Hypoxic Ishaemic Injury PN BMJ 2011

REVIEW

4 Practical Neurology

10.1136/jnnp.2010.235218

Pract Neurol 2011; 11: 418

Hypoxic-ischaemic brain injuryRobin S Howard,1 Paul A Holmes,1 Michalis A Koutroumanidis2

Hypoxicischaemic brain injury is common and usually due to cardiac arrest or profound hypotension. The clinical pattern and outcome depend on the severity of the initial insult, the effectiveness of immediate resuscitation and transfer, and the post-resuscitation management on the intensive care unit. Clinical assessment is diffi cult and so often these days compromised by sedation, neuromuscular blockade, ventilation, hypothermia and inotropic management. Investigations can add valuable information, in particular brain MRI shows characteristic patterns depending on the severity of the injury and the timing of imaging. EEG patterns may also suggest the possibility of a good outcome. There is no entirely reliable algorithm of clinical signs or investigations which allow a defi nitive prognosis but the combination of careful repeated observations and appropriate ancillary investigations allows the neurologist to give an informed and accurate opinion of the likely outcome, and to advise on management. Overall, the prognosis is extremely poor and only a quarter of patients survive to hospital discharge, and often even then with severe neurological or cognitive defi cits.

1Consultant Neurologist, Department of Neurology, Guys and St Thomas NHS Trust, London, UK

2Consultant Neurophysiologist, Department of Neurology, Guys and St Thomas NHS Trust, London, UK

Correspondence to Dr R S Howard, Department of Neurology, Guys and St Thomas NHS Trust, London SE1 7EH, UK; [email protected]

Resuscitation. Doctors performing cardiopulmonary resuscitation (CPR) on an unconscious man, following a cardiac arrest. The doctor on the right is giving heart massage (cardiac compression). Each downward compression on the chest squeezes blood out of the heart and around the body. The other doctor is using an Ambu bag to push air into the patients lungs, maintaining oxygenation of the blood and stimulating natural breathing.

Credit: AJ PHOTO / SCIENCE PHOTO LIBRARY

03_practneurol235218.indd 403_practneurol235218.indd 4 1/12/2011 1:49:19 PM1/12/2011 1:49:19 PM

5Howard, Holmes, Koutroumanidis

www.practical-neurology.com

INTRODUCTIONNeurologists are frequently asked to assess patients on intensive care units (ICUs) who have sustained hypoxicischaemic brain injury as a consequence of cardiac arrest or hypoxia during surgery or critical illness. Intensivists expect not only a prognosis for meaningful functional recovery but also guidance on management and, often, a con-tribution to communication with relatives. Although the assessment remains primarily clinical, it also requires the use of ancillary investigation. But, even so, it remains beset by the limitations in the sensitivity and speci-fi city of both the clinical and investigational tests, which is made even more diffi cult by the use of ever more sophisticated tech-niques of sedation, ventilation, hypothermia, neuromuscular blockade and haemodynamic management. This means that the traditional clinical indicators of prognosis, including brainstem refl exes and limb responses to noxious stimuli, are of less value than they once were.

The cost of inpatient care for hypoxicischaemic brain injury is enormous, both in the ICU and afterwards for survivors. There is therefore an urgent need for improved ways of reliably assessing prognosis in the early stages of ICU care and identifying those patients with a potentially favourable out-come and those where further efforts would be fruitless.1 The outlook for meaningful recovery of function is poor despite recent developments in resuscitation and intensive care. For example, of patients who have an in-hospital arrest, less than 40% even achieve successful restoration of spontaneous circu-lation, and


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inter alia, to failure of autoregulation. It is therefore important to maintain a relatively high mean arterial blood pressure (80100 mm Hg) with crystalloid infusion or vaso-pressor agents. Severe cerebral oedema is rare following

hypoxicischaemic brain injury but, when present, raised intracranial pressure (ICP) will further compromise CBF and may provoke herniation. ICP should be main-tained below 20 mm Hg and, if raised ICP is suspected clinically, treatment is with head positioning up, osmotherapy (mannitol, hypertonic saline), controlled hyperventilation and metabolic control (ie, treatment of fever, shivering, seizures, hypoglycaemia and hypokalaemia). There is no evidence to justify the use of direct ICP measurement.

Following successful resuscitation and transfer, the initial aims of management are to establish haemodynamic stability, and adequate tissue oxygenation, and to prevent secondary cerebral damage due to hypotension.

Intubation will usually have been under-taken and ventilation established by the time of admission for out of hospital incidents.

Sedation (eg, midazolam, fentanyl) will reduce the stress of procedures and facili-tate ventilation; neuromuscular blockade is occasionally necessary, particularly if therapeutic hypothermia is used.

Intensive care management following cardiac arrest or profound hypotensionAfter successful resuscitation there is a brief period of brain hyperaemia followed by reduced CBF (no-refl ow)8 9 as a result of microvascular thrombotic occlusion leading,

Table 1 Causes of hypoxicischaemic brain injury

Cardiac arrestProfound hypotension associated with: Pulmonary embolism Surgery Shock Sepsis Metabolic encephalopathy Drug overdoseHypovolaemia due to blood loss

Table 2 Causes of hypoxic brain injury

Suffocation (eg, smothering, gagging, anaphylaxis)Airway obstruction (eg, bolus, aspiration, manual compression of trachea)Strangulation (eg, neck constriction, manual strangulation, garrotting, mugging, hanging)DrowningChemical exposure (eg, carbon monoxide)

Table 3 Factors affecting the prognosis following cardiac arrest

Duration of arrest Precise duration of cessation of blood fl ow to the brain is the most important factor in determining outcome (ie, for 6 min or longer indicates poor prognosis)

Age Older patients have worse prognosisComorbidity Poor prognosis associated with comorbidities, including cardiac and

cerebrovascular disease, diabetes, obesity and renal diseaseCircumstances of arrest Out of hospital cardiac arrest carries a much worse prognosis than

in-hospital arrestWitness/immediate bystander resuscitation Prolonged unwitnessed pulseless arrest suggests a poor prognosisEffective cardiopulmonary resuscitation Effective chest compression is needed to maintain effective cardiac outputEarly attendance of paramedics Early defi brillation is associated with an improved prognosisCardiac rhythm Ventricular tachycardia/fi brillation are associated with a better prognosis

than pulseless electrical activity or asystoleResuscitation Duration, number of defi brillations, boluses of norepinephrine or atropine,

regaining pulse during the fi rst 10 min of resuscitationFever within fi rst 48 h Associated with worse prognosisAdvanced directive Advanced directives will infl uence the extent and duration of resuscitation,

and so the outcome




Blood sugar control is controversial (hypoglycaemia may reduce CBF); it is reasonable to aim for normoglycaemia.10

Fever and seizures, both of which increase metabolic demand on the brain, should be treated aggressively.

Neuroprotective agents have not been shown to be valuable.

After restoration of spontaneous circula-tion, systemic coagulopathy can occur, com-monly due to an increase in cytokines without adequate activation of endogenous fi brin-olysis. Aspirin should, therefore, be given on admission.

Induced hypothermiaA surprisingly good outcome can follow pro-longed cardiac arrest in hypothermic condi-tions (eg, drowning, severe hypothyroidism and survival in extremely cold climates). This observation led to the use of induced controlled hypothermia following cardiac arrest associated with ventricular fi brillation. Hypothermia causes a decrease in CBF and a consequent reduction of cerebral metabo-lism. A meta-analysis of randomised trials has shown that treated patients are more likely to be discharged with no or minimal neurologi-cal damage (relative risk 1.68) which translates into a number needed to treat of six patients.11 However, hypothermia can be diffi cult to apply and uncomfortable, patients require sedation and a neuromuscular blocking agent (vecuronium or pancuronium) to prevent shiv-ering, and so the technique is restricted to patients in coma. Complications include car-diac arrhythmias which develop if tempera-ture is 6 h. There are no spontaneous limb move-

ments or localisation to painful stimuli in the initial stages.

There is prolonged loss of pupillary responses (provided atropine has not been administered).

There is sustained conjugate eye deviation (upgaze or downgaze).

There are specifi c forms of abnormal eye movements (eg, upbeat and downbeat nystagmus, ping pong gaze or period alternating nystagmus).

There are myoclonic seizures. Lower cranial nerve function is involved

(eg, absent cough and gag refl exes).However, it must be emphasised that these

days the early assessment of the post-resus-citation state is unreliable for the reasons dis-cussed above and fraught with confounding factors that prevent the clinician being able to present a clear prognosis for outcome.

The assessment of coma has been reviewed in detail elsewhere. The conventional method used over many years has been the Glasgow Coma Score. This has proved valuable, robust and reproducible but it was designed to monitor patients with head injury and is not thorough or detailed enough to permit accu-rate assessment of medical causes of coma. Widjicks has introduced a wider ranging scale which corrects many of the omissions of the Glasgow Coma Score and may prove more sensitive and specifi c for recognising change in the conscious state of patients in coma due to hypoxicischaemic brain injury (the full outline of unresponsiveness (FOUR) score)13 (table 4).

Prognostic models to predict outcomeVarious prognostic models based on clini-cal fi ndings have been widely quoted, but



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not widely used, over many years.1419 None has adequate sensitivity or specifi city to be of value in determining management and, in particular, to guide when to abandon efforts to continue support in the hope of even-tual improvement. Most clinical algorithms depend on brainstem refl exes (particularly the absence of pupillary light, corneal and oculocephalic refl exes), spontaneous eye movements and motor responses (spontane-ous and evoked to painful stimuli) but each one of these has limitations in patients who are sedated.

More accurate predictive models, which include neurophysiological observations, have been proposed but these are diffi cult to con-struct because large numbers of patients must be included in any prospective study, and of course any prognostic model must be vali-dated in an independent data set. These mod-els may also be infl uenced by the use of early sedation.

In summary, a poor prognosis is likely, in the absence of sedating medication, which these days is unusual, if the corneal and pupillary light refl exes and motor responses are absent at 24 h and 72 h.

Epileptic seizuresFocal or generalised convulsive tonicclonic seizures are relatively unusual in the initial stages following hypoxicischaemic brain injury, but they may appear during the recov-ery period. Their occurrence implies severe but incomplete damage to the cortical and subcortical structures. Prolonged generalised seizure activity may not always be apparent in coma because of limited facial, limb or trunk movements due to sedation or damage to the motor pathways. Moreover, ictal movements may be restricted to blinking, fi xed or vary-ing eye deviations, or small repetitive facial or limb movements which are easily overlooked. Even non-convulsive status epilepticus may be missed for similar reasons. Generalised repeti-tive trunk and limb movements are not always ictal and may be due to brain stem shivering or the effects of medication.

Spontaneous, unrelenting generalised multifocal myoclonus (post-hypoxic myo-clonic status) may develop immediately after resuscitation when it typically causes bilateral synchronous local or generalised jerking of the face, limbs, trunk or diaphragm. The EEG shows limited background activity with a burst

Table 4 FOUR score (Full Outline of UnResponsiveness)

Eye response 4 Eyelids open, tracking or blinking to command3 Eyelids open but not tracking2 Eyelids closed but open to a loud voice1 Eyelids closed but open to pain0 Eyelids remain closed with pain

Motor response 4 Thumbs-up, fi st or peace sign3 Localising to pain2 Flexion response to pain1 Extension response to pain0 No response to pain, or generalised myoclonic

statusBrainstem refl exes 4 Normal pupil and corneal refl exes present

3 One pupil wide and fi xed2 Pupil or corneal refl exes absent1 Pupil and corneal refl exes absent0 Absent pupil, corneal and cough refl ex

Respiration 4 Not intubated, regular breathing pattern3 Not intubated, CheyneStokes breathing

pattern2 Not intubated, irregular breathing pattern1 Breaths above ventilator rate0 Breaths at ventilator rate, or apnoea

Focal or generalised convulsive tonicclonic seizures are relatively unusual in the initial stages




coma and interval between resuscitation and EEG recording. In the initial stages following resuscitation there may be electrical silence but distinct rhythms may gradually evolve which guide prognosis.

Several systems of classifi cation of the EEG in coma have been proposed but none can predict outcome with complete reliabil-ity. Reactivity of the EEG to external stimuli is more important than the dominant frequency alone; the presence of reactivity indicates a better prognosis (fi gure 1). A number of pat-terns suggest a poor prognosis including26: Generalised electrical suppression; elec-

trocerebral silence or generalised voltage suppression below 10 V for >24 h in nor-mothermic patients who are free of toxic ingestion or pharmacological sedation is the only reliable indicator that there is no chance of meaningful recovery.

Generalised burst suppression (fi gure 2) in a non-sedated patient indicates severe injury of the thalamus, cortex or their connections. It is associated with fatal outcome or vegetative state, particularly when bursts consist of epileptiform activ-ity (recovery has been reported when the pattern is present early and transiently after resuscitation).

Post-anoxic status epilepticus, either myoclonic (fi gure 3) or non-convulsive, (associated with periodic lateralised or

suppression pattern and intermittent genera-lised periodic complexes with no cortical focus. It responds poorly to medication and carries a uniformly poor prognosis.20

Another form of myoclonus (LanceAdams syndrome) can start 2448 h after resus-citation. It often follows a primary respira-tory arrest or anaesthetic event and tends to occur at a younger age than post-hypoxic myoclonic status. Consciousness is usually less deeply impaired, and focal myoclonus is often action or startle sensitive. The progno-sis is generally favourable and these patients continue to improve over time although cer-ebellar signs including ataxia, dysarthria and intention tremor may persist.21 The EEG shows a focal cortical origin with responsive cortical rhythms which progressively regain normal patterns. It responds reasonably well to anti-epileptic drugs including valproate, piracetam, levetiracetam and clonazepam.22

INVESTIGATIONSEEGThe EEG has been widely used over many years to assess the level of consciousness and to guide prognosis after hypoxicischaemic brain injury.2326 However, the appearances are infl u-enced by confounding factors, including med-ication, metabolic derangements and sepsis that bear upon the level of arousal, duration of

Figure 1Responsive cortical rhythms in a 37-year-old man after cardiac arrest. He showed no overt response to auditory stimuli but grimaced in response to noxious stimuli. Background rhythms consisted of a mixture of slow and faster frequencies and he responded to noxious stimuli (arrow). Note that faster rhythms slightly enhance immediately after the stimulus and the underlying slow rhythms attenuate for a while (34 s later), suggesting a change of vigilance. The presence of faster frequencies with spontaneous fl uctuation and reactivity to external stimuli are important predictive features. This patient was successfully discharged from hospital with minimal cognitive impairment.



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diffuse epileptiform discharges (PLEDs or Bi-PLEDs)) is considered a predictor of fatal outcome; occasionally, however, if EEG reactivity is preserved, such patients may have a favourable outcome with aggressive management.

Complex partial seizures or non-convul-sive complex partial status may also occur

(fi gure 4), often without associated clini-cal manifestations. The prognosis depends on the extent of cortical involvement.

Alpha coma consists of diffuse or fron-tally predominant, unresponsive rhythms with fi xed and unwavering alpha fre-quencies occasionally extending into the theta range (fi gure 5). It indicates a grave

Figure 2Three days after cardiac arrest post-anoxic myoclonus associated with burst suppression pattern on video EEG. The patient had continuous twitching of his facial muscles and of his upper body and arms throughout this test. He died 2 days after the recording. Note the ongoing diffuse and bilaterally synchronous bursts of spikes/polyspikes and their association with the recorded myoclonus (bottom tracing); EEG discharges are separated by intervals of generalised attenuation of all activity lasting for 0.51 s with the pattern being non-reactive to external noxious stimulation, including suction.

Figure 3Post-anoxic lateralised myoclonic status in a 54-year-old comatose man. Note the periodic epileptiform complexes over the left hemisphere (periodic lateralised epileptiform discharges (PLEDs)) that invariably precede the time locked electromyography potentials recorded from the right forearm (lowest trace). In between the PLEDs there is low voltage 16 Hz activity. The whole pattern, including the rate of the discharges, remained unresponsive to noxious stimuli, including suction (performed here between the two arrows).




Figure 4Non-convulsive complex partial status epilepticus. The EEG shows ongoing subclinical seizures over the right temporal areas without clinical accompaniments on video.

Figure 5Alpha/beta coma pattern. Note the diffuse unremitting low voltage rhythmic 1016 Hz activity that showed no response to external noxious stimuli, including suction (arrow); there were no changes in the ECG either. A follow-up EEG 7 days later off sedation showed only sparse low voltage activity, a stage before complete electrical suppression. The patient died 1 day later. The EEG changes seen during noxious stimulation are artefactual.

prognosis with about a 90% probability of death or vegetative state.

Somatosensory evoked potentialsShort latency somatosensory evoked poten-tials (SSEPs) are valuable in assessing prog-nosis because they provide information about the integrity of the afferent pathways via the

brainstem and thalamocortical projections to the primary somatosensory cortex. They are also less susceptible than the EEG to sedative drugs, metabolic factors and sepsis. Subcortical involvement is refl ected by slowing of the cen-tral conduction time and reduction of the N20 amplitude, while cortical injury causes absence of N20 only when there is extreme damage.

Short latency somatosensory evoked potentials (SSEPs) are valuable in assessing prognosis



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Bilateral absence of the cortical N20 response, in the absence of known pre-existing cortical lesions is interpreted as widespread cortical injury after cardiac arrest with a high speci-fi city for poor outcome.27 However, a normal N20 has poor accuracy for predicting good outcome.

Long latency SSEPs (N70) are thought to refl ect complex corticocortical connections important for intellectual functions, and their presence has been associated with a good outcome28; however, the predictive value of their absence for poor outcome is less certain than the N20.

ImagingIn the fi rst 2 days after hypoxicischaemic brain injury, CT may show diffuse swelling with effacement of the basal cisterns, ven-tricles and sulci, attenuation of the greywhite matter interface29 and hypodensity of the cortical grey matter and basal ganglia (caudate, lenticular nucleus, thalamus and putamen) due to cytotoxic oedema. There is also hypodensity of the white matter due to distension of the deep medullary veins and consequent obstruction of the cerebral venous drainage. Focal areas of infarction may develop in the basal ganglia or cortical boundary zone territories.

MRI is undertaken less commonly because patients often require sedation, ventilation and airway protection and, therefore, transfer to and from radiology departments is diffi cult, but it may be particularly helpful in revealing

the extent of damage. In the fi rst few days, diffusion weighted imaging (DWI) and fl uid attenuated inversion recovery (FLAIR) images show widespread hyperintensity, initially involving the basal ganglia, caudate, stria-tum and thalamus followed by the cortex and subcortical white matter, cerebellum and hippocampus.22 30 Conventional T1 and T2 weighted scans are normal. Diffusely abnor-mal fi ndings on DWI and FLAIR correlate with a poor outcome.31 32 Apparent diffusion coef-fi cient (ADC) mapping may add greater preci-sion with severe reduction in whole brain ADC predicting a poor outcome.

In the subacute phase (720 days) there is progressive resolution of brain oedema with disappearance of DWI hyperintensity (pseu-do-normalisation). Extensive basal ganglia, cortical and hippocampal grey matter change is seen on FLAIR and T2 weighted images but white matter hyperintensity may also develop on T2 weighted images. Similar changes are seen after predominantly hypoxic brain injury (fi gure 6). Figure 7 shows subacute changes after hypoxicischaemic brain injury. High signal persists on DWI but extensive changes are seen on T2 and FLAIR. The ADC shows pseudo-normalisation in the deep gray matter but restricted diffusion persists in the occipi-tal and perirolandic cortex. Rarely, there may be extensive, diffuse white matter change without involvement of the deep grey matter (fi gure 8).

In the chronic phase there is diffuse atro-phy. T1 and T2 sequences may show cortical

Figure 6Isolated hypoxic brain injury is usually caused by asphyxia such as after strangulation. Deep grey matter caudate, putamen and thalami show high signal on T2 MRI.




laminar necrosis (ie, cell death involving layers III and IV of the cortical mantle).

Infarction in boundary zone territories between the anterior, middle and posterior cerebral arteries (fi gure 9) and within the cer-ebellum often follows the more limited hypop-erfusion which may occur during prolonged cardiac bypass.

It has been suggested that DWI hyperinten-sity restricted to the thalamus and selected cortical regions occurs after primary hypoxic injury but otherwise any imaging changes are diffi cult to distinguish from hypoxicischae-mic injury. Delayed leucoencephalopathy may occur weeks or months after the initial insult and is more common after carbon monoxide poisoning or isolated hypoxic brain injury.

BiomarkersSeveral blood tests have been suggested as markers of neuronal damage in hypox-icischaemic brain injury. Neuron specifi c

enolase has been widely used after head injury, encephalitis and status epilepticus but data are confl icting following hypoxicischaemic brain injury. Although several prognostic studies have shown that signifi -cantly raised neuron specifi c enolase levels (>80 ng/ml) at days 14 post-resuscitation accurately predict poor outcome, there remains uncertainty about sensitivity and specifi city.33 The role of S100 as a prognostic marker is unproven.34

ASPECTS OF CLINICAL MANAGEMENTAs always in neurology, it is essential to take a meticulous history, from witnesses and fam-ily in this context, about any previous medical problems and the circumstances of the acute event and resuscitation. In the ICU situation this is often both diffi cult and distressing, and is therefore frequently neglected by the admit-ting medical and nursing teams.35 In patients

Figure 7After hypoxicischaemic brain injury, MRI changes include high signal in the caudate and putamen, less so in the thalami, with restricted diffusion on ADC in the occipital regions and perirolandic cortex. ADC, apparent diffusion coeffi cient; DWI, diffusion weighted imaging; FLAIR, fl uid attenuated inversion recovery.

It is essential to take a meticulous history, from witnesses and family



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who have been treated with hypothermia, or there is renal or hepatic impairment, the metabolism of sedatives and neuromuscu-lar blocking drugs is unpredictable and often delayed, making history taking even more diffi cult. The most valuable assessment of the

deeply unconscious patient is response to painful stimuli in the cranial nerve ter-ritory. The initial resulting limb response may be limited and it is often necessary to have another observer hold the limbs to feel whether fl exion or extension develops following noxious stimulation. A genera-lised fl exion response, however limited, is

perhaps the most helpful indicator that a good outcome is possible but this needs to be interpreted with caution depending on the coexisting circumstances, includ-ing the delay after the hypoxicischaemic event and the presence of coexisting sys-temic factors such as organ failure.

Always consider the possibility that the patient is locked-in where there is preser-vation of consciousness despite complete paralysis of cranial nerve and limb muscu-lature. Any residual responsive eye move-ments must be intensively sought.36

Ancillary investigations play an impor-tant role in the assessment and have

Figure 8Diffuse white matter high signal following hypoxicischaemic brain injury. ADC, apparent diffusion coeffi cient; DWI, diffusion weighted imaging.

Always consider the possibility that the patient is locked-in




traditionally been underused. As described above, MRI, EEG and SSEPs can provide detailed, accurate and reliable informa-tion about the distribution and severity of hypoxicischaemic brain injury.37

Inexperienced neurologists often feel pressurised to provide an instant and defi nitive prognosis. Often this is impos-sible in the early stages. Repeated clini-cal assessment may be necessary before the outcome can be predicted. Also, it is necessary to wait for any effects of medi-cation, hypothermia, sepsis and intercur-rent metabolic effects to resolve. As a rule, it is extremely diffi cult to provide a clear prognosis within 3 days of the acute event unless the initial insult was clearly overwhelming. If a clear prognosis can-not be determined, the patient should be monitored regularly with the ICU team. In practice a critical decision is whether an oropharyngeal tube should be replaced by

a cuffed tracheostomy which makes pro-longed survival more likely even if venti-latory support is reduced or withdrawn. This decision therefore requires very careful consideration between intensiv-ists, neurologists and the patients family. However, the decision to undertake tra-cheostomy does not have to be made in the acute stages and can often be delayed for several days. It is important to empha-sise that the decision to reduce or discon-tinue support cannot be rushed and all members of the team and the family must be in agreement with the management decisions.

It is important to maintain a clear and consistent approach in talking to rela-tives. A single doctor should lead the discussion. It is common for relatives to receive different opinions, confl icting advice or simply confusing and incom-plete information from different doctors.

Figure 9After severe circulatory compromise (eg, during problematic cardiac surgery), a pattern of boundary zone ischaemia and infarction often occurs. MRI shows high signal on T2 and FLAIR in these regions as well as restricted diffusion on ADC and high signal on DWI. ADC, apparent diffusion coeffi cient; DWI, diffusion weighted imaging; FLAIR, fl uid attenuated inversion recovery.

The decision to reduce or discontinue support cannot be rushed



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partially or totally reversible, or may progress to permanence or death.

The vegetative state can be considered permanent 3 months after injury but this fi gure is arbitrary and late recovery has been reported.3941 It can only be recognised on the basis of exhaustive clinical assessment. Recent functional imaging studies have shown patchy preservation of cognitive activity, including some apparent responsiveness, which indi-cates that our understanding of these states is still uncertain.42 43 Furthermore, it is clear that patients previously thought to be vegetative have varying degrees of awareness and, rarely, might even be locked-in. We have previously emphasised the importance of excluding this possibility by detailed and repeated examina-tion and EEG.

Progression from the vegetative state occurs with some patients regaining awareness and the development of appropriate responses. The minimally aware state (minimally conscious state)44 is characterised by the ability to follow a single command, to exhibit a gesture or ver-bal response to yes/no questions, the presence of intelligible verbalisation and responsive behaviours that are not refl exes or sustained visual pursuit to moving objects. The neurolo-gist must be sure that any problems are not a manifestation of severe motor weakness or of a partial locked-in state.

Movement disordersA variety of movement disorders may develop after hypoxicischaemic brain injury because the basal ganglia are particularly vulnerable. The pattern depends to some extent on the age of the patient and the severity of the insult. In younger patients with predominantly hypoxic brain injury, dystonia develops after several weeks, thought to be due to putaminal damage. In older patients with predominantly ischaemic insults, an akinetic rigid syndrome may develop as a consequence of pallidal damage. The onset of movement disorder may be delayed by sev-eral months, developing after a period of rela-tive stability, more often in young patients.36

Boundary zone infarctionBoundary zone infarction is associated with hypoxicischaemic brain injury due to cardiac arrest. It also occurs after prolonged cardiac bypass associated with hypotension and here may be in part due to multiple emboli and not

As neurologists, our fi rst responsibility should be to communicate with intensive care colleagues so that, as a team, we can all provide clear and decisive leadership and guidance to the patients families.

LONG TERM IMPLICATIONSFollowing resuscitation the patient with hypox-icischaemic brain injury generally remains in a coma for several days although rarely this may persist for longer. Even if the level of con-sciousness improves, many patients remain in a vegetative or minimally aware state for prolonged periods. Recovery is then associ-ated with a variable level of residual cognitive impairment.38

Impaired level of consciousnessPatients who have sustained a relatively mild hypoxicischaemic brain injury will regain consciousness within a few hours or, at most, 1 or 2 days. However, if the insult is more severe, recovery from coma is less certain and much slower, even in the absence of persist-ing metabolic, infl ammatory, toxic or infec-tious factors which might prolong coma. There is usually improvement over 24 weeks to a state of wakefulness with eyes opening, but persisting impaired or absent awareness of self or environment. This vegetative state may be

PRACTICE POINTS

Hypoxia and ischaemia are distinct mechanisms of brain injury but they usually coexist.

Ischaemic brain insults are more likely than hypoxic insults to cause perma-nent neurological sequelae.

The events surrounding cardiac arrest and resuscitation are critical in deter-mining outcome; these include the initial insult, the effectiveness of imme-diate resuscitation and transfer, and the post-resuscitation management on the ICU.

Clinical assessment of patients within 72 h of hypoxicischaemic brain injury remains a valuable guide but must be interpreted with caution, par-ticularly if the patient has been sedated at any time.

Neurophysiological tests are an important adjunct to diagnosis and deter-mining prognosis; there are some characteristic patterns which suggest a poor prognosis.

Brain imaging changes develop soon after hypoxicischaemic brain injury; MRI (particularly DWI) may show the extent and severity within 24 h.

The pattern of residual neurological sequelae is highly variable, ranging from subtle neurocognitive defi cits to severe permanent impairments in the level of awareness.




just hypotension. The vulnerable border zone regions lie between the territories of brain supplied by the three major cerebral arter-ies.45 The distribution and severity of clinical involvement is determined by the extent of the hypoxicischaemic insult and any under-lying stenosis or occlusion of the cervical and intracranial vessels (eg, unilateral boundary zone infarction may develop distal to severe disease of one internal carotid artery). Various clinical syndromes have been described.45

Cognitive impairmentThe pattern of cognitive problems in those who survive ranges from subtle impairment of recall to severe intellectual defi cits. Memory function is preferentially impaired, particu-larly spatial and verbal memory and recall. Following a brief period of circulatory arrest the patient may be transiently confused or develop a severe Korsakoff-like amnesic state with profoundly impaired recall and recogni-tion but retained short term memory. Amnesia following cardiac arrest is associated with lim-ited lesions affecting the hippocampi bilater-ally with little cortical damage.46 47 Recovery after more prolonged arrest is associated with intellectual defi cits, including disorders of attention, orientation, insight and judgement.

Delayed post-hypoxic leucoencephalopathyThis is a rare condition which was initially thought to follow only carbon monoxide poi-soning. However, it is now recognised after other insults causing primarily hypoxic injury (table 1). Patients seem to have made a com-plete recovery from hypoxic coma with nor-mal cognitive function for 14 weeks before a relapse occurs with cognitive deteriora-tion, frontal lobe (urinary incontinence and gait disturbance) and extrapyramidal signs (short stooping gait, parkinsonian expression and rigidity).48 T2 MRI shows extensive white matter change and involvement of the basal ganglia. Up to 50% are said to make a good recovery but residual cognitive and extrapyra-midal defi cits are also common and this syn-drome may even culminate in an unresponsive vegetative state.

ACKNOWLEDGEMENTSThis article was reviewed by Heini Mattle, Berne, Switzerland.

Competing interests None.

Provenance and peer review Not commissioned; externally peer reviewed.

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Hypoxic Ishaemic Injury PN BMJ 2011

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