Cerebral protection

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Chapter 45 Cerebral protection

Victoria Heaviside, Michelle Hayes

The cerebral circulation is arguably the most important and most vulnerable in the body. Arrest of the circulation for only a few minutes can cause neuronal death. The concept of cerebral protection has been engaged across a broad spectrum of clinical scenarios. It has been incorporated into the prophylaxis, treatment and subsequent management of ischaemia and infarction and even into attempts to ameliorate postischaemic or anoxic damage following cardiorespiratory resuscitation. A complete review is beyond the scope of this chapter, but an understanding of the current approaches to cerebral protection is certainly helpful in the management of cerebral insults.

NORMAL BRAIN PHYSIOLOGY

The brain has a high energy requirement, utilisng approximately 3–5 ml O2/min per 100 g tissue (45–75 ml O2/min per 1500 g brain) and 5 mg glucose/min per 100 g tissue (75 mg glucose/min per 1500 g brain). It has little ability to store precursors of metabolism and thus depends on a constant supply of nutrients from the blood.

At a cerebral blood flow (CBF) of 50 ml/min per 100 g tissue (750 ml/min per 1500 g brain) and a normal oxygen content of 20 ml O2/100 ml blood, the brain receives approximately 150 ml O2/min per 1500 g brain, or 2–3 times the amount needed for normal brain activity.

At the same CBF of 50 ml/min per 100 g tissue and a blood glucose concentration of 5.5 mmol/l (100 mg/100 ml blood), there is 50 mg/min per 100 g tissue (750 mg/min per 1500 g brain) delivery of glucose. Glucose extraction by the brain, at 5 mg/min per 100 g brain tissue, is a tenth of that delivered – minimal compared with oxygen.

Cerebral injury has many aetiologies, but the mechanisms of injury are thought to be few. The most common is lack of the essential nutrients, oxygen and glucose, either separately with preserved blood flow (i.e. hypoxia or hypoglycaemia), or together, because of reduced or absent perfusion (i.e. ischaemia or infarction). A reduction in these energy precursors is a major contributor in the mechanism of brain injury, regardless of the aetiology.

NATURAL PROTECTIVE MECHANISMS

The importance of the brain to the whole being is highlighted by the mechanisms in place to protect the cerebral elements from ischaemia.

COLLATERAL BLOOD SUPPLY

An elaborate vascular architecture is designed to ensure adequate CBF. The anterior cerebral circulation is provided by bilateral internal carotid arteries as they each divide into anterior and middle cerebral arteries. They provide approximately 70% of the cerebral circulation and supply the anterior cerebrum (frontal, parietal and temporal lobes) and anterior diencephalon (basal ganglia and hypothalamus). The remaining 30% of the cerebral circulation is provided posteriorly by the vertebrobasilar system which runs the length of the posterior fossa, supplying the brainstem, cerebellum and posterior portion of the cerebrum (occipital lobes) and diencephalon (thalamus). These two circulations are joined by communicating arteries, ultimately forming the circle of Willis (Figure 45.1). This joining of the anterior and posterior circulations at the base of the brain is the major component of cerebral vasculature in humans. Between these arterial distributions are watershed zones fed by leptomeningeal connections. In addition, persistent fetal arteries can infrequently provide collateral routes between the anterior and posterior arterial systems in the brain.

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Figure 45.1 Circle of Willis.

CEREBRAL BLOOD FLOW

CEREBRAL PERFUSION PRESSURE

The amount of blood delivered to the brain is highly regulated and is determined by several factors. CBF is determined in part by the perfusion pressure across the brain, called cerebral perfusion pressure (CPP). CPP, is the difference between the arterial pressure in the feeding arteries as they enter the subarachnoid space and the pressure in the draining veins before they enter the major dural sinuses. Because these pressures are difficult to measure, CPP is derived from the difference between the systemic mean arterial pressure (MAP) and the intracranial pressure (ICP), which is an estimate of tissue pressure.

The cerebral vessels change diameter inversely with changing perfusion pressure: as CPP rises, the vessels constrict and as CPP falls the vessels dilate, such that blood flow is kept constant over a wide range of CPP (Figure 45.2a). This pressure autoregulation is thought to be controlled by local myogenic responses of the vessel wall to changes in intra-arterial pressure. At pressures above and below this range of 6.7–20 kPa (50–150 mmHg), cerebral perfusion becomes pressure-passive and increases or decreases in direct proportion to changes in CPP. The autoregulatory range varies with age, being shifted to the left in newborns and to the right in those with chronic hypertension. The latter is important to remember to avoid overtreating systolic blood pressure in such patients and thus incur the risk of cerebral ischaemia at the lower limits of autoregulation. Alternatively, cerebral perfusion above normal can be caused by acute hypertension overcoming the upper limits of autoregulation. This may lead to cerebral oedema secondary to increased hydrostatic pressures (hypertensive encephalopathy) and potentially lead to seizures or cerebral haemorrhage.

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Figure 45.2 (a) The relationship between the partial pressure of oxygen (PO2) and carbon dioxide (PCO2) and cerebral blood flow (CBF). (b) The relationship between mean arterial pressure (MAP) and cerebral blood flow under normal circumstances, illustrating the range of autoregulation.

PaO2 AND PaCO2 EFFECTS

A second group of factors control CBF through an influence on the local metabolic milieu. Prominent in this mechanism are oxygen and carbon dioxide. Arterial content or partial pressure of oxygen in the normal or hyperoxic ranges causes very little change in CBF. Perhaps this represents a demand for another nutrient (i.e. glucose) or a need to remove waste products (i.e. carbon dioxide or metabolic acid). With the onset of hypoxaemia (PaO2 60 mmHg or 8 kPa), there is a prompt increase in CBF proportional to the decrease in blood oxygen content, in order to maintain oxygen delivery constant (Figure 45.2b).

There is also a direct relationship between CBF and PaCO2, such that cerebral perfusion increases with increasing PaCO2 (Figure 45.2b). This probably represents the need of the brain to maintain homeostatic pH by removing metabolic breakdown products more efficiently by increased blood flow. Unlike the response to oxygen, the CBF response to changes in PaCO2 is dramatic in the physiological range, such that for every 0.13 kPa (1.0 mmHg) change in PaCO2 there is a 1–2 ml/min per 100 g tissue change in CBF. Therefore, an increase in PaCO2 to 10.6 kPa (80 mmHg) will increase CBF to approximately 100 ml/min per 100 g and a decrease in PaCO2 to 2.7 kPa (20 mmHg) will decrease CBF to 25 ml/min per 100 g. Thus:

• doubling PaCO2 doubles CBF
• halving PaCO2 halves CBF within this range

Understanding this basic physiology will make treatment logical (see below), as increases in CBF often lead to increases in cerebral blood volume, which in turn can increase ICP – a common cause of cerebral ischaemia.

CEREBRAL INJURY

Vascular insufficiency or disruption, trauma, tumour, infection, inflammation and metabolic and nutritional derangement can all cause damage. Whatever the cause, the mechanism of injury is usually hypoxic and/or ischaemic injury.

• Hypoxia is lack of oxygen.
• Ischaemia is lack of flow.

Therefore, it is possible to have high flow but no oxygen or, alternatively, no flow but plenty of oxygen. At the cellular level the consequence is the same.

The protective mechanisms afforded by the ability to increase CBF manifold in response to hypoxaemia and the generous oversupply of nutrients under normal conditions allow for sufficient blood flow, with maintenance of oxygen delivery and supply of other nutrients in many cases. Limitation in the ability to alter CBF, whether through cerebrovascular disease restricting perfusion or intracranial masses, oedema and increased ICP exerting excess local pressure, and altering blood flow, will cause hypoxic/ischaemic injury. Systemic problems such as severe or prolonged hypoxaemia will eventually disturb systemic circulatory homeostasis, leading to hypotension and eventual ischaemia. Thus hypoxic and ischaemic injury may be considered synonymous, although there may be aetiological differences between them. A more important distinction is to be made between global and focal hypoxic or ischaemic insults.

GLOBAL HYPOXIC/ISCHAEMIC INSULTS

These types of insult are caused by hypoxaemia and cardiovascular insufficiency or arrest, respectively. These are usually sudden, short and severe. If there is to be recovery, prompt return of oxygen delivery and spontaneous circulation are necessary. The recovery may be variable, depending on the severity and duration of the insult and the selective vulnerability of the cell types involved. Different mechanisms are responsible for reversible loss of cellular function and for irreversible cell death and there are also differences between the mechanisms that cause death of neurones, glia and endothelial cells. After 4–6 minutes of complete global ischaemia, there are signs of permanent histological damage in selective neuronal populations and the beginnings of neurological deficits in survivors. Outcome worsens significantly after 15 minutes of global ischaemia.1

FOCAL HYPOXIC/ISCHAEMIC INSULTS

These insults often occur suddenly but are usually of more prolonged duration. Only a subtotal of the brain is affected and the injury may be less severe if the surrounding brain is preserved by collateral blood supply.

The area of the focal ischaemia supplied by end-arteries will result in cell death unless reperfusion is established rapidly. The periphery of an infarcted area is the ischaemic penumbra. Here, CBF is greater than at the infarcted core, but less than in the normal tissue around it. Animal studies suggest that the time course for infarction and irreversible damage to brain from a focal hypoxic/ischaemic event is around 30–60 minutes. The focus of therapeutic intervention is the penumbral area, on the basis that if blood flow can be normalised in this region, or pharmacological agents can be delivered despite the reduced blood flow, there is a potential for recovery. Conversely, failure to maintain this area will result in a coalescing of the penumbra into the infarcted area, as the ischaemic stimulus continues.

It is likely that the ongoing ischaemic penumbral area of a focal insult and transient whole-brain ischaemia (e.g. during early cardiac arrest, low-flow cardiopulmonary resuscitation (CPR) or elevated ICP states) are subject to similar pathophysiological processes. As pretreatment is usually impossible, prevention and treatment of the secondary insults are the focus in neuroprotection and tissue salvage strategies.

BRAIN ISCHAEMIC AND INFARCTION PROCESSES

Changes in normal physiology begin to occur when blood flow is reduced.

• At CBF below 50 ml/min per 100 g neurological function is impaired and there is slowing of the electroencephalogram (EEG).
• A CBF of 15–25 ml/min per 100 g results in loss of electrical activity.
• A CBF between 10 and 15 ml/min per 100 g can maintain adenosine triphosphate (ATP) levels sufficiently to support ionic pump function for a time, despite the lack of electrical activity and normal neurological function.
• At a CBF of 10 ml/min per 100 g membrane failure occurs, due to a critical loss of ATP, which causes ionic imbalance between the cell and the extracellular milieu. If prolonged or worsened, CBF at this level will lead to permanent neurological impairment as a result of cell death.

EFFECTS OF ISCHAEMIA

Ischaemia results in reduced available oxygen and glucose to support aerobic production of ATP. Levels of ATP are depleted within 2–3 minutes of complete ischaemia (animal studies). There is little brain storage of either glucose or oxygen, and ATP production during ischaemia relies on anaerobic glycolysis for as long as stores last. This results in continued ATP use, but suboptimal production of ATP to fuel aerobic metabolism, so a lactic acidosis develops. Loss of ATP causes failure of membrane ionic pump function, leading to an efflux of potassium and an influx of sodium, calcium and chloride ions, the beginnings of cytotoxic oedema.

This begins a cascade of events resulting in eventual cell death:

• Potassium leakage causes cell depolarisation, ion channel opening and the release of excitatory amino acid (EAA) neurotransmitters (glutamate and aspartate and others).
• EAA cause further depolarisation of neighbouring cells and distal, otherwise unaffected, parts of the brain which result in:
• sodium and chloride influx via kainate (K) and quisqualate (Q) receptors (with water worsening intracellular oedema)
• calcium influx via N-methyl-D-aspartate (NMDA) receptors
• release of excitatory transmitters
• conversion of phosphorylases, uncoupling of oxidative phosphorylation, activation of proteases, degradation of cystosolic protein and stimulation of lipases. Lipases liberate arachidonic acid and other free fatty acids that cause tissue damage via production of oxygen radicals and prostaglandins

Other effects within the cell influence DNA and RNA production, hence inhibiting protein production. This may explain why cellular and clinical recovery is partial, even with restoration of ionic equilibrium and near-normal ATP levels after successful reperfusion. Necrosis is thought to occur in the core of the cerebral infarct following acute vascular occlusion, with further neurodegeneration occurring more slowly in the penumbra, by apoptosis or release of various immunological mediators.2

EXTRACELLULAR EFFECTS

Leukocytes are thought to be major contributors to reperfusion injury in that:

• they may plug up small capillaries under conditions of low blood flow and prevent reflow in certain areas, thus hindering restoration of perfusion
• they may enhance production of oxygen radicals and begin a cascade of inflammatory mediators, which may potentiate cell destruction in injured tissue

This results in tissue oedema, which may affect the core lesion by narrowing blood vessels and worsening chances of reperfusion. Local mechanical compression of tissue or its blood supply can cause deterioration in neighbouring tissue. The alteration in volume is of extreme importance in the adult brain because the cranial vault is non-distensible, preventing accommodation to an expanding lesion. This will impede CBF both locally and globally.

Hypoxic/ischaemic insults are rarely predictable, so that the process is usually well established when clinicians intervene. It is therefore highly likely that the injury will be only partially remediable.

MANAGEMENT

In neurological injury, the initial aims are to provide basic support. Assessment of the airway and respiration are the first priority, closely followed by optimisation of the circulation.

In cases of head trauma, it is very important to prevent secondary brain injury. Reviews of intensive care practice have resulted in recommendations for treatment in this group of patients.3 These involve:

• institution of monitoring
• early treatment of hypotension, hypoxia, hyperthermia and intracranial hypertension
• maintenance of CPP

Following stroke, it is also important to optimise homeostasis and address any hypertension, hyperglycaemia, hyperthermia and intracranial hypertension, as these are independent factors of a poor prognosis.

HYPERTENSION

Most patients have elevated blood pressure in the early phase after an acute ischaemic stroke. The mechanism and effects of this blood pressure elevation are not well understood and the benefits of intervention remain debated. Most experts would not advocate antihypertensive treatment in the acute phase after stroke, unless the blood pressure is particularly high. Currently hypertension (systolic blood pressure > 180 mmHg) should be treated if thrombolytics are to be administered, based on the trials involving these agents in which the blood pressure was lowered prior to treatment.4 Ongoing studies such as Blood Pressure in Acute Stroke Collaboration (BASC) should help define optimal management.

HYPERGLYCAEMIA

Hyperglycaemia has also been associated with an increased mortality and reduced functional outcome after stroke irrespective of whether the patient has a diabetic history or not.5 Proposed explanations for this are:

• Hyperglycaemia may be directly toxic to the ischaemic brain.
• Decreased levels and reduced peripheral uptake of insulin in these patients result in increased cerebral glucose availability which may impair endothethelial-dependent vasodilatation.
• Hyperglycaemia may indicate dysglycaemia, which is associated with vascular disease and endothelial dysfunction, both of which may exacerbate ischaemic damage at the time of stroke.

Hyperglycaemia may result in a hypercoaguable state, with decreased plasma fibrinolytic activity, which may delay reperfusion and increase haemorrhagic infarct conversion in tissue plasminogen activator-treated patients.6

Insulin, as well as having a glucose-lowering effect, has also been shown to be directly neuroprotective and this is the subject of a number of ongoing trials7 (Treatment of Hyperglycaemia in Ischaemic Stroke (THIS) trial, the Glucose Regulation in Acute Stroke Patients (GRASP) trial and the Glucose Insulin Stroke Trial UK (GIST-UK).

HYPERTHERMIA

An increased temperature increases cerebral metabolism, oxygen requirements, CBF and ICP. Hyperpyrexia following acute stroke adversely influences stroke severity, infarct size, functional outcome and mortality.8 A raised temperature should, therefore, be treated aggressively and any evidence of infection identified early and treated with appropriate antibiotics.

REVASCULARISATION

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