membranes. By blocking calcium channels, the drug is able to prevent mast cell degranulation with its subsequent histamine release. It has traditionally been used in patients with asthma in whom exercise is a trigger. Exercise-induced asthma may, however, just be a marker of poorly controlled asthma. A 4–6 week trial is useful to assess responsiveness. It is given by inhaler in a dose of 5–10 mg (1 or 2 puffs) four times a day. Side-effects are rare but include coughing, transient bronchospasm and throat irritation. Very rarely, angioedema may be precipitated. Sodium cromoglicate can also be used topically for allergic conjunctivitis and orally for the prevention of food allergy.

Leukotriene Receptor Antagonists

The leukotriene receptor antagonists are an additional therapy useful in the management of chronic asthma. They may be used in addition to, or in place of, a long acting β2-receptor agonist such as salmeterol in Step 3 of the BTS guidelines (Fig. 9.2). There are two drugs in this class in common clinical use: montelukast and zafirlukast. They may be particularly beneficial in exercise-induced asthma and may also be used in patients with seasonal allergic rhinitis who have concomitant asthma. Two oral drugs in this class are prescribed commonly; montelukast 10 mg is given once a day, usually in the evening, or zafirlukast 20 mg can be given twice a day. The most common adverse effects are gastrointestinal upset and abdominal pain, with headache and insomnia also reported. These drugs have been associated rarely with the development of Churg-Strauss vasculitis and patients should be told to report any rash or worsening of pulmonary symptoms.

Antihistamines

Antihistamines are not used in the management of COPD or asthma but are used commonly for symptom control in hay fever and have a role in the management of anaphylaxis. Antihistamines may be classified as sedating (older compounds which easily cross the blood–brain barrier) and non-sedating (newer drugs which do not cross into the CNS). Indications for antihistamines include hay fever, urticaria, insect bites, pruritus, nausea and anaphylaxis. Many individual preparations exist but two of the most commonly used drugs are chlorphenamine (chlorpheniramine) and loratadine. Chlorphenamine is a sedating antihistamine given in a dose of 4 mg every 4–6 h to a maximum of 24 mg daily. For anaphylaxis, 10 mg can be given i.v. and may be repeated to a maximum of four doses daily. Loratadine is a non-sedating antihistamine taken as a 10-mg tablet once a day. Adverse effects from antihistamines are more commonly encountered with the older drugs and include sedation, headache and antimuscarinic effects such as urinary retention and dry mouth. Other rare adverse effects include liver dysfunction and angle-closure glaucoma.

DRUGS ACTING ON THE PULMONARY VASCULATURE

Physiological control of pulmonary vascular tone is mediated by neural and humoral influences. Many of these control mechanisms have mixed actions. Sympathetic nerves originating from T1–5 release noradrenaline, causing vasoconstriction via α-receptors. Parasympathetic nerves from the vagus cause vasodilatation via the action of acetylcholine on M3 receptors by a nitric oxide (NO) dependent mechanism. There are also non-adrenergic non-cholinergic (NANC) nerves which cause vasodilatation via NO release. Circulating catecholamines act on both α- and β2-receptors within the pulmonary vasculature, with the former vasoconstrictor effect predominating. Arachidonic acid metabolites such as thromboxane and most prostaglandins produce vasoconstriction. However, prostacyclin (PGI2) is a potent vasodilator. Other humoral influences include amines, peptides and nucleosides which have variable effects dependent upon resting vascular tone. Hypoxaemia and acidosis are well recognized to cause vasoconstriction and an increase in pulmonary vascular resistance.

The main therapeutic benefit of modifying pulmonary vascular tone is in reducing pulmonary vascular resistance (PVR) in disease states associated with pulmonary hypertension. Pulmonary hypertension is most commonly secondary to connective tissue disorders, chronic thrombotic disease, left heart failure or chronic hypoxaemia. It may rarely be due to idiopathic pulmonary arterial hypertension (IPAH), formerly known as primary pulmonary hypertension. With the exception of chronic thrombotic disease which may be successfully treated with by pulmonary artery embolectomy and lifelong anticoagulation, the other causes of pulmonary hypertension are managed by long-term manipulation of pulmonary vascular resistance.

Inhaled Agents

Nitric Oxide

Nitric oxide is a colourless and highly reactive gas, first studied by the English chemist Joseph Priestley in 1772. It is presented in grey/green cylinders, is highly lipid soluble, and easily crosses biological membranes.

Indications: Inhaled nitric oxide may be used in the management of critically ill patients with pulmonary hypertension or severe image mismatch. It may also form part of the management of persistent pulmonary hypertension of the newborn. Given as an inhaled preparation, it only vasodilates vessels close to well ventilated areas, thereby improving image matching (Fig. 9.3). It has negligible systemic effects because of its rapid inactivation by haemoglobin after diffusing into the pulmonary circulation.

Adverse Effects: One of the risks of NO therapy is its oxidation to nitrogen dioxide (NO2). The rate of oxidation is directly proportional to the concentration of oxygen in the gas mixture, duration of mixing and the square of the concentration of NO. These higher oxides may react with water to form nitric and nitrous acids which can lead to lipid peroxidation, impaired mitochondrial function, prolonged bleeding time and mutagenesis. Therefore all delivery systems should measure levels of NO2. NO therapy, especially in the newborn, may lead to methaemoglobinaemia. All patients receiving NO should have the methaemoglobin concentration monitored by arterial blood gas analysis; concentrations greater than 2% should be avoided. Some patients may display a rebound phenomenon on withdrawal of NO therapy, with worsening hypoxaemia and increased pulmonary vascular resistance. For this reason, NO therapy should be reduced gradually to allow endogenous production to restart.

Oral Agents

Intravenous Agents

Epoprostanol

Epoprostanol or prostacyclin has been shown to improve exercise tolerance and quality of life in patients with IPAH. Unfortunately, the drug has a short half-life of approximately 3 min and must therefore be administered as a continuous i.v. infusion. In practice, this requires the patient to have an indwelling, tunnelled central venous catheter such as a Hickman line. These long-term catheters are associated with infection risks and body image issues. The treatment was originally designed as a bridge to lung transplantation but data suggest that use of the drug may be associated with a similar improvement in life expectancy as lung transplantation. Adverse effects include flushing, headache and hypotension. Epoprostanol is also used commonly as a platelet inhibitor in renal replacement therapy.

DRUGS MODERATING VENTILATORY CONTROL

Respiratory Stimulants

Several classes of drug stimulate ventilation and may be used when ventilatory drive is inadequate. These agents increase respiratory drive through a variety of mechanisms. For example, strychnine blocks central inhibitory pathways, acetazolamide increases hydrogen ion concentration in the extracellular fluid around the respiratory centre and doxapram stimulates the respiratory centre directly. Only doxapram is now used commonly in clinical practice. Non-invasive ventilation (NIV) has now largely replaced respiratory stimulants in the management of respiratory failure. They may be used in the short-term if NIV is contraindicated or unavailable. Stimulants should not be used if muscle fatigue is thought to be contributing to respiratory failure.

Doxapram

Doxapram is the only specific respiratory stimulant available for use in anaesthesia and critical care.

OXYGEN THERAPY

Oxygen therapy may be regarded as a therapeutic intervention with indications, benefits and adverse effects. It is increasingly being considered to be a pharmacological agent or drug. Oxygen is a colourless, odourless gas which forms 20.93% (by volume) of the Earth’s atmosphere. It was first recognized as a distinct gas by Joseph Priestley in 1774 and was identified subsequently as the final universal oxidant in metabolic reactions. Atmospheric pressure at sea level is approximately 100 kPa and the partial pressure of oxygen which we breathe in air at sea level is 21 kPa. Alveolar oxygen partial pressure is reduced to 14.7 kPa by the addition of water vapour and carbon dioxide. Oxygen therapy is administered to hypoxaemic patients to increase alveolar oxygen partial pressure. The concentration of inspired oxygen administered depends on the condition being treated but should in most cases be titrated against either peripheral oxygen saturation or arterial oxygen tension. Administration of an excessive concentration of oxygen may be detrimental and, rarely, fatal. In patients with type 2 respiratory failure who rely on a hypoxic drive to breathe, sudden increases in inspired oxygen concentration may lead to apnoea.

Acute Oxygen Therapy

High-Concentration Oxygen Therapy

In most medical emergencies, oxygen therapy should be given quickly and in a high concentration because the avoidance of tissue hypoxia is of paramount importance. When managing patients with uncomplicated pneumonia, pulmonary embolism, sepsis, shock, trauma or anaphylaxis, up to 60% oxygen may be delivered via a simple oxygen mask (e.g. Hudson mask). Therapy should be titrated against peripheral oxygen saturations and in most patients a saturation of 94–98% is adequate. If higher concentrations are required, up to 80% oxygen may be given via a non-rebreathing or trauma mask in spontaneously breathing patients. During the management of cardiac arrest, 100% oxygen may be delivered via a closed circuit to an intubated patient. In severe carbon monoxide poisoning, hyperbaric oxygen therapy (HBOT) may be used to increase the partial pressure of alveolar oxygen to > 100 kPa.

Low-Concentration Oxygen Therapy

Low-concentration or controlled oxygen therapy is reserved for patients at risk of type 2 (hypercapnic) respiratory failure who may be harmed by uncontrolled high concentrations of oxygen. Patients with severe COPD, bronchiectasis, cystic fibrosis, severe kyphoscoliosis or ankylosing spondylitis are included in this group, as are patients with chronic musculoskeletal weakness on home ventilation therapy. Each case must be considered in the light of clinical findings but, as a general rule, oxygen therapy should be started at 24 or 28% and gradually titrated against oxygen saturation (SpO2) or preferably arterial oxygen tension. An SpO2 of 88–92% is often acceptable in these patients and may avoid pronounced hypercapnia and respiratory arrest. Patients are advised to carry an ‘oxygen alert card’ (Fig. 9.4) which, together with previous blood gas analysis results, may help to guide therapy.

Prescribing

The British Thoracic Society recommended in its 2008 publication ‘Guideline for Emergency Oxygen Use in Adult Patients’ that oxygen therapy should be prescribed by a doctor in common with other medical drugs. Both under-administration (e.g. postoperatively) and over-administration (e.g. in the COPD patient) of oxygen can cause harm. A prescription which includes target peripheral oxygen saturation (as described above) allows nursing staff to titrate the inspired oxygen concentration via various devices to achieve a measurable therapeutic end-point. The prescription should be signed when appropriate titration has occurred. Specialist prescription charts have improved patient safety with drugs such as theophylline and heparin, which require special monitoring; many centres are now introducing a similar chart with useful guidelines and flow charts for titrated oxygen therapy.

Long-Term Oxygen Therapy

Domiciliary or long-term oxygen therapy (LTOT) is prescribed for patients with severe COPD or a small number of other pulmonary diseases which lead to chronic hypoxaemia. Two studies in the 1980s suggested that using oxygen continuously for at least 15 h per day reduced mortality in patients with severe COPD. Other benefits of LTOT include a stabilization or small reduction in pulmonary arterial pressure, reduced polycythaemia and improved exercise tolerance. Some studies have shown that LTOT leads to an improved quality of life. The indications for LTOT are based on arterial oxygen tension measured by arterial blood gas analysis on two separate occasions, three weeks apart and at least four weeks after an acute exacerbation. COPD patients with a PaO2 < 7.3 kPa or a PaO2 < 8.0 kPa with secondary polycythaemia, peripheral oedema or pulmonary hypertension should be considered for home oxygen. Other conditions for which LTOT is considered, depending on the PaO2, include pulmonary hypertension, cystic fibrosis, interstitial lung disease, chronic asthma and heart failure. Oxygen is usually prescribed at 2 or 4 L min− 1 and can be supplied from either cylinders or an oxygen concentrator. Concentrators are provided for patients using oxygen for more than 8 h a day or consuming more than 21 cylinders a month. The oxygen is usually delivered via nasal cannulae, allowing the patient to talk, eat and drink. The patient should be advised to stop smoking and all smoking cessation therapy options should be explored. The prescriber should request the patient’s permission to pass their details on to the local fire brigade. Ambulatory oxygen may also be provided for LTOT patients who frequently travel or spend nights away from home. The benefits of ambulatory oxygen therapy include improved compliance with LTOT (aiming for a minimum of 15 h per day) and increased exercise capacity.

Oxygen Toxicity

Oxygen, an element essential to life, may under certain circumstances produce toxic effects. Breathing high concentrations of oxygen at atmospheric pressure may lead to pulmonary toxicity. After inspiring 100% oxygen for as little as 12 h, healthy subjects have reported retrosternal discomfort, coughing and the urge to breathe deeply. Tracheobronchitis quickly supervenes and continued oxygen exposure may lead to neutrophil recruitment, impairment of surfactant and acute lung injury (ALI). Exposure to high concentrations of oxygen for a week may lead to pulmonary fibrosis. This process occurs at much lower oxygen concentrations in patients taking some chemotherapeutic agents. Cancer patients recently treated with bleomycin or mitomycin C may develop accelerated ALI and respiratory failure after exposure to only 40–50% oxygen. Neonates are also thought to be particularly sensitive to the damaging effects of hyperoxia. Babies are at risk of developing retrolental fibroplasias if the eyes are exposed to a PO2 > 10.6 kPa for longer than 3 h while under the age of 44 post-conceptual weeks. Hyperbaric conditions may cause pulmonary, optic and central nervous system toxicity. Oxygen at 2 bar causes a decrease in vital capacity of healthy volunteers after only 8 h, which persists after exposure has ceased. Hyperbaric oxygen causes narrowing of the visual fields and myopia in adults. Eventually, symptoms and signs of central nervous system toxicity ensue with nausea, facial twitching, olfactory/gustatory disturbances and ultimately tonic-clonic seizures. The underlying pathophysiology of toxicity is not well understood but may involve reactive oxygen species such as singlet oxygen interfering with enzyme systems containing sulphydryl groups.

DRUGS AFFECTING MUCOCILIARY FUNCTION

The mucous found in the airways is a non-homogeneous viscoelastic substance consisting of two phases separated by a thin film of surfactant. A superficial gel-like layer lies on a more liquid or aqueous layer in contact with the epithelial cells. Secretions from goblet cells and bronchial glands maintain the normal airway surface liquid (ASL). Goblet cells secrete mucopolysaccharides which form the gel-like layer and are stimulated by irritant factors. Epithelial cells and bronchial glands secrete the low-viscosity aqueous layer and are under vagal control. Two mechanisms exist to clear mucous from the respiratory tract: mucociliary clearance and cough clearance. The former is the dominant mechanism in health and relies on the forward propulsion of the gel layer on the aqueous layer by epithelial cell cilia. The efficiency of mucociliary clearance is affected by ciliary and ASL factors. Ciliary factors include beat frequency, amplitude and cilia spacing, while ASL factors include the depth of both layers of ASL, and the elasticity of the gel layer. Optimal aqueous layer depth is essential to ensure that the tips of the cilia interact with the gel layer only on their forward stroke. Cough clearance becomes more important in various disease states associated with impaired mucociliary clearance such as cystic fibrosis. A high-velocity interaction at the air–mucous layer boundary causes wave formation in the mucous layer, leading to forward propulsion. Many physical factors influence mucociliary function (Table 9.6) and several pharmacological agents have been developed to optimise sputum clearance.

TABLE 9.6

Factors Affecting Mucociliary Function

Factors that Depress Mucociliary Function:
Extremes of temperature
Acidic environment
Smoking
Dehydration
Alcohol
Anaesthetics
Dry Gases

Factors that Optimize Mucociliary Function:
Temperature range 29–34 °C
Hydration
Humidification

Mucolytics

N-Acetylcysteine Derivatives

N-Acetylcysteine (NAC) is a cysteine derivative used commonly as a mucolytic. It is thought to induce physical changes in the structure of glycoproteins present in mucous. It reduces the disulfide bond (S–S) to a sulphydryl bond (–SH) which discourages cross-linking, thereby reducing the viscosity of the mucous. It may be used in patients with COPD or bronchiectasis, including patients with cystic fibrosis, to reduce the viscosity of sputum. Carbocisteine is an oral derivative of NAC; 2.25 g may be taken initially, reducing to 1.5 g daily as symptoms improve. Nacystelyn is an inhaled lysine derivative of NAC which has been shown to reduce the viscoelasticity of mucus in patients with cystic fibrosis. Adverse effects of NAC derivatives include gastric erosion and bleeding secondary to disruption of the normal gastric mucosal barrier.

Share this:

Related posts:

Anaesthesia for ENT, Maxillofacial and Dental Surgery Complications During Anaesthesia Preoperative Assessment and Premedication Basic Physics for the Anaesthetist Management of the Difficult Airway Anaesthesia Outside the Operating Theatre