{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T21:44:54Z","timestamp":1793742294506,"version":"4.6.1"},"reference-count":46,"publisher":"American Diabetes Association","issue":"10","content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2008,10,1]]},"abstract":"<jats:p>OBJECTIVE\u2014 Cerebral edema (CE) is a potentially life-threatening complication of diabetic ketoacidosis (DKA) in children. Osmotic fluctuations during DKA treatment have been considered responsible, but recent data instead suggest that cerebral hypoperfusion may be involved and that activation of cerebral ion transporters may occur. Diminished cerebral blood flow (CBF) during DKA, however, has not been previously demonstrated. We investigated CBF and edema formation in a rat model of DKA and determined the effects of bumetanide, an inhibitor of Na-K-Cl cotransport.<\/jats:p>\n               <jats:p>RESEARCH DESIGN AND METHODS\u2014 Juvenile rats with streptozotocin-induced DKA were treated with intravenous saline and insulin, similar to human treatment protocols. CBF was determined by magnetic resonance (MR) perfusion\u2013weighted imaging before and during treatment, and CE was assessed by determining apparent diffusion coefficients (ADCs) using MR diffusion\u2013weighted imaging.<\/jats:p>\n               <jats:p>RESULTS\u2014 CBF was significantly reduced in DKA and was responsive to alterations in pCO2. ADC values were reduced, consistent with cell swelling. The reduction in ADCs correlated with dehydration, as reflected in blood urea nitrogen concentrations. Bumetanide caused a rapid rise in ADCs of DKA rats without significantly changing CBF, while saline\/insulin caused a rapid rise in CBF and a gradual rise in ADCs. DKA rats treated with bumetanide plus saline\/insulin showed a trend toward more rapid rise in cortical ADCs and a larger rise in striatal CBF than those observed with saline\/insulin alone.<\/jats:p>\n               <jats:p>CONCLUSIONS\u2014 These data demonstrate that CE in DKA is accompanied by cerebral hypoperfusion before treatment and suggest that blocking Na-K-Cl cotransport may reduce cerebral cell swelling.<\/jats:p>","DOI":"10.2337\/db07-1410","type":"journal-article","created":{"date-parts":[[2008,7,16]],"date-time":"2008-07-16T04:18:47Z","timestamp":1216181927000},"page":"2588-2594","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":82,"title":["Cerebral Blood Flow and Cerebral Edema in Rats With Diabetic Ketoacidosis"],"prefix":"10.2337","volume":"57","author":[{"given":"Natalie","family":"Yuen","sequence":"first","affiliation":[{"name":"Department of Physiology and Membrane Biology, University of California, Davis, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven E.","family":"Anderson","sequence":"additional","affiliation":[{"name":"Department of Physiology and Membrane Biology, University of California, Davis, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Glaser","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of California, Davis, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel J.","family":"Tancredi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of California, Davis, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martha E.","family":"O'Donnell","sequence":"additional","affiliation":[{"name":"Department of Physiology and Membrane Biology, University of California, Davis, California"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","reference":[{"key":"2022031208251299400_R1","doi-asserted-by":"crossref","unstructured":"Faich G, Fishbein H, Ellis E: The epidemiology of diabetic acidosis: a population-based study. Am J Epidemiol\u2008117: 551, 1983","DOI":"10.1093\/oxfordjournals.aje.a113577"},{"key":"2022031208251299400_R2","doi-asserted-by":"crossref","unstructured":"Pinkney J, Bingley P, Sawtell P: Presentation and progress of childhood diabetes mellitus: a prospective population-based study. Diabetologia\u200837:70\u201374, 1994","DOI":"10.1007\/BF00428780"},{"key":"2022031208251299400_R3","doi-asserted-by":"crossref","unstructured":"Mahoney C, Vlcek B, Aguila MD: Risk factors for developing brain herniation during diabetic ketoacidosis. Pediatric Neurol\u200821:721\u2013727, 1999","DOI":"10.1016\/S0887-8994(99)00079-X"},{"key":"2022031208251299400_R4","doi-asserted-by":"crossref","unstructured":"Edge J, Hawkins M, Winter D, Dunger D: The risk and outcome of cerebral oedema developing during diabetic ketoacidosis. Arch Dis Child\u200885:16\u201322, 2001","DOI":"10.1136\/adc.85.1.16"},{"key":"2022031208251299400_R5","doi-asserted-by":"crossref","unstructured":"Glaser N, Barnett P, McCaslin I, Nelson D, Trainor J, Louie J, Kaufman F, Quayle K, Roback M, Malley R, Kupperman N: Risk factors for cerebral edema in children with diabetic ketoacidosis. N Engl J Med\u2008344:264\u2013269, 2001","DOI":"10.1056\/NEJM200101253440404"},{"key":"2022031208251299400_R6","doi-asserted-by":"crossref","unstructured":"Lawrence S, Cummings E, Gaboury I, Daneman D: Population-based study of incidence and risk factors for cerebral edema in pediatric diabetic ketoacidosis. J Pediatr\u2008146:688\u2013692, 2005","DOI":"10.1016\/j.jpeds.2004.12.041"},{"key":"2022031208251299400_R7","doi-asserted-by":"crossref","unstructured":"Daneman D: Diabetes-related mortality. Diabetes Care\u200824:801\u2013802, 2001","DOI":"10.2337\/diacare.24.5.801"},{"key":"2022031208251299400_R8","doi-asserted-by":"crossref","unstructured":"Edge J, Ford-Adams M, Dunger D: Causes of death in children with insulin-dependent diabetes 1990\u20131996. Arch Dis Child\u200881:318\u2013323, 1999","DOI":"10.1136\/adc.81.4.318"},{"key":"2022031208251299400_R9","doi-asserted-by":"crossref","unstructured":"Scibilia J, Finegold D, Dorman J, Becker D, Drash A: Why do children with diabetes die? Acta Endocrinol Suppl\u2008279:326\u2013333, 1986","DOI":"10.1530\/acta.0.112S326"},{"key":"2022031208251299400_R10","unstructured":"Hoffman W, Steinhart C, Gammal TE, Steele S, Cuadrado A, Morse P: Cranial CT in children and adolescents with diabetic ketoacidosis. Am J Neuroradiol\u20089:733\u2013739, 1988"},{"key":"2022031208251299400_R11","doi-asserted-by":"crossref","unstructured":"Krane E, Rockoff M, Wallman J, Wolfsdorf J: Subclinical brain swelling in children during treatment of diabetic ketoacidosis. N Engl J Med\u2008312:1147\u20131151, 1985","DOI":"10.1056\/NEJM198505023121803"},{"key":"2022031208251299400_R12","doi-asserted-by":"crossref","unstructured":"Glaser N, Wooton-Gorges S, Buonocore M, Marcin J, Rewers A, Strain J, DiCarlo J, Neely E, Barnes P, Kuppermann N: Frequency of sub-clinical cerebral edema in children with diabetic ketoacidosis. Pediatr Diab\u20087:75\u201380, 2006","DOI":"10.1111\/j.1399-543X.2006.00156.x"},{"key":"2022031208251299400_R13","doi-asserted-by":"crossref","unstructured":"Brillault J, Lam TI, Rutkowsky JM, Foroutan S, O'Donnell ME: Hypoxia effects on cell volume and ion uptake of cerebral microvascular endothelial cells. Am J Physiol Cell Physiol\u2008294:C88\u2013C96, 2008","DOI":"10.1152\/ajpcell.00148.2007"},{"key":"2022031208251299400_R14","doi-asserted-by":"crossref","unstructured":"Su G: Regulation of Na+-K+-Cl-cotransporter in primary astrocytes by dibutyryl cAMP and high [K+]o. Am J Physiol Cell Physiol\u2008279:C1710\u2013C1721, 2000","DOI":"10.1152\/ajpcell.2000.279.6.C1710"},{"key":"2022031208251299400_R15","doi-asserted-by":"crossref","unstructured":"Iadecola C: Mechansims of cerebral ischemic damage. In Cerebral Ischemia: Molecular and Cellular Pathophysiology. Walz W, Ed. Totowa, NJ, Humana Press, 1999, p. 3\u201334","DOI":"10.1007\/978-1-59259-479-5_1"},{"key":"2022031208251299400_R16","doi-asserted-by":"crossref","unstructured":"Kempski O, Rosen Sv, Weight H, Staub F, Peters J, Baethmann A: Glial ion transport and volume control. In Glial-Neuronal Interaction. Abbott NJ, Ed. New York, New York Academy of Sciences, 1991, p. 306\u2013317","DOI":"10.1111\/j.1749-6632.1991.tb15622.x"},{"key":"2022031208251299400_R17","doi-asserted-by":"crossref","unstructured":"Kimelberg HK: Cell swelling in cerebral ischemia. In Cerebral Ischemia: Molecular and Cellular Pathophysiology. Walz W, Ed. Totowa, NJ, Humana Press, 1999, p. 45\u201368","DOI":"10.1385\/0-89603-540-9:45"},{"key":"2022031208251299400_R18","doi-asserted-by":"crossref","unstructured":"Lam TI, Anderson SE, Glaser N, O'Donnell ME: Bumetanide reduces cerebral edema formation in rats with diabetic ketoacidosis. Diabetes\u200854:510\u2013516, 2005","DOI":"10.2337\/diabetes.54.2.510"},{"key":"2022031208251299400_R19","doi-asserted-by":"crossref","unstructured":"O'Donnell ME, Tran L, Lam TI, Liu XB, Anderson SE: Bumetanide inhibition of the blood-brain barrier Na-K-Cl cotransporter reduces edema formation in the rat middle cerebral artery occlusion model of stroke. J Cereb Blood Flow Metab\u200824:1046\u20131056, 2004","DOI":"10.1097\/01.WCB.0000130867.32663.90"},{"key":"2022031208251299400_R20","doi-asserted-by":"crossref","unstructured":"Rudin M, Baumann D, Ekatodramis D, Stirnimann R, McAllister KH, Sauter A: MRI analysis of the changes in apparent water diffusion coefficient, T2 relaxation time, and cerebral blood flow and volume in the temporal evolution of cerebral infarction following permanent middle cerebral artery occlusion in rats. Exp Neurol\u2008169:56\u201363, 2001","DOI":"10.1006\/exnr.2001.7650"},{"key":"2022031208251299400_R21","unstructured":"Robinson J: The Harriet Lane Handbook. 17th ed. Robinson J, Shilkofski N, Eds. Philadelphia, Mosby, 2005, p. 627\u2013628"},{"key":"2022031208251299400_R22","doi-asserted-by":"crossref","unstructured":"O'Donnell ME, Lam TI, Tran LQ, Foroutan S, Anderson SE: Estradiol reduces activity of the blood-brain barrier Na-K-Cl cotransporter and decreases edema formation in permanent middle cerebral artery occlusion. J Cereb Blood Flow Metab\u200826:1234\u20131249, 2006","DOI":"10.1038\/sj.jcbfm.9600278"},{"key":"2022031208251299400_R23","doi-asserted-by":"crossref","unstructured":"Tatlisumak T, Takano K, Carano RAD, Fisher M: Effect of basic fibroblast growth factor on experimental focal ischemia studied by diffusion-weighted and perfusion imaging. Stroke\u200827:2292\u20132298, 1996","DOI":"10.1161\/01.STR.27.12.2292"},{"key":"2022031208251299400_R24","doi-asserted-by":"crossref","unstructured":"Williams DS, Detre JA, Leigh JS, Koretsky AP: Magnetic resonance imaging of perfusion using spin inversion of arterial water. Proc Natl Acad Sci U S A\u200889:212\u2013216, 1992","DOI":"10.1073\/pnas.89.1.212"},{"key":"2022031208251299400_R25","doi-asserted-by":"crossref","unstructured":"Albuquerque ML, Leffler CW: pHo, pHi and pCO2 in stimulation of IP3 and [Ca2+] in piglet cerebrovascular smooth muscle. Proc Soc Exp Biol\u2008219:226\u2013234, 1998","DOI":"10.3181\/00379727-219-44336"},{"key":"2022031208251299400_R26","doi-asserted-by":"crossref","unstructured":"Kety SS, Polis BD, Nadler CS, Schmidt CF: The blood flow and oxygen consumption of the human brain in diabetic acidosis and coma. J Clin Invest\u200827:500\u2013510, 1948","DOI":"10.1172\/JCI101997"},{"key":"2022031208251299400_R27","doi-asserted-by":"crossref","unstructured":"Young E, Bradley RF: Cerebral edema with irreversible coma in severe diabetic ketoacidosis. N Engl J Med\u2008276:665\u2013669, 1967","DOI":"10.1056\/NEJM196703232761204"},{"key":"2022031208251299400_R28","doi-asserted-by":"crossref","unstructured":"Harris G, Fiordalisi I, Harris W, Mosovich L, Finberg L: Minimizing the risk of brain herniation during treatment of diabetic ketoacidemia: a retrospective and prospective study. J Pediatr\u2008117:22\u201331, 1990","DOI":"10.1016\/S0022-3476(05)82439-4"},{"key":"2022031208251299400_R29","doi-asserted-by":"crossref","unstructured":"Duck S, Wyatt D: Factors associated with brain herniation in the treatment of diabetic ketoacidosis. J Pediatr\u2008113:10\u201314, 1988","DOI":"10.1016\/S0022-3476(88)80521-3"},{"key":"2022031208251299400_R30","doi-asserted-by":"crossref","unstructured":"Hammond P, Wallis S: Cerebral oedema in diabetic ketoacidosis: still puzzling-and often fatal. BMJ\u2008305:203\u2013204, 1992","DOI":"10.1136\/bmj.305.6847.203"},{"key":"2022031208251299400_R31","doi-asserted-by":"crossref","unstructured":"Marsin JP, Glaser N, Barnett P, McCaslin I, Nelson D, Trainor J, Louie J, Kaufman F, Quayle K, Roback M, Malley R, Kuppermann N: Factors associated with adverse outcmes in children with diabetic ketoacidosis related cerebral edema. J Pediatr\u2008141:793\u2013797, 2002","DOI":"10.1067\/mpd.2002.128888"},{"key":"2022031208251299400_R32","doi-asserted-by":"crossref","unstructured":"Edge JA: Cerebral oedema during treatment of diabetic ketoacidosis: are we any nearer finding a cause? Diabetes\u2008Metab Res Rev\u200816:316\u2013324, 2000","DOI":"10.1002\/1520-7560(2000)9999:9999<::AID-DMRR143>3.0.CO;2-R"},{"key":"2022031208251299400_R33","doi-asserted-by":"crossref","unstructured":"Hoorn EJ, Carlotti AP, MacMahon B, Bohn G, Zietse R, Halperin ML, Bohn D: Preventing a drop in effective plasma osmolality to minimize th elikelihood of cerebral edema during treatment of children with diabetic ketoacidosis. J Pediatr\u2008150:467\u2013473, 2007","DOI":"10.1016\/j.jpeds.2006.11.062"},{"key":"2022031208251299400_R34","doi-asserted-by":"crossref","unstructured":"Salem MS, Matta LF, Tantawy AA, Hussein M, Gad GI: Single photon emission tomography (SPECT) study of regional cerebral blood flow in normoalbuminuric children and adolescents with type 1 diabetes. Pediatr Diab\u20083:155\u2013162, 2002","DOI":"10.1034\/j.1399-5448.2002.30306.x"},{"key":"2022031208251299400_R35","doi-asserted-by":"crossref","unstructured":"Glaser NS, Wootton-Gorges SL, Marcin JP, Buonocore MH, DiCarlo J, Neely EK, Barnes P, Bottomly J, Kuppermann N: Mechanism of cerebral edema in children with diabetic ketoacidosis. J Pediatr\u2008145:164\u2013171, 2004","DOI":"10.1016\/j.jpeds.2004.03.045"},{"key":"2022031208251299400_R36","doi-asserted-by":"crossref","unstructured":"Marchal G, Young A, Baron J: Early postischemic hyperperfusion: pathophysiologic insights from positron emission tomography. J Cereb Blood Flow Metab\u200819:467\u2013482, 1999","DOI":"10.1097\/00004647-199905000-00001"},{"key":"2022031208251299400_R37","doi-asserted-by":"crossref","unstructured":"Yang G-Y, Betz AL, Chenevert T, Brunberg JA, Hoff JT: Experimental intracerebral hemorrhage: relationship between brain edema, blood flow, and blood-brain barrier permeability in rats. J Neurosurg\u200881:93\u2013102, 1994","DOI":"10.3171\/jns.1994.81.1.0093"},{"key":"2022031208251299400_R38","doi-asserted-by":"crossref","unstructured":"Aronowski J, Strong R, Grotta JC: Reperfusion injury: demonstration of brain damage by reperfusion after transient focal ischemia in rats. J Cereb Blood Flow Metab\u200817:1048\u20131056, 1997","DOI":"10.1097\/00004647-199710000-00006"},{"key":"2022031208251299400_R39","doi-asserted-by":"crossref","unstructured":"Yan Y, Dempsey RJ, Sun D: Na-K-Cl cotransporter in rat focal cerebral ischemia. J Cereb Blood Flow Metab\u200821:711\u2013721, 2001","DOI":"10.1097\/00004647-200106000-00009"},{"key":"2022031208251299400_R40","doi-asserted-by":"crossref","unstructured":"Foroutan S, Brillault J, Forbush B, O'Donnell ME: Moderate to severe ischemic conditions increase activity and phosphorylation of the cerebral microvascular endothelial cell Na-K-Cl cotransporter. Am J Physiol Cell Physiol\u2008289:C1492\u2013C1501, 2005","DOI":"10.1152\/ajpcell.00257.2005"},{"key":"2022031208251299400_R41","doi-asserted-by":"crossref","unstructured":"Pedersen SF, O'Donnell ME, Anderson SE, Cala PM: Physiology and pathophysiology of Na+\/H+ exchange and Na+-K+-2Cl\u2212 cotransporter in the heart, brain and blood. Am J Physiol Reg Integr Comp Physiol\u2008291:R1\u2013R25, 2006","DOI":"10.1152\/ajpregu.00782.2005"},{"key":"2022031208251299400_R42","doi-asserted-by":"crossref","unstructured":"Menzies SA, Betz AL, Hoff JT: Contributions of ions and albumin to the formation and resolution of ischemic brain edema. J Neurosurg\u200878:257\u2013266, 1993","DOI":"10.3171\/jns.1993.78.2.0257"},{"key":"2022031208251299400_R43","doi-asserted-by":"crossref","unstructured":"Schielke GP, Moises HC, Betz AL: Blood to brain sodium transport and interstitial fluid potassium concentration during focal ischemia in the rat. J Cereb Blood Flow Metab\u200811:466\u2013471, 1991","DOI":"10.1038\/jcbfm.1991.89"},{"key":"2022031208251299400_R44","doi-asserted-by":"crossref","unstructured":"Gotoh O, Asano T, Koide T, Takakura K: Ischemic brain edema following occlusion of the middle cerebral artery in the rat. I: the time course of the brain water, sodium and potassium contents and blood-brain barrier permeability to 125I-albumin. Stroke\u200816:101\u2013109, 1985","DOI":"10.1161\/01.STR.16.1.101"},{"key":"2022031208251299400_R45","doi-asserted-by":"crossref","unstructured":"Yan Y, Dempsey RJ, Flemmer A, Forbush B, Sun D: Inhibition of Na-K-Cl cotransporter during focal cerebral ischemia decreases edema and neuronal damage. Brain Res\u2008961:22\u201331, 2003","DOI":"10.1016\/S0006-8993(02)03832-5"},{"key":"2022031208251299400_R46","doi-asserted-by":"crossref","unstructured":"Su G, Kintner DB, Flagella M, Shull GE, Sun D: Astrocytes from Na(+)-K(+)-Cl(-) cotransporter-null mice exhibit absence of swelling and decrease in EAA release. Am J Physiol Cell Physiol\u2008282:C1147\u2013C1160, 2002","DOI":"10.1152\/ajpcell.00538.2001"}],"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.org\/diabetes\/diabetes\/article-pdf\/57\/10\/2588\/507377\/zdb01008002588.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/57\/10\/2588\/507377\/zdb01008002588.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T16:13:31Z","timestamp":1667405611000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/57\/10\/2588\/13398\/Cerebral-Blood-Flow-and-Cerebral-Edema-in-Rats"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,10,1]]},"references-count":46,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2008,10,1]]}},"URL":"https:\/\/doi.org\/10.2337\/db07-1410","relation":{},"ISSN":["0012-1797","1939-327X"],"issn-type":[{"value":"0012-1797","type":"print"},{"value":"1939-327X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2008,10,1]]}}}