Neurological Intensive Care and Cerebral Protection
July 1, 1998 11 minutes read
Special Feature
Neurological Intensive Care and Cerebral Protection
By Charles G. Durbin, Jr., MD, FCCM
In the past several years, great strides have been made in our understanding of the physiological mechanisms underlying brain injury. With these ideas, numerous new drugs and methods for modulating the effect of brain injury on brain function have been suggested, tested in animal models, and are undergoing active clinical trials. This report will review several areas of active research and identify new therapies that may offer improvements in outcome. With our new understanding, fundamental recommendations for brain injury treatment (e.g., hyperventilation) are undergoing re-evaluation and being modified. New areas and current clinical approaches to selected brain syndromes will be reviewed.
Our old model of brain injury was that some cell death is inevitable, some cells are damaged but can recover (ischemic penumbra), and some areas are healthy and will not experience death unless the injury expands (secondary injury). There are basically two types of central nervous system (CNS) injury: focal injury or ischemia, and global ischemia or anoxia. The therapeutic approach to the first group of injuries was to support perfusion and protect the penumbra to prevent secondary injury that would increase in the size of the infarct. A major change in our understanding of neurophysiology and the response to injury is the recognition that neurons are tolerant to ischemia and that they can withstand hours of low or no flow and still survive. This allows a significant window of opportunity to salvage many cells that were previously thought to be unsalvageable. The approach now should be to restore circulation to ischemic areas before infarction is inevitable, using thrombolytic agents and drugs that improve cerebral perfusion.
Our understanding of secondary injury is also more complete. It is now believed that neurochemical (e.g., glutamate) and inflammatory mediators are at least as important as physical factors (edema, clot) in limiting cell survival. This allows development of specific pharmacological interventions directed at these mediators. However, while theoretically attractive, most of these novel approaches have not yet achieved clinical success.
Three distinct clinical pictures will be discussed, with emphasis on current therapy and experimental approaches: ischemic stroke, aneurysmal rupture, and traumatic brain and spinal cord injury. Little progress has been made in salvaging patients from unexpected total cerebral ischemia, such as occurs during cardiac arrest, and prognosis remains poor in this group. However, significant progress in brain protection has been seen in "elective" ischemia, that occurring during vascular surgery and interventional neuroradiology.
Ischemic Stroke
Rapid reperfusion following ischemic stroke has become a national and public mission. As with the acute myocardial infarction model, the American Heart Association has promoted "Brain Attack" to the lay public, and now includes thrombolysis as a treatment modality in the latest iteration of the Advanced Cardiac Life Support program. The chain of survival for stroke is: public recognition of stoke symptoms, activation of the emergency medical system, early CT scan (to rule out subarachnoid or intracranial bleed), and thrombolysis in appropriate patients. The promulgated time-standard goals are a door-to-thrombolytic drug time of less than 60 minutes, with total time from onset of symptoms less than three hours. As many as 75% of stokes are ischemic, and the potential for improved outcome with this protocolized approach is believed to be great. The contraindications to thrombolysis are significant, however, as listed in Table 1.
Table 1
Contraindications to Thrombolysis in Ischemic Stroke
Absolute Contraindications
Blood on CT scan
Rapidly improving or only minor symptoms
Suspicion of subarachnoid hemorrhage with normal CT
Internal bleeding within three weeks
Known bleeding disorder
Cranial surgery, stroke, or head injury within three months
Serious trauma or major surgery within two weeks
Relative Contraindications
Hypertension (Systolic >180, Diastolic >110)
Lumbar puncture within seven days
Arterial puncture
Past history of head injury or intracranial bleed
Past history of cerebral aneurysm
Recent seizure
Recent acute myocardial infarction
Intravenous tissue plasminogen activator (TPA) has been approved for use in ischemic stroke based on a single multi-institutional study demonstrating improved outcome at three and six months.1 Thrombolysis is associated with bleeding; in that study, intracranial and extracranial bleeding were 10 times more likely following TPA than in control (intracranial hemorrhage, 3% vs 0.3%; other hemorrhage, 6% vs 0.6%). Other thrombolytic agents have failed in multiple studies to produce improved outcomes.
Good general medical care and attention to contributing factors complete the care plan for acute ischemic stroke. Glucose-containing fluids should not be administered in ischemic injury, and hyperglycemia should be avoided. Airway management, with particular attention to the potential for aspiration, is especially important in patients with swallowing difficulties. In comatose patients, intubation and mechanical ventilation are indicated, although the prognosis in the face of this degree of neurologic compromise is poor.
Changing Role for Hyperventilation
Arterial PCO2 and pH should be maintained near normal, as hyperventilation may reduce cerebral blood flow and increase ischemia.2 Although hypercapnia and acidosis increase global cerebral blood flow, ischemic blood flow is unchanged or reduced, according to animal models.3 Patients with acute elevations in intracranial pressure (ICP) may benefit from a brief period of hyperventilation while other measures to control ICP are instituted (i.e., osmotherapy, surgical removal of clot or infarct, drainage of cerebrospinal fluid, or decompressive craniectomy). After several hours of hyperventilation, cerebral blood flow returns to normal. Routine use of sustained hyperventilation in ischemic stroke or other CNS injury should be avoided.
Changing Neurologic Examination
Following ischemic stroke, some degree of functional recovery is expected. However, edema is usually maximal in the first two or three days following infarction. Serial neurological examinations should be performed to immediately detect deterioration due to a remedial cause.
Neurological deterioration may be caused by extension of the infarct, acute hemorrhage, increasing edema, or the development of hydrocephalus. The CT scan is essential to identify causes of deterioration and to permit institution of appropriate treatments. Some of these treatments are listed in Table 2. Osmotherapy with mannitol, to raise serum osmolality from 290 to 310 mosm/L, may reduce edema and lower ICP. Mannitol also has important effects on blood rheology and may improve nutrient delivery to ischemic areas of brain. Mannitol is also an antioxidant, although its contribution to improved outcome by this mechanism is unproven. The marked diuresis and secondary edema caused by mannitol limit its usefulness in treating cerebral edema. Although large doses of corticosteroids (e.g., dexamethasone 0.1 mg/kg, or methylprednisolone 30 mg/kg) improve cerebral edema and reduce oxidative injury-induced lipid peroxidation in experimental models, no clear benefit has been demonstrated in human ischemic brain injury.
Table 2
Causes of Deterioration of Neurological Function Following Ischemic Stroke
| Cause | Confirmatory CT Findings | Possible Treatment |
| Elevated ICP from Edema | Midline shift, small ventricles, gyral effacement | Osmotherapy, (i.e., mannitol,steroids, infarctectomy, decompressive craniectomy) |
| Hydrocephalus | Enlarged lateral ventricles, gyrial effacement, transtentorial herniation | Ventriculostomy, high-volume spinal taps |
| Intracranial Hemorrhage | Clotted blood, mass effects | Normalize coagulation factors, clot removal, decompressive craniectomy |
| Extension of Infarct | Increase in hypodense areas, no change from previous scan | Anticoagulation, supportive care |
Experimental Neuroprotective Therapy
Neuroprotective agents and strategies for ischemic stroke that have shown promise in animal studies include calcium channel blockers, hypothermia, antioxidants, steroids, and n-methyl-d-aspartate (NMDA) antagonists. The calcium channel blockers, nimodipine and nicardipine, have been tested in humans and have demonstrated little improvement. Because they cause significant drops in blood pressure, they are difficult to administer safely. Timing and doses of these agents may not have been ideal in previous studies, and further investigation is needed in order to better define a role for calcium antagonism in stroke.
A most promising group of drugs appears to be the NMDA antagonists. Release of excitatory neurotransmitters, including glutamate and aspartate, seems to increase injury. By reducing their release or antagonizing their effects at the NMDA receptor, improvement in outcome may result. Most NMDA antagonists cause alteration in perception, confusion, hallucinations, and delirium, limiting their usefulness in treating stroke. Newer drugs, such as Cerestat (Cambridge Neuroscience, CNS 1102), have no bothersome side effects and are being developed and tested. Cerestat has shown improved functional outcome at three months following injury.4
Anti-inflammatory agents and free-radical scavengers have received significant attention in human studies. Tirilizad, a 21-amino steroid, was shown to improve outcome in several European trials but has failed to demonstrate consistent results in North America. Citocholine has been used in Europe for a range of neurological insults with uncontrolled trials demonstrating no toxicity, a long window of effect (up to 24 hours), and improved outcome from stoke. Citocholine is given orally for two weeks and is remarkably well tolerated. Phase III trials are being planned. Fosphentoin, a membrane stabilizer, may be a useful agent to reduce inflammation.
Profound hypothermia, using core temperatures in the 20-24°C range, is known to protect brain tissue from ischemic injuries. Evidence is now showing that even mild degrees of hypothermia, such as decreasing core temperature by 1-2°C, even after the insult has occurred, can improve functional outcome. While this approach remains experimental, aggressive prevention of hyperthermia is essential to optimize neuronal salvage.
Subarachnoid Hemorrhage
Subarachnoid Hemorrhage (SAH) associated with ruptured aneurysm is a frequent problem causing death and morbidity. For initial survivors, rebleeding and vasospasm are continuing risks. Early operative intervention or radiographic obliteration prevents rebleeding but increases the incidence of vasospasm. Calcium channel blockers reduce the incidence of vasospasm, but fail to change mortality. Nimodipine, 60 mg by mouth every four hours for 21 days, has been approved for prophylaxis of vasospasm following SAH.
Besides the usual treatments of stroke, patients with SAH should have the responsible aneurysm, if present, repaired as soon as possible. Not all SAH is due to a ruptured aneurysm, and some are due to AV malformations, vasculitis, or hypertension. The first angiogram may not reveal the aneurysm, due to local vasospasm, and a second or third study may be necessary in order to establish the cause of the bleed. Acute hydrocephalus is common following SAH, occurring in about 20% of patients on presentation, and ventricular drainage is associated with a higher risk of rebleeding.
Hypertension is frequent with SAH, and control of blood pressure prior to aneurysm control is necessary to reduce rebleeding. However, reduction of blood pressure may exacerbate ischemia induced by vasospasm. Table 3 lists some useful drugs for reducing blood pressure after SAH. In general, asystolic blood pressure less than 160 mmHg and a mean arterial pressure less than 100 mmHg are reasonable end points.
Table 3
Antihypertensive Agents Useful Following SAH
| Drug | Dose | Comments |
| Labetalol | 5-10 mg IV q 5 min (300 mg maximum) | Alpha and beta blocker improved effectiveness of other agents, may cause reversible renal abnormalities |
| Enalaprilat | 0.625-1.25 mg q 6 h | Converting enzyme inhibitor, |
| Esmolol | 50-200 mcg/kg/min | Beta blocker, titrated to heart rate |
| Metoprolol | 2.5-10 mg q 6 h | Beta blocker, useful to prevent tachycardia from vasodilators |
| Hydralazine | 5-20 mg q 4 h | Direct vasodilator, may increase heart rate and shear forces |
| Nicardipine | 0.075-0.15 mg/kg/hr | Calcium channel blocker, modest decrease in pressure, may have neuroprotective effect |
| Nitroprusside | 0.1-10 mcg/kg/min | Rapid acting, overshoot easy, reflex tacyhcardia, possible cyanide toxicity if > 2 mcg/kg/min for greater than 24 hours |
Cerebral Vasospasm Following SAH
Vasospasm risk is greatest for about two weeks following SAH and is greater after surgical repair. A changing neurological examination with altered level of consciousness is characteristic of vasospasm. Angiography usually demonstrates constricted vessels, although some patients having symptoms and normal angiograms are presumed to have vasospasm in smaller vessels. Transcranial doppler flow in the middle cerebral artery of the affected side usually demonstrates increased mean velocity (greater than 120 cm/sec). The actual pathophysiology causing vasospasm is not understood but is related to the amount of subarachnoid blood present. Prevention and treatment are often ineffective. Ischemia from vasospasm can progress to infarction.
Vasospasm prophylaxis can be attempted with nimodipine or nicardipine. Failing this, rescue therapy consisting of hypertension, hypervolemia, and hemodilution should be provided in patients with symptomatic vasospasm. The aneurysm must be secured for this therapy to be applied. Three to 6L of a mixture of colloid and isotonic crystaloid fluids can be administered per day, and a phenylephrine or neosynephrine infusion can be used to titrate blood pressure to the desired level. Hemoglobin should not be allowed higher than 11.5 gm% to prevent increased viscosity of the blood. Invasive cardiac monitoring may be necessary in frail patients to avoid congestive heart failure with this aggressive treatment. At least half of the patients who experience vasospasm respond to this therapy with some improvement in neurologic function.
Another approach to treatment of vasospasm is angioplasty. Anatomic improvement can sometimes be obtained this way. Papaverine may also be selectively infused into the vasospastic cerebral vessels. Changes in function may follow radiographic improvement, but this is not always true. Vasospasm risk declines dramatically 10-14 days following SAH, and, if patients' neurological status can be stabilized during this time period, recovery is excellent.
Head and Spinal Cord Injury
A major change in treatment of severe CNS injury is to avoid hyperventilation, unless herniation is imminent from elevated ICP. Head injury models and human studies confirm the release of excitatory neurochemicals, mainly glutamate and aspartate, early following head injury. These reach levels that are toxic to neurons.5 Seizure prophylaxis with phenytoin is common after head injury however, its effectiveness is not proven. Seizures should be controlled to prevent secondary neurological deterioration from hypoxia and hyperthermia. Midazolam in 1-2 mg boluses repeated every 1-2 minutes can be used to safely terminate seizures.
Identification and control of elevated ICP with sedation, osmotherapy, and decompressive craniectomy are the mainstay of treatment. Maintenance of normal blood pressure and adequate respiratory gas exchange are essential for support. Mild hypothermia has a salutary effect on neurological outcome. Prevention of hyperthermia is essential. Steroid treatment has not been shown to be effective in head injury but should be given to patients with spinal cord injury. Administration of methylprednisolone, 30 mg/kg within eight hours of injury, followed by 5.4 mg/kg/h for 23 hours, is associated with better functional outcome in patients with incomplete cord lesions.6 Twenty-one amino-steroids and other neuroprotective agents are undergoing trials and may achieve significant benefit for these injured patients in the future.
The grim prognosis once attributed to neurologic injuries and strokes is being modified by our understanding that brain cells are salvageable for a much longer period than previously thought. A window of opportunity to rescue neurons and several promising agents makes progress in the near future likely. Besides these novel approaches, good general care, avoiding hyperthermia, and possibly inducing mild hypothermia can improve outcome. Rapid reperfusion of ischemic brain is an appropriate goal.
References
1. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group: Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995;33:1581-1587.
2. Brian JE, Jr. Carbon dioxide and the cerebral circulation. Anesthesiology 1998;88:1365-1386.
3. Dettmers C, et al. CO2-reactivity in the ischemic core, penumbra, and normal tissue 6 hours after acute MCA-occlusion in primates. Acta Neurochir 1993; 125:150-155.
4. Edwards K. Cerestat in the treatment of acute ischemic stroke: Results of a phase II trial. Neurology 1996;46(Supl 2):A424.
5. Bullock RA. Opportunities for neuroprotective drugs in clinical management of head injury. J Emerg Med 1993;11:23-30.
6. Bracken MB, et. al. Administration of methylprednisolone for 24 or 48 hours or tirilazad mesylate for 48 hours in the treatment of acute spinal cord injury. Results of the Third National Acute Spinal Cord Injury Randomized Controlled Trial. National Acute Spinal Cord Injury Study. JAMA 1997;277(20): 1597-1604.
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