Treatment of Combined Acute Renal Failure and Cerebral Edema

Basic Pathophysiology of Cerebral Edema

In the normal, healthy adult, the skull acts as a rigid box, containing the brain (approximately 80% of the intracranial volume), with its vasculature (10%), and the cerebrospinal fluid (CSF) (10%). Because the skull is not compressible, the Monro-Kellie doctrine states that any increase in the volume of its contents will result in an increase in intracranial pressure (ICP), unless there is a compensatory reduction or displacement in the volume of the other components.

Intracranial volume can increase as a result of cerebral edema. Typically, cerebral edema is divided into cytotoxic and vasogenic edema. Cytotoxic edema develops as a consequence of neuronal and astrocyte cell swelling with maintenance of the integrity of the blood-brain barrier. Because glial cells outnumber neurons by 20:1, edema is mainly because of astrocyte swelling. Cytotoxic edema usually is caused by increased sodium (Na ⁺ ) and potassium (K ⁺ ) permeability of the cell membrane, energy depletion followed by failure of the energy-dependent ion pumps, the sustained uptake of osmotically active solutes, or some combination of these. In vasogenic edema, on the other hand, the integrity of the blood-brain barrier, comprising the endothelium and adjoining astrocytes, is disrupted, resulting in a protein-rich exudate with increased interstitial edema. Other causes of cerebral edema include interstitial edema that occurs in cases of severe hydrocephalus, wherein the CSF penetrates the adjacent brain because of the high CSF pressure, and osmotic cerebral edema, which is typified by the syndrome of inappropriate secretion of antidiuretic hormone, with an osmotic imbalance between the cerebral tissue and plasma.

ICP also can increase in association with increased cerebral blood volume, which can be caused by prolonged epileptiform neuronal activity, loss of vasoregulation resulting from disease, or physiologic stimuli such as hypercarbia or pharmacologic cerebral vasodilators. Similarly, hydrocephalus and space-occupying lesions can result in raised ICP.

Initially, the increasing intracranial volume is compensated by the combination of compression of the ventricles, displacement of CSF from the cerebral to the spinal subarachnoid space, increased CSF reabsorption by the arachnoid villi, and compression of the cerebral vasculature. CSF is produced in the choroid plexuses, mainly by the hydrostatic pressure gradient, so the CSF production rate falls as a result of the reduced arterial inflow and increased cerebral tissue pressure.

Because of these compensatory mechanisms, there is only a relatively small increase in ICP with increasing cerebral edema. However, eventually the buffering systems fail to compensate for further volume expansion, and then the ICP increases rapidly. This is shown in Fig. 131.1 . The ICP tracing shows not only a higher mean value but also the increasing pulse wave amplitude as the swollen brain becomes less compliant during systolic arterial inflow.

The rate of change of ICP with increasing intracranial volume depends on the cause of the cerebral edema. Slowly expanding mass lesions can be better compensated than rapidly evolving edema. Even so, the development of hypoxia and/or hypercarbia can lead to a sudden increase in ICP in a patient with a slowly expanding mass. Similarly, acute falls in mean arterial pressure (MAP), which lead to a reduction in cerebral perfusion, can trigger reflex vasodilatation with increased vascular flow and a secondary increase in ICP ( Fig. 131.2 ).

Patients at Risk of Cerebral Edema

In addition to patients with known space-occupying lesions (including tumors and abscesses), traumatic head injury, extradural or subdural hemorrhage, or acute intracranial or subarachnoid hemorrhage and those who have undergone neurosurgery, many medical patients are at risk of cerebral edema. These include patients with endothelial damage resulting from vasculitis, such as the primary small vessel vasculitides, including systemic lupus erythematosus, microscopic polyangiitis, and secondary forms of vasculitis associated with infections such as leptospirosis. Cerebral ischemia ranges from small-vessel occlusion associated with cerebral malaria; to thrombosis seen with thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, or antiphospholipid syndrome; to larger-vessel ischemia including acute embolic and/or ischemic stroke. Infections, particularly those causing generalized encephalitis or severe bacterial meningitis, may be complicated by severe cerebral edema. Prolonged epileptic seizures also lead to cerebral edema.

Metabolic causes of cerebral edema in adults generally are restricted to acute and acute-on-chronic liver failure, although, rarely, cerebral edema has been reported in chronic liver disease. Occasionally, runners develop cerebral edema on a hot day because of substantial retention of ingested water and renal failure caused by rhabdomyolysis and heat exhaustion. Patients can develop cerebral ischemia and edema after solid organ transplantation associated with abrupt changes in plasma sodium concentration and also related to immunophilin toxicity. Other drugs that can cause cerebral edema include the monoclonal antilymphocyte agent OKT3, and valproate (encephalopathy resulting from hyperammonemia), and occasionally night clubbers taking 3,4-methylenedioxymethamphetamine (MDMA) (ecstasy) in combination with unrestricted water consumption as a result of cerebral water intoxication.

In children, inborn errors of metabolism, including those affecting the urea cycle, may predispose to cerebral edema during times of stress and supplemental feeding. Similarly, cerebral edema may occur during the treatment of diabetic ketoacidosis, particularly in young children, which is associated with a rapid fall in plasma glucose. Acute kidney injury is not limited simply to the kidney; the inflammatory effect becomes systemic, as the kidney fails to effectively clear inflammatory cytokines and other mediators including damage-associated molecular patterns. The inflammatory response increases permeability of the blood-brain barrier, and the accumulation of azotemic toxins is controlled initially by brain astrocytes and pericytes, but once these homeostatic mechanisms have been overwhelmed, then changes in brain milieu develop, and as such the brain in patients with acute kidney injury is much more vulnerable to ischemic and other insults, including drug toxicity.

Supportive Management of Patients With Cerebral Edema