Intraarterial drug delivery for glioblastoma mutiforme: Will the phoenix rise again?

Intraarterial (IA) drug delivery is a physiologically appealing strategy as drugs are widely distributed throughout the tumor capillary network and high regional tissue concentrations can be achieved with low total doses. IA treatment of glioblastoma multiforme (GBM) has been attempted since the 1950s but success has been elusive. Although IA treatments have been embraced for the treatment of retinoblastoma and advanced liver cancers, this has not been the case for GBM. The development of IA drug delivery for the treatment of brain cancer over the last several decades reveals a number of critical oversights. For example, very few studies took into consideration the underlying hydrodynamic factors. Therapeutic failures were often blamed on an inability to penetrate the blood brain barrier or on the streaming of drugs. Similarly, there were few methods to investigate the ultra-fast pharmacokinetics of IA drugs. Despite past failures, clinical interest in IA drugs for the treatment of GBM persists. The advent of modern imaging methods along with a better understanding of hydrodynamics factors, better appreciation of the complex morphology of GBM, improved drug selection and formulations, and development of methods to minimize treatment-related neurological injury, promise to considerably advance the application of IA drugs for GBM treatment. There are several clinical trials with IA treatments in the National Trial Registry that are actively recruiting patients. This review of IA drug delivery for GBM treatment is therefore timely and is intended to assess how this method of drug delivery could be better applied to future treatments.

Effect of atropine dose on heart rate during electroconvulsive therapy.

INTRODUCTION: Transient bradycardia during the stimulation phase of electroconvulsive therapy (ECT) is a well-known clinical observation. The optimal dose of atropine needed to prevent bradycardia has not been determined. This study was designed to investigate the effect of low doses of atropine on heart rate during ECT. METHODS: Patients who received at least 2 different doses of atropine over their series of right unilateral ECT were included in the analysis. The anesthetic consisted of 0, 0.2, 0.3, or 0.4 mg of atropine, methohexital, and succinylcholine. Heart rate was measured by the RR interval, the time between sequential R waves on the electrocardiogram. Analysis was performed using logistic multivariate regression and repeated-measures multivariate analysis of variance. RESULTS: One hundred eighteen ECT sessions were identified from 19 patients. Patients were grouped into 4 groups by atropine dose (0, 0.2, 0.3, or 0.4 mg) with 9, 33, 13, and 63 ECT sessions identified for each dose, respectively. Patients who received atropine had significantly less bradycardia after electrical stimulus and a faster heart rate through the seizure than patients who did not receive atropine. There was no significant difference in heart rate between patients receiving 0.2, 0.3, and 0.4 mg of atropine at any time point. There was no significant difference in heart rate at time points after the seizure conclusion in any group of patients. CONCLUSION: Low-dose atropine results in significantly less bradycardia after electrical stimulus. There was no significant difference in heart rate across low doses of atropine.

Delayed arousal.

Elderly patients have medical and psychological problems affecting all major organ systems. These problems may alter the pharmacokinetics and/or pharmacodynamics of medications, or expose previous neurologic deficits simply as a result of sedation. Delayed arousal, therefore, may arise from structural problems that are pre-existent or new, or metabolic or functional disorders such as convulsive or nonconvulsive seizures. Determining the cause of delayed arousal may require clinical, chemical, and structural tests. Structural problems that impair consciousness arise from a small number of focal lesions to specific areas of the central nervous system, or from pathology affecting the cerebrum. In general, focal or multifocal lesions can be identified by computerized tomography, or diffusion-weighted imaging. An algorithm is presented that outlines a workup for an elderly patient with delayed arousal.

Effects of anesthesia on brain mitochondrial function, blood flow, ionic and electrical activity monitored in vivo.

Thiopental, a well-known barbiturate, is often used in patients who are at high risk of developing cerebral ischemia, especially during brain surgery. Although barbiturates are known to affect a variety of processes in the cerebral cortex, including oxygen consumption by the mitochondria, the interrelation between mitochondrial function and anesthetics has not been investigated in detail under in vivo conditions. The aim of this study was to examine the effects of thiopental on brain functions in normoxia and under partial or complete ischemia. The use of the multiparametric monitoring system permitted simultaneous measurements of microcirculatory blood flow, NADH fluorescence, tissue reflectance, and ionic and electrical activities of the cerebral cortex. Thiopental caused a significant, dose-dependent decrease in blood flow and a significant decrease in extracellular levels of potassium, with no significant changes in NADH levels in normoxic and ischemic rats. Following complete ischemia (death), the increase in the reflectance was significantly smaller in the anesthetized normoxic group versus the awake normoxic group. The time until the secondary increase in reflectance, seen in death, was significantly shorter in the anesthetized ischemic group. In conclusion, it seems that the protective effect of thiopental occurs only under partial ischemia and not under complete ischemia.

Takotsubo cardiomyopathy associated with anesthesia: three case reports.

Takotsubo cardiomyopathy is a form of transient, reversible left ventricular dysfunction that can mimic an acute coronary event. However, cardiac catheterization often reveals normal coronary arteries. Patients are often postmenopausal women who experience acute physical or emotional distress. The prognosis for this entity is quite favorable. In this report, we present three cases of Takotsubo cardiomyopathy in patients having procedures involving anesthesia. Each case illustrates a different etiology for the syndrome: Patient, procedure, and anesthetic management.

Intracarotid delivery of drugs: the potential and the pitfalls.

The major efforts to selectively deliver drugs to the brain in the past decade have relied on smart molecular techniques to penetrate the blood-brain barrier, whereas intraarterial drug delivery has drawn relatively little attention. Meanwhile, rapid progress has been made in the field of endovascular surgery. Modern endovascular procedures can permit highly targeted drug delivery by the intracarotid route. Intracarotid drug delivery can be the primary route of drug delivery or it could be used to facilitate the delivery of smart neuropharmaceuticals. There have been few attempts to systematically understand the kinetics of intracarotid drugs. Anecdotal data suggest that intracarotid drug delivery is effective in the treatment of cerebral vasospasm, thromboembolic strokes, and neoplasms. Neuroanesthesiologists are frequently involved in the care of such high-risk patients. Therefore, it is necessary to understand the applications of intracarotid drug delivery and the unusual kinetics of intracarotid drugs.

Targeting the brain: rationalizing the novel methods of drug delivery to the central nervous system.

Drug delivery to the brain has remained one of the most vexing problems in translational neuroscience research. This review rationalizes the strategies to target drugs to the brain. Factors such as the speed of intervention, the scale of intervention, the state of BBB, and the permissible risks, will all be critical in deciding how best to deliver drugs to a target site in the brain for a specific clinical situation.

Anesthesia techniques in complex spine surgery.

The safe performance of complex spine surgery requires the close collaboration of the anesthesiology and surgical teams. The avoidance of medical and anesthetic complications depends on the appropriate preoperative medical evaluation, patient positioning, selection and administration of anesthetic agents, management of intraoperative fluid status, emergence from anesthesia, and administration of postoperative analgesia.

Comparison of electrophysiologic monitors with clinical assessment of level of sedation.

OBJECTIVE: To assess the correlation between 2 clinical sedation scales and 2 electroencephalographic (EEG)-based monitors used during surgical procedures that required mild to moderate sedation. PATIENTS AND METHODS: Patients scheduled for elective surgery participated in this Institutional review board-approved study from March 2003 to February 2004. Level of sedation was determined both clinically using the Ramsay and the Observer's Assessment of Alertness/Sedation scales and with 2 EEG measures (the Bispectral Index version XP [BIS XP] or the Patient State Analyzer [PSA 4000]). Correlation between these 2 measures of sedation were tested using nonparametric statistical tests. RESULTS: The BIS XP monitor was used in 26 patients, and the PSA 4000 monitor was used in 24 patients. The Ramsay and Observer's Assessment of Alertness/Sedation scores correlated with each other (r = -0.96; P < .001) and with both the BIS XP (r = -0.89 and r = 0.91, respectively; P < .001) and the PSA 4000 (r = -0.80 and r = 0.80, respectively; P < .001) values. However, this correlation was strongest only at the extremes. Between the BIS XP and PSA 4000 values of 61 and 80, the clinical sedation scores varied greatly. CONCLUSION: On the basis of our results, these EEG-based monitors cannot reliably distinguish between light and deep sedation.

High dose magnesium infusions are not associated with increased pressor requirements after carotid endarterectomy.

INTRODUCTION: Although magnesium provides cerebral protection in animal stroke models, magnesium therapy has significant side effects in humans. Therefore, we sought to examine the incidence of alpha-agonist treated hypotension in our ongoing, prospective, randomized, double-blind, placebo-controlled Phase I/IIa dose escalation study of magnesium therapy in patients undergoing carotid endarterectomy. METHODS: Eighty patients undergoing elective carotid endarterectomy were randomly assigned to a placebo control group (n = 38) or to one of the three intravenous magnesium groups. Magnesium levels were obtained before induction, and then 15 minutes, 1 hour, 2 hours, 6 hours, 12 hours, and 24 hours after a loading dose and infusion. After surgery, a target systolic blood pressure range was chosen, and the amount and duration of phenylephrine needed to maintain that pressure was compared across treatment groups. RESULTS: All treatment groups achieved levels significantly different from baseline at 12 and 24 hours (P < 0.01). Magnesium treatment did not significantly increase the proportion of patients requiring pressure support. For those requiring pressure support, the amount and average duration of phenylephrine required was not different between control patients and those receiving magnesium, even when the individual minimum systolic blood pressures required were subdivided on the basis of dose of magnesium administered. CONCLUSION: There were no significant differences detected in the 1) percentage of patients requiring pressor support, 2) the duration of postoperative pressor support, or 3) the amount of phenylephrine support needed between controls and magnesium treated patients. The percentage of patients requiring pressure support depended on the minimum systolic blood pressure ordered after surgery.

Increased cerebral blood flow after brain arteriovenous malformation resection is substantially independent of changes in cardiac output.

Brain arteriovenous malformation (BAVM) resection can result in an acute increase in cerebral blood flow (CBF) of unclear etiology. This observational study investigated the relationship between changes in CBF and cardiac output (CO) in patients undergoing microsurgical resection of BAVMs. In 20 patients undergoing a BAVM resection during an isoflurane-based anesthesia, we measured CBF and systemic cardiovascular parameters immediately before and after BAVM resection. CBF was measured on the hemisphere ipsilateral to the lesions and on the contralateral side, using intravenous cold 133Xe washout. Cardiac output was measured using thermodilution technique via a pulmonary artery catheter. There was an increase in global CBF after resection (25 +/- 8 versus 31 +/- 13 mL/100 g/min, preresection versus postresection, mean +/- SD, P =.002), ipsilateral CBF (25 +/- 8 versus 31 +/- 13 mL/100 g/min, P =.002), and contralateral CBF (24 +/- 7 versus 30 +/- 13 mL/100 g/min, P =.003). There was no change in CO, mean systemic arterial pressure, central venous pressure, or pulmonary artery diastolic pressure. The change in CBFGLOBAL was not correlated with changes in CO (r =.154, P =.517). BAVM resection resulted in global increases in CBF that was not substantially related to changes in CO or other systemic parameters.

Patient State Index: titration of delivery and recovery from propofol, alfentanil, and nitrous oxide anesthesia.

BACKGROUND: The Patient State Index (PSI) uses derived quantitative electroencephalogram features in a multivariate algorithm that varies as a function of hypnotic state. Data are recorded from two anterior, one midline central, and one midline posterior scalp locations. PSI has been demonstrated to have a significant relation to level of hypnosis during intravenous propofol, inhalation, and nitrous oxide-narcotic anesthesia. This multisite study evaluated the utility of PSI monitoring as an adjunct to standard anesthetic practice for guiding the delivery of propofol and alfentanil to accelerate emergence from anesthesia. METHODS: Three hundred six patients were enrolled in this multicenter prospective randomized clinical study. Using continuous monitoring throughout the period of propofol-alfentanil-nitrous oxide anesthesia delivery, PSI guidance was compared with use of standard practice guidelines (both before [historic controls] and after exposure to the PSA 4000 monitor [Physiometrix, Inc., N. Billerica, MA; standard practice controls]). Anesthesia was always administered with the aim of providing hemodynamic stability, with rapid recovery. RESULTS: No significant differences were found for demographic variables or for site. The PSI group received significantly less propofol than the standard practice control group (11.9 microg x kg(-1) x min(-1); P < 0.01) and historic control group (18.2 microg x kg(-1) x min(-1); P < 0.001). Verbal response time, emergence time, extubation time, and eligibility for operating room discharge time were all significantly shorter for the PSI group compared with the historic control (3.3-3.8 min; P < 0.001) and standard practice control (1.4-1.5 min; P < 0.05 or P < 0.01) groups. No significant differences in the number of unwanted somatic events or hemodynamic instability and no incidences of reported awareness were found. CONCLUSIONS: Patient State Index-directed titration of propofol delivery resulted in faster emergence and recovery from propofol-alfentanil-nitrous oxide anesthesia, with modest decrease in the amount of propofol delivered, without increasing the number of unwanted events.