Ebook Oh''s intensive care manual (8/E): Part 2

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Acute cerebrovascular complications

Thearina de Beer

Cerebrovascular disease is common and its acute

man-ifestation – stroke – produces considerable

morbid-ity and mortalmorbid-ity Stroke is defined as an acute focal

neurological deficit caused by cerebrovascular disease,

which lasts for more than 24 hours or causes death

before 24 hours Transient ischaemic attack (TIA) also

causes focal neurology, but this resolves within 24

hours Stroke is the fourth largest cause of death in

the United Kingdom, the second largest worldwide

and is the most common cause of physical disability

in adults.1 Stroke can be categorised as ischaemic or

haemorrhagic (Table 51.1)

The main risk factors are increasing age,

hyper-tension, ischaemic heart disease, atrial fibrillation,

smoking, diabetes, obesity, some oral contraceptives

and raised cholesterol or haematocrit

PROGNOSIS IN ACUTE   

CEREBROVASCULAR DISEASE

Mortality after stroke averages 30% within a month,

with more patients dying after subarachnoid

haem-orrhage (SAH) or intracerebral haemhaem-orrhage than

after cerebral infarction, although survival to 1 year is

slightly better in the haemorrhagic group In all types

of stroke, about 30% of survivors remain disabled to

the point of being dependent on others Risk of stroke

increases with age and doubles every decade over the

age of 55.1 Thus stroke is often accompanied by

signifi-cant age-related medical co-morbidity In the past, this

may have been partially responsible for a relatively

non-aggressive approach to the treatment of stroke

patients, so the gloomy prognosis of stroke becomes

a self-fulfilling prophecy The challenge for

intensiv-ists is to identify those patients who are most likely to

survive, and not to offer aggressive therapy to those

who are not Stroke should be regarded as a medical

emergency Patients should initially be treated in a

stroke unit as there is good evidence of reduction in

both mortality and dependency compared with those

treated in a general ward The UK National Institute

for Health and Clinical Excellence (NICE) has

pub-lished guidelines aimed at ensuring early diagnosis

and aggressive therapy.2

CEREBRAL INFARCTIONInfarction of cerebral tissue (ischaemic stroke) occurs

as a result of inadequate perfusion from occlusion of cerebral blood vessels (large or small) in association with inadequate collateral circulation It may occur due to cerebral thrombosis or embolism

AETIOLOGY AND PATHOLOGY

CEREBRAL THROMBOSIS

Atherosclerosis is the major cause of major arterial occlusion and most often produces symptoms if it occurs at the bifurcation of the carotid artery or the carotid syphon Progressive plaque formation causes narrowing and forms a nidus for platelet aggregation and thrombus formation Ulceration and rupture of the plaque exposes its thrombogenic lipid core, activating the clotting cascade Hypertension and diabetes mel-litus are common causes of smaller arterial thrombosis Rarer causes of thrombosis include any disease result-ing in vasculitis, vertebral or carotid artery dissection (either spontaneous or post-traumatic) or carotid occlu-sion by strangulation or systemic hypotension after cardiac arrest Cerebral venous thrombosis, responsi-ble for less than 1% of strokes, may occur in hyper-coagulable states, such as dehydration, polycythaemia, thrombocythaemia, some oral contraceptive pills, protein C or S deficiency, or antithrombin III deficiency

or vessel occlusion by tumour or abscess Cerebral infarction may also result from sustained systemic hypotension from any cause, particularly if associated with hypoxaemia

CEREBRAL EMBOLISMEmbolism commonly occurs from thrombus or platelet aggregations overlying arterial atherosclerotic plaques, but 30% of cerebral emboli will arise from thrombus

in the left atrium or ventricle of the heart This is very likely in the presence of atrial fibrillation, left-sided valvular disease, recent myocardial infarction, chronic atrial enlargement or ventricular aneurysm The

Abstract and keywords 651.e1

KEYWORDSStrokeischaemic strokehaemorrhagic strokeintracerebral haemorrhageintracerebral bleedsubarachnoid haemorrhageendovascular coilingmechanical thrombectomy

ABSTRACT

Stroke, whether it is ischaemic or haemorrhagic, is

an acute medical emergency, and great strides have

been made in its treatment in the last 10 years It still

remains a high-ranking cause of death worldwide, but

outcomes have improved with the newer treatments

When a stroke is suspected, a computed tomography

scan of the brain needs to be performed within an hour

of presentation, and what type of stroke it is will

deter-mine further management Stroke patients should be

treated in hyperacute stroke centres with neurosurgical

support Subarachnoid haemorrhage patients should

be in a neurosurgical centre with access to

interven-tional neuroradiologists With rehabilitation, the stroke

survivors can make a significant recovery

652

thrombosis may produce deep coma and tetraparesis Pontine stroke may produce the ‘locked-in’ syndrome The precise clinical presentation depends on the size

of the infarcted area and its position in the brain cular lesions, such as carotid dissection, can present with ipsilateral Horner syndrome with facial pain, a painful Horner’s from local stellate ganglion damage

Vas-or if there is significant ischaemia from impaired flow

or emboli, then with contralateral signs consistent with infarction.3

INVESTIGATIONS

A full history and examination of the patient will produce a differential diagnosis that will require spe-cific investigations The aim is to make the diagnosis, establish the nature, size and position of the pathology,

so that correct treatment can target the effects of the primary injury, and prevent extension of the lesion or complications occurring

BLOOD TESTS

A blood glucose test should be done to exclude tes and rule out hypoglycaemia as a cause for symp-toms A full blood count should be taken to look for polycythaemia, infection or thrombocythaemia A raised erythrocyte sedimentation rate or C-reactive protein level may indicate vasculitis, infection or car-cinoma, warranting further appropriate investigations Cardiac enzymes and troponin should be taken after

diabe-an electrocardiogram (ECG) Urea diabe-and electrolytes, as well as creatinine and liver function tests, should be taken to rule out a metabolic component A coagula-tion screen should also be taken together with serum cholesterol, triglyceride and syphilis serology Spe-cific investigation for thrombophilia due to protein C, protein S, Leiden factor V and antithrombin III abnor-malities should be undertaken in patients with venous thrombosis or patients with otherwise unexplained cerebral infarction or TIA A pregnancy test should be performed on females under the age of 55

echocardiog-IMAGING

New guidelines suggest a computed tomography (CT) brain scan within 1 hour of presentation with

presence of a patent foramen ovale or septal defects

allows paradoxical embolism to occur Iatrogenic air

embolism may occur during cardiopulmonary bypass,

cardiac catheterisation or cerebral angiography

Embo-lisation may also occur as a complication of attempted

coil embolisation of cerebral aneurysms or

arterio-venous malformations (AVMs) after SAH

CLINICAL PRESENTATION

In cerebral thrombosis, there is initially no loss of

con-sciousness or headache, and the initial neurological

deficit develops over several hours Cerebral

embo-lism may be characterised by sudden onset and rapid

development of complete neurological deficit No

single clinical sign or symptom can reliably distinguish

a thrombotic from an embolic event

Where infarction occurs in a limited arterial

terri-tory the clinical signs are often characteristic The

com-monest site involves the middle cerebral artery, which

classically produces acute contralateral brachiofacial

hemiparesis with sensory or motor deficits,

depend-ing on the precise area of infarction Infarction of the

middle cerebral territory leads to a dense contralateral

hemiplegia, contralateral facial paralysis, contralateral

hemianopia and ipsilateral eye deviation Dominant

left-hemisphere lesions result in language difficulties

from aphasia, dysphasia, dysgraphia and dyscalculia

Non-dominant right hemispheric lesions cause the

patient to neglect the left side, and failure to

com-municate with anyone approaching from that side

In strokes involving the posterior fossa, the precise

pattern of symptoms depends on the arterial

territo-ries involved and the presence or absence of

collater-als The onset of symptoms, such as gait disturbance,

headache, nausea, vomiting and loss of consciousness,

may be very rapid Venous thrombosis may occur,

particularly in the cerebral veins, sagittal or transverse

dural sinuses, causing headache, seizures, focal

neurol-ogy and loss of consciousness Other cognitive effects

of stroke include memory impairment, anxiety,

depres-sion, emotional lability, aprosody and spatial

impair-ment Bilateral brainstem infarction after basilar artery

ISCHAEMIC STROKE CAN

BE DIVIDED INTO FIVE

TYPES:

HAEMORRHAGIC STROKE CAN BE DIVIDED INTO TWO TYPES:

2.  Subarachnoid haemorrhage (SAH)Table 51.1 Classification of stroke

Cerebral embolism 653

normocarbia is necessary to prevent exacerbation of cerebral oedema A multicentre international study demonstrated that ICU mortality was 37% and hospi-tal mortality was 45% for ventilated stroke patients; it also demonstrated a longer ventilation time and higher tracheostomy rate than non-neurological patients.5

CIRCULATORY SUPPORT

A large number of stroke patients will have raised blood pressure (BP) on admission, presumably as an attempt by the vasomotor centre to improve cerebral perfusion Hypertensive patients may have impaired autoregulation and regional cerebral perfusion may

be very dependent on BP The patient’s clinical dition and neurological status should determine treat-ment rather than an arbitrary level of BP Current recommendations are that emergency administration

con-of antihypertensive agents should be withheld unless the systolic pressure is >220 mm Hg or the diastolic pressure is >120 mm Hg Aggressive lowering of BP

is not without risk and may result in the progression

of ischaemic stroke, so reduction should be tored closely (not exceeding 15% of normal BP).6 It would seem reasonable on physiological grounds to avoid drugs that cause cerebral vasodilatation in that they may aggravate cerebral oedema, although there

moni-is no hard evidence for thmoni-is Cardiac output should

be maintained and any underlying cardiac ogy, such as failure, infarction and atrial fibrillation, treated appropriately

pathol-METABOLIC SUPPORT

Both hypo- and hyperglycaemia have been shown to worsen prognosis after acute stroke; therefore blood sugar levels should be maintained in the normal range (<8.6 mmol/L).7 In the long term, nutritional support must not be neglected, and early enteral feeding should

be instituted by nasogastric intubation if needed In the longer term, particularly where bulbar function is reduced, percutaneous endoscopic gastrostomy may

be necessary

ANTICOAGULATION

The routine use of prophylactic heparin in immobile stroke patients should be avoided as the risk of intra-cerebral bleeding is high Intermittent pneumatic com-pression should be used for 30 days or until mobile.2Anticoagulation can only be recommended in indi-viduals where there is a high risk of recurrence, such

as in those patients with prosthetic heart valves, atrial fibrillation with thrombus or those with thrombophilic disorders A CT scan must be obtained prior to com-mencing therapy to exclude haemorrhage, and careful monitoring used In patients with large infarcts, there

is always the risk of haemorrhage (haemorrhagic version) into the infarct and early heparinisation is best avoided Aspirin 160–300 mg should be given within 48 hours after thrombolysis and continued for 2

con-a suspected stroke.2 These techniques are used to

distinguish infarction from haemorrhage Tumour,

abscess or subdural haematoma may also produce

the symptoms and signs of stroke Early scanning is

vital if interventional treatment, such as thrombolysis,

thrombectomy, anticoagulation, antiplatelet therapy or

surgery, is planned

The CT scan may be normal or show only minor

loss of grey/white matter differentiation in the first 24

hours after ischaemic stroke, but haemorrhage is seen

as areas of increased attenuation within minutes After

a couple of weeks, the CT appearances of an infarct or

haemorrhage become very similar and it may be

impos-sible to distinguish them if CT is delayed beyond this

time CT angiography (CTA) will often demonstrate

vascular abnormalities and vasospasm but multimodal

magnetic resonance imaging (MRI), a combination of

diffusion and perfusion-weighted MRI and magnetic

resonance angiography (MRA), is much more

sensi-tive in demonstrating small areas of ischaemia Timing

from the onset of symptoms and the exclusion of

intra-cranial haemorrhage (ICH) determines the suitability

and benefit of thrombolysis.4 Where cerebral

infarc-tion has occurred as a result of venous thrombosis,

the best imaging technique is MRA Any patient with

a stroke or TIA in the internal carotid artery territory

should have duplex Doppler ultrasonography, which

may demonstrate stenosis, occlusion or dissection of

the internal carotid Where trauma is an

aetiologi-cal factor reconstruction CT bone window views are

required to demonstrate any site of fracture-associated

vascular injury

MANAGEMENT

There is strong evidence that admission to a

special-ised stroke care unit as soon as possible after the

occur-rence of a stroke provides a cost-effective reduction in

long-term brain damage and disability.2 In general,

only those patients with a compromised airway due to

a depressed level of consciousness or life-threatening

cardiorespiratory disturbances require admission to

medical or neurosurgical intensive care units (ICUs)

In either case, attention to basic resuscitation,

involv-ing stabilisation of airway, breathinvolv-ing and circulation,

is self-evident

AIRWAY AND BREATHING

Patients with Glasgow Coma Scores (GCS) of 8 or less,

or those with absent gag or defects of swallowing (both

of which may occur at higher GCS), will require

intu-bation to preserve their airway and to prevent

aspira-tion Where this requirement is likely to be prolonged,

early tracheostomy should be considered Adequate

oxygenation and ventilation should be confirmed by

arterial blood gas analysis, and supplemental oxygen

prescribed if there is any evidence of hypoxia If

hypercarbia occurs then ventilatory support to achieve

654

aged <60 years Decompressive craniectomy must be done within 48 hours of symptom onset The number needed to treat (NNT) for survival is 2 and for severe disability is 6 Untreated, MMCAS has a mortality of 80% and it is suggested craniectomy can reduce mor-tality to around 30%, but with residual neurological deficit This procedure is limited to specialist centres MMCAS development is predicted by middle cerebral artery (MCA) territory stroke of >50%, a perfusion deficit of >66% on CT, an infarct volume of >145 mL within 14 hours and >82 mL within 6 hours of onset Electroencephalography (EEG) and tissue cerebral tissue oxygenation have been used to predict cerebral oedema; intracranial pressure (ICP) monitoring has not been proven to change the outcome Craniectomy has to be large enough to extend past the margins

of the infarct This seems to be well tolerated even after thrombolysis There is no difference in outcome whether dominant or non-dominant hemispheres are involved The patients who survive after craniectomy have moderate to severe disability and may have

a high incidence of psychological complications A recent study has shown benefit in this procedure for patients over 60 years.11 Whether this is acceptable to patients has not been studied.12

Other forms of surgical intervention proven to be effective in making more intracranial space and reduc-ing ICP are drainage of secondary hydrocephalus by extraventricular drain (EVD) insertion or evacuation

weeks while antithrombotic therapy is commenced If

the patient is intolerant of aspirin, an alternative, such

as clopidogrel, should be used.2

THROMBOLYSIS

Thrombolysis with intravenous recombinant tissue

plasminogen activator (rtPA alteplase) is now an

estab-lished treatment for acute ischaemic stroke.8 There are

specific inclusion and exclusion criteria Inclusion

cri-teria are a diagnosis of ischaemic stroke causing

meas-urable neurological deficit, age over 18 with an onset

of symptoms to treatment time of less than 3 hours

Patients should be excluded if there is a history of

head trauma or stroke (ischaemic or haemorrhagic)

in the previous 3 months, evidence of subarachnoid

or ICH, intracranial neoplasma, AVM or aneurysm,

recent intracranial or intraspinal surgery, arterial

punc-ture in a non-compressible site in the past 7 days, any

active bleeding or bleeding diathesis including platelet

count less than 100,000/mm3, heparin within 48 hours,

current anticoagulant therapy, hypoglycaemia or

mul-tilobar infarction (more than one-third of a cerebral

hemisphere) on CT scan Relative contraindications

include minor or rapidly improving stroke symptoms,

seizure at time of stroke with residual postictal signs,

serious trauma or major surgery in the past 14 days,

gastrointestinal or urinary tract bleeding in the past

21 days, or myocardial infarction within the past 3

months or pregnancy

There is some evidence for improved clinical

outcome after rtPA use between 3 and 4.5 hours after

symptom onset, although the degree of clinical benefit

is less.6 Patients must be in an environment where they

can be monitored for potential complications, the most

serious of which is ICH The inclusion criteria must

be adhered to, age <80 years, not having a history of

diabetes AND stroke, not taking warfarin or other oral

anticoagulant (National Institutes of Health Stroke

Score, NIHSS), ≤25 This risk is reduced where there is

strict adherence to the inclusion and exclusion criteria

and the appropriate dose used

ENDOVASCULAR THERAPY

Several studies have shown positive results with

mechanical thrombectomy in immediate and 90-day

functional outcome, specifically for patients with a

large artery proximal occlusion in addition to

throm-bolysis and for patients who have contraindications to

thrombolysis but not mechanical thrombectomy.2,9,10

This procedure is available only in specialist

neuro-radiology departments, which have the support of a

neurosurgical centre

DECOMPRESSIVE CRANIECTOMY

Some patients with malignant middle cerebral artery

infarction syndrome (MMCAS) (Fig 51.1) may benefit

from decompressive craniectomy, especially patients

with large middle cerebral artery territory infarcts

Figure 51.1 Malignant MCA infarct. 

Intracerebral haemorrhage 655

destructive owing to the anatomical density of neural tracts and nuclei

CLINICAL PRESENTATIONUsually, there are no prodromal symptoms, and a sudden onset of focal neurology or depressed level

of consciousness occurs Headache and neck stiffness will occur in conscious patients if there is subarach-noid extension by haemorrhage into the ventricles Where intraventricular extension occurs there may be

a progressive fall in GCS as secondary lus occurs, and this may be accompanied by ocular palsies, resulting in ‘sunset eyes’ Early deterioration

hydrocepha-is common in the first few hours after haemorrhagic stroke and more than 20% of patients will drop their GCS by two or more points between the initial onset

of symptoms and arrival in the emergency ment.14 As with ischaemic stroke, focal neurology is determined by which area of the brain is involved The only way to differentiate absolutely between ischae-mic, intracerebral and SAH is by appropriate imaging The symptoms relate to tissue destruction, compres-sion and raised ICP, which, if progressive, will result

depart-in bradepart-instem ischaemia and death

INVESTIGATIONSThe general investigations are essentially those listed previously for ischaemic stroke, since it is difficult

of haemorrhage into infarcted areas, resulting in new

compressive symptoms This is especially useful in the

posterior fossa where the room for expansion of mass

lesions is limited by its anatomy

COMPLICATIONS

Local complications include cerebral oedema,

haemor-rhage into infarcted areas or secondary hydrocephalus

General complications include bronchopneumonia,

aspiration pneumonia, deep-vein thrombosis, urinary

tract infections, pressure sores, contractures and

depression Stroke patients who are ventilated seem

particularly susceptible to ventilator-acquired

pneu-monia.13 A team approach of specialist nursing,

physi-otherapists, occupational and speech and language

therapists is best able to avoid these complications

SPONTANEOUS INTRACRANIAL 

HAEMORRHAGE

Spontaneous ICH producing stroke may occur from

either intracerebral haemorrhage (10%) or SAH (5%)

INTRACEREBRAL HAEMORRHAGE

The incidence of intracerebral haemorrhage is about

9/100,000 of the population, mostly in the age range

of 40–70 years, with an equal incidence in males and

females

AETIOLOGY AND PATHOLOGY

The commonest cause is the effect of chronic systemic

hypertension This results in degeneration of the walls

of vessels or microaneurysms, by the process of

lipo-hyalinosis, and these microaneurysms then suddenly

rupture This may also occur in malignant tumour

neovasculature, vasculitis, mycotic aneurysms,

amy-loidosis, sarcoidosis, malignant hypertension, primary

haemorrhagic disorders and over-anticoagulation

Occasionally, cerebral aneurysms or AVMs may

cause intracerebral haemorrhage without SAH Where

intracerebral haemorrhage occurs in young patients,

the most likely cause is an underlying vascular

abnor-mality In some areas, this is also associated with the

abuse of drugs with sympathomimetic activity, such

as cocaine The rupture of microaneurysms tends to

occur at the bifurcation of small perforating arteries

Common sites of haemorrhage are the putamen (55%),

cerebral cortex (15%), thalamus (10%), pons (10%) and

cerebellum (10%) Haemorrhage is usually due to the

rupture of a single vessel, and the size of the

haem-orrhage is influenced by the anatomical resistance of

the site into which it occurs The effect of the

haemor-rhage is determined by the area of brain tissue that it

destroys Cortical haemorrhages tend to be larger than

pontine bleeds (Fig 51.2), but the latter are much more

Figure 51.2 Devastating intracerebral haemorrhage. 

656

benefitted from surgery within 96 hours, although this finding did not reach statistical significance.15Current recommendations of the American Heart Association/American Stroke Association (AHA/ASA) are: ‘Patients with cerebellar hemorrhage who are deteriorating neurologically or who have brain-stem compression and/or hydrocephalus from ven-tricular obstruction should undergo surgical removal

of the hemorrhage as soon as possible’.14 The ment of hypertension following spontaneous intracer-ebral haemorrhage may be difficult as too high a BP may provoke further bleeding, whereas too low a BP may result in ischaemia Current recommendations of the AHA/ASA are: ‘ICH patients presenting with SBP between 150 and 220 mm Hg and without contraindi-cation to acute BP treatment, acute lowering of SBP to

manage-140 mm Hg is safe and can be effective for improving functional outcome’.14 This should be done for 7 days.2The adoption of these guidelines may have significant resource implications regarding access to ICU beds

to provide the required levels of monitoring There is

no place for steroids, and hyperventilation to PaCO2

of 30 mm Hg (4 kPa) or less to control raised ICP will have detrimental effects on cerebral blood flow in other areas of the brain

SUBARACHNOID HAEMORRHAGESAH refers to bleeding that occurs principally into the subarachnoid space and not into the brain parenchyma The incidence of SAH is around 6/100,000; the appar-ent decrease, compared with earlier studies, is due to more frequent use of CT scanning, which allows exclu-sion of other types of haemorrhage Risk factors are the same as for stroke, but SAH patients are usually younger, peaking in the sixth decade, with a female-to-male ratio of 1.24 : 1 The only modifiable risk factors for SAH are smoking, heavy drinking, the use of sym-pathomimetics (e.g cocaine) and hypertension, which increase the risk odds ratio by 2 or 3 Overall mortal-ity is 50%, of which 15% die before reaching hospital, with up to 30% of survivors having residual deficit-producing dependency High-volume centres (>60 cases per year) have shown a much improved outcome over that of low-volume centres (<20 cases per year).16

AETIOLOGY AND PATHOLOGYThe majority of cases of SAH are caused by ruptured saccular (berry) aneurysms (85%), the remainder being caused by non-aneurysmal perimesencephalic haem-orrhage (10%) and rarer causes, such as arterial dis-section, cerebral or dural AVMs, mycotic aneurysm, pituitary apoplexy, vascular lesions at the top of the spinal cord and cocaine abuse Saccular aneurysms are not congenital, almost never occur in neonates and young children and develop during later life It is not

to distinguish between the two in the early stages

Patients undergoing treatment with oral

anticoagu-lants, particularly warfarin in atrial fibrillation, mean

that anticoagulant-associated ICH is increasing in

fre-quency and a full coagulation screen is essential.14 CT

and/or MRI should be performed at the earliest

oppor-tunity The early deterioration seen in ICH relates to

active bleeding and repeat imaging after 3 hours of

symptom onset often shows significant enlargement

of the initial haematoma CTA/MRA or

venogra-phy is very important to determine the cause of the

haemorrhage such as AVM, aneurysm or tumour

neo-vasculature Lumbar puncture may be performed to

exclude infection if mycotic aneurysm is suspected,

but only after CT has excluded raised ICP or

non-communicating hydrocephalus

MANAGEMENT

The general management principles are identical to

those for ischaemic stroke There is, of course, no place

for anticoagulation or thrombolysis, and reversal of

any coagulation defect, either primary or secondary

to therapeutic anticoagulation, must be undertaken as

a matter of urgency A full coagulation screen must

be performed and the administration of vitamin K,

fresh frozen plasma, cryoprecipitate, etc., directed by

the results Where emergency decompressive surgery

is indicated, warfarin-induced coagulopathy should

be corrected using prothrombin complex concentrate

(Beriplex or Octaplex) Intraventricular extension

occurs in around 45% of cases and the insertion of an

EVD may increase the conscious level, particularly in

the presence of secondary hydrocephalus The EVD

level should be set so that the cerebrospinal fluid (CSF)

drains at around 10 mm Hg The normal production of

CSF should produce an hourly output and a sudden

fall in output to zero should alert staff to the possibility

that the drain has blocked This is particularly likely

if the CSF is heavily blood-stained The meniscus of

the CSF within the drain tubing should be examined

for transmitted vascular pulsation or the level of the

drain temporally lowered by a few centimetres to see

if drainage occurs If the drain is blocked, secondary

hydrocephalus will recur Because of the risk of

intro-ducing infection and causing ventriculitis, the drain

must be unblocked in a sterile manner by the

neuro-surgeons Blood in the CSF acts as a pyrogen, but the

patient’s high temperature should never be ascribed

to this alone, and regular blood cultures and CSF

samples are required as part of sepsis surveillance

Operative decompression of the haematoma should

be undertaken only in neurosurgical centres, and safe

transfer must be assured if this is considered The

administration of mannitol prior to transfer should be

discussed with the neurosurgical unit There is some

evidence that patients with supratentorial intracerebral

haemorrhage less than 1 cm from the cortical surface

Subarachnoid haemorrhage 657

bleed Factors, such as acute hydrocephalus, early rebleeding, cerebral vasospasm, parenchymal haema-toma, seizures and medical complications, must be considered

REBLEEDING

This may occur within the first few hours after sion and 15% of patients may deteriorate from their admission status They may require urgent intubation and resuscitation, but not all rebleeds are unsurviv-able, and as such deterioration should be treated The chance of rebleeding is dependent on the site of the aneurysm, the presence of the clot, the degree of vasos-pasm and the age and sex of the patient Although most studies quote an incidence for rebleeding of 4% in the first 24 hours, more recent studies suggest an incidence

admis-of 9%–17% with most cases occurring within 6 hours

A few small studies have shown that antifibrinolytics, such as tranexamic acid, can be used early and short term (<72 hours) in patients who do not have a pre-existing high risk for thrombotic events, for the pre-vention of rebleeding while awaiting securing of the aneurysm It is an off-licence use of antifibrinolytics.16

ACUTE HYDROCEPHALUS

This may occur within the first 24 hours post ictus and

is often characterised by a drop in the GCS, sluggish pupillary responses and bilateral downward devia-tion of the eyes (‘sunset eyes’) If these signs occur, a

CT scan should be repeated and, if hydrocephalus is

known why some adults develop aneurysms at arterial

bifurcations in the circle of Willis and some do not It

was thought that there was a congenital weakness in

the tunica media, but gaps in the arterial muscle wall

are equally as common in patients with or without

aneurysms and, once the aneurysm is formed, the

weakness is found in the wall of the sac and not at its

neck.17 The association with smoking, hypertension

and heavy drinking would suggest that degenerative

processes are involved Sudden hypertension plays a

role in causing rupture, as shown by SAH in patients

taking crack cocaine or, rarely, high doses of

decon-gestants, such as pseudoephedrine

CLINICAL PRESENTATION

Classically, there is a ‘thunderclap’ headache

develop-ing in seconds, with half of the patients describdevelop-ing its

onset as instantaneous This is followed by a period of

depressed consciousness for less than 1 hour in 50% of

patients, with focal neurology in about 30% of patients

About one-fifth of patients recall similar headaches

and these may have been due to sentinel bleeds; this

increases the chances of early rebleed 10-fold The

degree of depression of consciousness depends upon

the site and extent of the haemorrhage Meningism

– neck stiffness, photophobia, vomiting and a

posi-tive Kernig’s sign – is common in those patients with

higher GCS A high index of suspicion is needed for

patients presenting with the classical headache; a

non-contrast CT is recommended and, if negative, a lumbar

puncture should be done 12 hours after ictus If that is

also negative, consider CTA

The clinical severity of SAH is often described by

a grade, the most widely used being that described

by the World Federation of Neurological Surgeons

(WFNS), which is summarised in Table 51.2 This

grading, together with the extent of the haemorrhage

and the age of the patient, gives some indication of the

prognosis, in that the worse the grade the bigger the

bleed, and the older the patient the less likely is a good

prognosis Another scale [Prognosis on Admission

of Aneurysmal Subarachnoid Hemorrhage (PAASH)

scale] has been validated for SAH prognosis, and has

shown some benefits over WFNS; however WFNS is

currently the most used and recommended scale.18

Other poor prognostic signs are pre-existing severe

medical illness, clinically symptomatic vasospasm,

delayed multiple cerebral infarction, hyperglycaemia,

fever, anaemia and medical complications, such as

pneumonia and sepsis Anatomical risk factors may

increase periprocedural risk of complications On the

other hand, better outcomes seem to be associated with

treatment in a high-volume neurosurgical centre

COMPLICATIONS

The clinical status of the patient may be complicated

by factors other than the physical effect of the initial

I Conscious patient with or without meningism

II Drowsy patient with no significant 

neurological deficitIII Drowsy patient with neurological deficit – 

658

arterial territory involved (Fig 51.3) Very rarely, a false-positive diagnosis may be made if there is severe generalised oedema resulting in venous congestion in the subarachnoid space Small amounts of blood may not be detected, and the incidence of false-negative reports is around 2%.19 It may be difficult to distinguish between post-traumatic SAH and primary aneurysmal SAH, which precipitates a fall in the level of conscious-ness that provokes an accident or fall MR scanning is particularly effective for localising the bleed after 48

confirmed or there is a large amount of intraventricular

blood, then a ventricular drain may be inserted This is

recommended by the AHA/ASA.19

DELAYED CEREBRAL ISCHAEMIA

Vasospasm is the term used to describe the

narrow-ing of the cerebral blood vessels in response to the

SAH seen on angiography It occurs in up to 70% of

patients, but not all of these patients will have

symp-toms Delayed cerebral ischaemia (DCI) refers to the

onset of focal neurological deficit, a drop in GCS by 2

or more points, and/or cerebral infarction that occurs

typically 4–12 days post SAH unrelated to aneurysm

treatment or other causes of neurological deficit, such

as hydrocephalus, cerebral oedema or metabolic

dis-order.20 The use of transcranial Doppler (TCD) to

esti-mate middle cerebral artery blood velocity has shown

that a velocity of more than 120 cm/s correlates with

angiographic evidence of vasospasm This technology

allows diagnosis in the ICU and provides a means of

monitoring the success of treatment to reduce DCI,

which is undertaken to reduce the severity of delayed

neurological deficit secondary to vasospasm The

problem is that not all patients who have angiographic

vasospasm or high Doppler velocities have symptoms

If there is evidence of a depressed level of

conscious-ness in the absence of rebleeding, hydrocephalus or

metabolic disturbances, but there is evidence of DCI

clinically, on TCD or angiogram, then it would seem

appropriate to initiate treatment If vasospasm occurs

at the time of angiography or coiling, then

intravas-cular vasodilators, such as papaverine or nimodipine

have been used CTA is the imaging modality of choice

unless intracerebral therapy is planned, then digital

subtraction angiography (DSA) is recommended as

first-line imaging

PARENCHYMAL HAEMATOMA

This may occur in up to 30% of SAH following

aneu-rysm rupture and has a much worse prognosis than

SAH alone If there is mass effect with compressive

symptoms then evacuation of haematoma and

simulta-neous clipping of the aneurysm may improve outcome

MEDICAL COMPLICATIONS

Medical complications will occur in 40% of SAH

patients The mortality due to medical complications

is almost the same as that due to the combined effects

of the initial bleed, rebleeds and DCI The types of

medical complication seen are shown in Table 51.3

INVESTIGATIONS

The general investigations for stroke should be

per-formed, and early CT imaging is mandatory Blood

appears characteristically hyperdense on CT and the

pattern of haemorrhage may enable localisation of the

BLOOD PRESSURE CONTROLElevation of BP is commonly seen after SAH and there are no precise data on what constitutes an unaccept-ably high pressure that is likely to cause rebleeding Equally, there are no precise data on a minimum level

of pressure below which infarction is likely to occur, since this will depend on the patient’s normal pres-sure, the degree of cerebral oedema and the presence

or absence of intact autoregulation One tional study has demonstrated reduced rebleeding, but higher rates of infarction, in newly treated com-pared with untreated post-SAH hypertensive patients Although there are no precise data on specific BP con-trols, the AHA guidelines recommend that systolic

observa-BP is kept <160 mm Hg or mean arterial pressure of

<110 mm Hg in a person with an unsecured mal SAH.19 Beta-adrenergic blockers or calcium antag-onists are the most widely used agents, since drugs producing cerebral vasodilation may increase ICP The choice is less important than the titratability of the drug, as the balance between the increased risk of rebleed and cerebral perfusion needs to be maintained

aneurys-If nimodipine causes severe hypotension, timing and dose need to be changed too (i.e 30 mg 2-hourly instead of 60 mg 4-hourly) If nimodipine still remains

a problem, consider omitting doses until the patient

is more cardiovascularly stable while maintaining euvolaemia

DELAYED CEREBRAL ISCHAEMIA

Angiographic demonstration of vasospasm may be seen in about 70% of SAH patients, but only about 30% develop cerebral symptoms related to vasospasm, hence the change of nomenclature

Symptoms tend to occur between 4 and 14 days post-bleed, which is the period when cerebral blood flow is decreased after SAH

hours when extravasated blood is denatured, and

pro-vides a good signal on MRI

Lumbar puncture is still necessary in those patients

where the suspicion of SAH is high despite a negative

CT, or there is a need to exclude infection There must

be no raised ICP and at least 12 hours should have

passed to give time for the blood in the CSF to lyse,

enabling xanthochromia to develop

Angiography via arterial catheterisation is still the

most commonly used investigation for localising

the aneurysm or other vascular abnormality prior to

surgery It is generally performed on patients who

remain, or become, conscious after SAH It is not

without risk and aneurysms may rupture during the

procedure, and a meta-analysis has shown a

complica-tion rate of 1.8% Other methods under investigacomplica-tion

include CTA and MRA DSA is the diagnostic tool of

choice in cases where CTA is still inconclusive.19

ICP monitoring is of limited use in SAH patients

except in those where hydrocephalus or parenchymal

haematoma is present, and early detection of pressure

increases may be the trigger for drainage or

decom-pressive surgery.21

Multimodal monitoring: TCD studies may be useful

in detecting vasospasm or those patients in whom

autoregulation is impaired.19 The technique is

depend-ent on there being a ‘window’ of thin temporal bone

allowing insonation of the Doppler signal along the

middle cerebral artery It is very user dependent and

15% of patients do not have an adequate bone window

Continuous EEG monitoring, cerebral blood flow

mon-itoring, jugular venous oximetry, brain tissue oxygen

oximetry and cerebral microdialysis have all been used

to diagnose DCI.22

MANAGEMENT

The initial management of SAH is influenced by the

grading, medical co-morbidity or complications, and

the timing or need for surgery Patients with decreased

GCS may need early intubation and ventilation, simply

for airway protection, whereas those with less severe

symptoms require regular neurological observation,

analgesia for headache and bed rest prior to

investiga-tion and surgery Other management opinvestiga-tions are stress

ulcer prophylaxis, deep-vein thrombosis prophylaxis

using compression stockings or boots, and seizure

control with phenytoin or barbiturates If the patient

is sedated and ventilated, the use of an analysing

cer-ebral function monitor should be considered to detect

subclinical seizure activity

Hyponatraemia is a common finding and adequate

fluid therapy with normal saline is required with

electrolyte levels maintained in the normal range

Occasionally, as in other types of brain injury,

exces-sive natriuresis occurs and may result in

hyponatrae-mic dehydration – cerebral salt-wasting syndrome

suit-if patients are elderly (>70 years) or have poor-grade SAH then coiling is preferred Stenting of acute SAH carries a worse prognosis.19

THERAPY OF MEDICAL COMPLICATIONSThis is specific to the type of complication Pneumo-nia may require continuous positive airway pressure

or ventilatory support together with directed microbial therapy; acute respiratory distress syndrome requires lung-protective/recruitment ventilatory strategies; and renal failure necessitates an appropri-ate means of renal replacement therapy Arrhythmias require correction of trigger factors, such as hypovolae-mia and electrolyte or acid-base disturbances prior to the appropriate antiarrhythmic drug or direct current cardioversion Cardiac function should be evaluated in patients with cardiovascular deterioration, by means

anti-of serial enzymes and echocardiography Cardiac output monitoring should be considered Neurogenic pulmonary oedema may be associated with severe car-diogenic shock, which may require inotropic support

or even temporary intra-aortic balloon tion The cardiogenic shock is reversible and patients can make a good recovery despite the need for aggres-sive support.25

counterpulsa-Hyper- and hyponatraemia are frequently seen, with hyponatraemia occurring in up to 30% of cases, and it

is implicated in the development of DCI The aim is for euvolaemia; if it cannot be achieved because of a per-sistent negative fluid balance as a result of CSWS, then fludrocortisone should be considered Hyponatraemia should be corrected by no more than 0.5 mmol/L per hour with a maximum of 8 mmol/L per day (if it is chronic; i.e of more than 48 hours’ duration) during which 4-hourly sodium levels should be taken This may be achieved by using intravenous fluid that has more sodium than the serum concentration of the patient In patients who are resistant to vasopressors, hypothalamic dysfunction should be considered and

PREVENTION

One method of pre-empting vasospasm is oral

nimodi-pine at 60 mg given 4-hourly for 21 days, which has

been shown to achieve a reduction in the risk of

ischae-mic stroke of 34% Intravenous nimodipine should be

used in the patients who are not absorbing enterally,

but it must be titrated against BP to avoid

hypoten-sion Aspirin, clazosentan, enoxaparin, erythropoietin,

fludrocortisone, magnesium, methylprednisolone,

nicardipine and statins have been in trials but have not

been shown to prevent DCI.22

TREATMENT

Low cerebral blood flow is known to worsen outcome

and this resulted in the development of prophylactic

hypertensive hypervolaemic haemodilution – so-called

triple-H therapy This has been shown to cause harm

The focus now is on euvolaemia and, if this is

indi-cated and the BP is not already raised, hypertension

is induced with vasopressors This needs to be done

in a stepwise fashion with assessment of neurological

function at each step.22 Cerebral angioplasty or direct

intracerebral vasodilators should be considered if

induced hypertension is not reversing the DCI

symp-toms Where symptoms develop it is important to

exclude other causes, such as rebleeding,

hydrocepha-lus or metabolic disorder Poor-grade SAH patients

who are sedated or have low GCS are clinically

diffi-cult to assess; multimodal monitoring is recommended

to look for deterioration.22

SEIZURES

Seizure occurs in up to 26% of SAH sufferers The

evidence for prophylactic use of anticonvulsants is

poor and not recommended Some prognostic

indica-tors for the development of seizures have been

iden-tified: increased intracerebral blood, poor-grade SAH,

rebleeding infarction and MCA aneurysm Patients

should be observed for seizure activity and treated

appropriately A patient with poor-grade SAH who

is not improving or is deteriorating neurologically,

from an unknown cause, should have continuous EEG

monitoring.16

SURGERY

Clipping of the aneurysm is the surgical treatment of

choice, with wrapping, proximal ligation or bypass

grafting being used if the aneurysm is inaccessible

to Yasargil clipping The timing of surgery remains

debatable Recommendations by the AHA are to

secure the aneurysm within 48 hours of ictus or 48

hours of presentation Large intracerebral haematomas

associated with the SAH and middle cerebral artery

aneurysms should be strongly considered for surgery

There is no good level-one evidence for the use of

induced hypertension or hypothermia during clipping,

but in certain patients it could be considered What is

References 661

hydrocortisone should be administered, but no more

than 300 mg/day

Blood glucose should be kept at 4.4–11.1 mmol/L

(80–200 mg/dL), as higher and lower levels of blood

glucose have been shown to be detrimental to the

outcome

Fever should be controlled by antipyretics as the

first-line treatment, especially when DCI is suspected

Cooling devices should be considered if first-line

antipyretics have failed, but care should be taken to

monitor for pressure ulcers and venous thrombotic

events Shivering needs to be addressed as this will

be counterproductive to therapy by increasing oxygen

consumption

Deep-vein thrombosis prophylaxis should be

insti-tuted as soon as possible in the form of graduated

compression devices; heparin (unfractionated or low

molecular weight) should be started 24 hours after

securing the aneurysm.16

Anaemia should be minimised by limiting the

amount of blood taken for blood tests A transfusion

trigger of 8 g/dL in patients without DCI and 9–10 g/

dL in patients with DCI has been recommended.22

3 Gottesman RF, Sharma P, Robinson KA, et al

Clinical characteristics of symptomatic vertebral

artery dissection A systematic review Neurologist

2012;18(5):245–254

4 Lansberg MG, O’Donnell MJ, Khatri P, et al

Antithrombotic and thrombolytic therapy for

ischemic stroke: antithrombotic therapy and

prevention of thrombosis, 9th ed: American College

of Chest Physicians Evidence-Based Clinical

Practice Guidelines Chest 2012;141(2 Suppl):

e601S–e636S

5 Pelosi P, Ferguson ND, Frutos-Vivar F, et al

Management and outcome of mechanically

ventilated neurologic patients Crit Care Med 2011;

39(6):1482–1492

6 Jauch EC, Saver JL, Adams HP, et al Guidelines

for the early management of patients with acute

ischemic stroke Stroke 2013 STR.0b013e318284056a.

7 Quinn TJ, Lees KR Hyperglycaemia in acute stroke

– to treat or not to treat Cerebrovasc Dis 2009;27(1):

148–155

8 NICE Alteplase for treating acute ischaemic stroke

Guidance and guidelines Available from: https://

www.nice.org.uk/guidance/ta264?unlid=838784

222016926215536

9 Goyal M, Menon BK, van Zwam WH, et al

Endovascular thrombectomy after large-vessel

ischaemic stroke: a meta-analysis of individual

patient data from five randomised trials Lancet

2016;387(10029):1723–1731

10 Powers WJ, Derdeyn CP, Biller J, et al 2015 AHA/ASA focused update of the 2013 guidelines for the early management of patients with acute ischemic

stroke regarding endovascular treatment Stroke

2015 STR.0000000000000074

11 Jüttler E, Unterberg A, Woitzik J, et al

Hemicraniectomy in older patients with extensive middle-cerebral-artery stroke; 2014 http://dx.doi org/10.1056/NEJMoa1311367 http://www.nejm org/doi/full/10.1056/NEJMoa1311367

12 Wartenberg KE Malignant middle cerebral

artery infarction Curr Opin Crit Care 2012;18(2):

14 Hemphill JC, Greenberg SM, Anderson CS, et al Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart

Association/American Stroke Association Stroke

2015;46(7):2032–2060

15 Vespa PM, Martin N, Zuccarello M, et al Surgical

trials in intracerebral hemorrhage Stroke 2013;44

(6 suppl 1):S79–S82

16 Diringer MN, Bleck TP, Claude Hemphill J,

et al Critical care management of patients following aneurysmal subarachnoid hemorrhage: recommendations from the neurocritical care society’s multidisciplinary consensus conference

Neurocrit Care 2011;15(2):211–240.

17 Backes D, Rinkel GJE, Laban KG, et al Patient- and aneurysm-specific risk factors for intracranial

aneurysm growth Stroke 2016;47(4):951–957.

18 van Heuven AW, Mees SMD, Algra A, et al Validation of a prognostic subarachnoid hemorrhage grading scale derived directly from the glasgow

coma scale Stroke 2008;39(4):1347–1348.

19 Connolly ES, Rabinstein AA, Carhuapoma JR, et al Guidelines for the management of aneurysmal

subarachnoid hemorrhage Stroke 2012;43(6):1711–

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of Subarachnoid Hemorrhage Detection and monitoring of vasospasm and delayed cerebral ischemia: a review and assessment of the literature

Neurocrit Care 2011;15(2):312–317.

21 Cossu G, Messerer M, Stocchetti N, et al Intracranial pressure and outcome in critically ill patients with aneurysmal subarachnoid hemorrhage: a systematic

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Crit Care 2016;20(1):277.

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hemorrhage: a systematic review World Neurosurg

2016;85:305–314

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‘The human brain has 100 billion neurons, each

neuron connected to 10 thousand other neurons

Sitting on your shoulders is the most complicated

object in the known universe.’

Michio Kaku

CEREBRAL PHYSIOLOGY AND ANATOMY

The brain receives around 15% of the cardiac output

(50 mL/100 g/min) and utilises around 3–5 mL O2/

min per 100 g tissue and 5 mg glucose/min per 100 g

tissue The grey matter of the brain, which consists

pri-marily of the neuronal cell bodies and synapses, has

a higher blood flow compared with the white matter,

which consists largely of fibre tracts Critical cerebral

blood flow (CBF) is around 20 mL/100 g/min, with

the electroencephalogram (EEG) becoming isoelectric

at 15 mL/100 g/min

The anterior cerebral circulation is provided by the

two internal carotid arteries which subdivide into the

anterior and middle cerebral arteries These provide

around 70% of the cerebral circulation supplying the

frontal, parietal and temporal lobes and the anterior

diencephalon (basal ganglia and hypothalamus) The

two vertebral arteries join to form the basilar artery

which supplies the posterior circulation; the

brain-stem, cerebellum, occipital lobes and the posterior

diencephalon (thalamus) The two circulations

(ante-rior and poste(ante-rior) are joined by communicating

arter-ies to form the circle of Willis at the base of the brain

As the circle facilitates collateral flow, obstruction to

one of the four principle arteries (right and left

inter-nal carotid, right and left vertebral) supplying the

brain may be clinically insignificant Damage to the

intracerebral vessels, however, often results in

signifi-cant damage due to the lack of anatomical reserve The

areas between those supplied by the principle cerebral

arteries are supplied by the leptomeningeal arteries

These areas are potential watershed areas that are

particularly at risk in conditions of low- or no-flow

such as cardiac arrest, severe sepsis or following major trauma (Fig 52.1)

CEREBRAL PERFUSIONCerebral perfusion is controlled in part by the per-fusion pressure across the brain (cerebral perfusion pressure or CPP) CPP is the difference between the cerebral arterial pressure and cerebral venous pres-sure As these pressures are difficult to measure, sys-temic mean arterial pressure (MAP) and intracranial pressure (ICP) are used as surrogates

CPP MAP ICP= −MAP can be estimated as equal to diastolic blood pressure + 1/3 pulse pressure In adults, the normal resting ICP is 0–10 mm Hg ICP can rise to 50 mm

Hg or higher during straining or sneezing with no impairment in cerebral function It is not, therefore,

an elevated ICP alone that is important in logical conditions CPP is around 60 mm Hg in the normal state

patho-CEREBRAL METABOLISMThe energy requirements of the brain are large, in order to maintain membrane integrity and to support the transmembrane ion gradients required for electri-cal activity and cell survival Energy is also required for the synthesis, storage and release of neurotrans-mitters Neurones produce adenosine triphosphate almost entirely by the oxidative metabolism of glucose and ketone bodies Over 85% of the glucose used by the brain undergoes oxidative metabolism with brain tissue having only very limited ability for anaerobic metabolism Consciousness is lost rapidly if the supply

of either oxygen or glucose is restricted Loss of sciousness will occur in less than 10 seconds following acute decompression at 50,000 ft, with the time delay resulting from the transit time of deoxygenated blood from the lungs to the brain.1 Similarly, unconscious-ness occurs swiftly following intravenous administra-tion of high doses of insulin.2

con-Abstract and keywords 663.e1

KEYWORDSSecondary insultsintracranial pressurecerebral perfusion pressuretime-critical

specialist care

ABSTRACT

The brain is arguably the most important organ in the

body and also one of its most vulnerable Primary brain

injury may result from conditions such as trauma,

stroke or intracerebral haemorrhage (ICH), or it may

be secondarily injured most commonly due to

circula-tory or respiracircula-tory disease Cerebral protection is the

application of often simple, therapeutic interventions

with the intention of limiting or preventing further

neuronal injury and thus improving the patient’s

ultimate neurological outcome The key to cerebral

protection is early intervention, as neuronal damage

can occur within minutes of an insult Prevention of

hypoxia, hyper- and hypocarbia, hyper- and

hypogly-caemia, seizures and maintenance of adequate cerebral

perfusion and osmolarity are all important Although

many therapeutic agents have been studied to try and

reduce neuronal damage, very few have been

success-fully transferred into clinical practice

664

and ICH Posterior reversible encephalopathy drome (PRES) may present with seizures, disturbed vision, headache and altered mental state.4 It is strongly linked to conditions that co-exist in patients with renal disease, such as hypertension, vascular and autoimmune diseases, immunosuppression, and organ transplantation More than 70% of patients are

syn-LOCAL CONTROL OF CEREBRAL BLOOD FLOW

AUTOREGULATION (MYOGENIC REGULATION)

Autoregulation ensures that CBF remains constant

between MAPs from 60 to 160 mm Hg The stimulus

for autoregulation is CPP Autoregulation is thought to

be a myogenic mechanism with reflex vasoconstriction

of cerebral vessels occurring in response to increases

in CPP and vascular wall tension, and vasodilatation

occurring in response to decreases in CPP and

reduc-tion in wall tension.3 Outside the values where

autoreg-ulation is effective, the relationship between CBF and

MAP is linear and CBF is pressure dependent (Fig

52.2) The range at which autoregulation can operate

varies with age and in certain pathological conditions

The range is shifted to the left in early life and to the

right in chronic hypertension A rapid reduction in the

blood pressure of a patient with chronic hypertension

risks inadequate perfusion of the brain, heart and/or

the kidneys Autoregulation may be also impaired by

hypoxia, ischaemia, hypercapnia, trauma and certain

anaesthetic agents

Rapid rises in systemic blood pressure are also

poorly tolerated Hypertensive emergencies occur

in an estimated 1–2/100,000 patients per year and

may be associated with retinopathy, papilloedema or

encephalopathy Hypertensive encephalopathy results

from cerebral oedema due to increased hydrostatic

pressures and can cause drowsiness, coma, seizures

Cortical border zone(between ACA and MCA)

Internal border zone(between LPA and MCA)

Cortical border zone(between MCA and PCA)

Figure 52.1 Axial view of the brain showing the major arterial territories. Watershed infarcts may occur at the border between the major cerebral arterial territories in conditions of low blood flow. These may be (a) cortical border zone infarcts (infarction of the cortex and neighbouring subcortical white matter at the border of the ACA and the MCA and/or the MCA and the PCA), or (b) internal border zone infarction of deep white matter (between the LPA and the deep cortical 

branches of the MCA or at the border zone of deep white matter branches of the MCA and the ACA). ACA, Anterior  cerebral artery; LPA, lentriculostriate perforating arteries; MCA, middle cerebral artery; PCA, posterior cerebral artery. 

Cerebral injury 665

extracellular or interstitial hydrogen ion tions Tight control of PaCO2 is essential if CPP is criti-cal; increases in CO2 cause vasodilatation and increased ICP, whereas decreases in PaCO2 below 4 kPa have been shown to result in vasoconstriction sufficient to precipitate critical cerebral ischaemia.8 Impaired CO2reactivity is associated with poor outcomes in patients with severe head injury.9

concentra-OXYGENCBF is not affected by changes in PaO2 within the normal range, but levels <50 mm Hg (6.65 kPa) result

in cerebral vasodilatation and increases in CBF Below

30 mm Hg (4 kPa), CBF is roughly doubled with a sequent increase in ICP (see Fig 52.4)

con-TEMPERATUREThe cerebral metabolic rate for oxygen (CMRO2) is reduced by around 8% for each degree Celsius reduc-tion in temperature Mild hypothermia remains rec-ommended for the management of patients who are resuscitated from cardiac arrest.10 More profound cooling enables patients to withstand prolonged periods of low CBF during cardiopulmonary bypass Application of cooling to unselected patients with trau-matic brain injury is now thought to be ineffective.11Avoidance of hyperthermia in cerebral injury remains important as CMRO2 is increased by a similar amount for every degree Celsius increase in temperature

CEREBRAL INJURYCerebral injury is commonly divided into primary and secondary Primary injuries include traumatic,

hypertensive Typical magnetic resonance imaging

(MRI) findings are of reversible, symmetrical,

poste-rior subcortical vasogenic oedema.5 If promptly treated

and managed, symptoms often resolve within a few

days to weeks

FLOW–METABOLISM COUPLING

Flow–metabolism coupling is the direct relationship

of the metabolic activity of the brain to CBF Increases

in metabolic demand are met rapidly by increases in

CBF and delivery of substrates (Fig 52.3) The exact

mechanisms that control flow–metabolism coupling

are unknown but may involve a variety of mediators

such as neurokinin-A, nitric oxide and substance P It is

not clear how the diameter of cerebral vessels upstream

to the area of activity can be altered so rapidly by

meta-bolic products which are being washed downstream It

is thought that there may be control neurons that act on

specific cerebral vessels that control local blood flow.6

Regional variations in cerebral metabolism can now be

visualised using techniques such as positron emission

tomography scanning, although the hypothesis that

such variations existed dates as far back as 1890.7

SYSTEMIC CONTROL OF CEREBRAL   

BLOOD FLOW

CARBON DIOXIDE

CBF increases by 3%–4% for each mm Hg increase in

PaCO2 A doubling of PaCO2 doubles CBF and

con-versely a halving of PaCO2 will halve CBF (Fig 52.4)

The responses to changes in PaCO2 occur rapidly,

within 30s, and are thought to relate to changes in

666

more definitive measures can be employed, there is now evidence of the effects of hypocarbia on cerebral vasculature with vasoconstriction and secondary ischaemia/hypoxia Levels of PaCO2 below 4 kpa should be avoided.8

Anaemia has been associated with poorer outcomes

in traumatic brain injury (TBI), aneurysmal SAH, ICH and ischaemic stroke Transfusion improves brain oxy-genation in some patients with TBI.18 Most critical care units now adopt a restrictive strategy to red cell trans-fusion using a trigger haemoglobin around 7–8 g/dL

In patients with TBI, neither administration of poietin nor maintaining a haemoglobin concentration

erythro->10 g/dL have resulted in improvement in cal outcome and the 10 g/dL threshold was associated with a greater incidence of adverse events.19

neurologi-The brain is particularly vulnerable to disturbances

of osmolality.20,21 Under physiological conditions, brain osmolality is in equilibrium with extracellular fluid osmolality When hyponatraemia occurs, the reduc-tion in plasma osmolality causes water movement into the brain along the osmotic gradient, causing cerebral oedema Cerebral volume increases by around 7% for every three milli-osmolar reduction in osmolality

METABOLIC AND BIOCHEMICAL PROCESSES   

IN CEREBRAL INJURYThe pathophysiology of brain injury is complex (Fig 52.5) Even brief disturbances in CBF and delivery of substrates can initiate a cascade of events leading to cellular death.22 Different areas of brain have differ-ing thresholds for damage, with the cell bodies (grey matter) being more resilient than the white matter (axons) Anaerobic metabolism results in intracerebral acidosis with accumulation of lactic acid and hydro-gen ions Loss of the normal homeostatic mechanisms responsible for the maintenance of ion gradients results

in abnormal sodium, potassium, calcium and chloride movements and the failure of glutamate reuptake into

ischaemic or hypoxic and may be focal or global

Sec-ondary injuries may be initiated as a consequence of

the primary injury and can contribute significantly to

the ultimate outcome of the patient

Primary traumatic brain injury may result in four

main pathological conditions which can all co-exist:

brain contusions, axial and extra-axial haematomas

(subdural, extradural and intracerebral), traumatic

subarachnoid haemorrhage (SAH) and diffuse axonal

injury (DAI) DAI results from dynamic deformation

of the brain with resultant shearing forces, affecting

the blood vessels and axons Areas commonly affected

include axons in the brainstem, the parasagittal

white matter near the cerebral cortex, and the corpus

callosum.12

Focal hypoxic or ischaemic insults often occur

acutely such as in acute stroke If the area supplied by

the affected artery has a good collateral supply, injury

may be modest If, however, the area is poorly supplied,

cell death will occur within minutes without

reperfu-sion Around areas of infarction there is an ischaemic

penumbra Interventions to preserve function in the

penumbral area are the key to optimising outcome

Global hypoxic-ischaemic conditions are often

sec-ondary to respiratory or cardiovascular insufficiency,

seen most severely in cardiorespiratory arrest

Recov-ery depends on rapid reversal of the primary cause

MRI examination of patients with persistent disorders

of consciousness following resuscitation from cardiac

arrest have shown regions of pathological white

matter signals in the frontal and occipital lobes and

in the periventricular regions.13 The total volumes of

the lesions have been associated with the severity of

the patients’ outcomes These patterns demonstrate the

different vulnerabilities of particular areas of the brain

to ischaemia-hypoxia

Secondary injury may be initiated as a consequence

of the primary injury The duration and severity of

sec-ondary insults can have a significant effect on patient

outcome and present an opportunity for prevention

or early clinical intervention.14–17 Intracranial

second-ary injury may be caused by expansion of intracranial

haematomas or the development of cerebral oedema

causing pressure effects on more distant parts of the

brain, distortion of blood supply or further axonal

shearing Shift of vital structures can ultimately lead to

herniation of the brain Secondary seizure activity can

rapidly deplete the brain’s supply of metabolites

Systemic secondary insults include hypoxia,

hypotension, hyper- or hypocarbia, hyperthermia,

hyper- and hypoglycaemia, anaemia and electrolyte

disturbances Many studies have demonstrated the

importance of the duration and severity of secondary

insults on the outcome from traumatic brain injury

(Table 52.1)

Although hyperventilation of patients with severe

brain injury has previously been recommended as a

short-term measure to manage elevated ICP before

INSULT

IMPACT

ON MORTALITY

IMPACT ON GLASGOW OUTCOME SCORE

AIRWAYRecommendations regarding securing of the airway in patients with brain injury include those patients with the following23:

• Glasgow Coma Score ≤8, or with a significantly deteriorating conscious level (i.e fall in motor score

of ≥ two points)

• Loss of protective laryngeal reflexes

• Hypoxia (PaO2 <13 kPa on oxygen)

• Hypercarbia (PaCO2 >6 kPa)

• Spontaneous hyperventilation causing PaCO2

<4.0 kPa

• Bilateral fractured mandible or copious bleeding into the mouth (e.g from skull base fracture)

• Seizures

cells Glutamate and aspartate are the main excitatory

neurotransmitters in the brain When uptake

mecha-nisms fail, toxic levels of glutamate can accumulate

in the extracellular space, causing a surge of neuronal

activity and membrane depolarisation The increases

in intracellular calcium and sodium activate pathways

mediated by Ca2+ dependent enzymes The restriction

of oxygen and substrates to mitochondria induces a

cellular metabolic crisis with disruption of cell

mem-branes and organelles, activation of cellular apoptosis,

activation of macrophages and platelet aggregation

causing secondary disturbances of the

microvascula-ture Cytotoxic oedema occurs due to failure of ionic

pumps with subsequent ion and fluid shifts

Vaso-genic oedema is due to mediator release with damage

to endothelium, basement membranes and glial cells

with breakdown of the blood-brain barrier

CEREBRAL PROTECTIVE STRATEGIES

For all patients, including those with brain injury,

the priorities are the assessment and management

of airway, breathing and circulation (ABC) over

Swelling/Oedema

• decreased cerebral blood flow via vascular compression

• hormonal dysfunctionFigure 52.5 Hypothesised model for progression from primary to secondary injury after trauma to the central nervous 

system. Modified from Reifschneider K, Auble BA, Rose SR Update of endocrine dysfunction following paediatric

traumatic brain injury J Clin Med 2015;4(8):1536–1560 (with permission).

trau-FLUIDSIsotonic crystalloid and blood (if required) are the mainstays of fluid replacement in patients with cer-ebral injury; 0.9% saline is the only isotonic crystal-loid solution that is commonly available Gelatins, albumin, Ringer’s lactate (compound sodium lactate), Ringer’s acetate and Plasma-Lyte should be avoided

as all are hypotonic when real osmolality (mosm/kg) is measured The Brain Trauma Foundation (BTF) recommends that the sodium be kept >140 mmol/L for patients with TBI.31 This avoids the risk of wors-ening cerebral oedema Hyperosmolar therapy such as mannitol (2 mL/kg of a 20% solution) or hypertonic saline are often used when ICP is critically elevated Despite clear effectiveness on measured ICP, there remains little evidence of improvement in clinical outcomes.32

POSITIONING 30 DEGREE HEAD UP  (WITH SPINAL PRECAUTIONS)

Measures such as elevating the head of the bed by 30 degrees, ensuring the head is in a neutral position and

in alignment with the body are important, simple steps that can reduce ICP For patients with potential spinal injuries, the whole bed should be tilted

TEMPERATURE CONTROLPyrexia is common following acute brain injury Vigi-lance for possible infective sources, drug reactions or physical causes such as venous thromboembolism is essential Central (neurogenic) fever can occur, thought due to disturbance of temperature regulation in the hypothalamus It is uncommon and characterised by

a constant fever which is often >40°C As the normal regulatory point has been altered, patients characteris-tically have an absence of the measures normally taken

to mitigate hyperthermia, such as sweating.33 nance of normothermia is common practice in special-ist intensive care units (ICUs) Although therapeutic hypothermia has been shown to reduce ICP in patients with TBI, its widespread use has not been found to

Mainte-be Mainte-beneficial in clinical trials.11 Targeted temperature

The projected clinical course of the patient should

also be considered Those requiring transfer for

defini-tive care or who are likely to require surgery for other

conditions may require early intubation

OXYGEN

The National Confidential Enquiry into Patient

Outcome and Death (NCEPOD) report, ‘Trauma: who

cares?’ published in 2007 found that administration of

oxygen was only documented to have occurred in 78%

of patients with neurological injury and that peripheral

oxygen saturations of <95% occurred in 28% of patients

pre-hospital.24 In mechanically ventilated patients with

TBI, avoidance of hypoxia may require application of

positive end-expiratory pressure (PEEP) especially in

patients with polytrauma Although there is a

theo-retical risk that the increase in intrathoracic pressure

can cause increased cerebral blood volume (CBV) and

ICP, application of PEEP up to 15 cm H2O has been

used successfully in cases of refractory hypoxaemia.25

National Institute for Health and Clinical Excellence

(NICE) recommendations are that patients with acute

stroke should have supplemental oxygen if the

periph-eral oxygen saturations fall below 95%.26

CARBON DIOXIDE

Tight control of PaCO2 is required for all mechanically

ventilated patients with acute cerebral injury This

can create difficulties in patients with co-existent lung

disease or acute respiratory distress syndrome (ARDS)

where a balance needs to be struck between the effects

of a raised PaCO2 on the brain and lung-protective

strategies.27–29 As detailed earlier, a target PaCO2 of

4.5–5 kPa is usual in the acute stages of injury

CEREBRAL PERFUSION (BLOOD   

PRESSURE TARGETS)

Cerebral perfusion depends on MAP and ICP If the

ICP is elevated due to the presence of intracranial

haemorrhage or swelling, MAP must be increased to

maintain CPP Many patients with isolated acute

intra-cranial injury have an initial period of arterial

hyperten-sion Generally this will reduce spontaneously or with

simple measures such as analgesia, relieving hypoxia

or hypercarbia, and ensuring that the patient does not

have other systemic disturbances such as urinary

reten-tion There have been concerns that reducing the blood

pressure acutely may risk the perfusion of penumbral

areas and worsen the clinical outcome Recent studies

have shown benefit with intensive management of

elevated blood pressure for patients with

spontane-ous ICH and in the early phase of management of

SAH before the aneurysm is secured.30 In patients with

acute ischaemic stroke, the blood pressure needs to be

less than 185/110 mm Hg prior to administration of

Cerebral protective strategies 669

been shown to be beneficial and the AHA recommends only treatment of clinical seizures.38

GLUCOSE CONTROLHyperglycaemia has been associated with poorer out-comes for a wide range of acute neurological condi-tions including TBI, SAH, ICH and acute ischaemic stroke.39 Studies of tight glycaemic control have been disappointing and guidelines recommend the avoid-ance of both hyperglycaemia and hypoglycaemia

SPECIFIC PHARMACOLOGICAL INTERVENTIONSAlthough many potential neuroprotective agents have been tried, most clinical studies have failed to show outcome benefits.22 Nimodipine is used to prevent cerebral vasospasm following aneurysmal SAH.40 The lack of evidence regarding pharmacological interven-tions emphasises the importance of the adoption of simple protective measures and rapid access to spe-cialist care

SPECIALIST MONITORING

INTRACRANIAL PRESSURE

The major intracranial contents are the brain, blood (both arterial and venous), and cerebrospinal fluid (CSF) When a new intracranial mass is introduced (haemorrhage, hydrocephalus or cerebral oedema), a compensatory change in volume must occur through

a reciprocal decrease in venous blood or CSF to tain a constant total intracranial volume This is the Monro-Kellie doctrine In young children, with open fontanelles and whose sutures have not yet fused, the cranium can expand to physically accommodate extra volume In the normal situation, changes in intracere-bral volume produce little or no change in ICP and the compensatory reserve is good If compensatory reserve

main-is poor, any changes in intracerebral volume produce

a rapid rise in ICP

Although there is a lack of Class 1 evidence to support the measurement of ICP and the targeting of CPP in severe head injury, there is good evidence that measurement of these as part of a guideline of care

on specialist units results in improvements in ity and functional outcomes following brain injury.31Measurement of ICP may be of use in a number of other neurological conditions.41 The value of ICP- based management for non-traumatic conditions is even less clear than in traumatic brain injury

mortal-The devices commonly used to measure ICP are intraventricular and intraparenchymal catheter tip microtransducer catheters Intraparenchymal monitors are most commonly placed by making a small incision

in the scalp, screwing a bolt into the skull and then passing a spinal needle through the lumen of the bolt,

management remains recommended for patients

who remain unresponsive after resuscitation from

cardiac arrest.10

SEDATION/ANALGESIA

Patients requiring intubation for cerebral protection

are usually managed using a rapid sequence

induc-tion technique (with in-line stabilisainduc-tion of the

cervi-cal spine for those with potential trauma) The use of

an opiate is recommended to mitigate rises in ICP

The induction agent and dose used should be chosen

to ensure maintenance of an adequate MAP

Com-monly, barbiturates or propofol are used Ketamine

may be useful in haemodynamically unstable patients

The concerns regarding potential increases in ICP and

cerebral metabolic rate with ketamine appear to be

clinically unfounded.34,35 Following intubation and

ven-tilation, sedation in brain-injured patients is commonly

maintained with continuous intravenous infusions of

propofol or midazolam Both reduce the cerebral

meta-bolic rate for oxygen and CBF High doses are often

required to decrease the ICP Use of continuous

infu-sions of an opiate may help in reducing the amount

of sedative required especially if there are concerns

regarding propofol infusion syndrome

SEIZURE CONTROL

Risk factors for early seizures following trauma (within

7 days of injury) include: Glasgow Coma Score (GCS)

≤10; immediate seizures, post-traumatic amnesia >30

minutes, linear or depressed skull fracture, penetrating

head injury, subdural, epidural, or intracerebral

hae-matoma, cerebral contusions, age ≤65 years, or chronic

alcoholism.31 Post-traumatic epilepsy is defined as

recurrent seizures occurring more than 7 days

follow-ing injury The BTF recommends the use of phenytoin

to decrease the incidence of early seizures when the

overall benefit is felt to outweigh the potential

compli-cations associated with treatment.31

Seizures occur at the time of bleeding in around 7%

of patients with SAH.36 Another 10% will develop

sei-zures over the first few weeks Risk factors for early

seizures include middle cerebral artery (MCA)

aneu-rysm, thickness of acute subarachnoid clot, associated

ICH, re-bleeds, cerebral infarction, poor

neurologi-cal grade and mode of treatment with endovascular

treatment having a lower risk of seizures.36 The

Euro-pean Stroke Organisation recommends antiepileptic

treatment only for those patients with overt seizures

The American Heart Association (AHA)/American

Stroke Association guidance states that prophylactic

anticonvulsants may be considered in the immediate

post-haemorrhagic period.37 Seizures occur in <16% of

patient within 1 week after ICH A cortical location of

the ICH is the most important risk factor for early

sei-zures Prophylactic anticonvulsant medication has not

670

in cerebral vasodilatation This results in increased ICP and further reduction in CPP until maximal cerebral vasodilatation occurs and the wave plateaus Early termination of Lundberg A waves can occur if MAP

is increased, thus restoring CPP Plateau waves are always pathological and indicative of reduced cerebral compliance Lundberg B waves are smaller changes in ICP that occur every 30 seconds to a few minutes and can be seen in normal individuals ICP rises to levels 20–30 mm Hg above baseline before falling Lundberg

C waves are of little clinical importance They are of low amplitude and occur with a frequency of 4–8/min and are associated with variations in blood pressure

OTHER FORMS OF NEUROLOGICAL MONITORING

Patients with neurological illness can be monitored using a wide range of different techniques depending upon the condition and the institution where they are treated In many specialist ICUs these techniques may

be combined, often known as multimodality toring (MMM) Despite widespread use in specialist centres, there is limited evidence to support their effec-tiveness in improving outcomes.43,44

moni-CEREBRAL OXYGENATIONBrain tissue oxygenation can be assessed using invasive

or non-invasive methods Intraparenchymal probes are available that measure brain oxygen content (Pbt )

puncturing the dura The monitor is then zeroed to

atmospheric pressure before the transducer is passed

through the bolt and into the brain parenchyma The

transducer is usually placed into the non-dominant

frontal lobe or the dominant frontal lobe if the

non-dominant lobe is the primary site of injury The drift

over time of modern intraparenchymal monitors is

insignificant, the rates of infection are low and there

is no need to routinely change the monitor Pressure

transducers in the subdural or subarachnoid space are

now rarely used

Intraventricular catheters are the gold standard

for monitoring ICP and also allow drainage of CSF if

the ICP is raised External ventricular devices (EVDs)

can be placed during craniotomy procedures or via a

burr hole in similar manner to the intraparenchymal

devices If the ventricles are compressed, placement

can be facilitated using ultrasound or stereotactic

computed tomography (CT) guidance The pressure

monitor is zeroed to the level of the external

audi-tory meatus The risks from EVDs include a rate of

<5% for placement-associated ICH (although the need

for neurosurgical evacuation is far smaller) and <20%

for catheter-related infections Infection rates increase

with the duration of placement and can be reduced by

strict attention to asepsis during manipulation or use

of antibiotic or silver-impregnated catheters

Non-invasive methods of measuring ICP include

transcranial Doppler (TCD), measurement of optic

nerve sheath diameter and tympanic membrane

displacement Operator experience and

reproduc-ibility have limited the clinical applications of these

techniques

INTRACRANIAL PRESSURE IN NORMAL AND 

PATHOLOGICAL CONDITIONS

The normal ICP trace looks similar to an arterial trace

(Fig 52.6A) The three peaks are: P1 – the percussion

wave caused by arterial pressure transmitted from the

choroid plexus to the ventricle; P2 – the tidal wave

thought to be due to brain compliance; and P3 – the

dicrotic wave resulting from closure of the aortic valve

If the intracranial volume is increased, the ICP

wave-form shows an initial increase in amplitude, although

the mean ICP remains largely unaltered As the brain

compliance reduces further, the P2 component of

the wave exceeds P1 and the wave becomes broader

(see Fig 52.6B)

In 1960, Lundberg described fluctuations in ICP

waves (Fig 52.7).42 Lundberg A waves or plateau

waves are slow vasogenic waves seen in patients with

critical cerebral perfusion These waves can reach

50–100 mm Hg and last between 5–20 minutes before

spontaneously subsiding Plateau waves cause critical

cerebral ischaemia within minutes and are thought to

result from spontaneous reductions in MAP, resulting

P3

Figure 52.6 Intracranial pressure waveforms in (A) the normal state and (B) when brain compliance is reduced. 

Intracranial pressure in normal and pathological conditions 671

Near-infrared spectroscopy (NIRS) measures regional cerebral oxygen saturation by measuring near-infrared light that is reflected from brain chromo-phores, the most commonly used of which is oxygen-ated haemoglobin The changes in the concentration of near-infrared light are measured as it passes through these compounds and these allow calculation of their oxygenation status Although NIRS has proved useful

in vascular and cardiothoracic surgery, its value in the ICU has not been proven

MICRODIALYSISBrain metabolism can be monitored using cerebral microdialysis probes Dialysis fluid is passed through the catheter which has a semipermeable membrane This allows molecules below the size of the membrane

to equilibrate along the concentration gradient The technique analyses substrates such as lactate, pyru-vate, glucose, glutamate and glycerol in the extracel-lular fluid of subcortical white matter Glutamate is

an excitatory neurotransmitter that is associated with injury and inflammation Glycerol is a lipid-rich com-ponent of neurons and is indicative of irreversible cell death when levels are elevated Lactate, pyruvate and the lactate/pyruvate ratio are used as markers of hypoxia or ischaemia

CEREBRAL BLOOD FLOWInvasive measurement of regional CBF can be achieved using thermal diffusion probes or laser Doppler flow-metry The thermal conductivity of brain tissue varies

in proportion to CBF The most commonly used CBF catheter introduces heat in subcortical white matter and calculates the rate of temperature dissipation at a set distance, allowing calculation of local CBF Laser Doppler flowmetry involves placement of a small Doppler probe within the brain tissue Doppler change

of laser light is used to measure the movement of red cells within the cerebral microcirculation Both tech-niques are limited to the assessment of a small area of cerebral tissue

TCD ultrasound measures blood flow velocity in the major intracranial vessels Although TCD meas-ures velocity rather than flow, it can be used to assess relative changes in CBF TCD is most widely used to assess vasospasm following SAH, high flow veloc-ity being indicative of a reduction in vessel diameter Comparison of the velocities in the MCA and the external carotid artery (the Lindegaard ratio) can help distinguish between vasospasm and hyperaemia

ELECTROENCEPHALOGRAPHYThe EEG represents the summation of the brain’s elec-trical activity as recorded from the scalp It can be used to detect seizure activity, especially when there

in the adjacent white matter PbtO2 is the product of

CBF and the arteriovenous tension of oxygen; brain

oxygenation depends on both the adequate supply of

oxygen and its extraction The normal range of PbtO2

is 20–35 mm Hg A level below 20 mm Hg has been

suggested as the threshold for therapeutic

interven-tion with increased morbidity and mortality associated

with levels less than 10 mm Hg

Jugular bulb venous oxygen saturation (SjvO2)

pro-vides information on the global utilisation of oxygen

by the brain A catheter is placed into the dominant

internal jugular vein and advanced into the jugular

bulb Normal values for SjvO2 are between 55% and

75% Low levels of SjvO2 are indicative of ischaemia

resulting either from reduced oxygen delivery or

increased demand High levels of SjvO2 may indicate

hyperaemia, reduced demand or tissue death

672

therapies such as intra-arterial thrombectomy,55 it is likely that there will be continued centralisation of care for acute stroke

REHABILITATIONEarly access to specialist rehabilitation that continues into the community is essential to maximise the recov-ery following neurological injury Early mobilisation has been shown to enhance recovery and improve functional outcomes for patients in acute and inten-sive care settings including neurosciences ICU.56 There

is now a substantial body of evidence to support the effectiveness and cost-effectiveness of specialist reha-bilitation.57 Despite a longer length of stay, the cost

of providing early specialist rehabilitation is offset by longer-term savings in the cost of community care.58

KEY REFERENCES

14 Andrews PJD, Piper IR, Dearden NM, et al Secondary insults during intrahospital transport of

head-injured patients Lancet 1990;335:327–330.

21 van der Jagt M Fluid management of the

neurological patient: a concise review Crit Care

2016;20:126

31 Brain Trauma Foundation Guidelines for the

management of severe traumatic brain injury, 4th ed; 2016 https://www.braintrauma.org/

36 Steiner T, Juvela S, Unterberg A, et al European Stroke Organization guidelines for the management

of intracranial aneurysms and subarachnoid

haemorrhage Cerebrovasc Dis 2013;35:93–112.

37 Connolly ES Jr, Rabinstein AA, Carhuapoma JR,

et al Guidelines for the management of aneurysmal subarachnoid haemorrhage: a guideline for healthcare professionals from the American Heart

Association/American Stroke Association Stroke

2012;43:1711–1737

46 Patel HC, Menon DK, Tebbs S, et al Specialist neurocritical care and outcome from head injury

Int Care Med 2002;28:547–553.

51 Dickinson P, Eynon CA Improving the timeliness

of time-critical transfers: removing ‘referral and

acceptance’ from the transfer pathway JICS

2014;15:2–6

54 Morris S, Hunter RM, Ramsay AIG, et al Impact

of centralising acute stroke services in English metropolitan areas on mortality and length of hospital stay: differences-in-differences analysis

BMJ 2014;349:g4757.

58 Turner-Stokes L, Paul S, Williams H Efficiency of specialist rehabilitation in reducing dependency and costs of continuing care for adults with

complex acquired brain injuries J Neurol Neurosurg

Psychiatr 2006;77:634–639.

 Access the complete references list online at http://www.expertconsult.com

is concern regarding non-convulsive status

epilepti-cus, to monitor the response to antiepileptic therapy

and to help to prognosticate in patients with

persis-tent coma.45 EEG monitoring is also useful in

diag-nosing pseudo-status epilepticus due to psychogenic

problems, allowing rapid withdrawal of inappropriate

drug therapies

TIMELINESS OF SPECIALIST CARE

There is a wide body of evidence supporting the care

of brain-injured patients in specialist facilities which

are often distant to the hospital of first attendance.46–50

Although many secondary preventive measures can

be successfully applied pre-hospital or in a regional

hospital prior to transfer to definitive care, rapid

diag-nosis and transfer is essential to optimise outcomes

The Society of British Neurosurgeons recommends the

evacuation of acute extradural or subdural

haemor-rhages within 4 hours Major trauma networks

advo-cate direct transfer to specialist care if patients are

within a certain time of the specialist centre Automatic

admission criteria have been developed to facilitate

rapid transfer from other hospitals without waiting for

‘permission’ to transfer.51

The primary treatment of SAH is occlusion of any

identifiable aneurysm that has ruptured Up to 15%

of patients re-bleed within a few hours of the initial

bleed, often before definitive treatment can be

under-taken The European Stroke Organisation recommends

that the aneurysm should be treated as early as

possi-ble to reduce the risk of re-possi-bleeding, ideally within 72

hours of onset of first symptoms.36 The volume of cases

treated and the availability of endovascular services

and neurological intensive care are also important

determinants of outcome from SAH The American

Heart Association recommends that low-volume

hos-pitals (<10 SAH cases per year) should consider early

transfer of patients to high-volume centres (>35 SAH

cases per year) with experienced neurovascular

sur-geons, endovascular specialists, and neuro-intensive

care services.37 Similarly, ICH is a medical emergency

that needs to be diagnosed and managed swiftly

Expansion of the haematoma and clinical deterioration

are common in the first few hours Among patients

undergoing head CT within 3 hours of ICH onset, up

to 38% have expansion of more than one third of the

initial haematoma volume on follow-up CT.38 While

awaiting transfer for specialist care, it is important to

minimise the risk of haematoma expansion by fully

reversing any prescription anticoagulants and

reduc-ing elevated blood pressure.52

In several countries, acute stroke care has also

been centralised, creating specialist centres to which

patients are taken rather than going to the nearest

hos-pital.53,54 This has increased access to specialist care and

thrombolysis With the advent of other time-critical

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updated perspectives Curr Neurol Neurosci Rep

2016;16:56

45 Claassen J, Taccone FS, Horn P, et al

Recommendations on the use of EEG monitoring

in critically ill patients: consensus statement from

the neurointensive care section of the ESICM Int

Care Med 2013;39:1337–1351.

46 Patel HC, Menon DK, Tebbs S, et al Specialist

neurocritical care and outcome from head injury

Int Care Med 2002;28:547–553.

47 Diringer MN, Edwards DF Admission to a neurologic/neurosurgical intensive care unit

is associated with reduced mortality rate after

intracerebral haemorrhage Crit Care Med 2001;29:

635–640

48 Samuels O, Webb A, Culler S, et al Impact of

a dedicated neurocritical care team in treating patients with aneurysmal subarachnoid

haemorrhage Neurocrit Care 2011;14:334–340.

49 Sadek AR, Eynon CA The role of neurosciences intensive care in trauma and neurosurgical

conditions Br J Hosp Med 2013;74:552–557.

50 Sadek AR, Damian M, Eynon CA The role of neurosciences intensive care in neurological

conditions Br J Hosp Med 2013;74:558–563.

51 Dickinson P, Eynon CA Improving the timeliness

of time-critical transfers: removing ‘referral and

acceptance’ from the transfer pathway JICS

2014;15:2–6

52 Kuramatsu JB, Gerner ST, Schellinger PD, et al Anticoagulant reversal, blood pressure levels, and anticoagulant resumption in patients with anticoagulation-related intracerebral haemorrhage

54 Morris S, Hunter RM, Ramsay AIG, et al Impact

of centralising acute stroke services in English metropolitan areas on mortality and length of hospital stay: differences-in-differences analysis

BMJ 2014;349:g4757.

55 Goyal M, Menon BK, van Zwam WH, et al Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual

patient data from five randomised trials Lancet

2016;387:1723–1731

56 Olkowski BF, Shah SO Early mobilization in the

Neuro-ICU: how far can we go? Neurocrit Care

2017;27(1):141–150

57 Turner-Stokes L, Pick A, Nair A, et al Multi-disciplinary rehabilitation for acquired brain

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58 Turner-Stokes L, Paul S, Williams H Efficiency of specialist rehabilitation in reducing dependency and costs of continuing care for adults with

complex acquired brain injuries J Neurol Neurosurg

Psychiatr 2006;77:634–639.

Brain death

Martin Smith

Death has important medical, legal and societal

impli-cations, making it imperative that its determination is

accurate, reliable and certain It was historically defined

only by confirmation of cessation of cardiorespiratory

function, but the concept of brain death, now more

accurately referred to as the determination of death by

neurological criteria, was introduced into clinical

prac-tice almost 50 years ago From a legal and scientific

perspective, brain death is a definable event which is

established as a legitimate definition of death in most

countries in the world Its confirmation provides a

pro-fessional and legal framework for the withdrawal of

life-sustaining therapies from an individual who can

no longer derive benefit from them, and additionally

allows the retrieval of organs for transplantation

BRAIN DEATH EPIDEMIOLOGY AND 

PATHOPHYSIOLOGY

The incidence of brain death is related to several

factors including national rates of catastrophic brain

injury, access to intensive care and neurosurgical

ser-vices, the presence of organ donation and

transplanta-tion systems, and patterns of professional practice The

true international incidence of brain death is unknown,

although it is estimated to account for 1%–2% of all

deaths in countries with advanced health care systems

and 5%–10% of deaths in comatose patients

admit-ted to intensive care units.1 Rates of brain death are

declining as the incidence of catastrophic brain injury

reduces in some parts of the world, and brain injury

management improves

The principal causes of brain death in adults are

severe traumatic and haemorrhagic brain injury and

cerebral hypoxia–ischaemia Brain death results from

a sustained rise in intracranial pressure above systemic

arterial pressure leading to the irreversible cessation of

brain activity due to permanent loss of blood flow and

oxygen supply to the brain Brainstem reflexes are lost

sequentially in a craniocaudal direction; this process

may take several hours to complete but finally results

in apnoea due to failure of the medulla oblongata

Because of the fundamental controlling role of the

brainstem, cardiovascular and other systemic organ

system functions deteriorate after the onset of brain

death resulting in profound physiological instability and ultimately asystolic cardiac arrest.2

DEVELOPMENT OF BRAIN DEATH CRITERIA

A state of unconsciousness, brainstem areflexia and absence of spontaneous respiration in patients sup-ported by mechanical ventilation was first reported

in 1959 by Mollaret and Goulon who described this state as ‘le coma dépasse’ – literally, a state beyond

coma Almost 10 years later, in 1968, ad hoc

Commit-tee of the Harvard Medical School in the United States developed and published the first widely accepted standard for the definition and confirmation of brain death.3 Because the brainstem is responsible for con-sciousness, breathing and circulatory regulation, and conduction of virtually all throughput to and from the brain, it is loss of brainstem function that is fundamen-tal to the state of irreversible coma described in the Harvard criteria.4 This concept was incorporated into the United Kingdom criteria for the diagnosis of brain (stem) death which was first published in 1976.5 A

2008 update retains the key components of those nal criteria and emphasises that a clinical diagnosis

origi-is sufficient for the determination of brainstem death subject to the fulfilment of essential preconditions and exclusion of reversible causes of coma and apnoea.6Unlike in the United Kingdom, the 1981 Uniform Determination of Death Act (UDDA) defined brain death in the United States as the irreversible ces-

sation of functions of the entire brain.7 The UDDA specified that, like death determined by cessation of cardiorespiratory function, the determination of brain death should be made in accordance with accepted medical standards The American Academy of Neurol-ogy published practice parameters in 1995, updated

in 2010, which have become the accepted medical standards for the determination of brain death in the United States.8

WHOLE BRAIN AND BRAINSTEM DEATHThere is broad consensus, particularly in Western cul-tures, that human death is ultimately death of the brain and that this crucially involves the irreversible loss of

Abstract and keywords 673.e1

KEYWORDSBrain deathbrainstem deathapnoea testancillary testsorgan donation

ABSTRACT

Death was historically defined only by confirmation of

cessation of cardiorespiratory function, but the concept

of brain death, now more accurately referred to as the

determination of death by neurological criteria, was

introduced into clinical practice almost 50 years ago

From a legal and scientific perspective, brain death is

a definable event which is established as a legitimate

definition of death in most countries in the world

Prac-tice guidelines for the determination of brain death are

widely available but there is large international

varia-tion in their content and applicavaria-tion Clinical

determi-nation is the gold standard for the diagnosis of brain

death in many countries, but ancillary investigations

are required in some The clinical determination of

brain death incorporates three sequential but

inter-dependent steps – fulfilment of essential preconditions,

exclusion of reversible causes of coma and apnoea, and

confirmation of brainstem areflexia and apnoea

674

even within, countries in the procedures for its mination.12 Some of these arise because of legal, reli-gious and cultural differences, whereas others relate

deter-to different approaches deter-to the clinical determination

of brain death and variable requirements for ancillary investigations In addition, there are well-documented failures to adhere to clinical practice guidelines for the determination of death by neurological criteria.13,14Another factor contributing to practice variability is that, unlike circulatory death which is relatively easily diagnosed, the determination of brain death is a much more complex process which requires expertise, famili-arity and diligence.7

The variability in brain death practices risks adversely influencing public and professional trust, and an international standard for the diagnosis of brain death would reduce such variability and increase public and professional confidence in the credibility of the determination of death by neurological criteria.10While it is by no means certain that a true international consensus can ever be reached, there are fundamental components that are common to the determination of brain death in all countries (Box 53.1).1

GENERAL PRINCIPLES FOR THE CLINICAL DETERMINATION OF BRAIN DEATHThe majority of countries have followed the lead of the United States and United Kingdom in specifying that a clinical diagnosis of brain death is sufficient for the determination of death in adults Three sequential but interdependent steps form the diagnostic criteria – fulfilment of essential preconditions, exclusion of reversible causes of coma and apnoea, and clinical con-firmation of brainstem areflexia and apnoea (Fig 53.1) While the third step, the clinical examination, demon-strates the absence of brainstem function, it is the first two that determine irreversibility and which require a greater degree of expertise to interpret.15

PRECONDITIONSThe patient’s comatose condition and apnoea must be due to irreversible brain damage of known aetiology This is established by clinical examination and cranial imaging that confirms a catastrophic brain injury

the capacity for consciousness combined with loss of

the capacity to breathe Taken together, these elements

represent the most basic manner in which human

beings can interact with their environment Despite

this consensus, debate continues over the extent of

brain functions that must cease in order to satisfy a

definition of brain death which, as outlined above, is

defined in two different ways based on ‘whole’ brain

and ‘brainstem’ formulations

The determination of whole brain death requires

confirmation, in theory at least, of the loss of all brain

function, including, but not limited to, the brainstem

The diagnosis of brainstem death on the other hand

requires confirmation of absence of brainstem

tion; it does not require that all other brain

func-tions have ceased, only that any funcfunc-tions that might

persist should not indicate any form of

conscious-ness The whole brain formulation is the standard for

the determination of death by neurological criteria in

many parts of the world, including the United States

and most European countries, whereas the United

Kingdom retains the brainstem formulation The

clini-cal determination of whole brain and brainstem death

is identical, and highlighting differences between them

is an unnecessary cause of confusion and controversy.9

Death is not a single event but a process that leads

progressively to the failure of all functions that

consti-tute the life of the human organism.10 Once a

thresh-old of irreversibility has been reached, and permanent

cessation of cardiorespiratory function or brain death

(however defined) marks such a point, it is not

neces-sary to wait for the death of the whole organism for

the inevitable consequence of its biological death to

be certain It is universally accepted that cessation of

cardiorespiratory function marks the death of an

indi-vidual, but nobody would claim that the whole human

organism is dead at this point The same is not yet the

case for brain death Reports of brain dead patients

‘being kept alive on a ventilator’ are familiar, and

ele-ments of the public continue to refuse to accept that

brain dead patients are actually dead.11 In a 2015

inter-national survey, 57% of physician respondents also did

not believe that brain death equates to death defined

by cardiorespiratory criteria.12 To minimise such

con-fusion, it has been recommended that death should

no longer be defined anatomically using terms such

as cardiac or brain death, which inaccurately imply

death of an individual organ, but functionally based

on confirmation of permanent non-function of the

brain subsequent to circulatory arrest or catastrophic

brain injury.1

VARIABILITY IN BRAIN DEATH PRACTICES

Although confirmation of brain death is legally

accepted as the death of an individual in the majority

of countries, there are major differences between, and

Box 53.1  Areas of consistency in international 

guidelines for the determination of  brain death

General principles for the clinical determination of brain death 675

consciousness of a given drug concentration in a cally ill brain-injured patient Administration of spe-cific antagonists to exclude opioid or benzodiazepine effects can also be considered Ancillary investiga-tions may be used to confirm the diagnosis of brain death in some jurisdictions when sedation drug effects cannot be excluded Residual pharmacological paraly-sis should be excluded by ‘train-of-four’ stimulation to confirm the absence of neuromuscular blockade

criti-HYPOTHERMIA

Although brainstem reflexes are likely to be absent only if body temperature falls below 28°C, tem-peratures between 32°C and 34°C have occasion-ally been associated with impaired consciousness Most guidelines recommend that core temperature should be at or near normal at the time of the clinical examination.12,16

ELECTROLYTE AND ENDOCRINE DISTURBANCE

All guidelines require that there should be no dence of severe electrolyte or endocrine disturbance, but ‘severe’ is rarely defined Diabetes insipidus-related hypernatraemia is a common consequence of brain death and a particular problem Many guide-lines recommend a target plasma sodium concentra-tion, while others acknowledge that delay in clinical testing because of strict adherence to a predetermined plasma sodium concentration is inappropriate in the

evi-Irreversibility might be obvious within a relatively

short period of time after severe traumatic brain injury

or intracranial haemorrhage, but it may take longer to

establish the diagnosis and be confident of prognosis

in patients with hypoxic-ischaemic brain injury

EXCLUSION OF POTENTIALLY REVERSIBLE 

CAUSES OF COMA AND APNOEA

Following confirmation of a diagnosis that is

compat-ible with brain death, potentially reverscompat-ible causes of

coma and apnoea must be excluded (Table 53.1) The

confounding effects of hypothermia, depressant drugs

and severe electrolyte abnormalities are consistently

cited in all clinical guidelines, but the thresholds vary

between them.12,16

DRUG EFFECTS

The effects of sedative and paralysing drugs must be

excluded as a cause of the patient’s unresponsive state

Sufficient time must be allowed for sedative drugs to

be metabolised and excreted; five half-lives in the

pres-ence of normal hepatic and renal function are usually

considered appropriate However, the presence of

hypothermia as well as hepatic or renal dysfunction

brings significant confounders to the confident

exclu-sion of residual drug effects The serum concentration

of some sedatives can be measured, but be difficult

to interpret because of the unpredictable effects on

Comatose patient dependent on mechanical ventilation

Irreversible brain damage of known aetiology Wait and reassess

Wait and reassess

Brain death confirmed

Reversible causes of coma and apnoea excluded

• absent motor response in cranial nerve distribution

• absent brainstem reflexes

• apnoea in presence of respiratory acidaemic stimulus

Wait and reassess or consider withdrawal oftreatment on grounds of futility

No

No

NoYes

Yes

YesYes

Figure 53.1 The three sequential but interdependent steps that form the criteria for the clinical determination of death by neurological criteria. 

676

CRANIAL NERVE EXAMINATION

Assessment of brainstem reflexes is common to all guidelines for the clinical confirmation of brain death (Box 53.2) In most jurisdictions the diagnosis is not invalidated if pupil response, corneal reflex and oculo-vestibular reflex are not assessable on one side because

of injury or disease Ancillary investigations should

be considered if bilateral assessment is impossible Absence of the oculocephalic reflex (‘doll’s-eye’ move-ments) is a required component of the clinical diagno-sis of brain death in some countries It can also be used

presence of other stigmata of brain death and when

the hypernatraemia can be confidently excluded as a

cause (rather than a result) of the clinical state Blood

glucose concentration should be normalised prior to

and during the clinical examination(s)

Several endocrine abnormalities can be associated

with impaired consciousness or present as acute coma,

but are rare and unlikely to co-exist in the presence

of known primary intracranial pathology Hormone

assays are generally only recommended if there is any

clinical suspicion of endocrine disturbance

CARDIORESPIRATORY DISTURBANCES

The onset of brain death is accompanied by intense

circulatory and respiratory disturbance Oxygen

satu-ration should be maintained greater than 95% and

systolic blood pressure above 100 mm Hg before and

throughout the clinical examination

CLINICAL EXAMINATION

The clinical examination is designed to confirm the

absence of brainstem reflexes and presence of

per-sistent apnoea, and should be performed only after

preconditions have been met and reversible causes of

coma excluded

•  serum drug levels should be measured where assays are available

•  no consensus regarding the minimal concentration at which brain death can be diagnosed

•  consider specific opioid or benzodiazepine antagonists

•  No residual effects of neuromuscular-blocking drugs

•  presence of deep tendon reflexes

•  train-of-four present on peripheral nerve stimulationHypothermia •  Temperature at or near normal

– pupils do not need to be maximally dilated, simply unresponsive

•  Corneal reflexes absent

•  Oculovestibular reflexes absent– no eye movements during or following slow injection

of 50 mL ice-cold water over 1 min into each external auditory meatus

– clear access to tympanic membrane must be confirmed

by direct inspection prior to testing– head at 30 degrees to the horizontal unless contraindicated by unstable spine injury

•  Oculocephalic reflexes absent– not required in all jurisdictions– eyes remain in mid-position during brisk turning of the head from side to side (‘doll’s eyes’)

– tested only if cervical-spine integrity ensured

•  No  facial  movement  to  adequate  stimulation  in  the trigeminal areas

– usually firm pressure over the supraorbital area or temporomandibular joint

•  No facial movement to noxious stimuli in all four limbs– spinal reflex limb responses are permissible

•  Cough reflex absent– no response to tracheal suctioning

•  Gag reflex absent– no response to stimulation (under direct vision) of the posterior pharynx

Ancillary tests 677

cases, whereas no minimum time is stipulated in others.16 A period of observation of at least 24 hours is usually required in coma related to hypoxic-ischaemic brain injury

Two clinical examinations are required to confirm brain death in many jurisdictions, although there is

no evidence that a second examination is necessary

A large study of brain dead adults showed that the second examination added nothing to the first, delayed the declaration of death, and reduced organ donation rates.17 The clinical diagnosis of brain death using standard criteria is robust,8 and there is an increasing trend towards a requirement for only a single exami-nation Where two examinations are required, there is often no specified time interval between them In the United Kingdom, for example, the second examination can be undertaken as soon as arterial blood gases have returned to baseline after the first apnoea test The legal time for certification of death is usually at the initial confirmation of brain death but, in Australia, the time

of death is that of the second confirmatory examination.The number of doctors required to determine brain death also varies In most jurisdictions a single doctor is sufficient, but in the United Kingdom, Aus-tralia and some states in the United States at least two medical practitioners are required The base specialty

of doctors confirming brain death is stipulated in some countries whereas, in others, relevant competencies are defined.12 To avoid any conflict of interest, the deter-mination of brain death should not be made by a phy-sician involved with organ transplantation

ANCILLARY TESTSClinical determination is the gold standard for the diagnosis of brain death in many countries, but ancil-lary investigations are mandatory in some.18 They are also useful if only a limited clinical examination is pos-sible or when confounding or special conditions are present.19 Ancillary investigations fall into two main categories assessing brain blood flow or electrophysi-ological activity, but there are limited data to confirm the applicability and reliability of any ancillary test for any particular circumstance.20

ASSESSMENT OF CEREBRAL BLOOD FLOWAbsence of blood flow to the brain is widely accepted

to be consistent with brain death Methods to confirm the absence of cerebral blood flow are less affected by confounding factors such as residual sedation, meta-bolic disturbance or hypothermia than electrophysi-ological methods, and are preferred

CEREBRAL ANGIOGRAPHY

Four-vessel digital subtraction cerebral angiograph (DSA) is the gold-standard confirmatory test for brain

as a ‘screening’ test; the presence of eye movements

indicates that brainstem function persists

APNOEA TEST

Confirmation of apnoea is fundamental to the

deter-mination of brain death in all guidelines, although

end-points differ.12 While the overall aim is to produce

an acidaemic respiratory stimulus, fewer than 60% of

jurisdictions specify a PaCO2 target for the end-point

of the apnoea test.16 In others there is no guidance

whatsoever or only a stipulation that the ventilator

should be disconnected for a defined period of time

The apnoea test should be performed only after

brainstem areflexia has been confirmed, and using a

technique that minimises the risk of significant

hypox-aemia, excessive hypercarbia or changes in mean

arte-rial blood pressure

The UK guidance provides a structured approach

for conduct of the apnoea test which maintains

physiological stability and allows successful

comple-tion in most circumstances The patient should be

pre-oxygenated with 100% oxygen for at least 10 minutes,

and arterial blood gases measured to correlate PaCO2

with end-tidal carbon dioxide (ETCO2) The

ventila-tion rate is then reduced to allow a slow rise in ETCO2

When ETCO2 rises above 6.0 kPa, arterial blood gases

are checked to confirm that PaCO2 is at least 6.0 kPa

and pH less than 7.40 In patients with chronic CO2

retention, PaCO2 can be allowed to rise above 6.5 kPa

to generate a pH less than 7.40 The patient is then

dis-connected from the ventilator, oxygen insufflated at

5 L/min via an endotracheal catheter, and the patient

observed for respiratory effort The ventilator should

always be disconnected during the apnoea test because

autocycling can incorrectly suggest the presence of

spontaneous respirations Apnoea is confirmed

follow-ing visual inspection for at least 5 minutes, and after

documentation of the absence of spontaneous

respira-tory activity in the presence of PaCO2 that has increased

to the target level This varies between jurisdictions;

most require that it should be greater than 8.0 kPa or

have increased by more than 0.5–2.5 kPa above a

base-line of 6.0 kPa The ventilator is then reconnected and

minute volume adjusted to allow a gradual return of

arterial blood gases to pre-test levels SpO2 should be

maintained above 95% and systolic blood pressure

above 100 mm Hg throughout the apnoea test If

ade-quate oxygenation proves difficult, a prior recruitment

manoeuvre and continuous positive airway pressure

via an appropriate circuit (e.g Mapleson B) minimises

the risk of desaturation during the test

TIMING AND REPETITION OF CLINICAL TESTS

There is no evidence to define a minimum period of

observation between the onset of apnoeic coma and

clinical examination to ensure irreversibility Some

countries recommend a minimum of 6 hours in all

678

ELECTROPHYSIOLOGYElectroencephalography (EEG) remains widely used in the diagnosis of brain death despite substantial disad-vantages and a requirement for specialist interpreta-tion The absence of cortical electrical activity during high-sensitivity recordings from 16 or 18 channels over

30 minutes is often taken as confirmatory evidence of brain death However, an isoelectric cortical EEG does not exclude activity in the brainstem or other deep structures, and electrical activity in some cortical cells does not confirm that the whole brain is functioning.18EEG examination is a mandatory part of a brain death diagnosis in many European countries and strongly recommended in some states in the United States where loss of whole brain function must be confirmed However, EEG is affected by hypothermia and seda-tion, and therefore of limited value in circumstances where a confirmatory investigation might be required Some experts argue that the substantial disadvantages

of EEG mean that it should no longer be used as an ancillary test for the diagnosis of brain death.20

Evoked potentials (EPs) monitor the integrity of crete sensory pathways and are able to assess compo-nents of brainstem function EP monitoring is feasible

dis-in the settdis-ing of hypothermia and sedation but, like EEG, requires specialist expertise for interpretation Because EPs rely on the integrity of the whole sensory pathway, a lesion affecting any point of the monitored pathway can result in an absent EP and false-positive result.18 EPs can also be transiently absent after a hypoxic/ischaemic insult making them unreliable as

an ancillary test for brain death

DIAGNOSING BRAIN DEATH IN   SPECIAL CIRCUMSTANCESAlthough there are no published reports of recovery of neurological function after a clinical diagnosis of brain death using standard criteria, there are numerous case reports highlighting situations or conditions that may mimic brain death and lead to erroneous conclusions

if unrecognised.23 Such diagnostic errors invariably involve failure to identify preconditions and exclude reversible factors

HYPOTHERMIA AND SEDATIVE DRUGS   AND HYPOTHERMIA

The effects of high-dose sedative or opioid infusions may persist for several days after discontinuation, par-ticularly in the presence of hypothermia In one report

of misdiagnosed brain death, the potential ing effects of a very high cumulative dose of fentanyl

confound-in a patient with renal and hepatic impairment who had been treated with therapeutic hypothermia after

a cardiac arrest appear to have been dismissed.24 This

death in some jurisdictions.18 Following bilateral

injec-tion of contrast into vertebral and carotid arteries,

absence of flow beyond the foramen magnum in the

posterior circulation and beyond the petrosal portion

of the carotid artery in the anterior circulation is

accepted to be indicative of brain death DSA is

relia-ble and easy to interpret, but invasive, time-consuming

and often available only in neuroscience units It also

requires administration of contrast agents which may

adversely affect graft function in donated kidneys

Non-invasive vascular techniques such as

com-puted tomography (CT) cerebral angiography (CTA)

are increasingly employed CTA has high sensitivity

for the confirmation of brain death in individuals who

fulfil clinical diagnostic criteria but there is insufficient

evidence to support its use as a screening tool.21 A

sig-nificant proportion of patients meeting clinical criteria

for brain death retain some evidence of contrast in the

proximal intracranial arteries with all angiographic

techniques False-negative results occur, particularly

after decompressive craniectomy and in the presence

of cerebrospinal fluid drains or low arterial blood

pres-sure Systolic blood pressure should be maintained

above 100 mm Hg during blood flow confirmation of

brain death.18

PERFUSION IMAGING

Contrast-enhanced CT cerebral perfusion techniques

are widely available, although there is little evidence

of advantages over CTA Positron emission

tomog-raphy measures regional cerebral metabolic rate for

glucose in addition to regional blood flow It has

theoretical advantages as an ancillary investigation

in the diagnosis of brain death but there are currently

no data to support its use in this situation Nuclear

imaging techniques are also able to confirm absent

cer-ebral perfusion; an ‘empty skull’ appearance in which

no intracranial contrast is visible is indicative of brain

death.18 False positives are rare, and no contrast agent

is required

TRANSCRANIAL DOPPLER ULTRASONOGRAPHY

Transcranial Doppler (TCD) is a non-invasive bedside

investigation that can be used as a confirmatory test

during the diagnosis of brain death.22 When

intra-cranial pressure exceeds mean arterial blood pressure,

TCD assessment of blood flow velocity in basal cerebral

vessels reveals systolic spikes with reversal of diastolic

flow Absence of a TCD waveform should never be

taken as confirmation of absent cerebral blood flow

because at least 10% of patients have no acoustic bone

window TCD examination has high sensitivity (86%)

and specificity (98%) for the diagnosis of brain death

when compared to clinical examination, with very few

false-positive cases reported in the literature.18 There is

significant operator dependence, and previous surgery

or open ventricular drains make TCD waveform

inter-pretation difficult

Summary 679

reflexes.26 The majority of countries have separate guidelines for the determination of brain death in infants and children, but clinical examination remains paramount in all.27 In those over 2 months of age, the general criteria are the same as for adults but the period of observation is often longer and ancillary investigations are required in some countries A higher PaCO2 target is also recommended during the apnoea test As in adults, the clinical confirmation of brain death must be undertaken by two competent physi-cians but, in the case of young children, one should

be a paediatrician and the other not directly involved

in the child’s clinical care Two clinical examinations, separated by an observation period that varies with age, are required to establish brain death in children in most countries.27

BRAIN DEATH AND ORGAN DONATIONDevelopment of the original Harvard brain death crite-ria was driven in part by advances in organ transplan-tation and the associated importance of determining death prior to organ retrieval Recent calls for an inter-national standard for brain death determination are also based as much on a need to improve the avail-ability of organs for transplantation as they are on a desire to establish a consensus for its determination Transplantation networks increasingly operate across national borders, arguing for consistency in the deter-mination of death in potential donors Despite the ines-capable link between brain death and organ donation and transplantation policies, it is vitally important that,

in the clinical setting, there is an inviolable separation between brain death and organ donation The primary reason for confirming brain death is to ensure profes-sional, legal and societal acceptability for the with-drawal of treatment, including mechanical ventilation, from a patient who can no longer derive benefit from

it, and to bring closure for family and friends mation of brain death is therefore in an individual’s best interests irrespective of any subsequent potential for organ donation.9 After brain death has been con-firmed, donation should of course be considered in all appropriate patients.2

Confir-SUMMARYFrom a legal and scientific perspective brain death, more accurately referred to as the determination of death by neurological criteria, is a definable event which is established as a legitimate definition of death

in most countries in the world Practice guidelines for the determination of brain death are widely available Although there is large international variation in their content and application, there are fundamental com-ponents that are common to the determination of brain

case illustrates the crucial importance of adherence to

a sequential approach to the clinical determination of

brain death, with confident exclusion of

confound-ing factors before proceedconfound-ing to the clinical

examina-tion As noted earlier, ancillary tests may have a role

if the clinical diagnosis of brain death is complicated

by the effects of prolonged sedation, particularly in the

context of hypothermia

INABILITY TO COMPLETE THE APNOEA TEST

In patients with high spinal cord injury, the

possibil-ity that apnoea might be related to the cord injury can

bring some uncertainty to the diagnosis of brain death

The degree of any cord injury should be quantified

clinically, structurally and functionally by meticulous

clinical examination, magnetic resonance imaging and

electrophysiological investigation prior to consideration

of a brain death diagnosis In other situations, such as

after polytrauma, it may not be possible to attempt or

complete the apnoea test because of haemodynamic

instability or poor oxygenation However, in the vast

majority of cases the apnoea test can be safely

com-pleted using an oxygen diffusion technique as described

earlier.25 Most guidelines consider the apnoea test to be

a fundamental component of the clinical determination

of death by neurological criteria, although in Australia

and New Zealand brain death can be confirmed by

demonstration of absent intracranial blood flow if the

apnoea test cannot be completed

OTHER CONDITIONS

Other brain death ‘mimics’, including baclofen and

valproic acid overdose, organophosphate intoxication

and some neurological conditions such as fulminant

Guillain-Barré syndrome or Miller-Fisher variant, have

been reported.23 Importantly, the preconditions for the

diagnosis of brain death are not met in any of these

conditions which should therefore never be mistaken

for brain death.7

EXTRACORPOREAL MEMBRANE OXYGENATION

There are a few case reports of patients who are

clini-cally brain dead while supported on extracorporeal

membrane oxygenation (ECMO) Because use of this

technology will increase and up to 20% of patients on

ECMO may become brain dead, protocols for conduct

of the apnoea test in this situation are required.7

CHILDREN

The clinical determination of brain death in infants

and children can be more problematic than in adults

because of difficulties performing the clinical

exami-nation and the relative immaturity of some brainstem

680

13 Greer DM, Wang HH, Robinson JD, et al Variability of brain death policies in the United

States JAMA Neurol 2016;73:213–218.

14 Shappell CN, Frank JI, Husari K, et al Practice variability in brain death determination: a call to

action Neurology 2013;81:2009–2014.

15 Smith M Brain death: the United Kingdom

perspective Semin Neurol 2015;35:145–151.

16 Wijdicks EF Brain death worldwide: accepted fact but no global consensus in diagnostic criteria

Neurology 2002;58:20–25.

17 Lustbader D, O’Hara D, Wijdicks EF, et al Second brain death examination may negatively affect

organ donation Neurology 2011;76:119–124.

18 Kramer AH Ancillary testing in brain death Semin

Neurol 2015;35:125–138.

19 Bernat JL Controversies in defining and determining

death in critical care Nat Rev Neurol 2013;9:

164–173

20 Wijdicks EF The case against confirmatory tests

for determining brain death in adults Neurology

2010;75:77–83

21 Brasil S, Bor-Seng-Shu E, de Lima-Oliveira M, et al Role of computed tomography angiography and perfusion tomography in diagnosing brain death:

a systematic review J Neuroradiol 2016;43:133–140.

22 Sharma D, Souter MJ, Moore AE, et al Clinical experience with transcranial Doppler ultrasonography as a confirmatory test for brain

death: a retrospective analysis Neurocrit Care 2011;

14:370–376

23 Busl KM, Greer DM Pitfalls in the diagnosis of

brain death Neurocrit Care 2009;11:276–287.

24 Webb AC, Samuels OB Reversible brain death after cardiopulmonary arrest and induced hypothermia

Crit Care Med 2011;39:1538–1542.

25 Datar S, Fugate J, Rabinstein A, et al Completing

the apnea test: decline in complications Neurocrit

Care 2014;21:392–396.

26 Shemie SD, Pollack MM, Morioka M, et al

Diagnosis of brain death in children Lancet Neurol

2007;6:87–92

27 Mathur M, Ashwal S Pediatric brain death

determination Semin Neurol 2015;35:116–124.

death in all jurisdictions A clinical diagnosis of brain

death is sufficient for the determination of death in

adults in many countries, although ancillary

investiga-tions are required in some

REFERENCES

1 Shemie SD, Baker A Uniformity in brain death

criteria Semin Neurol 2015;35:162–168.

2 Citerio G, Cypel M, Dobb GJ, et al Organ donation

in adults: a critical care perspective Intensive Care

4 Mohandas A, Chou SN Brain death A clinical and

pathological study J Neurosurg 1971;35:211–218.

5 Diagnosis of brain death Statement issued by the

honorary secretary of the Conference of Medical

Royal Colleges and their Faculties in the United

Kingdom on 11 October 1976 Br Med J 1976;2:

1187–1188

6 Academy of Medical Royal Colleges A code of

practice for the diagnosis and confirmation of death

London, UK: Academy of the Medical Royal

Colleges; 2008

7 Varelas PN, Lewis A Modern approach to brain

death Semin Neurol 2016;36:625–630.

8 Wijdicks EF, Varelas PN, Gronseth GS, et al

Evidence-based guideline update: determining

brain death in adults: report of the Quality

Standards Subcommittee of the American Academy

of Neurology Neurology 2010;74:1911–1918.

9 Smith M Brain death: time for an international

consensus Br J Anaesth 2012;108(suppl 1):i6–i9.

10 Shemie SD, Hornby L, Baker A, et al International

guideline development for the determination of

death Intensive Care Med 2014;40:788–797.

11 Magnus DC, Wilfond BS, Caplan AL Accepting

brain death N Engl J Med 2014;370:891–894.

12 Wahlster S, Wijdicks EF, Patel PV, et al Brain death

declaration: practices and perceptions worldwide

Neurology 2015;84:1870–1879.

Meningitis and encephalomyelitis

Michel Toledano, Nicholas WS Davies

INTRODUCTION

Infections of the cranial contents can be divided into

those affecting the meninges (meningitis; empyema)

and those affecting the brain parenchyma

(encephali-tis; abscess) Involvement of the spinal cord is termed

myelitis Chronic, insidious or rare infections are

beyond the scope of this chapter, which will focus on

acute bacterial and viral causes of meningitis,

encepha-lomyelitis, and abscess/empyema in adults

The crucial diagnostic questions to be considered

for an individual patient with a neurological infection

are to determine why this individual, in this place, has

developed this disease at this time.1

All patients presenting with symptoms or signs

sug-gestive of meningitis or encephalitis warrant

immedi-ate testing for human immunodeficiency virus (HIV)

infection

DEFINITIONS

• Meningitis: is inflammation of the meninges and

subarachnoid space, which may be caused by

infection Infection can be caused by viruses, bacteria,

fungi or protozoa Meningeal inflammation may also

be caused by subarachnoid haemorrhage, vaccination

or be a manifestation of other multiorgan diseases

such as systemic lupus erythematosus, sarcoidosis,

lymphoma or meningeal micrometastases from a

disseminated carcinoma

• Aseptic meningitis: is a generic term for cases of

meningitis in which bacteria cannot be isolated

from the cerebrospinal fluid (CSF) The differential

diagnosis includes: (1) viral meningitis, (2) partially

treated bacterial meningitis, (3) tuberculosis (TB)

meningitis, (4) fungal meningitis, (5) lymphoma,

(6) sarcoidosis, (7) drug-induced meningitis, and (8)

other collagen vascular diseases The most common

causes of aseptic meningitis are viral infections

• Encephalitis: is inflammation of the brain

paren-chyma, which can be due to infection or

immune-mediated processes Patients may have a history

of focal symptoms including preceding seizures

together with cognitive or behavioural symptoms

• Tuberculous meningitis: causes subacute lymphocytic

meningitis Patients may have a non-specific prodromal phase, including symptoms such as headache, vomiting and fever

• Subdural empyema: a suppurative process in the

space between the pia and dura maters

• Brain abscess: a collection of pus within the brain

tissue

BACTERIAL MENINGITISBacterial meningitis is an inflammatory response to infection of the leptomeninges and subarachnoid space This is characterised by the clinical syndrome

of fever, headache, neck stiffness and CSF pleocytosis Despite antibiotic therapy, some patients continue to suffer significant morbidity and mortality

Bacterial organisms are usually not confined to the brain and meninges and frequently cause systemic illness, for example severe sepsis, shock, acute respira-tory distress syndrome, and bleeding disorders such as disseminated intravascular coagulation (DIC).2,3

A variety of other pathogens cause meningeal inflammation, resulting in very similar clinical pres-entations Bacterial infections must be treated urgently and appropriately to limit ongoing central nervous system (CNS) damage It is also important to treat the complications of meningitis such as seizures and raised intracranial pressure (ICP)

Where possible, spinal fluid examination ing a lumbar puncture is required in order to confirm the diagnosis and establish the pathogenic organ-ism responsible.4 A CSF examination may be contra-indicated if there are signs of raised ICP including:

Abstract and keywords 681.e1

KEYWORDSMeningitisencephalitisbrain abscesssubdural empyemaepidural infection

ABSTRACT

Infections of the central nervous system can be divided

into those that affect the meninges (meningitis and

empyema) and those that affect the brain parenchyma

(encephalitis and abscess) Here we focus on the

diag-nosis and treatment of common viral, bacterial and

fungal acute meningeal and brain infections, as well as

on the management of common complications

NEUROSURGERY AND TRAUMAInfections following skull trauma are frequently caused

by Staphylococcus aureus and Staphylococcus epidermis,

which should be considered in those with shunts or other intracranial devices

CLINICAL PRESENTATIONThe history may reveal evidence of trauma or infect-ion Meningitis usually presents with an acute onset of:

CSF examination in order to rule out this

possibil-ity and lessen, but not obviate, the risk of cerebral

herniation Even if the CT brain scan is normal,

ICP may be raised The importance of performing

a safe CSF examination must be balanced against

the need to commence immediate treatment in each

individual patient.4–6

PATHOGENESIS

All three main causes of bacterial meningitis (see later)

are spread by droplet infection or exchange of saliva

Bacterial meningitis may occur when pathogenic

organisms colonise the nasopharynx and reach the

blood–brain barrier It can also occur as a consequence

of infection in the middle ear, sinus or teeth leading

to secondary meningeal infection Most bacteria obtain

entry into the CNS via the haematogenous route As

the organisms multiply, exponentially, they release

cell wall products and lipopolysaccharide, which can

generate a local inflammatory reaction that itself also

releases inflammatory mediators The net result of the

release of cytokines, tumour necrosis factor and other

factors is associated with a significant inflammatory

response Vasculitis of CNS vessels, thrombosis, cell

damage and exudative material all contribute to

vaso-genic and cytotoxic oedema, altered blood flow and

cerebral perfusion pressure Later on, infarction and

raised ICP occur.4,7

The inflammatory events seen with infection are

summarised in Fig 54.1

AETIOLOGIES

Acute bacterial meningitis can be caused by many

species of bacteria, although two organisms are

com-monly reported in resource-rich settings:

• Streptococcus pneumoniae

• Neisseria meningitidis

Until the advent of the meningitis vaccination

pro-gramme, Haemophilus influenzae type B was the most

common cause of bacterial meningitis S pneumoniae

and N meningitidis remain the most common causes of

bacterial meningitis in adults worldwide.4 Listeria

mono-cytogenes can occur in the elderly,

immunocompro-mised, or those with chronic illnesses such as alcohol

dependency, diabetes, or malignancy The emergence

of pneumococcal strains resistant to penicillin has also

influenced the epidemiology of meningitis.8

NOSOCOMIAL INFECTIONS

Common systemic nosocomial pathogens such as

Staphylococcus species (spp.) Escherichia coli,

Pseu-domonas spp., Klebsiella and Acinetobacter spp account

for a high percentage of nosocomial infections of

Inflamed meningesBreakdown blood–brain barrierCytotoxic oedema

VasculitisThrombosisAltered blood flow

Capillary permeabilityOedemaReduces flow of cerebrospinal fluid

Raised ICPImpaired blood flowHydrocephalusDecreased CPP

IschaemiaHypoxiaNeuronal damageFigure 54.1 Cascade of events in meningitis. CPP,  Cerebral perfusion pressure; ICP, intracranial pressure; 

IL, interleukin; PAF, platelet-activating factor; TNF, tumour 

necrosis factor. 

Bacterial meningitis 683

ethylenediaminetetraacetic acid (EDTA) blood sample for diagnostic polymerase chain reaction (PCR) studies.4Thereafter they should be given empirical intravenous (IV) antibiotics if there is likely to be any delay in further assessment (Table 54.1)

CEREBROSPINAL FLUID FINDINGS

A CSF examination is a vitally important investigation that will definitively confirm the diagnosis of bacterial meningitis Its value should, in this regard, not be dis-missed Concern about the risks of coning following lumbar puncture should be considered in the context

of patients’ symptoms where the presence of coma, zures, focal neurological signs and papilloedema may suggest raised ICP Neuroimaging may not always predict whether it is safe to lumbar puncture a patient, although it may provide some level of reassurance that

sei-it is safe to proceed A young patient who is alert, tated, immune competent and without focal signs can safely have a lumbar puncture without prior imaging.Bacterial meningitis is suggested when there is:

orien-• polymorphic leucocytosis

• low CSF glucose relative to the plasma value

• raised CSF protein concentration

• elevated CSF lactate (>3.5 mmol/L)

An urgent Gram stain and microbiological culture are mandatory The Gram stain is positive in approxi-mately 50%–60% of cases A CSF examination shortly after empirical antibiotics may, but does not necessar-ily, decrease the diagnostic sensitivity of CSF culture Bacterial latex agglutination tests applied to CSF have

no greater sensitivity than Gram stain and may give non-specific results; care should be taken with their interpretation and they should not be used alone to limit the spectrum of antimicrobial cover PCR tech-niques can now be used to detect the presence of dif-ferent organisms A throat swab should be routinely taken The clinical decision-making process to deter-mine whether a patient does or does not have bacterial meningitis cannot be modelled easily and is reliant on both clinical and laboratory findings as well as patient observations over time

However, in the immunocompromised, elderly or

infant patient, non-specific features such as a low-grade

fever or mild behavioural change may be all that is

appar-ent Many of the classic symptoms are late manifestations

of meningitis and are preceded by early symptoms such

as leg pain or cold hands, which may not immediately

suggest the more serious underlying diagnosis

If the presenting symptoms are highly suggestive

of pyogenic bacterial meningitis, empirical

administra-tion of a third-generaadministra-tion cephalosporin such as

cefo-taxime or ceftriaxone should be given

It is important to identify from the history any

reports of preceding trauma, upper respiratory tract

infection or ear infection Symptoms may develop over

hours or days Specific infections relate partly to an

individual’s age

Neurological signs can be present with meningitis,

but signs such as nuchal rigidity, stiffness and a positive

Kernig’s sign (pain and hamstring spasm resulting from

attempts to straighten, e.g with the hip flexed) are not

always present; a number of studies have shown that

the classic triad of signs were present in less than 50%

of cases There may be focal neurological signs

Sys-temic signs occur most often in meningococcal disease

where a haemorrhagic, petechial or purpuric rash may

be observed Digital gangrene or skin necrosis may

occur Some patients present severely septic with acute

respiratory distress syndrome and DIC

Approximately 25% of patients have a seizure

during the course of the illness Differential diagnoses

include subarachnoid haemorrhage, migraine,

enceph-alitis and tumour

INVESTIGATIONS

The patient with suspected bacterial meningitis

requires immediate blood cultures and collection of

Table 54.1 Cerebrospinal fluid changes in meningitis

CSF, Cerebrospinal fluid.

In all cases, it is important to monitor the cal response; antibiotics should be reviewed and appropriately altered once antibiotic sensitivities are known or if a patient is not improving A repeat CSF

clini-As spread is haematogenous, blood cultures

com-prise an important investigation in meningitis, and a

number of sets of cultures should be sent It is

advis-able to routinely check a full blood count, clotting

profile (to exclude DIC) and biochemistry including

blood glucose level A chest radiograph and blood

gases should be performed to identify systemic

involvement Relevant areas such as infected sinuses

or ears should be examined if there is any indication

they are implicated

MANAGEMENT

Broad-spectrum antibiotics should be started as early

as possible and continued until bacterial identification

is made (Table 54.2) Antibiotic selection is influenced

by the clinical situation in conjunction with known

allergies or local patterns of antibiotic resistance and

the CSF findings The patient’s travel history,

expo-sure risks and level of immunocompetence are key

to determining empirical antibiotic treatment Delay

in administering antibiotics is a significant risk factor

for a poor prognosis Adults with suspected

menin-gitis should receive empirical treatment with

ceftriax-one 2 g IV every 12 hours or 2 g cefotaxime IV every 6

hours (Table 54.3).4

If the patient has within the last 6 months been to a

country where resistant pneumococci are present, IV

vancomycin 15–20 mg/kg should be added (or 600 mg

rifampicin 12-hourly IV or orally) Up-to-date

informa-tion regarding antibiotic resistance in travellers can be

obtained from the World Health Organization (http://

bit.ly/1rOb3cx and http://bit.ly/1rOb3cx)

Those aged over 60 or immunocompromised

(including diabetics and those with a history of alcohol

<60 years Chloramphenicol 25 mg/kg 6-hourly

>60 years or impaired cell immunity

Chloramphenicol

Co-trimoxazole 10–20 mg/

kg (of the trimethoprim component)

In four divided daily doses

Table 54.3  Alternative antibiotic choices for empirical 

treatment of meningitis

Always check local sensitivity as resistance patterns are variable.