Clinical Bbbd Technique

intra-arterial infusion of a large volume of hypertonic mannitol (25 per cent, warmed). Focal motor seizures occur during approximately 7 per cent of BBBD procedures (most often in conjunction with methotrexate), thus general anesthesia provides the capability of rapid control of seizures if necessary. A femoral artery is catheterized and a selected intra-cranial artery (either an internal carotid or a vertebral artery) is accessed. The transfemoral catheter is placed at cervical vertebrae 1-2 for a carotid artery infusion of chemotherapy or at cervical vertebrae 6-7 for a vertebral artery infusion. The transfemoral catheter placement level is confirmed by fluoroscopy prior to mannitol, and also prior to chemotherapy infusion. Mannitol is delivered via infusion device at a predetermined flow rate of 3-12 cc/s into the cannulated artery for 30 s. The precise flow rate is determined by fluoroscopy, to just exceed cerebral blood flow.

Following administration of mannitol, the intra-arterial chemotherapy agent(s) are infused, each over

10 min. If chemotherapy is administered via the intravenous route, it is begun as soon as the patient is under general anesthesia, to allow time for the chemotherapy to be delivered to tumor while the barrier is open. If intra-arterial chemotherapy without BBBD is used, patients undergo monitored anesthesia care instead of general anesthesia, and treatment is on one day instead of two consecutive days every four weeks.

Immediately following the mannitol, nonionic contrast dye is administered intravenously. Following completion of chemotherapy, the patient undergoes a computed tomography (CT) brain scan (see Figs. 18.2A,B) [20]. Contrast enhancement in the disrupted territory of the brain is compared to the nondisrupted territory. The degree of disruption is graded using the results reported by RomanGoldstein et al. [21].

During each monthly treatment, one of the intra-cranial arteries (right or left internal carotid or a

FIGURE 18.2 Computed tomographic (CT) images of BBBD of the left cerebral hemisphere following mannitol infusion in the left internal carotid artery (A), and BBBD of the posterior fossa region following mannitol infusion in the vertebral artery (B) [20]. (Reprinted with permission from (1998): Doolittle, N. D., Petrillo, A., Bell, S., Cummings, P., and Eriksen, S. Blood-brain barrier disruption for the treatment of malignant brain tumors: The National Program. Journal of Neurosurgical Nursing 30(2), 80-91. Copyright 1998 by the American Association of Neuroscience Nurses.)

FIGURE 18.2 Computed tomographic (CT) images of BBBD of the left cerebral hemisphere following mannitol infusion in the left internal carotid artery (A), and BBBD of the posterior fossa region following mannitol infusion in the vertebral artery (B) [20]. (Reprinted with permission from (1998): Doolittle, N. D., Petrillo, A., Bell, S., Cummings, P., and Eriksen, S. Blood-brain barrier disruption for the treatment of malignant brain tumors: The National Program. Journal of Neurosurgical Nursing 30(2), 80-91. Copyright 1998 by the American Association of Neuroscience Nurses.)

vertebral artery) is infused the first day of BBBD treatment, and a different artery is infused on the second day of BBBD, depending on the tumor type, extent, and location. In tumors that are not localized to one brain hemisphere or arterial territory, and/or tumors that have widespread microscopic infiltration of the brain such as PCNSL, infusion of the arteries is rotated so that during a year of BBBD treatment, each of the three intracranial arteries is infused eight times, thus providing global delivery to all cerebral circulations.

Following BBBD and during their hospital stay, patients undergo close observation including frequent monitoring of vital signs, neurologic status, and fluid balance. Fluid balance is meticulously maintained with diuretics or fluid boluses. In patients treated with methotrexate, sodium bicarbonate is added to intravenous fluids and titrated to achieve a urine pH greater than 6.5. Leucovorin rescue is used in methotrexate-based protocols, beginning 36 h after the first dose of methotrexate. Patients treated with methotrexate receive 80 mg of Leucovorin (intravenous) followed by 50 mg (intravenous or orally) every 6 h, for a total of 20 doses. Ganulocyte-colony stimulating factor (G-CSF) is given subcutaneously 48 h after the second day of BBBD chemotherapy. If filgrastim (Neupogen) is used, 5 mg/kg is given daily until the WBC is > 5000/ml. If pegfilgrastim (Neulasta) is used, one dose of 6 mg is given. Following hospital discharge and between monthly BBBD treatments, complete blood counts are done twice a week for two weeks while the patient is receiving G-CSF. For the remaining two weeks, a complete blood count is done weekly.

Patients treated with BBBD may experience transient neurologic deficits after the BBBD procedure. In the setting of a good or excellent disruption, approximately 10 per cent of patients have decreased level of consciousness for up to 48 h, and this may be accompanied by temporary aphasia and/or weakness of the upper or lower extremities. In these instances patients are treated with dexamethasone, and usually return to baseline status within 48 h. The most common arterial injury that may occur during BBBD is a subintimal tear. These arterial injuries are usually asymptomatic and are noted during fluoroscopy of the carotid and vertebral arteries. If a subintimal tear occurs, mannitol and chemotherapy are not infused through the injured vessel, and the artery is re-assessed with angiography four weeks later, prior to resuming intra-arterial administration of mannitol or chemotherapy. There is a risk of deep venous thrombosis (DVT) in patients undergoing BBBD, thus patients routinely undergo Doppler monitoring of the extremities and those at high risk for DVT are placed on prophylactic anti-coagulation therapy.

Radiographic evidence of vascular injury, which may or may not be symptomatic, is seen in up to 5 per cent of patients after BBBD [12,16-18]. In the event of a stroke, in most cases the patient is asymptomatic with brain MRI changes consistent with a small infarction. In patients with MRI changes and associated neurologic deficits, the deficits usually occur within 24 h after BBBD, may include speech impairment and/or unilateral extremity weakness, and are usually caused by a small embolus resulting from the arterial catheter placement and infusion. The neurologic deficits may last greater than 48 h, however, most patients return to baseline neurologic status within 30 days.

Abnormal signal on cervical MRI has occurred in several patients treated with carboplatin-based chemotherapy with BBBD [22]. This toxicity requires immediate treatment with dexamethasone and very close observation of the patient. Carboplatin also causes high-frequency hearing loss when administered intra-arterially with BBBD [23]. This toxicity can be substantially decreased with delayed high-dose sodium thiosulfate (STS), a thiol chemo-protectant [24,25]. Additional side effects which are known to occur secondary to the chemotherapy drugs, such as nausea, fatigue, and myelosuppres-sion, occur in patients in the BBBD program. Of note, the above side effects and toxicities can often be avoided if standard BBBD patient care guidelines developed by the BBB Consortium are closely followed.

The above technique of BBBD is performed at institutions participating in the BBB Consortium which include the Ohio State University in Columbus, University of Oklahoma Health Science Center in Oklahoma City, University of Minnesota in Minneapolis, Cleveland Clinic Foundation in Cleveland, University of Kentucky in Lexington, Hadassah-Hebrew University Medical Center in Jerusalem, Centre Hospital Universitaire de Sherbrooke in Quebec, and Oregon Health & Science University, in Portland (the coordinating center). Standard guidelines for anesthesia, transfemoral arterial catheterization, radiographic assessment of disruption and of tumor response, mannitol and chemotherapy infusion, and patient care guidelines, are used by participating BBBD centers.

Since 1995, the BBB Consortium has held an annual scientific meeting. The meetings are partially funded by an NIH R13 grant, and provide a forum for the BBB Consortium to share advances, results, and problems with current consortium clinical protocols, and to discuss future clinical trials. Following each meeting, a summary report is written by meeting participants and submitted for publication [26-28].

0 0

Post a comment