BASIC SCIENCE FOR THE MRCS

192 SECTION TWO PHYSIOLOGY

Table 7.3 Normal daily gastrointestinal secretion volumes and electrolyte composition

Secretion Volume (L) Naþ (mmol/L) Kþ (mmol/L) ClÀ(mmol/L) HCO3À (mmol/L)
20–160
Saliva 1–1.5 20–80 10–20 20–40
Gastric juice 1–2.5 40–100 5–10 120–140 0
Bile 0.5–1.5 140–200 5–10 40–60 20–60
Pancreatic juice 1–2 130 5–10 10–60 80–120
Succus entericus 2–3 140 5 variable variable

Excessive insensible fluid loss osmotic pressure with artificial plasma substitutes,
is advantageous.
l Insensible fluid loss may be greatly increased in the l 20% albumin used for replacement of plasma
ill patient. protein:

l Pyrexia increases insensible losses by about 10% n in severe hypoproteinaemia in renal or liver
for each C rise in temperature. disease

l Loss is chiefly from the lungs as expired water n after large-volume paracentesis
vapour. n after massive liver resection.
l Some leaks through capillary membrane (in patients
l Excessive sweating causes loss of sodium-rich with capillary leak).
fluid, sweat containing about 50 mEq Naþ/L l Suppresses albumin synthesis.

l May be overlooked in the pyrexial patient in hot, Dextran
humid ward in summer months.
l Glucose polymers of different molecular weights.
COLLOID AND CRYSTALLOID l Dextran 70 formerly popular as plasma substitute.
SOLUTIONS l Interferes with cross-matching.
l Interferes with coagulation (factor VIII Q; inhibits
Colloids are osmotically active particles in solution.
platelet aggregation).
Types l Relatively high incidence of allergic reactions.

l Albumin: human albumin solution. Gelatins
l Dextran: dextran 70 in 0.9% saline or 5% glucose.
l Gelatin: polygeline (Haemaccel); succinylated gela- l Prepared by hydrolysis of bovine collagen.
l Do not affect coagulation per se.
tin (Gelofusin). l Low incidence of allergic reactions.
l Hydroxyethyl starch: hetastarch (Hespan). l Small average particle size; therefore, stay in intra-
l Pentastarch (Pentaspan).
vascular space shorter period of time.
Uses l Polygeline (Haemaccel):

l Maintenance of plasma volume. n contains Kþ; also contains Ca2þ, which can
l Acute replacement of plasma volume deficit. cause coagulation if mixed with citrated blood
l Short-term volume expansion (gelatin, dextran). in giving set
l Medium-term volume expansion (albumin, penta-
n stays shorter time in circulation.
starch). l Succinylated gelatin (Gelofusin):
l Long-term volume expansion (hetastarch).
n larger molecular weight than polygeline; there-
Albumin fore slightly longer effect

l 5% and 20% human albumin solution. n does not contain calcium.
l Used for replacement of plasma protein and expan-
Hydroxyethyl starch
sion of plasma volume.
l No evidence that maintenance of plasma albumin l Longer half-life in plasma.
l 10% solutions hyperoncotic; hence increasing
levels, as opposed to maintenance of plasma colloid
plasma volume by more than volume infused.

General physiology 7 193

l Hetastarch (Hespan): Crystalloids
n 6% in saline has largest molecular weight of
any plasma expander and therefore stays in Crystalloids are salt ions in water.
circulation longer
n most useful in capillary leak Common types
n may cause coagulopathy
n high degree of protection from metabolism. l Normal saline (0.9%).
l 4% dextrose/⅕ normal saline.
l Pentastarch (Pentaspan): l Glucose, e.g. 5% glucose or stronger solutions.
n lower degree of protection from metabolism l Sodium bicarbonate, e.g. 1.26%, 8.4%.
n shorter-lasting effect than Hetastarch. l Potassium chloride.
The content of these solutions is shown in Table 7.4.
Choice of plasma expanders
Uses
l Succinylated gelatin (Gelofusin) has most advan-
tages in acute hypovolaemia: l Provision of daily requirements of water and
n short-acting electrolytes.
n useful until blood becomes available
n no calcium, therefore does not cause coagula- l Plasma volume should be replaced with colloids,
tion if mixed with citrated blood in giving set since crystalloids are rapidly lost from plasma.
n cheap.
l Of a volume of crystalloid infused initially, one-third
l Hetastarch (Hespan): stays in intravascular compartment and two-thirds
n has most advantages in chronic (continuing) pass to ECF; therefore, risk of oedema if excessive
hypovolaemia infusion.
n longer-acting
n larger molecules better retained in circulation l Advantage that ECF deficit is replaced in shock.
when capillaries leaky, e.g. septic shock l 5% glucose is used to supply intravenous water
n high degree of protection from metabolism.
requirements, 50 g/L glucose being present to
General problems of plasma ensure an isotonic solution.
expanders l Hartmann’s solution has no practical advantages
over 0.9% saline for fluid maintenance; however,
l Dilution coagulopathy. may be useful if large volumes of crystalloid are
l Allergic reactions. exchanged (e.g. during continuous haemofiltration)
l Interfering with cross-matching (dextran 70). to maintain acid–base balance.
l Persistence of colloid effect dependent on molec- l Higher concentrations of glucose are used to
prevent or treat hypoglycaemia.
ular size and protection from metabolism. l Sodium bicarbonate is used to correct metabolic
l All artificial colloids are polydisperse, i.e. there is a acidosis.
l Potassium chloride is used to supplement Kþ in
range of molecular sizes. crystalloid fluids. Safety rules for giving Kþ include:

n urine output of at least 40 mL/h
n not more than 40 mmol to be added to 1 L of fluid
n infusion rate no faster than 40 mmol/h.

Table 7.4 Composition of common crystalloid solutions

mmol/L N saline Hartmann’s 4% dextrose/⅕ 5% Sodium
solution N Saline dextrose bicarbonate (1.26%)
Naþ 155
Kþ 0 131 30 0 150
Caþþ 0 5 0 0 0
ClÀ 2 0 0 0
HCO3 À 155 30 0 0
Osmolality (mosmol/L) 0 111 0 0
29a 284 278 150
308 280 300

a In the form of lactate which is metabolised to bicarbonate in the liver.

194 SECTION TWO PHYSIOLOGY

OEDEMA AND LYMPHATIC Arterial end Venous end
FUNCTION
Hydrostatic 32 Blood
Oedema is an increase in the volume of interstitial pressures 0 12
fluid above normal levels. (mmHg)
l A hydrostatic pressure difference across the 32 0 Interstitial
fluid
capillary endothelium results in flow from vessel Colloid 25
to tissue space. osmotic 5 12
l Retention of plasma proteins within the vasculature is pressures
an opposing force, i.e. the plasma oncotic pressure. (mmHg) 20 Blood
l The Starling equilibrium describes the relationship 25
between hydrostatic pressure, oncotic pressure
(colloid osmotic pressure) and fluid flow across 5 Interstitial
the capillary membrane. fluid
l The Starling equilibrium states:
20
n capillary hydrostatic pressure þ tissue oncotic
pressure (pressure tending to drive fluid out of Net hydrostatic Blood
the capillary) ¼ interstitial fluid pressure þ and colloid
plasma oncotic pressure (pressure tending to osmotic Interstitial
hold fluid into the capillary). pressures fluid
(mmHg) 8
The Starling equilibrium across the capillary is
shown in Figure 7.1. Filtration is favoured at the 12
arterial end of the capillary, while absorption is
favoured at the venous end of the capillary. Any fluid Filtration Reabsorption
not reabsorbed from the interstitium by the capil-
laries is returned to the circulation by the lymphatic Fig 7.1
system.
Starling equilibrium across capillary.
Causes of oedema
Obstruction to lymphatics
Causes of oedema are:
l Increased capillary hydrostatic pressure: Lymphatics remove protein and excess fluid that
has been filtered at the arterial end of the capillary
n chronic right heart failure and not reabsorbed at the venous end. If lymphatics
n venous obstruction are obstructed, then this fluid cannot return to the
n increased fluid volume (e.g. overtransfusion). vascular system and accumulates behind the ob-
l Decreased plasma oncotic pressure due to hypo- struction, causing oedema. Lymphatic obstruction
proteinaemia: may occur due to lymph node pathology as a
n starvation result of:
n cirrhosis l surgical removal, e.g. axillary clearance with
n nephrotic syndrome.
l Increased capillary permeability: mastectomy or block dissection
n inflammatory reactions l metastatic tumours
n allergic reactions. l irradiation
l Increased tissue oncotic pressure: l filariasis.
n lymphatic blockage
n protein accumulation in burns.

OSCE SCENARIOS General physiology 7 195

OSCE scenario 7.1 OSCE scenario 7.2

A 64-year-old male is admitted for a right hemico- An 82-year-old male is transferred to ITU following
lectomy and is found to have a serum sodium of a Hartmann’s procedure for perforated diverticular
120 mmol/L. disease. He has been anuric for 3 h. A number of
1. What are the possible causes of hyponatraemia fluid challenges have been given, achieving a BP of
120/90, pulse of 87 and a CVP of 10. ABG analysis
in this patient? shows a pH of 7.2 and U&Es reveal serum potas-
2. Describe what investigations you would carry sium of 7.1 mmol/L.
1. What are the possible causes of hyperkalaemia
out in order to identify the cause of the
hyponatraemia. in this patient?
3. How would you correct it? 2. What are the ECG changes associated with

hyperkalaemia?
3. What would be your possible treatment options

for this patient? Explain how each works to
lower the serum potassium.
Answers in Appendix page 455

SECTION TWO PHYSIOLOGY

CHAPTER 8

Respiratory system

INTRODUCTION n bronchoconstriction, under parasympathetic
control, leads to an increase in resistance
Components (R ) and thus a decrease in airflow

The respiratory system is composed of: n bronchodilatation, under sympathetic control,
l nasal passages leads to a decrease in resistance (R ) and thus
l olfactory system an increase in airflow.
l conducting airways:
l Protection against inhaled foreign material:
n nasopharynx n inhaled air is filtered by the nasal hairs
n larynx n any particles passing through the nose become
n trachea trapped on the mucus coating the airways
n bronchi n motile cilia lining the airways transport the
n bronchioles mucus to the pharynx, where it is swallowed
n respiratory portions of the lung (alveoli). n the epiglottis closes during swallowing, thus
preventing food matter from entering the
Function airways
n if any food matter is inhaled it stimulates a
The functions of the respiratory system include: reflex cough that will expel the material.
l cleaning of inhaled air
l warming or cooling of inhaled air l Warming and humidifying gases:
l moistening of inhaled air n as inhaled air passes through the respiratory
l respiratory gas exchange system it is warmed and saturated with water
l facilitation of olfaction and sound production. vapour; this produces a water vapour pressure
of 6.3 kPa (47 mmHg) at 37 C.

Airway function MECHANICS OF VENTILATION

The airways have three main functions: Pulmonary ventilation

n passage of inhaled gases l At the beginning of inspiration the intrapleural
n protection against inhaled foreign material pressure is around À4 cmH2O.
n warming and humidification of inhaled gases.
l Passage of inhaled gases: l Contraction of the respiratory muscles increases the
n the flow of gases depends on the pressure gra- volume of the chest; this decreases the intrapleural
pressure to about À9 cmH2O.
dient between the atmosphere and the alveoli
l The change in intrapleural pressure causes the lungs
Airflow ðVÞ ¼ PAlveoli À PAtmosphere to expand, and thus generates a negative intra-
R alveolar pressure as the alveoli are pulled open.

V ¼ rate of airflow l As the atmospheric pressure is higher and air flows
P ¼ pressure from high to low pressure, air is inhaled (approxi-
R ¼ resistance mately 500 mL air during quiet ventilation).
n the smooth muscle within the bronchi and
bronchioles can influence airflow l During exercise, other accessory muscles of respi-
ration are used and can generate more negative
196

Respiratory system 8 197

intrapleural pressures, i.e. À30 cmH2O. Pressures l The pressure in the alveoli equals the atmospheric
of this magnitude can lead to the inhalation of pressure as they are both in direct contact via the
2–3 L of air. airways; atmospheric pressure is zero and the intra-
l Expiration is a passive process due to the elastic pleural pressure is between À4 and À9 cmH2O.
recoil of the chest wall. This produces the transmural or transpulmonary
l During exercise, contraction of internal intercostals pressure; it is this that keeps the lungs distended.
and abdominal muscles can generate intrapleural
pressures as high as þ20 cmH2O to expel air more Surfactant and surface tension (Fig. 8.2)
rapidly.
l Phase one: it takes a considerable pressure
Lung pressures (Fig. 8.1) increase before there is a change in volume.

l There are three forces acting on the lung: l Phase two: expansion of the lung is proportional to
n elastic nature of the lungs: under normal con- the increase in pressure.
ditions the lungs are stretched; this results in a
force that pulls inwards on the visceral pleura l Phase three: maximum capacity.
n Surfactant: lines the alveoli and exerts an l Phase four: in the initial stage the lung volume is
inward or collapsing pressure
n negative intrapleural pressure: opposes the maintained until the pressure has fallen consider-
above two forces. This negative pressure is ably (approximately 8 cmH2O).
created by the chest wall and diaphragm pull- l The unequal pressure needed to maintain a given
ing the parietal pleura outwards. As the two lung volume in inspiration and expiration is called
layers of pleura are pulled in opposite direc- hysteresis.
tions, they generate a negative pressure. l Surfactant is a phospholipid-rich detergent pro-
duced by type II alveolar cells; it coats the luminal
Inspiration Expiration surface of alveoli and produces a force called
surface tension.
Volume (L) 4.0 l Surface tension is present at all air–fluid interfaces.
l Surface tension occurs because water molecules are
Pressure (cmH2O) 3.5 attracted more to each other than they are to gas
molecules. When any liquid surrounds a gas, i.e. in
3.0 the alveolus, this produces an inward pressure.
l Lungs inflated with normal saline do not exhibit hys-
A 2.5 teresis; there is no air–fluid interface, so there is no
+2 surface tension; the only force opposing expansion
0 is the elasticity of the lung parenchyma.
–2 l In air-inflated lungs the surface tension at the air–
–4 fluid interface opposes expansion; surface tension
–6 accounts for almost two-thirds of the elastic recoil
–8 of the lungs.
l Surfactant has several other functions:
B –10
+1 n by lowering the surface tension, surfactant
increases compliance and reduces the work
Pressure (cmH2O)0 of breathing

C –1 n prevents fluid accumulating in the alveoli
Fig 8.1 n reduces the tendency of alveoli to collapse
Graphs demonstrating the relationship between A
lung volume, B intrapleural, and C intra-alveolar (alveolar instability).
pressure during normal quiet respiration. l Alveolar instability is related to changes in alveolar

diameter and can be explained by the law of
Laplace:

DP 1 T
r

DP: alveolar distending pressure
T: surface tension
r: radius

198 SECTION TWO PHYSIOLOGY

Inflation with Inflation with
saline air

200 Phase 3

150 Phase 4

Volume (ml)100 Phase 2
Volume above FRC (L)
50 –10 Fig 8.2
Pressure (cmH2O)
Phase 1 Graph illustrating the differences in
0 compliance between the lungs inflated with
air and the lungs inflated with saline. The
0 –20 greater compliance in saline-filled lungs is
explained by the lack of surface tension.

l As alveoli decrease in size the radius (r) will tend to 0.5
increase (assuming surface tension [ T ] remains
constant). If surfactant were not present, this would 0.4 Expiration
mean that pressure would be greater in small alve-
oli and lower in larger alveoli; this would result in 0.3
collapse of the alveoli as air moves from the smaller Compliance
to the larger alveoli. Inspiration

l As the alveolar radius decreases then the concen- 0.2
tration of surfactant increases and thus reduces
surface tension ( T ). Therefore, surface tension 0.1
and radius increase or decrease in tandem and
this results in very little change in alveolar 0
pressure. –1 –2 –3 –4 –5 –6 –7 –8 –9 –10
Pressure (cmH2O)
Compliance (Fig. 8.3)
Fig 8.3
l Compliance is the ease with which the lungs can be Pressure–volume curve for a single respiratory cycle.
inflated: It represents the volume change if the work of
respiration was against elastic resistance only. To
Compliance ¼ DV the right of the compliance line represents the
DP additional pressure required to overcome airflow
resistance and other resisting forces. To the left of
500 mL the compliance line is the work required during
¼ passive expiration.

5 cmH2O l Normal lungs have high compliance as the elastic
¼ 100 mL=cmH2O tissue is easily stretched and surfactant reduces
surface tension.
DV : change in volume
DP : change in pressure l Conditions which decrease compliance include:
qcompliance means lungs are easy to expand. n scarring or fibrosis of lung parenchyma
Qcompliance means lungs resist expansion. n pulmonary oedema
l Two principal factors govern compliance:
n elasticity of the lung parenchyma
n surface tension.

Respiratory system 8 199

n deficiency of surfactant, e.g. premature babies Volume above FRC (L)1.0 Work against X = Work of
n decreased lung expansion, e.g. respiratory elastic expiration

muscle paralysis elements X + Y = Work of
n supine position inspiration
n mechanical ventilation (due to reduced pulmo- X

nary blood flow) Y
n age
n breathing 100% O2. Work against airways
l Conditions which increase compliance include: resistance, friction and
n emphysema (due to destruction of elastic fibres inertia

in the lung parenchyma). 20 –2 –4 –6 –8 –10
A Change in pressure (cmH2O)
Respiratory muscles
1.0 X Y
See anatomy section (Chapter 1).
Volume above FRC (L)
Work of breathing (Fig. 8.4)
Volume above FRC (L)2 0 –2 –4 –6 –8 –10
l Work of breathing is the work required to move the B Change in pressure (cmH2O)
lung and chest wall.
1.0
l During inspiration, work consists of two C
components: X
n work needed to overcome the elastic forces of
the chest wall and lungs 2 0 –2 –4 –6 –8 –10
n work needed to overcome non-elastic forces of C Change in pressure (cmH2O)
the chest wall and lungs.
Fig 8.4
l Non-elastic forces include: A Graph demonstrating the work of respiration. The
n airway resistance (most significant) increasing volume above FRC is plotted against the
n frictional forces change in intrapleural pressure. The work of inspiration
n inertia of the air and tissues. is greater than expiration. Energy for expiration is from
the stretching of elastic lung tissue. B The increased
l One-third of airway resistance occurs in the upper pressure required to move an equal volume of air with
airways—nose, pharynx and larynx. This can be reduced lung compliance. C The increased resistance to
greatly reduced by breathing through the mouth expiration and increased energy required to expire a
(e.g. during exercise). similar volume of air in a patient with increased airways
resistance.
l Two-thirds of the resistance is in the tracheobron-
chial tree, mainly in the medium-sized bronchi (high
flow but low cross-sectional area).

l Resistance in the terminal bronchioles is very low
due to the high cross-sectional area.

l Resistance falls as the volumes of the lungs in-
crease; the elastic parenchyma pulls open bronchi-
oles and thus resistance decreases.

Regional variations in ventilation

(Fig. 8.5)

l In the upright position the lung is not evenly venti-
lated; the upper parts are not ventilated as well as
the lower parts.

l There are two reasons to explain this:
n the weight of the lungs
n the compliance curve is sigmoid, and the upper
and lower parts of the lung lie on different parts
of this curve.

200 SECTION TWO PHYSIOLOGY

100

90

V
80

P

70

% Lung volume 60

50
40 V

30 P
FRC

20 X

10

0

0 15 30 cmH2O
Transpulmonary pressure

Fig 8.5

Pressure–volume curve for lung inflation and its influence on the distribution of ventilation during inspiration
from FRC.

l Transpulmonary pressure is the difference between n cancer
the intrapleural pressure and the alveolar pressure. n lung abscess.

l During phase one, when the lung volume is near resid- Traumatic (closed) pneumothorax
ual volume, the compliance is low, thus it takes a large l Iatrogenic, e.g. mechanical ventilation or lung
change in pressure to cause a change in volume.
biopsy.
l In phase two, the compliance is at its maximum and l Non-iatrogenic, e.g. stab wound or road traffic
lung volume increases linearly with an increase in
pressure. accident.

l In phase three, the compliance falls as the lungs Tension pneumothorax
become fully expanded. l A pneumothorax occurs when air enters the pleural

l The lower parts of the lungs lie on the diaphragm and space due to the disruption of either the visceral
are compressed, whereas the upper parts are already (ruptured pleural bleb) or parietal pleura (stab
stretched by their own weight; therefore, inflation wound).
begins further along the pressure–volume curve. l The air entering the pleural space leads to loss
of the negative intrapleural pressure and thus
Clinical physiology the lung collapses; this is the type of pneumotho-
rax seen in spontaneous and traumatic closed
Pneumothorax pneumothoraces.
l In a tension pneumothorax the lung injury may form
There are a number of types of pneumothorax: a valve in which air leaks into the pleural cavity dur-
ing inspiration but closes during expiration; this
Spontaneous (primary) pneumothorax leads to a positive intrapleural pressure (can be
l Occurs in young males. The cause is unknown; as high as 20 cmH2O), and pushes mediastinal
structures into the opposite side of the chest.
there is rarely any associated respiratory disease.
Occasionally the patient has Marfan’s syndrome Open pneumothorax or ‘sucking’ chest wound
with an associated apical pleural bleb. l In an open pneumothorax there is a defect in the

Spontaneous (secondary) pneumothorax chest wall, e.g. due to a gunshot wound; this allows
l Occurs in patients due to underlying respiratory intrathoracic pressure to equalise with atmospheric
pressure. If the defect is greater than two-thirds of
pathology; causes include:
n asthma
n chronic obstructive pulmonary disease (COPD)

Respiratory system 8 201

Box 8.1 Values for respiratory variables in a healthy n functional residual capacity (FRC): the volume
adult male of gas left in the lungs after expiration during
normal breathing
Lung volume Value (L)
n residual volume (RV): the volume remaining
Total lung volume 6.0 after maximal expiration; it cannot be mea-
sured directly but can be estimated from other
Vital capacity 4.8 lung volumes:

Residual volume 1.2 RV ¼ FRC À ERV

Tidal volume 0.5 n total lung capacity (TLC): the sum of all lung
volumes plus the residual volume
Functional residual capacity 2.2
n vital capacity (VC): the volume of air that is
Inspiratory capacity 3.8 expelled from maximal inspiration to maximal
expiration.
Expiratory reserve volume 1.0
l Normal spirometry traces are shown in Figure 8.6;
the diameter of the trachea then air will preferen- they may vary for size, weight and gender.
tially enter through the hole in the chest wall as this
is the path of least resistance; this leads to impaired l The FRC can be determined by the helium dilution
ventilation and hypoxia. method. The subject breathes normally from a
spirometer filled with a known volume of air and
Pulmonary assessment helium. As the subject breathes in and out the
helium is diluted in the air that is left in the lungs:
Lung volumes (Box 8.1)
FRC ¼
l Lung volumes can be measured using a spirometer.
l The definition of each lung volume is as follows: ðInitial helium concentrationÞ Â volume of spirometer
ðFinal helium concentrationÞ
n tidal volume (TV): the air taken in and exhaled
during quiet breathing l The RV can be calculated by the same method, but
the subject takes a maximal expiration (i.e. only RV
n inspiratory reserve volume (IRV): the maximum in the lungs) before breathing from the spirometer.
volume of air that can be inspired in excess of
normal inspiration Dead space and alveolar ventilation
rate
n expiratory reserve volume (ERV): the maximum
amount of air that can be forcefully expired l Dead space is the volume of air which has to be
after normal expiration ventilated, but does not actually take part in gas
exchange.

8Litres
Inspiratory
7 reserve
volume
6 Tidal

5 volume
Inspiratory
4 capacity

3 Vital
capacity
2 Expiratory
Expiratory capacity
Total lung capacity
1 reserve
volume Residual Functional residual
volume capacity
0
Time
Fig 8.6
Normal adult lung volumes.

202 SECTION TWO PHYSIOLOGY

EXP
100

Vol. expired (mL) % N2 50
Mid-point

200
150 Vol. of dead space

100

Fig 8.7
Fowler’s method for determination
0 of the anatomical dead space.

l Dead space can be anatomical or physiological: l A plot of exhaled volume to nitrogen concentration
n anatomical dead space is the volume of gas is produced; the dead space is the volume at the
that does not mix with the air in the alveoli midpoint between nitrogen first being detected
n physiological dead space is the volume of gas and its plateau.
that may reach the alveoli but, due to a lack of
perfusion, does not take part in gas exchange l Physiological dead space can be determined from
(this includes air in the anatomical dead space). the Bohr equation.

l The anatomical dead space can be determined l The principles of this equation rely on two facts:
using Fowler’s method (Fig. 8.7). The subject n all of the expired CO2 comes from the alveoli
breathes through a tube connected to a nitrogen n dead space is atmospheric air and thus has
analyser. The subject takes a single breath of pure negligible CO2 content.
oxygen, holds the breath for several seconds and
then breathes out. By performing this manoeuvre l The Bohr equation is:
the composition of air within the alveoli will differ
from that within the airways (i.e. alveoli will contain
nitrogen but airways higher up will have pure 1 À FE
oxygen). VD ¼ VE FA

l Subject breathes out pure O2 (from conducting VD: volume of dead space
airways). VE: volume of expired CO2
FE: fraction of expired CO2
l As subject starts to expire, the nitrogen content of FA: fraction of alveolar CO2
alveolar air is measured. l FE can be measured simply by measuring the CO2
content of expired air.

Respiratory system 8 203

Box 8.2 Factors increasing anatomical and l The significance of the closing capacity is that as air
physiological dead space leaves the lungs some airways close and trap air in
the alveoli; these alveoli cannot play a full part in
Anatomical dead Physiological dead respiratory gas exchange.
space space
l Closing capacity can be measured by the following
Increasing size of the Hypotension technique:
subject n the subject breathes out to residual volume and
then takes a maximal inspiration of 100% O2
Standing position Hypoventilation n the subject then takes a full expiration through
a nitrogen meter
Increased lung volume Emphysema and PE n the plot of nitrogen concentration to lung vol-
ume gives a characteristic plot with four phases
Bronchodilatation Positive pressure (Fig. 8.8):
ventilation l phase 1: pure dead space is exhaled and is
therefore 100% O2
l FA can be measured from: l phase 2: mixture of dead space and alveolar
n the last part of the expired air, which will have gas (nitrogen concentration from alveoli
the same composition as alveolar air increases concentration)
n arterial blood gas (more accurate). l phase 3: pure alveolar gas (plateau phase)
l phase 4: abrupt increase in nitrogen con-
l For a normal subject with a tidal expiration of centration as airways at the base of the lung
500 mL, expired CO2 ¼ 3.5% and alveolar close. Expired air at this point is from the
CO2 ¼ 5%; the dead space: apex, which has received less O2, and thus
the nitrogen is less dilute.
01
l Closing capacity is normally 10% of the vital capacity.
VD ¼ 500@1 À 3:5A l Factors affecting the closing capacity include:
5:0
n age: increases with age
VD ¼ 500 mL n posture: in a supine position in a 40-year-

l Factors that increase anatomical and physiological old subject, the closing capacity is equal to
dead space are given in Box 8.2. the FRC
n anaesthesia: decrease in lung volumes results
l Alveolar ventilation rate is the rate at which gas in in closing capacity exceeding FRC, even in the
the alveoli is replaced: youngest patients.

Alveolar ventilation rate ¼ ðTV À dead spaceÞÂ Flow–volume and volume–time curves
Respiratory rateðRRÞ
l Spirometry values should always be assessed with
¼ ð500 À 150Þ Â 12 flow–volume and volume–time curves. Diseases of
¼ 4.2 L=min the lung produce characteristically shaped curves.

Peak expiratory flow rate (PEFR) l Flow–volume curves (Fig. 8.9).
l Volume–time curves (Fig. 8.10).
l A simple bedside test of respiratory function.
l Patient is asked to take maximal inspiration and Diffusion capacity

then to blow out as fast as possible into the peak l Diffusion capacity (DLCO) or transfer factor (TLCO) is
flow meter. a test that reflects both the diffusion capacity of
l Values will vary for age, sex and weight, but a value the alveolar membrane and also the pulmonary
of around 4–500 L/min is normal. vasculature.
l Values will fall dramatically in respiratory disease;
PEFR is particularly useful in assessing the severity l It can be measured by inhaling very small concen-
of acute asthma attacks. trations of carbon monoxide and measuring the
increase in arterial CO.
Closing capacity
l DLCO is reduced with:
l This is the volume of the lungs at which small air- n qin diffusion distance, i.e. pulmonary oedema
ways at the base of the lung start to close. n loss of alveolar area, i.e. emphysema.

204 SECTION TWO PHYSIOLOGY

100 2 3 4
1

% N2

Closing
capacity

Fig 8.8

The concentration of nitrogen

following a single inspiration of

100% oxygen. The closing capacity

is indicated at the point of abrupt

TLC FRC CC RV increase in the nitrogen

Lung vol. (L) concentration.

PULMONARY BLOOD FLOW n pressure in the pulmonary veins (PV)
n pressure of air in the alveoli.
Structure of the lung l With these forces in mind the blood flow to the lung
can be divided into three zones:
See Anatomy section (Chapter 1). n zone 1: this is at the apex of the lung; the

Regulation of pulmonary blood flow alveolar pressure is similar to the PA pressure;
smaller vessels will be compressed and resis-
l Pulmonary arterioles do not appear to play an im- tance will be high. Blood flow is low in this zone
portant role in the regulation of pulmonary blood n zone 2: pressure in the PA is higher than the
flow, but the calibre of small alveolar vessels is alveolar pressure; blood flow is better in this
altered by the P O2 and P CO2. zone, increasing towards zone 3
n zone 3: PA pressure greatly exceeds the
l Hypoxia (QP O2) or hypercapnia (qP CO2) result in alveolar pressure and thus vessels are fully
constriction of vessels and thus divert blood to open. Blood flow is very good.
areas that are better oxygenated; this is termed l The variations in regional blood flow are abolished
hypoxic pulmonary vasoconstriction (HPV). on lying down.

l This is a local response and differs from other vas- Cardiac output and pulmonary
cular beds in that the opposite response is usually vascular resistance
seen (i.e. hypoxia causes vasodilatation).
l During exercise the CO to the lungs increases but
Regional variations in pulmonary the pressure within the PA changes relatively little;
blood flow this is due to two mechanisms which decrease
resistance when CO increases:
l Perfusion pressure and resistance determine flow. n distension of vessels already open
l Pressure in the pulmonary artery is low in compar- n recruitment of additional vessels (at rest many
capillaries are closed).
ison with the systemic circulation: 25/8 mmHg
compared with 120/80 mmHg. l The response to the increase in CO is passive.
l Blood flow in the lung is determined by three pressures:

n hydrostatic pressure in the pulmonary arteries
(PA)

Respiratory system 8 205

Flow (L/s) Vol (L) Ventilation and perfusion
Normal
l Ventilation and perfusion (V/Q) varies throughout the
A TLC RV lung depending on the height above or below the
origin of the PA.
Flow (L/s) Vol (L)
Obstructive l The V/Q ratio expresses this variation:
n in alveoli that are ventilated but not perfused
B TLC RV V/Q ¼ infinity
n in alveoli that are perfused but not ventilated
Flow (L/s) Vol (L) V/Q ¼ 0
Restrictive n at the apex V/Q ¼ 3, thus indicating that the
alveoli are ventilated better than they are
C TLC RV perfused
Fig 8.9 n at the base V/Q ¼ 0.6, thus indicating that the al-
A A normal flow–volume curve, B an obstructive veoli are perfused better than they are ventilated
defect with characteristic concave shape during n the ideal V/Q ¼ 1 and is found approximately
expiration, and C the relatively unaffected shape but two-thirds of the way up the chest
significantly decreased volume seen in restrictive n the average V/Q ratio, assuming an alveolar
lung disease. ventilation rate of 4.2 L/min, and a cardiac out-
put of 5 L/min, would be 0.84.

Clinical physiology

Pulmonary embolus

l A pulmonary embolus results from a thrombus
breaking off from a thrombus formed in the large
leg/pelvic veins; this clot then lodges in the pulmo-
nary arteries.

l A pulmonary embolus can also occur with fat, amniotic
fluid, air or tumour fragments; these are all very rare.

l The effect of the embolus will depend on its size:
clinical presentation varies from complete obstruc-
tion and sudden death, to the insidious development
of hypoxia due to numerous small emboli.

l The physiological changes associated with a pul-
monary embolus include:
n increased pulmonary vascular resistance
n pulmonary hypertension
n increased right ventricle (RV) afterload (leading
to RV dilatation and dysfunction)
n reduced left ventricle output
n impaired gas exchange, due to shunting of
blood through non-perfused segments of lung
n decreased lung compliance, due to bleeding
and loss of surfactant over the area affected
by the embolus.

Pleural effusion

l This refers to the abnormal presence of fluid within
the pleural cavity.

l The physiological consequences are similar to those
of pneumothorax, i.e. hypoxia occurs as lung tissue
is compressed by the fluid and prevents normal gas
exchange.

206 SECTION TWO PHYSIOLOGY

Normal
Restrictive

Volume
Normal

Obstructive

FEV1 FVC Fig 8.10
Time FEV1/FVC ratios. Normal ¼ 4 L/5 L ¼ 80%.
Obstructive FEV1/FVC ¼ 1.2/3 ¼ 40%.
l The fluid can be classified as a transudate or an Restrictive FEV1/FVC ¼ 2.9/3.2 ¼ 93%.
exudate:
n an exudate has a high protein content (> 30 g/L) n increased airway resistance: this can occur due
and is usually due to infection or cancer to the reduction in lung volume and fluid filling
n a transudate has a low protein content (< 30 g/L) the airways. Resistance is also due to reflex
and most commonly is due to left ventricular bronchoconstriction.
failure.
l Alveolar oedema leads to a ventilation–perfusion
Pulmonary oedema mismatch as alveoli filled with fluid are still per-
fused but not ventilated.
l Pulmonary oedema is the abnormal accumulation of
fluid in the lung parenchyma. l Pulmonary vascular resistance increases due to
hypoxic vasoconstriction and external compression
l Starling’s law states that hydrostatic forces push from interstitial oedema.
fluid out of the circulation and osmotic forces draw
fluid back. l There are numerous causes of pulmonary oedema;
these include:
l Normally the balance of hydrostatic and osmotic n raised pulmonary hydrostatic pressure, the
forces leads to 20–30 mL of excess fluid in the lung commonest cause, occurs with left ventricular
interstitium; this is transported back to the circula- failure—left atrial pressure rises and this is
tion as lymph. transmitted into the pulmonary circulation,
resulting in increased pulmonary capillary pres-
l Pulmonary oedema occurs in stages: sure, and thus capillary hydrostatic pressure.
n interstitial oedema: this has little effect on This type of pulmonary oedema can also be
respiration, but will eventually overwhelm seen with fluid or transfusion overload
lymphatic recirculation and lead to alveolar n increased pulmonary capillary permeability:
oedema this can occur with endotoxic shock, irritant
n alveolar oedema: as alveolar oedema develops, gases and adult respiratory distress syndrome
the alveoli fill with fluid; this increases surface (ARDS)
tension and causes the alveoli to shrink n blocked lymphatic drainage: this can occur in
n airway oedema: as fluid accumulation con- the face of normal pulmonary hydrostatic
tinues then fluid will begin to fill the airways; pressures and normal capillary permeability.
this presents as blood-tinged frothy sputum. The commonest cause is obstruction of
lymphatics due to tumour cells. The normal
l The physiological effects of pulmonary oedema 20–30 mL of interstitial fluid normally re-
include: moved by lymphatics accumulates and leads
n decreased lung compliance due to the reduc- to pulmonary oedema—it is called lymphangitis
tion in surface tension and alveolar shrinkage carcinomatosa

Respiratory system 8 207

n high altitude: the exact cause is unclear, but is n tissue factors: the tissue at the site of diffusion
likely to be due to hypoxic vasoconstriction lead- should have a large surface area and a short dif-
ing to elevated pulmonary artery pressure and fusion distance. The surface area of the lungs is
thus an increase in the hydrostatic pressure about 70 m2 and the diffusion distance is 0.2 mm.

n neurogenic: frequently seen in severe head l The diffusion distance for oxygen consists of:
injury patients, it is thought to occur due n pulmonary surfactant
to overactivity of the sympathetic nervous n alveolar epithelium
system. n alveolar epithelium basement membrane (BM;
often fused with capillary BM)
Adult respiratory distress syndrome n pulmonary capillary endothelium.

l ARDS is the pulmonary component of the systemic Gas exchange (Table 8.1)
inflammatory response syndrome (SIRS).
l The exchange of gases in both peripheral tissues and
l It can be caused by direct (contusion, near drown- alveoli relies on partial pressure gradients. In alveoli
ing, aspiration, smoke inhalation) or indirect the gradient is between alveolar gas and pulmonary
(trauma, sepsis, pancreatitis) insults. blood gas, while in the periphery the gradient is be-
tween capillary blood and metabolically active tissues.
l Criteria for its diagnosis include:
n known cause l Room air: mixture of nitrogen and oxygen, water va-
n acute onset of symptoms pour (variable) and a tiny amount of carbon dioxide.
n hypoxia refractory to O2
n new, bilateral ‘fluffy’ infiltrates on chest X-ray l Humidified air: inspired air becomes fully saturated
n no evidence of cardiac failure (pulmonary artery with water; the partial pressure of water vapour is
wedge pressure < 18 mmHg). 6.3 kPa; the addition of water vapour leads to a
decrease in the partial pressures of all other gases.
l ARDS develops in two phases:
1) acute exudative: the insult (direct or indirect) leads l Alveolar air: differs from room air due to the addition
of water vapour and the constant removal of oxygen
to neutrophil activation and the release of inflam- and carbon dioxide (QO2 and qCO2).
matory mediators such as tumour necrosis factor
(TNF), platelet activating factor (PAF), interleukin Gas transport (Fig. 8.11)
IL-1 and IL-6; there is also the release of proteases
and toxic oxygen radicals that damage the lung l Systemic venous blood is pumped into the pulmo-
parenchyma. This lung damage leads to increased nary artery from the right ventricle. P O2 is 5.3 kPa
capillary permeability and allows protein-rich and P CO 2 is 6 kPa. Alveolar P O2 is 13.7 kPa and
exudates to fill the alveoli and form hyaline the P CO2 is 5.3 kPa.
membranes. There is thrombosis in alveolar capil-
laries and haemorrhage into the alveoli. This leads l Following the principle of gases flowing from areas
to alveolar collapse and decreased surfactant pro- of high partial pressure to low partial pressure,
duction, leading to increased lung compliance oxygen will diffuse into the blood and carbon
2) late organisation: there is regeneration of type II dioxide will diffuse into the alveoli.
pneumocytes; the hyaline membranes organise
with pulmonary fibrosis, leading to interstitial l Oxygenated blood is returned to the heart via the
fibrosis and obliteration of alveolar spaces and pulmonary veins and then to the left ventricle.
alveolar microvasculature.
l P O2 of systemic blood is slightly lower than pulmonary
venous blood, due to the addition of deoxygenated
blood from bronchial veins (13.7 kPa ! 13 kPa).

GAS DIFFUSION AND EXCHANGE Table 8.1 Standard values for respiratory gases

Gas diffusion Room Humidified Alveolar air
(kPa)
l Three factors affect the diffusion of gases, both in Gas air (kPa) air (kPa)
the lungs and in the peripheral tissues:
n pressure gradient: gas flows from an area of N2 79.79 74.83 75.6
high pressure to an area of low pressure. This O2 21.17 19.87 13.7
is usually referred to as the partial pressure CO2 0.04 0.04 5.3
n diffusion coefficient: a measure of the ease with H2O 0 6.3 6.3
which a gas can diffuse. It is determined by its Total 101 101 101
solubility in water and its molecular weight

208 SECTION TWO PHYSIOLOGY

PO2 = 13.7 Alveoli l Oxygen dissociation curve (Fig. 8.12):
PCO2 = 5.3 n the oxygen dissociation curve illustrates the re-
lationship between the partial pressure of O2
O2 and the concentration of O2 in the blood
CO2 n the characteristic shape of the curve reflects
the increasing ability of Hb to take up O2 follow-
Pulmonary PO2 = 5.3 PO2 = 13.7 Pulmonary ing the binding of the first molecule
artery PCO2 = 6 PCO2 = 5.3 vein n the curve reaches a plateau at a PO2 of around
15–16 kPa
Right Left n a number of factors will alter the position of the
heart heart curve. A right shift decreases oxygen affinity
and thus oxygen will be released at a higher
Systemic PO2 = 5.3 PO2 = 13 Systemic partial pressure. A left shift increases oxygen
vein PCO2 = 6 PCO2 = 5.3 artery affinity
n a right shift is caused by:
Fig 8.11 l qtemperature
The gas exchange between the lungs and tissues. l q2,3-diphosphoglycerate (2,3-DPG)
l qHþ
l The deoxygenated blood from bronchial veins is n the right shift of the dissociation curve is called
referred to as ‘shunting’; it describes the passage of the Bohr effect; the factors causing a right shift
blood through the lungs without coming into contact would be present in active tissues; the Bohr
with ventilated alveoli. Other causes of shunt include: effect represents a mechanism to increase
n pneumonia (due to consolidation of lung oxygen extraction
parenchyma) n anaemia does not affect the dissociation curve.
n atrial septal defect The shape and position are the same; to see the
n ventricular septal defect effect of anaemia you would need to plot partial
n patent ductus arteriosus. pressure against oxygen content.

Oxygen transport l Fetal haemoglobin and myoglobin:
l Haemoglobin: n fetal haemoglobin (HbF) has different globin
chains to adult Hb (two a and two g); the
n consists of four peptide chains; two a and change in globin chain results in a greater
two b. Each peptide has a haem group which affinity for O2 and allows the fetus to extract
consists of a protoporphyrin ring surrounding blood from the maternal circulation
a ferrous iron molecule (Fe2þ) n the curve for HbF is to the left of adult Hb,
reflecting the increased affinity for O2
n each haemoglobin (Hb) molecule can carry four n the curve for myoglobin lies further to the left; it
oxygen molecules acts as an oxygen storage molecule and only
releases O2 when the partial pressure has fallen
n normal Hb for a male and female are 15 g/dL considerably
and 13 g/dL, respectively. Each gram of Hb n the function of myoglobin is to provide additional
can carry 1.34 mL of O2, therefore O2-carrying O2 in muscles during periods of anaerobic respi-
capacity varies between 20 and 17.5 mL per ration (i.e. during sustained contractions when
100 mL blood blood vessels are compressed).

n the vast majority of O2 is transported via Hb; Carbon dioxide transport
only a negligible amount is dissolved, approxi- l Carbon dioxide is transported in three main ways:
mately 0.225 per kPa of O2.
n carbamino groups: these are formed between
CO2 and proteins or peptides. Most of these reac-
tions are with the globin portions of haemoglobin,
accounting for 20–30% of transported CO2

n dissolved CO2 accounts for about 10% of the
transported CO2

Respiratory system 8 209

100

90

80

70

Saturation (%) 60

50

40

30

20

10

0
0 1 2 3 4 5 6 7 8 9 10 11 12 13

A PaO2 (kPa)

100 Myoglobin
100

75 75 Fetal Hb

50O2 saturation (%) PCO2, [H+] Adult Hb
O2 saturation (%)2,3-DPG50

TºC

25 25

PO2 PO2
0 0

0 2 4 6 8 10 12 14 16 (kPa) 0 2 4 6 8 10 12 14 16 (kPa)

B 0 20 40 60 80 100 120 (mmHg) C 0 20 40 60 80 100 120 (mmHg)

Fig 8.12

A Oxyhaemoglobin dissociation curve, B factors that shift the oxyhaemoglobin curve to the right and increase O2
dissociation, and C different O2 affinities for fetal haemoglobin and myoglobin in comparison with the O2

dissociation curve for adult Hb.

n HCO3À accounts for about 60–70% of the l The CO2 dissociation curve is for total CO2 and not
transported CO2. The CO2 diffuses into the one form; there are several differences between it
red blood cells and reacts with water to form
and the oxygen dissociation curve (Fig. 8.13):
carbonic acid (a reaction catalysed by the en- n the solubility of CO2 is greater than oxygen
n the normal range of CO2 is much smaller: 5.3–
zyme carbonic anhydrase). The carbonic acid 6 kPa compared with 5.3–13.3 kPa for oxygen
dissociates into Hþ and HCO3À; the Hþ binds
to haemoglobin and the HCO3À diffuses out n blood cannot be saturated with CO2, therefore
of the cell into the plasma. To maintain cellu- the graph has no plateau phase.
lar balance ClÀ diffuses into the red cell (chlo-
l The CO2 dissociation curve is influenced by the par-
ride shift). This process is reversed in the tial pressure of O2. Essentially the amount of carbon
dioxide carried increases as the oxygen level falls;
alveoli, producing CO2 in preparation for this effect is called the Haldane effect.
expiration.

210 SECTION TWO PHYSIOLOGY

60 Low (venous) PO2

CO2 contents (ml 100 mL–1 blood) 55 Y
High (arterial) PO2
50
X
45
5 67 Pco2 Fig 8.13
40 40 50 8 (kPa)
4 60 (mmHg) The CO2 dissociation curve—Haldane
effect. X indicates CO2 content in systemic
30 arterial blood (qO2) and Y indicates CO2
content in venous blood (QO2)

l The significance of the Haldane effect is that as increased respiration they fire action potentials
arterial blood (P CO2 5.3 kPa) passes through the during the inactive period of the inspiratory
capillary network (P CO2 6 kPa), the dissociation neurons to stimulate the internal intercostals
curve moves upwards and allows the increased and abdominal muscles to contract, and thus
uptake of CO2. aid expiration.
l Pons: there are two areas within the pons; they are
REGULATION OF RESPIRATION not essential for respiration, but can influence the
pattern of breathing:
The body maintains the amount of P O2 and P CO2 at n apneustic centre: this is located in the lower
appropriate levels through an interaction between pons; it tends to prolong inspiration and results
neurological and chemical control mechanisms. in short expiratory efforts
n pneumotaxic centre: this is located in the upper
Neurological regulation pons; it tends to inhibit the inspiratory neurons
and shortens inspiration.
l There are a number of areas in the brain that exert l Cerebral cortex: this can over-ride the neurons
differing degrees of control on respiration. These within the medulla and increase ventilation (hyper-
areas include: ventilate) or hold the breath.
n medulla oblongata l Limbic system and hypothalamus: in extreme states
n pons of emotion, such as fear or anger, these areas may
n cerebral cortex influence the respiratory pattern.
n limbic system and hypothalamus.
Chemical regulation
l Medulla oblongata: there are two groups of cells
within the respiratory centre in the medulla: l The rhythmical firing of neurons in the medulla is
n the inspiratory neurons: these demonstrate regulated by the input of a number of chemorecep-
rhythmical firing of action potentials with inter- tors, which monitor changes in chemical factors
vening periods of inactivity. These action po- and then signal the medulla to increase or decrease
tentials stimulate the diaphragm and external the respiratory rate to normalise the detected
intercostals to contract, and thus initiate inspi- chemical change.
ration. Expiration occurs during the intervening
pauses of inactivity l These chemoreceptors monitor changes in the
n the expiratory neurons: these neurons are following:
usually inactive during normal quiet respira- n arterial P CO2
tion; however, during periods of exercise or n arterial pH
n arterial P O2.

Respiratory system 8 211

l These chemoreceptors can be further subdivided function is unclear but injection of chemicals
into: into the pulmonary circulation triggers these
n central chemoreceptors receptors and causes a marked inhibition of
n peripheral chemoreceptors. inspiration
n irritant receptors: lie in the epithelia lining the
l Central chemoreceptors: airways; they respond to noxious gases and
n situated in the CNS, close to the respiratory cause bronchospasm and inhibition of
centre in the medulla inspiration
n particularly sensitive to changes in the arterial n vasomotor centre: low blood pressure detected
P CO2 by baroreceptors results in an increase in the
n CO2 diffuses from the blood into the brain and ventilatory rate. An increase in blood pressure
reacts with water to produce Hþ and causes has the opposite effect.
the pH to fall, thus directly stimulating the
chemoreceptors Hypoxia and respiratory failure
n any elevation in CO2 leads to a central acidosis
that stimulates the chemoreceptors and leads Hypoxia and hypoxaemia
to an increased respiratory rate in order to blow
off the excess CO2. The opposite effect is seen l Hypoxia: a deficiency of oxygen in the tissues.
with low levels of CO2 l Hypoxaemia: reduction in the concentration of
n central chemoreceptors are the main determi-
nant of respiration, as the level of CO2 is the oxygen in the arterial blood.
most important stimulus to respiration. l There are four types of hypoxia:

l Peripheral chemoreceptors: 1) Hypoxic hypoxia: results from a low arterial
n located in the carotid bodies, close to the bifur- P O2; examples include:
cation of the common carotid and in the aortic l high altitude
bodies, which lie along the aortic arch l pulmonary embolism
n less important than the central chemoreceptors l hypoventilation
n they respond to changes in arterial pH and to low l lung fibrosis
levels of PO2; the response to pH is of secondary l pulmonary oedema.
importance to respiratory control but does allow
compensation for acid–base disturbances 2) Anaemic hypoxia: a decrease in the amount
n for instance, a fall in arterial pH due to a met- of haemoglobin and thus a decrease in
abolic acidosis will stimulate respiration and oxygen content of arterial blood; examples
thus will lower the level of CO2 and favour an include:
increase in pH back towards normal. The oppo- l haemorrhage
site effect is seen with an alkalosis l decreased red cell production
n the response to low O2 only comes into effect l increased red cell destruction
when levels are abnormally low, i.e. P O2 l carbon monoxide poisoning.
8 kPa or less
n these receptors can become important in 3) Stagnant hypoxia: due to low blood flow;
severe longstanding lung disease with persis- examples include:
tently elevated levels of CO2. Patients may be- l vasoconstriction
come accustomed and lose the controlling l decreased cardiac output: due to the low
influence of CO2. They therefore rely on the blood flow there is increased extraction of
low level of O2 to stimulate respiration. This oxygen from the blood; this leads to very
is called hypoxic drive. low venous oxygen and produces peripheral
cyanosis.
l There are several other factors which may influence
respiration: 4) Histotoxic hypoxia: poisoning of the enzymes
n Hering–Breuer reflex: this reflex prevents over- involved in cellular respiration. Oxygen is avail-
inflation of the lungs. Stretch receptors in the able but cannot be utilised; the main example
lung send inhibitory signals via the vagus. Only is cyanide poisoning.
significant at high tidal volumes (> 1.5 L)
n ‘J’ receptors: these receptors lie in the alveoli l There are five main causes of hypoxaemia:
in close association with the capillaries. Their 1) Hypoventilation, accompanied by qP aCO2;
oxygen therapy can improve the hypoxaemia;
common causes of hypoventilation include:
l central depression of respiratory drive, e.g.
drugs

212 SECTION TWO PHYSIOLOGY

l trauma, i.e. cervical cord injury Clinical physiology
l neuromuscular disorders, e.g. myasthenia
Response to hypoxia
gravis
l chest wall deformity. Acute
2) Impaired diffusion: P aCO2 is usually normal l P aO2 is a relatively weak stimulus to respiration; the
due to its increased solubility; oxygen therapy
can also improve the hypoxaemia. Causes of respiratory rate does not alter significantly until
impaired diffusion include: P aO2 falls to 8 kPa.
l asbestosis l The carotid bodies are responsible for detecting
l sarcoidosis this change and initiating the physiological
l ARDS. changes—they respond to the decrease in P aO2
3) Shunt (see p. 208): P aCO2 is usually normal, but by increasing the rate and depth of respiration
unlike other causes of hypoxaemia the admin- (minute volume); this leads to a decrease in
istration of oxygen will not raise the PaO2; this P aCO2 and reduced respiratory drive from the
is characteristic of hypoxaemia due to shunt, central chemoreceptors.
and occurs because of the differences between l In these situations respiration is stimulated by
the dissociation curves for O2 and CO2. hypoxia rather than the level of CO2; this is called
4) Ventilation and perfusion inequality: (see p. 205), hypoxic drive.
usually seen in chronic lung disease, i.e. chronic l The carotid bodies also elicit cardiovascular
obstructive airways disease (COAD). It means changes in response to hypoxia:
that ventilation and blood flow are mismatched.
Oxygen therapy can improve the hypoxaemia. n increased heart rate
5) Reduction in inspired oxygen tension. n increased cardiac output
n vasoconstriction in the skin and splanchnic
Respiratory failure
circulation.
l Respiratory failure is present if P aO2 is < 8 kPa;
this can be further divided into type I and II based Chronic
on the level of carbon dioxide: There are several physiological changes that occur
1) Type I: PaCO2 is < 6 kPa; it is referred to as with chronic hypoxia; these include:
hypoxaemic respiratory failure. It is due to l q minute volume: although this causes a respi-
ventilation–perfusion mismatching. PaCO2 is
normal or low as the increased ventilatory ratory alkalosis by decreasing P aCO2, there is
rate in remaining alveoli can compensate for renal compensation by the excretion of excess
increases in CO2. Compensation cannot occur bicarbonate.
for O2, as the dissociation curve is sigmoid and l q number of red cells and haemoglobin: this is
will reach a plateau. stimulated by erythropoietin, released by the kidney
n Causes of type I respiratory failure include: in response to hypoxia. In addition there is in-
l pneumothorax creased 2,3-DPG by red cells; this shifts the oxygen
l pneumonia dissociation curve to the right and increases the
l contusion ease of oxygen release.
l pulmonary embolism l q cardiac output: this produces increased
l ARDS. blood flow to organs and thus increased oxygen
2) Type II: P aCO2 is > 6 kPa; it is referred to as ven- delivery.
tilatory failure and is due to inadequate move- l q vascularity of organs: the diameter of capillaries
ment of air. The relative state of hypoventilation increases and they become more tortuous; this aids
causes the P aO2 to fall and the P aCO2 to rise. in the delivery of oxygen to the tissues.
n Causes of type II respiratory failure include:
l COPD Oxygen therapy and mechanical
l neuromuscular disorders ventilation
l airway obstruction
l central respiratory depression Oxygen therapy
l chest wall deformity.
Oxygen therapy can be via variable or fixed perfor-
mance masks:
l Variable performance masks, i.e. Hudson mask or

nasal cannula, do not deliver a constant concentration

Respiratory system 8 213

of oxygen and are dependent on the patient’s peak n synchronised intermittent mandatory venti-
inspiratory flow rate (PIFR). As PIFR q then more lation (SIMV): the patient requires less seda-
air will be entrained and will decrease oxygen tion and paralysis; the patient receives a
concentration. combination of ventilator breaths and
l Fixed performance masks, i.e. Venturi masks, de- breaths initiated by the patient; the ventila-
liver a constant oxygen concentration, irrelevant tor co-ordinates the breaths so that they
of the patient’s PIFR. The mask entrains air at a do not occur together
fixed rate and thus oxygen dilution does not occur.
Different colours signify different oxygen flow n pressure controlled ventilation (PCV): in CMV
rates. and SIMV modes the ventilator will deliver
a given volume of air irrelevant of the pressure
Mechanical ventilation required to do so. Controlling the pressure
reduces the risk of barotrauma to the lung
Indications
These can be divided into: n pressure support ventilation (PSV): this mode of
l Inadequate ventilation: ventilation can be used with SIMV and PCV. It
allows the patient to wean from the ventilator
n apnoea by triggering each breath. The ventilator simply
n respiratory rate > 35 delivers a preset pressure to assist the patient;
n P aCO2 > 8 kPa. this pressure can be gradually reduced, allowing
l Inadequate oxygenation: P aO2 < 8 kPa with 60% the patient to do increasing amounts of work.
FiO2.
l Surgical indications: l Another important concept in mechanical ventila-
n head injury tion is the recruitment of collapsed alveoli by using
n chest injury positive pressure throughout the respiratory cycle.
n facial trauma This has the effect of allowing oxygenation to
n high spinal injury. occur throughout the respiratory cycle and also in-
creases FRC, which places the lung on the efficient
Intermittent positive pressure ventilation part of the compliance curve. Examples of this
(IPPV) include:
l The basis for mechanical ventilation is called inter- n PEEP: used during mechanical ventilation
n continuous positive airways pressure (CPAP):
mittent positive pressure ventilation (IPPV); the used during spontaneous breathing by a
principle of IPPV is the same as normal ventilation tight-fitting facemask
in the fact that air flows down a pressure gradient. n reversal of I:E ratio: normally the ratio is 1:2,
However, during normal ventilation air flows from which allows time for passive expiration; in-
atmospheric pressure to negative intra-alveolar creasing the inspiratory time and allowing less
pressure; in IPPV the driving pressure is positive time for expiration (i.e. 1:1, 2:1 or 3:1) will
to zero (as opposed to zero to negative). Expiration leave progressively more air in the alveoli
remains a passive event. and thus prevent their collapse; this is called
l Following the decision to commence mechanical auto-PEEP.
ventilation, the settings and mode of ventilation
must be selected. Complications
l An example of initial ventilator settings may be: The complications of mechanical ventilation include:
l ventilator-induced injury
n FiO2 ¼ 0.5 l volutrauma
n tidal volume ¼ 10–12 mL/kg l barotrauma
n respiratory rate ¼ 10–12 per min l hypotension and decreased cardiac output: de-
n inspiration:expiration (I:E) ratio ¼ 1:2
n limit airway pressure ¼ 40 cmH2O creased venous return due to positive intrathoracic
n positive end expiratory pressure (PEEP) ¼ pressure
l respiratory muscle atrophy
2.5–10 cmH2O. l nosocomial infections
l Modes of ventilation include: l technical complications, e.g. disconnection
l increase in intracranial pressure (ICP) due to the
n controlled mandatory ventilation (CMV): the increase in intrathoracic pressure.
patient makes no respiratory effort and the
ventilator delivers a set volume

214 SECTION TWO PHYSIOLOGY OSCE scenario 8.2

OSCE SCENARIOS A 52-year-old male, 7 days post-right total knee
replacement, has become acutely short of breath.
OSCE scenario 8.1 He has severe chest pain on inspiration.
1. What is the differential diagnosis?
A 59-year-old male with severe acute gallstone 2. What changes on ECG would support a
pancreatitis has been on the ward for five days.
He is complaining of acute shortness of breath with diagnosis of pulmonary embolism (PE)?
a respiratory rate of 32 and an SpO2 of 88% de- 3. What is the treatment of PE?
spite oxygen by facemask. The junior doctor has 4. Describe the physiological changes that lead to
obtained arterial blood gases, the results of which
are shown below: hypoxia and hypotension which occur in PE.
pH 7.25 Answers in Appendix page 456
PaO2 7.7 kPa
PaCO2 7 kPa
Base excess À9 mmol/L
HCO3À 18 mmol/L
1. What are the possible differential diagnoses for

the shortness of breath?
2. How is respiratory failure classified?
3. What is adult respiratory distress syndrome

(ARDS)?
4. How is ARDS diagnosed?
5. How is ARDS managed?

SECTION TWO PHYSIOLOGY

CHAPTER 9

Cardiovascular system

CARDIAC MUSCLE l Cardiac action potentials have different characteris-
tics in different regions of the heart: one for the Pur-
l Myocytes surrounded by cell membrane, in which kinje fibres and ventricular muscle, one for atrial
there are voltage-operated ion channels. muscle and one for the sinoatrial (SA) and atrioven-
tricular (AV) nodes.
l Myocytes contain myofibrils, which are made up of
sarcomeres. l A typical action potential is divided into four phases:

l Sarcomeres consist of actin (thin) and myosin (thick) Phase 0
filaments, which are responsible for contraction.
Initial rapid depolarisation, rapid increase in sodium
l Actin filaments are associated with troponin and tro- permeability.
pomysin, which regulate the process of contraction.
Phase 1
l Actin and myosin filaments slide over each other to
shorten the sarcomere. Shortening of several sarco- Rapid repolarisation, rapid decrease in sodium perme-
meres is the mechanism by which the myocyte ability, small increase in potassium permeability.
contracts.
25 mV
l In the absence of calcium the troponin/tropomysin
complex inhibits cross-bridging between actin SA node
and myosin filaments.
Atrial muscle
l When calcium binds to troponin, formation of cross- AV node
bridging occurs between the filaments. The filaments
then slide over one another to cause contraction. Bundle of His

l ATP is required to detach myosin and actin so that Purkinje fibres
the procedure can be repeated.
Ventricular muscle
l Functionally, heart must act as a syncytium, i.e. a
single cell formed from a number of fused cells. 100 ms
Therefore, when one part of the heart depolarises,
a wave of depolarisation passes through the entire Fig 9.1
cardiac muscle. Shape, duration and sequence of cardiac action
potentials; note also the delays caused by the
l Myocytes contain large numbers of mitochondria, anatomical sequence of depolarisation and by the
generating energy via aerobic metabolism. relative conduction velocities down the conducting
system.
l Myocyte function depends on optimal concentra-
tions of Caþþ, Naþ and Kþ. 215

l Myocytes have two systems of intracellular
membranes:
n T-tubules
n sarcoplasmic reticulum.

Cardiac action potential (Fig. 9.1)

l The action potential is the electrical signal that
travels throughout the cardiac muscle to initiate
contraction.

216 SECTION TWO PHYSIOLOGY

Phase 2 l From SA node, action potentials are conducted from
one atrial cell to another, ensuring that both atria
Slow repolarisation—plateau effect due to inward contract simultaneously.
movement of calcium. Plateau lasts about 200 ms
l AV node is located in the atrioventricular fibrous ring
Phase 3 on the right side of the atrial septum. It is the only
electrical pathway through the fibrous ring.
Rapid repolarisation—increase in potassium perme-
ability and inactivation of slow inward Caþþ l AV node is activated by atrial electrical activity,
channels. which results in activation of Purkinje cells.

Phase 4 l Conduction through the AV node is slow, delaying
transmission from atria to ventricles, ensuring that
The resting membrane potential of the ventricular atrial contraction is finished before ventricular con-
muscle is about À90 mV. The SA node and conducting traction begins.
system do not have a resting membrane potential—
they are constantly depolarising. l From the AV node, action potentials travel in the
bundle of His down the ventricular septum and
Excitation/contraction coupling along the right and left bundle branches to enter
the Purkinje system of fibres.
l Mechanism by which the cardiac action potential
causes the myofibrils to contract. l Conduction is rapid in the Purkinje cells and the
action potential is rapidly transmitted to myocytes
l Arrival of the action potential allows Caþþ to move at the apex of the heart.
from the sarcoplasmic reticulum into the cytoplasm.
l Myocytes at the apex of the ventricle are excited
l Caþþ binds to troponin C, eventually activating the and the action potential spreads upwards towards
actin–myosin complex, resulting in contraction. the fibrous ring.

l The plateau phase, the result of further calcium l Cells of the SA node, AV node, Purkinje system have
influx, prolongs and enhances contraction. the ability to depolarise themselves at regular inter-
vals (self-excitation).
l The cardiac action potential is very long (200–300 ms).
After the contraction there is a refractory period l These cells also have a long refractory period.
when no further action potentials can be initiated Therefore the cells with the highest frequency of
and therefore no contraction occurs. The long firing will control the heart rate.
action potential and refractory periods ensure con-
traction and relaxation of the heart, allowing the l A denervated heart (e.g. transplanted heart) will
chambers to fill during relaxation and empty during continue to beat. The rate can increase via circulat-
contraction. ing adrenaline but atropine does not have any effect
(vagal denervation) on the heart rate.
l Intracellular Caþþ is the most important factor con-
trolling myocardial contractility: l Failure of the SA node results in cells with the next
n increased intracellular Caþþ increases force of highest firing frequency, i.e. AV node, taking over
myocardial contraction pacemaker function.
n decreased intracellular Caþþ decreases the
force of myocardial contraction. l Vagal stimulation (parasympathetic) slows the heart
by action on the SA node. Stimulation of the
Generation and conduction sympathetic innervation and sympathomimetic
of cardiac impulse hormones act to increase the heart rate.

l Cardiac tissue has two types of cell: Generation of cardiac output
n cells that initiate and conduct impulses, i.e. SA,
AV nodes l All cardiac muscle has intrinsic capacity for
n cells that conduct and contract; muscle mass of rhythmic excitation.
the heart.
l Cardiac tissue spontaneously depolarises until an
l SA node is situated in the right atrium near the action potential occurs and contraction is initiated.
entrance of the superior vena cava (SVC). This is independent of other influences.

l SA node is the pacemaker dictating the rate of beat- l Various fibres have different rates of depolarisation,
ing of the heart because it has the highest frequency but since they form a functional syncytium with spe-
of firing. cialised conducting tissue, depolarisation spreads
from cell to cell leading to co-ordinated contraction.

l This rhythmic activity produces alternate contrac-
tion/relaxation, i.e. systole/diastole.

Cardiovascular system 9 217

PHASES OF THE CARDIAC CYCLE Phase IVc

(Fig. 9.2) l Atrial systole.
l SA node depolarises.
l Systole: l Atrial muscle contracts.
n contraction (I): mitral and tricuspid valves close l Blood flows through AV valves to ventricles, com-
n ejection (IIa, b): aortic and pulmonary valves
open. pleting the last 15% of ventricular filling.

l Diastole: Phase I
n relaxation (III): aortic and pulmonary valves close
n filling (IVa, b, c): mitral and tricuspid valves open. l Isovolumetric contraction of ventricles.
l AV valves close.
AS Systole Diastole l Aortic and pulmonary valves close.
120 l Volume of blood in heart remains constant as pres-

Pressure (mmHg) 100 Aorta sure rapidly increases (isovolumetric contraction).
80
Phase IIa
60 Ventricle
40 l Ejection.
l Pressure in ventricles exceeds that in aorta and
LEFT HEART 20
Atrium pulmonary artery; valves open.
l Blood ejected in aorta and pulmonary artery.
0
Phase IIb
120
l Ejection.
Volume (ml) 80 l Aortic and pulmonary pressures equalise with

40 ventricles.

20RIGHT HEART Pulmonary artery Phase III
Pressure (mmHG) Right ventricle
10 l Diastolic relaxation.
Right atrium l Isovolumetric relaxation.
0 l Ventricular pressure forms.
Left coronary l Aortic and pulmonary valves close.

blood flow Phase IVa
Zero flow 0
l Filling phase of diastole.
Right coronary l AV valves reopen.
blood flow l Passive ventricular filling.
l Rapid filling of ventricles.
Zero flow 0 l Low atrial pressures due to ‘suction’ effect results in

R 1st 2nd 3rd 4th R rapid filling.
P
T Heart sounds P Phase IVb

QS Q l Decline in rate of filling as atrial volume increases.
l Finally, active atrial contraction begins again, i.e.
ICP IRP
phase IVc.
0 0.2 0.4 0.6 0.8 l During phase III the ventricle ejects about 60% of its

Time (s) volume, i.e. the ejection fraction.

Fig 9.2 Ejection fraction ¼ Stroke volume ðSVÞ
Left ventricular end
The cardiac cycle. ICP ¼ isometric contraction
period, IRP ¼ isometric relaxation period, AS ¼ atrial diastolic volume ðLVEDVÞ
systole.
l During phase IVc the ventricles are topped up by
15% at rest, but more at higher heart rates.

l Failure of atrial contraction therefore at higher heart
rates, e.g. fast atrial fibrillation (AF); exercise may
be life-threatening.

218 SECTION TWO PHYSIOLOGY

INTRACARDIAC PRESSURES VENOUS PULSE (Fig. 9.4)

Normal values for aortic and intra-cardiac pressures a-wave
are shown in Figure 9.3.
l Atrial systole.
HEART SOUNDS l Absent in atrial fibrillation (AF).
l Cannon waves in complete heart block.
First heart sound l Giant waves in pulmonary hypertension, tricuspid

l Due to closure of AV valves. and pulmonary stenosis.
l Best heard at apex.
l Louder in mitral stenosis, hyperdynamic circulation, c-wave

tachycardia. l Bulging of tricuspid valve leaflets in right atrium
during isovolumetric contraction.
Second heart sound
l Synchronous with pulse wave in carotid artery.
l Due to closure of aortic and pulmonary valves.
l Physiological splitting may occur (A2–P2 intervals). v-wave

This is due to prolongation of ventricular ejection l Rise in right atrial pressure before tricuspid valve
periods during inspiration resulting from increased opens.
stroke volume secondary to increased venous
return. x-descent

Third heart sound l Due to tricuspid valve moving down during ventric-
ular systole.
l Due to rapid ventricular filling.
l Best heard in children. y-descent

Fourth heart sound l Tricuspid valve opens.
l Right atrial pressure falls as blood flows to right
l Due to ventricular distension (stiff ventricle) caused
by forceful atrial contraction. ventricle.

l Indicates ventricular hypertrophy or heart failure. CORONARY CIRCULATION

120/80 PA 25/15 See also Chapter 1—Blood supply of heart.
A l Coronary blood flow is about 250 mL/min at rest.
l Rises to 1 L/min on exercise.
RA LA l Coronary flow is reduced during systole (especially
0–4 5–10
during isovolumetric contraction) due to compres-
RV LV sion of the intramyocardial arteries.
25 120 l Coronary flow therefore occurs mainly during
0–4 0–10 diastole.
l Conditions resulting in low diastolic BP or increased
Fig 9.3 intramyocardial tension during diastole (e.g. an
increased end diastolic pressure) may compromise
Normal values for intracardiac, aortic and pulmonary coronary blood flow.
artery pressure (mmHg as measured by cardiac l Subendocardial muscle, where the tension is
catheterisation). A ¼ aorta, PA ¼ pulmonary artery, highest, is particularly vulnerable.
RA ¼ right atrium, LA ¼ left atrium, RV ¼ right l Diastolic time is important. At fast rates, inadequate
ventricle, LV ¼ left ventricle. myocardial perfusion occurs.
l Normally, autoregulation of coronary blood flow
occurs by changes in diameter in the coronary
vessels; the diameter is controlled by vessel tone
and wall pressure exerted by the myocardial
muscle.
l The tone of vessels is determined by local metab-
olites, adenosine, Kþ and lack of oxygen.

Cardiovascular system 9 219

a v
c

h

y
x

Fig 9.4
Venous pulses: ‘a’-wave: atrial systole, not seen in atrial fibrillation, increased in tricuspid or pulmonary
stenosis; heart block causes variable ‘a’-waves and even ‘cannon’ waves. ‘c’-wave: leaflets of the
tricuspid valve bulge into the right atrium during isovolumetric contraction. ‘v’-wave: right atrium is rapidly
filled while tricuspid valve is closed. ‘x’-descent: atrium relaxes and tricuspid valve moves down. ‘y’-descent:
tricuspid valve opens, and blood flows from right atrium to right ventricle.

CARDIAC OUTPUT (CO) Stroke volume (energy of contraction) Sympathetic
stimulation
l Cardiac output is the volume of blood ejected by the
heart in 1 min. Normal

CO ¼ stroke volume ðSVÞ Â heart rate ðHRÞ, Failing
i:e: 70 mL ðSVÞ Â 70 bpm ðHRÞ ¼ 5 L=min heart

ðapproximatelyÞ End diastolic volume
l May increase three- to fourfold in strenuous (initial length of muscle fibre)

exercise. Fig 9.5
l Cardiac index (CI) is the CO per square metre of Starling’s law of the heart. In humans the initial fibre
length cannot be measured, so end diastolic volume
body surface area (BSA), i.e. 3.2 L (average). is used instead.

Regulation of cardiac output l Up to a point, increasing the venous return in-
creases the force that the heart muscle can exert.
Regulation of the vascular system ensures that:
l Each organ receives its minimum required blood flow. l Beyond the critical point, further increase in the
l Redistribution of blood flow occurs where amount of blood decreases the force that the heart
muscle can exert.
appropriate.
l The heart is not overtaxed by providing maximal Factors modifying cardiac output

blood flow to organs that do not require it. l Heart rate:
l The heart has the capacity to increase or decrease n intrinsic rhythmicity
n extrinsic factors:
its output according to demand. l sympathetic increases rate and force
l Each organ has its own mechanism for achieving l parasympathetic reduces rate.

adequate blood flow. l Stroke volume:
n contractility
Starling’s law of the heart (Fig. 9.5) n preload
n afterload.
l Starling’s law: the energy of contraction of a cardiac
muscle fibre is a function of the initial length of the
muscle fibre.

l The greater the stretch of the ventricle in diastole,
the greater the stroke volume.

l The more blood in the heart, i.e. the higher the
end-diastolic volume, the more sarcomeres are
stretched.

220 SECTION TWO PHYSIOLOGY

1 Contractility MEASUREMENT OF CARDIAC
OUTPUT
l The force of myocardial contraction determines the
CO, SV and myocardial O2 demand. Cardiac output may be measured by the following
methods:
l Causes of increased contractility include: l Fick method.
n increased preload l thermodilution
n sympathetic nerve stimulation l dye dilution
n increased extracellular calcium l Doppler ultrasound.
n drugs: inotropes, digoxin The direct Fick method is rarely used in clinical prac-
n hormones: catecholamines, thyroxine, glucagons. tice, but most methods are based on this principle. The
thermodilution method and Doppler ultrasound are
l Causes of decreased contractility: more likely to be used in clinical practice.
n reduced filling (Starling’s law)
n hypoxia Fick method
n hypercapnia
n acidosis l Fick principle states that the amount of substance
n ischaemia and cardiac disease taken up by an organ per unit time is equal to the
n parasympathetic stimulation blood flow multiplied by the difference in concentra-
n electrolyte imbalance: Caþþ, Kþ tion of that substance between arterial and mixed
n drugs: beta-blockers, antiarrhythmic drugs, venous blood.
anaesthetics.
l O2 consumption by whole body is measured for
l Contractility measured by: about 15 min. During this time, blood samples are
n stroke volume and CO taken from a systemic artery and pulmonary artery
n ejection fraction on echocardiography. (mixed venous) blood:

2 Preload CO ¼ Oxygen consumption rate by body ðmL=minÞ
Arterial O2 À mixed venous O2
l Dependent on:
n venous return i:e: 250 mL O2=min O2=L blood
n atrial systole (fibrillation) 190 mL O2=L blood À 140 mL
n myocardial distensibility.
CO ¼ 5 L= min
l Measured by:
n central venous pressure (CVP) Thermodilution
n pulmonary artery occlusion pressure (PAOP).
This is the most commonly used technique in the
3 Afterload intensive treatment unit (ITU).
l A bolus of ice-cold 5% dextrose is rapidly injected
Afterload is the tension in the ventricular wall during
ventricular ejection. into the right atrium via the proximal lumen of a
l Increased by: pulmonary artery catheter.
l The dextrose mixes with blood and causes a fall in
n raised aortic pressure temperature, which is recorded by a thermistor at
n aortic valve resistance (aortic stenosis) the catheter tip in the distal pulmonary artery.
n ventricular cavity size; increased ventricular l Computerised integration of the temperature curves
allows derivation of the CO.
volume; requires greater tension to contract l When CO is known it is possible to calculate SVR,
(Laplace’s law) pulmonary vascular resistance (PVR) and ventricular
n raised systemic vascular resistance (SVR), e.g. stroke work.
shock
n increased afterload increases cardiac work and Dye dilution
therefore oxygen consumption.
l Decreased by: l Uses the same principle as the thermodilution
n vasodilator drugs: at constant preload and con- technique but a dye is used rather than ice-cold
tractility, SV is inversely related to afterload, i.e. dextrose.
decrease in the peripheral resistance with a
vasodilator increases SV
n vasodilator metabolites in septic shock.

Cardiovascular system 9 221

Doppler ultrasound Control of local blood pressure
and blood flow
l A Doppler probe is placed in the suprasternal notch.
l Changing frequency of ultrasound waves caused by The overall determinant of flow is CO, but each organ
has its own superimposed regulatory mechanisms.
reflection from blood moving through the ascending Regulation of blood flow is mainly achieved by alter-
aorta is detected. ation to the diameter of vessels, which is influenced by
l From analysis of the velocity waveform and aortic the smooth muscle of the vessel walls.
diameter, the stroke volume can be estimated
and hence CO measured. Tone in smooth muscle is affected by:
l neural activity, e.g. sympathetic, parasympathetic
BLOOD PRESSURE l hormones, e.g. adrenaline, noradrenaline, vaso-

l BP ¼ CO Â SVR. pressin, angiotensin
l Systolic pressure ¼ maximum pressure recorded l local control—autoregulation: hypoxia, adenosine,

during systole (100–200 mmHg). nitric oxide, CO2, Hþ, Kþ, prostaglandins.
l Diastolic pressure ¼ minimum pressure recorded
PERIPHERAL RESISTANCE
during diastole (60–80 mmHg). (SYSTEMIC VASCULAR
l Pulse pressure ¼ systolic pressure minus diastolic RESISTANCE; SVR)

pressure (40 mmHg). l Resistance to flow of blood through arterioles.
l Mean arterial pressure ¼ diastolic pressure plus ⅓ l By constricting and dilating, arterioles control the

of the pulse pressure (70 mmHg). blood flow to capillaries according to local needs.

Control of blood pressure (general Mean arterial pressure
systemic blood pressure)
SVR ¼ Àmean right atrial pressure
l Regulation of CO and SVR controls BP.
l Baroceptors of the autonomic nervous system Cardiac output

(aortic arch and carotid) and higher centres of l Repeated measurements of SVR in the critically ill
midbrain exert effects on BP. patient are useful in monitoring the effects of fluid
l Baroceptors are stretched by increased BP; this and inotropic therapy.
leads to reflex reduction in vasoconstriction, and
venoconstriction, and reduction in heart rate, with MONITORING THE CIRCULATION
consequent fall in SVR, CO and BP.
l When BP falls baroceptors are less stretched; l There is no one single monitoring measure which
vasoconstriction, venoconstriction and heart rate will define the problem.
increase and BP rises in reflex.
l Autonomic neuropathy may render these reflexes l A series of measurements and monitoring systems
ineffective. over a period of time is required.
l Renin–angiotensin mechanism also controls BP.
Methods used include:
Factors determining arterial l ECG
blood pressure l blood pressure
l central venous pressure
l Systolic pressure increases when there is an l pulmonary wedge pressure (pulmonary artery
increase in:
n stroke volume occlusion pressure)
n ejection velocity (without an increase in stroke l pulse oximetry
volume) l cardiac output
n diastolic pressure of the preceding pulse l urine output
n arterial rigidity (arteriosclerosis). l echocardiography
l echo Doppler.
l Diastolic pressure increases when there is an
increase in: ECG
n total peripheral resistance
n arterial compliance (distensibility) The events recorded in a standard ECG recording are
n heart rate. shown in Figure 9.6. The ECG gives information on:
l heart rate
l rhythm (regular or irregular)

222 SECTION TWO PHYSIOLOGY

R

QRS complex:
ventricular activation

P wave: T wave:
atrial ventricular
recovery T
activation

P QS

P wave QRS width
<0.12 s <0.10 s

PR interval QT interval < 0.42 sat Fig 9.6
<0.20 s rate of 60/min Standard ECG recording during the timing
of various events in the cardiac cycle.
l disorders of conduction or excitation
l size and muscle mass of the heart Central venous pressure
l damage, e.g. ischaemia or infarction, to different
l Gives a good indication of preload in patients with
parts of the heart normal heart.
l electrolyte disturbances, e.g. Kþ, Ca2þ
l pericardium, e.g. inflammation or effusion. l Useful guide to fluid replacement in hypovolaemic
patients, e.g. dehydration, haemorrhage.
Blood pressure
l Cannula inserted via internal jugular vein; tip should
l Monitored by manual sphygmomanometry, auto- be in right atrium.
matic dynamap, or best by intra-arterial catheter,
usually in the radial artery. l A correctly positioned catheter should give a normal
venous pressure wave form (i.e. a, c, v waves).
l In the critically ill there should be continuous obser-
vation of the pressure trace. l Measurement should be made after ‘zeroing’ the
transducer to the level of the right atrium.
l The rate of pressure increase (up-slope) of the pres-
sure trace is proportional to myocardial contractility. l Isolated readings are of little use due to:
n individual variations in the condition of the heart
l The area under the wave-form is proportional to n some patients can compensate with a remark-
stroke volume. able degree of vasoconstriction in the presence
of hypovolaemia, such that CVP may become
transiently elevated.

Cardiovascular system 9 223

l Normal CVP ranges 5–12 mmHg. n irregular pulse: atrial fibrillation
l Low CVP indicates hypovolaemia. n venous pulsation (tricuspid incompetence)
l High CVP usually indicates fluid overload. n hypotension
l If there is disparity between function of the right n vasoconstriction
n abnormal Hb (carboxy-), and methaemoglobin
and left ventricles (e.g. right ventricular infarc- n bilirubin
tion, pulmonary embolism [PE], left ventricular n methylene blue dye
disease), the filling pressure of the right heart, n other factors: electrical interference (dia-
i.e. CVP, may not reflect the filling pressure of
the left heart. Therefore CVP will not be accurate thermy), flickering lights, patient movement,
and pulmonary capillary wedge pressure mea- shivering, nail varnish (coloured or not).
surement is required.
Cardiac output
Pulmonary capillary wedge pressure
(pulmonary artery occlusion l Useful as part of overall assessment of circulation.
pressure; PAOP) l Once CO is known it is possible to derive values for

l PAOP reflects left atrial pressure as the resistance in SVR, the amount of work the heart is performing,
the pulmonary veins is low. oxygen delivery and oxygen consumption.
l Specific pharmacological therapy can then be given
l A flotation balloon catheter is passed through the to optimise the circulation.
right heart into the pulmonary artery.
Urine output
l Inflation of the balloon excludes flow from the right
side of the heart, allowing a fluid bridge to complete l Directly related to renal perfusion.
the connection to the left atrium. l Good indicator of overall fluid balance.

l The pressure at the catheter tip equates to that in Echocardiography
the left atrium.
l Transthoracic echocardiography allows non-
l The balloon is deflated between readings to avoid invasive real-time imaging at the bedside.
pulmonary infarction.
l Provides information on cardiac structure, function
l The normal pulmonary artery occlusion pressure and haemodynamics.
(PAO) is 6–12 mmHg. It should be kept below
15 mmHg to minimise the risk of pulmonary Echo Doppler
oedema.
l Measures blood flow in the aorta via an oesopha-
l The major advantage of the catheter is that it can be geal probe.
used to measure CO.
l Gives indication of contractility and CO.
Pulse oximetry l Contraindicated with oesophageal pathology, e.g.

l Measures the arterial oxygen saturation (SaO2). stricture and varices.
l It relies on the measurement of the different absorp-
CARDIOVASCULAR SUPPORT
tion of oxyhaemoglobin and deoxyhaemoglobin at
different wavelengths. l Ventilate.
l The instrument pulses infrared light at wavelengths l Infusion.
of 660–940 nm. l Pump.
l The pulsation component of absorption is measured
and the constant background component not due to Ventilate
arterial blood, i.e. absorption by skin, venous blood
and fat, is subtracted. l Improves oxygenation and gas exchange.
l Because oxygenated and deoxygenated Hb absorb l Controls acidosis (by CO2 control).
differing amounts at the two wavelengths, pulse ox- l Reduces oxygen demand by respiratory muscle.
imetry is able to calculate a percentage of saturated
Hb from the ratio of the two. Infusion
l The problems with pulse oximetry include:
l Ensure adequate filling pressure.
n delay: calculations are made from a number of l Fluid challenge with monitoring, e.g. CVP, PAOP.
pulses and there is a 20 s delay between actual
and displayed values Pump

l Maintain blood pressure.
l Monitor CO.

224 SECTION TWO PHYSIOLOGY

l Ensure organ blood flow. b1 receptors, resulting in increased cardiac con-
l If SVR low, use vasopressor to improve perfusion tractility and heart rate.
l High dose stimulates a-receptors, causing
pressure. vasoconstriction.

PHARMACOLOGICAL SUPPORT Dobutamine

l Inotropes: increase force of ventricular contraction, l b1 and b2.
usually b-effect. l Inotrope, vasodilator.
l b1 effect increases heart rate and force of
l Vasopressor: constricts blood vessels, a-effect.
l Vasodilator: dilates blood vessels. contraction.
l Chronotrope: increased heart rate, b-effect. l Mild b2 effect causes vasodilatation.
l First choice inotrope in cardiogenic shock due to left
Adrenaline
ventricular dysfunction.
l Both a- and b-effects. l Dobutamine and low-dose dopamine in conjunction
l Inotrope, vasopressor, chronotrope.
l b2-effect at low doses causes vasodilatation in used in cardiogenic shock to increase BP via
increased cardiac contractility and urinary output
skeletal muscle, lowering SVR. (UO; via increased renal perfusion).
l a-vasoconstrictor effect at higher doses increases
Dopexamine
SVR and myocardial oxygen demands, with adverse
effect on cardiac output. l b2 and D receptors.
l Inotrope, chronotrope.
Noradrenaline l Peripheral vasodilatation, increased splanchnic

l a-effect. blood flow and increased renal perfusion (in-
l Vasopressor. creased UO).
l Indicated in septic shock when hypotension due to
Vasodilators
peripheral vasodilatation persists despite adequate
volume replacement. l Nitrates: venodilators reducing preload.
l Nitroprusside: chiefly arterial vasodilator with short
Isoprenaline
half-life given by infusion.
l Exclusively b-effect. l Hydralazine: arterial vasodilator reduces afterload.
l Inotrope, chronotrope.
l Vasodilatation in skeletal muscle; therefore reduces Phosphodiesterase inhibitors

SVR. l Decrease the rate of breakdown of cAMP by phos-
l Tachycardia limits clinical use. phodiesterase III.
l Used to increase rate in heart block while awaiting
l Inotropic and vasodilator effect. Little chronotropic
pacing. effect.

Dopamine l Increased myocardial contractility (increased CO)
with reduced PAOP and SVR.
l Low dose dilates renal, cerebral, coronary and
splanchnic vessels, via D1 and D2 receptors and l No significant rise in heart rate or myocardial
oxygen consumption.

OSCE SCENARIOS Cardiovascular system 9 225

OSCE scenario 9.1 OSCE scenario 9.2

An 80-year-old male is 5 days post-repair of ab- An 89-year-old male is 8 days post-laparotomy for
dominal aortic aneurysm. He has suddenly devel- repair of a perforated duodenal ulcer. He has
oped a tachycardia and become hypotensive. His developed a severe postoperative chest infection
ECG shows atrial fibrillation with a rate of 140. and is pyrexial and hypotensive.
1. What are the causes of atrial fibrillation? 1. Describe your initial management of this
2. What are the physiological mechanisms which
patient.
explain the hypotension seen in fast atrial 2. Why does sepsis lead to hypotension?
fibrillation? 3. Which inotrope is commonly used in sepsis and
3. How would you diagnose atrial fibrillation?
4. Describe your initial management of the patient. what is its mode of action?
4. What is Starling’s law of the heart and how do

inotropes affect it?
Answers in Appendix page 457

SECTION TWO PHYSIOLOGY

CHAPTER 10

Gastrointestinal system

FUNCTIONS n myenteric or Auerbach’s plexus: this lies be-
tween the circular and longitudinal muscle
The functions of the various components of the layers; it is mainly involved in motor function
gastrointestinal (GI) system are:
l Oral cavity: teeth crush and tear food; the tongue n submucosal or Meissner’s plexus: this lies
within the submucosa; it is mainly sensory.
forms a food bolus in preparation for swallowing;
saliva secretion initiates carbohydrate digestion. l The enteric nervous system responds to numerous
l Pharynx and oesophagus: conveys food from the gut transmitters such as cholecystokinin, substance
oral cavity to the stomach. P, vasoactive intestinal peptide (VIP) and somato-
l Stomach: stores food; mechanically and chemically statin; it is responsible for the majority of gut secre-
digests food; regulates the passage of chyme into tion and motility.
the duodenum; secretes intrinsic factor.
l Small bowel: food passes from the stomach into the l The enteric nervous system also receives input from
small intestine; this is where the majority of food the autonomic (extrinsic) nervous system:
digestion and absorption occurs. n Sympathetic: fibres terminate in the submuco-
l Large bowel: water is removed from undigested sal and myenteric plexuses; stimulation of the
food which is then stored in the rectum in prepara- sympathetic system leads to:
tion to be excreted; vitamin K and some B vitamins l blood vessels: vasoconstriction
are produced by resident bacterial flora. l glandular tissue: inhibits secretion
l Liver: an important site for carbohydrate, protein l sphincters: contraction
and lipid metabolism; involved in the synthesis of l circular muscle of bowel: inhibits (Q motility).
several plasma proteins and clotting factors; the n Parasympathetic: fibres terminate in the myen-
primary site for detoxification and elimination of teric plexus only; stimulation of the parasympa-
body waste and toxins. thetic system leads to:
l Gall bladder: stores and concentrates bile. l glandular tissue: increases secretion
l Pancreas: has both exocrine and endocrine func- l sphincters: relaxation
tions, secreting the majority of digestive enzymes. l circular muscle of bowel: stimulates
(q motility).
NERVOUS AND HORMONAL
REGULATION WITHIN THE Hormones and neurotransmitters
GI TRACT
l Play an important role in regulating GI motility and
Nervous regulation secretion; these include:
n gastrin
The nervous system of the GI tract consists of: n secretin
l Intrinsic or enteric system. n cholecystokinin (CCK)
l Extrinsic system: n pancreatic polypeptide
n gastric inhibitory polypeptide (GIP)
n sympathetic n motilin
n parasympathetic. n enteroglucagons
l The intrinsic nervous system is found in the wall of n neurotensin.
the GI tract and forms two well-defined plexuses:
l These hormones and neurotransmitters will be dis-
226 cussed individually in the relevant sections.

Gastrointestinal system 10 227

ORAL CAVITY, PHARYNX n stimulation of mechanoreceptors and chemo-
AND OESOPHAGUS receptors in the mouth

Chewing n higher centres in the CNS, i.e. smelling or think-
ing about food.
l Food is ingested through the mouth and is divided
between two regions: l Parasympathetic impulses via cranial nerves VII and
n vestibule: space between the teeth, lips and IX stimulate saliva secretion; sympathetic impulses
cheeks lead to vasoconstriction and a decrease in saliva
n oral cavity: inner area bound by the teeth. secretion.

l Chewing or mastication has a number of functions: Swallowing
n teeth are able to cut, grind and tear food, allow-
ing it to be swallowed more easily Swallowing can be divided into a number of phases:
n mixes food with saliva and mucus; this lubri- l Oral phase: voluntary; a food bolus is pushed
cates it in preparation for swallowing, and
starts carbohydrate digestion with salivary against the roof of the mouth by the tongue; this
amylase. forces the food into the oropharynx and then into
the pharynx.
Saliva l Pharyngeal phase: involuntary; the superior con-
strictor raises the soft palate (preventing food enter-
l Saliva is secreted by a number of glands: ing the nasopharynx). In addition it initiates a wave
n parotid: watery secretion lacking mucus; ac- of contraction (peristalsis) that pushes the food
counts for around 25% of saliva secretion; also through the upper oesophageal sphincter. At this
contains salivary amylase and IgA stage respiration is inhibited so as to prevent food
n submandibular: produces a more viscous saliva entering the respiratory system.
(a mixed serous and mucosal saliva); accounts l Oesophageal phase: the wave of contraction, which
for approximately 70% of saliva secretion was initiated by the superior constrictor in the phar-
n sublingual: contains mucoproteins; accounts ynx, continues into the oesophagus. This wave of
for only 5% of saliva secretion. contraction propels the food into the stomach. If
the food fails to enter the stomach then the resulting
l Numerous saliva glands are present over the tongue distension initiates a secondary peristaltic wave.
and palate.
Oesophageal sphincter
l Saliva has a number of functions:
n lubrication to help swallowing: mucus l The oesophageal sphincter is an area of high pres-
n speech sure (15–25 mmHg) in the region 2 cm above and
n taste 2 cm below the diaphragm; it is a physiological
n antibacterial action: lysozyme and IgA sphincter as there are no anatomical differences
n starch digestion: amylase. to identify it as the sphincter.

l Formation of saliva within the salivary glands is a l The oesophageal sphincter acts to prevent gastric
two-stage process: juices refluxing from the stomach into the
1) Isotonic fluid of similar composition to the oesophagus.
extracellular fluid (ECF) is secreted by the
acinar component of the salivary gland. l In addition to the physiological sphincter there are a
2) The isotonic fluid is modified as it moves along number of other factors that assist in preventing
the duct; Naþ and ClÀ is removed and Kþ and reflux:
HCO3À are added by means of ATP transport n the right crus of the diaphragm compresses the
proteins. oesophagus as it passes through the oesopha-
geal hiatus
l During low rates of secretion the saliva is dilute as n the acute angle at which the oesophagus enters
there is plenty of time for ductal modification. the stomach acts as a valve
n mucosal folds in the lower oesophagus act as a
l During high rates of secretion the Naþ, HCO3À and valve
ClÀ content increases and is thus more concentrated. n closure of the sphincter is under vagal control;
however, the hormone gastrin causes the
l Control of the secretion of saliva is via the auto- sphincter to contract (secretin, CCK and gluca-
nomic nervous system; this reflex is stimulated by gon cause it to relax).
the salivary nuclei in the medulla; secretion of saliva
is stimulated by:

228 SECTION TWO PHYSIOLOGY

STOMACH Gastric secretion

Gastric mucosa Gastric acid (Fig. 10.1)

l The gastric mucosa contains a variety of secretory l The stomach secretes approximately 2–3 L/day; it
cells; the mucosa is divided into: contains:
n columnar epithelium: secretes a protective n hydrochloric acid
mucus layer n pepsinogen
n gastric glands: intersperse the mucosa; they n mucus
contain a variety of secretory cells. n intrinsic factor
n salt and water.
l These secretory cells include:
n mucus cells: secrete mucus and are situated at l Stomach acid has a pH of around 1–3; it plays a
the opening of the gastric gland number of roles:
n peptic or chief cells: found at the base of the n tissue breakdown
gastric glands and secrete pepsinogen n converts pepsinogen to the active pepsin
n parietal or oxyntic cells: secrete hydrochloric n forms soluble salts with calcium and iron; this
acid and intrinsic factor aids their absorption
n neuroendocrine cells: secrete a number of pep- n acts as an immune defence mechanism by kill-
tides that regulate GI motility and secretion, i.e. ing micro-organisms.
gastrin.
l Gastric acid is secreted by the parietal cells; when
l The predominant cell type in the gastric glands var- activated, deep clefts form in the apical membrane;
ies throughout the various regions of the stomach: these canaliculi allow the acid to be secreted into
n fundus and body: peptic and parietal cells the stomach.
predominate
n antrum and pylorus: parietal cells are less com- l Chloride and hydrogen ions are pumped from the
mon; mucus and neuroendocrine (secreting parietal cells; this process is energy-dependent.
gastrin) cells predominate
n cardia: gastric glands are composed almost l Hþ ions are pumped from the cell by the Hþ/Kþ
completely of mucus cells. ATPase system.

l ClÀ ions are pumped from the cell by two routes:
one is a chloride channel, the other is a ClÀ/Kþ
co-transport system (Kþ is thus cycled into the cell

+

D-cell + G-cell Entero-
ACh + chromaffin cells
Somatostatin + Gastrin
– +
+
– Histamine
Secretin
Duodenal +
mucosa
Parietal cell – Fig 10.1
H+ GIP
Regulation of acid secretion by the
K+ – parietal cell.
CCK

Gastrointestinal system 10 229

via the Hþ/Kþ ATPase system and out via the ClÀ/ descending input is parasympathetic and runs in
Kþ system). the vagus; vagal activity stimulates gastric secre-
l Hþ ions are produced by oxidative processes; this tion in a number of ways:
also produces a hydroxyl ion; in a reaction catalysed
by carbonic anhydrase this results in the formation n direct stimulation of the gastric glands via
of HCO3À which is then exchanged for ClÀ on the acetylcholine release
basolateral surface of the cell.
l The secretion of HCO3À is a protective mechanism n release of gastrin from the neuroendocrine
that prevents the gastric acid from damaging the cells (G-cells) in the antrum; gastrin stimulates
mucosa; it is referred to as the ‘alkaline tide’; acid and pepsin secretion
the production of HCO3À can be influenced by
prostaglandins. n release of histamine from mast cells; this
stimulates parietal cells via H2 receptors, which
Pepsinogen secretion leads to acid production (gastrin also stimulates
histamine release).
l The peptic cells produce pepsinogen, a proteolytic
enzyme that hydrolyses peptide bonds in proteins. l Gastric phase: food entering the stomach stimulates
the gastric phase; this is the primary stimulus to
l The enzyme is secreted into the gastric glands in an secretion and accounts for around 60% of gastric
inactive form (pepsinogen); exposure to the acid secretion. Distension of the stomach and the
environment in the stomach activates the enzyme chemical composition of food lead to acetylcholine
(pepsin). release from the vagus.

Mucus secretion l Intestinal phase: only accounts for 5% of gastric
secretion; the stimulation is the presence of food
l Mucus is secreted from cells at the neck of the in the duodenum; this results in the release of
gastric glands; the secreted mucus forms a layer gastrin from G-cells in the duodenal mucosa.
(mucosal barrier) over the gastric epithelium and
prevents the gastric acid and secreted pepsins from l There are a number of other influences on gastric
digesting the stomach lining. secretion:
n the secretion of gastrin is inhibited when the pH
l The mucus is alkaline; this helps to neutralise falls to around 2–3
gastric acid. n somatostatin secreted from neuroendocrine
cells (D-cells) inhibits gastrin secretion
l Additional factors which protect the stomach from n secretin from the duodenal mucosa is released
digestion include: in response to acid in the duodenum; it inhibits
n tight epithelial junctions prevent acid reaching gastrin release
deeper tissues n fatty food in the duodenum leads to the release
n prostaglandin E secretion has a protective role of CCK and GIP; both inhibit gastrin secretion.
by increasing the thickness of the mucus layer,
stimulating HCO3À production and increasing l The action of hormones released in the duodenum
blood flow in the mucosa (bringing nutrients is referred to as the enterogastric reflex.
to any damaged areas).
Gastric motility
Intrinsic factor secretion
l The main functions of the stomach are storage and
l Secreted from parietal cells; the stimulus for excre- mixing and propulsion of food into the intestine; the
tion is the same as for acid secretion. storage area consists of the fundus and body,
whereas the mixing and propulsion area is the
l Intrinsic factor (IF) binds to vitamin B12; it is then antrum and pylorus.
absorbed in complex with the IF via specialised
receptors in the ileum (see below). Storage

Regulation of gastric secretion l The stomach has a resting volume of around 50 mL
and an intragastric pressure of 5–6 mmHg; how-
l Divided into three phases: ever, it is able to accommodate significantly greater
n cephalic volumes with little change in pressure (approxi-
n gastric mately 1 L). As the stomach is distended, parasym-
n intestinal. pathetic input from the vagus inhibits muscle
contraction.
l Cephalic phase: sight, smell and even the anticipa-
tion of food lead to impulses from the appetite
centre in the hypothalamus to the stomach; it con-
tributes to almost 30% of gastric secretions. This

230 SECTION TWO PHYSIOLOGY

Mixing and propulsion nerves V, VII, IX and XII, and to the intercostals and
abdominal muscles and diaphragm.
l The stomach has three muscle layers: longitudinal, l Causes of vomiting include:
circular and oblique.
n stimulation of the posterior oropharynx
l Contractions in the stomach are more intense in the n excessive distension of the stomach or
more muscular pyloric area in comparison with
the gentle contractions in the storage area of the duodenum
fundus. n stimulation of the labyrinth, e.g motion sickness
n severe pain
l Peristaltic waves push food or chyme towards the n raised intracranial pressure
pylorus; as pressure increases the pyloric sphincter n stimulation of the chemoreceptor trigger zone
will open and a small amount of food is allowed
through to the duodenum. by noxious chemicals
n bacterial irritation of the upper GI tract.
l Parasympathetic impulses tend to increase motility
whereas sympathetic impulses decrease motility. Treatment of peptic ulceration

l The amount of food allowed in to the duodenum is l The treatment of peptic ulcer disease can be divided
carefully regulated by a number of factors: into medical and surgical.
n gastric volume:qvolume then more rapid
emptying Medical treatment
n fatty food: CCK and GIP are released by the l The choices for medical treatment are:
small intestine in response to fatty foods; they
increase contractility of the pyloric sphincter n reduce acid secretion
n proteins: proteins and amino acids stimulate n mucosal protection
gastrin release; gastrin increases contractility n antacids (pH increasers).
of the pyloric sphincter l There are three groups of drugs used in the reduc-
n acid: acid entering the duodenum results in a tion of acid secretion:
vagally mediated delay in gastric emptying n histamine (H2-receptor) antagonists, e.g.
and also leads to secretin release. Secretin
inhibits antral contractions and increases cimetidine and ranitidine: these drugs act by
contractility in the pyloric sphincter. Secretin blocking H2-receptors on parietal cells.
also stimulates HCO3À release from the Although these cells also possess gastrin and
pancreas to neutralise the acid muscarinic receptors, both gastrin and acetyl-
n hypertonic chyme: delays gastric emptying. choline mainly stimulate acid production indi-
rectly by stimulating histamine release. The
Clinical physiology blocking of H-receptors prevents the intracellu-
lar increase in cAMP, and thus acid production
Vomiting n muscarinic antagonists, i.e. pirenzepine: this is
only of historical value, as this drug is no longer
l The reflex action of ejecting the contents of the in clinical use. Pirenzepine was a selective
stomach through the mouth. M1-receptor antagonist that was selective for
the muscarinic receptors on parietal cells but
l Prior to vomiting, autonomic symptoms such as sal- did not produce the unwanted symptoms of
ivation, pallor, sweating and dizziness often occur. blurred vision, dry mouth, etc.
n proton pump inhibitors (PPIs), e.g. omeprazole:
l The events which occur during vomiting are: this group of drugs acts directly on the proton
n respiration is inhibited pump (Hþ/Kþ ATPase). It is inactive at neutral
n the larynx closes and the soft palate rises pH but is activated by the acidic conditions in
n the stomach and pyloric sphincter relax and the the stomach; it then irreversibly binds to sul-
duodenum contracts, propelling intestinal con- phydryl groups on the proton pump.
tents into the stomach l The mucosal protectants aim to support the mucus
n the diaphragm and abdominal wall contracts layer that normally protects the gastric mucosa;
! intragastric pressure rises there are three types:
n the gastro-oesophageal sphincter relaxes and n sucralfate: formed from sulphated sucrose and
the pylorus closes aluminium hydroxide, it polymerises at pH < 4
n stomach contents expelled through the mouth. to form a sticky layer that adheres to the base
of the ulcer
l The vomiting reflex is co-ordinated by the vomiting
centre in the medulla; stimulation of the vomiting
centre leads to motor impulses passing along cranial

Gastrointestinal system 10 231

n bismuth chelate: acts in a similar manner to palpitations. Late dumping is due to rapid swings
sucralfate; in addition it has been shown in insulin secretion in response to the glucose load
to eradicate Helicobacter pylori in the small bowel; this leads to rebound
hypoglycaemia.
n misoprostol: a synthetic analogue of prostaglan- l Diarrhoea: due to early gastric emptying and pas-
din E2. This prostaglandin is thought to protect sage of hyperosmolar chyme attracting fluid into
gastric mucosa by stimulating the secretion of the bowel.
mucus and bicarbonate, and increasing the l Bilious vomiting: the loss of the pylorus prevents
mucosal blood flow. reflux of duodenal contents; this leads to bilious
vomiting. The refluxed bile can also lead to gastritis
l Antacids are a very simple treatment for peptic and further ulcer development.
ulcers, and simply consist of alkaline substances l Infection: there is a decreased ability to destroy
that increase the pH within the stomach; examples bacteria, particularly tuberculosis.
include: l Carcinoma: the duodenal reflux increases the risk of
n sodium bicarbonate developing gastric cancer in the gastric remnant.
n magnesium hydroxide and magnesium
trisilicate Effects of vagotomy
n aluminium hydroxide. l Reduced gastric acid secretion.
l Delayed gastric emptying.
Surgical treatment l Failure of the pylorus to relax prior to gastric peri-
l With the advent of PPIs surgical treatment has
staltic wave.
become much less common. Indications include: l Reduced pancreatic exocrine secretions.
n chronic unhealed ulcer l Diarrhoea secondary to loss of vagal control of the
n failure to heal after more than two courses of
treatment small bowel.
n possible malignancy l Increased risk of large bowel cancer due to exces-
n complications, i.e. bleeding, perforation.
sive bile salts reaching the colon.
l The options for surgical treatment include
(Fig. 10.2): SMALL INTESTINE
n Bilroth I partial gastrectomy
n Bilroth II partial gastrectomy Small intestine mucosa
n truncal vagotomy and gastrojejunostomy
n truncal vagotomy and pyloroplasty l The primary function of the small bowel is the ab-
n selective vagotomy and pyloroplasty sorption of nutrients; a number of characteristics
n highly selective vagotomy (no drainage proce- make it particularly suited to this role:
dure needed). n large surface area
n circular folds called plicae circulares, which
l The surgical treatment of peptic ulcers is associated cause the chyme to spiral round, and thus in-
with a number of complications. These can be crease the time for absorption to take place
divided into post-gastrectomy syndromes and those n the circular folds are covered with villi—finger-
that occur post-vagotomy: like projections approximately 1 mm high; each
of these villi is further covered with microvilli
Post-gastrectomy syndromes (‘brush-border’). These serve to further in-
l Malnutrition: occurs due to small capacity stomach, crease the surface area.

rapid gastric emptying and rapid intestinal transit. l Interspersed among the villi are the crypts of Lieber-
l Deficiency: kuhn. These are analogous to the gastric glands and
contain a number of different cell types:
n iron deficiency, as it is in the wrong ionic state n undifferentiated cells that constantly replace
for absorption enterocytes
n D-cells: produce somatostatin
n vitamin B12 deficiency, due to a lack of intrinsic n S-cells: produce secretin
factor. n N-cells: produce neurotensin
n Enterochromaffin cells: produce 5-hydroxy-
l Dumping syndromes: these can be early or late. tryptamine.
Early dumping occurs 30–45 min after eating and
is due to rapid gastric emptying of a hyperosmolar
meal into the small bowel; this results in fluid mov-
ing into the small bowel by osmosis (third space
loss) and results in dizziness, weakness and

232 SECTION TWO PHYSIOLOGY Upper 1/3
stomach
Upper 1/3
stomach

Duodenum Duodenum

AB

Gastrojejunostomy Pyloroplasty
C D

EF

Fig 10.2

Surgical options for peptic ulceration. A Bilroth I, B Bilroth II or polya, C truncal vagotomy and gastrojejunostomy,
D truncal vagotomy and pyloroplasty, E selective vagotomy and pyloroplasty, F highly selective vagotomy
(no drainage procedure needed).

Gastrointestinal system 10 233

l The ‘brush-border’ secretes a number of enzymes l the bile salts disperse these globules into smaller
involved in digestion: droplets; this increases the surface area exposed
n disaccharidases: maltase, sucrase to pancreatic enzymes
n peptidases
n phosphatases l fatty droplets are broken down by pancreatic li-
n enteropeptidase or enterokinase (activates pases to monoglycerides and free fatty acids (FFA)
pancreatic trypsinogen)
n lactase (under 4 years). l the monoglycerides and FFAs combine with bile
salts to form micelles
l The duodenum contains Brunner’s glands, which
secrete mucus rich in bicarbonate (they are not pre- l micelles have a hydrophilic outer layer and are able
sent in the jejunum or ileum). to diffuse into the enterocytes; the bile salt stays in
the bowel lumen
Absorption (Table 10.1)
l in the enterocytes, the smooth endoplasmic reticu-
l The small intestine secretes 2–3 L/day of isotonic lum reforms triglycerides from the absorbed mono-
fluid; ClÀ is transported to the bowel lumen and glycerides and FFAs
Naþ and water follow. In addition, the bowel
secretes a number of hormones (see above) and l the reformed triglycerides are formed into particles
enzymes (see Pancreas section). of fat called chylomicrons, which are released from
the basal layer of the enterocyte to diffuse into the
l The absorption of nutrients in the small bowel can lacteals within the villi; from here they enter the
be divided into: lymphatic circulation and then into the venous
n carbohydrates circulation.
n fats
n proteins Protein (Fig. 10.5)
n fluids and electrolytes
n vitamins l Proteins are broken down into amino acids by the
n iron proteolytic enzymes released from the stomach
n calcium. (pepsin) and pancreas (see below).

Carbohydrates (Fig. 10.3) l A Naþ-dependent cotransport mechanism absorbs
amino acids.
Glucose and galactose are absorbed via a Naþ-
dependent process in which a Naþ/Kþ ATPase pumps l There are four transporters:
out Naþ. The glucose/galactose are then absorbed with n neutral amino acids
the Naþ via a cotransport protein. A Naþ-independent n basic amino acids
process absorbs fructose. n acidic amino acids
n proline and hydroxyproline.
Fats (Fig. 10.4)
l The majority of amino acids are absorbed in the up-
The absorption of fats is a complex multistage per small intestine; any that enter the large bowel
process: are metabolised by the resident bacterial flora.
l fats form globules in the stomach
l globules are coated with bile salts in the duodenum Fluids and electrolytes

l Approximately 2–3 L of fluid is ingested each day;
another 8–9 L is secreted into the GI tract, but only
100–200 mL is excreted in the faeces.

Table 10.1 Summary of the absorption and secretion of fluid within the GI tract

Absorbed Secreted/ingested

Mouth Nothing 2–3 L fluid ingested
1.5 L saliva secreted
Stomach Lipid-soluble compounds, e.g. alcohol 2–3 L gastric juices secreted
Gallbladder Absorbs water and concentrates bile 500 mL bile secreted
Pancreas Nothing 1.5 L pancreatic juices secreted
Small bowel 8–9 L fluid absorbed 1.5 L intestinal secretions
Large bowel 1 L of fluid absorbed 100 mL excreted in faeces

234 SECTION TWO PHYSIOLOGY

A Secondary active B ‘Facilitate’
transport diffusion

Glucose Fructose
Na+ Galactose

Na+ Primary active
transport
Glucose
Galactose ATP
K+

Fructose

Capillary Capillary

Key Movement against concentration gradient Fig 10.3
ATP Diffusion down concentration gradient
Carrier molecule Carbohydrate absorption mechanism.
ATP dependent pump A Glucose and galactose are absorbed
by an active transport mechanism using
Naþ as a cotransport, B fructose
absorption is passive, but utilises a
carrier molecule.

Micelles Amino Secondary active
Na+ acid transport
Monoglycerides
Fatty acids

Triglycerides Na+ Primary active
Chylomicrons transport
Amino
acid ATP
K+

Lacteals Capillary

Fig 10.4 Fig 10.5
Lipids are absorbed by diffusion as monoglycerides Amino acids are absorbed using a Naþ cotransport
and fatty acids. Inside the cell they are reconstituted to system.
triglycerides, packaged as chylomicrons, and then
enter the lymphatic channels (lacteals). l Anions such as ClÀ are generally absorbed by
electrochemical gradients created by Naþ
l Naþ absorption is coupled with the absorption of absorption.
glucose and amino acids; active absorption is stim-
ulated by aldosterone. l The absorption of water is a result of the osmotic
gradient established by the absorption of nutrients
l Kþ is absorbed along a concentration gradient and electrolytes.
(caused by water absorption); a small amount is
secreted in mucus.

Gastrointestinal system 10 235

Vitamins l Peristaltic contractions last a few seconds and
only propel the food a few centimetres; the
l Vitamins are divided into fat-soluble and water- MMC leads to contraction along the full length
soluble; this classification refers to the method of of the small bowel and lasts several hours. Their
absorption. purpose is to push any remaining food debris
into the colon. The stimulation for the MMC is
l Fat-soluble vitamins (A, D, E and K) are absorbed not fully understood, but may involve the hor-
within the micelles created during fat absorption. mone motilin.

l Water-soluble vitamins (C and B) are absorbed by l The movements of segmentation and peristalsis are
more specific mechanisms: intrinsic and result from the basal electrical rhythm
n vitamin C is absorbed by a Naþ-dependent in the intestine. It can be influenced by extrinsic
mechanism in the jejunum nervous input:
n vitamin B12 is absorbed in the ileum after intrin- n parasympathetic: increases rate of contraction
sic factor (secreted in the stomach) binds to its n sympathetic: decreases rate of contraction.
specific receptor. The IF–vitamin B12 complex
is then taken up into the cell l In addition to the autonomic input, there are
n the remaining B vitamins diffuse freely across several reflexes which also influence intestinal
the enterocyte cell membrane. contractility:
n ileogastric reflex: distension of the ileum
Iron decreases gastric motility
n gastroileal reflex: increase in gastric secretion
l Iron is absorbed in the duodenum and jejunum in or contractility increases ileal motility.
the ferrous (Fe2þ) and not the ferric (Fe3þ) form;
gastric acid is responsible for converting iron Clinical physiology
to the ferrous form. Absorption is then via the
transport protein transferrin. This binds iron and Physiological effects of duodenal
links to a membrane-bound receptor, and is then resection
taken into the cell via endocytosis; it is then
transferred to the plasma and binds to plasma Removal of the duodenum (duodenectomy) leads to a
transferrin. range of physiological abnormalities, including:
l Ulceration of small bowel: the duodenum is able to
Calcium
withstand gastric acid better than small bowel, this
l Absorption is dependent on a calcium-binding is due to HCO3À secreted from the Brunner’s
protein in intestinal cells; these receptors can be glands and from the pancreas—allowing the neu-
increased by vitamin D, and thus the rate of cal- tralisation of gastric acid within the chyme. Follow-
cium absorption can be increased when plasma ing duodenal resection, surgical reconstruction of
levels fall. bowel continuity often involves small bowel; the
rerouted gastric acid causes peptic ulceration in
Small intestinal motility the small bowel.
l Malabsorption: Fe2þ, Ca2þ and PO4À malabsorp-
l There are three types of movement in the small bowel: tion and impaired fat emulsification.
n segmentation (feeding) l Dumping: loss of control over gastric emptying
n peristalsis (feeding) leads to uncontrolled passage of chyme into the
n migrating motility complex (MMC) (fasting). small bowel, resulting in dumping.

l Segmentation is a movement that facilitates mixing Physiological effects of terminal
of chyme; the circular muscle layer contracts and ileal resection
relaxes in adjacent segments; this results in circular
movements of the chyme. Removal of the terminal ileum (ilectomy) leads to a
range of physiological abnormalities, including:
l Peristalsis is a propulsion movement that is triggered l Bile salt reabsorption: the terminal ileum is the site
by distension. The longitudinal muscle contracts;
midway through contraction of the longitudinal mus- of bile salt absorption; loss of this mechanism
cle the circular muscle also contracts. This pattern leads to:
of contraction is repeated and moves food through
the bowel. n bile salts in the colon; this alters the bacterial
flora and stool consistency, and can lead to
l Peristaltic contractions eventually reach the ileo- an increased risk of colonic malignancy
caecal valve and cause it to relax, thus allowing
food to enter the large bowel.

236 SECTION TWO PHYSIOLOGY

n due to the loss of enterohepatic circulation, Amylase
there is a decrease in bile salt pool; this predis- l Responsible for the majority of starch digestion; it
poses to cholesterol gallstones.
splits a-1,4-glycosidic bonds; the brush-border
l Vitamin B12 deficiency: receptor-mediated reab- enzymes of the small bowel digest the resulting
sorption in conjunction with intrinsic factor occurs oligosaccharides.
in the terminal ileum; resection of the ileum will re-
sult in deficiency of B12 and cause a macrocytic Lipolytic enzymes
anaemia and degeneration of the spinal cord if l As with proteolytic enzymes, the lipolytic enzymes
not corrected.
are excreted in an inactive form; they are all acti-
l Water reabsorption: the ileum plays an important vated by trypsin. These enzymes include:
role in the absorption of water from bowel contents
(especially in the elderly); this leads to diarrhoea n lipase: cleaves triglycerides to FFAs and glycerol
and an increase in stool frequency. n co-lipase: helps bind lipase to the lipids
n phospholipase A2: cleaves FFAs from
PANCREAS
phospholipids
Exocrine secretions n cholesterol esterase.

Fluid component Regulation of exocrine secretions

l The pancreas secretes approximately 1.5 L of fluid l As with gastric secretion, regulation of pancreatic
per day; it contains a variety of enzymes and is rich juice secretion is divided into three phases:
in bicarbonate. n cephalic: vagal
n gastric: vagal
l The epithelial cells that line the ducts form the fluid n intestinal: CCK and secretin.
component of pancreatic juice; HCO3À is transported
into the lumen in exchange for ClÀ and directly via a Cephalic
luminal channel. Sodium and potassium are ex- l During the cephalic phase the sight, smell and taste
changed for Hþ formed by the reaction catalysed by
carbonic anhydrase. Naþ follows HCO3À to maintain of food cause vagal (parasympathetic) stimulation
electrochemical neutrality and water follows by the and the release of acetylcholine (ACh) and VIP.
osmotic gradient created by the movement of Naþ These activate the acinar and ductal cells as well
and HCO3À. as increasing blood flow via vasodilatation. A small
stimulus also comes from gastrin released from the
Enzyme component gastric antrum cells.

l The enzymes secreted by the pancreas can be Gastric
divided into: l Accounts for a relatively small stimulus to secre-
n proteolytic
n amylase tion; gastrin secretion and distension (vagal
n lipolytic. gastropancreatic reflex) stimulate pancreatic
secretion.
Proteolytic enzymes
l These enzymes are secreted in an inactive form, Intestinal
l Accounts for 60–70% of the stimulus for pancreatic
called zymogen granules, from pancreatic acinar
cells. The key event in the activation of these secretions; two main hormones are responsible for
enzymes is activation of trypsinogen to trypsin. stimulating pancreatic secretions:
Activation of trypsinogen is by an enzyme secreted
by the duodenum (enterokinase) and the alkaline n cholecystokinin (CCK): release of a fluid rich in
environment. enzymes from acinar cells.
l Trypsin then activates the other enzymes:
n secretin: release of a bicarbonate-rich fluid.
n chymotrypsinogen: chymotrypsin (cleaves pep- l Factors that promote secretion of these hormones
tide bonds)
(from the duodenal mucosa) include:
n proelastase: elastase (cleaves peptide bonds) n lipids (CCK)
n trypsinogen: trypsin (cleaves peptide bonds) n peptides and amino acids (CCK)
n procarboxypeptidase: carboxypeptidase (cleaves n acid (secretin).

peptides at the C-terminus). Endocrine secretions

See Chapter 12.

Gastrointestinal system 10 237

Clinical physiology compound that is excreted in bile. In the intes-
tine bacteria convert these pigments to:
Physiological effects of pancreatic l urobilinogen: some is reabsorbed in the
resection
intestine and secreted back into the bile or
Removal of the pancreas (pancreatectomy) leads to a excreted in the urine
range of physiological abnormalities, including: l stercobilin and urobilin: give faeces brown
l Malnutrition: inadequate digestion of protein and colour
n cholesterol
lipids due to the loss of proteolytic and lipolytic en- n lecithin
zymes. The inadequate breakdown of protein leads n mucus.
to progressive weight loss and inadequate fat di- l There are two factors that govern bile secretion;
gestion; this leads to fatty stools and flatus (due one is dependent on bile acid recirculation
to bacterial overgrowth). The absorption of fat- (enterohepatic circulation), and the other is
soluble vitamins (A, D, E and K) is reduced, and independent of this:
leads to progressive deficiencies. n enterohepatic circulation: > 90% of secreted
l Malabsorption: loss of alkaline pancreatic secre- bile acids are reabsorbed from the intestine
tions leads to failure to neutralise gastric chyme (distal ileum) and returned to the liver via the
and leads to Fe2þ, Ca2þ and PO4À malabsorp- portal vein; the remaining 5–10% of bile acids
tion; this eventually leads to anaemia and are altered by bacterial flora and become insol-
osteoporosis. uble, and are thus excreted. The rate at which
l Diabetes mellitus: loss of the pancreas leads to an bile acids are returned to the liver will influence
absolute deficiency of insulin. the rate at which they are secreted into the
canaliculi
LIVER AND GALL BLADDER n the remaining components of bile (water, Naþ,
HCO3À) are secreted into the canaliculi indepen-
Liver dently of bile acid recirculation. HCO3À and Naþ
are both actively pumped into the lumen; water
Bile production (Fig. 10.6) follows due to the resulting osmotic gradient.
Secretion of the bicarbonate-rich fluid is stimu-
l Hepatocytes secrete fluid into the canaliculi; this fluid lated by secretin, gastrin and glucagon.
is very similar to plasma with reference to its ion l Regulation of secretion: CCK stimulates the con-
composition; however, it also contains: traction of the gall bladder and the release of bile
n bile acids: cholic acid and chendeoxycholic acid into the duodenum.
n bile salts: formed by linking the amino acids
glycine and taurine to bile acids. Bile salts have Metabolic functions
a hydrophobic and hydrophilic region (amphi-
pathic); this enables them to form an emulsion The liver is responsible for the handling of dietary
of lipids in the intestinal fluid. The emulsion carbohydrate, protein and lipids.
produces a large surface area for pancreatic
enzymes to act upon; in addition bile salts form Carbohydrate metabolism
smaller collections of FFAs and monoglycerides l Following a meal the digested components are de-
(micelles) to facilitate absorption into entero-
cytes. The bile salts are not absorbed during livered to the liver via the portal vein; the absorbed
this process, and remain in the bowel lumen glucose is then converted to glycogen (the principal
until the distal ileum where they are absorbed form of stored carbohydrate; glycogenesis). At
(see below) times of low blood glucose or high energy demand
n bile pigments: these are produced by the the glycogen within the liver is converted back to
breakdown of the haem unit of haemoglobin; glucose (glycogenolysis).
it gives bile its green/yellow colour. The de-
struction of ageing red blood cells (RBCs) takes Protein metabolism
place in the spleen; in this process bilirubin is l The liver has a number of roles related to protein
released into the circulation; it is poorly soluble
and is transported to the liver bound to albumin. metabolism:
The bilirubin is conjugated to glucuronic acid n able to produce glucose from amino acids and
in the hepatocytes, producing a water-soluble other non-carbohydrate substances (gluconeo-
genesis); this becomes particularly important in

238 SECTION TWO PHYSIOLOGY

Haemoglobin

Globin Haem

Fe2+ Porphyrin

Bilirubin

Plasma
albumin

Liver Kidney
Urobilinogen
Bilirubin
glucuronide

Small Urobilinogen
intestine

Stercobilinogen Absorbed
(= urobilinogen) Liver

A

Secreted
in bile

Reabsorbed Bile Small
B salts intestine

Fig 10.6

A Summary of bile pigment metabolism,
B Enterohepatic circulation of bile salts.

times of prolonged exercise and depletion of Lipid metabolism
glycogen stores during starvation l The liver is involved with several facets of lipid
n involved with synthesis of many of the
plasma proteins, such as albumin and clot- metabolism:
ting factors n glucose is converted to FFAs; this is then
n also handles the degradation products of amino transported to adipose tissue. It is then com-
acid metabolism. Use of amino acids through- bined with glycerol and stored as triglycer-
out the body results in the production of ammo- ides. During starvation these stores are
nia, which is converted to urea. released, providing fatty acids (provides
energy as ATP for gluconeogenesis) and

Gastrointestinal system 10 239

glycerol (acts as a non-carbohydrate sub- n hepatic (parenchymal)
strate for gluconeogenesis) n post-hepatic (cholestatic).
n synthesises lipoproteins and cholesterol. l This classification refers to the site of the obstruc-
tion or abnormality affecting normal bilirubin
Protein synthesis metabolism.
l The following is a summary of bilirubin metabolism:
l As mentioned above, the liver synthesises all the n RBCs are broken down in the spleen and
plasma proteins (other than immunoglobulins), all
the non-essential amino acids and many of the clot- release bilirubin, a breakdown product of the
ting factors. porphyrin ring of haemoglobin; at this stage
bilirubin is unconjugated
Vitamin D activation n unconjugated bilirubin is not water-soluble and
binds to albumin; it is in this form that it is
l Activation of vitamin D is a two-stage hydroxyl- transported to the liver
ation process. The liver performs the first n in the liver the bilirubin is conjugated to glucu-
hydroxylation to give 25-hydroxycholecalciferol, ronide; conjugated bilirubin is water-soluble
and the kidney performs the second to give n bilirubin is then stored in the gall bladder and
1,25-hydroxycholecalciferol. excreted in the bile
n once the bilirubin enters the bowel, intestinal
Detoxification bacteria convert it to urobilinogen. The uro-
bilinogen may be absorbed and recirculated
l The liver detoxifies a number of substances: back into the bile; some is excreted in the
n peptide hormones: insulin, ADH, growth hormone urine, the remaining urobilinogen that is not
n steroid hormones: testosterone, oestrogen, absorbed is excreted in the faeces; it gives
adrenal cortex hormones the faeces their brown colour. The urobilino-
n catecholamines gen that is excreted in the faeces is further
n drugs altered by bacterial flora and is referred to
n toxins. as stercobilinogen.

l The detoxification process involves two stages: Prehepatic jaundice
n stage 1: increase in the water solubility of the l This is caused by disorders that result in excessive
substrate (i.e. the cytochrome p450 system)
n stage 2: reduction in biological activity and destruction of RBCs (haemolysis); the liver is over-
toxic activity. whelmed by the bilirubin that is being produced and
is unable to conjugate it. The jaundice is thus re-
Vitamin and mineral storage ferred to as being an unconjugated hyperbilirubi-
naemia. This finding is highly suggestive of a
l The liver stores a number of substances; in addition prehepatic cause for the jaundice. Other laboratory
to glycogen and fats, it also stores: findings associated with prehepatic jaundice
n iron include:
n copper
n vitamin A, D, E, K and B12. n no bilirubin in the urine (unconjugated bilirubin
is not water-soluble)
Phagocytosis
n qurobilinogen in the urine (as a result of more
l Kupffer cells in the hepatic sinusoids remove bilirubin being broken down in the intestine)
bacteria, debris and old RBCs.
n reticulocytosis: in response to the need to
Haemopoiesis replace destroyed blood cells

l In the embryo the liver is involved in haemopoiesis; in n anaemia
adults it only plays a role in disease states such as n qlactate dehydrogenase (LDH)
chronic haemolysis (extramedullary haemopoiesis). n Qhaptoglobin: protein that binds free haemo-

Clinical physiology globin and transfers it to the liver.
l Common causes of prehepatic jaundice include:
Jaundice
n inherited:
l Defined as the yellow pigmentation of the skin and l red cell membrane defects, e.g. hereditary
eyes as a result of excess bilirubin in the circulation; spherocytosis
this usually becomes clinically detectable at plasma
levels > 40 mmol/L (normal range is < 22 mmol /L).

l Jaundice can be classified in three ways:
n prehepatic (haemolytic)

240 SECTION TWO PHYSIOLOGY

l haemoglobin abnormalities, e.g. sickle cell l hepatitis
disease l drugs
l cirrhosis
l metabolic defects, e.g. G6PD deficiency l primary biliary cirrhosis
n acquired: n extrahepatic cholestasis occurs due to obstruc-
tion of the large bile ducts distal to the
l immune, e.g. transfusion reactions canaliculi; causes include:
l mechanical, e.g, heart valves l gallstones
l acquired membrane defects, e.g. paroxys- l biliary stricture
l carcinoma: head of pancreas, ampulla, bile
mal nocturnal haemoglobinuria (PNH)
l infections duct (cholangiocarcinoma), malignant
l drugs lymph nodes at the porta hepatis
l burns. l pancreatitis
l In addition to the haemolytic causes of prehepatic l sclerosing cholangitis.
jaundice, there are a group of disorders known as l Laboratory tests demonstrate the following:
congenital hyperbilirubinaemias; these include: n bilirubin in the urine (characteristic dark col-
n unconjugated hyperbilirubinaemia: ouration); this occurs as the bilirubin is conju-
l Gilbert’s syndrome: due to an abnormality in gated and thus water-soluble
n no urobilinogen in the urine; due to the obstruc-
bilirubin uptake tion, no bilirubin enters the bowel to be con-
l Crigler–Najjar syndrome: due to the absence verted to urobilinogen
n qcanalicular enzymes: alkaline phosphatase
of glucuronyl-transferase and g-GT
n conjugated hyperbilirubinaemia: n qliver enzymes ALT and AST; not as significant
as seen in hepatocellular causes, but biliary
l Dubin–Johnson and Rotor’s syndrome: de- backpressure inevitably leads to mild hepato-
fects in the handling of bilirubin. cyte damage.

Hepatocellular jaundice Gall bladder
l This is caused by a variety of conditions that interfere
l The gall bladder stores bile; the bile from the liver is
with hepatocyte function. There is usually an element diverted into the gall bladder due to the high tone in
of cholestasis as hepatocytes swell and obstruct the the sphincter of Oddi. The bile is then concentrated
flow of bile. The hyperbilirubinaemia is a combination by the absorption of Naþ, HCO3À, ClÀ and water.
of conjugated and unconjugated, reflecting the im-
paired hepatocyte function and partial obstruction. l The bile is released into the duodenum when the
Laboratory tests demonstrate the following: gall bladder contracts; the major stimulus is the re-
lease of CCK from the duodenum in response to fats
n liver enzymes, i.e. q aspartate amino transfer- and acid. A small amount of gall bladder contraction
ase (AST) and q alanine amino transferase is mediated by the vagus when a fatty meal enters
(ALT); this reflects liver damage and thus the stomach.
release of these enzymes from hepatocytes
l CCK also stimulates pancreatic secretions and
n qalkaline phosphatase: reflects the partial reduces the tone within the sphincter of Oddi.
cholestasis
Clinical physiology
n abnormal clotting tests reflect the impaired
hepatocyte function. Physiological effects of
cholecystectomy
l Causes of hepatocellular jaundice include:
n viruses, e.g. hepatitis A, B, C and E, Epstein– l The removal of the gall bladder (cholecystectomy)
Barr virus (EBV) is usually well tolerated, but does have several
n autoimmune disorders, e.g. chronic hepatitis physiological consequences that may lead to
n drugs, e.g. paracetamol overdose symptoms:
n cirrhosis n the loss of the concentrating action of the gall
n liver tumours and metastasis. bladder can lead to increased flow of bile, lead-
ing to reflux and biliary gastritis
Cholestatic jaundice
l This is due to obstruction of the biliary system and

can be further divided into intrahepatic or extra-
hepatic obstruction:

n intrahepatic cholestasis is similar to hepatocel-
lular jaundice, as the obstruction is usually due
to hepatocyte swelling; causes include:

Gastrointestinal system 10 241

n the formation of micelles during fat absorption l The colon is able to influence gastric motility by re-
is disturbed, and can lead to fat intolerance and leasing enteroglucagon (also released from the dis-
malabsorption; this can produce abdominal tal ileum). This hormone is released in response to
pain and diarrhoea. glucose and fat in the ileum and colon, and inhibits
gastric and small bowel motility.
LARGE BOWEL
Defecation
Water absorption
l Mass movements lead to distension of the rectum
l The colon is the last site for water reabsorption; as faeces are pushed along; this leads to the sen-
it absorbs up to 1 L of water per day. Naþ is trans- sation of needing to defecate.
ported from the lumen under the influence of aldo-
sterone; water follows along the osmotic gradient. l The control of defecation (continence) is by sym-
pathetic and parasympathetic input, but is also
l Failure of fluid absorption in the colon leads to under somatic control. The nervous input supplies
diarrhoea (see below). two sphincters:
n internal sphincter: smooth muscle under involun-
Colonic flora tary control; sympathetic impulses lead to con-
traction of the sphincter and para-sympathetic
l The colon has a huge population of both aerobic impulses lead to relaxation
and anaerobic bacteria; these perform a number n external sphincter: composed of skeletal mus-
of roles: cle and allows voluntary control of defecation.
n fermentation of indigestible carbohydrate: pro-
duces fatty acids that the colonic mucosa is l The reflex arc that initiates defecation is (Fig. 10.7):
able to use as an energy source and a variety n rectal distension: when faecal material enters
of gases, such as carbon dioxide and methane; the rectum and causes distension, impulses
these are released as flatus from stretch receptors in the rectum travel
n degradation of bilirubin to urobilin, urobilinogen via parasympathetic fibres (S2, 3, 4) in the
and stercobilin sacral nerves
n synthesis of vitamins K, B12, thiamine and n conscious awareness: as a result of rectal dis-
riboflavin. tension there is activation of ascending sensory
pathways that allow differentiation of solid fae-
Large intestinal motility cal matter and flatus. Impulses also travel along
the pudendal nerve; this results in contraction
l Food traverses the small intestine in approximately of the external sphincter
5 h; colonic movements are considerably slower, n parasympathetic impulse: leads to an increase
taking up to 20 h or more before defecation. in the tone of the colon and relaxation of the
internal sphincter
l The colon has a number of movements: n not convenient to defecate: voluntary contraction
n mixing or retrograde peristalsis: the circular of the external sphincter; the urge to defecate
muscle contracts and narrows the lumen, the often subsides at this point. If the distension
longitudinal muscle is incomplete in the colon on the rectum is due to solid faecal matter then
and forms bands called taenia coli. Contraction descending impulses reinforce contraction of the
of the taenia coli appears to cause faecal matter external sphincter to maintain continence
to roll, and thus increase its exposure for absorp- n convenient to defecate: the external sphincter
tion (occurs predominantly in the right colon) relaxes, allowing faeces through the anus; this
n peristalsis and mass movements: these are is often aided by the contraction of abdominal
more common in the transverse and distal co- muscles.
lon, and move faecal matter towards the anus.
More prolonged contractions of the colon (mass Clinical physiology
movements) serve to empty the colon, and
invariably produce the desire to defecate as Diarrhoea
faeces are pushed into the rectum and anus.
Mass movements are initiated by distension l Defined as more frequent evacuation or the passage
of the stomach and duodenum (gastrocolic of liquid/soft faeces.
and duodenocolic reflexes).
l The pathophysiological mechanisms responsible for
l Vagal stimulation increases colonic motility and the diarrhoea can be classified as:
sympathetic stimulation decreases it.