(BQ) Part 2 book “Cerebral vasospasm - Advances in research and treatment” has contents: Experimental treatments, clinical—doppler and imaging, clinical—medical aspects, clinical—medical management, clinical—surgery and endovascular, clinical—treatment.
SECTION V Experimental Treatments 36 Prevention of Experimental Cerebral Vasospasm by Intrathecal Delivery of Liposomal Fasudil YOSHIHIRO TAKANASHI, M.D., PH.D., TATSUHIRO ISHIDA, PH.D., JOHN H ZHANG, M.D., PH.D., ISAO YAMAMOTO, M.D Abstract We investigated the safety and efficacy of a sustained release form of liposo mal fasudil for the prevention of cerebral vasospasm after experimental subarachnoid hemorrhage (SAH) in rats and dogs The safety of a large in trathecal dose of liposomal fasudil was tested in 18 rats Rats were divided into one of three groups Each group received either 2.5 m g / k g or m g / k g of liposomal fasudil or drug-free liposomes after SAH Next, experimental SAH was induced in 15 dogs by injection of autologous arterial blood into the cisterna magna twice following baseline vertebral angiography In six animals, 0.94 m g / k g of liposomal fasudil was injected into the cisterna magna (treatment group) In four animals, drug-free liposomes were simi larly injected (placebo group), and the remaining five animals were treated with no liposomal injection after SAH (control group) On day after SAH, angiography was repeated and cerebrospinal fluid was collected before sac rifice In the safety study in rats, histological examination of the brains re vealed no abnormalities In the placebo and control groups, significant vasospasm occurred in the canine basilar artery on day In the treatment group, vasospasm on basilar artery was significantly ameliorated (p < 01) More than 90% of fasudil was released from the liposomes into the cere brospinal fluid In conclusion, local delivery of liposomal fasudil is a safe and effective strategy for preventing vasospasm on experimental SAH Intrathecal drug therapy for cerebral vasospasm following subarachnoid hemorrhage (SAH) has some advantages over systemic delivery and may be more efficacious than systemic application 1–3 In the current study, we have devised a sustained-release form of fasudil (liposomal fasudil) that can be used intrathecally and can continuously release the drug for several days We investigated the safety and efficacy of liposo mal fasudil in a sustained-release form for the preven tion of cerebral vasospasm after experimental SAH Materials and Methods Safety of Liposomal Fasudil Preparation of liposomes was done as described in detail elsewhere.1,2,4 Eighteen Sprague-Dawley rats were divided into one of three experimental groups Experimental SAH was produced in all rats by two injections of autologous blood into the cisterna magna.5 Two hours after the second blood injection the animals received either 2.5 mg/kg of liposomal 153 154 SECTION V ■ EXPERIMENTAL TREATMENTS fasudil (n = 6), m g / k g of liposomal fasudil (n = 6), or drug-free liposomes (n = 6) injected into the cisterna magna Seven days after the initial blood injection, the brains were removed for histological examination Canine SAH Model Experimental SAH was induced in 15 dogs by injec tion of autologous arterial blood into the cisterna magna twice Vasospasm was assessed by comparision of vertebral angiograms taken at baseline and days after the first SAH In six animals, 0.94 m g / k g of liposomal fasudil was injected into the cisterna magna (treatment group) In four animals, drug-free liposomes were similarly injected (placebo group), and the remaining five animals were treated with no liposomal injection after SAH (control group) On day angiography was repeated, and cerebrospinal fluid was collected before sacrifice The percent change in basilar artery diameter was calculated by dividing the diameter of the basilar artery observed on the angiogram days after SAH by that of the control diameter obtained from the baseline angiogram Results Release of Liposomal Fasudil Ninety percent of the fasudil was released into the cerebrospinal fluid of dogs by days Studies in vitro showed that, in contrast, 69% of the fasudil was released from liposomes incubated in control cere brospinal fluid As expected, no fasudil was detectable in blood samples Safety Study On gross examination the brain, vessels, and meninges of all rats appeared normal Light microscopy of the brain parenchyma, ependyma, vessels, and basal meninges appeared histologically normal Changes in Basilar Artery Diameters Liposomal fasudil, at the nontoxic dose of 0.94 m g / k g , significantly prevented vasoconstriction in the canine basilar artery when compared with that of the control group and the placebo group (Fig 36–1) Discussion Although a therapeutic concentration of drug can be administered directly into the cerebrospinal fluid, with less total drug required than with systemic administra tion in many cases, the intrathecal route has drawbacks to adaptation for clinical use The time during which drug concentrations remain in the therapeutic window may be short even with intrathecal delivery Additional difficulties are the technical problems associated with intrathecal administration (complications associated with the prolonged presence of external catheters), risk of infection and bleeding, potential adverse effects on intracranial pressure, and the theoretical concern that drug distribution may be adversely affected in the patient with SAH Therefore, with regard to drug concentration, frequent or continuous drug infusion may be needed to maintain a therapeutic drug concen tration in the cerebrospinal fluid, the use of which is hampered clinically by the factors already cited To overcome some of these disadvantages, various methods of sustained local drug delivery have been introduced for the treatment of experimental va sospasm Inoue et al showed that intrathecal implan tation of a slow-release tablet containing calcitonin gene-related peptide prevents vasospasm following SAH in monkeys Shiokawa and colleagues used a prolonged-release pellet of papaverine that could be implanted intracranially at the time of surgery and FIGURE 36–1 The diameter of the dog basilar artery days after subarachnoid hemorrhage (SAH), expressed as a percent of the diameter observed on angiography before SAH on day Bars represent means ± standard deviations Treatment with liposomal fasudil significantly reduced the narrowing of the basilar artery on day (* p < 01 vs drug-free group and control group) CHAPTER 36 reported that this prevented vasospasm in dogs Both methods require craniotomy to implant intracranially because the drug was contained in a solid form On the contrary, liposomal fasudil that was used in this study is a liquid that can be delivered intracranially at the time of surgery or at other times by lumbar puncture This might have the advantage of diffuse distribution of the drug throughout the entire neuraxis An additional advantage of liposomal fasudil might be the prolonged half-life of the drug that may result from slow release from the liposomes This would have the advantage that a single intrathecal injection of liposomal fasudil might achieve a therapeutic drug concentration in the cerebrospinal fluid and prevent cerebral vasospasm, thus avoiding the need for fre quent or continuous drug infusion The results obtained from the current study may be an intriguing first step in applying the concept of sustained local drug delivery to the treatment of cerebral vasospasm in the clinical setting ■ INTRATHECAL LIPOSOMAL FASUDIL 155 REFERENCES Takanashi Y, Ishida T, Kirchmeier MJ, Shuaib A, Allen TM Neuroprotection by intrathecal application of liposome-entrapped fasudil in a rat model of ischemia Neurol Med Chir (Tokyo) 2001;41:109–115 Takanashi Y, Ishida T, Meguro T, Kirchmeier MJ, Allen TM, Zhang JH Intrathecal application with liposome-entrapped fasudil for cerebral vasospasm following subarachnoid hemor rhage in rats J Clin Neurosci 2001;8:557–561 Thomas JE, Rosenwasser RH, Armonda RA, Harrop J, Mitchell W, Galaria I Safety of intrathecal sodium nitroprusside for the treatment and prevention of refractory cerebral vasospasm and ischemia in humans Stroke 1999;30:1409–1416 Ishida T, Takanashi Y, Doi H, Yamamoto I, Kiwada H Encapsula tion of an antivasospastic drug, fasudil, into liposomes, and in vitro stability of the fasudil-loaded liposomes Int J Pharm 2002;232:59–67 Suzuki H, Kanamaru K, Tsunoda H, et al Heme oxygenase-1 induction as an intrinsic regulation against delayed cerebral vasospasm in rats J Clin Invest 1999;104:59–66 Inoue T, Shimizu H, Kaminuma T, Tajima M, Watabe K, Yoshimoto T Prevention of cerebral vasospasm by calcitonin generelated peptide slow-release tablet after subarachnoid hemorrhage in monkeys Neurosurgery 1996;39:984–990 Shiokawa K, Kasuya H, Miyajima M, Izawa M, Takakura K Prophylactic effect of papaverine prolonged-release pellets on cerebral vasospasm in dogs Neurosurgery 1998;42:109–116 37 Magnesium and Cerebral Vasospasm GAIL J PYNE-GEITHMAN, D.PHIL., SHINSUKE NAKAYAMA, M.D., D.PHIL., THOMAS A D CADOUX-HUDSON, M.D., PH.D., JOSEPH F CLARK, PH.D Abstract Magnesium (Mg 2+ ) is known to dilate vascular smooth muscle that has been contracted by various contractile agonists This study set out to determine whether Mg 2+ could be used to prevent or reverse vasospasm caused in vitro by the cerebrospinal fluid (CSF) removed from patients with vasospasm after subarachnoid hemorrhage (SAH) Oxygen consumption and isometric force measurements of the porcine carotid artery were used to assess the contractile and metabolic status of the vessels following stimulation by vasospastic CSF and the effect of manipulating Mg 2+ (as MgCl2) on these responses Mg 2+ caused a dose-dependent decrease in tension following contraction generated by CSF from patients with vasospasm The rate of relaxation after a stretch (control; 16.1 ± 4.9 N m / sec) was significantly decreased in the presence of CSF from patients with vasospasm Relaxation was normalized after loading tissue with Mg 2+ , 12 mmol/L (2.7 ± 0.7 vs 15.8 ± 4.2 N m / sec) Tissue loaded with 12 mmol/L Mg 2+ had a significantly decreased rate of oxygen consump tion in the presence of CSF from patients with vasospasm (0.71 ± 0.03 vs 0.46 ± 0.08 mmol / m i n / g ) These results suggest that Mg2+ is a potent vasodilator that helps to normalize contractile behavior and metabolism of the porcine carotid artery exposed to CSF from patients with vasospasm Cerebral vasospasm after subarachnoid hemorrhage (SAH) from a ruptured aneurysm is a well-studied form of vasospasm although the mechanism of the vasocon striction has yet to be elucidated 1–3 Treatments targeted to the cerebral blood vessels have not, so far, proven to be effective in producing cerebral vasodilation or a re versal of vasospasm Cerebral vasospasm occurs to days after the initial hemorrhage in around 40% of the patients who survive the hemorrhage Despite the pu tative treatment window between the hemorrhage and the onset of vasospasm (3 days), there are, as yet, no effective therapies available to dilate the cerebral vessels of these patients Ram et al reported that topical application of Mg 2+ to the basilar artery or intravenous 156 delivery of Mg 2+ significantly reversed vasospasm in a rat model of SAH.6 The effect, however, was transient and vasospasm recurred as soon as the Mg 2+ was removed Boet and Mee reported promising results in patients with SAH to whom a 20 mmol bolus followed by continuous infusion of 84.7 mmol per day of Mg 2+ was administered This dose resulted in a doubling of serum Mg 2+ levels Therapy was not started until to days posthemorrhage Based in part on these data, we hypothesize that acute (and/or chronic) administration of Mg 2+ will normalize the contractile and metabolic changes in the porcine carotid artery induced by vasospastic cerebrospinal fluid using our in vitro model of cerebral vasospasm after SAH.8 CHAPTER 37 ■ MAGNESIUM AND VASOSPASM 157 Methods These have been previously published Briefly, to model SAH-induced cerebral vasospasm in vitro, cerebrospinal fluid (CSF) from vasospastic patients was obtained and treated as described in our previ ously published work 4,8,9 CSF was characterized as vasospastic (CSFv) or nonvasospastic (CSFn) as described previously based on the ability of a in 30 dilution of the CSF to stimulate O2 consumption to ≥ 0.4 μ m o l / m i n / g dry weight Oxygen consump tion rates above 0.4 μ m o l / m i n / g dry weight were classified as CSFv and the CSF that did not stimulate O2 consumption as CSFn Results Chronic Magnesium Effects Loading the tissue with Mg 2+ (estimated to contain 1.2 mmol/L intracellular free Mg 2+ ) 10 had a significant (p < 05) effect on the maximum rate of O2 consump tion in response to CSFv (stimulated from 0.27 ± 0.06 to 0.46 ± 0.10 |xmol/min/g dry weight) compared with the condition in the absence of CSFv (Fig 37–1) The percent increase in the rate of oxygen consumption, however, was not significantly different Acute Mg 2+ Effects Figure 37–2A shows the relationship between the con centration of Mg 2+ in the organ bath and relaxation of tissue precontracted with KCl, 70 mmol/L or CSFv Each curve is the average of six separate dose-response curves performed on tissue from six different pigs In both cases, a dose-response curve with an overall relaxation of 56% was observed Figure 37–2B shows the effect of acutely adding Mg 2+ , 12 mmol/L, to tissue that had been contracted with CSFv as well as the lack of effect of rinsing off the CSF from the tissue treated with CSFv The reduction in tension upon the addition of Mg + , 12 mmol/L in the presence of CSF v -induced tension is 16.6 ± 1.5 m N / m m (n = 3) Figure 37–3 shows the effect of Mg 2+ on tissue contracted with CSFv The maximal contraction to CSFv was reduced by 26% when a bolus of Mg2+, 12 mmol/L, was added This reduction is greater, reaching 35%, when the tissue is preloaded with Mg2+, 12 mmol/L before the addition of CSFv and even greater still (50%) when the Mg2+ pre loaded, CSFv contracted tissue is then exposed to an acute bolus of Mg 2+ , 12 mmol/L Discussion Although there have been several studies describing partial reversal of vessel spasm with topical or FIGURE 37–1 (A) Rates of O2 consumption of the porcine carotid artery at 120 minutes without or with exposure to vasospastic cerebrospinal fluid (CSFv), under exposure to different concentrations of Mg2+ (0 mM, n = 6; 1.2 mM, n = 8; 12 mM, n = 6) Values are means ± standard deviation (*p < 05 compared with condition without CSFv) (B) Percent increase in O2 consumption between baseline and CSFv-stimulated porcine carotid arteries Values are means ± standard deviation (0 mM, n = 6; 1.2 mM, n = 8; 12 mM, n = 6) There were no significant differences between groups intravenous application of Mg + , these have been phenomenological, and there have, until here, been no attempts to elucidate the mechanism of protection/ reversal.6,7,11 Pretreating the vascular smooth muscle with Mg + lowers the baseline respiration of the porcine carotid artery, In addition, the rate of O2 consumption of the CSF v -stimulated, Mg 2+ -loaded tissue was lowered as well Nitric oxide-mediated pathways are not likely to be involved because neither adenylate cyclase nor guanylate cyclase is associated with Mg 2+ -induced relaxation 12 The observation that the dose-response curves for relaxation by Mg 2+ of tissue contracted with KCl, 70 mmol/L and CSFv overlay each other (Figure 37–2A) may indicate Ca 2+ -antagonistic activities of Mg 2+ The stimulation of a slow onset of pathological con striction/failure to relax by CSFv has so far proven to be resistant, at least in the vasospasm patient, to con ventional treatments 13 Mg 2+ caused a relaxation (see Fig 37–2B), which may be indicative of vasodilation, as well as protecting the metabolism, by decreasing 158 SECTION V ■ EXPERIMENTAL TREATMENTS FIGURE 37–2 (A) Dose response curve of Mg 2+ relaxation of the porcine carotid artery contracted with KCl,70 mmol/L (n = 6, values represent means ± standard deviations) (B) Representative trace of porcine carotid contracted with vasospastic cerebrospinal fluid (CSFv) The precontracted tissue exposed to Mg 2+ relaxed initially and then completely upon rinsing Rinsing had no effect on the tissue not exposed to Mg + This has been repeated at least five times the rate of O2 consumption of the porcine carotid artery This may also protect the mitochondria from demands placed on it by the contractile apparatus Ca 2+ antagonism by Mg 2+ could result in a lowered rate of respiration due to decreased Ca 2+ stimulation of the mitochondria 14 Another way in which Mg 2+ may affect the mitochondria is that the mitochondria need an optimum Mg 2+ concentration to function nor mally.15 Mg 2+ antagonism of Ca 2+ is a likely candidate in this case because the tissue change in O consump tion in response to CSFv remained constant despite the loading or depletion of intracellular Mg 2+ (see Fig 37–1B) We believe this also suggests that the stimula tion of respiration by CSFv is not exclusively Ca 2+ dependent because the absolute rate of respiration, but not the relative increase, was decreased in the presence of Mg 2+ Figure 37–3 suggests that both intracellular (bar C) and extracellular (bar B) Mg + may protect the vessels from stimulation by CSFv Smooth muscle contraction is initiated by the binding of Ca 2+ to calmodulin and the subsequent binding of this Ca + –calmodulin com plex to myosin light chain kinase This would result in a lower tension and therefore lower O consumption The results in Figure 37–3 also corroborate the FIGURE 37–3 (A) Chronic and acute effects of Mg2+ (12 mmol/L) on pig carotid artery contracted with va sospastic cerebrospinal fluid (CSFv) The loading of the tissue was performed in the organ bath at 37°C Bars are contrac tion elicited by CSFv under control Mg2+ (1.2 mmol/L) con ditions and set as 100%, and (B) percent of that contraction achieved when Mg2+, 12 mmol/L was added to the tissue contracted with CSFv (C) The percent of the CSFv-induced contraction achieved when the tissue is preloaded with Mg2+, 12 mmol/L and then rinsed before addition of CSFv (D) The percent of the CSFv-induced contraction achieved when the tissue is preloaded with Mg2+, 12 mmol/L and then exposed to CSFv in the presence of the Mg2+, 12 mmol/L Bars are means ± standard deviations and n = (different patient CSF samples) for each group (* indicates significant [p < 05] difference from control) findings of Boet and Mee in that an acute bolus of Mg 2+ in conjunction with tissue loading provides the most effective protection The Ca 2+ antagonist activ ity of Mg 2+ may not be the sole mechanism of protec tion because clinical trials involving Ca 2+ channel blockers have not shown prevention or reversal of vasospasm 16 Ca 2+ channel blockers and N-methyl-Daspartate receptor antagonists, including Mg + , may, however, have neuroprotective actions.16,17 Conclusion These data suggest that Mg + therapy in vitro can relax vascular smooth muscle that has been con tracted in response to CSF from patients with vasospasm, as well as protect the metabolism of the arteries This may lead to investigation of the possi ble benefits of Mg + therapy in the patient with SAH There is some evidence presented for the first time here that, although acute application of either topical or intravenous Mg + can elicit vasodilation in arteries contracted as described here, normal smooth muscle function is more effectively restored in vitro by first loading the tissue with Mg + This study suggests that Mg + therapy may be more CHAPTER 37 effective if the patients with SAH had intravenous Mg2+ administered as a preventative measure to protect against vasospasm, rather than after the onset of vasospasm Acknowledgments This research was funded by the Medical Research Council (MRC) of Great Britain, the MRC Collabora tive Centre, and a Sasakawa Foundation Travelling Fellowship The author wishes to thank Dr Shinsuke Nakayama of the University of Nagoya Medical School for his useful discussion of the data included in this chapter REFERENCES Endo S, Suzuki J Experimental cerebral vasospasm after sub arachnoid hemorrhage: development and degree of vasospasm Stroke 1977;8:702–707 Macdonald RL, Weir BK Cerebral vasospasm and free radicals Free Radic Biol Med 1994;16:633–643 Weir B The pathophysiology of cerebral vasospasm Br J Neurosurg 1995;9:375–390 Cadoux-Hudson T, Pyne GJ, Clark JF Subarachnoid hemor rhage induced cerebral vasospasm: a subcellular perspective on the control of tension Emerg Ther Targets 1999;3:439–452 Weir B, Grace M, Hansen J, Rothberg C Time course of vasospasm in man J Neurosurg 1978;48:173–178 Ram Z, Sadeh M, Shacked I, Sahar A, Hadani M Magnesium sulfate reverses experimental delayed cerebral vasospasm after subarachnoid hemorrhage in rats Stroke 1991;22:922–927 ■ MAGNESIUM AND VASOSPASM 159 Boet R, Mee E Magnesium sulfate in the management of patients with Fisher grade subarachnoid hemorrhage: a pilot study Neurosurgery 2000;47:602–607 Pyne GJ, Cadoux-Hudson TA, Clark JF The presence of an extractable substance in the CSF of humans with cerebral vasospasm after subarachnoid haemorrhage that correlates with phosphatase inhibition Biochim Biophys Acta 2000;1474:283–290 Pyne GJ, Cadoux-Hudson TA, Clark JF Cerebrospinal fluid from subarachnoid haemorrhage patients causes excessive ox idative metabolism compared to vascular smooth muscle force generation Acta Neurochir (Wien) 2001;143:59–62 10 Nakayama S, Tomita T Regulation of intracellular free magne sium concentration in the taenia of guinea-pig caecum J Phys iol 1991;435:559–572 11 Muir KW, Lees KR A randomized, double-blind, placebocontrolled pilot trial of intravenous magnesium sulfate in acute stroke Stroke 1995;26:1183–1188 12 White RE, Hartzell HC Magnesium ions in cardiac function: regulator of ion channels and second messengers Biochem Pharmacol 1989;38:859–867 13 Varsos VG, Liszczak TM, Han DH, et al Delayed cerebral va sospasm is not reversible by aminophylline, nifedipine, or pa paverine in a “two-hemorrhage” canine model J Neurosurg 1983;58:11–17 14 Poe M Kinetic studies of temperature changes and oxygen up take in a differential calorimeter: energy balance during cal cium accumulation by mitochondria Arch Biochem Biophys 1969;132:377–387 15 Sloane BF, Scarpa A, Somlyo AP Vascular smooth muscle mito chondria: magnesium content and transport Arch Biochem Biophys 1978;189:409–416 16 Pickard JD, Murray GD, Illingworth R, et al Effect of oral nimodipine on cerebral infarction and outcome after subarach noid haemorrhage: British aneurysm nimodipine trial BMJ 1989;298:636–642 17 Heath DL, Vink R Magnesium sulphate improves neurologic outcome following severe closed head injury in rats Neurosci Lett 1997;228:175–178 38 Phosphodiesterase III Inhibitor for the Treatment of Chronic Cerebral Vasospasm in Dogs MITSUHISA NISHIGUCHI, M.D., SHIGEKI ONO, M.D., TOMOHITO HISHIKAWA, M.D., SHINSAKU NISHIO, M.D., KOJI TOKUNAGA, M.D., KENJI SUGIU, M.D., ISAO DATE, M.D Abstract The smooth muscle cells of cerebral arteries contain a large amount of phospho diesterase (PDE) Milrinone inhibits cyclic adenosine monophosphate–specific PDE III in both cardiac and vascular muscle Vasodilation occurs because of the increase in cyclic adenosine monophosphate in vascular smooth muscle, facilitating Ca 2+ uptake into the sarcoplasmic reticulum and reducing the amount of Ca 2+ available for contraction and thus reducing vascular tone Although there are some reports that intra-arterial or intra venous injection of milrinone may reduce vasospasm, the time course of the effect of and most effective route for administration of milrinone against vasospasm has not been reported The present study investigated the effect of intra-arterial or intracisternal injection of milrinone on chronic experimental cerebral vasospasm in dogs A double-hemorrhage canine model of vasospasm was used After cerebral angiography was performed on days and and angiographic vasospasm was docu mented, milrinone was administrated intracisternally (0.1 mg) or intraarterially (0.3 m g / k g / min) Angiography was performed 30, 60, 120, 180, 240, 300, and 360 minutes later, and the diameter of the basilar artery was measured The degree of angiographic vasospasm was reduced with intracisternal injection of milrinone compared with baseline diameter on day (66% at just before administration, 101 at 30, 105 at 60, 98 at 120, 91 at 180, 83 at 240, 74 at 300, and 74% at 360 minutes later) On the other hand, the degree of vasospasm was not reduced as effectively with intraarterial injection (57% at just before administration, 72 at 30, 77 at 60, 74 at 120, 78 at 180, 69 at 240, 64 at 300, and 63% at 360 minutes later) These results show that intracisternal injection of milrinone was more effective than intra-arterial injection at reversing established vasospasm in a canine model, at least in the doses tested The effect, however, was transient and vasospasm recurred more than 180 minutes after injection 160 320 SECTION X ■ CLINICAL—TREATMENT We posit that these results are attributable to the fi brinolytic effects of urokinase and the ability of ascorbic acid to decompose oxyhemoglobin Com pared with the continuous irrigation group, the drained blood volume in the intermittent irrigation group was lower and the absorption spectrum at 576 nm was higher Although intermittent irrigation can be performed easily, it represents only a supplemen tary method to prevent vasospasm in patients with large residual SAH and those determined by postop erative CT scan to be at risk for vasospasm Because we infuse irrigation fluid containing urokinase (120 IU/mL) and ascorbic acid (4 m g / m L ) at a rate of 30 mL/hr, the daily delivery of urokinase and ascor bic acid is 86,400 IU and 2880 mg, respectively The intermittent injection protocol delivers only 6000 IU of urokinase and 200 mg of ascorbic acid per day Studies are under way in our laboratory to deter mine the appropriate urokinase and ascorbic acid concentrations for effective clot resolution and oxy hemoglobin breakdown and the optimal volume and frequency of irrigation Conclusion We evaluated the ability of intermittent cisternal irri gation with urokinase and ascorbic acid to prevent va sospasm Compared with cisternal drainage alone, intermittent irrigation removed a much greater amount of the clot Analysis of the absorption spec trum of the drained fluid showed that intermittent ir rigation effectively reduced the concentration of oxyhemoglobin We are continuing to analyze the in dications for administering intermittent irrigation in patients with SAH REFERENCES Kodama N, Sasaki T, Kawakami M, Sato M, Asari J Cisternal ir rigation therapy with urokinase and ascorbic acid for prevention of vasospasm after aneurysmal subarachnoid hemorrhage: out come in 217 patients Surg Neurol 2000;53:110–118 Sasaki T, Kodama N, Kawakami M, et al Urokinase cisternal irri gation therapy for prevention of symptomatic vasospasm after aneurysmal subarachnoid hemorrhage: a study of urokinase concentration and the fibrinolytic system Stroke 2000;31: 1256–1262 Osaka K Prolonged vasospasm produced by the break-down products of erythrocytes J Neurosurg 1977;47:403–411 Kawakami M, Kodama N, Toda N Suppression of the cerebral vasospastic actions of oxyhemoglobin by ascorbic acid Neuro surgery 1991;28:33–40 Sato M Prevention of cerebral vasospasm: experimental studies on the degradation of oxyhemoglobin by ascorbic acid Fukushima J Med Sci 1987;33:55–70 Hunt WE, Kosnik EJ Timing and perioperative care in intracra nial aneurysm surgery Clin Neurosurg 1974;21:79–89 Fisher CM, Kistler JR, Davis JM Relation of cerebral vasospasm to subarachnoid hemorrhage visualized by computerized tomo graphic scanning Neurosurgery 1980;6:1–9 Suzuki J, Komatsu S, Sato T, Sakurai Y Correlation between CT findings and subsequent development of cerebral infarction due to vasospasm in subarachnoid hemorrhage Acta Neurochir (Wien) 1980;55:63–70 Index N o t e : P a g e n u m b e r s followed by f or t refer to figures a n d tables, respectively A Acetylcholine, vascular response to, 83–85, 84f, 85f Acid–base imbalance, in vasospasm detection/prediction, 212–215 Actin a, in SAH–induced vasospasm, 51, 55 protein kinase C and, 104 Acute physiological and chronic health evaluation (APACHE) score, in vasospasm detection/prediction, 212–215, 213f, 214f Acute physiology (AP) score, in vasospasm detection/prediction, 212–215 Adenosine deaminase, magnesium deficiency and, 45 Adenosine diphosphate, in vascular metabolism, 52 Adenosine triphosphate, 52 Adenosine triphosphate–sensitive potassium channels, 35 Adenovirus, as vector for intravascular gene transfection, 112–115, 113f, 114f Adhesion molecules, 65–67 ADMA See Asymmetric dimethyl arginine b–Adrenergic receptors, and magnesium, 44–45 African Americans, SAH outcome in, 220–223 Age and risk of vasospasm, 194–196, 221 and type of SAH–induced vasospasm, 110 Albumin, circulating blood volume and, 231–233 Albumin transfusion, 233 Amino acids, excitatory, hypothermia and, 146–149,148f 4–Aminopyridine, 14 Anemia, circulating blood volume and, 231, 233 Aneurysmal subarachnoid hemorrhage See Subarachnoid hemorrhage; Subarachnoid hemorrhage–induced vasospasm Aneurysmal surgery early, fasudil for good grade SAH patients after, 288–291,290t intraoperative microvascular Doppler sonography monitoring in, 167–170, 168f, 169f lamina terminalis fenestration during, 263–266, 265f topical vasodilators during, 167–170 vasospasm caused by, 108, 109f, 110, 167–170 adjuvant therapies preventing, 250–251 versus endovascular treatment, 249–251,250t, 251t Aneurysm rupture location and size of, and grading of SAH, 197–200,198t Angiography, grading of SAH by, 200 Angioplasty, 108, 110,229,238,252–254,253t decision analysis of, 279–283, 281f, 282f, 282t intra–arterial fasudil with, 297–298 Anterior communication artery aneurysm surgery, lamina terminalis fenestration in, 263–266, 265f Anticonvulsants, interaction with tirilazad, 229 Antioxidants, clinical trials of, 227, 229 APACHE score, for vasospasm detection/prediction, 212–215, 213f, 214f Apoptosis, in endothelial cells, cytokines and, 97–99 Apoptotic proteins, 129–133 Arachidonic acid metabolism oxyhemoglobin and, 117 in SAH–induced vasospasm, 65,204 Arterial compliance, 61–64 Artery(s) See also specific arteries gene transfer into, 112–115,113f, 114f major, permeability changes in experimental vasospasm, 108 nicotine and, 122–125, 123f, 124f pathological, and vasospasm, 108–109 Ascorbic acid, cisternal irrigation with, 308–311,309t, 310t, 310f intermittent injection protocol for, 317–320, 318f, 319f and oxyhemoglobin levels, 216–218, 217f, 218f, 308–311, 317–320, 319f surgical procedures and postoperative management in, 312–316, 314f, 315t, 315f Aseptic hemogenic meningitis, 169 Aspartate, hypothermia and, 146–149, 148f Astrocyte activation, 60, 60f Asymmetric dimethyl arginine (ADMA), 71–73, 90–92 activation by BOXes, 71, 73, 74f pharmacologic prevention of, 72–73 cerebrospinal fluid levels of, 90–92, 91f inhibition of endothelial nitric oxide synthase by, 71–73, 72f, 73f, 90–92 Atherosclerosis, 108, 110 B Balloon angioplasty, 229, 238,252–254,253t decision analysis of, 279–283, 281f, 282f, 282t intra–arterial fasudil with, 297–298 BAPTA (calcium chelator), and tyrosine kinase inhibitors, 29–31 Barbiturate coma, vasospasm detection during, 212–215 Basilar artery vasospasm biphasic, 107 endothelin–1 and, 86–88,87f, 88f endothelin B receptor in, 75–77, 76f, 77f, 78f endothelin receptor phenotype and, 79–82, 81f ion channels and, 12–15 myosin light chain phosphorylation and, 36–39, 39f nicotine and, 122–125,123f, 124f potassium channels in, 20–23, 22f prevention of, intrathecal liposomal fasudil for, 153–155, 154f protein kinase C isoforms and, 36–39,38t, 138–141, 140f Rho kinase inhibitors and, 36–39, 37f, 38t, 39f, 138–141, 139f, 140f severity, in experimental model, 106f, 106–107 smooth muscle phenotype change and, 62–64, 63f sphingosine–1–phosphate and, 25–27, 26f Src tyrosine kinase and, 17–18 thromboxane A – oxyhemoglobin synergy in, 116–118, 117f transcranial Doppler monitoring for, 171–173, 172f treatment of, phosphodiesterase III inhibitor for, 160–163, 161f, 162f white thrombi and, 109f Big endothelin–1, 86–88,88f, 93–94 Bilirubin, 142–145, 144f Bilirubin oxidation products (BOXes), 51–55,53f, 54f, 71–73, 74f, 143 321 322 INDEX Bilirubin oxidation products (continued) ADMA activation by, 71, 73, 74f pharmacologic prevention of, 72–73 BOX A, 52 BOX B, 52 in cell culture, 55 chronic effects of, 55 structural analysis of, 54, 55f Biphasic vasospasm and vasodilatation, 107, 107f BK channels, 12–15, 14f, 15f, 20–23, 22f, 32–35 actions of, 33, 33f dysfunction of, 32–35 and tyrosine kinase inhibitors, 29–31 Blood–brain barrier (BBB) cytokines and, 99 Panax notoginseng saponins and, 237 Blood clot lysis of cisternal injections for, 227, 229, 238, 304–306 cisternal irrigation for, 216–218, 308–311, 317–320 intracisternal fibrinolytic therapy for, 304–306 intrathecal fibrinolytic therapy for, 300–303,301t, 302f Panax notoginseng saponins and, 236–238 thickness of, and grading of SAH, 197–200,198t Blood flow computed tomography of, 177–179,178f, 180–182,181t, 182f, 182t fasudil and, 284–287 hemodynamic therapy and, 227, 243–246 hypertonic saline infusion and, 234–235 hypothermia and, 147–149 interruption, for intravascular gene transfection, 114–115 monitoring, for SAH–induced ischemia, 183–185 Panax notoginseng saponins and, 236–238 PET studies of, comparison with transcranial Doppler, 174–176 SPECT studies of, correlation with transcranial Doppler, 171–173, 172f thermal diffusion flowmetry of, 183–185 transdermal nitroglycerin and, 274–277, 276f, 277f Blood pressure fasudil and, 287 hemodynamic therapy and, 201–202,227,243–246 inotrope augmentation of, 201–202 systolic, and grading of SAH, 197–200, 198t transdermal nitroglycerin and, 274–277 Blood rheology, hypertonic saline infusion and, 234–235 Blood volume cerebral, computed tomography of, 178f, 178–182, 181t, 182t circulating, after SAH, 231–233, 232f, 233f cisternal irrigation and, 312–314, 315t, 319f, 319–320 hydrocortisone and, 240–242 Brain cooling, instantaneous selective, 110 Brain injury, SAH–induced cerebrospinal fluid drainage and, 255–262 microglia activation in, 57–60, 59f, 60f nimodipine and, 201 Panax notoginseng saponins for prevention of, 236–238 surgery versus endovascular treatment, as cause of, 249–251, 250t, 251t transcranial Doppler versus PET in, 174–176 transdermal nitroglycerin and, 274–277 Brain stem hypoperfusion, and vasospasm risk, 171–173 hypoxia inducible factor–1 expression in, 134–137,136f C Calcimycin, vascular response to, 83–85, 84f, 85f Calcium cytosolic oscillations in, cisternal CSF and, 119–121,120f magnesium levels and, 43,158 MAP kinase and, mechanical trauma and, 169 phosphodiesterase III inhibitor and, 160–163 serum level of, and SAH outcome, 222 in smooth muscle contraction, 11 thromboxane A and, 118 tyrosine kinase and, Calcium channel(s), 12–15,14f magnesium and, 44 Calcium channel blocker(s), 43,158,238 with cerebrospinal fluid drainage, 255–262 clinical trials of, 227–228 fasudil as, 288–291 magnesium as, 43–44,158 Panax notoginseng saponins as, 236–238 prolonged–release implants of, 269–273,270t, 271f Calcium sensitization potassium channels and, 32–35 Rho kinase and, 25–27,36,103–104 sphingosine–1 phosphate and, 25–27 Calmodulin–sensor myosin light chain kinase, in smooth muscle contraction, 8–11 Calphostin C, and smooth muscle contraction, 8–11,10f Capillary circulation, fasudil and, 295 Carbon dioxide partial pressure (pCO2), and death from vasospasm, 191–192 Cardiac arrhythmia, hemodynamic therapy and, 245 Cardiovascular disease, and vasospasm, 220–221, 223 Carotid artery vasospasm, 52 magnesium and, 156–159,157f, 158f Caspase in cytokine–induced apoptosis, 97–99 in SAH–induced vasospasm, 129–133,130f–131f Caspase inhibitors, in vasospasm prevention, 97–99 Caucasians, SAH outcome in, 220–223 CD4:CD8T cell ratio, 66 Cerebellum hypoperfusion, and vasospasm risk, 171–173 Cerebral blood flow computed tomography of, 177–179,178f, 180–182,181t, 182f, 182t fasudil and, 284–287 hemodynamic therapy and, 227,243–246 hypertonic saline infusion and, 234–235 hypothermia and, 147–149 interruption, for intravascular gene transfection, 114–115 monitoring, for SAH–induced ischemia, 183–185 Panax notoginseng saponins and, 236–238 PET studies of, comparison with transcranial Doppler, 174–176 SPECT studies of, correlation with transcranial Doppler, 171–173,172f thermal diffusion flowmetry of, 183–185 transdermal nitroglycerin and, 274–277,276f, 277f Cerebral blood volume computed tomography of, 178f, 178–182,181t, 182t hydrocortisone and, 240–242 Cerebral perfusion pressure cerebrospinal fluid drainage and, 255–258 hemodynamic therapy and, 243–246 hypertonic saline infusion and, 234–235 Cerebral vasospasm age and, 110,194–196,221 INDEX biphasic, 107,107f clinical experiences in, 109–110 experimental studies of, 106–108 intraoperative monitoring for, 167–170,168f, 169f ion channels in, 12–15 pathological arteries in, 108 pathophysiology of, controversial issues in, 103–105 permeability changes of major cerebral arteries in, 108 pharmacologic study of, new model for, 107–108 prevention/reduction of antioxidants for, 227,229 ascorbic acid for, 216–218 calcium channel blockers for, 43,158,227–228 caspase inhibitors for, 97–99 cerebrospinal fluid drainage for, 255–258,256t, 257t, 259–262, 260f, 261f cisternal irrigation for, 216–218,217f, 218f, 308–311, 309t, 310t, 310f intermittent injection protocol for, 317–320, 318f, 319f surgical procedures and postoperative management in, 312–316, 314f, 315t, 315f fasudil for, 228–229 liposomal, 153–155,154f fenestration of lamina terminalis for, 263–266, 265f free radical scavengers for, 227, 229 gender and, 189–192,190t, 191t, 220–223 hydrocortisone for, 240–242 intracisternal fibrinolytic agents for, 227,229 magnesium for, 43–45, 156–159 nicardipine prolonged–release implants for, 269–273, 270t, 271f Panax notoginseng saponins for, 236–238 potassium channel agonists for, 13 probucol for, 73 protein kinase C inhibitors for, 36,104–105,138–141,139f, 140f Rho kinase inhibitors for, 4–5, 228–229,284–287 during surgery, adjuvant therapies for, 250–251 thromboxane A2 inhibitors for, 48 tissue plasminogen activator for intracisternal, 238,304–306 intrathecal, after endovascular treatment, 300–303,301t, 302f transdermal nitroglycerin for, 274–277, 276f, 277f tyrosine kinase inhibitors for, 4, 17–18,29–31 race and, 220–223 SAH–induced See Subarachnoid hemorrhage–induced vasospasm severity of, 106f, 106–107, 110 sex (gender) and, 189–192,190t, 191t, 220–223 signaling pathways in, 3–5 treatment of angioplasty for, 229, 238,252–254,253t outcomes analysis of, 279–283, 281f, 282f, 282t antioxidants for, 227, 229 calcium channel blockers for, 227–228, 238 cerebrospinal fluid drainage for, 255–258, 256t, 257t clinical trials of, 227–230 conservative management in, 279–283, 281f, 282t decision analysis in, 279–283, 281f, 282t, 282f endovascular, 229, 238,252–254,253t fasudil for, 228–229 for good grade SAH patients, after early surgery, 288–291, 290t insufficient or ineffective use of, 292–295, 293f, 293t, 294f intraventricular urokinase with, 296–299, 297f, 297t, 298f mechanisms of action, 284–287, 285t, 286f free radical scavengers for, 227, 229 323 gene therapy for, 112–115 hemodynamic therapy for, 43, 201–202,227,238 outcomes analysis of, 279–283, 281f, 282f, 282t safety and efficacy of, 243–246 hypothermia for, 110, 146–149 hypoxia inducible factor–1 for, 137 inotrope augmentation of blood pressure in, 201–202 instantaneous selective brain cooling for, 110 intra–arterial drug infusion for, 252–254,253t intracisternal fibrinolytic agents for, 227, 229,238 magnesium for, 43–44,156–159,157f, 158f phosphodiesterase III inhibitor for, 160–163, 161f, 162f putative window for, 156 transdermal nitroglycerin for, 274–277, 276f, 277f white thrombi and, 108, 109f Cerebrospinal fluid cisternal See also Cisternal injections; Cisternal irrigation cytosolic calcium oscillations induced by, in SAH, 119–121, 120f gene transfer into, 112–113 Cerebrospinal fluid analysis ADMA in,90–92,91f bilirubin levels in, 142–145,144f bilirubin oxidation products (BOXes) in, 51–55 C–terminal fragment in, 93–95, 95f endothelin–1 in, 93–95, 94t, 95f ferritin levels in, 142–145, 144f inflammatory cells in, 143, 145f iron levels in, 142–145, 144f total protein concentrations in, 143, 144f Cerebrospinal fluid drainage, 255–258, 256t, 257t, 259–262, 260f, 261f irrigation/injections with See Cisternal irrigation therapy Cerebrovascular resistance (CVR) hypertonic saline infusion and, 234–235 thermal diffusion flowmetry of, 183–185 Chelerythrine, for vasospasm prevention, 36, 104–105 Chinese medicine, for vasospasm and ischemia prevention, 236–238 Cholesterol levels, 108, 110 Chronic obstructive pulmonary disease (COPD), 221, 223 Cigarette smoking, and vasoconstriction, 122–125,123f, 124f Circulating blood volume, after SAH, 231–233,232f, 233f Cisternal injections of fibrinolytic agents, 227, 229,238,304–306 for gene transfer, 112–113 limitations of, 112–114 of liposomal fasudil, 153–155, 154f of nicardipine, 229 of papaverine, 229 of phosphodiesterase III inhibitor, 160–163, 161f, 162f Cisternal irrigation therapy absorption spectrum in, 319f, 319–320 with ascorbic acid, 308–311, 309t, 310t, 310f, 312–320 versus cisternal drainage alone, 320 cisternography in, 313, 315f complications of, 308, 314–316 drained fluid analysis in, 312–315, 318–319,319f duration of, 312–313, 319 intermittent injection protocol for, 317–320, 318f, 319f intraoperative, 250–251 oxyhemoglobin concentration changes in, 216–218, 217f, 218f, 308–311 riskibenefit ratio of, 311 surgical procedures and postoperative management in, 312–316, 314f, 315t, 315f with urokinase, 216–218, 217f, 218f, 297, 308–311, 309t, 310t, 310f, 312–320 324 INDEX Cisternography, in cisternal irrigation, 313, 315f Clinical trials, for prevention and treatment, 227–230 Cognitive impairment See also Neurologic deficit microglia activation and, 57–60 Coil embolization intrathecal fibrinolytic therapy after, 300–303,301t, 302f versus surgery, 249–251,250t, 251t Comorbid conditions, 220–223 Complement activation, 66 Computed tomography (CT) of cerebral blood flow, 177–179,178f, 180–182,181t, 182f, 182t dynamic perfusion concordance with other diagnostic modalities, 177,179,179f correlation with transcranial Doppler, 177,179,179f, 180–182, 181t, 182f, 182t in severe symptomatic vasospasm, 177–179,178f, 179f versus SPECT, 178f, 178–179 of hypertonic saline effects, 234–235 in subarachnoid hemorrhage for grading, 194–196, 200 S–100B and neuron specific enolase and, 208–210, 209f, 210f timing, for vasospasm detection/prevention, 109 Congestive heart failure hemodynamic therapy and, 245 and vasospasm, 221,223 Connective tissue, proliferation of, 61–64 Conservative management, decision analysis of, 279–283, 281f, 282t Constant flow perfusion system, for pharmacologic study, 108 Cooling See also Hypothermia instantaneous selective brain, 110 Copper, magnesium deficiency and, 45 CPI–17,104 Cranial window technique, 53f, 53–54,54f Craniotomy, for cisternal irrigation, 312–316 Creatinine, in vasospasm detection/prediction, 215 Cromakalim, in vasospasm prevention, 13 CT See Computed tomography C–terminal fragment (CTF), in cerebrospinal fluid, 93–95, 95f Cyclic adenosine monophosphate (cAMP) and calcium channels, 44 and magnesium, 44–45 phosphodiesterase III inhibitor and, 160–163 Cyclic adenosine monophosphate–dependent protein kinase, fasudil and, 285t Cyclic guanosine monophosphate, in smooth muscle relaxation, 12, 275 Cyclic guanosine monophosphate–dependent protein kinase, fasudil and, 285t Cyclic guanosine triphosphate, and calcium channels, 44 Cytokine(s) and blood–brain barrier, 99 cytotoxic effects on endothelial cells, 97–99 in SAH–induced brain injury, 57–60, 60f in SAH–induced vasospasm, 65–67, 97–99, 213 Cytokine receptors, in SAH–induced vasospasm, 65 Cytotoxicity of cytokines, 97–99 magnesium deficiency and, 45 D Damnacanthal, 17–18 Decision analysis, in vasospasm treatment, 279–283,281f, 282t, 282f Delayed vasospasm, 54–55 endothelial dysfunction and, 71–73 oxyhemoglobin–thromboxane A synergy in, 116–118,117f prevention of, Panax notoginseng saponins for, 236–238 smooth muscle phenotype change in, 61–64 three–stage hypothesis of, 71–73, 74f Deoxyhemoglobin after subarachnoid hemorrhage, 18 ferrous iron component of, 142–143 heme oxygenase–1 and, 142 Diabetes mellitus, 108,110,220–221,223 Dilantin, interaction with tirilazad, 229 Dimethyl arginine dimethylamino hydrolase (DDAH), in resolution of vasospasm, 71, 74f Diuresis, hydrocortisone and, 240–242 Dopamine, for blood pressure augmentation, 201–202 Drainage, of cerebrospinal fluid, 255–258,256t, 257t, 259–262, 260f, 261f cisternal irrigation therapy versus, 320 irrigation/injections with See Cisternal irrigation therapy Dynamic perfusion computed tomography concordance with other diagnostic modalities, 177,179,179f correlation with transcranial Doppler, 177,179,179f, 180–182, 181t, 182f, 182t in severe symptomatic vasospasm, 177–179,178f, 179f versus SPECT, 178f, 178–179 E Ebselen, clinical trials of, 229 Edema, hemodynamic therapy and, 245 Elderly, SAH–induced vasospasm in, 110 Electrolytes, and vasospasm, 222 Encephalopathy, microglia activation and, 57–60 Endoplasmic reticulum Ca2+ adenosine triphosphatase, and cytosolic calcium oscillations, 119–121,120f Endothelial cytotoxicity of cytokines, 97–99 oxidative, magnesium deficiency and, 45 Endothelial differentiation genes (EDGs), 26,26f Endothelial dysfunction, 71–73, 74f primate model of, 83–85, 84f, 85f Endothelial nitric oxide synthase (eNOS), inhibition of, 129–133,257 by ADMA, 71–73, 72f, 73f, 90–92 Endothelin–1, 66, 75–77, 79–82, 81f, 169 cerebrospinal fluid levels of, 93–95, 94t, 95f increased contractile effect of, 86–88, 87f, 88f MAP kinase enhanced by, precursor of (big endothelin–1), 86–88, 88f, 93–94 synthesis of, 94 as therapeutic target, 88 Endothelin, magnesium deficiency and, 45 Endothelin receptors contractile effects of, 87–88 ETA, 87–88, 128f ETA and ETB interactions in, 79–82, 81f ETB, 75–77, 76f, 77f, 78f, 87–88, 128,128f inhibition by protein kinase C, 128 phenotype alteration of, 79–82, 81f as therapeutic target, 88 Endothelium cytosolic calcium oscillations in, cisternal CSF in SAH and, 119–121, 120f gene transfer into, 112–115 nicotine and, 122–125, 123f, 124f Endothelium–derived relaxing factor See Nitric oxide Endovascular treatment of aneurysms, 108,110 versus surgery, 249–251, 250t, 251t for cerebral vasospasm, 252–254, 253t INDEX intracisternal fibrinolytic therapy during, 304–306 intrathecal fibrinolytic therapy after, 300–303, 301t, 302f England northern, SAH–induced vasospasm in, 194–196, 196f sex (gender) and cerebral vasospasm in, 189–192, 191t, 192t Erythrocytes, in drained cisternal fluid, 312–314, 315t, 318–319 Erythrocyte transfusion, 233, 233f Erythropoietin, hypoxia inducible factor–1 and, 134,136 E–selectin, 65 Estrogen, and subarachnoid hemorrhage, 189–190 Excitatory amino acids, hypothermia and, 146–149,148f Extracellular regulated kinase (ERK), 4, 17, 65 F Fasudil as calcium antagonist, 288–291,295 clinical trials of, 228–229 for good grade SAH patients, after early surgery, 288–291,290t in infarction prevention, 285–286,292–295 insufficient or ineffective use of, 292–295,293f, 293t, 294f intra–arterial, 285,286f, 292–295,293f, 293t, 294f with angioplasty, 297–298 intraventricular urokinase with, 296–299,297f, 297t, 298f in ischemia prevention/treatment, 285 liposomal, 153–155,154f intrathecal delivery of, 153–155 safety of, 153–154 mechanisms of action, 4,284–287,286f versus nimodipine, 284–287,295 in protein kinase inhibition, 4,25,284–287,285t, 289,295, 297–298 during surgery, 250–251 Fenestration of lamina terminalis, 263–266,265f Ferritin, 142–145,144f Fibrin degradation products, in drained cisternal fluid, 312–314, 315t, 318–319 Fibrinolytic therapy See also Tissue plasminogen activator; Urokinase intracisternal, 227,229,238, 304–306 intrathecal, after endovascular treatment, 300–303, 301t, 302f Fludrocortisone, for salt wasting, after SAH, 233 Fluid overload, 245 Fluid resuscitation and circulating blood volume, 233 clinical trials of, 227 hydrocortisone with, 240–242 inotrope augmentation with, 201–202 safety and efficacy of, 243–246 Fluorescent resonance energy transfer (FRET), 8–11,9f, 10f Free radical(s) fasudil and, 287 ferrous iron and, 142–143 isoprostane as metabolite of, 204,206 magnesium levels and, 43,45 nitric oxide donors and, 277 oxyhemoglobin and, 117 and potassium channel dysfunction, 32–35 Free radical scavengers, 227, 229 G b–Galactosidase, gene transfection of, 112–115,113f, 114f Gamma aminobutyric acid, hypothermia and, 146–149,148f Gender, and cerebral vasospasm Mississippi study of, 220–223 United Kingdom study of, 189–192,190t, 191t 325 Gene expression, 65, 67 Gene therapy, 112–115 Gene transfection intravascular, with adenovirus vector, 112–115,113f, 114f via cisternal injections, 112–113 Genistein, potassium channels and, 29–31 Glial cell damage, in vasospasm and infarction, 210 Glucose arteriovenous difference of, isoprostane and, 205–206,206t hypothermia and, 146–149,148f Glucose transporter, hypoxia inducible factor–1 and, 134,136 Glutamate, hypothermia and, 146–149,148f Glutamine, hypothermia and, 146–149,148f G protein(s), and magnesium, 44–45 G–protein coupled receptor agonists, in tyrosine kinase activation, Grading scales, for SAH CT–based, and risk of vasospasm, 194–196 Hunt and Hess, 199–200, 220–223 modification of World Federation of Neurological Surgeons Scale, 197–200,198t, 199f, 199t and outcome, 221 Granulocyte–macrophage colony–stimulating factor (GM–CSF), 65 GriPGHS, in SAH–induced vasospasm, 65 Growth factors magnesium levels and, 43,45 in SAH–induced vasospasm, 45 in tyrosine kinase activation, H HA–1077 (Rho kinase inhibitor), 4–5 Headache, premonitory, 194–196 Heart rate, in vasospasm detection/prediction, 212–215 Hematocrit, circulating blood volume and, 231–233 Heme metabolism, after SAH, 142–145 Heme oxygenase–1,59, 65,142–145 Hemoconcentration, fasudil and, 287 Hemodilution See Hypertensive, hypervolemic, and hemodilutional therapy Hemodynamic therapy, 43,238 adverse effects of, 243,245 with cerebrospinal fluid drainage, 255–262 clinical trials of, 227 decision analysis of, 279–283,281f, 282f, 282t fasudil with, 288–291 hydrocortisone with, 240–242 inotrope augmentation in, 201–202 safety and efficacy of, 243–246 Hemoglobin, 18, 71–73, 74f cerebrospinal fluid drainage and, 255–258 and cytosolic calcium oscillations in endothelial cells, 119–121 in drained cisternal fluid, 312–314, 315t, 318–319 lamina terminalis fenestration and, 263–266 MAP kinase enhanced by, nitric oxide trapped by, 71–73, 72f, 73f, 74f, 117, 257 in SAH–induced brain injury, 57–60 sink effect of, 72, 73f Src tyrosine kinase enhanced by, thromboxane A and, 116–118,117f Histamine, magnesium deficiency and, 45 Histidine, hypothermia and, 146–149, 148f Hormone replacement therapy, and subarachnoid hemorrhage, 189–190 Horseradish peroxidase (HRP), in experimental study of vasospasm, 108 326 INDEX Human leukocyte antigen(s) B14, and risk of vasospasm, 194–196 CW4, and risk of vasospasm, 194–196 CW8, and risk of vasospasm, 194–196 Hunt and Hess scale, 199–200 correlation with outcome, 220–223 Hydrocephalus, 222 cerebrospinal fluid drainage and, 255–262 lamina terminalis fenestration and, 263–266 Hydrocortisone, and natriuresis, 240–242,241t, 242f, 243f Hydroxyfasudil See also Fasudil and myosin light chain kinase, 5–Hydroxytryptamine See Serotonin Hypertension history of, and grading of SAH, 197–200,198t and vasospasm, 108,110,194–196,220–221,223 Hypertensive, hypervolemic, and hemodilutional therapy clinical trials of, 227 decision analysis of, 279–283,281f, 282f, 282t inotrope augmentation in, 201–202 safety and efficacy of, 243–246 Hypertonic saline, in poor grade SAH, cerebrovascular effects of, 234–235 Hypervolemia, therapeutic See also Hypertensive, hypervolemic, and hemodilutional therapy safety and efficacy of, 243–246 Hypomagnesemia, 43–45 See also Magnesium Hyponatremia circulating blood volume and, 231–233 and death from vasospasm, 191–192 hydrocortisone and, 240–242, 241f, 242f in vasospasm detection/prediction, 212–215 Hypoperfusion computed tomography of, 183–185 hypertonic saline infusion and, 234–235 hypothermia and, 147–149 PET studies of, comparison with transcranial Doppler, 174–176 SPECT studies of, correlation with transcranial Doppler, 171–173, 172f thermal diffusion flowmetry of, 183–185 Hypotension fasudil and, 287 nitroglycerin and, 277 treatment of, safety and efficacy of, 243–246 Hypothermia metabolic alterations reduced by, 146–149,148f, 149f vasospasm detection in patient treated with, 212–215 for vasospasm treatment, 110, 146–149 Hypovolemia after SAH, 231–233, 232f, 233f hydrocortisone and, 240–242 treatment of, safety and efficacy of, 243–246 Hypoxanthine, 45 Hypoxia inducible factor–1,134–137,135f, 136f activation, regulation of, 136 a and b subunits of, 136 neuroprotective effects of, 134,136–137 I Iberiotoxin, and tyrosine kinase inhibitors, 29–31 Ik B kinase (IKK), 129–133, 130f–131f Immunodeficiency, 65 Immunoglobulins, 66 Indocyanine green pulse spectrophotometry, of circulating blood volume, after SAH, 231–233,232f, 233f Inducible nitric oxide synthase (iNOS), 129–133,130f–131f, 132f Infarction as cause of disability, 43 computed tomography studies of risk, 180–182 predictors of, S–100B and neuron specific enolase as, 208–210, 209f, 210f prevention of decision analysis of, 279–283,281f, 282t, 282f fasudil for, 284–287 insufficient or ineffective use of, 292–295, 293f, 293t, 294f Inflammatory response, 213 magnesium deficiency and, 43, 45 new perspectives on, 65–67 protein expression in, 129–133 in SAH–induced brain injury, 57–60 Inositol–triphosphate, thromboxane A and, 118 Instantaneous selective brain cooling, 110 Intercellular adhesion molecule–1,65–67 Interferon receptor type–1,65 Interferon regulatory factor–1, 65 Interleukin–1 IL–la, 65–67 IL–la, 97–99 cytotoxic effects in endothelial cells, 97–99 in SAH–induced brain injury, 57–60, 60f, 66 magnesium deficiency and, 45 Interleukin–6, 65–67 magnesium deficiency and, 45 in SAH–induced brain injury, 57–60, 60f Intermittent cisternal irrigation, 317–320, 318f, 319f International Subarachnoid Hemorrhage Trial, 249 Intra–arterial drug infusion, 252–254,253t Intracranial hemorrhage, cisternal irrigation and, 308,310,315–316 Intracranial pressure cerebrospinal fluid drainage and, 255–258 in cisternal irrigation, 313, 314f, 318 hemodynamic therapy and, 243–246 hypertonic saline infusion and, 234–235 Intraoperative microvascular Doppler (IMD) sonography, for monitoring vasospasm, 167–170,168f, 169f Intraparenchymal small arteries, changes in vasospasm, 47t, 48–49 Intrathecal delivery of liposomal fasudil, 153–155,154f of prolonged–release nicardipine, 269–273,270t, 271f risks and limitations of, 154 tablet implantation for, 154–155 of tissue plasminogen activator, after endovascular treatment, 300–303,301t, 302f Intravascular gene transfection, 112–115,113f, 114f Inwardly rectifying potassium channels, 12–15,35 Ion channel(s) See also Calcium channel(s); Potassium channel(s) after subarachnoid hemorrhage, 12–15,14f, 15f Iron CSF levels of, 142–145,144f detoxification, after SAH, 142–145 magnesium deficiency and, 45 Panax notoginseng saponins and, 236–238 Ischemia as cause of disability, 43 cerebral blood flow monitoring for, 183–185 computed tomography of, 177–185 hypothermia and, 110,146–149 hypoxia inducible factor–1 in, 134,136–137 inotrope augmentation of blood pressure in, 201–202 intraparenchymal small artery changes and, 47t, 48–49 isoprostane in, 204–206 platelet hyperactivity and, 47t, 47–48 INDEX prevention of cerebrospinal fluid drainage and, 255–262 fasudil for, 284–287 Panax notoginseng saponins for, 236–238 transdermal nitroglycerin for, 274–277 pulmonary hypertension induced by, 287 Isoprostane, 204–206,205f, 206t cerebral uptake of, 204, 206 L Lactate accumulation, hypothermia and, 146–149,148f, 149f arteriovenous difference of, isoprostane and, 204–206,206t Lamina terminalis fenestration, 263–266,265f Large–conductance, Ca 2+ –activated potassium (BK) channels, 12–15,14f, 15f, 20–23,22f, 32–35 actions of, 33,33f dysfunction of, 32–35 and tyrosine kinase inhibitors, 29–31 Leukocytes, 66 in drained cisternal fluid, 312–314, 315t fasudil and, 287 Lindegaard ratios, 175,206,210 transdermal nitroglycerin and, 274–277, 276f Lipid peroxidation ferrous iron and, 142–143 nitric oxide donors and, 277 oxyhemoglobin and, 117 Liposomal fasudil safety of, 153–154 for vasospasm prevention, 153–155,154f intrathecal delivery of, 153–155 12–Lipoxygenase, in SAH–induced vasospasm, 65 L–type calcium channels after subarachnoid hemorrhage, 12–15,14f magnesium and, 44 Lumbar cerebrospinal fluid drainage, 255–258,256t, 2571, 259–262, 260f, 261f M Macrophage(s), 66 Macrophage inflammatory protein–2 (MIP–2), 65 Magnesium acute effects of, 157,157f, 158f antagonism of calcium, 43,158 as calcium channel blocker, 43–44,158 chronic effects of, 157,158f deficiency of and inflammatory response, 43,45 and oxidative endothelial cytotoxicity, 45 and SAH–induced vasospasm, 43–45 and signaling pathways, 44–45 dose–response curve for relaxation by, 157,158f for prevention of vasospasm, 43–45,156–159 for treatment of vasospasm, 43–44,156–159,157f, 158f Magnetic resonance spectroscopy (MRS), of hypothermia effects, 146–149 Manganese superoxide dismutase, 65 MAP kinase See Mitogen–activated protein kinase Matrix metalloproteinases, 65 Mean transit time (MTT), computed tomography of, 178f, 178–182, 181t, 182t Mechanical trauma, and vasospasm, 108,109f, 110,167–170 surgical versus endovascular cause of, 249–251,250t, 251t Medical history, 220–221,223 Membrane depolarization, potassium channels and, 20–23 327 Membrane potential, 20–23 Men, cerebral vasospasm in Mississippi study of, 220–223 United Kingdom study of, 189–192, I90t, 191t Meningitis aseptic hemogenic, 169 cisternal irrigation and, 308,310, 314–315 Messenger ribonucleic acid (mRNA), 129–133 Methemoglobin after subarachnoid hemorrhage, 18 oxyhemoglobin oxidation into, 117 4–Methyl–3–vinylmaleimide, 52 MgSO , for vasospasm treatment, 229 Micro–balloon catheters, intravascular adenoviral gene transfection using, 112–115,113f Microcirculatory changes, 47t, 47–49 Microdialysis, for study of hypothermia effects, 146–149 Microdrop system, in cisternal irrigation, 313,314f Microglia activation, in SAH–induced brain injury, 57–60,59f, 60f Microthrombosis, in symptomatic vasospasm, 47–48 Middle cerebral artery flow in dynamic perfusion CT of, 177–179,178f, 179f hypertonic saline infusion and, 234–235 PET versus transcranial Doppler of, 174–176 vasospasm of endothelial dysfunction and, 83–85 endothelin receptor phenotype and, 79–82, 81f, isoprostane and, 204–206 S–100B and neuron specific enolase as predictors of, 208–210 white thrombi and, 109f Millipore filter, in cisternal irrigation, 313,314f Milrinone histology and immunohistochemistry of effects, 162f, 163 intra–arterial versus intracisternal injection of, 160–163,161f, 162f for treatment of chronic vasospasm, 160–163,161f, 162f in vitro effects of, 162 Mississippi, sex and racial factors in SAH outcome in, 220–223 Mitochondria failure of, and vascular dysfunction, 52 uncoupling of, 53 Mitogen–activated protein (MAP) kinase, 3–4, 17–18 after subarachnoid hemorrhage, 17–18 interactions with tyrosine kinases, magnesium deficiency and, 44 oxyhemoglobin and, 117 Monocyte chemotactic protein–1, 67 Mouse model, of chronic cerebral vasospasm, potassium channels in, 32–35,34f Multivariate logistic regression, for SAH analysis, 195–196, 196f Myosin light chain, phosphorylation of, 4–5, 25–27, 36–39, 103–104, 138–141 protein kinase C and, 104 Rho kinase and, 103–104,138–141 Rho kinase inhibitors and, 36–39, 39f sphingosine–1 phosphate and, 25–27 Myosin light chain kinase, 4–5, 36–39 calmodulin–sensor, in smooth muscle contraction, 8–11 inhibition by fasudil, 284–287, 285t, 289, 295,298 N Natriuresis, hydrocortisone and, 240–242,241f, 241t, 242f Neurologic deficit, SAH–induced cerebrospinal fluid drainage and, 255–262 microglia activation in, 57–60, 59f, 60f nimodipine and, 201 328 INDEX Neurologic deficit (continued) Panax notoginseng saponins for prevention of, 236–238 surgery versus endovascular treatment, as cause of, 249–251, 250t, 251t transcranial Doppler versus PET in, 174–176 transdermal nitroglycerin and, 274–277 Neuronal nitric oxide synthase (nNOS), destruction of, 71–73,73f, 74f Neuron specific enolase (NSE), as predictor of vasospasm and infarction, 208–210,209f, 210f Neuroprotection by fasudil, 284–287 by hypothermia, 110,146–149 by hypoxia inducible factor–l, 134,136–137 by magnesium, 43–45,156–159 by Panax notoginseng saponins, 236–238 Neurotransmitters, hypothermia and, 146–149 NG2 (oligodendrocyte progenitor), 57–60,59f Nicardipine, 44 clinical trials of, 228,269–273 fasudil versus, 295 intracisternal, 229 prolonged–release implants of, 269–273, 270t, 271f Nicorandil, in vasospasm prevention, 13 Nicotine, and vasoconstriction, 122–125,123f, 124f Nimodipine, 43–44,238 with cerebrospinal fluid drainage, 255–262 clinical trials of, 227–228 fasudil versus, 284–287,295 intravenous, and death from vasospasm, 191–192 and neurological deficits, 201 Nitric oxide (NO), 12, 71–73, 74f, 169,274–275 “first and second h i t s ” on, 73 hemoglobin trapping of, 71–73, 72f, 73f, 74f, 117, 257 physical properties of, 169 in SAH–induced brain injury, 60 synthesis of, nicotine and, 122–125,124f Nitric oxide (NO) donors, 274–277 intraoperative use of, 167–170 Nitric oxide synthase (NOS) endothelial, inhibition of, 71–73,74f, 90–92,129–133,257 inducible, 129–133,130f,–131f, 132f neuronal, destruction of, 71–73, 73f, 74f Nitric oxide (NO) therapy, 72 Nitrites/nitrates, 72–73, 74f in nitroglycerin biotransformation, 275 Nitroglycerin biotransformation of, 275 reduction of, rebound of vasospasm after, 277 risks of, 277 tolerance to, 275,277 transdermal, for vasospasm prevention/treatment, 274–277, 276f, 277f N–methyl–D–aspartate (NMDA) receptor antagonists, 158 Norepinephrine, for blood pressure augmentation, 201–202 Nuclear factor–k B (NF–kB), 66,129–133,130f–131f activation of, 99 cytosolic calcium oscillations and, 119–121 O Obesity, 220–221, 223 Occipital lobe hypoperfusion, and vasospasm risk, 171–173 Okadaic acid, 51–52, 55 OKY–046 (thromboxane A inhibitor), 48 OX–42 (activated microglial marker), 57–60,59f Oxidative endothelial cytotoxicity, magnesium deficiency and, 45 Oxidative stress mediators, 65 Oxygen, arteriovenous difference of, isoprostane and, 204–206, 206t Oxygenation, brain tissue, hemodynamic therapy and, 243–246 Oxygen consumption, magnesium and, 156–159,157f Oxygen homeostasis, hypoxia inducible factor–l and, 134,136–137 Oxygen metabolism, 52–53 Oxygen partial pressure (pO2), and death from vasospasm, 191–192 Oxyhemoglobin, 18, 71–73, 74f, 116–118, 169 ascorbic acid and, 216–218,308–311,317–320 cisternal irrigation and, 216–218,217f, 218f, 308–311 analysis of drained fluid for, 312–314,315t intermittent injection protocol for, 317–320,319f ferrous iron component of, 142–143 heme oxygenase–1 and, 142 inhibition by Y–27632,103 and mitogen–activated protein kinase, 117 nitric oxide depletion by, 71–73, 73f, 74f, 169 oxidation into methemoglobin, 117 synergy with thromboxane A ,116–118,117f Ozagrel sodium, intraoperative use of, 250–251 P Panax notoginseng saponins, for vasospasm and ischemia prevention, 236–238 Papaverine, 107,169 with balloon angioplasty, 252–254 intra–arterial infusion of, 252–254 intracisternal, 229 topical, use during aneurysmal surgery, 167–170 Perfusion cerebrospinal fluid drainage and, 255–258 computed tomography of, 183–185 correlation with transcranial Doppler, 177,179f, 180–182,181t, 182t, 182f in severe symptomatic vasospasm, 177–179,178f hemodynamic therapy and, 243–246 hypertonic saline infusion and, 234–235 inotrope–induced changes in, 201–202 Panax notoginseng saponins and, 236–238 PET of, comparison with transcranial Doppler, 174–176 in SAH–induced vasospasm, 147 hypothermia and, 147–149 SPECT of, correlation with transcranial Doppler, 171–173,172f thermal diffusion flowmetry of, 183–185 Permeability changes, of major cerebral arteries, 108 Peroxynitrite, 72 and potassium channels, 32–35 PET See Positron emission tomography pH, in vasospasm detection/prediction, 212–215 Phorbol esters in protein kinase C activation, 104 in smooth muscle contraction, 11 Phorbol–12 myristate–13 acetate (PMA), 51,55 Phosphatase inhibition, 52 Phosphatidyl inositol–3 kinase tyrosine kinase, Phosphodiesterase isoforms of, 163 in smooth muscle, 160–161,163 Phosphodiesterase III inhibitor histology and immunohistochemistry of effects, 162f, 163 intra–arterial versus intracisternal injection of, 160–163,161f, 162f for treatment of chronic vasospasm, 160–163,161f, 162f in vitro effects of, 162 Phospholipase C, 118 Platelet–derived growth factor–AB (PDGF–AB), 45 Platelet hyperactivity, in ischemia during vasospasm, 47t, 47–48 INDEX Poly(ADP–ribose) polymerase (PARP), 66 cytokines and, 97–99 Positron emission tomography (PET) comparison with transcranial Doppler, 174–176 of inotrope–induced changes in perfusion, 201–202 Posterior circulation vasospasm, transcranial Doppler monitoring for, 171–173,172f Posterior communicating artery vasospasm, endothelin receptor phenotype and, 79–82 Potassium, serum level of, and SAH outcome, 222 Potassium channel(s), 12–15,14f, 15f, 20–23,22f, 32–35 actions of, 33, 33f dysfunction of, 32–35 types in vascular smooth muscle, 35 and tyrosine kinase inhibitors, 29–31 Potassium channel agonists, in vasospasm prevention, 13 PP2 Src inhibitor, and reduction in cerebral vasospasm, 17–18 Premonitory headache, 194–196 Prevention antioxidants for, 227, 229 ascorbic acid for, 216–218 calcium channel blockers for, 43, 158,227–228 caspase inhibitors for, 97–99 cerebrospinal fluid drainage for, 255–258,256t, 257t, 259–262, 260f, 261f cisternal irrigation for, 308–311,309t, 310t, 310f intermittent injection protocol for, 317–320,318f, 319f oxyhemoglobin concentration changes in, 216–218,217f, 218f surgical procedures and postoperative management in, 312–316,314f, 315t, 315f clinical trials of, 227–230 ebselen for, 229 endothelin B receptor null mutation in, 75–77 fasudil for, 228–229 liposomal, intrathecal delivery of, 153–155,154f fenestration of lamina terminalis for, 263–266,265f free radical scavengers for, 227,229 hydrocortisone for, 240–242 intracisternal fibrinolytic agents for, 227,229 magnesium for, 43–45,156–159 nicardipine prolonged–release implants for, 269–273,270t, 271f Panax notoginseng saponins for, 236–238 potassium channel agonists for, 13 probucol for, 73 protein kinase C inhibitors for, 36, 104–105,138–141,139f, 140f Rho kinase inhibitors for, 4–5,103,228–229,284–287 during surgery, adjuvant therapies for, 250–251 thromboxane A2 inhibitors for, 48 tirilazad for, 229 tissue plasminogen activator for intracisternal, 238, 304–306 intrathecal, after endovascular treatment, 300–303, 301t, 302f transdermal nitroglycerin for, 274–277,276f, 277f tyrosine kinase inhibitors for, 4, 17–18,29–31 Primate model, of endothelial dysfunction, 83–85, 84f, 85f Probucol, 73 Prostaglandin receptors, 65 Protein expression, 129–133,130f–131f, 132f Protein kinase A, and serotonin receptors, 128 Protein kinase C, 104–105, 118 activation of, nicotine and, 122–125, 124f inhibition of endothelin receptors by, 128 isoforms of a, 36–39, 103–105, 138–141,140f d, 36–39, 103–105, 138–141,140f h, 104 329 Rho kinase and, 103, 138–141,139f, 140f Rho kinase inhibitors and, 36–39,37f, 38t, 138–141, 139f, 140f in SAH–induced vasospasm, 36–39,104–105,138–141 initiation versus maintenance, 138, 140–141 z,104 mechanical trauma and, 169 in myosin light chain phosphorylation, 104,138–141 in smooth muscle contraction, 8–11,10f versus Src tyrosine kinase, tonic cerebral vascular contraction induced by, 104 Protein kinase C inhibitor(s) fasudil as, 284–287, 285t, 289 in vasospasm prevention, 36, 104–105,138–141,139f, 140f, 284–287 P–selectin, 65 Pulmonary edema, hemodynamic therapy and, 245 Pulmonary hypertension, ischemia–induced, fasudil and, 287 Q Quality–adjusted life expectancy (QALE), treatment modalities and, 279–283 R Race, and SAH outcome, 220–223 Ras–protein, tyrosine kinase and, Reactive oxygen species (ROS), and potassium channel dysfunction, 32–35 Recombinant tissue plasminogen activator (rt–PA), intracisternal thrombolysis with, 304–306 Red blood cells, in drained cisternal fluid, 312–314,315t, 318–319 Red blood cell transfusion, 233,233f Regional cerebral blood flow (rCBF) See also Cerebral blood flow computed tomography of, 177–179,178f correlation with transcranial Doppler flow velocities, 171–173, 172f Respiratory rate, in vasospasm detection/prediction, 212–215 Rho kinase, 4–5,25–27,36–39,103–104 in calcium sensitization, 25–27,36,103–104 and myosin light chain phosphorylation, 103–104 and protein kinase isoforms, 103, 138–141,139f, 140f in smooth muscle contraction, 8–11, 103 sphingosine–1 phosphate and, 25–27, 26f Rho kinase inhibitor(s) fasudil as, 25, 284–287,285t, 289 ,295,297–298 and myosin light chain phosphorylation, 36–39, 39f, 103 and protein kinase C isoforms, 36–39, 37f, 38t, 138–141, 139f, 140f and smooth muscle contraction, 8–11,10f and sphingosine–1 phosphate, 25–27, 26f in vasospasm prevention, 4–5, 103,228–229,284–287 Rottlerin, for vasospasm prevention, 36,104–105,138–141, 139f, 140f S SAH See Subarachnoid hemorrhage Saline, hypertonic, in poor grade SAH, cerebrovascular effects of, 234–235 Salt wasting syndrome, 215 circulating blood volume and, 231,233 hydrocortisone and, 242 S–100B, as predictor of vasospasm and infarction, 208–210, 209f, 210f Second messengers, 65 Seizures, cisternal irrigation and, 308,310 Selectins, in SAH–induced vasospasm, 65 330 INDEX Serotonin, 126–128 magnesium and, 44 in smooth muscle contraction, 11 thromboxane A and, 118 Serotonin receptors, 126–128,127f, 128f Sex, and cerebral vasospasm Mississippi study of, 220–223 United Kingdom study of, 189–192,190t, 191t Shear stress, and endothelial nitric oxide synthase, 71–72 Signaling pathways, 3–5 magnesium deficiency and, 44–45 Single photon emission computed tomography (SPECT) correlation with transcranial Doppler flow velocities, 171–173 versus dynamic perfusion CT, 178f, 178–179 Sink effect, of hemoglobin on nitric oxide, 72, 73f Small vessel changes, 47t, 48–49 Smooth muscle contraction calcium–dependent, 11 calcium–independent, 11 calmodulin–sensor myosin light chain kinase and, 8–11 mechanism of, new approach to, 8–11 phases of, 11 Rho kinase and, 8–11,103 tyrosine kinase and, 3–4 Smooth muscle phenotype change, in SAH–induced vasospasm, 61–64, 63f, 104 contractile, 61, 64 dedifferentiated synthetic, 61, 64 Smooth muscle relaxation, 12, 275 magnesium and, 156–159 Panax notoginseng saponins and, 236–238 phosphodiesterase III inhibitor and, 160–163 Sodium serum level of circulating blood volume and, 231–233 and death from vasospasm, 191–192 hydrocortisone and, 240–242, 241f, 242f hypertonic saline infusion and, 234–235 and SAH outcome, 222 in vasospasm detection /prediction, 212–215 urine level of circulating blood volume and, 231–233 hydrocortisone and, 240–242, 242f Sodium chloride therapy, after SAH, 233 Sodium nitroprusside intraventricular, for vasospasm treatment, 229 topical, use during aneurysmal surgery, 167–170 Spasm Symposium in Kyoto, 106 SPECT See Single photon emission computed tomography Sphingosine–1 phosphate, 4–5, 25–27, 26f, 27f Sphingosylphosphorylcholine, Src tyrosine kinase, 4,17–18 magnesium deficiency and, 44 versus protein kinase C, Src tyrosine kinase inhibitors, 17–18 Subarachnoid hemorrhage (SAH) circulating blood volume after, 231–233, 232f, 233f clinical management of, 289, 289t grading of Hunt and Hess scale for, 199–200, 220–223 modification of World Federation of Neurological Surgeons Scale, 197–200, 198t, 199f, 199t and outcome, 221 and risk of vasospasm, 194–196 natriuresis after, 240–242, 241f, 242f poor grade, hypertonic saline effects in, 234–235 Subarachnoid hemorrhage–induced vasospasm, 106–111 age and, 110, 194–196,221 asymmetric dimethyl arginine in, 71–73, 74f, 90–92 bilirubin oxidation products (BOXes) in, 51–55, 53f, 54f, 71, 143 cerebral blood flow monitoring in, 183–185 cerebrospinal fluid analysis in See Cerebrospinal fluid analysis cisternal CSF and cytosolic calcium oscillations in, 119–121, 120f clinical and laboratory variables in, 194–196 clinical experiences in, 109–110 comorbid conditions and, 220–223 computed tomography of, 183–185 correlation with transcranial Doppler, 177, 179,179f,180–182, 181t, 182f, 182t dynamic perfusion, 177–179, 178f timing for detection/prevention, 109 cranial window technique for study of, 53f, 53–54, 54f current management and prevention of, 43 cytokines in, 57–60, 60f, 65–67, 97–99, 213 delayed, 54–55 three–stage hypothesis of, 71–73, 74f disability causes in, 43 endothelial dysfunction in, 71–73, 74f primate model of, 83–85, 84f, 85f endothelin–1 in, 66, 75–77, 169 cerebrospinal fluid levels of, 93–95, 94t, 95f increased contractile effect of, 86–88, 87f, 88f endothelin receptors in contractile effects of, 87–88 ETA, 87–88,128f ETA and ETB interactions in, 79–82, 81f ETB, 75–77f 76f, 77f, 78f, 128,128f phenotype alteration of, 79–82, 81f experimental studies of, 106–108 ferritin in, 142–145,144f gene expression studies of, 65–67 growth factors in, 45 heme oxygenase–1 in, 59, 65,142–145 hypoxia inducible factor–1 in, 134–137,135f, 136f inflammation and, 213 new perspectives on, 65–67 intraoperative monitoring for, 167–170,168f, 169f intraparenchymal small artery changes in, 47t, 48–49 ion channel changes in, 12–15,14f, 15f isoprostane in, 204–206, 205f, 206t key factors expressed in, 129–133 magnesium in, 43–45 messenger ribonucleic acid in, 129–133 microcirculatory changes in, 47t, 47–49 microglia activation in, 57–60, 59f, 60f microthrombosis in, 47–48 murine model of, 66 myosin light chain phosphorylation in, 4–5, 36–39,103–104 nicotine and, 122–125, 123f, 124f in northern England, 194–196, 196f oxygen metabolism in, 52–53 oxyhemoglobin–thromboxane A synergy in, 116–118,117f pathological arteries in, 108,110 pathophysiology of, controversial issues in, 103–105 permeability changes of major cerebral arteries in, 108 pharmacologic study of, new model for, 107–108 platelet hyperactivity in, 47t, 47–48 potassium channels in, 12–15, 14f, 15f, 20–23, 22f, 30–35 prediction of APACHE score for, 212–215, 213f, 214f S–100B and neuron specific enolase in, 208–210,209f, 210f presence on admission, and outcome, 197–200,198t INDEX prevention/reduction of antioxidants for, 227,229 ascorbic acid for, 216–218 calcium channel blockers for, 43,158,227–228 caspase inhibitors for, 97–99 cerebrospinal fluid drainage for, 255–258,256t, 257t, 259–262, 260f, 261f cisternal irrigation for, 216–218, 217f, 218f, 308–311, 309t, 310t, 310f intermittent injection protocol for, 317–320, 318f, 319f surgical procedures and postoperative management in, 312–316, 314f, 315t, 315f clinical trials of, 227–230 fasudil for, 228–229 liposomal, 153–155,154f fenestration of lamina terminalis for, 263–266, 265f free radical scavengers for, 227, 229 hydrocortisone for, 240–242 intracisternal fibrinolytic agents for, 227,229 magnesium for, 43–44, 156–159 nicardipine prolonged–release implants for, 269–273,270t, 271f Panax notoginseng saponins for, 236–238 potassium channel agonists for, 13 protein kinase C inhibitors for, 36,104–105,138–141,139f, 140f Rho kinase inhibitors for, 4–5,228–229, 284–287 during surgery, adjuvant therapies for, 250–251 thromboxane A2 inhibitors for, 48 tissue plasminogen activator for intracisternal, 238, 304–306 intrathecal, after endovascular treatment, 300–303,301t, 302f transdermal nitroglycerin for, 274–277,276f, 277f tyrosine kinase inhibitors for, 17–18, 29–31 protein expression in, 129–133, 130f–131f, 132f protein kinase C isoforms in, 36–39 race and, 220–223 Rho kinase in, 4–5,36–39 serotonin receptor phenotype change in, 126–128, 127f severity of, 106f, 106–107, 110 sex (gender) and, 189–192,190t, 191t, 220–223 signaling pathways in, 3–5 smooth muscle phenotype change in, 61–64, 63f, 104 sphingosine–1 –phosphate and, 25–27, 26f, 27f surgery versus endovascular treatment, as cause of, 249–251, 250t, 251t survival analysis of, 194–196, 196f thermal diffusion flowmetry in, 183–185 transcranial Doppler in comparison with PET, 174–176 correlation with computed tomography, 177, 179f, 180–182, 181t, 182t, 182f correlation with SPECT, 171–173,172f treatment of angioplasty for, 229, 238,252–254, 253t outcomes analysis of, 279–283, 281f, 282f, 282t antioxidants for, 227, 229 calcium channel blockers for, 227–228, 238 cerebrospinal fluid drainage for, 255–258, 256t, 257t clinical trials of, 227–230 conservative management in, 279–283,281f, 282t decision analysis in, 279–283, 281f, 282t, 282f endovascular, 229, 238,252–254, 253t fasudil for, 228–229, 284–287, 285t, 286f for good grade patients, after early surgery, 288–291,290t insufficient or ineffective use of, 292–295, 293f, 293t, 294f intraventricular urokinase with, 296–299, 297f, 297t, 298f mechanisms of action, 284–287,285t, 286f 331 free radical scavengers for, 227,229 gene therapy for, 112–115 hemodynamic therapy for, 43, 201–202, 227, 238 outcomes analysis of, 279–283,281f, 282f, 282t safety and efficacy of, 243–246 hypothermia for, 110, 146–149 hypoxia inducible factor–1 for, 137 inotrope augmentation of blood pressure in, 201–202 instantaneous selective brain cooling for, 110 intra–arterial drug infusion for, 252–254,253t intracisternal fibrinolytic agents for, 227,229, 238 magnesium for, 43–44,156–159,157f, 158f putative window for, 156 transdermal nitroglycerin for, 274–277, 276f, 277f two–type hypothesis of, 110 vascular dysfunction in, 52–53 white thrombi and, 108, 109f in young versus elderly, 110 Subarachnoid hemorrhage syndrome, 106–111 Substance P, vasodilatation induced by, nicotine and, 122–125,123f, 124f Suppressor of cytokine signals (SOCS), 65 Suramin, vasospasm inhibited by, Surgery in cisternal irrigation therapy, 312–316,314f early, fasudil for good grade SAH patients after, 288–291,290t intraoperative microvascular Doppler sonography monitoring in, 167–170,168f, 169f lamina terminalis fenestration during, 263–266,265f topical vasodilators during, 167–170 vasospasm caused by, 108,109f, 110,167–170 adjuvant therapies preventing, 250–251 versus endovascular treatment, 249–251,250t, 251t Survival analysis, 194–196,196f Syndrome of inappropriate secretion of antidiuretic hormone (SIADH), 215 Systemic inflammatory response syndrome (SIRS), in vasospasm detection/prediction, 212–215, 213f, 214f Systolic blood pressure, and grading of SAH, 197–200,198t T Tachycardia, in vasospasm detection/prediction, 212–215 Tachypnea, in vasospasm detection/prediction, 212–215 Taurine, hypothermia and, 146–149,148f T cells, 66 Temperature, lowering of See Hypothermia Thalamic hypoperfusion, and vasospasm risk, 171–173 Thapsigargin, and cytosolic calcium oscillations, 119–121,120f Thermal diffusion flowmetry, of cerebral blood flow, 183–185 Three–stage hypothesis, of delayed vasospasm after SAH, 71_73 r 74f Thrombi, white, and vasospasm, 108,109f Thromboxane A endogenous distribution of, 117–118 synergy with oxyhemoglobin, 116–118,117f Thromboxane A inhibitors, for vasospasm prevention, 48 Tirilazad clinical trials of grading scale developed during, 197–200 for vasospasm prevention/treatment, 229 drug interactions of, 229 Tissue factor pathway inhibitor–1 (TFPI–1), 65 Tissue inhibitor of matrix metalloproteinase 2, 65 Tissue plasminogen activator intracisternal, 238, 304–306 intrathecal, after endovascular treatment, 300–303, 301t, 302f 332 INDEX Topical vasodilators, use during aneurysmal surgery, 167–170 Traditional medicine, for vasospasm and ischemia prevention, 236–238 Transcranial Doppler (TCD) comparison with PET, 174–176 correlation with computed tomography, 177,179f, 180–182,181t, 182t, 182f correlation with SPECT, 171–173 flow velocities in, and vasospasm risk, 171–173,172f of isoprostane concentrations, 206,206t of nitroglycerin effects, 274–277,276f Transdermal nitroglycerin, 274–277,276f, 277f Transforming growth factor–b , 45 Transluminal balloon angioplasty, 229,238,252–254,253t decision analysis of, 279–283, 281f, 282f, 282t intra–arterial fasudil with, 297–298 Treatment angioplasty for, 229,238,252–254,253t outcomes analysis of, 279–283, 281f, 282f, 282t antioxidants for, 227,229 calcium channel blockers for, 227–228, 238 cerebrospinal fluid drainage for, 255–258, 256t, 257t clinical trials of, 227–230 conservative management in, 279–283,281f, 282t decision analysis in, 279–283, 281f, 282t, 282f ebselen for, 229 endovascular, 229, 238,252–254,253t fasudil for, 228–229 for good grade SAH patients, after early surgery, 288–291,290t insufficient or ineffective use of, 292–295, 293f, 293t, 294f intraventricular urokinase with, 296–299, 297f, 297t, 298f mechanisms of action, 284–287, 285t, 286f free radical scavengers for, 227, 229 gene therapy for, 112–115 hemodynamic therapy for, 201–202, 227,238, 279–283, 281f, 282f, 282t outcomes analysis of, 279–283, 281f, 282f, 282t safety and efficacy of, 243–246 hypothermia for instantaneous selective brain cooling for, 110 metabolic alterations reduced by, 146–149, 148f, 149f hypoxia inducible factor–1 for, 137 inotrope augmentation of blood pressure in, 201–202 intra–arterial drug infusion for, 252–254, 253t intracisternal fibrinolytic agents for, 227, 229 magnesium for, 43–44,156–159,157f, 158f papaverine for, 169 phosphodiesterase III inhibitor for, 160–163, 161f, 162f putative window for, 156 tirilazad for, 229 transdermal nitroglycerin for, 274–277,276f, 277f Triple H therapy clinical trials of, 227 decision analysis of, 279–283, 281f, 282f, 282t inotrope augmentation in, 201–202 safety and efficacy of, 243–246 Tumor necrosis factor a, 66, 97–99 cytotoxic effects in endothelial cells, 97–99 magnesium deficiency and, 45 in SAH–induced brain injury, 57–60, 60f Tyrosine kinase, 3–4,17–18 interaction with MAP kinases, magnesium deficiency and, 44 in smooth muscle contraction, 3–4 Tyrosine kinase inhibitors, in vasospasm prevention, 4, 17–18 potassium channels and, 29–31 Tyrphostin A–23, potassium channels and, 29–31 Tyrphostin A–25, potassium channels and, 29–31 U U–46619 (thromboxane A2 analogue), synergy with oxyhemoglobin, 116–118, 117f Ultrasonography intraoperative microvascular Doppler, 167–170,168f, 169f transcranial Doppler comparison with PET, 174–176 correlation with computed tomography, 177, 179f, 180–182, 181t, 182t, 182f correlation with SPECT, 171–173 flow velocities in, and vasospasm risk, 171–173,172f of isoprostane concentrations, 206,206t of nitroglycerin effects, 274–277, 276f United Kingdom, SAH–induced vasospasm in, 194–196,196f sex (gender and), 189–192, 191t, 192t Urine volume after SAH, hydrocortisone and, 240–242 fasudil and, 287 Urokinase cisternal injection of, 227,229,238 cisternal irrigation with, 297 and changes in oxyhemoglobin levels, 216–218, 217f, 218f intermittent injection protocol for, 317–320, 318f, 319f surgical procedures and postoperative management in, 312–316, 314f, 315t, 315f intraventricular, with intra–arterial fasudil, 296–299, 297f, 297t, 298f V Vascular contraction, 52 Vascular endothelial growth factor (VEGF), 45,134–137 hypoxia inducible factor–1 and, 134, 136 Vascular metabolism, 52 Vascular relaxation, tyrosine kinase–induced, potassium channels and, 29–31 Vascular remodeling, 51–55 Vasodilatation, biphasic, 107, 107f Vasospasm See Cerebral vasospasm; Subarachnoid hemorrhage–induced vasospasm Ventricular tapping, for cisternal irrigation, 313 Ventriculostomy, for cisternal irrigation, 313 Vertebral artery, gene transfer into, 112–115,113f, 114f Vitamin E, magnesium deficiency and, 45 Voltage–gated calcium channels, magnesium and, 44 Voltage–gated potassium channels, 12–15, 20–23, 22f, 35 W Water balance, hydrocortisone and, 240–242 White blood cells, 66 in drained cisternal fluid, 312–314, 315t fasudil and, 287 White thrombi, and vasospasm, 108, 109f Women, cerebral vasospasm in Mississippi study of, 220–223 United Kingdom study of, 189–192, 190t, 191t World Federation of Neurological Surgeons (WFNS) Scale, modification of, 197–200,198t, 199f, 199t X Xanthine oxidase, 45 INDEX Y Y–27632 (Rho kinase inhibitor), in vasospasm prevention, 4,103 effect on myosin light chain phosphorylation, 36–39, 39f, 103 effect on protein kinase C isoforms, 36–39, 37f, 38t, 138–141, 139f, 140f effect on smooth muscle contraction, 8–11,10f effect on sphingosine–1 phosphate, 25–27, 26f Yorkshire, sex (gender) and cerebral vasospasm in, 189–192, 191t, 192t Young persons, SAH–induced vasospasm in, 110 Z Z–DEVD–FMK, and cytotoxic effects of cytokines, 98 Zinc, magnesium deficiency and, 45 333 ... contraction is initiated by the binding of Ca 2+ to calmodulin and the subsequent binding of this Ca + –calmodulin com plex to myosin light chain kinase This would result in a lower tension and therefore... fasudil, into liposomes, and in vitro stability of the fasudil-loaded liposomes Int J Pharm 20 02; 2 32: 59–67 Suzuki H, Kanamaru K, Tsunoda H, et al Heme oxygenase-1 induction as an intrinsic regulation... in crease in the permeability of the cell membranes with subsequent intracellular loading of free Ca 2+ (Ca2+ overloading) The Ca 2+ is able to activate Ca 2+ calmodulin-dependent protein kinase