Shailendra Joshi

Feeding Artery Pressure and Venous Drainage Pattern Are Primary Determinants of Hemorrhage From Cerebral Arteriovenous Malformations

PURPOSE The purpose of this study was to define the influence of feeding mean arterial pressure (FMAP) in conjunction with other morphological or clinical risk factors in determining the probability of hemorrhagic presentation in patients with cerebral arteriovenous malformations (AVMs). METHODS Clinical and angiographic data from 340 patients with cerebral AVMs from a prospective database were reviewed. Patients were identified in whom FMAP was measured during superselective angiography. Additional variables analyzed included AVM size, location, nidus border, presence of aneurysms, and arterial supply and venous drainage patterns. The presence of arterial aneurysms was also correlated with site of bleeding on imaging studies. RESULTS By univariate analysis, exclusively deep venous drainage, periventricular venous drainage, posterior fossa location, and FMAP predicted hemorrhagic presentation. When we used stepwise multiple logistic regression analysis in the cohort that had FMAP measurements (n = 129), only exclusively deep venous drainage (odds ratio [OR], 3.7; 95% confidence interval [CI], 1.4 to 9.8) and FMAP (OR, 1.4 per 10 mm Hg increase; 95% CI, 1.1 to 1.8) were independent predictors (P < 0.01) of hemorrhagic presentation; size, location, and the presence of aneurysms were not independent predictors. There was also no association (P = 0.23) between the presence of arterial aneurysms and subarachnoid hemorrhage. CONCLUSIONS High arterial input pressure (FMAP) and venous outflow restriction (exclusively deep venous drainage) were the most powerful risk predictors for hemorrhagic AVM presentation. Our findings suggest that high intranidal pressure is more important than factors such as size, location, and the presence of arterial aneurysms in the pathophysiology of AVM hemorrhage.

Abnormal pattern of Tie-2 and vascular endothelial growth factor receptor expression in human cerebral arteriovenous malformations

OBJECTIVEHuman cerebral arteriovenous malformations (AVMs) are speculated to result from abnormal angiogenesis. Vascular endothelial growth factor receptors (VEGF-Rs) and Tie-2 play critical roles in vasculogenesis and angiogenesis. We hypothesized that the abnormal vascular phenotype of AVMs may be associated with abnormal expression of VEGF-Rs and Tie-2. METHODSWe measured the expression of Tie-2, VEGF-R1, and VEGF-R2 in AVMs and normal brain tissue, using immunoblotting. To assess active vascular remodeling, we also measured endothelial nitric oxide synthase expression. CD31 expression was used to control for endothelial cell mass for Tie-2, VEGF-Rs, and endothelial nitric oxide synthase. Immunoblotting data were presented as relative expression, using normal brain tissue values as 100%. RESULTSCD31 was expressed to similar degrees in AVMs and normal brain tissue (99 ± 29% versus 100 ± 20%, mean ± standard error, P = 0.98). Tie-2 expression was markedly decreased in all AVMs, compared with normal brain tissue (16 ± 9% versus 100 ± 37%, P = 0.04). VEGF-R1 expression was decreased in four of five AVMs, but the difference between the mean values was not significant (35 ± 8% versus 100 ± 42%, P = 0.14). VEGF-R2 expression was decreased in all AVMs, compared with normal brain tissue (28 ± 6% versus 100 ± 29%, P = 0.03). There was no difference in endothelial nitric oxide synthase expression between AVMs and normal brain tissue (106 ± 42% versus 100 ± 25%, P = 0.91). CONCLUSIONAVM vessels exhibited abnormal expression of Tie-2 and VEGF-Rs, both of which may contribute to the pathogenesis of AVMs.

Evidence of increased endothelial cell turnover in brain arteriovenous malformations.

OBJECTIVEWe hypothesized that human brain arteriovenous malformations (BAVMs) are nonstatic vascular lesions with active angiogenesis or vascular remodeling. To test this hypothesis, we assessed endothelial cell turnover in BAVMs. METHODSWe identified nonresting endothelial cells by use of immunohistochemistry for the Ki-67 antigen. From archived paraffin blocks, we selected BAVM vessels without intravascular thrombosis or embolic material in areas nonadjacent to the nidus edge. For controls, we used 50- to 100-&mgr;m diameter cortical vessels from temporal lobe cortex removed for epilepsy treatment. The Ki-67 index was calculated as a percentage of Ki-67-positive endothelial cells. The data were analyzed by the nonparametric Mann-Whitney test and reported as mean ± standard deviation. RESULTSThirty-seven specimens that met the above criteria were selected. There were 26 ± 15 vessels counted in each BAVM specimen versus 18 ± 5 in each control cortex (n = 5). The mean Ki-67 index was higher for BAVM vessels than control cortical vessels (0.7 ± 0.6 versus 0.1 ± 0.2%;P = 0.005), which represented an approximately seven-fold increase in the number of nonresting endothelial cells. In the BAVM group, there was a trend for younger patients to have a wider variation and higher Ki-67 index than older patients; no trend was evident in the control group. CONCLUSIONCompared with control vessels, BAVM vessels have higher endothelial cell turnover, which suggests the presence of active angiogenesis or vascular remodeling in BAVMs.

A Prospective Evaluation of Clinical Tests for Placement of Laryngeal Mask Airways

Background Reliable tests of correct anatomic placement of the laryngeal mask airway (LMA) may enhance safety during use and minimize the need for fiberoptic instrumentation during airway manipulation through the device. This study assessed the correlation between the outcomes of nine clinical tests to place the LMA and the anatomic position of the device as graded on a standard fiberoptic scale. Methods During 150 anesthetics, the outcome of nine clinical tests of correct placement was individually scored as satisfactory (positive) or unsatisfactory (negative) for clinical use of the LMA. Anatomic placement was assessed (by fiberoptic evaluation) by an anesthesiologist, who was blinded to the placement of the device, as grade 1, vocal cords not seen; grade 2, cords plus the anterior epiglottis seen; grade 3, cords plus the posterior epiglottis seen; and grade 4, only vocal cords seen. The outcomes of clinical tests were correlated with fiberoptic grade. Results Tests that correlated with the fiberoptic grade were the ability to generate an airway pressure of 20 cm water, the ability to ventilate manually, a black line on the LMA in midline, anterior movement of the larynx, outward movement of the LMA on inflation of the cuff, and movements of the reservoir bag with spontaneous breathing. Two tests, ability to generate airway pressure of 20 cm water and ability to ventilate manually, correlated with fiberoptic grades 4 and 3 combined (i.e., the epiglottis was supported by the LMA) and grade 2 (the epiglottis was not supported by the LMA). Tests with poor correlation with fiberoptic grade were the presence of resistance at the end of insertion, inability to advance LMA after inflation of the cuff, and presence of a capnographic trace. Conclusions The outcome of clinical tests correlates with the anatomic placement of LMAs, as judged by fiberoptic examination. Two tests that best correlated with the fiberoptic grade were the ability to generate airway pressure of 20 cm water and the ability to ventilate manually.

Adenosine-induced ventricular asystole to induce transient profound systemic hypotension in patients undergoing endovascular therapy. Dose-response characteristics.

BackgroundAdenosine-induced asystole has been used to induce transient systemic hypotension for various vascular procedures. Dose–response characteristics of adenosine-induced ventricular asystole have not been determined. MethodsDuring endovascular embolization of cerebral arteriovenous malformations, the authors performed a series of adenosine test injections to establish a dose–response relation in each patient. After an interval of 3–10 min, the dose was escalated by 10–20 mg for each injection to achieve an end point of 20–30 s of stable mean arterial pressure (MAP) reduction to 25–30 mmHg. All patients received constant infusion of nitroprusside (≈ 1 &mgr;g · kg−1 · min−1) throughout the procedure. ResultsThe authors studied four adult patients (age, 22–44 yr; two patients had two separate procedures) and one pediatric patient (age, 4 yr). Twenty-three adenosine injections resulted in measurable asystole. The adenosine dose was 0.98 ± 0.40 mg/kg (mean ± SD), and the dose range was 0.24–1.76 mg/kg (6–90 mg). The duration of asystole, MAP < 30 mmHg, and MAP < 50 mmHg, were 8 ± 3 s, 18 ± 12 s, and 50 ± 29 s, respectively. The minimum MAP and the MAP for the first 20 s were 16 ± 3 mmHg and 30 ± 9 mmHg, respectively. There was a linear relation between adenosine dose and the duration of hypotension with MAP < 30 mmHg and MAP < 50 mmHg. ConclusionsIn the dose range studied, a series of adenosine test injections can be used to determine optimal adenosine dose for induction of transient profound hypotension.

Adenosine-induced cardiac pause for endovascular embolization of cerebral arteriovenous malformations: technical case report.

OBJECTIVE Extremely high flow through arteriovenous malformations (AVMs) may limit the safety and effectiveness of endovascular glue therapy. To achieve a more controlled deposition of glue, we used transient but profound systemic hypotension afforded by an intravenously administered bolus of adenosine to induce rapidly reversible high-degree atrioventricular block. METHODS AND CASE REPORT A patient with a large high-flow occipital AVM fed primarily by the posterior cerebral artery underwent n-butyl cyanoacrylate glue embolization. Nitroprusside-induced systemic hypotension did not adequately reduce flow through the nidus, as determined by contrast injection in the feeding artery. In a dose-escalation fashion, boluses of adenosine were administered to optimize the dose and verify that there was no flow reversal in the AVM and no other unexpected hemodynamic abnormalities by arterial pressure measurements and transcranial Doppler monitoring of the posterior cerebral artery feeding the AVM. Thereafter, 64 mg of adenosine was rapidly injected as a bolus to provide 10 to 15 seconds of systemic hypotension (approximately 20 mm Hg). Although there were conducted beats and some residual forward flow through the AVM during this time, the mean systemic and feeding artery pressures were roughly similar and remained relatively constant. A slow controlled injection of n-butyl cyanoacrylate glue was then performed, with excellent filling of the nidus. CONCLUSION Adenosine-induced cardiac pause may be a viable method of partial flow arrest in the treatment of cerebral AVMs. Safe, deep, and complete embolization with a permanent agent may increase the likelihood of endovascular therapys being curative or may further improve the safety of microsurgical resection.

Intra-arterial Nitrovasodilators Do Not Increase Cerebral Blood Flow in Angiographically Normal Territories of Arteriovenous Malformation Patients

BACKGROUND AND PURPOSE The mechanism of adaptation to chronic cerebral hypotension in normal brain adjacent to cerebral arteriovenous malformations (AVMs) is unknown. To clarify these mechanisms, we performed cerebral blood flow (CBF) studies in structurally and functionally normal vascular territories during 53 distal cerebral angiographic procedures in 37 patients with AVMs. METHODS CBF was measured using the superselective intra-arterial 133Xe method before and after a 3-minute infusion of either verapamil (1 mg.min-1, n = 23), acetylcholine (1.33 micrograms.kg-1.min-1, n = 7), nitroprusside (0.5 microgram.kg-1.min-1, n = 16) or nitroglycerin (0.5 microgram.kg-1.min-1, n = 7). RESULTS Mean +/- SD systemic (76 +/- 13 mm Hg) and distal cerebral arterial (55 +/- 16 mm Hg; range, 20 to 97 mm Hg) pressures were not different among groups. Verapamil increased CBF (45 +/- 12 to 65 +/- 21 mL.100 g-1.min-1, P < .001). There was no effect of acetylcholine (no change [46 +/- 9 to 46 +/- 9 mL.100 g-1.min-1], NS) or nitroglycerin (36 +/- 14 to 36 +/- 13 mL.100 g-1.min-1, NS). Nitroprusside decreased CBF (40 +/- 12 to 31 +/- 11 mL.100 g-1.min-1, P < .001). The percent change in CBF after drug administration was proportional to cerebral arterial pressure for verapamil only (r = .57, P = .0051). CONCLUSIONS When infused intra-arterially in clinically relevant doses in both hypotensive and normotensive normal vascular territories remote from an AVM nidus, calcium channel blockade caused vasodilation, but there was an absence of response to nitric oxide-mediated vasodilators. These data suggest that (1) the nitric oxide pathway probably is not involved in the adaptation to chronic cerebral hypotension in AVM patients and (2) if our findings in vessels remote from or contralateral to the AVM are applicable to vessels of patients with other forms of cerebrovascular disease, clinically relevant doses of intra-arterial nitrovasodilators may not be useful in the manipulation of cerebrovascular resistance.

Enhanced disruption of the blood brain barrier by intracarotid mannitol injection during transient cerebral hypoperfusion in rabbits.

Fairly large volumes of intracarotid mannitol (20% to 25%) are required to disrupt the blood brain barrier (BBB), that is, 200 to 300 mL/30 s in humans or 10 mL/40 s in rabbits. During transient cerebral hypoperfusion blood flow to the rabbit brain is decreased to 0.2 to 0.3 mL/30 s. We therefore hypothesized that if the disruption of the BBB by intracarotid mannitol was primarily due to its osmotic effects, injection of 0.2 to 0.3 mL of mannitol during transient cerebral hypoperfusion will be sufficient to disrupt the BBB, thereby dramatically (by 20-folds) decrease the dose requirements compared with injections during normal blood flow. After preliminary studies, 4 doses of intracarotid mannitol were first tested: (1) 2 mL with cerebral hypoperfusion, (2) 4 mL with cerebral hypoperfusion, (3) 4 mL without cerebral hypoperfusion, and (4) 8 mL without cerebral hypoperfusion. Next, we compared the extent to which methods of drug delivery (infusion vs. bolus injection) affected BBB disruption in 12 rabbits. Finally, we assessed the duration of BBB disruption with intracarotid mannitol in another 12 rabbits. We observed that BBB disruption during injection of 4 mL of mannitol with cerebral hypoperfusion was comparable to 8 mL mannitol without cerebral hypoperfusion. Bolus injections of 4 mL mannitol were more effective than steady-state infusions. The BBB disruption with intracarotid mannitol lasted for 60 minutes postinjection. We conclude that cerebral hypoperfusion decreases the dose of intracarotid mannitol by a modest 2-fold. Our results suggest that mechanical factors may play a significant role in the osmotic disruption of the BBB by intracarotid mannitol.

Optical method for real-time monitoring of drug concentrations facilitates the development of novel methods for drug delivery to brain tissue

The understanding of drug delivery to organs, such as the brain, has been hampered by the inability to measure tissue drug concentrations in real time. We report an application of an optical spectroscopy technique that monitors in vivo the real-time drug concentrations in small volumes of brain tissue. This method will facilitate development of new protocols for delivery of drugs to treat brain cancers. The delivery of many anticancer drugs to the brain is limited by the presence of the blood-brain barrier (BBB). Mitoxantrone (MTX) is a water-soluble anticancer drug that poorly penetrates the BBB. It is preliminarily determined in an animal model that the brain tissue uptake of chemotherapy agents-in this demonstration, MTX-delivered intra-arterially is enhanced when the BBB is disrupted.

Clinical utility of quantitative cerebral blood flow measurements during internal carotid artery test occlusions

OBJECTIVE Internal carotid artery (ICA) balloon test occlusions (BTOs) are performed in the angiography suite to predict whether the patient has adequate collateral circulation to prevent stroke when permanent ICA occlusion (PCO) is required for treatment. Although many criteria have been proposed to facilitate predictions of stroke risk after PCO, no BTO techniques have been subjected to predictive validity testing in outcome studies. We describe a prospective case series study that tests the predictive validity of quantitative cerebral blood flow (CBF) measurements during ICA BTO. METHODS Thirty-three patients with clinical indications for PCO underwent ICA BTO and then PCO. During BTO, standard neurological examinations, sustained-attention testing, and quantitative CBF measurements were performed. Two scalp scintillation detectors recorded washout data after ipsilateral intracarotid injection of xenon-133 through a port at the tip of the ICA-occluding balloon. Patients were monitored for the outcome measure of ipsilateral stroke for a mean of 34 months. The variables of quantitative CBF values, neurological examination results, sustained-attention test results, age, sex, and side of occlusion were examined with Kaplan-Meier log-rank tests, predictive validity analyses, and logistic regression analyses. RESULTS CBF of less than 30 ml/100 g/min during BTO was the only variable that predicted stroke after PCO (log rank = 5.87, P = 0.015). The negative and positive predictive values for CBF findings were superior to those for standard neurological examination findings and sustained-attention test results. Age, sex, and side of occlusion did not predict stroke. CONCLUSION Quantitative CBF testing, via the intracarotid injection technique, during BTO seems to be an important predictor of stroke after PCO.