Intensive and Postoperative Care of Intracranial Tumors

Although patients who have just been operated on for tumor occupy a large proportion of beds in many neurological intensive care units (neuro-ICUs), little attention has been given to the subject. The main critical care problems that are associated with cerebral tumors relate to the postoperative state and clinical signs of mass effect and raised intracranial pressure (ICP). Some of these issues are addressed in general terms in Chapter 3. Here, it must be acknowledged that the intensivist largely acts as an agent for the neurosurgeon and to some extent, for the neuroanesthesiologist. In a few instances, complications of a large tumor may justify critical care attention on their own, particularly when manifestations of increased intracranial pressure, hydrocephalus, or status epilepticus bring the brain tumor to attention. Numerous medical complications of neurological disease, such as a pulmonary embolus and gastric hemorrhage, also require critical care at different stages of the disease. Certain cerebral neoplasms call for special attention as well; for example, pituitary apoplexy or tumors in the posterior fossa involve structures that affect breathing and swallowing. Tumor recurrence after treatment by surgery, radiation therapy, and chemotherapy, in most cases, is viewed as a less critical circumstance and is usually addressed on the ward, but the intensivist can provide valuable aid in the way of advice on the management of raised intracranial pressure in these cases.

Intracranial tumors can arise from any structure within the intracranial cavity (Tables 16.1 and 16.2). Most begin in the brain, but the pituitary, pineal, cranial nerves, and leptomeninges are additional sites of origin. Furthermore, any intracranial structure may be the site of metastatic spread from tumors that begin outside the nervous system. Patients with parenchymal brain tumors (i.e., gliomas, lymphomas, brain metastases) are the most likely candidates for intensive care management; these tumors are considered in this chapter. The concepts of critical care management presented also apply to patients with other intracranial tumors who develop serious complications.

In adults, most primary brain tumors arise in the cerebrum; the commonest of these are gliomas: astrocytomas (25%); high-grade gliomas (including glioblastoma) (20%); meningiomas (25%; more common in women than men); and a number of miscellaneous tumors, including primary central nervous system (CNS) lymphomas, which follow in frequency (1,2). The incidence of virtually all adult tumors increases with age, gliomas being more likely to be of higher grade with increasing age.

It has been recognized in recent years that the incidence of primary lymphomas of the CNS has increased markedly (3). Part of the increase is the result of the acquired immunodeficiency syndrome (AIDS) epidemic, but independent of this, there has been at least a threefold increase in primary CNS lymphomas in immunocompetent patients over the past decade. At the Sloan-Kettering Hospital the frequency of primary CNS lymphomas
in immunocompetent patients has gone from less than 1% of primary brain tumors to 15% (4).

TABLE 16.1. Major intracranial tumors in adults by percent

Metastatic	%	Primary brain tumor	%	Other intracranial tumors	%
Lung	40	Glioblastoma	40	Meningioma	80
Breast	20	Anaplastic astrocytoma	20	Acoustic neuroma	10
Melanoma	20	Astrocytoma	15	Pituitary adenoma	5
Miscellaneous	20	Lymphoma	10	Miscellaneous	5
		Oligodendroglioma	5
		Miscellaneous	10

According to some authorities, there is also evidence that other primary brain tumors may be increasing in incidence, at least in the elderly. There has been an apparent twofold increase in “brain cancer” (primarily high-grade gliomas) in patients 75 to 79 years old, four-fold in patients 80 to 84 years old, and five-fold in patients 85 years old and upward between 1973 and the current era (5). It is unclear whether this represents a real increase, better ascertainment because of better diagnostic techniques, or both.

In children, brain tumors arise largely in the posterior fossa and include cerebellar astrocytomas (20%), medulloblastomas (20%), brainstem gliomas (15%), and ependymomas (10%). Their peak age incidence is 5 to 10 years (6,7).

As mentioned, metastatic intracranial tumors are more common than primary ones, occurring in about 25% of cancer patients who come to autopsy (8,9). Of these, more than half are symptomatic making patients with them likely to appear regularly in any large general intensive care unit (8,10,11). All primary cancers can metastasize to the nervous system, but the common ones, well known to clinicians, are lung, breast, and malignant melanoma. In approximately 50% of patients, the brain metastasis is single; in another 20% there are two brain metastases. Approximately 10% of patients with lung cancer present with a brain metastasis before the lung cancer is diagnosed.

TABLE 16.2. Major intracranial tumors in children by percent

	Primary (% of total brain tumors)	Supratentorial (% by compartment)	Infratentorial (% by compartment)
Pilocytic astrocytoma	19	23	29
Medulloblastoma	17	2	32
Ependymoma	8	5	12
Craniopharyngioma	7	15	2
Anaplastic astrocytoma	6	13	2
Others	45	52	23

CLINICAL FINDINGS

Pathophysiology of Peritumoral Brain Edema

Intracranial tumors tend to cause signs and symptoms while still relatively small when compared with tumors in other organs. The tumor itself may invade, replace, or compress cranial tissues, leading either to failure of function or to seizures. The tumor usually causes an opening of the blood-brain barrier (BBB), with resulting brain edema. The combination of the tumor mass and the surrounding edema produces mass effect that shifts normal structures from their usual position and may interfere with cerebrospinal fluid (CSF) flow, leading to increased intracranial pressure (ICP)
with or without hydrocephalus (Chapter 2). The result may be symptoms that are only indirectly related to the presence of the tumor itself, so-called false localizing signs.

The edema associated with brain tumors is considered to be largely of the “vasogenic” type, meaning a leakage of water and plasma ultrafiltrate through the vascular BBB (12). In part, it results also from neovascularization engendered by the tumor. Some edema fluid also may arise from breakdown of the BBB in the edematous area immediately surrounding the brain tumor. The edema is distributed more readily through the white matter extracellular space in comparison to the gray matter, possibly because of a lower mechanical resistance. This pattern of distribution is apparent on scans and in autopsy specimens in which the fluid follows white matter tracts more or less radially outward from the site of the tumor. The edema often creates more mass effect than the tumor itself and may be correspondingly responsible for more symptoms than is the mass of the tumor. Whether focal neurological symptoms are attributable to edema per se has not been satisfactorily resolved, but the clinical improvement that usually accompanies a reduction in edema in response to corticosteroids suggests that there is a relationship.

The breakdown of the BBB within the tumor probably results from a number of factors, including the aforementioned angiogenesis, particularly because these new vessels do not possess tight junctions that are usually found at sites of the BBB in normal cerebral vasculature. Factors such as vascular endothelial growth factor that are elaborated by cerebral tumors are currently proposed to be the cause of angiogenesis. Furthermore, metastatic tumors appear to contain fenestrated endothelium, as in vessels elsewhere in the body. Both lead to the passage of large molecules (e.g., albumin) into the tumor interstitial space, resulting in a loss of intravascular oncotic pressure. Primary brain tumors also secrete permeability factors that promote vasogenic edema. The exact nature of these factors is not known, but a variety of substances such as metabolites of arachidonic acid, especially the leukotrienes (13, 14 and 15), glutamate (16), and so-called vascular permeability factor (17) have been implicated. Some investigators have found a correlation between the degree of macrophage infiltration and peritumoral edema. Macrophages secrete enzymes, platelet-activating factors, and free radicals that may contribute to the development of edema (18). Finally, and perhaps most salient for the ICU, pressure on the cortex from intraoperative brain retraction and brain manipulation, as well as reperfusion at the end of surgery, may exacerbate cerebral edema (19, 20, 21, 22 and 23).

Symptoms and Signs of Brain Tumor

As a general rule, low-grade cerebral tumors are more likely to present with seizures, whereas higher-grade and more rapidly growing gliomas typically cause early focal signs (e.g., hemiparesis) or signs of generalized dysfunction (e.g., headache and diminished consciousness). Lymphomas rarely produce seizures but may produce behavioral changes. Slowly growing tumors such as meningiomas, particularly those that arise in relatively silent areas of the brain (e.g., frontal pole), are more likely to cause false localizing signs than are rapidly growing ones (24).

The site of the lesion, of course, also plays an important role. Frontal tumors cause behavioral changes, whereas tumors closer to the motor strip and in the parietal lobe are more likely to cause seizures, focal weakness, or sensory change. Posterior fossa tumors often cause cranial nerve or cerebellar signs, but because they also obstruct the ventricular system, generalized symptoms and signs include headache, nausea, vomiting, and papilledema, often occurring early in the course of the disease.

Focal or generalized seizures occur in 20% to 50% of patients with tumors and are the usual presenting complaint in patients with low-grade gliomas. When focal, the seizure localizes the site of the tumor. Seizures represent a threat in patients with brain tumors beyond the usual risks of aspiration, respiratory arrest, and physical injury from convulsion,
because the increased blood flow caused by either a focal or generalized seizure further increases ICP and may lead to exaggeration of brain edema.

Seizures appear to be more common in patients with metastatic melanoma than other brain metastases, probably because the gray matter is more frequently involved in this tumor than in other types. Seizures are a common presenting problem in meningiomas as well and may be more common in the postoperative period than after removal of other tumors (25,26).

Focal seizures may be difficult to diagnose in patients with brain tumors. They frequently last longer and are more complex than in patients with other intracranial lesions. They are also more likely to be associated with headache and to produce “negative” than “positive” symptoms. As a result, they may be mistaken either for transient ischemic attacks or late-life migraine and not recognized as focal seizures.

TREATMENT

Patients with brain tumors may require intensive care treatment in the preoperative period, usually to treat seizures or increased ICP with herniation and in the immediate postoperative period to treat the complications of surgery. Many of the critical care problems associated with brain tumors are similar to those associated with other CNS disorders and are discussed in detail in Chapters 3 and 10.

Preoperative and Perioperative Period

Seizures

Seizures, either focal or generalized, can occur at any time during the course of a brain tumor but are most frequent as the presenting complaint before the diagnosis is established. Most are individual focal or generalized seizures, but in occasional patients, repetitive focal seizures and status epilepticus may be the central problem (Chapter 20). If seizures raise intracranial pressure, as mentioned, they may in turn lead to herniation or permanent brain damage.

The choice of anticonvulsants for brain tumor patients is not straightforward. Phenytoin, the one most commonly used, increases the metabolism of dexamethasone and some chemotherapeutic agents, often rendering them less effective (27). Furthermore, patients on phenytoin whose steroids are to be tapered and who are being treated with radiation therapy within a month after beginning the drug may have a slightly increased risk of Stevens-Johnson syndrome (27). Carbamazepine also induces microsomal enzymes in the liver, leading to increased metabolism of other drugs, and also may lead to Stevens-Johnson syndrome when combined with brain radiation therapy. Furthermore, carbamazepine suppresses the white count, a potentially undesirable effect in patients who receive myelosuppressive chemotherapy (27). Phenobarbital causes excessive sedation in patients already lethargic from their brain tumors and, in up to 20% of patients with brain tumors, leads to a rheumatic disorder with pain and often limited mobility in the shoulder contralateral to the brain tumor (27). Valproate is a generally effective drug, but its effect on the liver is problematic when used in conjunction with multiple chemotherapeutic agents.

Nonetheless, most intensivists begin the treatment of seizures with phenytoin. If the patient is having frequent seizures, 1.0 to 1.25 g intravenously (i.v.) is administered at a rate not exceeding 50 mg/minute with cardiac monitoring during the loading dose. A maintenance dose of approximately 5 mg/kg maintains serum levels at 10 to 20 mg/L in most patients. Stable blood levels are often difficult to maintain because of interactions with other medications. Oral loading, 1 g over 24 hours followed by 300 to 400 mg daily, is safer than i.v. loading and indicated for most patients not having repetitive seizures.

Treatment of generalized repetitive seizures or status epilepticus follows the lines given in Chapter 20. The initial situation
should be controlled with i.v. midazolam, diazepam (5 to 10 mg over 1 to 2 minutes) or lorazepam (1 to 3 mg over 1 to 2 minutes). If the patient was not previously treated with a conventional anticonvulsant, 15 to 18 mg/kg phenytoin is begun and then the patient is placed on a maintenance dose. If these measures fail to abort repetitive seizures, the further measures used in an intensive care unit setting are discussed in Chapter 20.

The patient with a brain tumor who is having seizures, of course, should be evaluated for metabolic derangements that lower the seizure threshold, particularly hypocalcemia, hyponatremia, hypoglycemia, and renal or hepatic failure (which may be manifestations of metastatic disease) or alcohol withdrawal.

Preoperative prophylactic anticonvulsants may be considered in patients with primary brain tumors who have not had previous seizures but several recent trials have failed to show a clear benefit. One prospective controlled study of supratentorial operations in 281 patients showed a reduction in seizure incidence in patients given prophylactic phenytoin (25,26). The protective effect was most dramatic in the first month, but 75% of seizures in both groups occurred within the first 3 months. These authors recommended phenytoin prophylaxis for 3 months in most cases. Meningiomas have a higher postoperative seizure rate than other tumors and it has been suggested that they should be prophylactically treated for 12 months. Therapeutic anticonvulsant levels must be attained for the drug to be effective after surgery.

The use of prophylactic anticonvulsants for metastatic tumors is more complicated. There are several prospective studies that have been summarized by Glantz and colleagues (28). The summary of their analysis is that there is no advantage to prophylactic anticonvulsants in patients with metastatic tumors for which reason our approach has generally been not to use these drugs except with malignant melanoma, which has a higher overall seizure rate than other metastatic tumors.

Patients with primary or metastatic tumors who receive iodinated contrast materials for CT scanning are at slightly increased risk for seizures, and a prophylactic dose of diazepam 5 to 10 mg orally 30 to 60 minutes before the injection of contrast reduces the incidence of seizures; however, we often do not use this approach (29).

Increased Intracranial Pressure

The treatment of intracranial hypertension is discussed in detail in Chapter 3 and only a few aspects specifically related to brain tumors are discussed here. Glucocorticoids are particularly effective in the management of patients with brain tumors and peritumoral edema. With one exception (see the following), once a diagnosis of intraparenchymal brain tumor with cerebral edema or shift is made, we start most patients on dexamethasone (or an equivalent steroid) in a dose of approximately 8 to 16 mg/day. In many patients, the symptoms caused by the tumor resolve within 48 hours. Generalized symptoms such as headache respond better than focal symptoms. If symptoms persist, the dose of steroids can be doubled every 48 hours until a clinical response has been achieved or until no response occurs at a dose of 100 mg/day.

For acutely decompensating patients, dexamethasone may be given as a 100-mg bolus followed by 100 mg/day in divided doses. When combined with i.v. hyperosmolar agents (mannitol) and, if necessary, hyperventilation, most patients herniating from the effects of brain tumor stabilize and improve.

The exception to the early use of steroids referred to above is in patients suspected of harboring brain lymphoma (4) because the oncolytic and antiedema effects of corticosteroids cause the tumor to become temporarily inapparent on scans in as many as 40% of patients. This may prevent definitive diagnosis by needle biopsy.

Corticosteroids are continued in the postoperative period (see the following) and during the course of radiation therapy if that
modality is indicated. They can be tapered gradually during radiation therapy but should not be discontinued until the radiation has been completed. We usually begin radiation therapy while the patient is on a dose of 12 to 16 mg dexamethasone per day and taper by approximately 2 mg a week such that the patient ends the steroid course soon after the radiation is completed. If the symptoms of the tumor are exacerbated during the course of the taper, the dose is raised temporarily and the taper begun again. Others have reported a more rapid taper to be equally effective and safe (30).

Steroids may induce hyperglycemia or exacerbate diabetes. Management of diabetes in the perioperative period is important, and we typically check blood glucose levels every 4 hours when the patient is not eating in preparation for surgery. The evening before surgery, patients receiving intermediate-acting insulin (NPH, Lente, Monotaid) should have this dose decreased to one third with short-acting insulin kept at the same preoperative dose. After an i.v. line has been started with a dextrose infusion just before surgery, the intermediate-acting insulin should be administered at one half the normal dose, with the regular insulin given at one third the normal dose. Glucose determinations should be taken hourly during surgery. Postoperatively, the patient may be managed on sliding scale regular insulin every 6 hours, until able to take a regular diet. During a steroid taper, adjustments in insulin dosage are also required.

Patients on oral hypoglycemics should usually be maintained on an appropriate diet until surgery. Oral hypoglycemics should be withheld the day of surgery and until the patient is taking the normal preoperative diet.

Patients on steroids are at risk for developing gastrointestinal perforation. The problem is particularly common in patients who are severely constipated. The classical peritoneal signs caused by the inflammation may be masked by the steroids, but the diagnosis generally can be made by detection of free air under the diaphragm on upright films of the abdomen. Prevention of constipation, which includes laxatives, enemas, and manual disimpaction, often prevents this serious side effect (31).

Gastritis, peptic ulceration, and gastrointestinal bleeding are serious consequences of steroid administration but are much less common than generally believed. There is little evidence to support the widespread use of gastric acid prophylaxis in patients on corticosteroids. There is evidence suggesting that patients on respirators in ICUs may have a decreased incidence of gastrointestinal bleeding if treated prophylactically (32). Histamine H₂ receptor blockers have been used routinely, but their occasional side effects of psychosis and thrombocytopenia may limit their usefulness in patients with brain tumors. Their tendency to raise gastric pH may lead to an increased incidence of pneumonia because of colonization of the stomach by bacteria that are then aspirated into the lungs. Antacids and sucralfate are good alternatives, but these drugs must be given orally or by nasogastric tube.

Corticosteroids increase the susceptibility of a patient with brain tumor to infection. A particular problem has occurred with Pneumocystis carinii (Pneumocystis jiroveci) infection occurring during the tapering of steroids in patients with brain tumors (33). Some investigators have recommended prophylaxis with trimethoprim/sulfamethoxazole using one double-strength tablet twice a day for 3 days per week. No controlled trials have demonstrated the effectiveness of this method in patients with brain tumors, although it appears to be useful in preventing Pneumocystis carinii infection in patients with leukemia.

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