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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.
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