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Section 4

Chapter

46

Neurophysiology

Intracranial pressure and head injury

What is intracranial pressure?

How is it measured?

The ICP is simply the hydrostatic pressure within the

skull, but reflects the pressure of the CSF and brain

parenchyma At rest in a normal supine adult, ICP is

5–15 mmHg; ICP varies throughout the cardiac and

respiratory cycles Even in a normal brain, coughing,

straining and sneezing can transiently increase ICP to

as high as 50 mmHg

Unfortunately, ICP cannot be estimated, only

invasively measured ICP may be measured by a

var-iety of devices, each with their advantages and

disadvantages:

ventricle, which is considered the ‘gold standard’

for measuring ICP In addition to ICP

measurement, an EVD can be used to remove CSF

for diagnostic and therapeutic purposes (to reduce

ICP – see later) and for the administration of

intrathecal medication However, to measure ICP,

the EVD must be ‘clamped’; that is, CSF cannot be

simultaneously drained An EVD may be

surgically challenging to insert, especially if the

ventricles are small or displaced Also, EVDs are

frequently complicated by blockage and are

associated with an infection risk of up to 5%

catheter placed within the brain parenchyma

through a small burr hole An intraparenchymal

probe is much easier to insert than an EVD, and

can be used in situations where the ventricles are

compressed or displaced Measurement of ICP

using an intraparenchymal probe is almost as

accurate as an EVD, and infection rates are

substantially lower However, there are concerns

about the accuracy of intraparenchymal catheters

used for prolonged periods: the catheter is zeroed

at the time of insertion, and cannot be recalibrated

in vivo However, drift has been shown to be aslittle as 1 mmHg after 5 days’ use An

intraparenchymal probe only measures thepressure of the brain parenchyma in which it islocated, which may not represent global ICP

obsolete The subarachnoid probe is easier toinsert and is associated with a low infection rate,but is much less accurate than the first twomethods

Like the subarachnoid probe, the subduralprobe is easier to insert and has a lowerinfection risk than the first two methods, but isless accurate and prone to blockage, requiringregular flushing

What is the Monro–Kellie hypothesis?The Monro–Kellie hypothesis states that the cranium

is a rigid box of fixed volume, which contains:

intracranial volume

volume

approximately 10% of intracranial volume

An increase in the volume of any of these intracranialcontents will increase ICP, unless there is also a cor-responding reduction in the volume of one or both ofthe other contents

For example:

localized (for example, a brain tumour or abscess)

or generalized (such as occurs with cerebraloedema)

hydrocephalus (see Chapter 43)

201

 The volume of intracranial blood may be

increased following haemorrhage (extradural,

subdural or intraparenchymal) or venous sinus

thrombosis

When one of the intracranial contents increases in

volume, there is a limited capacity for displacement of

the other contents:

spinal subarachnoid space Whilst the rate of CSF

production remains approximately the same, CSF

absorption by the arachnoid villi is increased

venous blood into the internal jugular vein, thus

reducing the volume of intracranial blood

After these small compensatory changes have

occurred, ICP will rise The only options left are then

potentially disastrous: a reduction in arterial blood

volume or displacement of brain parenchyma

through the foramen magnum (Figure 46.1)

– A headache that is worse in the morning and is

exacerbated by straining and lying flat

– Nausea and vomiting

– A bulging fontanelle in infants and neonates

– Papilloedema

– Altered level of consciousness

additional signs, as a result of brain displacement:– Cranial nerve palsies – most commonly theabducens (cranial nerve VI)

– Pupillary dilatation – caused by compression

of the oculomotor nerve (cranial nerve III).– Cushing’s triad:

Can you explain Cushing’s triad?

As discussed in Chapter 45, CPP is related to ICP:

According to this equation, an increase in ICP results

in a decrease in CPP, unless MAP also increases.Between a CPP of 50 and 150 mmHg, cerebral auto-regulation maintains CBF at its normal value of

50 mL/100 g of brain tissue/min (see Chapter 45and Figure 45.1)

The Cushing response is a late physiologicalresponse to increasing ICP When CPP falls below 50mmHg, the cerebral arterioles are maximally vasodilatedand cerebral autoregulation fails CBF falls below the

‘normal’ value of 50 mL/100 g/min, resulting in cellularischaemia

Volume of expanding intracranial mass (mL)

Focal ischaemia

Compensatory mechanisms

Figure 46.1 Change in ICP with increasing intracranial volume.

Section 4: Neurophysiology

In the event of brainstem ischaemia, the brain has

an ‘emergency’ hypertensive mechanism: the

vaso-motor area dramatically increases sympathetic

ner-vous system outflow, triggering an intense systemic

arteriolar vasoconstriction that results in systemic

hypertension The rise in MAP restores perfusion,

and hence CBF, to the brainstem In response to

systemic hypertension, the arterial baroreceptors

induce a reflex bradycardia

If ICP continues to rise, the brain parenchyma

starts to be displaced downwards The cerebellar

tonsils are pushed through the foramen magnum, a

process referred to as ‘tonsillar herniation’ or ‘coning’

The cerebellar tonsils compress the brainstem,

caus-ing the failure of brainstem functions:

compression of the respiratory centre

(GCS) of 3–5 is usual

compressed

The Cushing reflex is a desperate attempt to maintain

CPP (and therefore CBF) in the face of substantially

increased ICP Unless (and often despite) swift action

is taken, brainstem death is inevitable

How may intracranial pressure

be reduced?

The Monro–Kellie hypothesis states that an increase

in the volume of one of the three intracranial contents

will cause an increase in ICP, unless there is also a

reduction in the volume of one or both of the other

components It therefore follows that ICP may be

reduced if the volume of one or more of the

intracra-nial contents is reduced:

EVD This method can be used to reduce ICP even

when hydrocephalus is not the cause Even the

removal of a few millilitres of CSF can result in a

significant decrease in ICP

raised ICP is a haematoma, this should be

urgently evacuated Otherwise, in the context of

raised ICP, intracranial venous and arterial blood

can be considered as two entirely different entities:

– Venous blood Intracranial venous blood serves

no useful purpose and should be permitted to

drain from the cranium As ICP increases, thedural venous sinuses are compressed,

displacing blood into the internal jugular vein,thereby reducing the volume of intracranialvenous blood As discussed in Chapter 42, thedural venous sinuses do not have valves

Therefore, venous drainage from the cranium

is entirely dependent on the venous pressuregradient between the venous sinuses and theright atrium Venous drainage is thereforepromoted by:

removing neck collars and tight-fittingETT ties, which prevents kinking orocclusion of the internal jugular veins

pressure reduces the venous pressuregradient Therefore, in ventilated patients,PEEP should be reduced to the lowest valuerequired to achieve adequate oxygenation

coughing and straining, both of whichtransiently increase intrathoracic pressure.– Arterial blood An adequate volume ofwell-oxygenated arterial blood is essential tomeet the metabolic demands of the brain, butCBF in excess of that required merely serves

to increase ICP Therefore, the aim is toprovide just sufficient CBF to meet the brain’smetabolic needs Two main strategies areemployed:

metabolism coupling, CBF is related toCMR Seizure activity substantiallyincreases CMR, which in turn increasesCBF and consequently increases ICP –seizures should be rapidly treated withbenzodiazepines and anti-epileptic drugs.CMR may be reduced to sub-normal levelsthrough the use of drugs (propofol,thiopentone or benzodiazepines such asmidazolam) or through therapeutic cooling(CMR is reduced by 7% per 1 °C reduction

in brain temperature) Therapeuticcooling has not yet been proven to reducemortality, and is not recommendedunless the patient is pyrexial

Chapter 46: Intracranial pressure and head injury

203

▪ Preventing hypoxaemia or hypercapnoea.

As discussed in Chapter 45, hypoxaemia

and hypercapnoea both trigger cerebral

arteriolar vasodilatation, which increases

CBF and consequently increases ICP In

between 4.5 and 5.0 kPa

– Severely raised ICP may be temporarily

reduced by decreasing brain ECF volume

through osmotherapy, following intravenous

administration of an osmotic diuretic; for

example, mannitol or hypertonic saline

– When raised ICP is caused by a brain tumour,

the volume of surrounding oedema may be

reduced by using dexamethasone, or surgical

excision may be considered

– The volume of a cerebral abscess may be

reduced by surgical drainage and by antibiotic

therapy

How is head injury classified?

Head injury is defined as any trauma to the head,

whether or not brain injury has occurred Head injury

may be classified by:

traffic collision or fall) or penetrating (gunshot or

stab wounds) In the military setting, blast injury

can also occur Blunt head injury may be:

– Closed, where the dura mater remains intact

– Open, where the dura mater is breached,

exposing the brain and CSF to environmental

microorganisms

Penetrating head injury is, by definition, open

patients may have an isolated head injury or there

may be accompanying traumatic injuries

Where a head injury results in a TBI, further

classifications can be made:

of TBI is commonly assessed using the GCS:

– Mild TBI corresponds to a GCS score of 13–15

– Moderate TBI corresponds to a GCS score of

9–12

– Severe TBI corresponds to a GCS score of 3–8

Patients presenting with mild TBI have a goodprognosis with a mortality of 0.1% However,patients with moderate and severe TBI have a muchhigher mortality, around 10% and 50% respectively.Many survivors are left with severe disability

(for example, extradural haematoma, contusions)

or diffuse (for example, diffuse axonal injury,hypoxic brain injury), but both types of injurycommonly coexist

What is the difference between primary and secondary brain injury?Brain injury may be classified as primary orsecondary:

during the initial injury caused by mechanicalforces: stretching and shearing of neuronal andvascular tissue Neuronal tissue is moresusceptible to damage than blood vessels; this iswhy diffuse axonal injury frequently accompaniesinjuries where there has been vessel disruption; forexample, extradural haematoma or traumaticsubarachnoid haemorrhage

cellular damage caused by the pathophysiologicalconsequences of the primary injury Cells injured

in the initial trauma trigger inflammatoryreactions, resulting in cerebral oedema and anincrease in ICP Secondary brain injury occurshours to days after the primary injury through anumber of different mechanisms:

– damage to the BBB– cerebral oedema– raised ICP– seizures– ischaemia– infection

Once primary brain injury has occurred, it cannot

be reversed Prevention of trauma is the best method

of reducing primary brain injury: reducing speedlimits, safer driving strategies, and so on The impact

of trauma on the brain can be reduced by the use ofairbags and seatbelts in cars, and of helmets for cyc-lists and motorcyclists Medical and surgical effortsare concentrated on preventing secondary braininjury: preserving as many neurons as possible

Section 4: Neurophysiology

How would you approach the

management of a patient with

traumatic brain injury?

Patients with TBI frequently present with other,

more immediately life-threatening injuries The broad

principles of initial trauma management are the same

whether in the emergency department or the

pre-hospital setting: with a multidisciplinary team

following an airway–breathing–circulation–disability–

exposure (ABCDE) approach, ensuring spinal

immo-bilization and treating life-threatening injuries first

Following the initial resuscitation phase, patients

with suspected TBI will require rapid transfer for

brain imaging, the results of which will help guide

further medical and surgical management

What are the main principles of medical

management in a patient with

traumatic brain injury?

The medical management of TBI is concerned with

preventing secondary brain injury and reducing ICP

It is divided into maintenance of:

kPa) is associated with a worse outcome following

TBI, due to its detrimental effects on CBF and

hence ICP Hypoxaemia may occur for a number

of reasons, such as airway obstruction, associated

chest injuries and aspiration pneumonitis In the

initial resuscitation phase, all trauma patients

patients with the potential to develop hypoxaemia

(for example, those with a low GCS) should be

intubated at an early stage

leads to failure of cerebral autoregulation, reduced

CBF and cellular ischaemia Therefore, in the

neurointensive care unit, when ICP is being

measured, CPP should be kept above 60 mmHg

Unfortunately, trauma patients do not arrive in

hospital with ICP monitoring in situ – the

Association of Anaesthetists of Great Britain

and Ireland (AAGBI) recommends maintaining

initially using fluid resuscitation, and then

by using vasopressors Even a single episode

Hypercapnoea causes cerebral arteriolarvasodilatation, increasing CBF above 50 mL/100g/min, which consequently increases ICP

Hypocapnoea causes cerebral arteriolarvasoconstriction, reducing CBF to below 50 mL/

100 g/min, inducing cellular ischaemia Inaddition, hypocapnoea causes a respiratoryalkalosis that shifts the oxyhaemoglobin

unloading to the tissues; as discussed above, low

and ICP The AAGBI recommends maintaining

glucose as its sole metabolic substrate The stressresponse to TBI commonly results in

hyperglycaemia, which is associated with a worseoverall outcome Insulin therapy is indicatedwhen plasma glucose rises, and is typicallyinstituted at a plasma glucose concentration of

10 mmol/L

Hypoglycaemia is rarely the direct result of TBI, but

a hypoglycaemic episode in an insulin-dependentdiabetic may have been the cause of the traumaticincident Hypoglycaemia further exacerbates cellu-lar acidosis within the brain; prolonged hypogly-caemia may result in neuronal cell death

increases CMR, which leads to an increase in CBFand consequently an increase in ICP

Hyperthermia should therefore be treatedpromptly using an antipyretic (such asparacetamol) and external cooling devices

nursing the patient in a 30° head-up tilt, with

a neutral head position and ensuring that ETTties are loose Minimal PEEP should be used

Chapter 46: Intracranial pressure and head injury

205

Further reading

R T Protheroe, C L Gwinnutt Early hospital care of

severe traumatic brain injury Anaesthesia 2011; 66(11):

1035–47

I K Moppett Traumatic brain injury: assessment,

resuscitation and early management Br J Anaesth 2007;

99(1): 18–31

H B Lim, M Smith Systemic complications after head

injury: a clinical review Anaesthesia 2007; 62(5): 474–82

L A Steiner, P J D Andrews Monitoring theinjured brain: ICP and CBF Br J Anaesth 2006; 97(1):26–38

K Pattinson, G Wynne-Jones, C H E Imray

Monitoring intracranial pressure, perfusion andmetabolism Contin Educ Anaesth Crit Care Pain 2005;5(4): 130–3

K Girling Management of head injury in the intensive-careunit Contin Educ Anaesth Crit Care Pain 2004; 4(2):52–6

Section 4: Neurophysiology

Section 4

Chapter

47

Neurophysiology

The spinal cord

Describe the anatomy of the spinal cord

The spinal cord is part of the CNS, located within the

spinal canal of the vertebral column The spinal cord

begins at the foramen magnum, where it is

continu-ous with the medulla oblongata The spinal cord is

much shorter than the vertebral column, ending at a

vertebral level of L1/2 in adults, but at a lower level of

around L3 in neonates

Like the brain, the spinal cord is enveloped in

three layers of the meninges: pia, arachnoid and dura

mater CSF surrounds the spinal cord in the

subar-achnoid space, and extends inferiorly within the dural

sac to approximately S2 level After the spinal cord

terminates, the pia and dura merge to form the filum

terminale, which tethers the cord to the coccyx

The spinal cord is divided into 31 segments, each

emitting a pair of spinal nerves There are:

pair of cervical nerves emitted than there are

cervical vertebrae

With the exception of C1 and C2, the spinal nerves

exit the spinal canal through the intervertebral

foramina

The spinal cord enlarges in two regions:

corresponding to the brachial plexus, which

innervates the upper limbs

corresponding to the lumbar plexus, which

innervates the lower limbs

At the terminal end of the spinal cord:

portion of the cord

that continue inferiorly in the spinal canal afterthe cord has ended, until they reach theirrespective intervertebral foramina

Describe the cross-sectional anatomy

of the spinal cord

In cross-section the spinal cord is approximately oval,with a deep anterior median sulcus and a shallowposterior median sulcus The centre of the cord con-tains an approximately ‘H’-shaped area of greymatter, surrounded by white matter:

the cell bodies of interneurons and motorneurons Located in the centre of the grey matter

is the CSF-containing central canal The points ofthe ‘H’ correspond to the dorsal and ventral(posterior and anterior) horns There are alsolateral horns in the thoracic region of the cord,which correspond to pre-ganglionic sympatheticneurons

axons, called tracts These tracts are organized into:– ascending tracts, containing sensory axons;– descending tracts, containing motor axons.The most important ascending tracts are shown inFigure 47.1:

nerves concerned with proprioception (positionsense), vibration and two-point discrimination(fine touch)

carry sensory information about pain,temperature, crude touch and pressure

carry proprioceptive information from themuscles and joints to the cerebellum

207

The most important descending tracts are

(Figure 47.1):

known as the pyramidal tracts, carry the axons

of upper motor neurons In the ventral horn of

the spinal cord, these axons relay to α-motor

neurons (or lower motor neurons) that innervate

muscle

tectospinal, vestibulospinal, olivospinal and

reticulospinal tracts The extrapyramidal neurons

originate at brainstem nuclei and do not pass

through the medullary pyramids Their primary

role is in the control of posture and muscle tone

Describe the blood supply to

the spinal cord

The spinal cord is supplied by three arteries, derived

from the posterior circulation of circle of Willis (see

Chapter 42) However, the blood flow through these

vessels is insufficient to perfuse the cord below the

cervical region – an additional contribution fromradicular arteries is essential The three spinal arteriesare:

branches of the right and left vertebralartery (see Figure 42.1) The anterior spinalartery descends in the anterior median sulcusand supplies the anterior two-thirds of thespinal cord, essentially all the structures withthe exception of the dorsal columns Theanterior spinal artery is replenished along itslength by several radicular arteries, the largest

of which is called the artery of Adamkiewicz.The location of this vessel is variable, but ismost commonly found on the left betweenT8 and L1

the posterior inferior cerebellar arteries (seeFigure 42.1) The posterior spinal arteries arelocated just medial to the dorsal roots, and supplythe posterior one-third of the cord Again, theposterior spinal arteries are replenished byradicular arteries

ASCENDING DESCENDING

Anterior median sulcus

Gracile tract

Cuneate tract

Anterior spinothalamic tract

Lateral spinothalamic tract

Posterior

spinocerebellar tract

Anterior

spinocerebellar tract

Lateral corticospinal tract

Anterior corticospinal tract

Central canal

Dorsal (posterior) horn

Ventral (anterior) horn

Lateral horn (present in thoracic segments only) Dorsal columns

Figure 47.1 Cross-section of the spinal cord (extrapyramidal tracts not shown).

Section 4: Neurophysiology

Blood from the spinal cord is drained via three

anterior and three posterior spinal veins, located in

the pia mater, which anastomose to form a tortuous

venous plexus Blood from this plexus drains into the

epidural venous plexus

Clinical relevance: anterior spinal artery syndrome

The artery of Adamkiewicz most commonly arises

from the left posterior intercostal artery, a branch of

the aorta Damage or obstruction of the artery can

occur through atherosclerotic disease, aortic

dissec-tion or surgical clamping during aortic aneurysm

repair As the anterior spinal artery supplies the

anterior two-thirds of the spinal cord, cessation of

blood flow can have profound consequences (see

Figure 47.4)

Signs and symptoms of anterior spinal artery

syndrome are:

 Paraplegia, as a result of involvement of α-motor

neurons within the anterior horn of the cord (i.e

a lower motor neuron deficit at the level of the

lesion), and the corticospinal tracts carrying the

axons of upper motor neurons (i.e an upper

motor neuron deficit below the level of the

lesion)

 Loss of pain and temperature sensation, due

to involvement of the spinothalamic tracts

 Autonomic dysfunction involving the bladder

or bowel, due to disruption of the sacral

para-sympathetic neurons

Crucially, proprioception and vibration sensation

remain intact These sensory modalities are carried

in the dorsal columns, which are supplied by the

posterior spinal arteries and thus remain unaffected

Describe the main sensory afferent

pathways

The somatosensory nervous system consists of:

repetitive firing of action potentials The different

sensory receptor types are specific to their sensory

modalities: proprioceptors, nociceptors,

thermoreceptors and mechanoreceptors relay

sensory information concerning limb position,

tissue damage (potentially causing pain),

temperature and touch respectively The

perception of the stimulus is dependent upon the

neuronal pathway rather than the sensory receptor

itself For example, pressing on the eye activates

the optic nerve and gives the impression of light,despite the stimulus being pressure rather thanphotons

from sensory receptors to the spinal cord, wherethey synapse with second-order neurons Theseneurons are pseudounipolar with their cell bodieslocated in the dorsal root ganglion, a swelling ofthe dorsal root just outside the spinal cord

to the thalamus, where they synapse with order neurons

cerebral cortex via the internal capsule

the cerebral cortex that receives and performs aninitial processing of the sensory information Theprimary somatosensory cortex is located in thepost-central gyrus of the parietal lobe It isorganized in a somatotropic way with specificareas of cortex dedicated to specific areas of thebody, known as the sensory homunculus Of note:the hands and lips make up a major component,reflecting their tactile importance Inputs fromspecific sensory modalities end in specificcolumns of cerebral cortical tissue

There are two major pathways by which sensoryinformation ascends in the spinal cord:

pathway carries sensory information about point discrimination, vibration and

two-proprioception (Figure 47.2a) The name of thepathway comes from the two structures throughwhich the sensory signals pass: the dorsal columns

of the spinal cord and the medial lemniscus in thebrainstem:

– The first-order neuron is extremely long Itenters the dorsal root of the spinal cord andascends in the dorsal columns on the same side(ipsilateral) Sensory neurons from the lowerbody travel in the medial gracile tract andsynapse in the gracile nucleus in the medullaoblongata, whilst sensory neurons from theupper body travel in the lateral cuneate tractand synapse in the cuneate nucleus

– In the medulla, first-order neurons synapsewith second-order neurons, which then crossover to the contralateral side and ascend to the

Chapter 47: The spinal cord

209

thalamus After this sensory decussation, the

fibres ascend through the brainstem in a tract

called the medial lemniscus

information about crude touch, pressure,

temperature and pain (Figure 47.2b) In contrast

to the DCML pathway, the spinothalamic tract

crosses the midline at the level of the spinal cord

rather than the medulla:

– The first-order neurons enter the dorsal root

of the spinal cord, and may ascend or descend

one or two vertebral levels (along Lissauer’s

tract) before synapsing with second-order

neurons in the dorsal horn

– The axons of the second-order neurons

decussate anterior to the central canal of the

spinal cord, in an area called the anterior

commissure, before ascending to the thalamus

in the contralateral spinothalamic tract

Clinical relevance: dissociated sensory lossDissociated sensory loss is a relatively rare pattern ofneurological injury characterized by the selective loss

of two-point discrimination, vibration-sense and prioception without the loss of pain and tempera-ture, or vice versa This is due to the different points

pro-of decussation pro-of the DCML and spinothalamic tracts.Causes of dissociated sensory loss include:

 Brown-Séquard syndrome, in which ahemi-section of the spinal cord causes ipsilateralmotor weakness, ipsilateral loss of two-pointdiscrimination, proprioception and vibrationsensation with contralateral loss of pain andtemperature sensation below the level of thelesion (see Figure 47.4) Hemi-section of the cordmay be the result of trauma (such as a gunshotwound), inflammatory disease (for example,multiple sclerosis), or by local compression: spinalcord tumour or infection (for example,

tuberculosis)

(a) Dorsal column–medial lemniscuspathway

First-order neuron from lower limbs

First-order neuron from upper limbs

Gracile tract Dorsal root ganglion

Cuneate tract

Cuneate nucleus Gracile nucleus Medial lemniscal tract

Medulla oblongata

Fibres cross the midline

(b) Spinothalamic pathway

First-order neuron from lower limbs

First-order neuron from upper limbs

Third-order neurons

Second-order neurons within spinothalamic tract

Second-order fibres cross in anterior commissure

Figure 47.2 The two major sensory pathways: (a) DCML; (b) spinothalamic.

Section 4: Neurophysiology

 Syringomyelia, a condition in which the central

canal of the spinal cord expands over time (referred

to as a syrinx), destroying surrounding structures

The axons of the spinothalamic tract that decussate

at the anterior commissure are usually the first to

be damaged The clinical consequence is loss of

pain and temperature sensation at the level of the

syrinx, usually involving the upper limbs, with

preservation of two-point discrimination,

proprioception and vibration sensation

 Lateral medullary syndrome, a brainstem stroke

in which occlusion of the posterior inferior

cere-bellar artery causes infarction of the lateral medulla,

a very important area containing, amongst other

structures,1the spinothalamic tracts from the

contralateral side of the body and the trigeminalnerve nuclei Clinically, therefore, lateral medullarysyndrome is characterized by loss of pain andtemperature sensation on the contralateral side ofthe body and the ipsilateral side of the face

Describe the course of the corticospinal tract

The corticospinal tract, also known as the pyramidaltract, is the most important descending tract as it isthe primary route for somatic motor neurons Thecorticospinal tract is composed of (Figure 47.3):

gyrus This area is the brain’s final commonoutput, resulting in the initiation of movement

Motor cortex

90% of fibres decussate in the medulla Internal capsule

Lateral corticospinal tract

Anterior corticospinal tract

Most of the remaining 10% of fibres

decussate in the anterior commissure

To skeletal muscles

Lower motor neurons

Upper motor neurons

Figure 47.3 The corticospinal tract.

1 Other important structures affected are the vestibular

nuclei (resulting in nystagmus and vertigo), the inferior

cerebellar peduncle (resulting in ataxia), the nucleus

ambiguus (affecting cranial nerves IX and X, resulting in

dysphagia and hoarseness) and the sympathetic chain(resulting in an ipsilateral Horner’s syndrome)

Chapter 47: The spinal cord

211

 An upper motor neuron, which originates in the

motor cortex and descends through the spinal

cord within the corticospinal tract:

– Upper motor neurons travel through the

posterior limb of the internal capsule

– At the level of the pons, a significant

proportion of upper motor neurons synapse in

the pontine nuclei, forming the ventral part of

the pons These post-synaptic fibres then travel

posteriorly to reach the cerebellum through

the middle cerebral peduncle

– At the medullary pyramids, 90% of the

remaining nerve fibres decussate and descend in

the lateral corticospinal tract of the spinal cord

– The 10% of nerve fibres that do not decussate

descend in a separate ipsilateral tract: the

– When they have reached their intended

vertebral level in the spinal cord, the upper

motor neurons synapse with lower motor

neurons in the ventral horn of the spinal cord

innervate skeletal muscle There are two types of

lower motor neuron:

– α-motor neurons leave the anterior horn,

forming the spinal nerve The spinal nerve exits

the spinal canal via the intervertebral foramen,

becoming a peripheral nerve Ultimately, the

skeletal muscle, causing muscle contraction

– γ-motor neurons innervate the intrafusal fibres

of skeletal muscle (the ‘muscle spindles’),

which are involved in proprioception (see

Chapter 52)

How can acute spinal cord injury

be classified?

Spinal cord injury is often devastating – permanent

neurological injury is common Spinal cord injury

can be classified in a number of ways:

the cervical and thoracic regions of the spinal

cord – lumbar cord injuries are much less

common A higher level of the cord injury results

in a greater loss of neurological function

column is anatomically divided into anterior,middle and posterior columns Unstable vertebralfractures (those potentially involving anythingother than solely the anterior column) requireimmobilization to prevent further damage to thespinal cord The high mobility of the cervical spinemakes it especially vulnerable to unstable fractures;fortunately, the spinal cord has more space withinthe spinal canal at the cervical level than elsewhere

of spinal cord injuries involve complete transection

of the cord, with an absence of motor and sensoryneurological function below the level of injury

A spinal cord injury is said to be ‘incomplete’ ifsome neurological function remains below thelevel of injury; for example, sacral sparing

How does the level of a complete spinal cord injury affect the different body systems?

The spinal cord is the exclusive relay of sensory,motor and autonomic (with the exception of thevagus nerve) information between the CNS and theperipheries The level of spinal cord injury determineswhether individual organs will remain in communi-cation with the brain:

common after spinal cord injury; respiratorycomplications are the most common cause ofdeath The higher the spinal cord lesion, thegreater the impact on ventilation:

– Injury above T8 vertebral level will causeintercostal muscle weakness or paralysis The

‘bucket-handle’ mechanism is abolished, anddiaphragmatic contraction becomes the solemechanism of inspiration The loss of intercostalmuscle tone reduces the outward spring of thechest wall FRC (the point at which the inwardelastic recoil of the lung equals the outwardspring of the chest wall) is therefore reduced.– Injury below C5 vertebral level does notdirectly affect diaphragmatic contraction (thephrenic nerve is formed by the C3, C4 and C5nerve roots) However, diaphragmaticcontraction is indirectly affected as a result of

2 Most of these upper motor neurons decussate in the

spinal cord (through the anterior commissure) before

synapsing with a lower motor neuron

Section 4: Neurophysiology

intercostal muscle paralysis: the loss of

intercostal muscle tone results in paradoxical

movement of the chest wall – it is drawn

inwards during diaphragmatic contraction

As a result, VC reduces by up to 50%

– Injury at C3 vertebral level and above will result

in paralysis of all respiratory muscles Patients

have gross ventilatory impairment requiring

immediate ventilatory support These patients

usually require long-term mechanical

ventilation or phrenic nerve stimulation

Spinal cord injury also alters lung mechanics

in other ways:

– Paralysis of the external intercostal muscles and

the abdominal muscles results in markedly

significantly reduced and cough is severely

impaired, leading to impaired clearance of

respiratory secretions

– Impaired inspiration results in basal atelectasis,

reduced lung compliance and V̇/Q̇ mismatch

– As a consequence of the lower lung volume,

the production of pulmonary surfactant is

reduced Lung compliance is further decreased,

which increases the work of breathing

– Rarely, neurogenic pulmonary oedema can

result from cervical cord injury, though the

mechanism for this is unclear

system, the cardiovascular consequences of spinal

cord injury are more significant with higher

spinal cord lesions Adverse cardiovascular effects

result from the interruption of the sympathetic

nervous system:

– Injury above T6 vertebral level results in

hypotension, known as neurogenic shock

Sympathetic nervous outflow to the systemic

arterioles is interrupted, resulting in arteriolar

vasodilatation Similarly, venodilatation leads

to venous pooling, which increases the risk of

thromboembolic disease and reduces venous

return to the heart, further contributing to

hypotension

– Lesions above T1 vertebral level can result in

bradycardia; the sympathetic

cardioacceleratory nerves are disconnected

from the heart, allowing unopposed

parasympathetic activity CO cannot be

increased by the normal mechanism of

sympathetic stimulation of HR SV musttherefore be maintained by adequate cardiacpreload; hypovolaemia is poorly tolerated inhigh spinal cord injury

the motor, sensory and autonomic fibres:

– Initially, there is flaccid paralysis and loss

of reflexes below the level of the spinal cordlesion; this is referred to as spinal shock(note: neurogenic shock refers to thecardiovascular collapse that accompaniesspinal cord injury)

– Over the next 3 weeks, spastic paralysis andbrisk reflexes develop

– Below the level of injury, somatic and visceralsensation is absent

is semi-autonomous, it is still affected by thesudden disruption of sympathetic fibres, resulting

in unopposed parasympathetic input via thevagus nerve:

– Delayed gastric emptying and paralytic ileusare common Abdominal distension mayfurther impair ventilation

– In high spinal cord lesions, gastric ulceration

is almost inevitable without gastric protection

as ranitidine) Gastric ulceration is thought

to be due to the unopposed vagal stimulation

of gastric acid secretion

– Patients usually become constipated as thesensations of defecation are lost; regularlaxatives and bowel care regimes are important

to prevent faecal impaction

metabolic consequences:

– Thermoregulation may be impaired due to theloss of sympathetic outflow below the level ofthe spinal cord injury:

result in heat loss

may cause hyperthermia, as sweating isimpaired

– Hyperglycaemia is common followingspinal cord injury as a result of the stressresponse; good glycaemic control is needed

to prevent exacerbation of ischaemic cord injury

Chapter 47: The spinal cord

213

Describe the common patterns of

incomplete spinal cord injury

Incomplete spinal cord injury describes a situation in

which there is partial damage to the spinal cord: some

motor and sensory function remains below the level

of the cord lesion Important patterns of incomplete

cord injury are shown in Figure 47.4:

described above, results in paraplegia, loss of pain

and temperature sensation, and autonomic

dysfunction below the level of the lesion

Crucially, proprioception and vibration sensation

remain intact

incomplete spinal cord injury:

– Central cord syndrome results from

hyperextension of the neck, usually in older

patients with cervical spondylosis, but

sometimes in younger patients involved in

high-force trauma

– Signs and symptoms are upper and lower limb

weakness below the level of the lesion, with a

varying degree of sensory loss Autonomic

disturbance is common, especially bladder

dysfunction

– Central cord syndrome is now thought to be

due to selective axonal disruption of the lateral

columns at the level of the injury, with relative

preservation of grey matter

above, results in three characteristic clinical

features: ipsilateral motor weakness, ipsilateral

loss of two-point discrimination, proprioception

and vibration sensation with contralateral

loss of pain and temperature sensation below

the level of the lesion

syndrome is not strictly speaking a spinal cord

injury, it is sufficiently similar to be included:

– In adults, the spinal cord ends at L1/2 vertebral

level, where it gives rise to the ‘horse-tail’ of L1

to S5 nerve roots: the cauda equina A lesion at

or below the level of L2, therefore, compresses

these nerve roots rather than the spinal cord;

this is called cauda equina syndrome

– The nerve roots carry sensory afferent nerves,

parasympathetic nerves and lower motor

neurons

– Patients typically present with severe legweakness, with at least partially preservedsensation ‘Saddle anaesthesia’ (sensory lossaround the anus, buttocks, perineum andgenitals) is the most common sensorydisturbance Autonomic disturbance is extremelycommon; urinary retention is almost universal.– The most common cause of cauda equinasyndrome is an acute central intervertebraldisc herniation: a surgical emergencyrequiring lumbar discectomy Other causes aremetastatic disease, trauma and epiduralabscess Of particular interest to theanaesthetist: there is an association betweencauda equina syndrome and the technique ofcontinuous spinal anaesthesia with fine-borespinal catheters It is not clear whether this isdue to the hyperbaric 5% lignocaine that wasused in the technique, or the introduction ofsmall amounts of neurotoxic chlorhexidinecleaning solution into the CSF

Describe the initial management of acute spinal cord injury

Trauma patients frequently have multiple injuries; forexample, 25% of patients with a cervical spine injuryalso have a TBI Unfortunately, nothing can be done toreverse the mechanical aspects of a spinal cord injury;for example, an axonal injury due to rotational andshearing forces The aim of medical management isthe prevention of secondary spinal cord damage Themost common cause of secondary damage is cordischaemia resulting from systemic hypoxaemia, or cordhypoperfusion due to vascular damage, cord oedema orsystemic hypotension

The anaesthetic management of patients with spinalinjury frequently starts in the resuscitation room of theemergency department, and increasingly in the pre-hospital setting Patients should be managed following

algorithms), treating life-threatening problems first.Whenever spinal trauma is suspected, spinal immobil-ization must be maintained throughout to prevent anyfurther mechanical spinal cord injury The cervicalspine is immobilized by means of a hard collar,sandbags either side of the head and straps holdingthe patient’s head to a backboard The thoracicand lumbar spine are immobilized simply by the patient

Section 4: Neurophysiology

lying still on a flat surface If the patient needs to be

moved, the spine is kept in alignment by ‘log-rolling’

Aspects of anaesthetic management specific to

spinal injuries are:

that does not risk displacing a cervical fracture.Oxygenation should be maintained – either by

Dorsal columns – proprioception and vibration

Corticospinal tract – motor fibres

Spinothalamic tract – pain and temperature

Normal spinal cord

Anterior spinal artery syndrome

Sparing of dorsal columns

Central cord syndrome

Lateral horn – sympathetic fibres

Brown–Séquard syndrome

Loss of ipsilateral proprioception and vibration sense

Loss of ipsilateral motor function

Loss of contralateral pain and temperature sensation

Loss of all other motor and sensory function

Motor fibre involvement

Autonomic fibre involvement

Some sensory sparing Some involvement of dorsal columns

Figure 47.4 Characteristic patterns of incomplete spinal cord injury.

Chapter 47: The spinal cord

215

patient, or by intubation and ventilation in an

unconscious patient If intubation is likely to be

required, this should take place at an early stage to

prevent hypoxaemia-related secondary cord

damage A difficult intubation should be

anticipated, owing to:

– sub-optimal positioning of the patient on the

spinal board;

– RSI with cricoid pressure;

– manual in-line stabilization of the

cervical spine;

– associated maxillofacial injuries;

– blood and debris in the oral cavity

Nasal intubation should be avoided owing to

the possibility of associated basal skull fractures

pulmonary aspiration necessitates RSI The choice

of intravenous induction agent is a matter of

personal preference, but in the setting of trauma a

cardio-stable drug (ketamine or etomidate) may

be required The muscle relaxant of choice in the

acute phase of spinal cord injury is

suxamethonium However, from 24 h after the

injury, the use of suxamethonium is

may occur due to the depolarization of the newly

developed extra-junctional ACh receptors (see

Chapter 50) If head injury is suspected (which it

is in arguably all major trauma patients), some

means of obtunding the sympathetic response to

laryngoscopy should be used to avoid a rise in

ICP; for example, by administering a fast-acting,

strong opioid

be kept above 10 kPa Oxygenation may

be impaired by associated chest injuries

(for example, flail chest, haemothorax), which

should be dealt with promptly As discussed

above, the respiratory consequences of cervical

spine injury make hypoxaemia particularly

common; if a conscious patient is unable to

maintain adequate arterial oxygenation or

becomes hypercapnoeic, intubation and

ventilation are indicated

promptly with fluids to minimize secondaryischaemic damage of the spinal cord In a traumapatient, hypotension is most likely to be the result

of haemorrhage – the search for the site ofbleeding is both clinical and radiological: chestand pelvic X-rays, abdominal ultrasound andcomputed tomography (CT) Bradycardia withhypotension may be due to spinal cord injury withunopposed parasympathetic innervation of theheart – atropine or glycopyrrolate should be given

include an assessment of conscious level using theGCS or the ‘alert, voice, pain, unresponsive’(AVPU) scale, pupil size and reactivity, andtendon reflexes Patients with a reduced level

of consciousness will almost inevitablyrequire imaging of their brain in addition totheir spine

should be tested and abnormalities corrected

A full secondary survey should be carried outwhen the patient has been stabilized – thisincludes log-rolling the patient to examine thespine, flanks and anal motor tone Care should betaken to keep the patient warm; hypothermia iscommon, due to prolonged exposure to theenvironment at the scene of trauma, coldintravenous fluids and blood, and removal ofclothes for clinical examination

Further reading

J A Kiernan, R Rajakumar Barr’s The Human NervousSystem: An Anatomical Viewpoint, 10th edition.Lippincott Williams and Wilkins, 2013

J H Martin Neuroanatomy Text and Atlas, 4th edition.McGraw-Hill Medical, 2012

M Denton, J McKinlay Cervical cord injury and criticalcare Contin Educ Anaesth Crit Care Pain 2009; 9(3):82–6

J Šedy, J Zicha, J Kuneš, et al Mechanisms of neurogenicpulmonary edema development Physiol Res 2008; 57:499–506

P Veale, J Lamb Anaesthesia and acute spinal cord injury.Contin Educ Anaesth Crit Care Pain 2002; 2(5): 139–43.Section 4: Neurophysiology

Section 4

Chapter

48

Neurophysiology

Resting membrane potential

The membrane potential of a cell is the electrical

voltage of its interior relative to its exterior At rest,

the membrane potential is negative, and is then

described as being polarized The resting membrane

non-excitable cells The action potential (see Chapter 49)

is a transient change in the membrane potential from

the RMP to a positive value; the cell membrane is then

described as being depolarized

How is the membrane potential

produced?

When there are exactly equal numbers of positively

and negatively charged ions on either side of the cell

membrane, the electrical potential across the

mem-brane will be zero Inequalities in the distribution of

charged ions across the cell membrane result in an

electrical potential For example:

 A negative membrane potential is produced

when there are a greater number of positively

charged ions on the outside of the cell membrane

relative to the inside

 A positive membrane potential is produced when

there are a greater number of positively charged

ions on the inside of the cell membrane relative to

the outside

The distribution of ions across the cell membrane

is due to the combined effects of:

 The different ionic compositions of the ICF

and ECF

 The selective permeability of the cell membrane to

the different ions

 Negatively charged intracellular proteins, whose

large MW and charge means that they are unable

to cross the cell membrane These proteins tend to

bind positively charged ions and repel negativelycharged ions

The RMP is influenced by the concentrations andmembrane permeability of three major ions:

concentration (5 mmol/L) The phospholipid

ions, as they are polar However, the cell

gradient, from the ICF to the ECF

concentration (20 mmol/L) The resultingelectrochemical gradient, therefore, tends to drive

the membrane are normally closed at RMP,leaving the resting cell membrane impermeable to

Na+.2

 Cl : membrane permeability varies with cell type:

impermeable to Cl : permeability to Cl is

therefore its contribution is often ignored

channels Cl therefore distributes itself acrossthe cell membrane passively according to itselectrochemical gradient At RMP, Cl isdriven out of the cell by the negatively charged

1 These are also called two-pore-domain K+channels

2 In reality, the resting cell membrane is not completelyimpermeable to Na+, as the K+leak channels are notcompletely specific to K+ Overall, Na+permeability isabout 100 times less than that of K+

217

cell interior However, membrane

depolarization results in a positively charged

cell interior, producing a Cl influx

Therefore, in most cells, Cl movement does

not influence the RMP; rather, the membrane

potential passively influences Cl movement

What is the Nernst equation?

Consider a particular membrane-permeant ion, X:

 X will distribute on either side of a cell membrane,

according to its chemical (i.e concentration) and

electrical gradients across the membrane

 The movement of X ceases when the net

chemical and electrical gradients of X across

the membrane are zero; that is, at electrochemical

equilibrium

 The contribution that ion X makes to the RMP

may be calculated using the Nernst equation from

its valency, the concentration difference across the

membrane, and the temperature:

Key equation: the Nernst equation

EX¼RT

zFln

½XŠo

½XŠiwhere EX(mV) is the Nernst potential for a particular

ion, R is the universal gas constant (8.314 J/(K mol)),

T (K) is the absolute temperature, F is the Faraday

constant, the electrical charge per mole of electrons

(96 500 C/mol), z is the valency of the ion, [X]o(mmol/

L) is the ion concentration outside the cell and [X]i

(mmol/L) is the ion concentration inside the cell

calcu-lated as follows:

Assuming a temperature of 37 °C (i.e 310 K), with

inter-ior down its concentration gradient, driving themembrane potential towards the Nernst potential

increasingly negatively charged, thus generating an

efflux

In contrast, there is a considerably lower resting

little contribution from the transmembrane

( 70 mV) is close to the calculated Nernst potential

permeability

What is the Goldman equation?

As discussed above, the Nernst equation is used tocalculate the membrane potential for a single ion,assuming that the cell membrane is completely per-meable to that ion However, the cell membrane hasdiffering permeability to a number of ions The RMPcan be more precisely quantified by considering allthe ionic permeabilities and concentrations using theGoldman–Hodgkin–Katz equation

Key equation: the Goldman–Hodgkin–Katzequation

Em¼RT

F ln

PK½K+Šo+ PNa½Na+Šo+ PCl½Cl ŠiPK½K+Ši+ PNa½Na+Ši+ PCl½Cl Šowhere Em(mV) is the calculated membrane potentialand PXis the permeability of the membrane to ion X.Note:

 If the membrane is permeable only to K+, then

PNaand PClequal zero and the equation reduces

to the Nernst equation for K+

 There is no valency term as only monovalent ionsare considered

 The concentrations of Cl are shown opposite tothose of K+and Na+to account for its negativevalency

Section 4: Neurophysiology

How does the Na+/K+-ATPase

contribute to the resting membrane

potential?

the following consequences:

concentration, and conversely the high

concentration, which ultimately generate

the RMP

 The osmotic effect of the high extracellular

osmotic effect of the high intracellular

concentration of negatively charged protein,

thereby ensuring an osmotic balance across the

cell membrane

activity results in the net loss of one positive

charge from the cell, making the cell interior

slightly more negative (i.e hyperpolarization) by

cell membrane resistance

Clinical relevance: the effect of electrolyte

disturbances

As discussed above, the RMP depends on the relative

concentrations of ions on either side of the cell

membrane Changes in extracellular ionic

concentra-tion may therefore alter the RMP (Figure 48.1):

 K+.– Hyperkalaemia depolarizes the RMP From theNernst equation, an increase in extracellular

K+concentration from 4.0 to 7.5 mmol/Lchanges the Nernst potential for K+from 90

to 80 mV The RMP approaches thresholdpotential (the potential at which an actionpotential is triggered), making spontaneousgeneration of action potentials more likely

In the heart, dangerous arrhythmias such

as ventricular fibrillation (VF) may occur

– Hypokalaemia causes the opposite effect:

the cell membrane becomes hyperpolarized

It becomes harder to generate and propagateaction potentials Muscular weakness andECG changes may occur

 Na+ As discussed above, the cell membrane isrelatively impermeable to Na+at rest Therefore,changes to the Na+extracellular concentrationwould be expected to make little difference tothe RMP However, hyponatraemia alters thedistribution of water in the body (see Chapter 65).The reduced ECF osmolarity causes cells toswell – for example, severe hyponatraemia leads

to cerebral oedema The additional intracellularwater causes a fall in intracellular K+concentra-tion, which in turn leads to cell membranedepolarization towards threshold potential;

spontaneous action potentials are morelikely to be generated This is in part whycerebral oedema secondary to hyponatraemia

is associated with seizure activity

 Ca2+ As discussed above, K+is the major minant of the RMP – Ca2+essentially plays norole However, Ca2+is integral to the normal

Figure 48.1 Changes to RMP and threshold potential with electrolyte disturbances.

Chapter 48: Resting membrane potential

219

function of the cell membrane Na+channels;

hypocalcaemia activates these Na+channels,

bringing the threshold potential nearer to

RMP The clinical result is spontaneous

depolarization of neurons; that is, tetany

and parasthesias

Ca2+may be given for cardioprotection in

hyper-kalaemia, allowing time for the underlying cause

to be dealt with Administering Ca2+ does not

change intracellular Ca2+ concentration

signifi-cantly, as the membrane is impermeable to Ca2+

at rest However, Ca2+has a membrane-stabilizing

effect due to the ‘surface charge hypothesis’ Ca2+

binds to the outside of the cell membrane,attached to glycoproteins This increases theamount of positive charge directly apposed

to the extracellular side of the membrane,which causes a temporary hyperpolarization ofthe RMP

Further reading

R D Keynes, D J Aidley, C L-H Huang Nerve andMuscle, 4th edition Cambridge, Cambridge UniversityPress, 2011

S H Wright Generation of resting membrane potential.Adv Physiol Educ 2004; 28: 139–42

Section 4: Neurophysiology

Section 4

Chapter

49

Neurophysiology

Nerve action potential and propagation

What is an action potential?

An action potential is a transient reversal of the

mem-brane potential that occurs in excitable cells,

includ-ing neurons, muscle cells and some endocrine cells

(Figure 49.1) The action potential is an ‘all or

noth-ing’ event: if the triggering stimulus is smaller than a

threshold value, the action potential does not occur

But once triggered, the action potential has a

well-defined amplitude and duration Action potentials

allow rapid signalling within excitable cells over

rela-tively long distances

Describe the events that result in the

nerve action potential

Action potentials usually begin at the axon hillock of

motor neurons, or at sensory receptors in sensory

(Figure 49.1):

90 mV

synapse or another part of the nerve results in

depolarization of the cell membrane:

channels, primarily responsible for the RMP

(see Chapter 48) The cell membrane returns

– If the stimulus is large enough, depolarizing the

there is a significant activation of

known as the ‘threshold potential’

channels, thus further increasing the membrane

further membrane depolarization, resulting inthe rapid upstroke of the action potential

This drives the membrane potential towards

of approximately +50 mV However,the action potential never reaches thistheoretical maximum, as two further eventsintervene:

transition from the open state, to a closed

decreases

channels: membrane depolarization slowly

membrane potential back towards the Nernst

90 mV

more negative than the RMP Thisafter-hyperpolarization occurs because of

channels

In summary, the action potential results from a

followed by a slower increase in membrane

1 Threshold potential is dependent on a number of factors,

but is commonly between 55 and 40 mV

221

How are action potentials propagated

along nerve axons?

Electrical depolarization propagates by the formation

of local circuits (Figure 49.3):

cell membrane is negatively charged

of cell membrane depolarizes, resulting

in the intracellular surface becomingpositively charged The action potential

is limited to a small portion of cellmembrane; neighbouring segments remainquiescent

membrane results in current flow; theneighbouring quiescent portions of cellmembrane become depolarized

Figure 49.2 Changes in the membrane permeability of Na + and

K + throughout the action potential.

Voltage-gated K+ channels open

Voltage-gated K + channels start to close

Resting membrane potential Hyperpolarization

Depolarization

Repolarization

Voltage-gated Na +

channels start to close

Figure 49.1 The nerve action potential.Section 4: Neurophysiology

 Current decays exponentially along the length of

the nerve axon, with a length constant of a few

propagated depolarization in the previously

quiescent cell membrane is sufficient to reachthreshold potential, an action potential isgenerated

This process of local circuit propagation and actionpotential generation is continued until the actionpotential reaches its destination (Figure 49.3)

The velocity of action potential conduction isaffected by several factors:

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ + + + +

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ + + + + + + + + + + + + + +

+ + + + + + + + + + + + + + + +

Action potential is

initiated by stimulus

Stimulus _ _ + + _ _ Area undergoing an

action potential

Induced local electrical currents

_ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ + + + + + + + + + + + +

+ + + + + + + + + + + +

Action potential

propagation

_ _ _ _ + + + + + + + + _ _ _ _

_ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ + + + + + + + +

_ _ _ _ _ _ _ _

+ +

+ +

+ + + +

_ _ Membrane

_ _ _ _

+ + + + + + + +

Wave of repolarization Wave of depolarization

Figure 49.3 Action potential propagation in unmyelinated neurons.

2 Longitudinal current is reduced by a deposition of charge

on intervening membrane, as well as its leak across the

membrane into the ECF

Chapter 49: Nerve action potential and propagation

223

 The axon diameter Just like a copper wire, the

ICF within a larger nerve axon diameter has a

smaller resistance to the longitudinal flow of

current, thereby permitting a higher conduction

velocity

how easily current may flow out of the nerve

and into the ECF A higher transmembrane

resistance reduces this loss of current

flow, thereby enhancing conduction

Myelination increases the transmembrane

resistance as the myelin sheath is made

of insulating lipids

the capacitance of the membrane, the

longer it takes to alter the membrane

polarity, thus slowing action potential

propagation Myelination decreases membrane

capacitance

ion channels is very dependent on temperature

The rate of ion channel opening increases

around three- or fourfold with a 10 °C

increase in temperature Therefore, the

rapidly, increasing the velocity of action

potential propagation

How does myelination alter the nature

of action potential propagation?

Larger diameter nerve axons are coated in a white

lipid-rich insulating material called myelin The

myelin sheath is produced by Schwann cells in

the PNS, and by oligodendrocytes in the CNS The

myelin sheath covers the nerve axon except at

regu-larly spaced gaps known as nodes of Ranvier These

exposed regions of membrane are densely populated

The electrical impulse propagates across the

internode (where the axon is covered by the myelin

Figure 49.3 As discussed above, the myelin sheath

insulates the nerve axon, preventing loss of current

to the ECF and decreasing the effect of membrane

capacitance This ensures that the membrane is

depolarized in excess of the threshold potential at

the adjacent node of Ranvier The action potential

therefore appears to ‘jump’ from node to node; this

is known as saltatory conduction (Figure 49.4).Action potential conduction velocity increases from

2 m/s in unmyelinated nerves to up to 120 m/s inmyelinated axons

Clinical relevance: demyelination

As discussed above, myelination is an extremelyimportant determinant of nerve conduction velocity.The myelin sheath is especially important in nervesthat require the rapid conduction of action potentialsfor their function; for example, motor and sensorynerves

There are two important diseases in whichthere is autoimmune destruction of the myelinsheath: multiple sclerosis (where CNS neuronsdemyelinate) and GBS (where demyelination occurs

in the PNS)

A demyelinated neuron is not the same as

an unmyelinated neuron Demyelinated neuronshave Na+ channels tightly packed at the nodes

of Ranvier, but do not have adequate numbers

of Na+ channels in the newly exposed areas ofcell membrane Therefore, action potentials oftenfail to be conducted effectively along demye-linated axons In contrast, whilst unmyelinatedaxons conduct action potentials slowly, they arereliably conducted along the entire length of theneuron

The clinical features of demyelinating disease aretherefore deficiencies in sensation, motor function,autonomic function or cognition, depending on thetype and location of the nerves involved

How are nerve fibres functionally classified?

Nerves can be classified based on their diameter andconduction velocity:

diameter (12–20 μm) with a conduction velocity

of 70–120 m/s Type A fibres are subdivided into

α, β, γ and δ, in order of decreasing nerveconduction velocity:

– Aα motor fibres supply extrafusal musclefibres; that is, those involved in skeletal musclecontraction

– Aβ sensory fibres carry sensory informationfrom receptors in the skin, joints and muscle.– Aγ motor fibres supply intrafusal musclespindle fibres

Section 4: Neurophysiology

– Aδ sensory fibres relay information from fast

nociceptors and thermoreceptors

myelinated fibres Their conduction velocity is

correspondingly lower, at 4–30 m/s The

pre-ganglionic neurons of the ANS are type B fibres

unmyelinated axons with a correspondingly slow

conduction velocity (0.5–4 m/s) Post-ganglionic

neurons of the ANS and slow pain fibres are type

C fibres

Clinical relevance: local anaesthetics

Local anaesthetics act by blocking fast voltage-gated

Na+channels, thereby preventing further action

poten-tials being propagated The mechanism of action is:

 Local anaesthetics are weak bases

 Only unionized local anaesthetic can diffuse

across the phospholipid bilayer of the neuronal

cell membrane

 The lower pH within the axoplasm means that

as soon as the local anaesthetic has crossed thecell membrane it is protonated (becomesionized) and therefore cannot diffuse back intothe ECF

 The ionized local anaesthetic blocks thevoltage-gated Na+channels by binding to theinner surface of the ion channels when they are

in their refractory state

 In other words, local anaesthetics indefinitelyprolong the absolute refractory period (ARP);

further action potentials are prevented

Some nerves are more sensitive to local thetics than others In general:

anaes- Small nerve fibres are more sensitive to localanaesthetics than large nerve fibres are

 Myelinated fibres are more sensitive to localanaesthetics than equivalent-diameterunmyelinated fibres are This is probablyowing to myelinated fibres having only small

+ +

+ + _ _ _ _

_ _

_ + +

+ + + +

+ +

+ + _ _ _ _

_ _

_ + +

+ + + +

Induced local electrical currents

Myelin sheath Node of Ranvier

_ _

_ _ + + + +

+ + _ _ _ _

_ _

_ + +

+ + + +

_ _

_ _ + + + +

+ + _ _

_ _

_ _

_ + +

+ + + +

areas of cell membrane exposed (nodes of

Ranvier), in which the Na+channels are densely

packed

The overall clinical effect is:

 Intermediate-sized myelinated fibres are the

easiest to block; for example, Aδ (which relay fast

nociceptive signals) and B fibres (pre-ganglionic

autonomic fibres)

 Larger Aα, Aβ and Aγ fibres (which relay touch,

pressure and proprioception) are the next easiest

The refractory period describes the time following an

action potential when a further action potential either

cannot be triggered whatever the size of the stimulus

(ARP), or only with application of a stimulus ofincreased size (relative refractory period (RRP)):

continues until repolarization is one-thirdcomplete (a period of around 1 ms) The basis

of the ARP is:

have opened, they become refractory

refractory state, and are incapable ofreopening until the membrane regains itsnegative potential

has ended The mechanism behind the RRP is asfollows:

therefore at its highest

– During this period the threshold potential is

higher, as a greater stimulus is required to

The refractory period is important for two

reasons:

action potentials When a segment of a cell

membrane depolarizes, the trailing region of cell

membrane is in its refractory state, whilst the

leading segment of cell membrane is in its

resting state

refractory period limits the number of actionpotentials that can be generated in a given timeperiod

Further reading

R D Keynes, D J Aidley, C L-H Huang Nerve andMuscle, 4th edition Cambridge, Cambridge UniversityPress, 2011

A Scholz Mechanisms of (local) anaesthetics on gated sodium and other ion channels Br J Anaesth 2002;89(1): 52–61

voltage-Chapter 49: Nerve action potential and propagation

227

A synapse is the functional point of contact between

two excitable cells, across which a signal can be

trans-mitted There are two types of synapse:

by means of a chemical messenger called a

neurotransmitter Arrival of an action potential

triggers neurotransmitter release into the

synaptic cleft, a narrow (20–50 nm) gap between

the pre- and post-synaptic membranes, which

excites or inhibits the post-synaptic cell An

example of a chemical synapse is the NMJ: the

synapse with the motor end plate of a skeletal

muscle cell Chemical synapses are unidirectional:

the signal can only be transmitted from pre- to

post-synaptic cell

post-synaptic cells are joined by gap junctions that

allow electric current to pass; an action potential

in the pre-synaptic cell induces a local current in

the post-synaptic cell, which triggers an action

potential Signals are transferred from neuron to

target cell much faster when the cells are

connected by an electrical synapse than by a

chemical synapse This is exemplified by cardiac

muscle, where gap junctions are essential for the

rapid conduction of action potentials (see

Chapter 54) Electrical synapses are bidirectional:

the signal can be transmitted from pre- to

post-synaptic cell, or vice versa

What are neurotransmitters?

A neurotransmitter is a substance released by a

neuron at a synapse, which then affects the

post-synaptic cell There are four classical requirements

for a substance to be a neurotransmitter:

membrane in sufficient quantity to trigger aneffect at the post-synaptic membrane

mimic the physiological effect

the synapse

Neurotransmitters may be classified as:

classes:

– Amines – ACh, histamine, serotonin (5-HT),catecholamines (noradrenaline, adrenaline,dopamine)

– Amino acids – γ-amino butyric acid (GABA),glycine, glutamate

– Purines – ATP, adenosine

known, including:

– Opioids – β-endorphin, enkephalins

– Tachykinins – substance P, neurokinins.– Secretins

– Somatostatins

Most neurotransmitters exert excitatory effects

on the target cell, which may result in the triggering

of an action potential (if the target cell is a nerve ormuscle) or secretion (if the target cell is a gland).The most prevalent excitatory neurotransmitter isglutamate, present in over 90% of synapses in thebrain Some neurotransmitters are inhibitory, causing

conduct-ance at the post-synaptic membrane, thereby cing the likelihood of an action potential beinggenerated GABA, the second most prevalent neuro-transmitter in the brain, is the major inhibitoryneurotransmitter Glycine is an inhibitory neuro-transmitter particularly widespread in the spinal cordand brainstem

redu-Occasionally, neurotransmitters have an

excita-tory effect at one synapse, whilst having an inhibiexcita-tory

effect at another For example, ACh is an excitatory

neurotransmitter at the nicotinic receptors of the

NMJ, whilst producing an inhibitory response at the

How are neurotransmitters released

into the synaptic cleft?

Neurotransmitters are stored in packets called vesicles

which are docked at the active zone of the pre-synaptic

membrane When the action potential propagates down

the axon and into the terminal bouton (Figure 50.1a),

a well-defined sequence of events occurs:

Depolarization results in the opening of

its electrochemical gradient from the ECF to the

neuron interior (Figure 50.1b)

spontaneously fuse with the pre-synaptic membrane,

releasing their neurotransmitter contents into the

synaptic cleft Following an action potential, axonal

synaptotagmin which, in conjunction with proteins

known as SNAREs, triggers 50–100 vesicles to

undergo exocytosis Thus, a very large number of

neurotransmitter molecules are released into the

synaptic cleft following an action potential

neurotransmitters diffuse down their

concentration gradient, travelling the short

distance to the post-synaptic membrane

Neurotransmitters that reach the post-synaptic

membrane bind to specific receptors, resulting in

excitation or inhibition of the membrane

(Figure 50.1c)

What are ionotropic receptors?

At the post-synaptic membrane, neurotransmitters

encounter two types of receptor:

ion channels

chemical second messengers

Ionotropic signalling may produce either an excitatory(EPSP) or inhibitory (IPSP) post-synaptic potential,depending on the flow of ions at the post-synapticion channel:

post-synaptic membrane opens non-specificcation channels

post-synaptic cell from the synaptic cleft,

intracellular movement of positively chargedions causes a depolarization of the post-synaptic membrane, the EPSP

– There is usually an excess of post-synaptic ionchannels; the size of the EPSP is thereforedependent on the number of neurotransmittervesicles released

vesicle of neurotransmitter results in asmall 0.5 mV depolarization Thisdepolarization is not large enough to reachthreshold potential, and the EPSP will fadeback to the RMP

number of neurotransmitters are releasedinto the synaptic cleft The depolarizingeffect of each vesicle’s contents at the post-synaptic membrane is additive; to exceedthreshold potential and generate an actionpotential at the post-synaptic cell, manyvesicles must be released simultaneously(Figure 50.2a)

gradient, from the post-synaptic cell to thesynaptic cleft The efflux of positively chargedions hyperpolarizes the cell membrane,making it more difficult to reach thresholdpotential (Figure 50.2b)

– Cl -mediated IPSP: binding ofneurotransmitter opens Cl channels Theresulting intracellular movement of Cl ionsusually makes little difference to the

Chapter 50: Synapses and the neuromuscular junction

229

post-synaptic membrane potential, as the

Nernst potential of Cl ( 70 mV) is

approximately the same voltage as the RMP

However, to reach threshold, an excitatory

exceed the combined effects of Cl influx and

depolarize the cell membrane; this is known as

the ‘chloride clamp’

Clinical relevance: mechanism of action of generalanaesthetics

Despite general anaesthetics having been tered since 1846, their exact mechanism of actionremains a matter of debate The most likely explan-ation is a receptor theory, whereby general anaes-thetics interact with two main transmembraneproteins in the CNS:

adminis- .

. .

. .

. .

. .

Action potential

Vesicles containing neurotransmitter Terminal bouton

Synaptic cleft Pre-synaptic membrane

Post-synaptic membrane

Chemically gated ion channel (closed)

.

. .

.

. . . . .

Voltage-gated Ca 2+

channels open

Neurotransmitters released

Vesicles fuse with synaptic membrane

post- .

.

. . . .

.

Open ion channel

 The GABAAreceptor utilizes the inhibitory

neurotransmitter GABA The receptor has five

subunits arranged around a Cl channel

A number of drugs act at this receptor:

– Benzodiazepines – a subset of GABAA

recep-tors bind benzodiazepines in addition to

GABA The benzodiazepine binding site is

located at a different site to that of GABA,

between the α- and γ-subunits Following the

binding of a benzodiazepine, the GABAA

receptor changes its conformation, which

increases its affinity for GABA

– Propofol, thiopentone and etomidate – all these

drugs act, at least in part, at the GABAA

recep-tor Like the benzodiazepines, all bind at a site

distant to the GABA binding site, and act byincreasing the conductance of Cl The exactbinding site and why their effects differ fromthose of the benzodiazepines are not yetknown

 The N-methyl-D-aspartate (NMDA) receptor is

a tetrameric receptor, which utilizes theexcitatory neurotransmitter glutamate A number

of anaesthetic agents are thought to act byantagonizing this excitatory receptor, thusreducing neurotransmission:

– Ketamine binds at a site distant to theglutamate binding site A conformation changeoccurs in the NMDA receptor that preventsthe subsequent binding of glutamate

Resting membrane potential

IPSP: membrane potential is further from the threshold potential, inhibiting action potential generation

(b) Inhibitory post-synaptic potential

Multiple vesicles of

neurotransmitter

released simultaneously When the EPSP exceeds threshold,

an action potential is triggered

Figure 50.2 Excitatory and inhibitory post-synaptic potentials.

Chapter 50: Synapses and the neuromuscular junction

231

– N2O, Xe – both are also thought to exert their

anaesthetic effects through antagonism of

the NMDA receptor

What are metabotropic receptors?

Some synapses are metabotropic rather than

ionotro-pic Binding of a neurotransmitter causes a

metabo-tropic receptor to change its conformation, but unlike

ionotropic receptors the conformation change does

not directly result in ion channel opening Instead,

metabotropic receptors are indirectly linked to

mem-brane ion channels through intermediate chemical

messengers, usually involving a G protein An

important example of a metabotropic synapse is the

in the heart (see Chapter 54)

How is neurotransmission terminated?

Once released, neurotransmitters are rapidly removed

from the synaptic cleft This prevents repetitive and

unwanted stimulation of the post-synaptic cell There

are three possible mechanisms by which this takes

place:

the synaptic cleft along their concentration

gradients This is a minor and relatively slow

mechanism

synaptic cleft may inactivate the

neurotransmitters An important example is the

hydrolysis of ACh by AChE into acetic acid and

choline

actively transported back into the pre-synaptic

membrane Instead of synthesizing large amounts

of new neurotransmitter, the pre-synaptic nerve

recycles the neurotransmitter molecules, storing

them in vesicles ready for release This occurs with

catecholamine neurotransmitters such as

noradrenaline and dopamine, which are

metabolically expensive to produce In clinical

practice, the action of neurotransmitters may be

prolonged through the use of reuptake inhibitors

Examples include selective serotonin reuptake

inhibitors (SSRIs), which prevent the reuptake of

serotonin in the CNS, and cocaine, which blocks

the reuptake of dopamine in the CNS

What is the neuromuscular junction?

neuron and a muscle cell The transmission of motoraction potentials, or indeed their prevention, is ofobvious importance to anaesthetists The NMJ exem-plifies many of the features of synapses discussedabove, but its importance makes it worth reiteratingthe key features

of the spinal cord Its axon is myelinated, as theconduction of motor action potentials needs to berapid Before the axon reaches the NMJ, it branches

to innervate several muscle cells A motor unit

innervates

The NMJ itself consists of (Figure 50.3):

which are located vesicles containing theneurotransmitter ACh

diffuse

which is folded into peaks and troughs; the peaksare densely packed with ACh receptors (AChRs),whilst the troughs contain the enzyme AChE.There are estimated to be in excess of 1 000 000AChRs at each motor end plate

Before the action potential arrives, the NMJ must

be ready for neurotransmission to occur:

terminal, ACh is synthesized from choline andacetyl CoA, a reaction catalysed by the enzymecholine-O-acetyltransferase Choline originatesfrom the diet or by hepatic synthesis, whilst acetylCoA is produced in the axon mitochondria

into vesicles Each vesicle contains around

5000 ACh molecules, known as a ‘quantum’.There are functionally three types of vesicle:– Vesicles in the active zone (1% of the vesicles) –these vesicles are ‘docked’ at the pre-synapticmembrane, ready for immediate release.– Vesicles in the reserve pool (around 80% ofvesicles) – these vesicles move forward to replacethe vesicles in the active zone as they are used.– Vesicles in the stationary store (around 20%) –these vesicles cannot release their ACh

Section 4: Neurophysiology

Neurotransmission occurs as follows:

channels to open:

axoplasm

triggers the vesicles of the active zone to fuse

with the pre-synaptic membrane, releasing

their contents by exocytosis Typically, 50–100

the synaptic cleft

ligand-gated non-specific cation channel It has

some important features:

– AChRs are densely packed into the peaks of the

post-synaptic membrane, directly opposite to

the active zone of the pre-synaptic membrane

– The AChR is composed of five subunits:

The subunits are arranged in a cylinder,forming a central ion channel

– To open the ion channel, two ACh molecules

may then diffuse along their electrochemicalgradients; the net influx of cations depolarizesthe post-synaptic membrane The AChR ionchannel stays open for a very brief period,around 1 ms

– Following an action potential, a significant excess

of ACh molecules is released; the resulting synaptic depolarization (the end-plate potential)easily exceeds threshold potential, therebytriggering an action potential in the muscle cell.This safety margin is clinically important:

post-70–80% of AChRs must be blocked by musclerelaxants to prevent neurotransmission

Stationary store of vesicles

Action potential

Myelin sheath

Reserve pool of vesicles Vesicles in active zone,

ready for immediate release

Extra-junctional ACh receptors

ACh receptors opposite

to the active zone

Motor end plate, folded into peaks and troughs

Pre-synaptic ACh receptors

 Termination of neurotransmission ACh is

rapidly removed from the synaptic cleft, mainly by

degradation:

– ACh is rapidly hydrolysed by the enzyme

AChE to choline and acetic acid These

breakdown products are actively transported

into the pre-synaptic membrane for the

resynthesis of ACh

– AChE is mainly found in the junctional folds

of the synaptic cleft

– The structure of AChE is of pharmacological

importance The active site of the enzyme has

two binding sites: anionic and esteratic

Anticholinesterases, drugs that inhibit the

AChE enzyme, reversibly or irreversibly bind

to these binding sites

Clinical relevance: drugs acting at the

neuromuscular junction

Neurotransmission at the NMJ may be blocked by a

number of means, not just the muscle relaxants

(though these are the only clinically practical drugs):

 Inhibition of ACh synthesis: hemicholinium

blocks the uptake of choline in the nerve axon,

preventing ACh synthesis

 Inhibition of vesicle exocytosis may occur

through two mechanisms:

– Mg2+and aminoglycosides block the

pre-synaptic voltage-gated Ca2+channels

With-out Ca2+influx, vesicles cannot release their

contents into the synaptic cleft This is why

patients receiving prolonged Mg2+infusions

(for example, in pre-eclampsia) are at risk of

muscle weakness

– Botulinium toxin degrades a protein called

SNAP-25 that is required for vesicle docking

at the pre-synaptic membrane If vesicles

cannot dock, ACh cannot be released into the

synaptic cleft

 Blockage of the AChR There are, of course, two

classes of drug which act at the AChR:

– Depolarizing muscle relaxants; for example,

suxamethonium Chemically, suxamethonium

is two ACh molecules joined end-to-end The

spacing between the ACh components is

exactly right for both to bind to the two

α-subunits of the AChR Because it acts like ACh,

suxamethonium opens the AChR cation

channel, causing depolarization of the

post-synaptic membrane In contrast to ACh,

however, suxamethonium is not hydrolysed

by AChE The AChR remains open for a longed period, and the muscle membraneremains depolarized The muscle actionpotential can only fire once: the fast voltage-gated Na+channels which open during cellmembrane depolarization become inacti-vated and cannot return to their resting stateuntil the cell membrane repolarizes, whichcannot happen until suxamethonium diffusesaway from the AChR Clinically, depolarizingblock is characterized by muscle fascicula-tions followed by flaccid paralysis

pro-– Non-depolarizing muscle relaxants:

aminosteroids and benzylisoquinoliniums.These drugs compete with ACh for its bindingsite at the AChR Non-depolarizing musclerelaxants have no intrinsic activity at the AChR –they merely antagonize ACh Insufficient AChreaches the AChRs to trigger an action potential

in the muscle cell Clinically, non-depolarizingmuscle relaxants cause flaccid paralysis withoutany initial muscle contraction

Where else are acetylcholine receptors found?

In addition to the post-synaptic membrane, AChRsare found:

exocytosis, some ACh binds to pre-synaptic AChRs,

This triggers the mobilization of vesicles from thereserve pool to the active zone, ready for release

extra-junctional AChRs In health, only a small number

of AChRs are present on areas of the muscle cellmembrane outside the motor end plate However,following denervation, extra-junctional AChRsproliferate over the entire muscle cell membrane,with significant implications for the anaesthetist(see Clinical relevance box below)

Clinical relevance: myasthenia gravis

MG is an autoimmune condition characterized byfatigable weakness, in which immunoglobulin

G (IgG) autoantibodies are directed at the nicotinicAChR of the NMJ:

 Autoantibody attack of AChRs results in mation that not only reduces the number ofAChRs, but also flattens the folds of the post-Section 4: Neurophysiology

inflam-synaptic membrane, widening the distribution of

AChRs and AChE

 The overall effect is a reduction in the number of

ACh–AChR interactions, which reduces the size of

end-plate potential and decreases the likelihood

of an action potential being triggered in the

muscle cell, leading to weakness

 There is also autoimmune destruction of

pre-synaptic AChRs Therefore, in MG, when action

potentials are repeatedly fired, fewer vesicles are

moved from the reserve pool to the active zone

Consequently, as fewer vesicles are available for

release, fewer molecules of ACh are released into

the synaptic cleft This is the basis of the

fatig-ability associated with MG

Note: 10% of patients with MG are sero-negative;

that is, do not raise autoantibodies against the

nico-tinic AChR Instead, they generate autoantibodies

against another protein at the post-synaptic

mem-brane: MuSK This causes inflammation at the motor

end plate, with the same clinical effects

Clinical relevance: denervation hypersensitivity

Extra-junctional AChRs are structurally different to

those at the motor end plate: they also have five

subunits, but the adult ε subunit is replaced by the

fetal γ subunit Classic examples of acute denervation

include burns and acute spinal cord injury However,

chronic denervation also leads to proliferation of

extra-junctional AChRs; for example, motor neuron

disease and some peripheral neuropathies (for

example, Charcot–Marie–Tooth)

Extra-junctional AChRs are not just of academic

interest Following administration of the depolarizing

muscle relaxant suxamethonium, a potentially fatal

hyperkalaemia can occur This is due to:

 Suxamethonium binding to both junctional and

extra-junctional AChRs, opening their

non-specific cation channels Owing to the sheer

number of AChRs activated, the K+efflux is nificantly greater

sig- Once open, extra-junctional AChRs remain openfor up to 10 ms, much longer than their junc-tional counterparts

The combination of these two effects has the tial for a life-threatening increase in plasma K+concentration

poten-Following acute denervation, extra-junctionalAChRs take a little time to develop – clinically signifi-cant hyperkalaemia is a risk from 24 h post-injury.Therefore, suxamethonium can safely be adminis-tered for up to 24 h following the insult After around

100 days, the risk of hyperkalaemia is thought toreduce sufficiently to permit the cautious use of sux-amethonium In chronic denervation, suxametho-nium has an unpredictable response, depending onthe numbers of extra-junctional AChRs formed

Further reading

R Khirwadkar, J M Hunter Neuromuscular physiologyand pharmacology: an update Contin Educ Anaesth CritCare Pain 2012; 12(5): 237–44

P L Chau New insights into the molecular mechanisms ofgeneral anaesthetics Br J Pharm 2010;

161(2): 288–307

M J Fagerlund, L I Eriksson Current concepts inneuromuscular transmission Br J Anaesth 2009; 103(1):108–14

A Srivastava, J M Hunter Reversal of neuromuscularblock Br J Anaesth 2009; 103(1): 115–29

C J Weir The molecular mechanisms of generalanaesthesia: dissecting the GABAAreceptor Contin EducAnaesth Crit Care Pain 2006; 6(2): 49–53

J M King, J M Hunter Physiology of the neuromuscularjunction Contin Educ Anaesth Crit Care Pain 2002;2(5): 129–33

M Thavasothy, N Hirsch Myasthena gravis Contin EducAnaesth Crit Care Pain 2002; 2(3): 88–90

Chapter 50: Synapses and the neuromuscular junction

235

The primary function of skeletal muscle is

locomo-tion: contraction of muscle reduces the distance

between its sites of origin and insertion, thereby

pro-ducing movement Skeletal muscle has a number of

additional roles:

achieved through tonic contraction of multiple

synergistic and opposing muscle groups

abdominal wall and pelvic floor support and

protect their underlying viscera

tracts: skeletal muscle provides voluntary control

over swallowing, defecation and micturition

background muscle metabolic rate and shivering

(repeated muscle contraction and relaxation)

Describe the macroscopic and

microscopic anatomy of skeletal muscle

Skeletal muscles are made up of many muscle fibres

(myocytes), which are served by blood vessels and

nerves, and supported by a number of connective

tissue layers:

surrounding each myocyte

surrounded by perimysium are called fascicles

that encases the entire muscle

At each end of the muscle, the layers of connective

tissue (endomysium, perimysium and epimysium)

merge to form a tendon or an aponeurosis, which

usually connects the muscle to bone

Myocytes have a number of unusual anatomicalfeatures:

entire length of the muscle, and have a diameter of

up 50 μm

smooth muscle, have a striped or ‘striated’appearance due to regularly repeating sarcomeres(see below)

Myocytes have a number of specialized cellular tures in addition to the usual complement of Golgiapparatus, mitochondria and ribosomes:

the muscle surface membrane, or sarcolemma,capable of relaying action potentials deep into themyocyte interior

are arranged in parallel with one another spanningthe entire length of the myocyte Because

myofibrils are anchored to the sarcolemma ateither end of the myocyte, the whole myocyteshortens when they contract

of myofilaments, containing the contractileproteins actin and myosin

energy for muscle contraction

What is a sarcomere?

A sarcomere is the functional unit of skeletalmuscle It contains interdigitating thick, myosin-containing, and thin, actin-containing, filaments(Figure 51.1a) These are arranged in a regular,repeating overlapping pattern, giving an alternating

Cut end allows actin and myosin filaments to be seen

Figure 51.1 Structure of (a) the sarcomere and (b) the myofibril.

Chapter 51: Skeletal muscle

237

sequence of dark and light bands, resulting in a

striated appearance Key features of the sarcomere

are:

bisecting the I band

are joined at one end to the Z disc The

thick filaments are at the centre of the

sarcomere, interdigitating with thin

filaments

of the thin filament that does not overlap with

the thick filament

of the thick filament, including regions that

overlap the thin filament

contains only myosin

Each mammalian sarcomere, therefore, contains

one A band and two half I bands (Figure 51.1b)

Describe the key structural features of the thick and thin filaments

Key features are:

myosin, a large protein that has two globular

‘heads’ and a long ‘tail’ The myosin headshave distinct binding sites for actin and ATP(Figure 51.2a) Each thick filament is surrounded

by six thin filaments, in an approximatelyhexagonal arrangement

three proteins: the contractile protein actin, andthe regulatory proteins tropomyosin and troponin(Figure 51.2b):

– Actin is a globular protein that formschains that are twisted together in doublestrands Each thin filament containsaround 300–400 actin molecules, withregularly spaced myosin binding sites alongits length

Two myosin heads per myosin protein

Myosin tails

(a) Thick filament

Actin binding site ATP binding site

(b) Thin filament

Actin protein (note: for clarity, only a single strand of actin is shown instead of a double strand)

Myosin binding site

Tropomyosin

Troponin C Troponin I Troponin T

Troponin complex

Myosin binding site blocked by tropomyosin

Z disc

Ca 2+ binding site

Figure 51.2 Structure of (a) the thick filament and (b) the thin filament.Section 4: Neurophysiology

– Tropomyosin is a fibrous protein chain that

lies in the groove between the two strands of

actin Tropomyosin covers the myosin binding

site, preventing crossbridges forming between

actin and myosin

– Troponin This protein complex is located at

regularly spaced intervals along the

tropomyosin protein chain The troponin

complex is made up of three subunits, each

with its own role:

to tropomyosin (hence ‘T’)

troponin C causes tropomyosin to roll

deeper into the actin groove, which

uncovers the myosin binding site, allowing

crossbridges to form between actin and

myosin

What is meant by ‘excitation–

contraction coupling’?

Excitation–contraction coupling refers to the

pro-cesses linking depolarization of the muscle cell

membrane to the initiation of myocyte contraction

In common with neurons, the sarcolemma has

excitable properties:

Chapter 48)

potentials (see Chapter 49): synaptic activity at

the motor end plate causes depolarization of the

sarcolemma, triggering an action potential

that propagates along the myocyte surface

membrane

Excitation–contraction coupling occurs as follows:

deep into the myocyte interior, and close to the

the depolarization of a T-tubule The DHPR is a

channel; depolarization causes a conformation

physical contact with the cytoplasmic portion of

RyR also contains an intramembrane portionembedded within the SR membrane Following aconformation change in the DHPR, these physicalconnections cause the RyR to open and release

of 2000

conformational change of the whole troponin–tropomyosin complex The myosin binding site isuncovered, which allows actin–myosin

It is now known that the genetic defect in MH is aRyR mutation Once triggered, the abnormal RyRallows uncontrolled Ca2+release from the SR Clinic-ally, this results in tetanic muscle contraction, whichconsumes ATP and generates heat Prolongedmuscle tetany may result in rhabdomyolysis Mean-while, the SR has increased activity, sequesteringcytosolic Ca2+through its Ca2+-ATPase, which exacer-bates this ATP consumption The resulting

1 A very small quantity of Ca2+passes through the DHPR,but this Ca2+influx is of insufficient quantity and has atime course that is too slow to trigger muscle contraction;therefore, its function remains unclear Some studiessuggest it may be important in controlling geneexpression within the muscle fibre (so-called ‘excitation–transcription coupling’)

2

Note: the mechanism of excitation–contraction coupling

is different in cardiac muscle Here, Ca2+enters thecardiac myocyte during the plateau phase of the actionpotential, triggering Ca2+-induced Ca2+release at the SR(see Chapter 54)

Chapter 51: Skeletal muscle

239

hypermetabolic state increases total O2consumption

and CO2 production, and generates a metabolic

acidosis

In addition to supportive measures, the only

spe-cific treatment for MH is dantrolene, which is thought

to bind to the RyR, inhibiting further Ca2+ release

Untreated, the mortality for MH is very high, in the

order of 80% However, the introduction of

dantro-lene together with a greater awareness of the

condi-tion has led to a much lower mortality of 2–3%

How does skeletal muscle contract?Exposure of the myosin binding site on the actinfilament permits the process of crossbridge cycling,which in turn generates mechanical force:

ATP molecule is hydrolysed to ADP and

energy transferred to the myosin head Energizedmyosin heads are now able to bind to their

Leftward movement

Actin filament

Myosin binding sites

Myosin head Myosin tail

(a) When myosin binds ATP, its affinity for actin is low:

Z disc

(b) ATP is hydrolysed, energizing the myosin head and allowing crossbridges to form:

(c) The myosin head flexes and ADP dissociates – this is the ‘power stroke’:

(d) ATP binds, reducing the affinity of myosin for actin – the crossbridges are broken:

ADP

PiADP ADP

ATP ATP ATP

ATP ATP ATP

Pi Pi

Figure 51.3 Sliding filament theory.Section 4: Neurophysiology