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Intracarotid Nitroprusside Does Not Augment Cerebral Blood Flow in Human Subjects Shailendra Joshi, M.D.,* William L

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Intracarotid Nitroprusside Does Not Augment Cerebral Blood Flow in Human Subjects Shailendra Joshi, M.D.,* William L Anesthesiology 2002; 96:60–6 © 2002 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Intracarotid Nitroprusside Does Not Augment Cerebral Blood Flow in Human Subjects Shailendra Joshi, M.D.,* William L. Young, M.D.,† Huang Duong, M.D.,‡ Beverly A. Aagaard, M.D.,§ Noeleen D. Ostapkovich, R.E.E.G.T.,ʈ E. Sander Connolly, M.D.,# John Pile-Spellman, M.D.** Background: The recent resurgence of interest in the cerebro- sospasm, intrathecal nitroprusside increases CBF and vascular effects of nitroprusside can be attributed to the possi- results in angiographic and neurologic improvement.2,3 bility of using nitric oxide donors in treating cerebrovascular However, despite extensive investigations, the effect of insufficiency. However, limited human data suggest that intra- carotid nitroprusside does not directly affect cerebrovascular nitroprusside on CBF of resting humans as well as non- resistance. In previous studies, physiologic or pharmacologic human primates remains controversial (tables 1 and 2). reactivity of the preparation was not tested at the time of nitro- As is evident from table 1, most human studies have used Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/96/1/60/404471/0000542-200201000-00016.pdf by guest on 01 October 2021 prusside challenge. The authors hypothesized that if nitric ox- intravenous infusion of nitroprusside. Intravenous nitro- ide is a potent modulator of human cerebral blood flow (CBF), prusside not only decreases mean arterial pressure then intracarotid infusion of nitroprusside will augment CBF. 4,5 Methods: Cerebral blood flow was measured (intraarterial (MAP) but can also increase intracranial pressure, im- 6 7 133Xe technique) in sedated human subjects undergoing cere- pair autoregulation, and change cardiac output. bral angiography during sequential infusions of (1) intracarotid Changes in any of these parameters could indirectly saline, (2) intravenous phenylephrine to induce systemic hy- affect CBF during intravenous nitroprusside infusion. In pertension, (3) intravenous phenylephrine with intracarotid ؊ ؊ contrast to an intravenous infusion, intracarotid infusion nitroprusside (0.5 ␮g·kg 1 · min 1), and (4) intracarotid vera- pamil (0.013 mg · kg؊1 · min؊1). Data (mean ؎ SD) were ana- of a drug limits the initial volume of distribution to one lyzed by repeated-measures analysis of variance and post hoc cerebral hemisphere. Therefore, intracarotid infusions Bonferroni–Dunn test. can isolate the regional vascular effects of a drug from Results: Intravenous phenylephrine increased systemic mean their systemic effects. To date, only two studies in hu- ؍ ؎ ؎ arterial pressure (from 83 12 to 98 6 mmHg; n 8; P < mans have investigated the effect of intracarotid infusion 0.001), and concurrent infusion of intravenous phenylephrine and intracarotid nitroprusside reversed this effect. However, of nitroprusside on CBF. These studies were undertaken compared with baseline, CBF did not change with intravenous on awake subjects undergoing angiography for sus- phenylephrine or with concurrent infusions of intravenous pected neurologic diseases, and they failed to demon- phenylephrine and intracarotid nitroprusside. Intracarotid ve- strate an increase in CBF after nitroprusside infusion.8,9 ؊1 ؊1 ؎ ؎ rapamil increased CBF (43 9to65 11 ml · 100 g · min ; A confounding effect of intracranial pathology on the P < 0.05). Conclusions: The authors conclude that, in humans, intraca- outcome of these studies cannot be ruled out. rotid nitroprusside sufficient to decrease mean arterial pres- The release on NO from nitroprusside is a one-stage sure during recirculation, does not augment CBF. Failure of nonenzymatic reaction.10 Infusion of nitroprusside in intracarotid nitroprusside to augment CBF despite demonstra- coronary and brachial arteries of human subjects in- ble autoregulatory vasoconstriction and pharmacologic vasodi- creases regional blood flow.11–13 Therefore, in noncere- lation questions the significance of nitric oxide–mediated vaso- dilation in human cerebral circulation. bral vessels, it is generally accepted that NO generated from nitroprusside can penetrate the basement layer of 14 IN rodents, intracarotid infusion of sodium nitroprus- the endothelium to reach smooth muscle cells. In the side, an endothelium-independent nitric oxide (NO) do- smooth muscle cell, NO activates guanylate cyclase, in- nor, augments cerebral blood flow (CBF) and reduces creases cyclic guanosine monophosphate, and causes ischemic cerebral injury.1 In patients with cerebral va- vascular relaxation. We hypothesized that, similar to the peripheral circulation, if endothelial NO is a significant modulator of CBF, then NO generated after intracarotid * Assistant Professor, Department of Anesthesiology, ʈ Associate Research Sci- infusion of nitroprusside should be able to diffuse across entist, Department of Neurology, # Assistant Professor, Department of Radiology, ** Professor, Departments of Radiology and Neurological Surgery, College of the blood–brain barrier, relax the vascular smooth mus- Physicians and Surgeons, Columbia University. † Professor, ‡ Assistant Profes- cle cells, and increase CBF. sor, § Postdoctoral Fellow, Departments of Anesthesiology, Neurosurgery, and Neurology, University of California, San Francisco, California. Our studies were conducted on normal hemispheres Received from the Departments of Anesthesiology, Neurological Surgery, and of patients undergoing four-vessel cerebral angiography Radiology, College of Physicians and Surgeons of Columbia University, New for suspected intracranial vascular pathologies. Because York, New York. Submitted for publication February 15, 2001. Accepted for publication July 27, 2001. Supported in part by grants No. RO1 GM 00698 (to Dr. nitroprusside can impair cerebral autoregulation, the Joshi) and RO1 NS27713 and K-24 NS 02091 (to Dr. Young) from the National drug infusion protocol was designed to avoid hypoten- Institutes of Health, Bethesda, Maryland. Presented at the annual meetings of the Association of University Anesthesiologists, Salt Lake City, Utah, May 4, 2000, and sion during intracarotid nitroprusside infusion. The pro- the American Society of Anesthesiologists, San Francisco, California, October 17, tocol also tested physiologic autoregulation and the 2000. 2ϩ Address reprint requests to Dr. Joshi: Department of Anesthesiology, P& S P pharmacologic response to a Ca channel blocker, ve- Box 46, College of Physicians and Surgeons, Columbia University, 630 West rapamil. In human cerebral circulation, intraarterial ve- 168th Street, New York, New York 10032. Address electronic mail to: [email protected]. Individual article reprints may be purchased through the rapamil augments CBF; therefore, the drug was used as a 9,15 Journal Web site, www.anesthesiology.org. positive control. Anesthesiology, V 96, No 1, Jan 2002 60 NITROPRUSSIDE FAILS TO AUGMENT HUMAN CBF 61 Table 1. Effect of Sodium Nitroprusside on Human Cerebral Blood Flow Reference Author (Year) Route CBF Technique Experimental State Outcome: Effect on CBF No. Griffiths et al. (1974) IV IC 133Xe During anesthesia No change 33 Brown et al. (1977) IV IC 133Xe Awake, neurologic Decrease in CBF during nitroprusside 34 patients for hypotension angiography Pinaud et al. (1979) IV IC 133Xe During anesthesia No change in CBF 35 Larsen et al. (1982) IV Argon washout During anesthesia No change in 7 of 9 patients, in 2 increase 7 in CBF associated with increased output Henriksen et al. (1982) IV IC 133Xe During anesthesia Decrease in CBF 36 Henriksen and Paulson IV and IA IC 133Xe Awake, neurologic No change with IC and a decrease with IV 8 (1982) patients infusion Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/96/1/60/404471/0000542-200201000-00016.pdf by guest on 01 October 2021 Henriksen et al. (1983) IV IC 133Xe During anesthesia No change 37 Bunemann et al. (1987) IV IV 133Xe During anesthesia No change 38 Rogers et al. (1989) IV IA 133Xe During anesthesia No change in CBF during cardiopulmonary 39 bypass Pinaud et al. (1989) IV IA 133Xe During anesthesia No change despite increase in cardiac index 40 Thomsen et al. (1989) IV IV 133Xe During anesthesia No change in CBF in 9 of 10, 1 of 10 patient 41 critical decrease in CBF Bunemann et al. (1991) IV IV 133Xe During anesthesia Nitroprusside with metoprolol pretreatment, 42 no change in CBF Rogers et al. (1991) IV IA 133Xe During anesthesia Decrease in CBF during cardiopulmonary 43 bypass Joshi et al. (1997) IA IA 133Xe Awake neurologic Decrease in regional CBF 9 patients Butterworth et al. IV Single photon Awake patient with Nitroprusside increased CBF and decreased 44 (1998) emission acute stroke platelet aggregation tomography Viguera et al. (1998) IV Transcranial Awake Case report: atenolol pretreatment and 45 doppler nitroprusside did not affect CBF before ECT Thomas and IT Transcranial NA Case series: increase in CBF in three 3 Rosenwasser (1999) doppler patients with subarachnoid hemorrhage angiography and vasospasm Vajkoczy et al. (2000) IT Thermal diffusion NA Case series: increase in CBF in patients with 2 vasospasm Studies with intraarterial drug infusion are shown in italic. CBF ϭ cerebral blood flow; IV ϭ intravenous; IC ϭ intracarotid; IA ϭ intraarterial (superselective); IT ϭ intrathecal; ECT ϭ electroconvulsive therapy; NA ϭ patients with impaired consciousness. Materials and Methods diography, end-tidal carbon dioxide concentration, arte- rial oxygen saturation, blood pressure,
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