Adult hypoxic and ischemic lesions

TERMINOLOGY

Although ‘hypoxia’ (reduction in oxygen supply or impairment of its utilization) and ‘ischemia’ (reduction in blood supply) are often used interchangeably, and the term ‘hypoxic-ischemic encephalopathy’ is utilized widely in everyday practice, these conditions can have different etiologies, pathophysiologic mechanisms and clinical, as well as morphologic, sequelae in the CNS.

Hypoxia

Blood flow to the CNS may be entirely normal or even somewhat increased. The CNS is relatively resistant to pure hypoxia, but hypoxia

CEREBRAL BLOOD FLOW (CBF)

CBF = cerebral perfusion pressure (CPP)/cerebrovascular resistance (CVR)

CPP = systemic arterial blood pressure − intracranial pressure (ICP)

CBF is approximately 750 mL/min, representing 15% of cardiac output.

As long as mean CPP remains above approximately 5.3 kPa (∼ 40 mmHg), the tone of vascular smooth muscle in intracranial arteries and arterioles (and hence CVR) adjusts in response to changes in CPP to maintain CBF in a constant range of 50–55 mL/100 g/min in adults (the value is higher in children). This is the phenomenon of autoregulation.

Though overall CBF remains constant while CPP remains above the threshold for autoregulation, blood flow varies by anatomic region, according to demand for oxygen and glucose (largely dependent upon neuronal activity), a process described as functional hyperemia or neurovascular coupling. This variability of local blood flow is also used to advantage in functional MRI studies.

The density of capillaries is greater in gray than white matter, reflecting the pronounced difference in their metabolic requirements and resulting in a corresponding difference in blood flow:

• 80–100 mL/100 g/min in gray matter

• 20–25 mL/100 g/min in white matter.

If mean CPP falls below about 5.3 kPa, autoregulation becomes impaired or fails entirely, and CBF falls dramatically.

Threshold CBF for infarction in primate brain is estimated to be 10–12 mL/100 g/min.

exacerbates the damage produced by ischemia. In practice, many causes of stagnant or hypoxemic hypoxia (e.g. cardiac arrest and carbon monoxide poisoning, respectively) also depress cardiac output, resulting in combined hypoxic/global ischemic brain injury.

Global brain ischemia

This occurs with a pronounced decrease in cerebral perfusion pressure (CPP) to a level below the threshold required for optimal vascular autoregulation. Reduced systemic blood pressure or raised intracranial pressure produces such a deleterious reduction in CPP. Cardiac pathologies (producing arrest, dysrhythmia, or tamponade) or traumatic hemorrhage dominate the causes of reduced systemic blood pressure, but these are very varied. Severe head injury is a leading cause of raised intracranial pressure. Resulting brain damage is accentuated in watershed/borderzone regions, the boundaries between vascular territories, especially in the depths of sulci.

CELLULAR MECHANISMS OF ISCHEMIC CELL DEATH

Depolarization of neuronal/axonal membranes within 60–180 seconds of global anoxia leads to changes in extracellular and intracellular electrolyte composition and a decrease in ATP (secondary to impaired glycolysis and oxidative phosphorylation), with associated release of lactate and hydrogen ions and acidosis. ATP may decline to <25% of that in normally perfused tissue.

Ionic fluxes include increased potassium ions (K⁺) in the extracellular space and decreased extracellular calcium ions (Ca⁺⁺), with concomitant rise in intracellular Ca⁺⁺ by up to 25%, a process mediated in part by NMDA receptors.

Increased intracellular Ca⁺⁺ activates calpain and other molecules, with deleterious effects on cytoskeletal and membrane structures.

Mitochondrial injury secondary to Ca⁺⁺ influx causes further decrease in ATP, an increase in free radicals, and a progressive inability to buffer Ca⁺⁺ loads.

Cytoskeletal damage can affect the machinery of protein synthesis, but this may eventually recover.

Lipases, proteases and nucleases are activated, also with deleterious effects.

Free radicals and NO/peroxynitrite, a mediator of NO toxicity, increase.

Excitotoxic activation of glutamate receptors causes induction of heat shock proteins and rapid transcription of IE genes.

Local brain ischemia

This usually results from arterial stenosis and/or mural thrombosis, atheroemboli, or thromboembolic arterial occlusion, any resulting infarct being within the perfusion territory of an affected artery.

ROLE OF ASTROCYTES

Though preservation of neuronal function and circuitry is the goal of resuscitation after cardiac arrest, astrocytes have a major role in mediating either a suboptimal or excellent clinical outcome.

Neurons deplete stores of ATP more rapidly than astrocytes, but astrocytes (like neurons) can release vesicles that contain glutamate or ATP.

Astrocytes are a reservoir of glycogen (by comparison with neurons); during intense activity, astrocytes can convert glycogen to lactate and pass this substrate on to adjacent neurons as an energy source.

Astrocytes play a crucial role in modulating glutamate levels, thus affecting excitotoxicity during ischemic injury.

Astrocytes have a high density of glutamate receptors that may facilitate uptake of extracellular glutamate during hypoxia-ischemia, thus modulating excitotoxic neuronal injury.

REPERFUSION AFTER CIRCULATORY ARREST

After return of spontaneous circulation (following cardiac arrest), a short-lived hyperemia (15 min) is followed by hypoperfusion (‘no-reflow phenomenon’).

Microcirculatory abnormalities include narrowing of capillary lumens due to endothelial swelling (site of the blood–brain barrier/BBB) and perivascular cells; BBB permeability may therefore alter dramatically.

As soon as cerebral circulation is re-established, ‘reperfusion injury’ may occur – with free radical formation, NO toxicity, glutamate release and dramatic calcium shifts.

Edema and microhemorrhages may result.

PATHOPHYSIOLOGIC CONSIDERATIONS

Adult and infant brains react differently to hypoxia and ischemia. In general, infant brains are more resistant than those of adults; hypoxic-ischemic lesions have a different distribution in infants and adults reflecting an age-related differential (selective) vulnerability to such insults (Fig. 8.1). Because of the brain’s immense metabolic demands, after the onset of ischemia levels of brain glycogen, glucose, ATP and phosphocreatine plummet and are often depleted within 10 min of the acute event. After 15 min of cardiac arrest, up to 95% of the brain may be damaged. Primary respiratory arrest (e.g. due to aspiration, anaphylaxis, or airway trauma) may cause transient brain dysfunction, but less severe damage than ischemia. Optimal brain function and respiration are dependent upon the availability of glucose; however, the neuropathology of hypoglycemic brain injury differs from that due to hypoxia-ischemia.