Chào các bạn! Vì nhiều lý do từ nay Truyen2U chính thức đổi tên là Truyen247.Pro. Mong các bạn tiếp tục ủng hộ truy cập tên miền mới này nhé! Mãi yêu... ♥

c5,hh

C5.Respiratory diseases

Respiratory diseases are major worldwide causes of morbidity and mortality, especially in Third World countries and those affected by war and natural disasters. The World Health Organization estimates that tuberculosis infects one-third of the world population, causing about 1400 deaths in the UK in 2004. This imposes great health burdens and large economic costs in terms of lost productivity, and comprises a major restraint on the growth of poorer economies. Developed Western societies are also affected. Increasing asthma is the most common chronic disease in the UK and affects about 12 million North Americans. Further, acute respiratory infections are still important causes of death in the elderly. 

The respiratory tract is exposed to environmental hazards to a greater extent than any organ 

system except the skin. Lung tissue is extremely delicate and has limited protective mechanisms, 

so it is easy to understand the high incidence of respiratory diseases. It is somewhat surprising 

that these are not more common, given the increasing airborne insults from expanding industrial 

activity and population growth. Respiratory infections (i.e. pneumonia and tuberculosis) are dealt 

with in Chapter 8.

Anatomy and clinical physiology of the 

respiratory system

Anatomy

The lungs are intimately connected with the 

heart in that they receive and process the entire 

cardiac output. To appreciate the effects of respi-

ratory diseases it is essential to understand the 

cardiovascular system (CVS; Chapter 4). This 

chapter outlines the anatomy and physiology of 

the respiratory system as an introduction to the 

aetiology,  pathology  and  management  of  its 

important diseases.

The gross anatomy of the respiratory tract is illustrated in Figure 5.1(a). The various parts have specialized functions, reflected in the types of tissue of which they are composed (Table 5.1). 

Most of the structures only serve to conduct 

gases  between  the  air  and  the  acinus,  the 

smallest functional respiratory unit (Figure 5.2). 

This  comprises  a  terminal  bronchiole  that 

communicates with the respiratory  bronchi-

oles, alveolar sacs  and alveoli. Most of the 

exchange of oxygen and carbon dioxide between 

the inspired air and the capillary blood occurs 

across the walls of approximately 300 million 

alveoli, each about 250 lm in diameter, which 

together provide about 70 m2  of membrane for 

gas exchange. The alveoli are not isolated units 

but are interconnected by pores.

Some   of   these   structural   and   functional aspects (Table 5.1) are of interest here. Only those conducting airways that are not substan- tially  supported  by  cartilage  can  be  reduced considerably in bore by smooth muscle spasm, 

so it is these small airways that are involved 

in asthma and, to a lesser extent, in chronic 

obstructive    pulmonary    disease(COPD): 

supported  airways  can  constrict  to  a  lesser 

extent. Thus, bronchodilators can be beneficial 

only if there is smooth muscle spasm causing 

bronchiolar constriction and airways obstruc- tion. Further, because mucous glands and goblet cells occur primarily in the larger airways, their stimulation to produce excessive amounts of

mucus, as in COPD and bronchiectasis, does not affect the smallest airways and the alveoli. In

these  diseases  it  is  medium-to-small  airways

obstruction, due to variable degrees and combi-

nations of bronchoconstriction and mucus plug- ging, which causes the problems. In addition, damage to the pulmonary blood vessels occursbetamethasone  over48 h.  Artificial  surfactants

in COPD and bronchiectasis.

Ciliated  epithelium  provides  an  important 

defence mechanism. The cilia beat in organized 

waves,  sweeping  mucus  (and  microorganisms 

and other particles trapped in it), towards the 

larynx.  The  mucus  and  its  trapped  contents 

are usually swallowed and digested, but if large 

quantities are produced the sputum is coughed 

up.

Elastic tissue is present throughout the lungs 

and is especially important in the alveolar walls. 

The muscles of the airways and the thorax also 

have elastic properties. Although this elasticity 

produces a tendency for the expanded lungs to 

collapse, it accounts for only about one-third of 

the total recoil effect. The remainder is caused by 

interfacial tension within the film of fluid lining 

the alveoli, but this is counteracted by surfac-

tant   lipoproteins  derived   from   dipalmitoyl 

lecithin, produced by specialized alveolar cells. 

These surfactants assist spreading of the fluid 

over the alveolar surfaces, help to keep the deli-

cate  tissues  moist  to  provide  for  good  gas 

exchange, and reduce both the tendency of the 

alveoli to collapse at low lung volumes and the 

work required to expand the lungs during inspi-

ration. A brief increase in alveolar surface area 

increases the benefit of the surfactant. Hence the 

importance of the occasional deep breath or sigh 

during quiet breathing - this expands any respi-

ratory lobules (Figure 5.2) that have collapsed 

under interfacial tension.

During the first 4 weeks of life, a congenital 

deficiency   of   natural   surfactant   results   in 

hyaline membrane disease in a small propor-

tion of neonates, especially in premature infants. 

If the deficiency is severe, the lungs collapse 

completely at the end of expiration and are diffi-

cult to re-expand. This is respiratory distress 

syndrome of the newborn (RDSN). If neonatal 

artificial ventilation is unsuccessful, the infant 

may die in the immediate postnatal period or, 

depending on the extent of the deficiency, in 

early infancy. Some 40-50% of the complica-

tions of RDSN may be prevented by giving the 

mother a short course of corticosteroids at least

24 h before a premature birth, i.e.37 weeks’ 

gestation.  This  is  done  preferably  between 

the 24th  and  34th  weeks,  e.g. 20-40 mg  of 

(e.g. beractant and poractant alfa) are available for neonatal treatment, and a liposomal formula-

tion of prostaglandin E is in clinical trial. Other surfactants (e.g. colfosceril palmitate and pumac-

tant)  and  natural  respiratory  surfactant   are available in other countries.

RDSN should not be confused with adult respi-

ratory distress syndrome, which is usually due to trauma or inhalation of toxic material.

Pleural membranes

Each lung is surrounded by a double membrane, 

the pleura, and is attached to the inner of these 

membranes.  The  outer  membrane  forms  the 

lining  of  the  thoracic  wall,  diaphragm,  and 

the lateral aspect of the mediastinal organs (see 

below). The pleural  cavity  between them is 

filled with a few millilitres of fluid, which is 

normally maintained at a slight negative pres-

sure relative to the lung tissue. This negative 

pressure is essential for respiration because if air 

enters the pleural cavity (i.e. a pneumothorax 

due to trauma or disease), the affected lung tends 

to  collapse.  The  pleural  fluid  lubricates  the 

membranes, permitting them to slip easily over 

each other during breathing. Inflammation or 

infection of these membranes (pleurisy) causes 

the cavity to fill with inflammatory exudate, 

resulting in adhesions (see Chapter 2, p. 54) 

between the layers of membrane and a variable 

degree   of   inspiratory   pain   which   enforces 

shallow, rapid respiration.

Mediastinum

The mediastinum is the central space between 

the pleural sacs around each lung (Figure 5.1(a)), 

and contains the heart and major blood vessels, 

the trachea and bronchial bifurcation, important 

nerves (vagus, cardiac, phrenic and splanchnic), 

the oesophagus, lymphatic vessels and tissues 

(thoracic duct, lymph nodes) and the thymus 

gland.

Although mediastinal diseases are outside the 

scope of this chapter, the course of the recurrent 

laryngeal nerves, especially the left (which loops under the aortic arch before ascending to the 

larynx),  has  important  implications  for  the 

occurrence  of  certain  respiratory  symptoms. 

Notably, persistent hoarseness may be produced 

by  any  condition  causing  pressure  on  these 

nerves, e.g. tumours or an aortic aneurysm.

Clinically relevant aspects of respiratory physiology

The lungs have three interdependent functions:

1. Conduction of inspired air to the alveoli and 

of expired gases to the trachea.

2. Maintenance of blood flow to and from the 

alveoli.

3. Exchange  of  oxygen  and  carbon  dioxide 

between the alveolar spaces and the blood.

 iology of the respiratory system275

Regulation of respiration

Respiration consists of two phases: inspiration is 

the expansion of the lungs and the conduction 

of air to the alveoli (alveolar ventilation) and 

expiration  is the relaxation of the expanded 

lungs and the expulsion of alveolar gas. A combi-

nation of chemical and nervous stimuli adjusts 

the alveolar ventilation almost exactly to the 

bodily requirements, so that the arterial partial 

pressures of oxygen (PaO2) and of carbon dioxide 

(PaCO2)  in  the  arterial  blood  are  relatively 

constant over a wide range of systemic demands.

These  stimuli  are  derived  from  sensors  in various  organs  and  tissues  and  the  principal factors that influence respiration are summarized in Table 5.2.

Central nervous reflex signals arise primarily 

from chemoreceptors in the cerebral ventricles, 

carotid bodies, aortic arch and brainstem, which 

are sensitive primarily to carbon dioxide levels in  the blood, and so to pH. The cerebral cortex and the respiratory muscles (see below) also drive respiration (and heart rate) according to volun-

tary exercise demand. The signals from all of 

these are coordinated in the ‘respiratory centre’ 

in the brainstem (medulla and pons). Perhaps 

surprisingly for such an important function, the 

respiratory  centre  is  not  well  defined,  there 

being three widely separated groups of neurones 

located in the upper part of the brainstem that 

interact  and  send  appropriate  signals  to  the 

respiratory muscles.

These   central   mechanisms   interact   with 

peripheral ones to form a series of complex inter-

relationships  and  feedback  mechanisms.  The 

most important peripheral input is derived from 

chemoreceptors that respond to blood levels of 

carbon dioxide, pH and oxygen, in that order of 

importance   under   normal   conditions.   The 

partial  pressure  of  carbon  dioxide  in  arterial 

blood (PaCO2) exerts by far the greatest influ-

ence, there being an approximately eightfold 

increase in respiration rate from low to high values (Figure 5.3(a)). Conversely, PaO2 has little 

influence because, as the shape of the oxygen/ 

Hb dissociation curve shows, there is an almost 

complete saturation of oxygen-carrying capacity 

over the whole of the normal range of oxygen 

levels (Figure 5.3(b)), and because a change in 

PaO2  increases the sensitivity of the respiratory 

centre to carbon dioxide. A change in blood pH 

has a similar sensitizing effect on the respiratory 

centre   and   influences   the   oxygen-carrying 

capacity of Hb more than oxygen does in the 

normal range (Figure 5.3(b)). Further, both the 

PaCO2   and  pH  mechanisms  react  to  exert  a 

braking  effect  on  the  response  to  oxygen. 

Although the effect of pH appears to be small, if 

all other parameters are controlled, the principal 

agent acting on the respiratory centre becomes 

the hydrogen ion, because changes in carbon 

dioxide levels immediately change the pH:

[CO2]

[H÷]    K  -------(5.1)

[HCO3-]

The hydrogen ions reach the respiratory centre primarily via the blood and to a lesser extent via the cerebrospinal fluid (CSF).

Although the carbon dioxide effect is large 

initially, if hypercapnia (high PaCO2, also known as hypercarbia) is sustained, as in severe COPD, the respiratory centre becomes desensitized to the level of carbon dioxide. The patient then 

depends on their PaO2  to provide their respira-

tory drive. This has important implications for oxygen therapy in COPD (see p. 338).

Respiratory muscles

Inspiration is an active process, the principal 

mechanism being contraction of the phrenic 

(diaphragm)  muscles  and to a lesser extent 

of   the   external   intercostal (rib)   muscles. 

However, during quiet breathing expiration is a 

passive process that depends on the elastic recoil 

of the stretched muscles and lung tissue, and 

interfacial tension effects in the alveoli. The 

force of expiration during exercise is increased 

by   the   action   of   the   internal   intercostal 

muscles.

In severe respiratory deficit the muscles of the 

shoulders, chest wall and abdomen are used to 

increase the force applied for both inspiration 

and expiration, so these are known as the acces-

sory muscles of respiration. Use of these can be 

recognized in a patient by excessive movements 

of the shoulders and abdomen - in very severe 

disability the patient will grasp the arms of a 

chair or other surface strongly in an attempt to 

increase   the   applied   force.   However,   these 

manoeuvres may be counter-productive, because 

excessive respiratory force increases the intra-

thoracic pressure abnormally, so that the airways 

tend to collapse, especially if they are weakened 

by disease, thus increasing the resistance to expi-

ratory flow (see below). Thus, difficulty in expi-

ration may often be the first sign of respiratory 

obstruction.

Respiratory mechanics

Airways resistance

This  is  measured  as  the  pressure  difference 

between the mouth and the alveoli per litre of 

gas flow. It is the result of friction between the 

gas  molecules  themselves,  and  between  them 

and the walls of the airways. Quiet breathing 

produces laminar gas flow but rapid breathing 

causes turbulence, so a greater pressure differ-

ence  is  then  required  to  maintain  the  flow. 

Anything  that  causes  airways  narrowing  (e.g. 

bronchoconstriction in asthma or mucus plug-

ging in COPD), will increase airways resistance 

markedly. In COPD and emphysema there is a 

variable combination of airways inflammation 

and loss of both tissue supporting the airways 

and  the  elastic  recoil  pressure  of  the  lungs. 

This makes the airways more likely to collapse 

on  expiration,  when  intrathoracic  pressures 

increase, thus increasing resistance and making 

it  difficult  to  exhale.  Even  small  changes  in 

airways  bore  make  large  differences  to  flow 

rate: Poiseuille’s law (see also Chapter 4) states 

that flow through a tube is proportional to the 

fourth  power  of  its  radius.  However,  bron-

choconstriction  may  have  some  beneficial 

physiological  effects,  because  it  reduces  the 

dead  space (p. 278),  and  this  improves  the

iology of the respiratory system277

efficiency  of  ventilation  when  tidal  volumes are low.

In   normal   respiration,   airways   resistance reduces gas flow almost to zero by the time the air reaches the entrances to the alveolar sacs, so diffusion is the final mechanism by which the gas molecules travel to and from the alveolar 

membranes and blood vessels.

Mechanical factors affecting gas flow

The lungs and respiratory muscles resist changes in size and shape because of tissue viscosity and elasticity.

Compliance is the term used to describe the 

ability of the lungs and thoracic wall to expand, 

and is a reflection of elasticity, the converse of 

stiffness. Compliance is reduced by any disease 

that  increases  lung  stiffness,  e.g.  pulmonary 

fibrosis and oedema (pp. 282, 325), pneumonic 

consolidation and TB (Chapter 8). Compliance 

is  increased  in  emphysema (p. 333),  due  to 

destruction of lung tissue, and in old age due to 

tissue degeneration.

However, such factors account for only about 

20%  of  the  total  pulmonary  resistance  and 

become a problem only if fibrosis or oedema are 

extensive.  When  this  occurs,  patients  often 

breathe shallowly but rapidly. This is a normal 

physiological response that minimizes the effort 

required, but is very inefficient (see below).

Work of breathing

The energy expended during respiration is that 

required  to  overcome  airways  resistance  and 

mechanical   factors(e.g.   lung   compliance, 

muscular work). During normal quiet breathing 

this amounts to only about 2% of the total 

bodily energy requirement, and is negligible. 

However, disease may increase this so greatly 

that there is insufficient oxygen available for 

other purposes and patients become exercise-

limited (e.g. in pulmonary fibrosis), or may be 

exhausted on admission to hospital (e.g. severe 

asthma).

Figure 5.4 shows the effect of lung volume on 

the change in pressure required to produce a unit 

change in that volume. Because air trapping 

occurs  in  obstructive  lung  disease (p. 284), increasing the total lung capacity (TLC, Figure 

5.6), patients with severe asthma and COPD have 

to exert a much greater effort to move air in and 

out of their lungs than do normal subjects, and 

this requires the expenditure of more energy.

Ventilation and perfusion

The  composition  of  the  alveolar  gas  varies 

markedly  depending  on  the  respiration  rate, 

blood   flow,   diffusion   across   the   alveolar 

membrane, Hb concentration, carbon dioxide 

production, etc. Further, the alveolar gas cannot 

be expelled completely from the lungs at expira-

tion because about 150 mL of it is contained in 

the conducting airways (the anatomical dead 

space). This residual gas is the first to be washed 

into   the   alveoli   during   inspiration   and   is 

removed only by dilution with the inspired air. 

Hence shallow, rapid breathing may do little 

more than move this volume of gas in and out of 

the alveoli, and is a very inefficient mode of 

ventilation.

The alveolar ventilation, the total volume of 

gas exchanged in all the alveoli in unit time, is 

approximately 5 L/min during quiet breathing. 

The lungs receive the entire cardiac output, so in 

a normal resting adult the pulmonary perfu-

sion is approximately 5 L/min. Thus, the overall 

resting  ventilation/perfusion  ratio (VPR)  is about 1.0. However, this overall balance masks large differences that occur throughout the respi-

ratory cycle and regional differences within the lungs. An imbalance between ventilation and 

perfusion is known as mismatching.

The  resting  value  of  VPR  is  not  constant 

throughout   the   lung   because   blood   flow 

decreases markedly from base to apex in an 

upright individual, whereas ventilation is less 

affected. Figure 5.5 shows that ventilation/perfu-

sion mismatching is greatest in the upper lobes, 

so that oxygenation of the blood is relatively 

poor there. Ventilation is particularly unevenly 

distributed at the low lung volumes that occur at 

the end of expiration or the beginning of inspi-

ration, because the lungs are suspended in the 

chest only at the hilum, and so the weight of 

their upper part plus the weight and hydrostatic 

pressure of the blood contained in the lungs 

compresses the lower lobes. When we breathe in 

after a maximum expiration, air initially enters 

the upper lobes, which are less compressed, but 

when about 1 L has been inhaled the situation is 

reversed, the lower zone airways open and the 

lung bases are better ventilated.

The volume at which the lower airways close 

(closing volume), due to intrathoracic pressure 

exceeding   airways   pressure,   increases   with 

increasing age (due to reduced elastic recoil) 

until it encroaches on normal breathing. Conse-

quently,  elderly  normal  subjects  often  have 

poorly ventilated lungs with poor gas exchange 

and are exercise-limited. An increased closing 

volume may be a sensitive early indicator of lung 

disease such as smoking damage or emphysema.

The  VPR  is  a  crucial  parameter  affecting 

oxygen delivery to the tissues. The systemic PaO2 

results  from  a  balance  between  the  rates  of 

oxygen delivery to the lungs, i.e. ventilation, 

and its removal in the blood, due to perfusion. 

Thus high values of VPR lead to high values of 

PaO2, and vice versa. At the extreme limits, zero 

ventilation would give a PaO2  equal to that of 

venous blood, and zero oxygen uptake, whereas 

minimal perfusion would give a PaO2  equal to 

that of the inspired gas, but little or no oxygen 

would be carried to the tissues. Such conditions 

can occur only locally, because neither of them is 

compatible with life if they were to occur widely. 

However, very high oxygen levels in the alveoli 

give  only  a  limited  increase  in  the  oxygen-

carrying  capacity  of  the  blood,  because  Hb 

saturation  is  almost  maximal  under  normal 

conditions (Figure 5.3), so a high VPR in one 

localized area of lung cannot compensate for low 

values elsewhere.

Although the alveolar-arterial deficit (i.e. the 

difference   between   the   partial   pressures   of 

oxygen across the alveolar membrane) is negli-

gible in the normal lung, it may be very large in 

disease. The body attempts to compensate for 

this  by  vasoconstriction  in  hypoxic  areas  of 

lung, thus diverting blood from poorly venti-

lated or presumably damaged areas to those that 

are better ventilated, and this does give some 

improvement.   However,   if   lung   damage   is 

widespread this process becomes maladaptive, 

because  the  pulmonary  vasoconstriction  pro-

duces pulmonary hypertension and this may 

lead to heart failure (cor pulmonale, p. 285; see 

also Chapter 4). Nevertheless, the VPR is the key 

factor controlling oxygenation of the blood, and 

no amount of increased ventilation or circula-

tory diversion can compensate for ventilation-

perfusion   mismatch   in   the   diseased   state: 

exercise limitation is inevitable.

The VPR is always grossly abnormal in COPD 

(p. 326), due to a combination of hypoventila-

tion and a variable degree of diffusion limita-

tion. Additionally, beta2-bronchodilators tend to 

reduce the PaO2  by about 10% in some patients 

with  COPD  and  asthma  because  they  cause 

non-selective pulmonary vasodilatation and so

 increase  blood  flow  to  unventilated  alveoli. 

However,  the  favourable  action  of  broncho-

dilators in reducing airways resistance, and so 

increasing ventilation, outweighs this. Thus this 

adverse  effect  is  negligible  unless  the  patient 

is  grossly  hypoxaemic,  when  the  additional 

oxygen deficit caused by the bronchodilator may 

be important.

Gas transfer

The   transfer   of   gases   across   the   alveolar membrane    depends    on    the    functional 

membrane area, the membrane thickness, the 

concentration gradient across the membrane, 

and the diffusion coefficient of the gas.

The diffusion coefficient of a gas is propor-

tional to its solubility in extracellular fluid and 

inversely proportional to the square root of its 

molecular weight. Thus, carbon dioxide diffuses 

about 20 times as rapidly as oxygen due to its 

high solubility, so its diffusion is not a limiting 

factor.  Consequently,  as  ventilatory  function 

deteriorates  in  COPD  the  PaO2 tends  to  fall 

before the PaCO2 rises.

The functional membrane area is the most 

important parameter controlling diffusion, and 

this is reduced in emphysema and by ventila-

tion-perfusion abnormalities. The latter are also 

important in concentration  gradient  effects, 

because  hypoventilation  reduces  the  alveolar 

oxygen concentration. Diseases causing alveolar 

fibrosis or oedema produce a membrane that is 

up to five times thicker than normal and inter-

feres markedly with gas exchange, primarily that of oxygen (especially if it is fibrosed).

The transfer factor is an overall measure of 

the effectiveness of diffusion, and is expressed 

as the rate of gas transfer per unit of partial pres-

sure. It is determined by taking a single breath of 

helium/air mixture containing a small amount 

of  carbon  monoxide,  which  is  absent  from 

normal blood, combines readily and completely 

with Hb, and is easily measured: hence the term 

TCO  (transfer factor for carbon monoxide). The 

old term, diffusing capacity, DLCO, is now out of 

favour, because diffusion is only one aspect of 

gas transfer. The use of helium enables the alve-

olar volume to be determined. TCO  is reduced in  fibrosis,  oedema,  emphysema,  pulmonary 

embolism, severe anaemia and in smokers, but 

is   increased   in   polycythaemia,   ventilation-

perfusion remodelling and alveolar bleeding.

The overall effects of the ventilatory and meta-

bolic processes are summarized in Table 5.3. 

There is a progressive fall in PaO2 from the alveoli 

to the tissue cells, and a converse increase in 

PaCO2. Under conditions of normal ventilation 

and blood flow, about 11 mmol/min of oxygen and 9 mmol/min of carbon dioxide are trans-

ported  in  and  out  of  the  body  respectively, giving values for PaO2  of 10.6-13.3 kPa and for PaCO2 of 4.5-6.0 kPa.

Gas transport in blood

Table 5.3 also gives the relative proportions of 

oxygen and carbon dioxide that are transported 

by various mechanisms. Although most of the 

oxygen is carried by Hb, that dissolved in the 

plasma may be important in patients in whom 

the oxygen-carrying capacity of the blood is 

significantly  reduced,  e.g.  in  severe  anaemia. 

Because Hb is almost completely saturated under 

normal conditions, increasing the dissolved frac-

tion may be the only way of increasing the 

oxygen content of the blood.

This is one rationale for the use of hyperbaric 

(high-pressure) oxygen chambers. An increase in 

dissolved oxygen level is useful in severe carbon 

monoxide poisoning, in which most of the Hb is 

bound firmly to carbon monoxide and is not 

available  to  bind  oxygen.  The  high  oxygen concentration  also  assists  the  dissociation  of carbon monoxide from Hb.

The oxygen saturation of arterial blood (SaO2) is given by the expression:

O2 combined

with Hb

SaO2100%(5.2)

Total O2 capacity of 

the blood

the denominator being the sum of the oxygen 

combined with Hb and the dissolved oxygen. 

This is an important parameter if a patient is 

severely anaemic. Cyanosis, due to the blue-

purple colour of reduced Hb, is an unreliable 

indicator of low oxygen saturation because its 

recognition   varies   with   skin   pigmentation, 

lighting, etc. and it is difficult to detect if the Hb 

concentration is low (i.e. in anaemia) and hence 

the need to measure arterial blood gases (e.g. in 

a very severe asthma attack). Conversely, in the presence of polycythaemia, i.e. an increased red 

cell count, cyanosis may be marked because of 

the  high  concentration  of  reduced  Hb.  This 

produces the ‘blue bloater’ of COPD (p. 331). 

Cyanosis is best observed under the nails or 

in the tongue in good lighting. Oxygen satura-

tion is usually measured by the colour of the 

blood in the nail bed, which is why hospital 

patients are told not to use nail varnish.

Because of its high aqueous solubility, most of the carbon dioxide is carried in solution as bicar-

bonate,   these   two   compounds   forming   an important pH buffering system. Hb is an impor-

tant intermediary, picking up carbon dioxide in the tissues in exchange for oxygen.

Lung volumes and capacities

An idealized spirogram for a normal young adult 

male is shown in Figure 5.6. This illustrates the 

trace  obtained  when  the  subject  is  initially 

breathing  quietly  at  rest,  and  what  happens 

when they then inhale and exhale maximally 

and as rapidly as possible. The residual volume 

(RV) cannot be used for ventilation but it plays 

an important part in buffering against the large 

swings that would occur in blood gas partial 

pressures if there were no gases in the lungs that 

aspects of respiratory disease281

could be exchanged with those in the blood at the end of expiration.

Clinical aspects of respiratory disease

Classification

It will be obvious from the preceding discussion 

that the respiratory process can go wrong in 

various ways, and these are summarized in Table

5.4. There may be one of four basic problems:

1. Obstruction of gas flow in the airways.

2. Impaired alveolar diffusion.

3. Reduced  lung  compliance  or  a  restricted 

thoracic capacity and expansibility.

4. Impaired ventilatory drive.

Obstructive defects (p. 292, Figure 5.8) are the 

most common, and usually affect the smaller 

airways. They may be a consequence of broncho-

constriction, inflammation or excessive mucus 

production. However, bronchiectasis  (chronic 

airways dilatation, usually resulting from infec-

tive  damage,  and  normally  associated  with 

massive sputum production; p. 340) affects the 

larger and medium-sized airways. Large airways 

may also be blocked by a foreign body: this may be inhaled food or, in children, almost any small toy or object, and is a medical emergency.

Chronic diffusion defects, in which there is 

impaired   gas   transfer   across   the   alveolar 

membrane, usually result from a thickening of 

the respiratory (alveolar) membrane as a result 

of chronic inflammation leading to permanent 

fibrotic   damage.   However,   in   pulmonary 

oedema,   e.g.   following   LVF   or   pulmonary 

thromboembolism (p. 342, Chapter 4), the accu-

mulated alveolar fluid also acts as a physical 

barrier to prevent oxygen diffusion. An acute 

failure of pulmonary perfusion, or of the general 

circulation, e.g. due to MI or shock, will cause 

hypoxaemia and central cyanosis.

In  restrictive  defects  (p.  342)  there  is  an 

inability to expand the lungs adequately. Such 

defects may be caused by reduced lung compli-

ance, but are often due to problems outside the

 lungs.  Thus  pleural  disease,  causing  fibrosis, 

effusion or adhesions, will limit expansion of 

the  underlying  lung.  A  similar  effect  results 

from a pneumothorax, because if gas leaks into 

the pleural space following rupture of periph-

eral lung tissue (e.g. due to emphysema, infec-

tion, trauma or surgery), a lung may collapse 

partially  or  completely.  Provided  there  is  no 

serious underlying pathology the damaged area 

will heal, and fluid and gas will be reabsorbed 

fairly  quickly  by  the  pleural  capillaries,  thus 

restoring normality. Rib cage and spinal defects, 

e.g.  due  to  congenital  TB  or  ankylosing 

spondylitis (see Chapters 8 and 12), also restrict 

lung expansion.

Respiratory (ventilatory) failure is the result 

of an inadequate ventilatory drive to the respira-

tory muscles or inability of these to respond. A 

primary loss of the central drive to breathe is rare 

except in:

•  head trauma;

•  CNS disease and central depression by drugs, 

e.g.opioids,    anaesthetics    and,    rarely

nowadays, barbiturates;

•  neuromuscular damage due to disease, e.g. 

Guillain-Barré   syndrome,   motor   neurone

disease,   multiple   sclerosis,   poliomyelitis, 

diphtheria, severe hypokalaemia and chest 

trauma;

•  severe airways obstruction, causing cyanosis 

and carbon dioxide retention;

•  obesity,   especially   associated   with   rapid 

weight gain.

Clinical features

As in any other clinical situation an accurate 

history and examination are the essential first 

steps, and will often permit a reasonably confi-

dent diagnosis to be made before any investiga-

tions are carried out. The following symptoms 

and signs are characteristic of respiratory diseases.

Dyspnoea

This  is  a  subjective,  unpleasant  sensation  of 

breathlessness (shortness of breath, SOB) that 

probably results from an inappropriate effort of 

breathing. It does not correlate with blood PaO2. 

Objective signs, e.g. laboured breathing, rapid 

breathing (tachypnoea), breathing with pursed 

lips, hypoxaemia and hypercapnia, may also be 

present. The UK Medical Research Council has

 aspects of respiratory disease283

published a subjective graded dyspnoea scale 

(Table 5.5).

The  time  course  for  the  development  of 

breathlessness may help in diagnosis:

•  Months to years: COPD, thyrotoxicosis. •  Weeks: anaemia, tumours.

•  Hours to days: LVF, pneumonia.

•  Minutes:    acute    severe    asthma,    major 

pulmonary embolism, pneumothorax.

Reduced exercise tolerance will initially present 

as exertional dyspnoea and should be defined 

quantitatively in terms of the patient’s ability to 

walk on the flat or to climb stairs. However, 

there are many possible causes for dyspnoea 

apart  from  lung  disease,  e.g.  cardiac  disease, 

obesity, anaemia, anxiety and hyperthyroidism.

Orthopnoea  is  dyspnoea  that  occurs  only 

when  lying  down.  The  symptom  disappears 

when the patient is erect because fluid that has 

distributed from the legs to the lungs and inter-

feres with oxygen absorption redistributes to the 

lower body, especially the ankles. It may be of 

cardiac origin, and is consequent on the reduced 

gravitational load on the circulation when the 

patient lies down. This produces an increased 

venous return and pulmonary congestion, i.e. 

an excessive volume of blood in the lungs. Redis-

tribution  of  fluid  throughout  the  lungs  also 

occurs. If there is airways obstruction, limitation 

of diaphragm movement when lying down will 

also   produce   dyspnoea,   especially   in   obese 

patients. These patients are also dyspnoeic on 

bending over. 

 Pursed   lip   breathing  occurs   when   lungwith  pain  or  significant  sputum  production.

compliance is increased by disease, e.g. emphy-

sema causing loss of lung tissue (Figure 5.20), so that  the  airways  have  less  support  and  an 

increased tendency to collapse on expiration. 

The patient then unwittingly breathes shallowly through partly closed lips to maintain a greater positive   pressure   than   normal   within   the airways, thus keeping them open.

Breath sounds

Audible on examination

Wheezes  (rhonchi) are sounds caused by gas 

flowing through airways obstructed by spasm or 

excessive  secretions.  This  causes  an  obvious, 

more or less musical note that is usually more 

marked on expiration (see below). It is usually a 

symptom of obstruction but may be secondary 

to  cardiovascular  problems (so-called ‘cardiac 

asthma’).

Stridor is a harsher, inspiratory sound caused by obstruction of the larynx, trachea or other 

major airway.

Audible on auscultation

In the normal lung, respiration usually gives 

gentle,   rustling   sounds   in   the   stethoscope. 

Bronchial breathing consists of higher-pitched 

sounds found on both inspiration and (more 

prolonged)  on  expiration.  Crackles (crepita-

tions, ‘creps’;  râles)  are  fine  crackling  noises 

caused by the opening of blocked, small airways 

at the periphery of the lung. Coarse crackles 

are  caused  by  gas  bubbling  through  copious 

secretions  in  larger  airways.  A  friction  rub 

results from friction between inflamed pleural 

membranes,  similarly  to  pericardial  friction. 

Wheezes are also heard.

The  complete  absence  of  lung  sounds  is  a very sinister sign that indicates an inability to move air in and out of the lung, e.g. in a very 

severe asthma attack, severe thoracic trauma or physical obstruction of a major airway.

Cough and sputum

Coughing is usually caused by minor infection. 

It is abnormal when it is persistent, or associated

Although the nature of the cough may indicate 

the underlying pathology (e.g. the characteristic 

inspiratory ‘whoop’ of whooping cough or the 

softer, longer cough resulting from paralysis of 

the vocal chords), the associated features are 

usually more informative. A ‘dry’ cough (unpro-

ductive of sputum), may occur in asthma, early 

acute bronchitis or pneumonia. Post-nasal drip, 

the drainage of discharge from infected sinuses, 

etc. into the throat, also causes coughing.

A  productive  cough  is  one  caused  by  the formation of excessive sputum. Mucoid sputum (white or grey) is usually produced in COPD, fibrosing alveolitis or asthma. Purulent sputum (green  or  yellow,  containing  pus)  indicates infection, usually bacterial.

Haemoptysis (coughing up of blood or blood-

streaked sputum) is an alarming symptom that is 

usually due to an acute lung infection (pneu-

monia or TB), or to an exacerbation of COPD. It 

may  also  indicate  the  possibility  of  serious 

disease such as pulmonary oedema (producing 

pink, frothy sputum), bronchial carcinoma or 

pulmonary embolism.

Hyperinflation

Because expiration through obstructed airways is 

more difficult than inspiration, severe obstruc-

tive airways disease leads to progressive air trap-

ping, because not all of the inspired volume of 

gas in the lungs can be exhaled before the next 

inspiration   occurs.   The   chest   thus   remains 

partially expanded at all times and, in extreme 

cases,  this  may  eventually  lead  to  a ‘barrel 

chest’. There will then often be abnormally large 

cavities (bullae) in the lung parenchyma, which 

may   be   detectable   by   hyper-resonance   on 

percussion.   Hyperinflation   tends   to   occur 

together with pursed lip breathing (see above).

Chest pain

Pain of respiratory origin may be due to pleurisy 

(i.e. pleural inflammation or infection), and a 

pneumothorax  (i.e.  air  in  the  pleural  space, 

usually due to trauma), may give a similar sharp 

pain.   Acute   tracheitis   or   bronchitis   and pulmonary emboli may also give pain, particu-

larly if embolism causes infarction, but disease in 

the  lung  parenchyma  is  normally  painless. 

However, infarction is rare in lung tissue because 

of   the   excellent   oxygen   supply.   Bronchial 

carcinoma may give only a vague, aching pain.

Chest pain may also be due to trauma, cardio-

vascular (see  Chapter 4)   or  gastrointestinal 

conditions, bone tumours, herpes zoster (shin-

gles), etc. Such pain may often be referred to the 

neck, back or abdomen because many major 

nerve tracts run in the mediastinum and may be 

affected secondarily. Thus, pain is a very non-

specific diagnostic feature in most respiratory 

disease, even if linked to respiratory movements.

Finger clubbing

The cause of this sign (Figure 5.7) is unknown, 

but it often indicates a serious chronic chest 

disease that produces chronic hypoxaemia (e.g. 

bronchial  and  other  tumours,  bronchiectasis, 

advanced TB, cystic fibrosis and lung abscesses). 

However, it may also be due to congenital heart 

disease or chronic gastrointestinal disease and 

may even occur as a familial trait. The early 

changes are subtle, there being the loss of the 

angle between the nail and the skin at its base. 

Eventually  there  is  pronounced  longitudinal 

curvature of the nail, softening of the nail bed 

and ‘drum-stick’ fingers.

Heart failure due to lung disease

Right ventricular failure  (RVF; see Chapter 4) secondary  to  lung  disease  is  known  as  cor pulmonale. It is a consequence of pulmonary 

hypertension produced by:

•  Alveolar and arterial hypoxia causing wide-

spread   pulmonary   vasoconstriction   and

hypertrophy of pulmonary vascular smooth muscle.

•  Distortion  and  fibrosis  of  the  pulmonary 

blood vessels.

•  Destruction   of   pulmonary   arterioles   and 

arterioles when alveoli are destroyed.

•  Increased   blood   viscosity   due   to   the

polycythaemia    resulting    from    chronic hypoxaemia.

The  outstanding  feature  in  these  patients  is 

fluid  retention,  with  the  usual  symptoms  of 

ankle  oedema  and  progressive  dyspnoea  and 

exercise limitation. The increased afterload on 

the right ventricle, which has to work harder in 

order to perfuse the lungs, eventually leads to 

heart failure. However, in the early stages the 

heart may compensate for the failure by right 

ventricular  dilatation (see  Chapter 4,  Figure

4.12).

Investigation

Examination

From the above review of the clinical features the following are clearly relevant:

•  Observation: pattern of respiration, cough, 

cyanosis, finger clubbing.

•  Palpation:  lymph  nodes,  diversion  of  the 

trachea(by   a   mass   or   pneumothorax),

tenderness.

•  Percussion: both sides are normally equally 

resonant. Hyper-resonance indicates a loss of

tissue  (a  cavity)  and  dullness  an  area  of consolidation, e.g. fluid in pneumonia.

•  Auscultation  (listening   to   breath   sounds,

etc.). 

•  Cardiovascular examination. 

Imagingvisualize blood vessels, without having to inject

contrast medium.

A plain CXR is the most valuable adjunct to the

history  and  examination.  An  erect  postero-

anterior (PA) view, i.e. the X-rays pass from back 

to front, is usually preferred because there is less 

magnification of the image. It shows the loca-

tions and sizes of the heart and other organs as 

well as lung tissue abnormalities. The lung fields 

should be evenly translucent and without shad-

owing, except in the hilar regions (where the 

main blood vessels and bronchi enter the lungs) 

and from the ribs (see Figure 5.1). Excessive 

spacing between the ribs and a gap between the 

apex (bottom)   of   the   heart   and   the   left 

diaphragm indicate hyperinflation.

Complete collapse of a lung will cause a shift 

of the heart and other mediastinal structures 

into  the  area  of  collapse.  Lesser  degrees  of 

collapse produce a well-defined shadow due to 

the increased density of the collapsed lung.

Ultrasound scanning  has a limited role in 

investigating chest problems because currently it is possible only to visualize objects that are in contact with the chest wall with this technique. However, it is useful when guiding a needle for biopsy or aspiration of an effusion.

Computed tomography (CT) and magnetic 

resonance imaging (MRI) are widely used and 

provide valuable additional information. Both 

techniques   permit   accurate   visualization   of 

major  organs  and  highlight  the  nature  and 

extent of any abnormal or doubtful shadows in 

the CXR. Conventional CT scanning involves a 

high radiation dose, e.g. 40 to 250 times that of 

a normal CXR, but the advent of ‘spiral’ scan-

ning, in which patients are moved slowly length-

wise while the X-ay beam is rotated around 

them, enables data to be obtained rapidly. This is 

less stressful to patients, reduces the X-ray dose 

and can provide dynamic information, e.g. visu-

alization of pulmonary emboli by demonstrating 

obstruction  to  blood  flow,  using  an  injected 

venous contrast medium.

MRI involves no radiation dose, and gives 

detailed images of the lung parenchyma. The 

introduction of rapid acquisition scanning has 

improved patient acceptability. Another tech-

nique,  magnetic  resonance  angiography,  a 

form of functional MRI (fMRI), may be used to

Fluoroscopy  is an X-ray technique used to 

visualize dynamic events (e.g. the movements of 

organs,  etc.,  such  as  refluxing  of  stomach 

contents into the oesophagus) that may cause 

chest pain (GORD; see Chapter 3), and is used 

only for specialized investigations. The use of 

image  intensifiers  and  a  television  monitor 

display reduces the high radiation dose received 

formerly by radiologists, and has improved the 

utility of the technique. However, it has been 

largely replaced by ultrasound scanning.

Bronchoscopy and biopsy

Flexible fibre-optic endoscopes (see Chapter 3, Figure 3.5) are indispensable for the direct obser-

vation of the airways and the biopsy of lesions located by imaging. Bronchial brushings and 

washings can also be taken for cytological and bacteriological examination. Modern broncho-

scopes will reach nearly all parts of the lungs, especially in the upper lobes.

Most   bronchoscopies   are   performed   to diagnose potential malignancy, infections and diffuse  parenchymal  disease,  and  to  confirm uncertain diagnoses. Obstructing tumours may also  be  treated  through  the  endoscope  by 

diathermy or lasers if they are small enough. 

Older-type  rigid  bronchoscopes  are  still  used occasionally for the removal of small inhaled 

foreign bodies from the trachea.

Superficial  lesions  and  the  pleura  may  be biopsied percutaneously using special needles, usually guided by X-ray or CT, and are less inva-

sive. Open lung biopsy is done as an adjunct to essential surgery.

Lung function tests

These are used to determine the type of disease, 

its severity and the response to therapy. Ventila-

tory  function  is  assessed  using  a  recording 

spirometer,  such  as  the  Vitalograph (Figure

5.8(a)) or the Microflow, both of which work on 

a simple bellows principle. The patient inspires 

maximally and then blows as hard and as fast as 

possible   into   the   mouthpiece,   producing   a recording similar to that shown in Figure 5.8(b).the FEV1 and the FVC similarly, so that the ratio

Several parameters can be derived from the curve, the most useful being the forced vital capacity (FVC), the maximum volume of gas that can be blown out, and the forced expiratory volume, 

usually recorded as the volume forced out in 1 second (FEV1). The predicted values of these for a normal subject can be estimated from nomo-

grams that relate them to age, height and sex. 

These parameters are relatively independent of the force applied during expiration.

Generally,  a  fit  young  adult  will  have  an 

FVC of 4-5 L and the FEV1 will be at least 75% of 

this, i.e. the forced expiratory ratio (FEV1/FVC) 

exceeds 0.75,  indicating  efficient  ventilation. 

Obstruction of the airways leads to a low FVC 

and to forced expiratory ratios of0.65 (curve O, 

Figure 5.8(b)); in severe disease it may be as low 

as 0.3. Restrictive patterns of disease reduce both 

is  normal  (curve  R,  Figure  5.8(b);  Table  5.6). 

Forced  expiratory  ratios  of  about 0.6 lead  to 

dyspnoea only on severe exertion, at 0.5 there 

will be significant exercise limitation, and below

0.3 there is likely to be chronic disability, orth-

opnoea (breathlessness that occurs when lying down), hypercapnia and frequent invalidism.

Figure 5.8(b) shows that the spirometer can 

also be used for a diagnostic trial of drugs and to 

monitor the benefits of therapy objectively. If an 

obstructive pattern is seen, the patient inhales a 

dose of a bronchodilator and repeats the test 

after 20-30 min. Good to moderate reversibility 

( 15% improvement) is observed in asthmatics 

(e.g. curve T), in whom there may be a return to 

a near-normal trace (curve P). There may be 

some reversibility in chronic bronchitics, but 

this rarely exceeds 5%.

The flow-volume loop is obtained by asking the patient to inspire maximally and to blow 

into  the  instrument  as  hard  as  possible  to 

maximal expiration and then to inhale again to TLC. This is a sensitive test that will discriminate between  asthma  and  other  types  of  airways obstruction (Figure 5.9).

The   peak   expiratory   flow(PEF),   the 

maximum   expiratory   flow   rate   in   L/min 

measured over the first 10 msec of expiration, 

may  be  determined  directly  from  the  flow-

volume loop (Figure 5.9) or calculated from the 

initial slope of the spirometer curve shown in 

Figure 5.8(b). However, PEF is much more easily 

determined using a peak flow meter or gauge 

(Figure 5.10), although this measures flow over 

only the first 2 ms of forced expiration. A nomo-

gram, a simple ‘slide rule’ or a chart (Figure 5.11) 

is used to predict normal values. The PEF is a 

simple and sensitive indicator of the presence 

and severity of airways obstruction, so the deter-

mination is popular in chest clinics and general 

practice as a simple, rapid, cheap diagnostic and 

monitoring tool. However, the accuracy of the 

test depends on the instrument used and on 

the patient making a maximal inspiration and 

applying  maximal  force  during  expiration, 

whereas  the  FEV1 is  less  energy-dependent. 

Further, lung function is overestimated in indi-

viduals with moderate reduction in airflow. The 

PEF is not diagnostically reliable because it will 

not distinguish between the different types of 

airways  obstruction,  unlike  the  flow-volume 

loop, but is strongly suggestive.

Peak flow gauges are particularly useful for 

observing rapid changes and monitoring the 

severity of disease and the effects of medication 

in an individual, especially in asthma. They are 

invaluable  for  the  routine  home  self-moni-

toring  of  patients  with  significant  asthma. 

Because the same instrument is always used, 

the absolute accuracy of the instrument is not 

important, because it will still show relative 

changes in lung function. If a diary is kept, 

patients can detect the warning signs of an 

impending,  possibly  severe,  attack  and  take 

appropriate  therapeutic  measures (p. 311). 

However, one study has shown that a high 

proportion  of  patient  diaries  are  unreliable. 

Furthermore, PEF measurements are less useful 

in  those  with  chronic  asthma (p. 309)  or

aspects of respiratory disease289

COPD (p. 326), where there is significant fixed (irreversible) airways obstruction.

Other tests may be performed in specialist 

centres, e.g. determination of lung compliance, TCO, ventilation/perfusion estimates and lung volumes and capacities.

Blood gases

Measurements of PaO2, PaCO2 and pH, done on a 

sample of arterial blood taken from the radial 

artery or the ear lobe, provide valuable informa-

tion on the levels of hypoxaemia and hyper-

capnia,  the  response  to  oxygen  and  other 

therapy, the adequacy of ventilation, and the 

nature  and  severity  of  any  metabolic  distur-

bance. They are mandatory in hospital for the 

management of seriously ill patients. SaO2 is 

determined readily by pulse oximetry, which 

measures the level of blood oxygenation from 

the colour of the blood in the nail bed or the 

earlobe.   However,   this   is   unreliable   if   the 

peripheral circulation is impaired.

Exercise testing

It  is  preferable  to  use  a  treadmill  or  cycle 

ergometer because performance can be related 

directly to predetermined levels of effort. The 

speed,  slope  or  resistance  is  increased  pro-

gressively  until  the  patient  stops  because  of 

breathlessness,  chest  pain,  etc.,  or  reaches 

their predetermined safe heart rate. In health 

the  heart  rate  should  never  be  allowed  to 

exceed220 (age   in   years) beats/min   and 

should  preferably  be  kept  below  70%  of  this 

rate.  The  ventilation  rates,  composition  of 

the  expired  gas  mixture  and  oxygen  satura-

tion of the blood are measured (preferably by 

pulse oximetry) and an ECG is recorded (see 

Chapter 4)  and  the  SaO2 falls  if  there  is 

ventilation-perfusion mismatch, e.g. in obstruc-

tive   pulmonary   disease.   These   parameters 

enable the severity of lung disease to be deter-

mined, abnormalities of ventilation or oxygen 

uptake  to  be  assessed,  and  pulmonary  or 

cardiac causes of disability to be distinguished.

However, simple walking tests are often done, 

in which the patient is asked to walk up and 

down a corridor for 2, 6 or 12 min. The distance 

walked in the time is measured, or the time or 

distance reached when breathlessness or pain 

forces cessation.

Obstructive pulmonary disease

 Asthma

Definition

No   entirely   satisfactory   definition   exists, although the following covers most patients:

A chronic inflammatory disease of the airways, the  precise  cause  of  which  is  incompletely understood. In susceptible individuals, inflam-

matory symptoms are usually associated with widespread, variable airflow obstruction and an increase in airways’ response to a variety of 

stimuli. Obstruction is usually reversible, either spontaneously or with treatment’.

This   somewhat   vague   clinical   definition 

reflects our lack of knowledge about the precise 

nature of the disease. Winsel (see References and 

further  reading,  p. 364)  has  proposed  that 

asthma is probably an overlapping complex of 

separate, genetically defined syndromes - this 

could explain the imprecise definition.

Thus diagnosis depends on clinical judgement in addition to airflow measurement, provoking factors and reversibility on treatment. This is 

‘bronchial asthma’: the term ‘cardiac asthma’ has been used to denote pulmonary oedema 

consequent on LVF (see Chapter 4) but this usage is now obsolete and ‘asthma’ now invariably 

means ‘bronchial asthma’.

Epidemiology and natural history

There was an international increase in asthma 

prevalence from 1979 to 1990. This trend was 

confirmed by an 18-country study of hospital 

admissions for asthma. Since then, the preva-

lence of asthma has declined (Table 5.7). The 

reasons for these changes are not clear. In devel-

oped countries, the prevalence is currently about 

20%, with about 10-15% of the 10-20-year age 

group being affected. Studies of occupational 

asthma indicate that up to 20% of workers may 

develop   symptoms   if   they   are   exposed

 to sensitizing agents. The consulting rate for 

asthma doubled in the decade 1971/2 to 1981/2 

but has since stabilized. Some of this increase 

may be due to increased awareness of the disease 

and  expectations  of  effective  treatment  and 

some to improved diagnosis, but it is considered 

to reflect a real change. The prevalence in some 

developing countries (e.g. South America and 

Fiji) appears to be similar, but is much lower in 

some African and Far Eastern countries.

The incidence peaks at age 10-12 years, with 

about 20% of children wheezing annually, and 

there is a secondary peak at about 65 years (6%). 

These two peaks correspond to the two main 

clinical types of disease (Table 5.8). If triggered 

by identifiable external allergens in atopic indi-

viduals  the  condition  is  called  extrinsic  or 

episodic asthma. In other patients the agents, 

circumstances   or   conditions   responsible   for 

attacks are unknown or poorly defined. This 

latter form tends to be chronic, or becomes so 

after a time: this is intrinsic  or cryptogenic 

asthma. Extrinsic asthma tends to occur in the 

younger age group, is usually relatively mild and 

is related to atopy, i.e. sufferers have a general 

allergic tendency and often have hay fever and 

eczema (see   Chapter 13).   In   contrast,   the

intrinsic asthmatic is usually older, with more persistent disease. However, this distinction is of only limited value because about 30% of patients have mixed-type disease and it does not materi-

ally affect management. On average, each doctor in the UK will have about 125 asthma patients, and a community pharmacy can expect to see about twice this number.

Up to 80% of children suffer episodic symp-

toms of wheezing, usually associated with respi-

ratory  infections,  but  most  of  these  are  not 

regarded  as  asthmatics.  Asthma  is  the  most 

common chronic disease in the UK and the prin-

cipal cause of childhood morbidity. It is the 

commonest cause of absence from school on 

medical grounds. Boys are more likely to develop 

asthma than girls, the relative prevalence before 

puberty being M : F2 : 1. In many children, the 

frequency and severity of attacks declines from 

the age of 6-8 years, with at least 30% growing 

out of the condition by puberty, at which point 

the sex prevalence is about equal. However, a 

tendency  to  bronchial  hyper-reactivity  may 

persist throughout life, with a highly variable 

frequency  of  attacks  or  chronic  wheeziness. 

Above the age of 20 years, more women are

Asthma293

affected, the M : F ratio of incidence being about

1 : 1.5.

Interestingly, a high salt intake has been shown 

to increase bronchial hyper-responsiveness in 

men,  but  not  in  women.  Further,  an  above 

average dietary intake of magnesium has been 

shown to improve the FEV1 and to reduce hyper-

reactivity  and  wheezing.  Clearly,  the  role  of 

dietary minerals needs to be explored more fully.

The increasing prevalence of asthma suggests 

the   probable   importance   of   environmental 

agents as triggers for the onset of the disease in 

genetically predisposed individuals, but evidence 

for  this  is  equivocal.  In  the  UK,  a  recent 

study found little urban-rural or geographical 

variation in prevalence. The prevalence in the 

unpolluted Scottish highlands was found to be 

similar   to   that   in   nearby   urbanized   areas. 

Further, the prevalence in New Zealand, with a 

favourable climate and an unpolluted atmos-

phere,  is  one  of  the  highest  in  the  world. 

However, studies in the USA have implicated 

outdoor, and especially indoor, air contaminants 

as important risk factors for the development of 

childhood   asthma   and   as   determinants   of 

severity. One possible reason for this discrepancy 

may be the larger number of centrally heated,Pathophysiology

air-conditioned homes in the USA with limited

fresh air exchange - conditions that favour the persistence  of  dust  mite,  animal  and  other airborne allergens and irritants.

The indicators of a poorer prognosis are:

•  severe or early onset; •  persistent attacks;

•  an atopic patient;

•  a family history of atopy; •  female sex.

Asthma accounts for about 1400 deaths annu-

ally in the UK, and many of these are the result 

of under-diagnosis and under-treatment. A 1998 

study of 12-14-year-olds found that 4% had 

been diagnosed as asthmatic but were poorly 

controlled, and a further 1-3.4% had moderate 

to severe symptoms but were undiagnosed and 

untreated. Also, patients may not appreciate the 

severity  of  an  attack.  The  British  Thoracic 

Society (BTS)  surveyed 90  asthma  deaths  in 

north-west England in 1998 and found that 

only 36 of the patients had been sufficiently 

alarmed to see their doctors, and of those only 

nine were then managed appropriately, though 

unsuccessfully.  A 1999  survey  in  Scotland 

produced similar results. All of these factors are 

theoretically preventable. Although the situa-

tion has improved since these reports, there is 

still a great deal to be done before the 2.1 

million symptomatic people with asthma are 

treated  satisfactorily  and  preventable  asthma 

deaths are reduced substantially.

However,  a  2006  systematic  review  of  19 

trials(34000asthma   patients)   worldwide 

found that 80% of deaths were related to the 

use of long-acting beta2-agonists (LABAs; salme-

terol and formoterol; see below). The data indi-

cate that patients taking LABAs are 3.5 times 

more  likely  to  die  from  asthma  than  those 

taking a placebo and 2.5 times more likely to 

be admitted to hospital. Of particular concern 

is the finding that LABAs can trigger bronchial 

inflammation   and   hyper-reactivity   without 

prior  warning  signs.  This  seems  to  bear  out 

long-standing  concerns  about  the  safety  of 

LABAs,  although  some  respiratory  physicians 

have some reservations, awaiting confirmation 

of the data.

The  underlying  problem  is  intense  airways 

inflammation,  leading  to  bronchial  hyper-

reactivity. Inflammation is present even when 

patients are asymptomatic. Everyone’s airways 

will become constricted if exposed to a sufficient 

dose of a bronchoconstrictor, e.g. histamine or 

methacholine. Following viral respiratory tract 

infection the airways of non-asthmatics will be 

more sensitive than usual for up to 6 weeks as a 

result of mucosal damage and the exposure of 

receptors for physiological mediators (e.g. hista-

mine, kinins, LTs and PAF; see Chapter 2). Asth-

matics may be up to 100 times more sensitive 

than  normal  subjects  and  atopic  individuals 

suffering from hay fever but not asthma form an 

intermediate group.

The  precise  cause  of  this  hyper-reactivity  is 

unknown, though LTs are definitely implicated, 

and LT receptor antagonists are used in therapy 

(see below). Also, remodelling over time causes 

changes  in  all  the  layers  of  the  airway  walls 

(e.g.  goblet  cell  hyperplasia,  shortening  of 

smooth muscle cells and swelling of the adven-

titia),  which  contribute  to  hyper-reactivity, 

especially  in  chronic  asthma.  A  number  of 

other putative mediators have been identified 

and we know of many factors that may precip-

itate attacks (Tables 5.9 and 5.10; Figure 5.12). 

Although some patients are sensitive to only a 

single  trigger  factor,  most  are  sensitive  to 

several, so attacks may be due to the combined 

effects of two or more of these. Inflammation 

is clearly the single most significant sign. In an 

acute attack, the epithelium is intensely infil-

trated with eosinophils, causing the release of 

pro-inflammatory   eosinophil   products(e.g. 

proteins and neurotoxins), which damage the 

epithelium.

Other    inflammatory    cells(mast    cells, 

basophils, etc.) also accumulate and release a 

wide  variety  of  inflammatory  mediators,  e.g. 

histamine,  LTs,  PGs,  thromboxanes  and  PAF. 

These cause bronchiolar smooth muscle contrac-

tion  and  marked  oedema  of  the  bronchial 

mucosa,   epithelial   shedding   and   receptor 

exposure. The extent of the damage produced is 

reflected   in   the   degree   of   airways   hyper-

responsiveness   produced.   Lymphocytes   and macrophages are also abundant, but less so than 

eosinophils.   Goblet   cell   hyperplasia   causes 

hypersecretion of mucus, which may be abnor-

mally viscous and may plug the smaller airways.

The initial step in this inflammatory process is believed to be T cell activation (see Chapter 2). Lymphokines are produced which amplify the immune response, notably by the production of IgE antibodies and their induction of allergic 

reactions.  Allergic  mechanisms  are  especially important in episodic asthma associated with 

ocupational allergens.

Bronchoconstriction may also be mediated by 

cholinergic action via the vagus nerve. Although 

there is no adrenergic innervation of the airways, 

alpha- and beta-receptors are present and are 

targets  for  bronchodilating  drugs.  Emotional 

upset does not normally trigger an attack but it 

may aggravate symptoms. However, severe stress, 

e.g. battle fatigue in soldiers, can exacerbate an 

asthmatic  tendency  and  cause  symptoms  in 

patients with a subclinical condition.

About  80%  of  asthmatics  suffer  nocturnal 

attacks,  described  as ‘morning  dipping’ (see 

below and Figure 5.13), during which the early 

morning peak flow may fall by as much as 50%. 

This  marked  diurnal  variation  in  respiratory function is much greater than is seen in normalAlthough it has been suggested that a fish oil

subjects, in whom nocturnal falls are about 8%. 

The tendency to nocturnal attacks is exacerbated 

by  allergen  exposure,  especially  following  a 

severe  attack,  when  patients  are  particularly 

vulnerable. It is tempting to associate this with 

the  nadir  of  adrenal  cortical  activity,  which 

occurs at a similar time, though evidence for this 

is lacking. The principal factor appears to be other 

physiological changes that occur during sleep, 

e.g.  lower  levels  of  blood  sympathomimetic 

amines, reduced sympathetic outflow, increased 

vagal (cholinergic) activity and reduced mucocil-

iary clearance. Airways cooling during the night 

may  also  make  a  small,  though  significant, 

contribution,  so  it  is  reasonable  to  counsel 

patients not to sleep in cold rooms.

diet may be beneficial by promoting the forma-

tion of 5-series LTs as opposed to the 4-series compounds derived from arachidonic acid (see Chapter 12, Figure 12.9), available data indicate that they are not clinically beneficial and may even be harmful. No fish oil product is licensed for asthma treatment in the UK.

Exercise-induced  asthma  occurs  in  many 

patients, especially the young. The attack comes 

on after a short bout of vigorous exercise or 

during a prolonged sporting period, e.g. a foot-

ball match, and may be the only symptom of 

asthma. The trigger seems to be the excessive 

cooling and drying of the airways epithelium by 

the increased airflow during exercise, because 

inhalation of cold, dry air can also provoke attacks, whereas swimming is the exercise least 

likely   to   do   so.   However,   exercise-induced 

asthma may indicate poor asthma control, so 

patients  who  suffer  such  attacks  should  be 

reassessed to ensure their treatment is optimal.

The complexity of the mechanisms and medi-

ators that appear to underlie asthma (see Figure

5.12) may reflect our limited understanding of 

the pathological processes concerned. However, 

these uncertainties may be resolved within the 

next 10 years by the application of new tech-

niques  from  the  rapidly  expanding  fields  of 

genetics, immunology and molecular biology.

Occupational asthma is estimated to cause 

5-10% of cases in adults aged 20-44 years in 

industrialized countries, notably cleaners, spray 

and other painters, and plastics workers. Agricul-

tural workers also have a high risk, but it is 

unclear how much of this is due to modern farm 

chemicals and how much to exposure to fungal 

spores. A partial listing of possible agents is given 

in Table 5.9.

Clinical features

The classic symptoms of asthma are attacks of 

breathlessness, wheezing, ‘chest tightness’ and

 cough that start within 15 min of exposure to a 

trigger factor. Depending on the severity of the 

attack, peak flow may fall to 25-75% of that 

recorded between attacks, and usually recovers 

over a period of 60-90 min without treatment 

(Figure 5.14),  but  more  promptly  if  a  bron-

chodilator is used. Between attacks, patients may 

have an apparently normal respiratory function.

However, this pattern is shown in only about 

the 20%  of  patients  showing  an  immediate 

allergic (type I) hypersensitivity reaction (see 

Chapter 2). About 50% of asthmatics experience 

delayed attacks (see below) and a further 30% 

suffer both immediate and delayed attacks.

Dyspnoea in asthmatics is worse in the early 

hours of the morning, whether they experience 

acute severe nocturnal attacks or not, and most 

asthma deaths occur at night or in the early 

morning.

The  criteria  for  a  diagnosis  of  acute  severe 

asthma  in  children  and  adults  are  given  in 

Table 5.11.  In  a  severe  attack  there  will  be 

hyperventilation  and  hyperinflation,  to  the 

extent that patients are incapable of speaking 

in complete sentences, with prolonged expira-

tion  and  the  use  of  the  accessory  muscles  of 

respiration.   Peak   flow   may   fall   below 

100 L/min. Patients are very anxious, the heart rate  may  exceed  120  beats/min,  and  there 

may be palpable pulsus paradoxus (see below) and  peripheral  cyanosis.  A ‘quiet  chest’  on auscultation,  indicating  very  poor  air  flow, also indicates a severe attack.

Many   patients   experience   a   variety   of non-respiratory symptoms before an attack:

•  Mild to moderate chest pain (about 75%), the 

severity being unrelated to asthma severity.

The pain worsens on coughing, deep inspira-

tion and most changes in position, but 65% obtain relief by sitting erect. This may result in fruitless investigations for cardiac problems or pulmonary embolism (p. 342).

 •  Other  symptoms  include  nose  or  throat 

irritation,  sleepiness,  dry  mouth,  thirst,

urinary  frequency,  flushing,  irritability  and depression.

Diagnosis

This is based on the history, examination and 

the investigations outlined below. It must be 

remembered that patients with episodic asthma 

may appear completely normal between attacks 

unless provocation testing is used, but this is 

potentially   hazardous.   Those   with   chronic asthma will show abnormal signs at all times,severe  attacks,  or  in  chronic  asthma,  this

depending on severity.

Moderate asthma exacerbations

The following features may be found:

•  Forced expiratory ratio0.65 (normal0.75).

A spirogram has the general appearance of that in Figure 5.15(b).

•  PEF  reduced  to  50-75%  of  the  predicted

normal or best value.

•  Flow-volume loop showing air trapping with 

increased TLC and RV (Figure 5.9).

•  Blood   gases   are   not   normally   measured 

in  moderate  exacerbations,  but  should  be

done for all asthmatic patients admitted to 

hospital.

•  WBCs:   eosinophils0.5109/L(normal

0.4109/L) in extrinsic asthma and they 

may be present in sputum.

•  Reversibility  with  an  inhaled  beta2-agonist 

(Figure 5.8):  a 15%  increase  (or  more)  in

FEV1  or PEF is conclusive: lesser degrees of 

reversibility   do   not   distinguish   between 

asthma and COPD (see Table 5.20). In very

reversibility may not be seen, because the 

airways become unresponsive.

Severe attacks

Retention of carbon dioxide in near-fatal asthma 

may be indicated by drowsiness, sweating and 

cyanosis, and a high-volume, bounding pulse. 

Central cyanosis is a serious sign but its absence 

does not preclude a life-threatening attack.

Pulsus paradoxus  is a pulse that decreases 

markedly in pressure during inspiration and is a sign of LVF. Although it is mentioned in many texts, it is present in less than half of patients 

and is consequently an unreliable sign.

Other features have been described above.

Other investigations

IgE  blood  levels  may  be  raised  indicating 

atopic  reactivity  and  are  determined  by  the 

radioallergosorbent   test(RAST)   procedure 

(Figure 5.16), but this is used for patients who 

are  difficult  to  diagnose (see  below),  as  a

tool  and  to  guide  treatment  with 

omalizumab (p. 324).

The  aetiology  may  be  ascertained  by  skin 

testing with allergens (see Chapter 13) as a guide 

to allergen avoidance, though it may be imprac-

ticable to avoid allergens, especially if patients 

react   to   several   simultaneously.   However, 

negative skin tests may indicate the need to 

investigate an alternative diagnosis. Bronchial 

challenge   by   inhaling   suspected   allergen 

aerosols may be conclusive, but is hazardous, 

with a risk of anaphylactic shock (see Chapter 2), 

and   should   not   be   attempted   unless   full 

resources   for   resuscitation   are   immediately 

available.

Exercise stress testing may also be helpful, 

especially in children, to assess the degree of 

exercise limitation and the role of exercise in 

inducing attacks.

Diagnostic problems

The following features may cause difficulties:

•  Dry cough, sometimes with the production of 

small amounts of very viscid sputum. Cough,

particularly  troublesome  at  night,  may  be the  only  presenting  symptom  of  asthma, especially in young children.

 •Many   infants   have   attacks   of   wheezing,

possibly   because   they   have   rather   small

airways  as  a  result  of  maternal  smoking 

during pregnancy, but only about one-third 

of these go on to develop asthma. Diagnosis 

in very young children is clearly difficult but 

relief  following  a  trial  of  drugs (e.g.  the 

inhalation of a nebulized beta-agonist bron-

chodilator held near the nose) may be diag-

nostic. The likelihood of asthma is increased 

if wheezing is unrelated to respiratory infec-

tion or there is a family history of atopy 

(asthma, eczema or hay fever).

•Delayed attacks that occur some 6-8 h after

provocation (Figure 5.14) and recover slowly

over a period of hours without treatment. 

These are associated with increased bronchial hyper-reactivity   and   are   caused   by   an immune  complex  hypersensitivity  reaction (type III; see Chapter 2).

•Recurrent ‘chest colds’ or ‘wheezy bronchitis’

in children, and sometimes adults, may be

due to undiagnosed asthma. A proportion of children eventually diagnosed as asthmatics have had repeated visits to their doctors with respiratory  complaints (the ‘wheezy  baby’ syndrome), for a year or more.

•Persistent  airflow  obstruction  in  an  older

patient with a limited degree of reversibility may be due to asthma, COPD or emphysema.General measures

It  may  be  impossible  and  unnecessary  to distinguish between these because they may coexist: what counts is the extent to which 

treatment is effective.

•Paroxysmal  nocturnal  dyspnoea  (PND;  see

Chapter 4) may mimic nocturnal asthma, but

is due to orthopnoea, i.e. accumulated fluid 

from  the  lower  body  redistributes  to  the 

lungs, causing pulmonary oedema (so-called 

‘cardiac asthma’). PND is often the first sign 

of LVF. A therapeutic trial of a bronchodilator, 

with or without corticosteroids, will distin-

guish   between   these   conditions,   because 

asthma will be relieved but not PND. The 

latter is relieved merely by standing erect, 

when the fluid flows back to the lower body. 

Moreover,  pulmonary  oedema  will  usually 

show characteristic X-ray, ECG and clinical 

signs, e.g. a raised venous pressure and the 

presence of a third heart sound.

•Some undiagnosed asthmatics present for the

first time with cor pulmonale (see Chapter 4).

•Recurrent  respiratory  tract  infections  may

cause difficulty. However, there will not be

significant   airflow   obstruction   or   diurnal variation in PEF between infections.

•Large airways obstruction (outside the lungs)

will usually be persistent, show inspiratory

stridor rather than expiratory wheeze, and 

give a characteristic flow-volume loop (see Figure 5.9).

•Delayed  attacks  (see  above  and  p.  297)

apparently unrelated to allergen exposure.

Management

Aims

The aims of management are to:

•  control  symptoms,  minimize  anxiety  and 

permit as normal a life as possible, including

participation in sports;

•  minimize the need for reliever medication 

and eliminate exacerbations;

•  educate the patient about the disease and its 

treatment;

•  identify    and    eliminate    triggers,    thus 

minimizing morbidity and preventing death.

General  management  measures  include  the following:

•Environmental control, as far as is possible,

by:

-  Stopping smoking, in both patients and 

their families.

-  Removing pets, using non-allergenic bed 

clothing, etc. and minimizing house dust,

e.g.  by  moist  dusting  and  eliminating 

carpets.  These  measures  are  particularly 

important in childhood asthma. However, 

it is not possible or practicable to eliminate 

all environmental allergens, e.g. normal 

vacuum  cleaning  does  not  significantly 

reduce the concentration of house dust 

mite allergens in the atmosphere, although 

cleaners with high-efficiency particulate air 

(HEPA) filtered output are now available 

and  may  help  some  patients.  However, 

there is little evidence to support their use.

•Reduce stress by effective treatment.

•Control infections promptly.

•Physiotherapy, especially supervised swim-

ming, may help to develop respiratory func-

tion: the humid atmosphere of a swimming bath helps to avoid exercise-induced attacks and is less stressful physically.

•Patient education has a crucial role. There

are repeated reports that patients are confused

about their medication and its proper use. 

Patients(and   their   families,   teachers, 

employers,  etc.)  need  to  understand  the 

nature of the disease and how to prevent 

exacerbations and manage them effectively if 

they occur. Pharmacists can and should play 

an important part in this process: they under-

stand the drugs and products and are readily 

accessible   to   patients.   Active   pharmacist 

counselling   has   been   shown   to   reduce 

markedly both morbidity and the demands 

made   on   the   community   and   hospital 

medical services. Additionally, there are the 

substantial benefits of increased patient well-

being, less time off work or school and the 

satisfaction of patients being in control of 

their disease, rather than vice versa. Further, if 

patients  are  properly  counselled  and,  for 

those who have moderate to severe exacerba-

tions, keep a diary, they can detect the first 

signs of deterioration in their condition (i.e. 

increasing   dyspnoea,   declining   PEF   and 

increasing medicines usage). They can then 

adjust their medication to respond to the 

problem immediately, hopefully aborting an 

attack, before seeing their doctor. Patients are 

reported  as  having  a  different  perception 

of   well-being   from   health   professionals. 

Whereas patients see good disease control 

as  freedom  from  constraints  on  activity, 

professionals  use  objective  measures,  e.g. 

absence of symptoms, low (or no) medicines 

usage. This gap can be closed by effective 

counselling, with improvement in patients’ 

satisfaction with treatment.

Pharmacotherapy: general aspects

Drug treatment is often thought of in terms of 

either prophylaxis or the relief of symptoms. In 

asthma, both approaches are commonly used 

concurrently,   and   combination   therapy   is 

normal. However, effective prophylaxis should 

minimize exacerbations and avoid the need for 

rescue therapy.

General strategy

A general approach to the control of the two 

cardinal features of asthma, airways inflamma-

tion  and  bronchoconstriction,  is  outlined  in 

Table 5.12.

A stepwise addition of medication is used after 

diagnosis,  starting  at  the  step  most  likely  to 

abolish symptoms. At all steps the patient should 

have  an  inhaled,  short-acting  beta2-agonist 

(SABA)  bronchodilator  (‘reliever’)  available  for 

mild infrequent attacks, but this should need to 

be used only occasionally. Regular use of this is no 

longer recommended and indicates the need for 

patient reassessment. Many patients are main-

tained with a regular inhaled corticosteroid, at 

appropriate dosage, plus the occasional use of a 

reliever (Tables 5.13 and 5.14).

However, if attacks are frequent, or moderate 

to severe (i.e. PEF 50-80% of predicted or best), it 

is   preferable   to   gain   control   of   symptoms 

promptly with greater initial intervention and to 

‘step   down’   treatment   once   this   has   been 

achieved. Control is usually gained with anti- 

Asthma303

inflammatory agents, usually low-dose or high-

dose  inhaled  corticosteroids  or  an  LTRA.  An 

LABA  bronchodilator  may  be  added  if  the 

asthma is still not well controlled, provided that 

the continuing symptoms are unacceptable to 

the patient and that they accept the risk of a 

serious  cardiovascular  event (see  above).  The 

LABA should be stopped if it does not give objec-

tive benefit. All of these may be used concur-

rently in severe cases. An SABA should also be 

available for rescue treatment. Additional drugs 

may need to be introduced at any stage as the 

patient’s condition and progress dictate.

All changes of treatment should be validated by 

careful monitoring of PEF and medicines usage, 

or FEV1 and FVC if the equipment is available in 

GP surgeries, with ample time for prophylactic 

medication to take full effect (see below). Inhaled 

corticosteroids, bronchodilators and LTRAs, and 

nedocromil sodium for children 5-12 years, used 

singly or in combination, will give excellent, safe 

control in most patients. Sedatives must never be 

used  to  aid  sleeping  or  control  restlessness, 

because they may dangerously depress an already 

compromised respiratory function.

The   BTS   and   the   Scottish   Intercollegiate 

Guidelines   Network (SIGN)   have   published 

evidence-based guidelines for the management 

of asthma, summarized in Table 5.13 for adults 

and schoolchildren, and Table 5.14 for younger 

children.  More  detailed  information  on  the 

drugs and their delivery systems are given below, 

but some general points are now discussed.

Treatment in an acute attack

This  is  designed  to  promote  recovery  and 

prevent deterioration to the point when hospital treatment becomes necessary.

The  techniques  of  inhalation  therapy  are discussed on pp. 348-360, but it is sufficient here to say that pressurized metered-dose inhalers 

(pMDIs)  or  dry  powder  inhalers (DPIs)  are normally used. If higher than normal doses are necessary, a nebulizer may be required.

Occasional attacks in an adult can be treated 

with an inhaled selective SABA bronchodilator 

(p. 314). If a consistent trigger can be identified 

(e.g. sport, infection, drugs or visits to a home 

having a pet), prior use of an SABA inhaler or 

regular  use  of  a  corticosteroid  inhaler  may 

prevent attacks (Table 5.13, Step 2). If there are 

more frequent or more severe episodes, routine 

prophylactic treatment is added. This usually 

starts  with  an  inhaled  regular  standard-dose 

corticosteroid,  plus  an  inhaled  SABA  bron-

chodilator  when  required.  The  beta2-agonists 

enhance the anti-inflammatory effects of the 

corticosteroid on cells. If a corticosteroid cannot 

be used an LTRA, e.g. montelukast or zafirlukast, 

may be substituted. There is one report that 

adding  an  LTRA  in  patients  taking  a  stable 

dose of budesonide may reduce night disturbance 

and increase the number of asthma-free days. 

However, there is no clear consensus about the 

place of LTRAs in therapy, but a trial of LTRA

therapy is warranted in patients whose asthma is   inadequately   controlled   on   conventional treatment.

Because of fears of side-effects, especially of corticosteroids, and if they do not understand 

the principles of prophylaxis, patients often do not adhere to regular use of their corticosteroid inhalers,  with  a  consequent  deterioration  in symptom control.

Patients should have their response to therapy, their   inhaler   technique   and   concordance 

reviewed regularly. Those who still have not 

responded   adequately   should   have   their 

corticosteroid dose doubled and this may avoid instituting an oral corticosteroid. 

Chronic management in children aged under

12 years

At all levels of management patients should have 

an SABA available for the control of symptoms. 

With frequent or moderate to severe episodes 

(see Table 5.13) an inhaled corticosteroid may be

used, e.g.  200-400 lg of beclometasone dipropi-

onate (BDP) daily, or the equivalent of another 

corticosteroid (see  notes  to  Table 5.14).  The 

starting dose should be appropriate to symptom 

severity. High doses carry a significant risk of 

serious side-effects, notably growth retardation, osteoporosis   and   adrenal   suppression,   and should be used as sparingly as possible. However, short high-dose courses are safe, and failure to control  asthma  symptoms  may  itself  cause growth retardation.

If a corticosteroid cannot be used an LTRA may 

be tried as an alternative regular prophylactic. If 

this therapy is not effective, it may be necessary 

to double the corticosteroid dose. Similar consid-

erations regarding inhaler technique, response 

and concordance to those outlined above apply 

here also.

If this does not achieve satisfactory control alter-

native prophylactic measures need to be consid-

ered. Cromones, e.g. nedocromil sodium, may be 

beneficial  and  modified-release  theophylline  or 

aminophylline may have to be used. Because the 

methylxanthines have a different mode of action, 

they may augment the response to other agents. 

Use of some theophylline preparations in 6-year-

olds and under is not recommended (see the BNF 

and manufacturers’ literature).

Sodium  cromoglicate  may  help  as  a  regular 

prophylactic for exercise-induced asthma in chil-

dren, but this may indicate poor control and the 

child should be reassessed; it is of no value for 

acute asthma attacks. In some children aged 

under 5 years, ipratropium bromide may be useful.

Children under 2 years who are inadequately controlled with a daily use of an SABA plus up to 400 lg of BDP (or its equivalent) daily are best managed by a paediatric respiratory physician. This also applies if the use of an oral corticos-

teroid is being considered as a measure of last resort when adequate trials of the other agents fail to give satisfactory control.

It may take 3-4 weeks to establish the level of 

response to prophylactic inhalation therapy, so

Asthma309

persistence is required on the part of patient, 

doctor and carer. This places a premium on early initial control to create patient confidence in 

their doctors and cooperation with them, and 

adherence to their prescribed medication.

Chronic adult asthma

The management of chronic asthma in adults 

and children over the age of 12 years is similar to 

that just described and is based on the use of 

inhaled  corticosteroids.  The  starting  dose  is 

usually in the range 200-800 lg of BDP or its 

equivalent daily; most patients are started on 

400 lg of BDP (or an equivalent). If the response 

is inadequate, an LABA may be added (but see

p. 294).

With a partial but inadequate response the 

LABA should be continued and the corticos-

teroid dose increased to 800 lg of BDP or its 

equivalent  daily,  provided  that  dose  is  not 

already being used. If the LABA does not give 

demonstrable benefit, it should be stopped.

If control is still inadequate, a trial of an LTRA 

or  a  modified-release  methylxanthine  should 

be  instituted.  Persistent  poor  control  should 

prompt an increase in the inhaled corticosteroid 

to 2000 lg of BDP or its equivalent daily (see 

below), plus an LTRA, a slow-release methylxan-

thine or an oral beta2-agonist (see Table 5.13, 

steps 4 and 5).

The final step to achieve adequate control is to 

add an oral corticosteroid, e.g. prednisolone, at 

the lowest dose that controls symptoms. The 

inhaled   high-dose   corticosteroid   and   other 

medications  that  have  given  benefit  should 

always be continued to minimize the oral cortico-

steroid dose. At this stage the patient should be 

in the care of a specialized respiratory team. Older   adults(aged50 years)   may   notMorning dipping (see Figure 5.13) was tradi-

respond  adequately  to  beta2-bronchodilators, 

probably because of a deficiency of bronchiolar 

beta2-receptors,  so  the  antimuscarinic  agent 

ipratropium bromide may give better results as a 

reliever  in  these  patients;  however  the  first 

dose should be used under medical supervision 

because   it   may   trigger   paradoxical   bron-

chospasm. If all this amounts to so many inhala-

tions  daily  that  adherence  is  compromised, 

tiotropium may be an alternative antimuscarinic, 

which is given via a DPI once daily and is suit-

able for prophylactic use only and not for the 

relief of acute bronchospasm. Tiotropium is not 

suitable for children and adolescents under 18 

years and its use in asthma is an unlicensed indi-

cation: it is licensed for use in COPD (see below). 

The use of antimuscarinics in this older age 

group needs to be managed carefully, because 

they may cause or exacerbate glaucoma, diffi-

culty in micturition, even acute urinary reten-

tion in men with an enlarged prostate gland, and 

tachycardia or atrial fibrillation (see Chapter 4).

High-dose  inhaled  corticosteroids  (see  the 

notes to Table 5.13) may avoid the need for oral 

steroids completely, or enable the dose of the 

latter to be reduced substantially. In the commu-

nity a large-volume spacer device (see p. 352) 

should be used to reduce the risk of oropharyn-

geal thrush (see below). A nebulizer (p. 354) can 

be used to deliver doses higher than those readily 

obtained with pMDIs. The choice of drug delivery 

system in a hospital setting will depend on the 

patient’s general condition, e.g. an oxygen-driven 

nebulizer, IPPV (p. 361) or parenteral medication. 

The  dose-response  curve  for  inhaled  cortico-

steroids flattens at moderate doses and increasing 

the dose above 800 lg of BDP daily, or the equiv-

alent of another corticosteroid, may give little or 

no further improvement but cause increased side-

effects.  LTRAs  may  be  preferred  because  their 

effect is additive to that of a steroid. Clearly, there 

will  be  no  further  benefit  if  the  response  to 

existing therapy is the maximum that can be 

achieved in damaged lungs.

All  of  these  agents  should  be  given  an 

adequate trial before using an oral steroid, the 

latter being a measure of last resort in patients 

who  are  poorly  controlled  despite  standard 

treatment.

tionally managed with an oral slow-release bron-

chodilator (beta2-agonist or a methylxanthine) 

taken before retiring, but an LTRA may now be 

preferred.

Moderate exacerbations of asthma in adults are characterized by worsening symptoms, with no features of acute severe asthma.

Appropriate treatment in the community is to step up the patient’s usual treatment.

The clinical features of acute severe asthma 

in adults are given in Tables 5.11 and 5.13. 

Treatment in the community then includes:

•  High-flow  oxygen  (40-60%  by  face  mask;

p. 361), if available.

•  Oxygen-driven nebulized salbutamol or terbu-

taline (if available) for 15 min (or 4-6 puffs

from a pMDI with a large-volume spacer, each puff taken separately. The response should be monitored 15-30 min later.

•  Nebulized ipratropium bromide, especially for 

those not responding to beta2-agonists.

•  Hospital  admission  if  any  two  of  severe

breathlessness, high respiratory or heart rate are present or the patient’s condition persists or deteriorates.

•  Oral prednisolone 40-50 mg daily for 5 days or 

until recovery. IV hydrocortisone 100 mg four

times daily is an alternative if the patient 

cannot swallow tablets.

•  There should be a review within 24 h, and if 

the patient has improved, review standard

medication after stopping prednisolone  (this short period of corticosteroid treatment does not require gradual step-down).

In  life-threatening  asthma  the  patient  will 

exhibit one or more of the signs given in Table

5.11.

Immediate hospital admission is necessary if 

any  of  those  above  features  is  present  or  the 

patient’s condition persists or deteriorates. Referral 

to an intensive care unit should be considered.

Emergency   treatment   in   the   community includes:

•  High-flow oxygen (p. 361), if a suitable supply 

is  available.  If  a  patient  is  already  using

oxygen, they must seek immediate medical treatment and should not rely on oxygen to treat a severe attack.

•100 mg IV hydrocortisone.

•  Nebulized salbutamol or terbutaline with nebu-

lized  ipratropium,  preferably  oxygen-driven.

The nebulized beta2-agonist should still be 

given if a suitable oxygen supply (p. 358) is not available.

•  The  patient  should  be  supervised  by  the 

doctor until the ambulance arrives.

•  An   IV   infusion   of  1.2-2.0 g   magnesium

sulphate (p. 293) should be given over 20 min,

after consultation with a senior doctor.

We have already noted that the severity of such 

attacks is often not appreciated by the patients 

or  their  doctors,  so  many  patients  arrive  at 

hospital virtually moribund. Some patients are 

not distressed, or the severity of symptoms may 

be masked by over-enthusiastic use of beta2-

agonists, especially with a nebulizer (p. 354). It is 

better  to  recognize  that  a  severe  attack  is 

impending and treat the patient aggressively at 

the first signs to gain control and prevent deteri-

oration,  because  it  is  more  difficult  to  treat 

severe symptoms once they are established. Even 

large doses of beta2-agonist bronchodilators and 

corticosteroids,  given  by  MDIs  with  a  large-

volume spacer or nebulized, are safe in the short 

term. However, patients are often unresponsive 

to bronchodilators in severe attacks, so it may be 

dangerous to persist with these because they 

may aggravate hypoxia (p. 315). If a patient is 

unresponsive to a nebulized beta2-agonist it may 

be better to use IV aminophylline  (see below), 

which has a different mode of action.

The groups most at risk in an acute severe 

attack are patients who:

•  are aged between 12 and 25 years; 

•  are    immigrants,    migrant    workers    or

holiday-makers;

•  were in hospital for asthma in the previous 

year;

•  have a history of severe attacks; 

•  use three or more classes of medication; 

•  have initiated an emergency call or repeatedly

attended  an  A&E  department  for  asthma treatment.

In addition, these patients may have:

•  progressive  symptoms  or  signs  (nocturnal

episodes, declining or increasingly labile PEF);

 Asthma311

•  exposure   to   seasonal   or   occupational 

allergens;

•  psychosocial  problems,  i.e.  stress  in  their 

lives;

•  denial of the severity of their condition; 

•  obesity, which should be addressed after the

severe attack has subsided.

The general management strategy is outlined in 

Figure 5.17, but this is empirical and needs to be 

considered  in  light  of  the  patient’s  current 

therapy. Thus if this already includes a nebulized 

beta2-adrenergic bronchodilator and oral cortico-

steroids, it may be appropriate to give a slow IV 

bolus of aminophylline. If the patient is already 

taking  oral  theophylline,  the  initial  loading  IV 

dose  should  be  omitted  and  the  patient 

observed  for  cardiac  arrhythmias.  Emergency 

self-admission (‘open door’) schemes may be life-

saving.  The  A&E  doctor,  or  other  admitting 

doctor,  should  be  notified  if  the  patient  is 

already taking a methylxanthine.

Following admission, PEF or FEV1  and serum 

electrolytes  are  monitored.  Blood  gases  are 

measured   in   life-threatening   and   near-fatal 

attacks. The serum potassium level is particularly 

important,  because  there  is  a  risk  of  serious 

hypokalaemia  with  beta2-agonists (see  below 

and Chapter 4) and this may be exacerbated by 

high-dose  corticosteroid  and  methylxanthine 

use.

All patients should be educated to recognize any significant deterioration in their condition, e.g. with home monitoring of PEF, and about 

what  action  to  take.  These ‘personal  action plans’ may involve:

•  A protocol agreed with the patient’s GP or 

consultant   and   instructions   to   see   their

doctor without delay.

•  Increasing the dose of their inhaled cortico-

steroid,  if  appropriate,  or  using  an  oral

corticosteroid at the first signs of significant deterioration.

•  Reserve supplies of:

-  oral and high-dose inhaled corticosteroid;

-  antibiotics,  if  severe  attacks  are  known

to   be   triggered   by   antibiotic-sensitive 

infection (the routine use of antibiotics 

is  inappropriate  if  there  is  no  positive 

indication).

Brittle asthma.   This describes the condition inFirst-line prophylaxis against exercise-induced

a few patients who suffer sudden, severe attacks 

with very few or none of the warning signs 

described above. The peak flow charts of these 

patients will show a chaotic pattern. Provided 

that such patients are measuring and recording 

their PEF correctly, they need reserve supplies of 

drugs as described above, so that they can start 

intensive treatment immediately an exacerba-

tion occurs (according to protocol; see above). 

They must also obtain expert assistance without 

delay and often have special arrangements with 

their local hospital. Clearly, these patients will 

need to have been thoroughly assessed by a 

specialist respiratory physician and trained in 

the use of the equipment (i.e. peak flow meters, 

inhalers and nebulizers), and their medication. 

Asthma in children (see also above).   Children 

cannot   coordinate   the   relatively   complex 

manoeuvres required to use an unmodified MDI 

(pMDIs, p. 349; see Figure 5.23) before the age of 

5-7 years. A range of specially designed spacers 

and face masks for use with pMDIs is available 

for  young  children (Figure 5.23).  For  older 

children,  breath-actuated  pMDIs  or  DPIs  are 

preferred.  Nebulized  drugs (p. 354)  or  oral 

medication may be used at any age, especially in 

infants and during severe attacks. Children vary 

enormously in their rates of mental and physical 

development, so the route of administration has 

to be tailored to their abilities and tolerance of 

treatment.  Their  parents  or  carers  should  be 

educated to recognize the warning signs of dete-

rioration and to know how to respond appropri-

ately. Regular monitoring is especially important 

in this age group because their requirements 

change rapidly with age.

Within  these  constraints,  and  with  appro-

priate dosage, the management of childhood 

asthma (Tables 5.13 and 5.14) is generally similar 

to  that  in  adults.  However,  adrenergic  bron-

chodilators are often ineffective in young chil-

dren because only a small proportion of the dose 

may reach the lungs. It has been shown that a 

beta2-agonist bronchodilator used with a large-

volume spacer is more effective than a nebulizer 

in children aged over 3 years with acute asthma. 

This finding requires confirmation, but provides 

a less costly and simpler alternative to nebulizer 

treatment.

bronchoconstriction includes low-dose cortico-

steroids and sodium cromoglicate, or an SABA used 

before  anticipated  activity.  Higher  doses  of 

inhaled corticosteroids, administered via a spacer 

device (p. 352), are introduced as necessary. One 

study has shown that the early use of an inhaled 

corticosteroid may prevent the development of 

acute, severe airways obstruction. However, trial 

results are conflicting and one trial found that 

doubling the dose of inhaled corticosteroid did 

not improve symptom scores and reduced growth 

velocity after 1 year of treatment. This confirms 

the  known  flat  response  with  corticosteroid 

dosage and emphasizes the need for objective 

assessment following any medication change and 

for regular medication review.

Oral corticosteroids must be avoided if possible, 

because  they  retard  growth,  even  if  given  in 

alternate-day dosage, but it has been shown that 

nebulized budesonide, and presumably BDP also, 

may permit a dramatic reduction in oral cortico-

steroid usage. Alternate-day dosing is unsuitable 

in asthma because patients deteriorate on the 

steroid-free days. The possibility of growth retar-

dation should always be borne in mind. One 

systematic review found a clear preference by 

children’s parents for inhaled corticosteroids over 

placebo. As usual with severe chronic diseases, 

effective control comprises a sometimes difficult 

balance  between  the  harmful  effects  of  the 

disease and the side-effects of treatment.

Severe   childhood   asthma.   Young  children 

present special problems in diagnosis and treat-

ment. The emotional response of the child (and 

its parents) to the knowledge that they have a 

potentially severe, chronic disease, and the loss 

of  time  from  school,  are  also  important,  so 

careful counselling of the child and its parents, 

siblings and teachers (with the parents’ permis-

sion), is essential. Features of acute severe and 

life-threatening asthma in children are given in 

Table 5.11 but children may not show obvious 

signs of distress.

Emergency treatment in the community may include:

•  Referral to a children’s hospital.

•  Nebulized SABA (oxygen-driven if possible) or 

10 puffs from an SABA pMDI via large-volume 

spacer (with a face mask in the under 5s). If there  is  a  favourable  response,  repeat  as necessary.

•  Start   a   short   course   of   oral   soluble 

prednisolone, e.g. daily doses of:

-  10 mg2 years 

– 20 mg 2-5 years

–30-40 mg5 years

–  IV hydrocortisone should be considered if 

unable to take prednisolone tablets.

•  If unresponsive or there is a relapse within 

3-4 h:

-  Refer to hospital immediately.

-  High-flow oxygen, if available, via a face 

mask.

-  Nebulized SABA (oxygen-driven if possible) 

plus nebulized ipratropium bromide (250 lg

every 20-30 min).

•  Children over 12 years are treated as adults.

Immunotherapy

Hyposensitization.   Many attempts have been made   to ‘desensitize’   patients   to   allergens. Because episodic asthma is often associated with high levels of IgE, it is attractive to try to prevent IgE  production  or  to  prevent  the  resultant 

hypersensitivity reaction.

In  the  past,  this  has  been  attempted  by 

injecting a minute dose of an identified allergen 

and  following  this  with  regularly  increasing 

doses, none of which must provoke a significant 

reaction.  Theoretically,  this  should  result  in 

effective immunization with the production of 

sufficient IgG (so-called ‘blocking antibody’) to 

scavenge any allergen before it is able to elicit 

the formation of IgE.

However, it is rarely possible to achieve this 

effectively because, even if patients can be desen-

sitized to a single allergen, they are usually sensi-

tive to several allergens at first diagnosis and do 

not  respond  adequately.  Further,  being  atopic 

they will later become sensitive to other allergens. 

Hyposensitization has largely been abandoned in 

the UK following a number of severe anaphylactic 

events and 11 deaths. The UK’s Committee on 

Safety  of  Medicines (CSM)  has  advised  that 

desensitizing vaccines should not be used unless 

full cardiorespiratory resuscitation facilities are 

immediately  available  and  patients  can  be 

observed for 2 h following each injection.

Asthma313

Current  research  in  this  field  is  directed 

towards the minimization of major reactions 

during   immunization   by   using   modified 

allergens or immunomodulatory agents. A more 

fundamental   approach   to   immunotherapy 

involves the control of IgE production in atopic 

individuals   by   promoting   TH1   lymphocyte 

differentiation and suppressing TH2 responses 

and so the production of IL-4 (see Chapter 2). 

The role of immunotherapy, used in carefully 

selected patients under controlled conditions, 

requires continual reappraisal in the light of our 

increasing  understanding  of  clinical  immun-

ology. There is now, current interest in this.

Immunosuppression.   The   term‘immuno-

therapy’  may   be   stretched   to   include   the 

blocking of the release or action of inflammatory 

eicosanoids and cytokines by lymphocytes. The 

first agents with such properties are the LTRAs 

(see below) and omalizumab (p. 324), a recombi-

nant, humanized, monoclonal antibody against 

Ig E. The latter has been introduced recently and 

is licensed as additional therapy for those with a 

proven   IgE-mediated   basis   to   the   attacks. 

However, it has to be given by SC injection in a 

dose  determined  by  the  IgE  level  and  body 

weight. It should be initiated only by a physician 

experienced   in   the   management   of   severe 

asthma.

In a small number of patients, who are not 

well   controlled   despite   all   of   the   above 

agents, conventional immunosuppressive anti-

inflammatory drugs, e.g. ciclosporin  or metho-

trexate, have been used. These agents should be 

prescribed by clinicians who are experienced in 

their use and patients supervised closely with 

appropriate  monitoring  of  the  blood  picture 

and kidney function (see Chapters 10, 12, 13 

and 14).

Drugs used in obstructive pulmonary disease

This  section  includes  the  treatment  of  both asthma and COPD. A summary of the treatment of target features was presented in Table 5.12 and the topic of inhalation therapy is dealt with separately on pp. 348-360.

Beta2-agonist bronchodilatorsaction, but the difference is not clinically rele-

vant. Both of these are therefore used for asthma

Mode of action

management as relievers.

These drugs interact with a membrane-bound

receptor coupled to an intracellular protein with 

a   subunit   that   regulates   effector   molecule 

activation in the cell, e.g. adenylcyclase, phos-

pholipases, ion channels or transport proteins. 

Beta2-receptors ultimately cause the opening of 

Ca2÷  channels and reduce both the phosphory-

lation  of  myosin  light  chains  and  calcium-

dependent  actin-myosin  coupling,  producing 

smooth muscle relaxation.

Secondary effects relevant to asthma are:

•  Increased  mucociliary  clearance  from  the 

airways, reducing obstruction.

•  The reduction of bronchial reactivity to a 

variety of stimuli, due to:

-  decreased    microvascular    permeability, 

reducing the recruitment of inflammatory

cells;

-  inhibition of phospholipase A2 activity. 

•  Inhibition of the liberation of LTs, especially

IL-4 and histamine from mast cells and other effector cells.

These secondary effects are probably less impor-

tant acutely, but may contribute to the beneficial effect of the beta2-agonists when they are used regularly. Because the density of beta2-receptors is  greatest  in  the  smaller  airways,  it  is  there (the site of the problem in asthma) that the 

beta2-agonists exert their major effect.

Use

The short-acting beta2-agonists are the drugs of 

first choice in the treatment of mild asthma 

and are used therapeutically as ‘relievers’ to 

control  occasional  acute  attacks  and  break-

through  attacks  in  otherwise  well-controlled 

patients.

Short-acting  agents  (SABAs).   The  currently 

available   drugs,   salbutamol   and   terbutaline 

sulphate,   have   very   similar   pharmacokinetic 

characteristics.  The  most  widely  used,  salbu-

tamol, has an intermediate duration of action of 

about 4 h and a rapid onset of action, with a 

peak effect about 60 min after inhalation. Terbu-

taline seems to have a slightly longer duration of

Long-acting agents (LABAs).   Bambuterol (not 

in children) requires only once-daily oral dosing, 

while formoterol and salmeterol (in children over

6 and 4 years, respectively) are usually inhaled 

twice daily, enhancing convenience and patient 

compliance. It is important to note that these 

long-acting agents are not replacements for the 

shorter-acting drugs because they are suitable 

only for regular prophylaxis and not as relievers 

for ‘rescue therapy’: the shorter-acting drugs are 

the drugs of choice for treating the occasional 

acute attack.

However,   a   recent   systematic   review   has concluded   that   LABAs   are   associated   with increased death in severe asthma (p. 294). This needs  urgent  clarification,  because  they  are otherwise valuable in those patients who show significant morning dipping, or who continue to wheeze despite using low-dose inhaled steroids and short-acting bronchodilators.

Side-effects.   It is clear from the distributions 

of the two types of beta-adrenoreceptors (Table

5.15)  that  the  SABAs  are  without  significant 

adverse cardiac effects at normal dosage. This 

selectivity  is  enhanced  because  they  can  be 

delivered directly to their sites of action in the 

bronchioles,  where  they  are  very  effective  at 

about one-tenth of the oral dose. They are thus 

very safe and have replaced the non-selective 

adrenergic   agents(adrenaline(epinephrine), 

isoprenaline (isoproterenol),  etc.),  the  CNS 

(restlessness,   agitation)   and   cardiovascular 

(increased heart rate) side-effects of which are 

particularly harmful in patients who are stressed 

by  a  severe  asthma  attack.  Inhaled  doses  of 

terbutaline  eight  times  the  normally  recom-

mended maximum have been used to achieve 

greater bronchodilatation, with no increase in 

side-effects.

The    selective    beta2-agonists    are    not 

completely  receptor-specific  and  so  do  have 

some predictable side-effects (e.g. central stimu-

lation   and   insomnia,   headache,   peripheral 

vasodilatation  and  tachycardia),  especially  if 

they are inhaled excessively (e.g. with nebu-

lisers) or taken orally. Tremors, usually a fine 

hand tremor (caused by direct stimulation of 

beta2-receptors in skeletal muscle), are common 

and are a significant problem in a minority of 

patients. A very small proportion of patients may 

experience   paradoxical   bronchospasm   with 

inhaled bronchodilators, possibly due to direct 

bronchial irritation. Although it is very rare, 

perhaps as low as one in 50 million doses, this 

possibility should be borne in mind. Because of 

the adverse cardiac effects of the oral use of these 

drugs, inhaled forms (which use lower doses) are 

always preferred, especially if there is evidence of 

cardiac disease.

The beta2-agonists, especially in high doses, 

are known to cause serious hypokalaemia by 

increasing   cellular   potassium   uptake(see 

Chapter 4). This effect is potentiated by hypoxia 

and concomitant treatment with methylxan-

thines, steroids and diuretics. Life-threatening 

hypokalaemia is fortunately rare, but the poten-

tial is clearly greatest during severe exacerbations 

of asthma when hypoxia and the use of drug 

combinations occur concurrently. Serum potas-

sium levels should always be monitored during 

severe episodes.

Bronchodilators should be used with caution 

in patients with hyperthyroidism (because they 

exert  many  of  the  symptoms  just  described), 

or  with  cardiovascular  problems  and  in  the

 elderly.  The  beta2-agonists  tend  to  aggravate 

hypoxaemia  in  severe  asthma,  so  nebulizer 

therapy with oxygen as the driving gas may be 

the  preferred  mode  of  administration  in  this 

situation.

As usual, they should be used with care in 

pregnancy,  but  the  benefits  of  good  asthma control   outweigh   any   slightly   detrimental cardiovascular effects on the mother or fetus. 

Beta2-agonists are used by inhalation (to mini-

mize effects on the fetus), to control premature uterine contractions in the last trimester; oxygen must  be  given  to  counter  the  possibility  of maternal and fetal hypoxia.

Antimuscarinic agents

Mode of action

Antimuscarinic drugs are competitive inhibitors 

of  acetylcholine  at  muscarinic  receptors,  of 

which there are several subtypes. M1  receptors 

are present in ganglia in the airways walls and 

M3  receptors in airways smooth muscle. Ipra-

tropium  and  oxitropium  block  the  uptake  of 

acetylcholine at both of these receptor types, 

reducing muscle tone and producing dilatation 

of both larger and small airways. They do not 

affect  M2 receptors,  which  are  widespread 

elsewhere in the body.

UseSide-effects

Although  anticholinergics  were  used  widelyThere are few significant problems. Nebulized

in  the  past  in  the  form  of  belladonna  or 

hyoscyamus galenicals, and more recently as 

atropine, they were largely abandoned because of 

widespread  antimuscarinic  adverse  reactions. 

However,  inhaled  ipratropium  and  tiotropium 

bromides are useful because they appear to be 

fairly specific for lung tissue and are virtually 

without side-effects. This results from their poor 

absorption, a consequence of their highly polar, 

quaternary ammonium structure. Because they 

do not penetrate mucous membranes they do 

not   reduce   mucus   secretion,   although   an 

antimuscarinic agent should theoretically do so, 

and there is no convincing evidence that any of 

these drugs, including atropine, affect sputum 

volume or viscosity. Further, they do not inter-

fere with mucociliary clearance, so mucus is 

cleared normally.

The antimuscarinics seem to show some syner-

gism  with  beta2-adrenergic  bronchodilators, 

enhancing   and   prolonging   their   activity, 

although this has been disputed. This discrep-

ancy seems to have been resolved by a survey of 

schoolchildren  and  adolescents,  which  found 

little support for using the combination routinely 

and  for  mild  to  moderate  exacerbations  of 

asthma. However, the addition of multiple doses 

of an antimuscarinic to beta2-agonist inhalations 

improved lung function and reduced hospital 

admission in severe exacerbations.

Antimuscarinics   are   particularly   useful   in 

older, chronic asthmatics in whom responsive-

ness to beta2-agonists tends to decline progres-

sively   from   age 40,   probably   owing   to   a 

reduction in the number of bronchiolar beta-

receptors. They are more useful in the treatment 

of COPD (p. 326) and the long-acting tiotropium 

is licensed in the UK only for this purpose. 

However, there is a special problem in this older 

group of patients (see below).

Ipratropium bromide has a slightly slower onset 

of action (30-60 min, peak effect at 90-120 min) 

and a slightly longer duration of action than the 

beta2-agonists and so is normally used three 

times  daily,  for  prophylaxis  only.  The  long-

acting agent tiotropium is used only once daily, 

given by a DPI, usually for the maintenance 

treatment of COPD.

ipratropium  bromide  occasionally  causes  para-

doxical    bronchospasm    although    isotonic, 

preservative-free formulations have been intro-

duced to minimize this risk. Even so, this form of 

treatment should be initiated only in hospital 

with  careful  supervision  for  the  first  week, 

though this should not be a problem if it is 

added to a regimen comprising an SABA.

Although ipratropium is poorly absorbed topi-

cally, it sometimes causes dry mouth, headache 

and constipation and (rarely) urinary retention. 

It may also cause acute angle closure glaucoma 

in the elderly when used by nebulization, as a 

result of escape of drug aerosol and direct eye 

contact. This occurs especially in conjunction 

with salbutamol, and probably also with other 

SABAs.   Thus   nebulized   ipratropium   bromide 

should be used with care in glaucoma patients 

and in the elderly, and precautions must always 

be  taken  to  prevent  escape  of  aerosol  from 

masks, which should fit closely: mouthpieces are 

preferable.  The  occasional  patient  may  react 

adversely to the bromide radical.

Tiotropium  has  similar  side-effects  to  ipra-

tropium and may also cause candidiasis, pharyn-

gitis  and  sinusitis.  It  is  not  suitable  for  the 

treatment of acute bronchospasm and is used for 

the  treatment  of  moderate  to  severe  COPD 

(Table 5.22).

Methylxanthine bronchodilators

Mode of action

Theophylline is the most potent of these agents. 

For many years it was thought to act solely as a 

cyclic  nucleotide  phosphodiesterase  inhibitor 

(PDI), thus increasing the levels of cyclic 3 ,5 -

adenosine monophosphate (cAMP) in cells and 

causing airways relaxation. However, relaxation 

of the airways occurs in vitro at concentrations 

that have no effect on cellular cAMP levels. Also, 

several PDIs that are more potent than theo-

phylline provide no significant benefit in asthma.

However, theophylline is now known to have other actions:

•  Antagonism of receptor-mediated adenosine-

induced bronchospasm.

•  Direct effects on intracellular Ca2÷ concentra-

tion and indirect effects via cell membrane

hyperpolarization.

•  Uncoupling of intracellular Ca2÷ concentration 

from muscular contraction.

Thus, despite some 150 years of use the precise 

mode of action of the methylxanthines remains 

obscure.   Other   possible   actions   have   been 

suggested, e.g. increased mucociliary clearance, 

inhibition of mediator release, central stimula-

tion of ventilation and improved contractility of 

the respiratory muscles. However, it is doubtful 

whether  these  can  contribute  materially  to 

the observed increases in FEV1  or PEF. Recent 

evidence suggests that theophylline also has anti-

inflammatory,  immunomodulatory  and  bron-

choprotective effects that may contribute to its 

usefulness as an asthma prophylactic.

There is evidence that cAMP modulation of intracellular calcium levels may be a common pathway for bronchodilatation, however caused, and it is interesting that beta2-agonists share this effect. The action of theophylline  to mobilize intracellular calcium as referred to above may prove to be its principal effect.

Use

Theophylline(1,3-dimethylxanthine)   itself   is 

relatively   insoluble   but   is   well   absorbed 

(although slowly) from solutions, capsules and 

uncoated  tablets,  with  peak  concentrations 

occurring  after 1-2 h.  However,  clearance  is 

very  variable (see  below).  Thus  microfined, 

slow-release oral formulations have been intro-

duced  that  provide  therapeutic  blood  levels 

which  persist  over  approximately  12 h.  These 

slow-release forms are used for prophylaxis and 

are  taken  once  or  twice  daily.  Because  peak 

blood levels tend to occur after about 8 h, the 

evening dose should be taken at about 8 p.m. 

to  minimize  morning  dipping.  Methylxan-

thines  should  not  be  used  unless  the  patient 

has failed to respond adequately to high-dose 

inhaled corticosteroids.

Theophylline, when combined with ethylenedi-

amine as aminophylline, is much more soluble 

and in this form is used parenterally, preferably 

as a low-volume IV infusion. However, it is very 

irritant.

Asthma317

Side-effects

Theophylline  can  cause  numerous  side-effects 

[e.g.   central   nervous (headache,   irritability, 

insomnia)   and   gastrointestinal (nausea   and 

vomiting)],  even  when  its  serum  levels  are 

within   the   therapeutic   range (10-20 mg/L). 

Above  this  level  serious  CNS  reactions  can 

occur, e.g. seizures, encephalopathy, coma, even 

death,  and  convulsions  may  occur  without 

warning   signs,   especially   if   the   patient   is 

hypoxic,  because  cerebral  hypoxia  is  exacer-

bated. Because the side-effects of methylxan-

thines and beta2-agonists are additive, and both 

cause  hypoxaemia  and  are  frequently  used 

together, the risk of convulsions is increased 

with this combination.

A   similar   situation   occurs   due   to   the hypokalaemic effect. Hypoxaemia, SABAs and corticosteroids all cause hypokalaemia and theo-

phylline is usually added to a regimen containing these. Thus the UK’s CSM advises that blood potassium levels should always be monitored in severe asthma attacks.

Theophylline has been considered suitable for use in pregnancy. However, it needs especially careful   therapeutic   drug   level   monitoring because blood levels are affected by the stage of pregnancy and by delivery.

Aminophylline is more irritant than theophylline 

by all routes. Even normal therapeutic oral doses 

may cause nausea and vomiting, although this is 

less  likely  with  the  modern  modified-release 

products.   Suppositories   may   cause   proctitis. 

When given intravenously, aminophylline is best 

given as a very slow or continuous IV infusion, 

because venous irritation may cause phlebitis 

and rapid bolus injections may cause cardiac 

arrhythmias,    profound    hypotension    and 

hypokalaemia,  resembling  an  acute  overdose 

situation. A very few patients may be hypersen-

sitive to the ethylenediamine component. In 

emergency  situations  in  the  community,  it 

may be given as a very slow bolus IV injection 

over 20 min.  However,  it  is  best  given  as  a 

small-volume   IV   infusion,   if   circumstances 

permit.

Toxicity and therapeutic levels of theophylline 

and aminophylline.   The therapeutic range of 

theophylline is rather narrow, and non-pulmonary 

side-effects may occur at plasma concentrationsnot known whether levels in the therapeutic

below 10 mg/L. Thus, it is preferable to institute 

treatment with plasma level monitoring, espe-

cially if the patient has been taking an oral form 

and receives IV treatment in an emergency or if 

there is any evidence of theophylline toxicity (see 

below) or hepatic impairment. Blood samples 

must be taken at steady state: approximately 

4-6 h after the start of an infusion and 8-12 h 

after an oral dose of a modified-release product. 

Theophylline  is primarily cleared by the liver, 

only 10% of a dose being excreted renally, so 

renal impairment should not affect blood levels 

significantly unless there is renal failure in a 

patient whose blood level is approaching toxi-

city. Regrettably, many patients in the commu-

nity are given slow-release oral preparations on a 

standard dosage regimen and, because absorp-

tion may be erratic and metabolism variable, it is 

range are achieved: an appreciable proportion 

has   sub-therapeutic   blood   concentrations. 

However,  some  benefit  may  be  achieved  at 

concentrations   below10 mg/L,   so   patient 

response   must   guide   low-dose   regimens.   A 

summary   of   the   factors   that   influence 

theophylline serum levels is given in Table 5.16.

Because of the variations in patient response 

to the different formulations, modified-release 

forms from different manufacturers should not 

be changed without careful clinical and blood 

level monitoring. The brand of product should 

be stated on prescriptions. In emergency admis-

sions, hospital A&E doctors must be informed if 

patients are taking an oral theophylline product, 

in which case the usual parenteral loading dose 

of  aminophylline  should  be  omitted  to  avoid 

serious toxicity. In the absence of blood level monitoring, not more than four 250-mg doses should be given in 24 h. If therapeutic drug 

monitoring  is  available,  an  infusion  rate  of 500 lg/kg/h is appropriate for maintenance in 

adults. To avoid overdosage in obese patients, doses should be calculated on the basis of the ideal weight for height.

Despite their potential toxicity, methylxan-

thines have been widely used as the drugs of first choice in North America. However, they are used less frequently now and have been supplanted by the inhaled long-acting beta2-agonists and 

corticosteroids. Nevertheless, there is a subgroup of  patients  who  seem  to  respond  better  to theophylline than to other drugs.

Other  xanthine  derivatives  are  used  in  the 

USA  and  continental  Europe.  Enprofylline (3-

propylxanthine)   is   a   soluble,   well-absorbed, 

potent  compound  that  does  not  yield  theo-

phylline on metabolism and does not have many 

of its side-effects. Further, because it is excreted 

unchanged  via  the  kidneys,  it  does  not  have 

the complex pharmacokinetics and interactions 

of   theophylline.  However,  it  tends  to  cause 

headaches. Diprophylline (dyphylline, dihydroxy-

propyltheophylline)   has   similar   kinetic   and 

toxic  properties  to  enprofylline  and  is  better 

tolerated than theophylline or aminophylline.

Glucocorticosteroids

These are the most potent anti-inflammatory 

drugs available and thus are used extensively in 

the treatment of asthma and other respiratory

 Asthma319

diseases  (Table  5.17).  They  are  life-saving  in 

severe asthma attacks and may modify disease 

progression   in   intractable,   infiltrative   lung 

diseases, e.g. rheumatoid lung disease, SLE and 

polyarteritis nodosa (PAN; see Chapter 12).

Mode of action

These agents are presumed to diffuse passively 

into cells, bind to a specific receptor protein and 

finally stimulate the synthesis of lipocortin. The 

latter  inhibits  phospholipase  A2 and  in  turn 

the  synthesis  of  PG  and  LT  mediators  from 

macrophages, monocytes and mast cells. The 

formation and release of potent inflammatory 

cytokines interleukin 1 (IL-1), IL-2, IL-3, IL-6, 

TNFa, interferon (IFN) gamma and the produc-

tion of complement (C3) acute phase reactants 

are also blocked (see Chapter 2).

Thus,  steroids  inhibit  the  production  and 

release of a number of pro-inflammatory agents 

from a variety of immune and inflammatory 

cells, e.g. vasoactive and chemoattractive factors, 

lipolytic and proteolytic enzymes. Additionally, 

the extravasation of lymphocytes, fibrosis and 

production of PAF (an important inflammatory 

mediator) and IgE are also reduced. These actions 

combine to reduce inflammatory damage in the 

airways and hyper-reactivity.

Use

Inhalation   therapy.   For   the   treatment   of 

asthma,  corticosteroids (beclometasone,  budes-

onide and fluticasone, all available in pMDIs and 

DPIs; see p. 349) are preferably given by inhala-until symptoms have remitted) may be needed

tion. Mometasone is available as a dry powder inhalation. Ciclesonide is a new long-acting agent and is given as a single daily pMDI dose. They are used prophylactically only, being particularly useful in controlling the delayed inflammatory response (see Figure 5.14).

It may take 7-14 days or more to obtain the 

maximal therapeutic response so a single dose 

will not control an attack and they cannot be 

used as rescue medication (but see below). Since 

the   fundamentally   inflammatory   nature   of 

asthma has been recognized, inhaled cortico-

steroids are introduced at an early stage, for 

example if:

•  there  are  significant  nocturnal  symptoms, 

causing waking on more than one night per

week;

•  there are three or more wheezy episodes per 

week;

•  short-acting bronchodilators are used more 

than two to three times weekly;

•  there   has   been   a   moderate   to   severe 

exacerbation of asthma in the last 2 years.

However, many patients, and some doctors, are 

reluctant to use these valuable agents because 

of   unjustified   fears   of   serious   side-effects, 

arising from experience with oral corticosteroids. 

The   approximate   relative   anti-inflammatory 

potencies of these drugs are given in Table 5.18.

The dose requirement varies widely between 

patients  and  in  any  one  patient  over  a  long 

period.  Although  a  high  dose  (e.g.  40-50 mg 

prednisolone orally daily in adults for 5 days or

initially  to  control  symptoms,  it  may  be 

possible to reduce the dose substantially once 

symptoms  are  well  controlled.  Gradual  step-

down is not necessary after the short periods 

used  to  treat  exacerbations  of  asthma,  but  is 

needed  if  treatment  has  lasted  more  than  21 

days,  especially  in  COPD.  Once  stabilized, 

short-term dose increases can be instituted by 

the patient (under an agreed protocol) to treat 

exacerbations.

Even if it is decided to give an oral cortico-

steroid,  a  high-dose  corticosteroid  inhalation 

and other anti-asthmatic medication should be 

continued to spare the corticosteroid dose. A 

beclometasone or budesonide inhaler, used with a 

spacer and face mask (p. 352), may be particu-

larly suitable for young children who are unable 

to use a pMDI, which delivers only about one-

tenth of the oral dose required to give a compa-

rable effect, so only minor local and systemic 

side-effects occur (see below).

Oral use: maintenance therapy.   Prednisolone 

and   comparable   agents (e.g.   betamethasone, 

deflazacort,   dexamethasone,   methylprednisolone, 

etc.; see Table 5.18) may be taken orally as a last 

resort in chronic (intrinsic) asthma and may be 

the only practicable means of controlling symp-

toms adequately. However, as usual, dosage must 

be kept to a minimum to avoid their well-known 

long-term side-effects as far as possible.

Oral    use:    aborting    exacerbations.   The 

prompt  use  of  glucocorticosteroids  may  be invaluable in aborting a severe asthma attack 

that occurs against a background of worsening 

symptoms  and  decreased  response  to  bron-

chodilators (see above). However, the full anti-

inflammatory effects of this will not be apparent 

for some days and these agents should not be 

confused with the use of beta2-agonists or other 

short-acting drugs used for rescue therapy. Doses 

equivalent to 40-50 mg or more of prednisolone 

daily (Table 5.18)  may  be  required  for  about

5 days initially in adults, depending on the 

severity of symptoms. When the patient has 

been stabilized, the dose may be reduced (see 

Tables 5.13  and 5.14),  but  it  is  essential  to 

continue treatment until it is clear that dose 

reduction does not lead to relapse. Peak flow 

monitoring, or FEV1 if available, should be main-

tained during and after the treatment of exacer-

bations  to  ensure  adequate  control  and  the 

absence of deterioration. There is evidence that 

some patients are relatively steroid-resistant and 

that this is a reflection of a generalized tissue 

resistance to steroids, and is not confined to the 

lungs.

Alternate-day dosing, which is often used in 

other situations to minimize steroid side-effects, 

especially adrenal suppression, is usually unsuit-

able in asthma because patients tend to deterio-

rate on the corticosteroid-free day. As usual, dose 

reduction must always be gradual after more 

than  21 days  of  corticosteroid  use  to  permit 

recovery  from  adrenal  suppression  and  the 

resumption  of  adequate  endogenous  cortisol 

secretion. However, it is rare for asthma patients 

to require prolonged ‘rescue’ therapy. It is more 

common in COPD.

Patients on long-term corticosteroids require 

temporary increases in dose to cover exception-

ally   stressful   situations (e.g.   severe   illness, 

surgery or trauma), for which the body requires 

higher   than   normal   corticosteroid   levels, 

because the normal adrenal response does not 

occur.

Parenteral   use.   In   acute   severe   asthma,

hydrocortisone  (up  to  2 g  daily)  or  methylpred-

nisolone (up to 500 mg daily) is given by slow 

IV infusion, with transfer to oral therapy as the 

patient improves (see Figure 5.17). However, it 

has been suggested that oral dosage of 40 mg

 Asthma321

prednisolone  may  be  equally  effective.  Oral corticosteroids  may  also  be  useful  in  the 

occasional  patient  who  bronchoconstricts  in response to IV hydrocortisone.

Side-effects

Too much emphasis has been placed on the 

harmful side-effects of using steroids in asthma, 

leading  to  an  aversion  on  the  part  of  both 

doctors and patients, and subsequent under-use. 

As usual, the hazards of therapy need to be 

weighed against their undoubted benefits in the 

treatment of this potentially debilitating and 

occasionally life-threatening disease. It is clearly 

important to use minimal doses. This discussion 

deals primarily with the side-effects of inhaled 

corticosteroids.   Those   occurring   with   oral 

administration are discussed in connection with 

rheumatoid disease (see Chapter 12).

Inhaled steroids usually cause very few, minor 

adverse reactions, the most common being mild 

throat  irritation  and  hoarseness (dysphonia). 

The  oral  deposition  of  drug  may  sometimes 

cause oral thrush (candidiasis). These effects can 

largely be prevented by twice-daily administra-

tion, which is as effective as the same total dose 

given four times daily, by rinsing the mouth 

with water (or a mouthwash if preferred) or 

brushing the teeth after using the inhaler, and 

using a spacer device (p. 352). If thrush does 

occur,   it   is   readily   controlled   with   topical 

nystatin, amphotericin or an imidazole, e.g. keto-

conazole or miconazole. If these prove inadequate 

to control the candidiasis, or if topical treat-

ments are not suitable (e.g. if saliva production is 

poor), a triazole (e.g. fluconazole) may be given 

orally. The triazoles are best reserved for resistant 

infections (see Chapter 8).

Although adverse systemic effects are unlikely 

unless the daily dose exceeds 1500-2000 lg of 

inhaled BDP or equivalent, osteoporosis, dermal 

thinning and, in children, growth retardation 

may occur. Toothbrushes have been reported to 

be reservoirs of Candida  infection in patients 

using inhaled corticosteroids: patients should be 

advised  to  change  their  toothbrush  if  they 

develop hoarseness or a significant sore throat or 

mouth during treatment.

Long-term research in Scotland has shown 

that side-effects on the height and weight of 

children are significant only in those on Step 3Mode of action 

of the BTS’s treatment protocol (see Tables 5.13 

and 5.14). This effect was less than the effects of 

social deprivation, and independent of them. 

The risks are small and although there may be 

some retardation of growth velocity with normal 

doses, this does not appear to affect the ultimate 

adult height. However, growth is also affected by 

the severity of asthma and the degree of control, 

so it may be necessary to accept some drug-

related   growth   retardation   to   prevent   that 

arising from severe disease.

Nebulized steroids given with a face mask may 

cause facial eczema and, if this treatment mode 

is used over a long period, unacceptable skin 

damage may occur. This may be prevented by 

coating  the  skin  under  the  mask  with  soft 

paraffin and washing the face thoroughly imme-

diately after dosing. Masks should fit closely, or a 

mouthpiece may be preferred. Rarely, a patient 

may be sensitive to the drug or the propellant of 

a pMDI.

Chronic oral therapy may lead to the well-

known side-effects of these drugs (see Chapters

12 and 13), e.g. Cushing’s syndrome, growth 

suppression  in  children,  hypertension,  elec-

trolyte  disturbances  and  immunosuppression, 

though these should be mild if the daily dose 

does not exceed 7.5 mg daily of prednisolone or 

its equivalent (in adults and older children). 

Young children who require chronic oral corti-

costeroids should be supervised by a paediatric 

physician. A few patients may become steroid-

dependent  and  rely  on  continuous  therapy, 

relapsing whenever an attempt is made to reduce 

the dose.

Relative   contra-indications   include   hyper-

tension,   obesity,   diabetes   mellitus,   peptic ulceration, psoriasis, pregnancy, childhood and intercurrent infection (especially TB).

Anti-allergic drugs: cromones

Considerable  attention  has  been  focused  on drugs that prevent the release from leucocytes and mast cells of the pharmacological mediators of bronchospasm and bronchial inflammation. These  include  sodium  cromoglicate (SCG)  and nedocromil sodium (NDCS). 

The mode of action of these drugs is still uncer-

tain, despite intensive research. SCG has been 

regarded as the classic drug, alleged to stabilize 

mast cell membranes, preventing both imme-

diate and delayed degranulation, and so the 

release of mediators of bronchoconstriction. This 

antagonism  occurs  whether  the  stimulus  is 

immunological (IgE) or irritant (due to exercise, 

cold air or inhaled hypertonic saline). The devel-

opment of bronchiolar hyper-responsiveness is 

also blocked by pretreatment with SCG. NDCS is 

a  much  more  potent  inhibitor  of  mediator 

release than is SCG, and also inhibits WBC, 

macrophage and platelet activation. However, 

doubts have been expressed about the impor-

tance of mast cell stabilization, and the true 

mode of action of these drugs in asthma remains 

to be elucidated.

Some stimuli, e.g. sulfur dioxide, are believed 

to produce bronchoconstriction via a neuronal 

mechanism involving the release of the peptide 

neurotransmitter, substance P, at the endings of 

unmyelinated C-fibres. Substance P is a potent 

airways constrictor, the action of which in the 

lungs is also blocked by SCG and NDCS: it is also 

involved in the transmission of pain sensation 

(see Chapter 7). SCG  also affects phosphodi-

esterase   enzyme   levels   and   calcium   influx 

into  cells,  thus  influencing  smooth  muscle 

contraction.

Use

The cromones are not absorbed orally and so 

must  be  administered  by  inhalation.  SCG  is 

particularly useful in exercise-induced asthma in 

children, but rarely in adults. However, exercise-

induced asthma may reveal that control is inad-

equate, so these children should be reassessed. It 

can only be used prophylactically and may take 

up to 4-6 weeks to achieve its full effect.

NDCS has similar properties to SCG but is a 

more potent anti-inflammatory agent. It appears 

to have a wider spectrum of clinical activity and 

is more effective in children aged 6-12 years, 

having a steroid-sparing effect, although it is 

difficult to predict those who will benefit. It may 

be useful in mild to moderate asthma and for 

those patients (and their parents) who are fearful 

of using corticosteroids. However, it is less effec- tive  than  corticosteroids  and  should  not  be regarded as a replacement for them, so it is used only rarely.

Side-effects

SCG  is a very safe drug, the most common 

adverse reaction being a transient bronchospasm 

from the DPI presentation, although the pMDI 

form avoids this problem and is cheaper. If a 

patient cannot use the DPI, a beta2-adrenergic 

bronchodilator may be inhaled beforehand.

NDCS  tends  to  cause  slightly  more  unde-

sirable   effects   than   SCG,   e.g.   headache, nausea  and  vomiting,  dyspepsia  and  abdom-

inal  pain,  although  these  do  not  normally 

cause  discontinuation  of  treatment.

Biological agents

Leukotriene receptor antagonists (LTRAs)

Mode of action.   The leukotrienes (LTs) are 

straight-chain eicosanoids derived from arachi-

donic acid, and are potent pro-inflammatory 

agents. They are mostly produced from arachi-

donic acid by the phospholipase A2 pathway (see 

Chapters 2 and 12). This pathway is activated by 

a  specific  protein, 5-lipoxygenase  activating 

protein (FLAP), which binds the enzyme to the 

cell membrane.

Leukotriene  B4  (LTB4)  is  derived  from  the 

labile intermediate LTA4 and is mostly produced 

by neutrophils. It is a potent neutrophil chemo-

tactic agent. However, the role of neutrophils in 

asthma is controversial because they are only 

found in the lungs in appreciable numbers in 

patients   with   some   types   of   occupational 

asthma.  Although  eosinophils  are  present  in 

increased numbers in the lungs of asthmatic 

patients, LTB4  probably plays only a minor role 

in eosinophil recruitment. It has only a weak 

effect on eosinophils, with other chemoattrac-

tants (e.g. PAF, IL-2, IL-5) being much more 

potent.

LTA4  is  also  converted  into  the  cysteinyl 

leukotrienes  LTC4,  LTE4  and  LTF4,  initially  by 

conjugation  with  glutathione.  All  of  these 

have been implicated in asthma because they 

are  potent  bronchoconstrictors  and  can  be 

produced  by  a  range  of  effector  cells,  e.g. 

granulocytes  and  monocytes,  mast  cells  and

 Asthma323

macrophages. The LTs have a long persistence in lung tissue and also stimulate mucus secre-

tion, cause mucosal oedema and sensitize the 

airways  to  other  spasmogens.  The  LTC4/D4/E4 mixture  used  to  be  known  as  SRS-A (slow reacting substance of anaphylaxis).

LTs act via at least three distinct receptors, for 

LTB4, LTC4 and LTD4/LTE4, which are blocked by 

the LTRAs. The CysLT1  receptor is activated by 

LTC4/LTD4/LTE4 and  is  also  blocked  by  the 

LTRAs.

There are thus two routes by which LT activity may  be  reduced  in  asthma:  by  preventing 

their formation, inhibiting phospholipase A2, 5-

lipoxygenase,   FLAP   or   LT   synthase,   or   by blocking LT receptors in the lung.

The first 5-lipoxygenase inhibitor, zileuton, is 

licensed in the USA for the prophylaxis and 

treatment of chronic asthma and two LTRAs, 

montelukast  and  zafirlukast,  are  available  in 

the UK.

Use.   These agents are useful adjuncts when 

existing  treatment  with  inhaled  beta-agonists 

and  corticosteroids  fails  to  provide  adequate 

control. They are not substitutes for existing 

treatments,   but   may   have   advantages   over 

corticosteroids  because  they  inhibit  broncho-

constriction induced by exercise and allergens, 

against which corticosteroids are relatively inef-

fective. They are well tolerated, and fit into Step

4 of the BTS and SIGN guidelines for adults and schoolchildren (see Table 5.13) and Step 2 of those for young children (see Table 5.14), i.e. as an adjunct to an inhaled beta2-agonist plus 

an inhaled high-dose corticosteroid, or as an 

alternative if the latter cannot be used.

Because they are oral products they may be of special benefit to patients who have compliance problems with inhaled therapy, e.g. the elderly and mentally or physically handicapped.

Side-effects.   These are usually mild and infre-

quent, but abdominal pain, hypersensitivity and 

skin   reactions   occur.   CNS   stimulation   and 

headache   have   also   been   reported.   Churg-

Strauss  syndrome (asthma,  sinusitis,  rhinitis, 

eosinophilia   and   systemic   vasculitis)   has 

occurred when they are used in combination 

with  corticosteroids  and  patients  should  be 

warned to report any rashes, worsening symp-Oxygen

toms or possible cardiac problems. They thus avoid  the  principal  disadvantage  of  cortico-

steroids  but  have  their  own  problems.  Once again,  a  balance  has  to  be  struck  between benefits and disadvantages.

Zafirlukast has the possible additional problem 

of   severe   hepatic   problems(e.g.   malaise, 

vomiting and jaundice) and patients must be 

warned   to   report   any   of   these   symptoms 

promptly.

Omalizumab

This recombinant, humanized, monoclonal anti-

body combines with IgE (see Chapter 2) and so prevents its allergenic effects.

Use.   It is licensed for use as add-on prophy-

lactic therapy in those who have severe persis-

tent allergic asthma associated with elevated IgE levels (pp. 300, 313) and whose asthma is not controlled satisfactorily with full doses of cortico-

steroids plus an LABA (p. 294), though the status of the latter is in doubt.

Administration is by SC injection every 2 or

4 weeks, in a dose determined by a patient’s IgE level and body weight. It is not recommended for use in children under 12 years of age.

Side-effects.   Omalizumab should be used with 

caution  in  those  who  have  an  autoimmune 

disease,  hepatic  or  renal  impairment  or  are 

pregnant.   Because   it   increases   susceptibility 

and the immune response to helminth infec-

tions, precautions are necessary in areas where 

these are endemic and should be discontinued 

if a helminth infection does not respond to 

treatment. It is contra-indicated if a mother is 

breastfeeding.

Common side-effects include headache and injection  site  reactions.  Gastrointestinal  and CNS reactions, and rashes, pruritus, flushing, photosensitivity  and  influenza-like  symptoms are less common.

Like all injected proteins, the possibility of 

severe allergic reactions on repeated administra-

tion, including anaphylaxis, must be borne in 

mind. There may also be a loss of effectiveness, due to the production of Igs. 

Oxygen may be life-saving in acute severe asthma 

and should be given in these circumstances, 

even if there is no overt cyanosis. Because the 

pure gas causes pulmonary damage and retinal 

fibrosis (retrolental  fibroplasia)  it  is  always 

mixed with air. If there is no history of COPD 

(see below), patients may be given 35% oxygen 

while being transferred to hospital, and up to 

60% may be used for short periods after admis-

sion. The hazards associated with higher concen-

trations   mean   that   artificial   ventilation   by 

intermittent   positive   pressure   ventilation 

(IPPV,  p. 361)  is  preferable.  Concentrations 

greater than 28% are not suitable for chronic 

bronchitics with type 2 respiratory failure (see

p. 347).

If alveolar ventilation is inadequate in a seri-

ously ill patient, both PaO2  and PaCO2  may be 

reduced initially and patients may be cyanosed 

even when breathing oxygen-enriched air. Later, 

the PaO2  may continue to fall while the PaCO2 

rises, producing respiratory acidosis. This may 

occur very rapidly in children. Any increase in 

PaCO2  is a serious sign in an asthmatic patient. 

Blood gases should be determined initially, and 

if  the  PaO2 is8 kPa,  serial  determinations 

should be made to monitor therapy. The PaO2 

may rise only slowly in these circumstances.

High-flow    oxygen(giving50-60%)   is 

normally given with a suitable mask (see Table

5.27 and p. 361), but if patients are exhausted then NIPPV may be used. The techniques of 

oxygen therapy are discussed on p. 360.

Other drugs

Immunoglobulins  are   sometimes   used   for severe asthma, e.g. in the final step in Tables 5.13 and 5.14 and Figure 5.17.

A number of fixed drug combinations (e.g. a non-selective  sympathomimetic  agent  plus  a methylxanthine)   were   used   before   effective asthma treatments became available, and some of these are still marketed. Most are oral formu-

lations that are not now prescribed in the UK, but if older patients who are already using them find that they give adequate relief there is no 

reason to change that situation. 

Non-selective   bronchodilators  are   rarely prescribed for asthma treatment because of their undesirable   cardiovascular   effects.   Broncho-

dilators  combined  with  sedatives  should  be avoided  because  they  may  cause  respiratory depression   in   patients   whose   ventilatory 

function is already compromised.

The respiratory stimulant doxapram is gener-

ally of no value in asthma and may be harmful: 

it should be used only under expert supervision 

in  hospital.  In  situations  where  it  might  be 

considered  necessary,  artificial  ventilation  is 

preferred, but it may have a limited role in 

community practice to support a patient while 

awaiting transport to a remote hospital.

Antihistamines (H1-blockers) are not useful in 

asthma and do not prevent histamine-induced 

bronchospasm in normal dosage. However, some 

of  the  newer  H1-blockers,  e.g.  azelastine  and 

cetirizine,   have   interesting   anti-inflammatory 

properties, including effects on kinin, LT and PG 

production, and may be the precursors of new 

anti-asthma drugs.

Many   investigational   drugs   are   being 

explored, e.g. alpha-adrenergic receptor antago-

nists, inhibitors of lipocortin and PGs (E series), 

and    potassium    channel    activators(e.g. 

cromakalim).  Intense  research  activity  is  also 

directed  towards  methods  of  modifying  LT 

activity other than by the LTAs. Inhibitors of 5-

lipoxygenase prevent the conversion of arachi-

donic acid to LTB4 and the cysteinyl LTs (C4, D4 

and E4). Thus, future progress is likely to be in 

the more specific control of bronchial inflamma-

tion   and   hyper-reactivity.   Interferons   and 

inhibitors of TNFa  and other cytokines have 

been introduced for the treatment of conditions 

such as rheumatoid diseases (see Chapter 12) 

and skin diseases (see Chapter 13), but for the 

present  the  beta2-agonists  and  corticosteroids 

have a central role in asthma management.

Other allergic lung diseases

Bronchopulmonary aspergillosis

Spores of the mould Aspergillus fumigatus  are 

ubiquitous and sometimes cause infections or

 Other allergic lung diseases325

allergy, resulting in asthmatic attacks, COPD (see below), bronchiectasis and fibrosis. Other species of Aspergillus are occasionally involved.

Extrinsic allergic alveolitis

Although this is a restrictive disease, not obstruc-

tive (see Table 5.4), e.g. ‘farmer’s lung’ and mush-

room worker’s lung, it is convenient to include it 

here. A variety of environmental or occupation 

allergens  may  cause  type  III  hypersensitivity 

reactions that affect the lung parenchyma (Table

5.19). Following an initial exposure to these anti-

gens, subsequent exposure may produce a tran-

sient mild asthmatic type attack followed after 

4-6 h by a 24-h episode of cough and dyspnoea 

with fever, chills, headache, etc. With repeated 

exposure, pulmonary fibrosis and a diffusion 

defect occur and pulmonary function tests then 

show marked respiratory restriction. Diagnosis 

is complicated by the interval between expo-

sure and the onset of symptoms so that the 

connection between them is often not made.

Pulmonary eosinophilia

This term includes a number of conditions in 

which  dyspnoea  and  radiologically  identified lung changes occur, together with a very highover  several  months.  The  disease  is  caused

blood eosinophil count. Asthmatic attacks may also occur. Cases may be due to aspergillosis, drugs (e.g. sulphonamides), intestinal or other parasites and, rarely, PAN (Chapter 12).

Management.   In pulmonary eosinophilia and extrinsic    allergic    alveolitis    this    involves treatment of any infection, antigen avoidance 

and  the  use  of  corticosteroids  to  minimize inflammatory lung changes.

Chronic obstructive pulmonary disease

Introduction

Chronic obstructive pulmonary disease (COPD), 

sometimes known as chronic obstructive lung 

disease (COLD) or chronic obstructive airways 

disease (COAD),  is  the  collective  term  for  a 

number of chronic, slowly progressive condi-

tions,  most  of  which  are  either  caused  by 

tobacco  smoking  or  are  exacerbated  by  it.  It 

has supplanted the term ‘chronic bronchitis’. 

The conditions produce widespread, persistent 

airways obstruction that is largely irreversible 

but   somewhat   amenable   to   inhaled   bron-

chodilator   and   corticosteroid   therapy.   The 

conditions are the result of chronic inflamma-

tion and recurrent infection of the airways, and 

cause dyspnoea and abnormal blood gas levels. 

The  underlying  condition  in  all  of  these  is 

usually COPD or emphysema (or a combination 

of these) but chronic asthma may also present 

similarly. Bronchiectasis and cystic fibrosis are 

less common causes.

Definitions

Members of this group of diseases may occur together. The descriptive definition of the BTS and SIGN guidelines, published in collaboration with NICE (2004), is as follows:

‘Chronic obstructive pulmonary disease (COPD) 

is  characterised  by  airflow  obstruction.  The 

airflow obstruction is usually progressive, not 

fully reversible and does not change markedly

predominately by smoking.’

•Airflow obstruction is defined as a reduced

FEV1  (forced expiratory volume in 1 s), i.e.

80% predicted for a particular patient and a 

reduced FEV1/FVC ratio (where FVC is forced 

vital capacity), such that FEV1/FVC is less 

than 0.70.

•The airway obstruction is due to a combina-

tion of inflammation, mucus secretion and

parenchymal damage.

•The damage is the result of chronic inflam-

mation that differs from that seen in asthma

and which is usually the result of inhaling 

tobacco smoke.

•Significant airflow obstruction may be present

before the individual becomes aware of it.

•COPD  produces  symptoms,  disability  and

impaired quality of life that may respond to

pharmacological  and  other  therapies  that have limited or no impact on the airflow 

obstruction.

•Other   factors,   particularly   occupational

exposures,   may   also   contribute   to   the

development of COPD.

•COPD  is  now  the  preferred  term  for  the

conditions  with  airflow  obstruction  previ-

ously  diagnosed  as  chronic  bronchitis  or emphysema, or a combination of these. There is no single diagnostic test for COPD. Making a diagnosis relies on clinical judgement based on a combination of history, physical exami-

nation and confirmation of the presence of 

airflow obstruction using spirometry.

The term ‘bronchitis’ describes inflammation of the larger airways and should now be restricted to the acute condition (see below).

COPD is usually associated with a chronic 

cough with the production of sputum on most 

days for at least 3 consecutive months of the year 

in at least 2 successive years. This is an epidemi-

ological, symptomatic definition, which enables 

patients to be classified for statistical purposes, 

but a lesser degree or duration of symptoms 

clearly indicates the early stages of the disease.

The  disability  and  impaired  quality  of  life caused by airways obstruction is the principal problem   for   patients   and   occurs   especially during the winter months.

Emphysema    is    permanent    destructive 

enlargement of the lung parenchyma distal to 

the  terminal  bronchioles,  i.e.  the  respiratory bronchioles,  alveolar  ducts  and  alveolar  sacs. This defines a pathological lesion, not a clin-

ical syndrome, which may occur as a separate entity but often accompanies COPD.

Acute bronchitis is occasionally caused by the 

inhalation of irritants but is usually due to viral 

infection accompanied by opportunistic bacte-

rial infections (see Chapter 8). The outstanding 

symptom is cough, initially dry, but becoming 

productive of copious sputum. Young children 

may have a very severe, harsh cough with inspi-

ratory stridor, the condition known as croup. 

Inflammation of the smaller airways (bronchi-

olitis) may also occur in infants, but this should 

settle in 3-4 days, though the cough may persist 

for 2-3 weeks.   Acute   respiratory   distress   in 

young children should always be taken very 

seriously.

A comparison of asthma and COPD is given in Table 5.20.

COPD

Epidemiology and natural history

COPD is much more common in the UK and in 

Eastern Europe than in most developed coun-

tries. It was known in Western Europe as the

 obstructive pulmonary disease327

‘English disease’, a consequence of being the first 

intensively  industrialized  country  at  a  time 

when  the  health  hazards  of  environmental 

pollution and the effects of occupational expo-

sure to airborne dusts and toxins were not appre-

ciated. The overall prevalence of COPD in the 

UK is about 4% in men aged about 50 years, 9% 

at 60 years, 12% at 80 years, but only 3% in 

women.

This sex difference is wholly attributable to 

differences in smoking habits: in fact, the differ-

ence increases with advancing age because of the 

cumulative effects of long-term smoking in men. 

However, changes in smoking habits over the 

past 50 years, with an increasing proportion of 

girls and young women smoking cigarettes, may 

be expected to minimize the difference. These 

prevalence rates are about three times that for 

angina pectoris.

In the 19th and early 20th centuries COPD 

was due to a combination of occupational and 

domestic air pollution, largely from the use of 

coal as the principal fuel, and to poor living 

conditions. However, there has been a switch to 

cigarette smoke as the prime cause of COPD 

since the 1920s introduction of factory-made 

cigarettes.

COPD    is    responsible    for    considerable 

morbidity and time off work, and caused about 

30000 deaths in 1999 in the UK (male:female 

ratio about 5:1). Almost 30% of these deaths 

occur before retirement, although the death rate 

 is declining with reduced smoking in men, lessdence of severe respiratory infections is lower in

air pollution and better treatment.

The disease is characterized by an insidious 

onset, starting with a ‘smoker’s cough’ that is 

usually   disregarded.   Significant   symptoms 

may  not  appear  until  after  some  20  years  or 

more of smoking, by which time there is appre-

ciable irreversible lung damage. There is then 

a progressive  decline  over 10-40 years  with 

increasing  dyspnoea,  exercise  limitation,  diffi-

culty   in   expectoration   and   an   increased 

frequency of alarming, acute infectious exacer-

bations, necessitating hospital admission. Occa-

sionally,  an  acute  respiratory  infection  is 

identified as the trigger for the initial onset of 

overt symptoms.

The prognosis can be related to the degree of exercise limitation: about 40% of patients with significantly reduced walking ability on the flat die within 5 years, usually of heart failure.

Aetiology and histopathology

The  disease  is  multifactorial  in  origin,  but 

prolonged bronchial irritation and damage is the 

major contributor. The prime cause is cigarette 

smoking, and almost all clinical parameters, e.g. 

symptoms, work lost, hospital admissions and 

deaths, correlate with the extent of smoking. The 

death rate from COPD is increased about 10-fold 

for each 15 cigarettes smoked daily and regularly 

in the past. However, the statistic usually used is 

pack years, i.e. (number of cigarettes smoked per 

day20)number of years smoked. Environ-

mental pollution and some occupations (e.g. 

coal mining) potentiate the effect of smoking, 

and the effects of urbanization are very marked 

in smokers. However, the major improvement in 

urban pollution in the last 50 years means that 

there   are   now   only   very   small   effects   in 

non-smokers unless it is extreme.

Climate   plays   a   minor   role,   although 

morbidity is higher in the colder and wetter 

regions in the north and west of the UK, after 

allowing  for  the  effects  of  urbanization.  In 

Australia and New Zealand the age-mortality 

curve is displaced relative to that for the UK to 

higher age groups by about 10-15 years. This 

shift is due primarily to less urban pollution and 

differences in smoking habits. Also, the inci-

the better climate.

A low socioeconomic status predisposes to 

both morbidity and mortality. The mortality in 

Class V (unskilled) is six times that in Class II 

(administrative). This is related to differences in 

smoking  habits,  hygiene,  nutrition,  attitudes 

towards achieving a healthy lifestyle and usage 

of healthcare facilities. Educational and cultural 

differences lead to a lack of awareness in the 

lower socioeconomic groups of the importance 

of symptoms, or disregard of them, the need for 

medical care and the benefits that modern medi-

cine can produce. Similar considerations apply 

to most diseases.

There may be a slight familial tendency predis-

posing to bronchial mucus hypersecretion, but this is heavily outweighed by the effects of the risk factors outlined above. Respiratory infec-

tions have a very small role in causation, though they produce the severe exacerbations seen in the winter months and contribute significantly to the progressive lung damage.

The histological appearance of the lung tissues 

in COPD is illustrated in Figures 5.18 and 5.19.

The outstanding histopathological features in COPD leading to airways obstruction include the following:

•  Increased thickness of the bronchiolar wall 

due to inflammation and hyperplasia of the

mucous glands. The latter represent about 

two-thirds of the bulk of the increased tissue mass compared with one-third of the normal thickness (Figure 5.19).

•  Hypersecretion of mucus from the increased 

number of mucous glands and from irritated

goblet cells.

•  Chronic insult damages the cilia, leading to 

impaired mucociliary clearance, and mucus

plugs  obstruct   the   airways   partially   or completely (Figure 5.18(b)).

•  Numerous mucus-containing inflammatory 

cells (Figure 5.18(b)) and trapped bacteria, the

latter producing the infective exacerbations. 

•  A   modest,   variable   degree   of   broncho-

constriction.

In late-stage disease there is extensive destruc-

tion of the lung parenchyma (see Figure 5.20), 

i.e. emphysema. Fibrosis contributes to obstruc- tion,  reduces  lung  compliance,  increases  the work of breathing and exacerbates dyspnoea, 

especially during passive expiration.

Clinical features

The cardinal early symptoms are as follows:

•‘Smoker’s cough’: initially present on winter

mornings, but later throughout the year.

•  Sputum:   usually   copious   and   tenacious 

(mucoid). It may be yellow, green or khaki-

coloured  (mucopurulent)  during  infective exacerbations, but clear or greyish between the   infective   episodes,   and   occasionally streaked with blood.

•  Dyspnoea:  as  with  all  obstructive  airways 

diseases  expiration  is  the  difficult  phase, 

the spirogram being similar to that shown 

in  Figure  5.15(b)  and  (c).  Wheezing  may occur, especially in the morning.

•  Fever and the usual signs of infection during 

exacerbations.

In mild disease cough may be the only abnor-

mality. Patients with moderate disease also have 

excess sputum, breathlessness (with or without 

wheezing), and a general reduction in breath 

sounds on auscultation (caused by total occlu-

sion of some airways). In late-stage disease there 

is usually breathlessness at rest or on any exer-

tion, together with a prominent wheeze and a

productive cough. The following features may also be present:

•  Cyanosis: if the respiratory deficit is severe; 

frank  central  cyanosis  is  discernible  when

there  is  about  5 g/dL  of  deoxygenated  Hb 

in the blood, i.e. about 30% of the total Hb, 

the   PaO2 being   about 6 kPa (normal

12-13.3 kPa).

•  Heart failure (cor pulmonale, p. 285) and 

peripheral oedema.

•  Plethoric complexion: patients may have a 

high facial colour due to secondary poly- cythaemia (erythrocytosis, a raised red cell 

count), a normal physiological response to 

hypoxaemia, high levels of carbaminohaemo-

globin (carrying  CO2)  and  carboxyhaemo-

globin (carrying CO from incomplete tobacco 

combustion)   that   decreases   the   oxygen-

carrying capacity of the blood. The resultant 

increased blood viscosity causes dilatation of 

the  skin  capillaries,  which  are  filled  with 

blood containing high Hb levels, thus causing 

the high skin colour.

•  Hyperinflation:   a   consequence   of   air 

trapping.

At the extremes, two classic clinical patterns may 

be seen in patients. At one extreme is the type A 

(‘pink puffer’, the ‘emphysemic type’), a thin, 

usually elderly patient with intense dyspnoea, 

pursed lip breathing and rapid shallow respira-

tion, who uses the accessory muscles of respira-

tion. The advantage of pursed lip breathing is 

that it creates a back-pressure in the airways and 

so helps to prevent them from collapse, which 

the  inflamed,  weakened  airways  tend  to  do

under the increased intrathoracic pressure that occurs  in  forced  respiration.  These  patients produce little sputum but have severe airways obstruction with hyperinflation and radiological and spirometric evidence of emphysema. They have good respiratory drive and maintain near-

normal blood gas levels at the expense of being short  of  breath.  Their  thinness  may  reflect weight  loss  due  to  the  energy  required  to 

maintain adequate ventilation.

At the other extreme, the type B patient (‘blue 

bloater’, the ‘bronchitic’ type) is obese, has a 

plethoric complexion and moderate dyspnoea, 

lapsing readily into heart failure and presenting a 

picture of poor respiratory drive. Type B patients 

adjust  to  their  abnormal  blood  gases  at  the 

expense of reduced exercise tolerance, but do not 

experience dyspnoea at rest. There are consider-

able degrees of overlap between these patient 

groups, and their different appearances cannot 

be  used  diagnostically  as  most  patients  show 

elements of both types. The reasons for the occur-

rence of the two physical types are not clear, but 

may represent differences in ventilatory control.

Pulmonary function tests

diseases

Additional   investigations   that   may   aid 

management include:

These show the characteristic changes outlined 

in Table 5.6. If peak flow testing is used, serial 

recordings should be made over a week to show 

the absence of variability. The RV may be normal 

or, later, be somewhat increased by air trapping 

and destruction of lung tissue. However, these 

are not the principal criteria but are aids to 

diagnosis  and  judging  severity.  Diagnosis  is 

based on:

•  Patient over 35 years who smokes regularly, has 

a chronic cough, regular sputum production,

wheezing and frequent winter ‘bronchitis’. 

•  Weight loss (usually), due to increased energy

costs of respiration. Weight gain may occur later, as the result of:

-  exercise limitation (Table 5.5) and effort 

intolerance;

-  fluid retention, with ankle swelling, due to 

the  oedema  of  right  heart  failure (see

Chapter 4).

•  Waking at night with symptoms. •  Fatigue.

•  Occupational respiratory hazards.

Chest pain and haemoptysis are uncommon in COPD and suggest an alternative diagnosis, e.g. lung cancer.

Spirometry results should be used to assist 

diagnosis or to reconsider the diagnosis if there is an exceptionally good response to treatment, which may suggest asthma. The European Respi-

ratory Society has published reference values (see References and further reading, p. 364), but these may lead to underdiagnosis in the elderly and are not applicable to Blacks or Asians.

Testing   the   reversibility   of   symptoms   by 

medication is not usually part of the diagnostic 

procedure because it may be unhelpful (owing to 

poor   reproducibility   or   inconsistency),   mis-

leading (unless the change in FEV1 is400 mL), 

and does not predict outcome. Distinction of 

COPD from asthma is made primarily on clinical 

grounds (Table 5.20).

Other  useful  investigations  include  a  full blood  count,  to  identify  anaemia  or  poly-

cythaemia (see Chapter 11), and a chest X-ray. The body mass index should be calculated (BMI 

weight(height in metres2).

•  Serial domiciliary peak flow measurements. 

•  Alpha1-antitrypsin (AAT) levels, if the condi-

tion is of early onset (  40 years), there is a 

minimal smoking history, or a family history of emphysema (see below).

•  TLCO.

•  CT chest scan, e.g. to detect primary lung 

cancer   or   metastatic   spread   from   other

neoplasms.

•  ECG,  to  assess  cardiac  status  if  there  are 

features of cor pulmonale (see below).

•  Echocardiogram,    to    detect    pulmonary

embolism.

•  Pulse oximetry, to assess the need for oxygen 

therapy.

•  Sputum   culture,   if   the   patient   produces 

persistent  purulent  sputum,  to  determine

appropriate antibiotic treatment.

Breathlessness

This is assessed by the ability to perform specific 

tasks (e.g. stair climbing, walking distance) or to 

manage the activities of everyday living (e.g. 

shopping).

Blood gases

These may be near normal until the later stages 

of the disease. The PaO2 becomes reduced gradu-

ally and this effect becomes more severe during 

sleep,  when  patients  may  snore  heavily  and 

show ‘sleep apnoea’ (i.e. brief, frequent periods 

of failure to breathe during sleep). Although the 

PaCO2 is usually within the normal range in the 

early stages, severely impaired respiratory drive 

may cause the PaCO2  to rise progressively later, 

when patients may be in chronic respiratory 

failure (p. 346).

Chest X-ray

This is usually normal, though in the later stages the heart may be enlarged and there may be 

evidence of emphysema and lung fibrosis.

Sputum microbiology

This is usually performed routinely in hospital. 

Most infections in COPD are due to Haemophilus 

influenzae, Streptococcus pneumoniae and viruses, 

so community treatment is usually initiated on a 

‘best guess’ basis. This may compromise subse-

quent sputum investigation even though the 

patient continues to produce purulent sputum. 

A sputum sample should always be taken before 

initiating antibiotic treatment, following usual 

good practice.

The management of COPD will be discussed with that of emphysema.

Emphysema

When this occurs as part of the COPD syndrome it affects the alveoli closest to the respiratory 

bronchioles.  Emphysema  that  is  not  part  of COPD is uncommon and is more generalized: these patients usually show the clinical pattern of the ‘pink puffer’ group (p. 331).

Aetiology and pathology

The aetiology of emphysema is illustrated in 

Figure 5.21. The principal underlying problem is 

reduced AAT activity. This enzyme is a highly 

polymorphic glycoprotein produced by the liver and alveolar macrophages, especially in chronic 

inflammation. In the lungs, the function of the 

enzyme is to protect the delicate alveolar tissue 

from autodigestion by elastase and other prote-

olytic   enzymes   that   are   produced   to   clear 

inhaled debris and the proteinaceous products of 

inflammation. Smoking produces both increased 

amounts of cell debris and reduced AAT levels, 

and may also cause lung parenchymal damage 

by direct toxicity.

Hereditary  AAT  deficiency  is a rare auto-

somal recessive trait; it may be heterozygous or 

homozygous.  AAT  is  encoded  for  by  the  Pi 

(protein inhibitor) gene on chromosome 14, of 

which more than 90 alleles are known. Disease is 

associated only with those mutations causing 

significant deficiency or greatly impaired func-

tion of the enzyme. The gene defects occur in 

between 1/2000 and 1/7000 European neonates 

and are the most common cause of liver disease 

in infancy and childhood. It is postulated that 

liver disease results, at least partly, from failure to 

clear abnormal forms of AAT. However, some 

further   unknown   genetic   or   environmental 

trigger is required because, although more than 50% of infants with total AAT deficiency haveBecause the damage is irreversible, treatment is

abnormal liver function tests, only about 13% 

develop overt liver disease, usually by the age of

4 months. About 5% of these require liver trans-

plantation by the age of 4 years, but the condi-

tion settles in the remainder, with a reasonable 

quality of life. Some 10% of the group suffer 

from malabsorption of vitamin K and the resul-

tant   kernicterus (bilirubin   encephalopathy) 

causes permanent CNS damage if not treated 

early. A further 1-2% without any history of 

infantile jaundice present later in childhood or 

as adults with liver cirrhosis (see Chapter 3). 

Some develop emphysema as young adults. It 

seems likely that these various manifestations 

are associated with different alleles of the Pi 

gene. Symptoms are twice as common in males 

as in females.

The symptoms of emphysema are accelerated by environmental factors, especially smoking. Most emphysemics are smokers in whom the 

resultant  chronic  inflammation  damages  the alveoli rather than the airways, as in COPD. 

However, there is considerable overlap between emphysema and COPD.

Because lung tissue is destroyed (Figure 5.20), 

the  TLC  is  increased,  at  the  expense  of  an 

increased (unusable) RV, and the area available 

for gas exchange is reduced. The residual alveolar 

walls become thickened and fibrosed, causing a 

diffusion defect.

Diagnosis

Diagnosis of emphysema rests on the evidence of 

obstructive lung disease associated with charac-

teristic radiographic changes, though the latter 

are not always present. Obstruction results from 

weakened,  narrowed,  small (2-mm  diameter) 

airways  that  tend  to  collapse  on  expiration 

(p. 277),  owing  both  to  inflammation  and 

atrophy of their walls and the destruction of 

supporting alveolar tissue. Alveolar destruction 

also  results  in  loss  of  the  elastic  tissue  that 

provides an important proportion of the expira-

tory force at rest. A definitive diagnosis may not 

be made during life and is often reached on inad-

equate evidence. Although any doubt can be 

resolved by bronchoscopic biopsy, this is rarely 

done because it does not influence management.

usually only symptomatic.

Management of COPD

Because most patients have a combination of 

inflammation and AAT deficiency, their treat-

ment is based on similar principles. There is 

unlikely to be a significant reversible element.

Aims

The aims of management of COPD are to:

•  educate the patient about their disease and 

•  prevent deterioration;

•  minimize   the   frequency   and   severity   of 

exacerbations and complications;

•  give the best possible symptomatic relief; •  achieve a reasonable quality of life.

The  ways  in  which  these  are  achieved  are discussed below, and summarized in Tables 5.21 and 5.22.

General measures

General measures in the management of COPD include the following:

•  Education is essential to any programme of 

rehabilitation. In a chronic condition such as

COPD,   patients   need   to   understand   the relevance of the general and pharmacothera-

peutic   measures   and   appreciate   what   is reasonable to expect from management.

•  Stop smoking: this may reduce the risk of

further deterioration substantially, and the 

patient  may  improve  somewhat.  In  long-

standing disease, significant improvement is 

not a realistic objective because irreversible 

damage may mean that the patient’s lung 

function does not improve, merely that the 

decline is slowed or arrested. However, even a 

small improvement in lung function can give 

considerable   subjective   benefit.   Bupropion, 

varenicline  and  nicotine  replacement  therapy 

(NRT)  are  useful  aids.  Patients  should  be 

referred  to  a  smoking  cessation  clinic  for 

behavioural support, if available. The NICE 

guidance is that these drugs should only be 

prescribed via the NHS for those who have 

committed to a target date for smoking cessa-

tion. The initial amount prescribed should be 

sufficient to last only 2 weeks beyond the stop 

date for NRT or 3-4 weeks for bupropion, and a 

second prescription issued only if the patient 

is   making   a   continuing   effort   to   stop 

smoking.  If  the  patient  is  unsuccessful,  a 

further prescription should not normally be 

issued within 6 months. There is currently 

insufficient  evidence  to  justify  the  use  of 

bupropion  and  NRT  together.  Varenicline  is 

started 2 weeks before the target stop date 

and continued for 10 weeks afterwards. The 

treatment may be repeated if necessary.

•  Avoid irritant and dusty environments. 

•  Weight  loss  and  dietary  advice  if  obese,

i.e.  BMI30 kg/m2,  to  reduce  the  oxygen 

demand  and  the  workload  on  the  heart. 

Healthy eating should be encouraged and a

planned exercise programme helps to improve 

cardiac   and   respiratory   function.   Type   A 

patients (p. 331), in whom the respiratory effort 

has caused weight loss, need dietary advice 

and supplements to regain an ideal weight.

•Pulmonary   rehabilitation:   trained   teams

deliver   a   multidisciplinary   approach   to

improving the use of what respiratory func-

tion remains and teach postural drainage. 

For the latter the patient lies face down and 

on each side in turn, and their chest wall, ribs 

and  backs  are  percussed  to  help  dislodge 

secretions. If secretions are very copious or 

tenacious, a head-down position may help.

•Occupational therapy (i.e. aids in the home,

etc.) and social support  (e.g. more appro-

priate  housing  and  transport  to  day  care 

centres) may help severely exercise-limited 

patients to enjoy a reasonable quality of life.

•Influenza   vaccination  annually   in   the

autumn is recommended for all patients with 

chronic respiratory disease, regardless of age. 

Home management

Patients with stable COPD (who are in generally 

good condition, have mild breathlessness and 

are  not  confused)  can  often  be  managed  at 

home, provided they have good social support. 

Other factors favouring home management are

SaO290%, arterial pH7.35 and PaO27 kPa, but these will be determined in hospital.

Pharmacotherapy

A general approach to the management of COPD is given in Tables 5.21 and 5.22. The National Collaborating Centre for Chronic Diseases guide-

lines, published by NICE, set out the treatment of COPD according to symptoms.

Bronchodilatation

There  may  be  an  element  of  reversibility  of 

airways   obstruction,   so   bronchodilators   are 

the cornerstone of therapy. The antimuscarinic 

and corticosteroid treatments used in asthma 

should also be given a controlled trial. The drugs 

should be introduced singly at first, with careful 

supervision  to  ensure  that  there  is  clinical 

improvement, and discontinued if ineffective. 

Respirometry,  which  is  essential  in  asthma, 

is not necessary to demonstrate reversibility in 

COPD.   Even   a   modest   improvement   in 

pulmonary  function  may  give  an  apparently 

disproportionate symptomatic relief in a patient 

with   severely   compromised   lung   function, 

because a small increase in PaO2 greatly improves 

Hb saturation.

The   antimuscarinic   bronchodilators,   ipra-

tropium and tiotropium (p. 315), seem to be as effective as the beta2-agonists and a combina-

tion of a beta2-agonist and an antimuscarinic 

gives somewhat superior results to either used alone, but the benefit may be small.

Corticosteroid therapy and antibiotics

Inhaled corticosteroids should be prescribed to 

patients with an FEV150% predicted, who are 

having more than two exacerbations requiring 

treatment with antibiotics or corticosteroids in a 

12-month period, to reduce exacerbation rates 

and slow the decline in health status. Although 

it  has  been  alleged  that  corticosteroids  are 

overused in COPD, a careful study of nearly 1000

obstructive pulmonary disease337

patients found that inhaled fluticasone reduced the decline in FEV1  by 32% over a 3-year trial period  and  the  exacerbation  rate  by 25%. 

However,  there  is  an  increased  incidence  of bruising and oral candidiasis.

RCTs have indicated clearly that the combina-

tion of a corticosteroid plus an LABA (fluticasone 

plus salmeterol  and budesonide  plus formoterol) 

improve   lung   function   and   quality   of   life 

compared to the individual agents. These results 

were  obtained  in  patients  with  moderately 

severe disease and are applicable to those with 

FEV150% predicted and who have frequent

exacerbations, i.e.3 in the preceding 3 years. However,  the  safety  of  such  treatment  in  a patient group that tends to cardiac failure must be questioned (p. 294).

It is important to remember that a substantial 

response  to  treatment,  especially  to  cortico-

steroids, raises the possibility that some patients 

diagnosed as having COPD have either chronic 

asthma   or   asthma   concurrent   with   COPD. 

This  should  prompt  reassessment,  including 

respirometry.

Oral  corticosteroids  are  also  euphoriant  in 

most patients, so they may feel well despite the 

underlying disease state, and it may be difficult 

to wean them from the drug. However, a propor-

tion of patients feel anxious and/or depressed, 

and this may need conventional treatment (see 

Chapter 6).

Maintenance   treatment   with   oral   cortico-

steroids should be used only when they cannot 

be withdrawn after an exacerbation. As usual, 

the lowest possible dose should be used. Patients 

under 65 years  receiving  oral  corticosteroids 

should be monitored for osteoporosis and given 

prophylactic treatment when indicated by X-ray 

densitometry, using a bisphosphonate, e.g. alen-

dronic acid or risedronate sodium, plus calcium and 

ergocalciferol tablets if they are housebound or 

have   a   poor   diet:   inadequate   exposure   to 

sunlight reduces vitamin D production. Those 

over 65 years taking a corticosteroid long term 

should  be  prescribed  prophylactic  treatment 

routinely.

Although acute exacerbations of COPD are 

due   to   infections,   the   immunosuppressant 

action of steroids does not appear to compro-

mise patients. However, the harmful effects of corticosteroids,   i.e.   bruising,   oropharyngealby at least 50%. Increasing this to 19 h/day more

candidiasis and osteoporosis, must be weighed against their benefits.

Similarly,  trials  of  prophylactic  antibiotics 

conducted some 30 years ago showed a reduced 

frequency   of   exacerbations.   However,   these 

results are unlikely to be applicable to current 

practice   and   routine   prophylactic   antibiotic 

medication is not recommended because the 

benefits are outweighed by the disadvantages, 

notably the selection of resistant organisms (see 

Chapter 8).

Oxygen

Oxygen used for at least 15 h daily (long-term 

oxygen  therapy (LTOT),   p. 361)   improves 

mobility,   relieves   hypoxaemia   and   reduces 

mortality in those with severe hypoxaemia, i.e.

PaO28 kPa, and those who experience hypox-

aemia only at night. Superior results are achieved 

by treatment for 20 h daily. In hospital, IPPV 

(p. 361)  may  be  used  to  assist  respiration. 

However, the oxygen concentration must always 

be carefully controlled because patients become 

unresponsive to their chronically raised carbon 

dioxide levels and depend on hypoxic drive to 

maintain  ventilation (p. 360).  If  the  PaO2 is 

raised excessively by administering oxygen the 

patient may stop breathing completely: the aim 

is to improve the PaO2  somewhat, producing a 

significant  increase  in  Hb  saturation (SaO2), 

without  unduly  increasing  PaCO2 or  exacer-

bating    respiratory    acidosis    and    without 

impairing respiratory drive. The patient’s clinical 

condition and arterial blood gases must be moni-

tored carefully, and the oxygen flow rate adjusted 

to  give  optimal  oxygenation.  However,  such 

careful monitoring is not possible in a commu-

nity setting, where the oxygen flow rate should 

not  exceed 2-4 L/min,  to  give  a  maximum 

concentration of 28% oxygen in the inspired air 

with a suitable mask (p. 361) or nasal prongs. 

Even 24% oxygen  may be excessive for some 

patients, so oxygen therapy should be initiated 

cautiously under careful supervision, preferably 

in hospital.

Evidence from two large trials indicates that 

continuous   prophylactic   oxygen   used   for

15 h/day   in   appropriately   selected   patients 

increases the untreated 5-year survival rate (30%)

than doubled the survival rate without oxygen; use for 12 h/day did not improve survival. Thus in the late stages of the disease, if a patient has cor pulmonale or is in demonstrable respiratory failure,  LTOT  is  indicated.  Oxygen  therapy  is discussed more fully on pp. 360-364.

Treatment of complications

Heart failure.   Cor pulmonale (p. 285) should 

be treated (see also Chapter 4). Venesection 

(removing 500-1000 mL of blood, the old stan-

dard blood-letting treatment) may be used some-

times if polycythaemia causes such an increase 

in  blood  viscosity  that  cardiac  function  is 

compromised,  i.e.  packed  cell  volume (PCV)

56%.

Oxygen  prevents  progression  of  pulmonary hypertension and is the mainstay of therapy. A diuretic is indicated if there is peripheral oedema and a raised JVP. Pulmonary vasodilatation with a beta2-agonist, CCB or alpha-adrenergic blocker may also be helpful.

Respiratoryacidosisconsequent     on 

hypercapnia  must  be  treated  promptly (see 

Chapter 14).

Cough

Steam inhalations may assist expectoration by dilution of mucus, but there is no evidence that ‘expectorants’ can materially assist expectoration, so they are primarily placebos.

Mucolytics,  e.g.  carbocisteine  or  mecysteine 

hydrochloride,  may  reduce  the  frequency  and 

duration of exacerbations, but the evidence for 

this is not strong, though some patients may 

obtain  subjective  relief.  This  issue  is  being 

addressed in a large multicentre European trial. 

It has been suggested that the benefits of the 

mucolytics are due to their antioxidant proper-

ties rather than their effects on mucus. However, 

mucolytics may damage the gastric mucosa, and 

must be used carefully if there is a history of 

peptic ulceration (see Chapter 3).

Short-term use of dornase alfa (rhDNase, phos-

phorylated  glycosylated  recombinant  human deoxyribonuclease 1) to reduce sputum viscosity was not beneficial.

Cough suppressants should not normally be 

used because, although effective, they may cause 

respiratory depression. However, a few patients have a troublesome unproductive night cough and this may need to be controlled.

Prophylaxis

Pneumococcal    vaccination    and    annual 

influenza vaccination should be offered to all 

patients, to reduce the frequency of exacerba-

tions. Annual pneumococcal revaccination is not 

indicated because of sustained protection and the 

possibility of adverse reactions, but patients with 

splenetic dysfunction, nephrotic syndrome (see 

Chapter 14),  or  who  have  had  their  spleen 

removed need revaccination every 5 years.

Acute infective exacerbations

Infections may be bacterial or viral in origin (see 

Chapter 8) and should be treated aggressively at 

the first signs, especially if purulent sputum is 

present, but it is important to take a sputum 

sample for laboratory analysis before starting 

blind treatment because a significant proportion 

of bacterial strains are antibiotic-resistant.

Broad-spectrum   antibiotics  for   empirical 

treatment (e.g. amoxicillin, trimethoprim, tetracy-

clines or a macrolide) are chosen based on local 

sensitivity data. They are those usually active 

against  the  most  likely  bacterial  pathogens, 

often pneumococci, Haemophilus influenzae  or 

Moraxella catarrhalis. Ciprofloxacin is present in 

high concentrations in bronchial secretions, but 

it is not clear whether this translates into addi-

tional benefit. However, it has limited activity 

against pneumococci and numerous side-effects 

(see Chapter 8) and is not usually appropriate for 

first-line empirical treatment.

Oral  corticosteroids  (e.g.  30 mg/day  pred-

nisolone for 1 week) may be appropriate if the 

patient  is  known  to  respond  to  them  or  is 

already being maintained on a lower steroid 

dose, if there is no response to a bronchodilator 

or if this is the first presentation of increased 

airflow obstruction.

Some patients whose microbial status is well 

established can have a reserve supply of anti-

biotics and corticosteroids available to start on 

their own initiative when they notice the first 

signs that usually presage deterioration in their 

condition. However, they should subsequently 

see their doctor as soon as possible. In such situ-

obstructive pulmonary disease339

ations, either a bronchodilator may be added if it is not already being used, or the dose may be 

increased after first checking inhaler technique (see Table 5.26).

Oxygen therapy (p. 360) may be required if it is not already being used. Respiratory failure 

may need to be managed in hospital by IPPV or NIPPV (p. 361). Respiratory stimulants are used occasionally (e.g. doxapram, only in hospital), to tide  patients  over  a  bout  of  hypoventilation while other treatments are pursued.

When the patient has recovered sufficiently 

they should have a full medication review. If 

hospital treatment was required there should 

also  be  detailed  consideration  of  social  and 

financial   circumstances   when   planning   for 

discharge.

Pure emphysema uncomplicated by an appre-

ciable  element  of  COPD  is  uncommon,  and 

patients primarily require oxygen because they 

are very breathless. Oxygen therapy will depend 

on the condition of the patient, and the ‘pink 

puffer’ type, with relatively normal blood gases, 

will tolerate higher oxygen concentrations than 

those   with   a   poor   respiratory   drive   and 

hypercapnia (PaCO29 kPa).  Management  is 

otherwise as for COPD.

Natural AAT prepared from pooled plasma is available in the USA and has been given intra-

venously  weekly,  though  there  is  little  good evidence of benefit. Recombinant human AAT is in  development.  Inhalation  of  AAT  is  under investigation. However, the use of AAT replace-

ment therapy is not supported by the evidence and is not recommended currently.

Other   experimental   treatments   for   AAT deficiency include:

•  All-trans retinoic acid (see Chapter13). 

•  Inhalation of hyaluronidase, as a mucolytic. 

•  Vitamins A, C and E, to prevent oxidation of

AAT, but the evidence for this is poor. 

•  Stem cell therapy and gene therapy are being

explored, and may become feasible in the 

future.

Lung  surgery.   Rarely,  the  eradication  of  a 

single giant bulla (air space) in the lungs may 

relieve symptoms by relieving the compression 

of surrounding lung tissue. Patients who are still 

breathless, with marked restriction in the activi-Clinical features

ties of daily living despite maximal pharma-

cotherapy  and  pulmonary  rehabilitation,  are 

candidates for lung volume surgery. This helps 

by reducing dead space (see p. 278) and so the 

volume of air that has to be moved in each 

breath. They need to meet all of the following 

criteria:

•  FEV120% predicted.

•  PaCO27.3 kPa.

•  Emphysema primarily confined to the upper 

lobes.

•  TLCO20% predicted.

Some patients with severe COPD, who do not have significant comorbidity, may be candidates for lung transplantation.

However,   many   patients   present   with 

advanced   disease   that   is   not   amenable   to treatment.

Bronchiectasis

Definition and epidemiology

This is abnormal dilatation of the bronchi, their 

walls becoming inflamed, thickened and irre-

versibly damaged. It often follows pneumonia or 

other  severe  bacterial  lower  respiratory  tract 

infection, which may start in childhood as a 

sequel to measles or whooping cough. There is 

impaired  mucociliary  clearance,  and  chronic 

local inflammation. Recurrent pyogenic infec-

tions cause massive mucus hypersecretion and 

airways obstruction.

Trapping of pus in the airways may also occur 

in cystic fibrosis and bronchial carcinoma and 

may   cause   similar   damage.   Bronchiectasis 

may also accompany COPD and, occasionally, 

asthma.

The disease is much less common in devel-

oped countries now that effective antibiotics are 

available, cystic fibrosis being the most common 

cause. Bronchiectasis persists in the Third World 

and in areas where natural disasters or wars 

disrupt   social   and   political   structures   and 

medical services.

These vary greatly, depending on the severity of 

the disease, but the principal features include:

•  chronic cough, often productive of copious 

purulent sputum;

•  a variable degree of haemoptysis; •  breathlessness;

•  febrile  episodes  associated  with  infection, 

sometimes pneumonia;

•  anorexia and weight loss; •  night sweats;

•  finger clubbing (Figure 5.7) in the later stages 

if there is persistent infection;

•  immunodeficiency in about 10% of patients.

Investigation

Investigations of bronchiectasis include:

•  chest and sinus X-rays;

•  high-resolution CT chest scanning; 

•  sputum   culture   and   antibiotic   sensitivity

•  serum Igs.

Occasionally bronchoscopy, sweat sodium levels (increased  in  cystic  fibrosis)  and  a  test  for mucociliary clearance are also required.

Management

The aims of management are to improve respira-

tory  function  and  prevent  deterioration  by 

eradicating   infection,   if   possible.   Treatment 

includes:

•  Postural drainage of sputum (p. 335). 

•  Bronchodilators to improve airflow.

•  Corticosteroids (inhaled or oral), to reduce

inflammation and slow disease progression. 

•  Antibiotics: selection depends on local policy

and   previous   experience   in   the   patient. 

Common practice is to use the same agents as 

are indicated for exacerbations of COPD or 

pneumonia (see Chapter 8), and flucloxacillin 

if Staphylococcus aureus is isolated. Other IV or 

inhaled  antibiotics  are  used  according  to 

organism   sensitivity.   Inhaled   antibiotics may be used for prophylaxis, especially for Pseudomonas   aeruginosa,   but   specific   IV antipseudomonal antibiotics are required for significant exacerbations.

•  Heart/lung transplantation in rare cases.

Cystic fibrosis

Epidemiology and pathology

This  is  the  commonest  autosomal  recessive 

disorder, the carrier frequency being 1 in 22 in 

Caucasians. Characteristic symptoms occur in 

individuals who are homozygous for the disease 

allele. It affects about 1 in 2500 live births. The 

usual form is due to a single nucleotide deletion 

in the gene on the long arm of chromosome 7.

This produces a defect in the cystic fibrosis 

transmembrane  conductance  regulator  (CFTR) 

protein, which is a crucial regulator of chloride 

flow  across  the  cell  membranes  of  exocrine 

glands, and there are widespread consequences. 

In the airways there is a decreased flow of chloride 

out  of  the  epithelial  cells  lining  the  mucous 

glands and goblet cells. Consequent retention of 

chloride causes a threefold increase in sodium 

reabsorption into these cells. These abnormalities 

combine to hold water in the glandular epithelial 

cells, causing a greatly increased viscosity of the 

airways mucus. In sweat glands there is a CFTR-

independent  excess  excretion  of  chloride  and 

sodium into the sweat, which yields a concen-

tration of60 mmol/L and forms the basis of 

one of the diagnostic tests for cystic fibrosis.

Numerous other mutations occur in the cystic 

fibrosis gene and a precise diagnosis requires 

genetic   analysis,   but   this   does   not   affect 

treatment.

Clinical features

These include:

•  Failure to thrive in early life. In neonates, the 

first sign is likely to be an abnormally viscous

meconium, the green mucilage present in the ileum and colon of all newborns.

obstructive pulmonary disease341

•Respiratory symptoms are the most obvious.

Bouts of severe coughing are due to the very

tenacious mucus. Dyspnoea and haemoptysis occur in the later stages. There is also sinusitis and  nasal  polyps,  and  spontaneous  pneu-

mothorax may occur. The end result is cor 

pulmonale and respiratory failure.

•Retention of mucus causes recurrent bron-

chopulmonary infections, often with resistant

Gram-negative organisms, pneumococci and Staphylococcus aureus.

•Gastrointestinal   effects   include   chronic

pancreatitis,   causing   poor   digestion   and

malabsorption, the latter causing steatorrhoea (see Chapter 3). In older patients, small bowel obstruction   may   occur   and   there   is   an increased   frequency   of   peptic   ulceration, 

gastrointestinalcarcinoma,cholesterol gallstones and hepatic cirrhosis.

•Males are usually sterile, due to failure of the

vas  deferens  and  epididymis  to  develop.

Females   can   conceive,   but   the   normal 

monthly cycle fails as the disease progresses.

•In the kidney, unusually rapid excretion of

antibiotics may result in inadequate plasma

concentrations and treatment failure.

•Defects   in   other   body   systems   include

delayed  puberty  and  skeletal  growth  and

arthropathies.   Insulin-dependent   diabetes mellitus occurs in about 10% of patients.

Diagnosis

This depends on:

•  A family history of cystic fibrosis: prenatal 

diagnosis can be done in this situation.

•  High sweat sodium levels.

•  Radiology,  the  picture  resembling  that  of 

bronchiectasis.

•  Finger clubbing occurs eventually. 

•  Absence in males of the vas deferens and

epididymis.

•  Genetic analysis.

Diagnosis may be difficult and children may be treated for whooping cough or asthma before a definitive diagnosis is made.

Management and pharmacotherapyRestrictive lung disease

General  measures  include  physiotherapy,  i.e.

postural drainage, to improve expectoration of the tenacious mucus. A nutritious high-calorie diet is needed to counter malnutrition.

Patients and their families require counselling and support. Because infection with multiple-

resistant organisms is usual, and spread is person to person, they should not associate with other cystic fibrosis sufferers.

Pharmacotherapy has been revolutionized as 

knowledge of the disease has grown. It includes:

•Treatment as for bronchiectasis (see above),

notably   with   antibiotics   effective   against

Pseudomonas   aeruginosa  and   Staphylococcus 

aureus.  Ciprofloxacin  is  useful  initially  but 

resistance  develops  rapidly.  Ceftazidime  is 

used in hospital because it must be given by 

IV   infusion.   Nebulized   tobramycin,   etc. 

gives   high   sputum   levels.   Opportunistic 

infection with Burkholderia cepacia (formerly 

Pseudomonas   cepacia),   normally   a   plant 

pathogen, is a serious complication.

•Inhaled corticosteroids may help to reduce

airways inflammation.

•Vitamins should be given and H2-RAs (p. 103)

are often required.

•Enteric-coated  pancreatic  supplements  are

needed, but high lipase doses in particular

may cause colonic damage.

•Because some of the viscosity of the mucus is

due  to  DNA  from  dead  endothelial  cells,

inhaled dornase alfa  (rhDNase) may reduce sputum  viscosity  and  improve  respiratory function.

•Sodium  reabsorption  may  be  reduced  by

amiloride. Chloride excretion can be increased

by adenosine or uridine triphosphates (ATP, 

UTP).

Prognosis

The  outlook  has  improved  greatly  and  the average expectation of life is now over 40 years. Respiratory   failure   and   consequent   cardiac complications    may    lead    to    heart/lung 

transplantation.

In restrictive lung disease (RLD) the problem is 

an inability to expand the lungs normally, even 

though the airways are unobstructed. There are 

many diverse causes, some of which are given in 

Table 5.23.

A result of this diverse aetiology is that treat-

ment of RLD is often symptomatic rather than 

specific, because by the time symptoms occur 

the pathological changes may be irreversible. 

Infections should be treated and any precipi-

tating factors avoided as far as possible. There is 

clearly no effective way of treating thoracic cage 

deformity   once   it   is   established,   although 

physiotherapy   and   surgery   as   soon   as   the 

problem is perceived may do much to help. 

Early orthopaedic surgery is highly desirable. 

Physiotherapy may enable patients to make the 

best use of their limited ventilatory function.

However, some forms of RLD (e.g. Wegener’s 

granulomatosis, WG; see Chapter 12 and Table

12.18) are eminently treatable, so it is important 

to reach a definitive diagnosis. Treatment of WG 

usually involves corticosteroids and cytotoxic 

drugs.

Diseases of the pulmonary circulation

Pulmonary embolism

Aetiology, epidemiology and pathology

This important, often preventable, condition has 

a 10% fatality rate. Pulmonary embolism is a 

sequel to thrombosis in the systemic veins, espe-

cially the pelvic, abdominal and leg veins, but 

10% of emboli are cardiac in origin. The latter 

are due to right atrial fibrillation causing right 

atrial thrombosis, or to right ventricular or septal 

infarction and resultant right ventricular throm-

bosis. Clot fragments break away from venous 

thrombi and travel through the veins, which 

widen  progressively,  then  through  the  right 

ventricle and usually become trapped in the 

pulmonary circulation where the arteries begin 

to narrow (the pulmonary arteries carry venous 

blood). Because the lungs receive the whole of 

the cardiac output, and the lungs are the first 

organ to receive pooled venous blood from the 

right heart, most emboli lodge in the lungs.

Emboli arising from the left heart lodge in the 

brain, causing strokes or TIAs, or in the renal 

arteries,  leading  to  various  degrees  of  renal 

failure. However, some renal artery occlusion 

may be due to in situ thrombosis, as is nearly all 

coronary artery occlusion (see Chapter 4).

The factors predisposing to venous thrombosis are dealt with in Chapter 11.

Whenever  there  is  a  risk  of  a  deep-vein 

thrombosis(DVT),   prophylactic   measures

should be taken. Low-dose heparin is appropriate 

after surgery and there should be passive exer-

cising during a period of bed rest, with early 

mobilization. Low-molecular weight heparin  is 

preferred and may be combined with rhythmic 

external compression applied to the legs. Elastic 

stockings are also used, but are less effective. 

Aspirin taken before long-distance travel, prefer-

ably combined with elastic hosiery and avoid-

ance of dehydration, is used widely and may 

help.

After embolism, the area of lung affected is 

ventilated but not perfused and this leads, after 

some hours, to failure of surfactant production 

and alveolar collapse. Lung tissue often does not infarct because it obtains sufficient oxygen byThe extent of obstruction of the pulmonary

diffusion from the airways and the bronchial 

circulation.

Clinical features

The presentation will depend largely on the size and site of the emboli.

Small to medium emboli

These usually present with severe pleuritic chest pain,  cough  with  bloody  sputum  and  fever. 

Breathlessnessand    hyperventilation    are 

common  but  may  be  absent.  Recurrence  is unlikely, but any lung damage that may have 

occurred is irreversible.

Massive pulmonary embolus

This  produces  a  precipitous  fall  in  cardiac 

output, the result of loss of preload to the  left 

ventricle (see Chapter 4), so the patient will be 

shocked,   pale   and   cyanosed,   with   marked 

tachypnoea and a raised JVP. Severe central chest 

pain occurs, due to cardiac ischaemia. There is a 

30% fatality rate, sometimes immediate.

Repeated small emboli

These slowly produce progressive breathlessness 

and hyperventilation. Patients will become exer-

cise-limited and may have angina pectoris (see 

Chapter 4) owing to widespread restriction of 

pulmonary  perfusion  and  consequent  severe 

limitation of the coronary circulation. They may 

also faint on exercise in the later stages, when 

they will also be chronically tired. Investigation 

will  show  the  ECG  changes  associated  with 

right ventricular hypertrophy and evidence of 

pulmonary   hypertension.   The   condition   is 

progressive.

Investigation and diagnosis

Small to medium emboli

The symptoms and signs are often non-specific, 

but the diagnosis should be suspected if unex-

plained  new  pulmonary  symptoms  or  tachy-

cardia is present. The CXR and ECG are often 

normal.

circulation  may  be  determined  using  tech-

netium (99mTc) Macrosalb Injection [equivalents 

are Albumin Aggregated Injection (USP) and the 

Microspheres  Injection (Eur.  Ph.)]  for  radio-

isotope scanning. The labelled particles lodge 

throughout  the  lung  capillaries  and  so  will 

show  unperfused (non-radioactive)  areas,  in 

which the circulation is blocked by an embolus 

when  the  chest  is  scanned  with  a  gamma 

camera.  This  is  preferably  combined  with  a 

133Xe ventilation scintigram, the two investiga-

tions (V/Q scan) showing unperfused but venti-

lated  areas.  However,  the  V/Q  scan  is  not 

conclusive  and  must  be  read  in  conjunction 

with the examination and other investigations.

Medium-sized  emboli  are  best  detected  by 

spiral CT scanning with IV contrast media, or 

by MRI if the CT scan is contra-indicated because 

the patient is allergic to X-ray contrast media. 

CT angiography  (spiral CT with IV contrast 

agents, e.g. diatrizoate meglumine and meglumine 

iodipamide) or MRI  have good specificity and 

sensitivity for medium-sized emboli. If plasma 

D-dimer, a breakdown product of fibrin, is not 

detected this positively excludes a pulmonary 

embolus. Raised ESR and lactate dehydrogenase 

(LDH) levels indicate pulmonary damage. The 

CXR and ECG are usually normal.

Ultrasound may be used to detect DVT in the 

legs, pelvic or iliac region, but is not reliable for 

detecting below-knee thrombosis. However, the 

syndrome of calf pain with swelling, redness and 

prominent  superficial  veins,  and  sometimes 

ankle swelling, is strongly suggestive. If there is 

doubt, venography (i.e. injecting in the foot 

with   radiocontrast   medium   followed   by 

X-radiography)  is  conclusive.  This  cannot  be 

done if the patient is allergic to the contrast 

agent.

Massive pulmonary embolus

The ECG exhibits characteristic changes. Ultra-

sound (echocardiogram)  shows  an  actively 

contracting left ventricle (an attempt to restore 

adequate  systemic  circulation)  and  there  may 

be  a  clot  in  the  pulmonary  trunk  or  a 

main  pulmonary  artery.  Blood  gas  examina-

tion   shows   hypoxaemia   and   hypercapnia. 

Pulmonary  angiography  will  locate  emboli 

rapidly, but the technique is hazardous and isPulmonary oedema and pulmonary

usually  undertaken  as  a  prelude  to  surgeryhypertension

(embolectomy).

Pathology, clinical features and diagnosis

Repeated small emboli

Any of the tests described above may be done, especially CXR, ECG and V/Q scan, but may appear normal, so extensive investigations may be required.

Management

This includes:

•  High-flow  oxygen,  unless  the  patient  has 

COPD (p. 360).

•  Analgesics,  including  opioids  if  necessary, 

taking care to avoid respiratory depression. 

•  Anticoagulants:  heparin,  to  prevent  further

embolization,   changing   to   warfarin  after 

confirmation of the diagnosis, usually about

48 h (see Chapter 11).

For large emboli, management includes:

•  Intensive care.

•  Fibrinolytic therapy, e.g. streptokinase (by IV 

infusion over 24-72 h) or alteplase (bolus IV

injection, then IV infusion over 90 min), may precede anticoagulation (Chapter 11).

•  Surgical embolectomy (clot removal, rarely)

if cardiac function is severely impaired.

For   repeated   small   emboli,   management 

involves:

•  Anticoagulants: these are continued for 3-6 

months, but lifelong treatment may be neces-

sary if there is a chronic thromboembolic 

disorder.

•  Antiplatelet drugs (aspirin, clopidogrel or dipyri-

damole; see Chapter 11, but note interactions

with warfarin and other anticoagulants) may also be appropriate. The glycoprotein IIb/IIIa inhibitors abciximab, eptifibatide and tirofiban are used only when there is a significant risk of major cardiovascular complications.

•  If   the   condition   does   not   respond   to

anticoagulant  therapy,  or  if  anticoagulants are   contra-indicated   in   the   patient,   an inferior  vena  cava  filter  can  be  inserted percutaneously.

Pulmonary oedema can develop precipitately, e.g. as a sequel to MI (see Chapter 4), and can be rapidly  fatal.  Acute  pulmonary  oedema  is  a medical emergency.

The condition is usually the result of increased 

pulmonary capillary pressure, due to left heart 

failure or mitral stenosis (see Chapter 4), which 

causes  the  accumulation  of  fluid  in  the  nor-

mally  minimal  interstitial  space  of  the  lungs 

(see Figure 5.1(d)). The increased vascular pres-

sure compresses the bronchioles and reduces 

lung  compliance,  ventilation  and  perfusion. 

These changes are more marked initially in the 

lung bases because of the effect of gravity. If the 

condition persists, or occurs acutely, fluid even-

tually flows into the alveoli and the terminal 

bronchioles, producing severe dyspnoea. Some 

precipitants  of  acute  pulmonary  oedema  are 

given in Table 5.24.

If   the   condition   is   of   gradual   onset 

(pulmonary hypertension), the initial symp-

toms and signs are dyspnoea on exercise, then 

shortness  of  breath,  cough,  orthopnoea  and 

paroxysmal   nocturnal   dyspnoea(PND;   see 

Chapter 4, p. 195). If symptoms are untreated, or 

if the onset is acute, these lead to extreme dysp-

noea, tachypnoea, cyanosis, and coughing up of 

foamy, bloody sputum. Unsurprisingly, patients 

are extremely anxious and fearful and sweat 

profusely.  There  is  tachycardia  and  a  raised 

pulmonary  arterial  pressure,  and  the  X-ray 

shows characteristic changes. Diagnosis is based 

on these features.

Management

Pharmacotherapy of acute pulmonary oedema involves:

•  An   IV   loop   diuretic,   which   sometimes 

produces   a   dramatic   improvement(see

below).

•  High-flow (60%), short-term oxygen to relieve 

dyspnoea.

•  Opioid analgesia: morphine  causes systemic 

venodilatation,  reducing  cardiac  workload 

and   tachypnoea,   and   is   sedative   and 

euphoric.

•  Vasodilators to increase cardiac output. 

•  Aminophylline, given intravenously to control

bronchospasm.

•  Management of the underlying condition.

Diuretics have a dual action in this setting. In 

pulmonary oedema consequent on heart failure 

they reduce the blood volume and in turn the 

cardiac preload and cause vasodilatation, thus 

further reducing cardiac preload and afterload. 

These combined actions improve cardiac func-

tion and reduce pulmonary venous pressure. If 

the condition is of renal origin, diuretics also 

reduce the hypervolaemia consequent on acti-

vation  of  the  renin/aldosterone  mechanism. 

Diuretics do not act directly to clear the oedema 

fluid,  which  is  cleared  spontaneously  when 

cardiac function improves and the pulmonary 

capillary pressure falls (see Chapter 4).

Treatment    of    pulmonary    hypertension 

depends on the underlying condition, and may 

involve:

•  Diuretics in RVF, taking care to avoid volume 

depletion.

•  Oxygen. Long-term oxygen therapy in COPD 

(p. 361).

•  Lowering of pulmonary artery pressure with 

bosentan (oral), sometimes nebulized iloprost.

Epoprostenol, given by continuous IV infusion 

as an antiplatelet agent and vasodilator, is 

also used, especially in primary pulmonary 

hypertension, i.e. without discernible cause. 

•  Heparin anticoagulation initially, followed by

oral warfarin.

•  Transplantation in otherwise suitable patients 

who fail to respond, e.g. in those:

-  who   fail   to   respond   despite   optimal 

medical management

-  with   FEV125%   predicted   and   no

reversibility, and/or PaO27.3 kPa 

–  with raised PaO2 and using long oxygen

therapy who continue to deteriorate

-  with no other serious chronic disease

-  who are55-65 years, dependent on the

type  of  operation  contemplated.  Older patients   tolerate   operations   of   this 

magnitude poorly.

Respiratory failure

Respiratory failure occurs when there is signifi-

cant hypoxaemia with or without hypercapnia 

and may be classified into two types (Table 5.25). 

Type  I  respiratory  failure (acute  hypoxaemic 

respiratory failure) is the condition in which the 

PaO2  is low and the PaCO2  is normal or low. 

It   occurs   in   pneumonia (see   Chapter 8), 

pulmonary oedema and fibrosing alveolitis (see 

above). In type II respiratory failure (ventilatory 

failure) the PaO2  is also low and the PaCO2  is 

high.

Oxygenation  of  the  blood  is  usually  moni-

tored by pulse oximetry (p. 291). Hypoxaemia 

is  regarded  as  severe  if  the  PaO2 is  less  than 

about 5 kPa. If sufficiently severe, hypercapnia 

(high  blood  carbon  dioxide,  also  known  as 

hypercarbia)  causes  acidosis  (blood  pH  7.3  or 

lower).

The management of type I respiratory failure 

involves high-flow oxygen (6-10 L/min), usually 

via a variable performance mask, and treatment of 

the underlying disease state. In type II failure, 

high-flow  oxygen  is  not  used  because  patients 

either require mechanical ventilation or depend 

on a low PaO2 to provide their respiratory drive, 

e.g. in COPD (p. 276). Mechanical ventilation is 

needed in opioid overdose, myasthenia gravis 

(see Chapter 6) and Guillain-Barré syndrome, an 

acute,  usually  demyelinating  polyneuropathy

Respiratory failure347

causing paralysis, often following infection by 

cytomegalovirus or Campylobacter jejuni. These 

patients may develop severe respiratory acidosis, 

which must be treated vigorously (see Chapter 14).

In  acute  respiratory  failure,  extracorporeal 

oxygenation   in   an   external   system(for 

neonates   and   adults)   or   carbon   dioxide 

removal  (for  adults)  are  controversial  but  are used in specialist centres.

The best respiratory stimulant  is vigorous 

physiotherapy,   but   drugs   are   used   very 

occasionally. Doxapram is a short-acting respira-

tory stimulant that is given by continuous IV 

infusion and should be used only under expert 

supervision: oxygen should be used with it and a 

beta2-agonist bronchodilator added if there is 

significant bronchoconstriction. Active physio-

therapy  should  also  be  given.  Doxapram  has 

numerous side-effects and regular blood gas and 

pH  measurements  should  be  used  to  guide 

treatment. It is contra-indicated in severe hyper-

tension, acute severe asthma, coronary artery 

disease, thyrotoxicosis, epilepsy and respiratory 

tract  obstruction.  It  may  be  used  to  counter 

the depressant effect of oxygen in type II failure 

and to treat significant respiratory depression 

following anaesthesia. 

Inhalation therapyroute, which avoids first-pass hepatic metabo-

lism, e.g. heparin and vasopressin, and insulin is

now licensed for use by inhalation in certain

This section does not cover the inhalation of

gases. Oxygen therapy is dealt with separately.

Advantages

The  development  of  inhalation  therapy  has 

produced   considerable   benefits   for   patients 

suffering  from  respiratory  diseases,  not  only 

asthma but also COPD, bronchiectasis and cystic 

fibrosis. Although simple devices had been used 

for many years, inhalation therapy was given 

a  powerful  impetus  in 1969  with  the  intro-

duction   of   the   first   selective   beta2-agonist 

bronchodilator (salbutamol) and the associated 

equipment to deliver precise doses direct to the 

lungs.  The  technique  has  subsequently  been 

used successfully for the administration of:

•  beta2-agonists, e.g. salbutamol and terbutaline; 

•  corticosteroids, e.g. beclometasone  and bude-

sonide;

•  anticholinergics, e.g. ipratropium  and tiotro-

pium;

•  anti-allergics,  e.g.  sodium  cromoglicate  and 

nedocromil sodium;

•  antibiotics,   e.g.   bacitracin,   aminoglycosides, 

cephalosporins, colistin, penicillins and poly-

myxin, and the antifungal agent amphotericin. In terminal care it is used for administering:

•  mucolytics, e.g. normal and hypertonic saline, 

N-acetylcysteine and dornase alfa;

•  opioids, e.g. morphine, diamorphine and fen-

tanyl;

•  local  anaesthetics,  e.g.  lidocaine  and  bupi-

vacaine.

Other applications include the administration of 

local anaesthetics before endotracheal intuba-

tion or bronchoscopy, water or saline for humid-

ification of inspired air, cytotoxic agents for lung 

cancer chemotherapy, vaccines for immuniza-

tion and DNA for gene therapy in cystic fibrosis. 

Inhalation is also used in one form of NRT to 

assist   smoking   cessation.   It   has   also   been 

proposed that many other drugs could be admin-

istered by this well-tolerated and non-invasive

patients (see Chapter 9), thus avoiding the need 

for repeated injections. This has become possible 

due to the availability of virtually unlimited 

supplies of safe, cheap human insulin by genetic 

engineering.

In respiratory disease inhalation therapy is a 

simple, rapidly effective technique that delivers 

a small dose of drug directly to what is usually 

the desired site of action deep within the lungs. 

This gives a high local concentration and avoids 

the side-effects that occur when larger doses of 

drug are given systemically to achieve a similar 

effect. However, the inhalation route does not 

avoid the side-effects completely, because some 

is absorbed from the lungs or swallowed from 

impinged drug in the oropharynx (see below), 

but minimizes them considerably. By avoiding 

first-pass   metabolism,   the   bioavailability   of 

drugs   may   be   enhanced.   The   very   high 

pulmonary blood flow and surface area, together 

with the very thin alveolar walls, may also serve 

to enhance absorption.

Factors influencing pulmonary drug deposition

The principal factors are the particle size of the drug, the patient, the delivery system and the 

environment.

Particle size

The target area in the lungs depends on the site 

of the pathological changes, and may be the 

tracheobronchial region, the bronchioles or the 

respiratory bronchioles and alveoli. In adults, 

only some 8-12% of the inhaled dose reaches 

the distal lung, even with optimal delivery, and 

this may fall to below 1% in young children. 

The remainder is deposited in the oropharynx 

and is swallowed. This mechanism may also 

dispose  of  insoluble  drugs  deposited  in  the 

bronchi and escalated from there by mucociliary 

clearance.

Optimal particle size is crucial. Particles need 

to be about 2 lm in diameter or less to reach the bronchioles and0.7 lm to reach the respira-

tory bronchioles. Below approximately 0.5 lm, 

particles will reach the alveolar sacs, but because 

this region does not possess any smooth muscle, 

bronchodilators will not have any effect there, 

although other drugs may do so, e.g. cortico-

steroids in extrinsic allergic alveolitis. Very small 

particles ( 0.5 lm) may remain suspended in 

the alveolar gas and be exhaled (about 1% of the 

inhaled dose).

Larger particles (  10 lm) are deposited in the 

mouth and oropharynx by inertial impaction 

(about 60% of the dose) and are swallowed, as 

are a large proportion of those in the 5- to 10-lm 

range. This gives rise to most of any systemic 

effects that occur. In the 2- to 5-lm range, parti-

cles  are  carried  in  the  air  stream  until  the 

velocity is slowed sufficiently by airways resis-

tance to permit deposition in the bronchioles by 

gravitational   sedimentation.   Below   approxi-

mately 2 lm,   particles   deposit   on   mucous 

surfaces, following diffusion, accidental contact 

produced   by   air   turbulence   and   Brownian 

motion. Thus, for most purposes we need the 

majority  of  particles  to  be  in  the  range  of 

1-5 lm, with a median aerodynamic diameter of 

about 3 lm.

However,   recent   research   with   respirable 

polymer-coated insulin particles has shown that 

low-density  particles ( 0.4 g/cm3)5 lm  in 

diameter can be aerosolized more easily than the 

conventional higher density, smaller diameter 

ones. Further, the light, large particles evade 

pulmonary phagocytosis, giving high bioavail-

ability and more sustained drug release (96 h 

versus 4 h).  This  technology  offers  exciting 

possibilities for controlled, systemic drug admin-

istration  via  the  lungs  of  many  drugs  that 

currently are given only by injection.

Patient (physiological) factors

Although very difficult to quantify, these are 

among   the   most   important   considerations. 

Modern equipment is well designed and manu-

facturers take great care to produce aerosols of 

effective drugs having the appropriate particle 

size characteristics. Unfortunately, there is little 

control over what happens in use, especially if 

patients are counselled inadequately or if the

Inhalation therapy349

devices are used without proper ongoing super-

vision by knowledgeable staff. The age of the 

patient,  their  ability  to  coordinate  breathing 

with drug delivery, airways geometry, inspiratory 

and   expiratory   flow   rates   and   times,   tidal 

volumes, breath holding and the proportions of 

mouth and/or nose breathing may all influence 

the deposition of the drug in the lungs.

We can be certain only on some points, e.g. 

that pulmonary deposition is reduced in propor-

tion to the severity of the ventilatory abnor-

mality,  with  poor  technique  and  in  young 

children. It is clearly impossible to predict the 

response of an individual patient to a drug deliv-

ered from a particular piece of equipment. As in 

most fields of therapy, there is no substitute for 

monitoring the actual clinical response and, if 

this is unsatisfactory, varying the conditions of 

use in a controlled way to determine whether 

this can be improved. If necessary, the drug and 

the delivery system itself may also be changed.

Drug delivery systems

There   are   four   types   available:   pressurized metered  dose  inhalers (pMDIs),  dry  powder 

inhalers(DPIs),   gas-driven   nebulizers,   and ultrasonic nebulizers.

Pressurized metered dose inhalers

This type of inhaler is the most widely used 

because it is so convenient. It consists of a metal 

canister filled with a suspension of a micronized 

drug in a propellant that is liquefied under pres-

sure (Figure 5.22). The special metering valve 

gives doses that are reproducible within 5%.

The   older   pMDIs   use   CFC  (chlorofluoro-

carbon, freon) propellants. Because of worries 

about the effects of CFCs on the ozone layer and 

the  consequent  environmental  impact,  these 

propellants are being replaced rapidly by hydro-

fluoroalkanes (HFAs). However, the latter still 

have  some  ‘greenhouse’  effect.  The  doses  of 

propellant usually delivered are considered to be 

non-toxic, though they may cause small reduc-

tions  in  respiratory  function.  There  do  not 

appear to be any toxicity problems with these 

new inhalers.

However,  in  one  new  HFA  formulation  of 

beclometasone (Qvar) a change in particle size has 

resulted in an increase from about 25% to 60% 

of  the  dose  being  in  the  respirable  range, 

producing significantly greater dose delivery to 

the small airways and acini. There is evidence 

that inflammation in these small airways is an 

important component in both acute and chronic 

asthma.  Thus  the  absolute  loaded  dose  of 

beclometasone   from   this   device   is   halved 

compared to the older pMDIs, with a reduction 

of about 30% in side-effects at similar clinical 

effectiveness. However, the Qvar inhaler is not 

recommended for use in children.

There may be additional features that may 

worry patients when they are changed to HFA 

inhalers:

•  An altered sound made when the dose is 

released.

•  A change in the taste of the aerosol. •  Reduced pharyngeal impact.

•  Incompatibility  with  their  existing  spacer 

device (see below).

Thus patients should be counselled on these 

points: this also provides a good opportunity to

check compliance and inhaler technique (see 

below).

The   European   Commission   has   expressed concern about possible propellant toxicity and has urged careful supervision of patients who are changed  to  CFC-free  inhalers.  However,  the propellants are regarded as being safe. Patients with ‘brittle’ asthma, in which there is a sudden onset of severe or life-threatening attacks, will need especially close attention.

Patients using pMDIs need careful counselling 

to ensure maximum benefit. Good coordination 

is essential for correct dose delivery and this is 

more difficult for the young, the elderly and the 

very anxious patient. It is essential to teach 

proper procedures and to check regularly that 

these are being maintained. A moderate inspira-

tory flow rate (about 30 L/min) gives the best 

lung deposition and devices are available to help 

train patients to inspire adequately. Pharmacists, 

doctors and nurses need to acquire and maintain 

a good technique themselves (Table 5.26) and be 

able to teach this to patients: one survey showed 

that only 28% of adult patients and 48% of 

hospital pharmacists had a good inhaler tech-

nique, but this situation has improved recently If good coordination cannot be achieved, if 

patients dislike the sensation of the jet of cold 

aerosol impinging on the back of the mouth, or 

if it causes them to gag and involuntarily to stop 

inhaling momentarily, then several alternatives 

are available. These are the automatic (breath-

actuated)   inhalers,   spacer   devices   and   dry 

powder aerosols.

Breath-actuated inhalers

In these devices the inhaler cartridge has the 

same construction as in the normal pMDI, but a 

trigger release mechanism is set before inhaling. 

Release of the dose is actuated automatically 

when the patient seals their lips around the 

mouthpiece  and  creates  a  sufficient  pressure 

differential at the start of inhalation. However, some of these inhalers also have problems in use.

Patients may dislike the sharp noise and the

impact as the mechanism is activated in some

inhalers. Further, a proportion of patients do not 

have sufficient inspiratory capacity at all times 

to trigger the mechanism or may not achieve a 

good   enough   seal   around   the   mouthpiece. 

Recent designs have mitigated these problems. 

Once again, good counselling is essential for 

effective use.

Spacer devices

The object of these is to avoid the need for good 

coordination of dose release and inhalation for 

effective  drug  delivery,  to  maximize  clinical 

benefit, and to minimize adverse reactions. The 

dose is fired into a reservoir (Figure 5.23) from 

which the patient then inhales, using several 

successive breaths if necessary. This gives compa-

rable results to the use of a pMDI with good 

coordination (Figure 5.24), so patients with good 

inhaler technique will derive little benefit from 

using a spacer, apart from possibly experiencing 

fewer   side-effects,   e.g.   with   corticosteroid 

inhalers. However, another important function 

of the reservoir is to slow down the aerosol 

droplets  so  that  there  is  more  time  for  the 

propellant to evaporate before inhalation occurs; 

in this way the aerosol particles are smaller and 

thus more likely to penetrate the bronchiolar 

tree. The reduced speed of the particles also 

reduces oropharyngeal impaction of drug. Thus 

the proportion of the dose swallowed and the 

incidence   of   hoarseness   and   oropharyngeal 

thrush   with   the   corticosteroid   aerosols   is 

reduced.

Several commercial types of spacer are avail-

able (Figure 5.23). The large-volume (750 mL) 

devices, e.g. Figures 5.23(a) and (b), can be used 

flexibly: several breaths can be taken to achieve 

complete inhalation of the available drug and it 

is possible to discharge a number of puffs into 

the chamber to give a higher dose. In the latter 

case, each puff should be inhaled separately. 

Research has shown that a spacer used in this 

way can provide an equivalent alternative to the 

use of a nebulizer (see below and Figure 5.24) for 

giving   larger   drug   doses   in   severe   attacks. 

Further, it has the considerable benefit that a 

patient who is not using a nebulizer can obtain a

larger than usual dose of inhaled drug promptly at home, before seeking medical help. However, this must be done as part of an agreed protocol and patients must not rely exclusively on this 

procedure in severe attacks.

Spacers  increase  the  lung  deposition  from 

monodisperse  aerosols,  perhaps  doubling  the 

lung deposition from single doses (Figure 5.24), 

with a significant increase in clinical response. 

These  spacers  have  a  one-way  valve  through 

which only inspiration is possible, exhaled air 

and waste aerosol passing out through side vents.

However, the larger spacers are too bulky for 

convenient use outside the home. Many manu-

facturers supply smaller tube spacers with their 

pMDIs  (see  Figure 5.24(c)).  Almost  any  tube 

device will have a similar, though smaller, effect 

to a large-volume spacer and extemporaneous 

devices have been used but give unpredictable 

results. Recently, spacers specially designed for 

young children have been introduced. These 

have a smaller volume, may be fitted with a 

paediatric face mask and require less inspiratory 

effort  in  use.  Although  spacers  increase  the 

inhaled dose, this must not be relied on to 

increase   clinical   benefit,   which   has   to   be 

established   objectively,   e.g.   with   improved 

respirometry results (not applicable in young 

children).

A significant proportion of the aerosol dose is 

deposited on the walls of the spacers, largely due 

to electrostatic attraction, so spacers should be 

washed not more than once a month with a 

dilute detergent solution, as an antistatic, and 

allowed to drain. They should not then be rinsed 

with water or wiped dry. More frequent washing 

removes the antistatic film of detergent and 

wiping dry increases the static charge, so there is 

a consequent reduction in drug delivery.

Dry powder inhalers

These devices are inherently breath-actuated and 

so, like breath-actuated inhalers and spacers, do 

not depend on good coordination for satisfac-

tory performance. However, an adequate inspira-

tory airflow is still required. The dose is released 

into the inspired air when the patient inhales. 

There is no propellant, so these inhalers are more 

suitable   for   the   occasional   patient   who   is 

affected by the propellant or who is worried 

about its possible side-effects. Several types of

inhaler are available (Figure 5.25), some of which use a lactose carrier for the drug, whereas others deliver pure drug. Although a number of innov-

ative designs are in development these will have to demonstrate significant benefits in terms of clinical effectiveness or cost or both if they are to replace the Accuhaler and Turbohaler.

Some devices provide single doses from hard gelatin capsules, which have to be loaded into the device before each use. The newer ones 

provide a number of doses (up to 200) without recharging. They have either a dose counter or end-of-charge  indicator  so  that  the  patient 

knows when a replacement is required. If pure, carrier-free  drug  is  used  patients  are  scarcely aware that a powder is being inhaled.

Like the pMDIs, the DPIs are rather inefficient 

devices for the delivery of drug to the lungs. 

Many patients distrust the very idea of inhaling 

a   powder,   and   some   dislike   the   sensation produced. Patients with poor respiratory func-

tion may need to inhale several times to obtain the  full  dose  from  a  single  actuation  and 

coughing occurs occasionally.

High    inspiration    rates(approximately

60 L/min) are required to produce an adequate 

concentration of respirable particles to improve 

drug  deposition  within  the  lungs.  Sustained 

breath holding does not seem to be necessary.

However,  DPIs  are  simple  to  use  and  are 

generally   more   suitable   for   children.   More 

importantly, the devices give a similar clinical 

benefit to that attainable with a pMDI. If envi-

ronmental pressures against aerosol propellants 

are maintained, DPIs may become predominant.

Nebulizers

General principles

Nebulizers are devices for producing an aerosol from  an  aqueous  solution  of  a  drug.  Two 

methods are generally used:

•  Jet  nebulizers  (Figure  5.26)  use  a  jet  of

compressed gas (air or oxygen) to break a fine 

stream of liquid into an aerosol, the smaller

droplets emerging from the outlet as a fine 

mist.

•  Ultrasonic    nebulizers   use    electrically-

induced ultrasonic vibrations to disperse the

drug solution into an aerosol.

In the UK, nebulizers can be prescribed only via hospitals or must be purchased by patients. The following is a brief review of the topic: for more detailed information, readers are referred to the Thorax supplement listed in the References and further reading section (p. 364).

Indications for nebulizer therapy

Nebulizers may be preferred for a number of 

reasons:

•  Because young children, the elderly and very 

infirm patients may find it difficult to use

pMDIs and DPIs correctly or with sufficient benefit.

•  Because some patients may require a higher 

dose than can be delivered by pMDIs and

DPIs and may be poorly controlled on these, notably some chronic asthmatics and those with COPD and cystic fibrosis.

•  For self-medication at home, to give a larger 

dose of a drug when patients are inadequately

controlled with a pMDI, e.g. in severe or 

chronic asthma, exacerbations of COPD and 

chronic airflow obstruction, but see above. 

•  In acute severe asthma, either in hospital, in

the doctor’s surgery, or as an alternative to parenteral medication.

•  When inhalation is desirable but drugs are 

not produced in a convenient pMDI or DPI 

form.

The latter point is especially applicable in the case of:

•  Antimicrobials for cystic fibrosis, bronchiectasis 

and HIV infection or AIDS.

•  Dornase alfa for reducing sputum viscosity in 

cystic fibrosis to aid expectoration?

•  In  palliative  care,  e.g.  local  anaesthetics 

(lidocaine or bupivacaine) for relief of persis-

tent  dry  cough  and  opioids  for  terminal dyspnoea.

The need for a nebulizer should be validated byfor 3-4 weeks to assess benefit adequately and if

proof of additional benefit (Figure 5.27). Patients 

must be carefully trained in the use and limita-

tions of nebulizers because they may rely on them 

excessively and delay seeking effective treatment, 

with  a  consequently  increased  morbidity  and 

mortality. Trials of therapy need to be continued

bronchodilators are used they should normally give at least a 15% improvement over existing baseline to be considered worthwhile. However, due  account  should  be  taken  of  a  patient’s subjective perception of benefit, in addition to measurements of PEF or FEV1.

Types of jet nebulizer

These  work  on  the  Venturi  principle.  High-

pressure gas (air or sometimes oxygen) is forced 

through a very small aperture (venturi). As the 

gas escapes from the venturi it expands rapidly 

and gains velocity as it passes across the end of a 

liquid  feeder  tube.  The  low  pressure  created 

sucks liquid up the feed tube and the liquid 

stream is broken into droplets that impinge onto 

a baffle. The largest droplets are trapped on the 

baffle and intermediate ones on the walls of the 

chamber. All of these drain back into the liquid 

reservoir.   Only   the   smallest   droplets   are 

entrained in the gas stream and inhaled by the 

patient.   The   performance(dose   delivery) 

depends on the precise sizes and designs of the 

feeder tube, venturi, baffles and chamber. The 

design is crucial to the droplet size produced and 

the   presence   of   a   baffle   distinguishes   the 

nebulizer from a simple atomizer. Two forms of 

modern jet nebulizer are illustrated in Figure

5.26.

Older, simple nebulizer designs that have been 

in  use  for  many  years  are  very  inefficient 

because:

•  They may produce50% of particles in the

1- to 5-lm range.

•  Some 95% of the primary droplets are trapped 

on internal baffles.

•  About  65%  remains  in  the  chamber  after 

nebulization and 65% of the inhaled aerosol

is exhaled.

Thus only about 10% of the dose placed in a 

nebulizer may reach the desired sites of action in the lungs. This situation can be improved in 

various ways.

Open vent nebulizers  (e.g. the Sidestream) 

have an additional vent through which the low 

pressure in the chamber sucks additional air. The 

extra gas flow entrains more respirable particles, 

giving shorter nebulization times and possibly 

reducing  particle  size.  Further,  cheaper,  low-

output  compressors  can  be  used.  However, 

patients with a low inspiratory flow, e.g. young 

children and the elderly infirm, may inspire less 

drug because more is carried to waste in the 

increased exhaust stream.

This drug loss may be overcome by the newer 

breath-assisted   open   vent   nebulizers  that

Inhalation therapy357

incorporate two valves (e.g. the Pari LC Plus 

(Figure 5.26(b)) and Ventstream). An inlet valve opens only on inspiration, admitting ambient 

air as with the open vent design. On expiration the inlet valve closes and an outlet valve opens, so aerosol loss is not increased by extra air flow through the inlet valve.

Aerosol   loss   when   exhaling   can   also   be reduced by using a holding chamber with a 

conventional jet nebulizer. This makes the set-up rather bulky and there is no device of this type currently available in the UK.

Some factors affecting the performance of jet nebulizers

Gas flow rate.   This is the major determinant 

of output from a particular nebulizer, as particle 

size decreases markedly with increasing gas flow. 

The   flow   rate   may   be6-8 L/min(high),

4-6 L/min (medium) or occasionally,4 L/min 

(low), but that required to yield the desired 

droplet  size  characteristics  and  dose  output 

differs appreciably with different nebulizers. The 

manufacturer’s  recommendations  on  air  flow 

should be strictly observed. High flow rates are 

needed to nebulize viscous solutions, e.g. anti-

biotics and rhDNase. Modern jet nebulizers have 

output   rates   comparable   with   those   from 

ultrasonic devices.

Domiciliary oxygen equipment cannot deliver 

more than 4 L/min without a special controller 

and is unsuitable for use with most jet nebu-

lizers.  Electrically  driven  air  compressors  are 

preferred unless the patient needs oxygen (see 

below). However, if patients in the community 

need oxygen, a low-flow ( 4 L/min) nebulizer 

(e.g. Cirrus or Pari LC Plus) can be used with an 

oxygen  cylinder.  Alternatively,  a  flow  head 

capable of delivering up to 8 L/min from a gas 

cylinder should be used with a suitable nebu-

lizer, e.g. Permaneb (4-6 L/min); or Micromist or 

Ventstream (6-8 L/min). If high flow rates are 

used, the normal-size oxygen cylinder will have 

a very short life and the cost of supplying the 

oxygen will be very high. If oxygen is used, the 

patient must be capable of an adequate inhala-

tion rate. Oxygen concentrators are unsuitable 

for driving nebulizers.

The inhalation rate and pattern have only a 

small effect on particle size, but may be very 

important if oxygen is used as the driving gas 

and in determining pulmonary drug delivery.

Driving gas.   Under hospital conditions either 

piped oxygen or compressed air may be used. 

However many patients, especially those with 

COPD,  are  intolerant  of  oxygen.  At  the  low 

inhalation rates that occur with exhausted and 

very infirm patients, the oxygen concentration in 

the inspired air mixture may be very high (Figure

5.28), so air is the preferred driving gas for 

hypoxic patients with carbon dioxide retention. However, some patients tolerate oxygen or may need it, e.g. in an acute severe asthma attack the patient may be severely hypoxaemic and this 

may be aggravated by the bronchodilator, so 

oxygen is then preferred.

Diluent, volume and formulation of solution. 

The  preferred  diluent  for  nebulizer  solutions 

is sterile 0.9% saline, because hypotonic solu-

tions may cause bronchoconstriction in some 

patients. Solutions diluted ready for use are used 

in all areas of practice because there is no preser-

vative to cause reactions and no possibility of a 

patient using a concentrated solution in error. 

However, concentrated respirator solutions are 

available for use with ventilators and these must 

be diluted with sterile 0.9% saline for use in nebulizers.

The fill volume of solution must be adjusted 

to suit the nebulizer being used, because some 

have an appreciable RV (residual volume), and 

to give the desired delivery rate. The delivery 

rate of many nebulizers falls off markedly below 

approximately 2 mL RV. Tapping the chamber 

sharply  and  repeatedly  throughout  dosing  to 

shake solution from the walls and baffles to the 

bottom  of  the  reservoir  improves  maximum 

delivery somewhat. Because of evaporation, the 

RV underestimates the residual mass of drug at 

the  end  of  nebulization,  but  there  is  little 

information on this because it is influenced by 

numerous   factors,   e.g.   the   humidity   and 

temperature  of  the  driving  gas.  Inhalation  of 

the more concentrated drug solution may cause 

respiratory irritation in some patients towards 

the end of a treatment session.

The fill volume also controls the time over 

which the dose is delivered, this being one of the 

advantages of nebulizer therapy because there is 

then adequate time (10 min) for a physiological 

response (e.g. bronchodilatation) to occur and so 

better penetration of the latter part of the dose. 

Patients will not usually tolerate delivery times 

longer than 10 min.

Solutions of lower surface tension give greater volume deliveries because they adhere less to the walls and baffles of the nebulizers. Drug solu-

tions may be diluted with sterile 0.9% saline if a longer inhalation time is required.

Hygiene.   Nebulizers  must  be  kept  clean  to 

avoid microbial growth and consequent infec-

tion and are best washed out after each use, or at 

least daily. The manufacturer’s instructions must 

be  followed  closely  to  avoid  damage  to  the 

plastic precision mouldings that are used.

Delivery   of   drug   solution.   This   is   the 

most significant attribute of a nebulizer, and 

solution   outputs   can   vary   in   the   range

0.01-0.75 mL/min, depending on the type of 

nebulizer and the gas flow rate. It is impossible to predict the actual delivery of drug from a 

particular nebulizer to a specific patient. We can only choose the device and adjust the conditions to get the best clinical response.

Nebulizer wear.   Some nebulizer chambers are 

durable, but should be replaced after about a 

year (e.g.  Pari  LC  Plus,  Sidestream  Durable). 

However, most wear more rapidly and must be 

discarded after 3 months or if there is any sign of 

wear, e.g. an increasing nebulization time or a 

changed noise. The compressors have a very 

long life.

Ancillary equipment

A wide range of ancillary equipment is available 

from manufacturers. Either mouthpieces or face 

masks   may   be   used,   with   similar   clinical 

responses. Young children and exhausted or very 

infirm patients usually do better with face masks 

because they are easier to use, but it is often a 

matter of patient preference. Very young chil-

dren are often intolerant of masks, but reason-

able results are sometimes achieved by merely 

holding the outlet tube or mask near the child’s 

nose and allowing normal breathing. Although 

this reduces dose delivery substantially, it may 

accustom the child to the treatment and permit 

subsequent use of a more effective technique.

The masks should fit the face well to avoid 

adverse effects on the skin or eyes. However, it is 

sometimes difficult to get a good fit with a mask 

and avoid leakage of aerosol, so mouthpieces 

may be preferred for use with corticosteroids, 

which may damage the perioral and perinasal 

skin, and with antimuscarinic bronchodilators, 

which risk causing or exacerbating glaucoma in 

the elderly.

There are concerns about the effects of drugs 

such as antibiotics on the environment and the 

possibility of spreading infections due to highly 

resistant microorganisms. For this sort of applica-

tion closed systems (e.g. with exhaust filters) are 

used in hospitals to prevent cross-contamination. 

This is probably unnecessary for home use unless 

others in the family are at risk from respiratory 

infection, though nebulizers should be used in 

well-ventilated rooms.

Compressors must match the chosen nebulizer: many are supplied as complete outfits.

Ultrasonic nebulizers

Ultrasonic nebulization may be very fast, and 

output increases as the solution heats because of 

the associated fall in viscosity (whereas with jet

Inhalation therapy359

nebulizers the output falls with time). The user can usually adjust the output. Some patients find the warm wet mist they produce is unpleasant, especially if a face mask is fitted, and provokes coughing.  Ultrasonic  nebulizers  are  generally quieter than jet nebulizers and do not need a 

compressor or gas supply.

Improvements in nebulizers

Pharmacists should be familiar with the charac-

teristics of the nebulizers they supply, especially the gas pressures and flow rates, to be able to 

give good patient advice.

The   British   Standard   for   jet   nebulizers 

(BS7711,  Part 3, 1994)  requires  them  to  be 

marked with maximum filling levels and recom-

mended  gas  flows.  Manufacturers  must  also 

supply details of:

•  Intended use and any contra-indications. 

•  Gas  pressures,  respirable  outputs  and  RVs

corresponding    to    the    recommended, 

minimum and maximum flow rates.

•  Aerosol   particle   size   distribution   at   the

recommended flow rates.

•  Suitability   for   use   with   ventilators   and 

anaesthetic systems.

However, BS7711 does not address many of the problems raised above.

Conclusion

Inhalation therapy has become a highly tech-

nical and sophisticated method of drug delivery that  has  brought  tremendous  advantages  to sufferers  from  respiratory  diseases.  This  is  a research  area  of  great  interest  and  intense 

activity.  Most  difficult  cases  of  asthma,  in particular, can be controlled by the appropriate use of this technique, though occasionally oral medication may also be required.

Many new devices are likely to be introduced 

in the next few years, most of which are breath-

actuated and provide more consistent dosing. 

For example, one new battery-powered DPI is 

claimed to deliver about 30% of the absolute 

loaded dose, i.e. some three times that from a 

conventional DPI. Another novel pMDI delivers 

a high respirable fraction at a lower velocity than 

current devices, similarly delivering some 30% ofhigh-concentration (40-60%) oxygen is required,

the absolute loaded dose. If these and similar 

devices perform to this level in daily clinical use they  should  permit  significant  reductions  in loaded doses, and so also reduce both adverse reactions  and  drug  costs.  However,  all  new devices  will  have  to  demonstrate  significant cost-benefit advantages.

The principal barrier to more effective control 

is largely a lack of appreciation of the potential 

benefits of inhalation therapy and inadequate 

understanding of the proper use of the equip-

ment. The result is inadequate patient coun-

selling and adherence, and sub-optimal control 

of the disease state. Although the situation has 

improved  over  recent  years,  more  can,  and 

should,   be   done   to   reduce   morbidity   and 

mortality. These comments apply to all health 

workers, including pharmacists.

Oxygen therapy

Aims

The aim of oxygen  therapy is to increase the 

amount  of  oxygen  carried  by  the  blood  in 

hypoxaemia by increasing either the Hb satura-

tion or the amount of oxygen carried in solution 

in the plasma, normally 10 lmol O2/L/kPa.

Increasing the oxygen concentration in poorly 

ventilated but well-perfused alveoli increases the 

PaO2  and also counteracts a reduced diffusing 

capacity. Patients with anaemia or heart failure 

may  have  good  oxygen  saturation  but  poor 

oxygen delivery to the tissues, due to low Hb 

levels and low cardiac output, respectively. These 

patients will benefit from an increase in the 

dissolved oxygen concentration in the plasma.

Problems

It is important to remember that oxygen is a drug: 

high concentrations of oxygen are toxic, espe-

cially to lung tissue and the CNS, can cause 

blindness in premature infants and pulmonary 

oedema and irritation in adults, so concentra-

tions60% in the inspired air are rarely used. If

it should be given continuously and patients 

watched for any evidence of hypoventilation 

(i.e. respiratory depression), which may appear 

rapidly or develop gradually. However, it is safe 

for patients with pneumonia, pulmonary throm-

boembolism and fibrosing alveolitis, in which 

carbon dioxide retention and hypoventilation 

are unlikely.

Patients who have had hypercapnia for some 

time (e.g. in COPD) rely on a low PaO2 to provide 

their   respiratory   drive,   because   the   carbon 

dioxide and pH sensors in the respiratory centre 

become   fatigued   or   down-regulated.   Thus 

increasing the PaO2  artificially will inhibit this 

drive and may suppress respiration substantially. 

This aggravates the hypercapnia, and the raised 

carbon dioxide level finally acts as a further 

respiratory depressant (CO2 narcosis). Thus those 

patients who most need oxygen are often intol-

erant  of  it.  Optimal  delivery  of  oxygen  to 

patients with prolonged hypercapnia can only 

be achieved by careful blood gas monitoring and 

clinical supervision.

Oxygen, unless from a concentrator, is supplied 

as a pure gas that must be diluted with air to a 

suitable  concentration.  If  the  concentration 

exceeds 40% the gas should be humidified with 

a  nebulizer (preferably  warmed),  but  masks 

delivering 35%  oxygen  or  less  usually  carry 

sufficient moisture in the entrained air.

In  the  UK,  domiciliary  oxygen  equipment 

supplied through NHS sources will deliver up to 

28% oxygen, depending on the type of mask 

used.  If  concentrations  other  than  this  are 

required  the  appropriate  equipment  must  be 

purchased or provided by a hospital. This long-

term low concentration oxygen therapy has been 

shown to improve survival in type B COPD 

patients (‘blue bloaters’, p. 331) with both dysp-

noea and peripheral oedema (i.e. cor pulmonale) 

by up to 5 years. Although it does not arrest 

disease progression it does improve both exercise 

tolerance and the quality of life. In other forms 

of   severe   advanced   respiratory   disease   it 

improves well-being, but does not prolong life.

In England and Wales, oxygen equipment is 

supplied and installed by nominated suppliers in 

various regions. In Scotland, oxygen cylinders 

and   associated   equipment   are   supplied   by 

community pharmacists who have contracted to supply oxygen services. In this case, pharmacists who provide domiciliary oxygen must ensure that a member of the family or helper is available and properly instructed in the use of the equip-

ment, in addition to the patient. Oxygen is a fire hazard: it must not be used while smoking or 

near naked flames: if patients need oxygen they should not be smoking anyway!

Methods of administration

Types of supply

In hospital, oxygen is piped to bedside outlets. 

For   UK   domiciliary   use,   either   cylinders 

(containing 1360 L)  or  oxygen  concentrators 

may be supplied; the latter provide 95% oxygen 

plus 5% argon at 2 L/min, dropping to 85-90% 

oxygen at higher flow rates. Small, lightweight, 

portable   cylinders   can   be   supplied   by   the 

hospital or purchased by the patient and refilled 

from a liquid oxygen container, giving improved 

mobility to suitable patients.

Oxygen cylinders are suitable only for inter-

mittent use, giving an 11-h supply at the low 

setting (2 L/min) and half this at the high setting 

(4 L/min).   When   long-term   oxygen  therapy 

(LTOT) is required, i.e.8 h/day or21 cylin-

ders per month, oxygen concentrators are used. 

These are small portable machines for domicil-

iary use that can be set to deliver 24-28% oxygen 

via  a  nasal  cannula  at 1-2 L/min.  They  are 

cheaper and more convenient than cylinders, 

but cannot meet all types of requirement. If 

higher flows are required, two concentrators can 

be linked in parallel using a Y-piece. Although 

the initial cost is high, this is justified when 

there is a need for sustained usage, i.e. 15 h or 

more per day over a long period.

In the USA, about half a million patients use 

liquid oxygen, which is very flexible in use. A 30-

to 40-L container lasts 8-10 days at 2 L/min 

output. Liquid oxygen is available in the UK for 

patients requiring more than 2 h of ambulatory 

use, and those needing2 L/min for30 min. It 

is appropriate for patients who have exercise 

desaturation  and  in  whom  oxygen  provides 

demonstrated improvement in exercise capacity 

and dyspnoea. It is not recommended in those

Oxygen therapy361

with COPD if PaO27.3 kPa and there is no 

exercise desaturation. Small cylinders, with or 

without oxygen-conserving devices, are available 

for patients requiring oxygen for up to 4 h.

Cylinders  with  normal  head  units,  oxygen concentrators and liquid oxygen containers are unsuitable for driving nebulizers.

Tents, masks and cannulae

For  hospital  patients  who  are  severely  ill  or 

debilitated, or for whom minimal attachment 

of equipment is desirable, an oxygen tent or 

‘oxygen   hood’   may   be   used,   but   this   is 

uncommon. It is more usual to use masks, which 

cover the mouth and nose, or nasal cannulae. 

Fixed performance masks are preferable because 

the concentration delivered by variable perfor-

mance masks varies with the patient’s breathing 

pattern.

These devices are illustrated in Figure 5.29 and 

their  characteristics  are  summarized  in  Table

5.27. Nasal cannulae have the advantage that 

there is no restriction on eating, drinking and 

talking, because the mouth is not obstructed. 

Further, patients in respiratory distress often do 

not tolerate masks. Although nasal cannulae give 

poor  control  of  the  oxygen  concentration  in 

the inspired air, they are generally preferred for 

the delivery of LTOT (see below). Endotracheal 

cannulae  are  sometimes  used  in  hospital  to 

achieve better control. Oxygen concentrators are 

designed to be used only with nasal cannulae.

Reservoir systems are available to reduce the 

wastage of oxygen in the expired air and can 

reduce the oxygen requirement by about 50%. 

Pulsed  systems  that  deliver  oxygen  only  on 

inspiration can reduce this to about 25%. The 

latter are unsuitable for use with concentrators. 

These arrangements are available in the UK in 

hospitals and for providing ambulatory oxygen 

(see above).

Intermittent positive pressure ventilation (IPPV)

These devices provide control of five parameters:

•  Pressure of delivery of gas to the lungs. •  Duration of each pressure pulse 

•  Degree of oxygen enrichment of the air. •  Inspiratory trigger pressure.

•  End-expiratory pressure.

Initially, a low trigger pressure and a long, high-

pressure oxygen pulse are used, forcing gas into 

the lungs. This removes the work of breathing

from the patient but care is needed to avoid lung damage due to excessive pressures (barotrauma). As improvement occurs, the trigger pressure is increased  and  the  degree  of  assistance  and oxygen enrichment reduced. A nebulizer is used to humidify the gas, so the equipment can also be used to deliver drugs. However, if respiratory function is reasonable there is no evidence that the routine use of IPPV simply to deliver drugs is beneficial.

IPPV is instituted in hypoxaemic respiratory failure if the patient is in respiratory distress 

despite  maximal  treatment,  e.g.  exhaustion, inability to speak and a high respiration rate. 

IPPV  requires  endotracheal  intubation,  rarely tracheostomy,  and  also  skilled  initiation  and supervision. A recent innovation is IPPV via a nasal mask (non-invasive IPPV, NIPPV), which is of  particular  value  in  sleep  apnoea.  Assisted ventilation has numerous hazards.

Guidelines for domiciliary oxygen therapy

Because of the cost of providing this service and the need to select patients and define objectives carefully, the Royal College of Physicians (RCP) has published the following guidelines:

•Oxygen should be given only after a careful

evaluation of the needs of the patient and

never   as   a   placebo.   Assessment   requires 

measurement of blood gas tensions on two 

occasions at least 3 weeks apart, and not less 

than 4 weeks after an exacerbation of their 

disease, to demonstrate clinical stability.

•Patients  should  be  supervised  carefully,  at

least initially. A few patients may revert to an

adequate PaO2  (  8 kPa) after several months 

of therapy, so oxygen may then be withdrawn. 

• Intermittent   therapy,   using   cylinders,   is

suitable for patients with:

-  Hypoxaemia  of  short  duration,  e.g.  in 

asthma,   pneumonia   and   pulmonary

oedema.

-  Advanced irreversible respiratory disease to 

improve mobility and quality of life, e.g. in

COPD,  emphysema,  pulmonary  fibrosis, 

pulmonarythromboembolismand pulmonary hypertension.

•LTOT implies the use of oxygen for at least

15 h/day (including the night), so it is used

for patients with chronic hypoxaemia and cor 

pulmonale. In these cases it is more econom-

ical  to  use  a  concentrator.  The  aim  is  to 

maintain the PaO2  at about 10 kPa without 

producing   hypercapnia,   consequent   on

Oxygen therapy363

reducing   the   ventilatory   drive.   This   can usually be achieved with a nasal cannula and a flow rate of 1.5-3 L/min. Because there are advantages  for  only  a  limited  number  of patients,  the  RCP  also  defines  the  groups likely to benefit, i.e. patients with:

-COPD (FEV11.5 L, FVC2.0 L) associ-

ated with hypoxaemia when breathing air 

(PaO27.3 kPa) and hypercapnia (PaCO2

6 kPa) who have peripheral oedema.

-COPD with PaO2 7.3-8 kPa in the presence

of   secondary   polycythaemia,   nocturnal hypoxaemia,    peripheral    oedema    or evidence of pulmonary hypertension.

-Interstitial lung disease with PaO28 kPa

and those with PaO28 kPa and disabling dyspnoea.

-Cystic fibrosis when PaO27.3 kPa or if it

is in the range 7.3-8 kPa in the presence of secondary    polycythaemia,    nocturnal 

hypoxaemia, pulmonary hypertension or peripheral oedema.

-Pulmonaryhypertensionwithout

parenchymal lung involvement when PaO2 

8 kPa.

-Neuromuscular or skeletal disorders, after

specialist assessment.

-Obstructive sleep apnoea despite contin-

uous  positive  airways  pressure  therapy,

after specialist assessment.

-Pulmonary malignancy or other terminal

disease with disabling dyspnoea.

-Heart failure with daytime PaO27.3kPa

on air or with nocturnal hypoxaemia.

-Paediatricrespiratorydisease,after

specialist assessment.

Respiratory depression is seldom a problem in 

patients with stable respiratory failure treated 

with low oxygen concentrations, although it 

may occur during exacerbations. Patients, rela-

tives and carers should be warned to call for 

medical help if drowsiness or confusion occur.

•  Further criteria need to be satisfied before 

LTOT is prescribed:

-  Patients   should   be   non-smokers   and 

compliant,  already  on  optimal  medical

treatment.

-  Oxygen concentrators are more econom-

ical if patients require oxygen for8 h/day or21  cylinders/month.  Exceptionally,Cole R B, McKay D (1990). Essentials of Respiratory

the output from two can be combined.

-  A nasal cannula is preferred but may cause

nasal dermatitis and mucosal drying in 

sensitive individuals.

There are special arrangements for prescribing 

oxygen concentrators in the UK. The criteria for 

LTOT are liable to periodic revision and the BNF 

section 3.6 should be consulted for the latest 

information. Different criteria are used in other 

countries, e.g. the presence of cor pulmonale, 

oedema or polycythaemia (PCV56%). Oxygen 

may be prescribed much more loosely there, 

possibly because of the emotive nature of the 

therapy, but this lacks scientific support.

Almitrine  dimesilate  (unlicensed  in  the  UK) 

stimulates the carotid body and improves both 

ventilation and ventilation-perfusion mismatch. 

Given with oxygen, the drug further improves 

PaO2 levels.

Bạn đang đọc truyện trên: Truyen247.Pro

Tags: #ssf