Published by Maney Publishing (c) W. S. Maney & Son Limited 10.1179/016164107X181815 # 8 publication for 2006. Accepted March [[email protected]] Boston, USA. 175 Hospital, 02114, MD, General MA, Massachusetts Singhal, 300, B. Suite Aneesh Street, to: Cambridge requests reprint and Correspondence acute for stroke Drug treatment and ischemic Food (FDA)-approved only (i.v. the is Administration activator agent, $56 States, thrombolytic plasminogen exceeding the United cost tPA), tissue the indirect Intravenous in and direct death billion. and annual of disability an cause long-term with of leading cause third leading the the is Stroke INTRODUCTION tde.Acrflaayi fteltrtr,athorough a literature, in the efficacy of show analysis animal necrosis. careful to numerous A in failed promise ischemic studies. despite far within trials so reduce clinical tension three has would is oxygen HBO it However, raising tissues because that decades ischemic for believed advocated widely been has (HBO) thrombolysis and advancement. stroke significant neurons for a window a ischemic be time would Clearly, salvage the studies. both extend safely can animal that in human III strategy promise phase narrow despite in neuro- its effective no studies of proved Second, has because hours). drug patients (3 protective to window restricted stroke is time of tPA limited therapeutic 5% of is use than therapy First, stroke less problems. of major field after two death the by cell present, ischemic of At pathways stroke. the of more interrupt or be that one also therapies can ‘neuroprotective’ outcome with stroke improved that believed is it beneficial, 07W .Mny&SnLtd Son & Maney S. W. 2007 shmcsrk hrp ihhprai oxygen hyperbaric with therapy stroke Ischemic ewrs yebrcoye hrp;nroai xgnteay erpoeto;acute neuroprotection; therapy; oxygen encephalopathy normobaric hypoxic–ischemic therapy; therapy; and stroke animal oxygen of results Hyperbaric of the Keywords: and evidence of diseases. HBO for administration cerebrovascular imaging of stroke rationale the in action with current of hyperoxia for of and patients mechanisms of time’ history the era in studies ‘buy the stroke, human reviews or to in modern article therapy used onset oxygen This this be stroke using drugs. could If neuroprotective In after therapy significance. or hours oxygen reperfusion. renewed thrombolytic few tissue, have tissue brain first may salvageable therapy with the not three oxygen did within patients in trials neuroimaging, to applied efficacy Previous time advanced in delayed pressures. show and as chamber be to benefit such excessive thrombolysis powerful may failed factors of to long-term (NBO) far use attributable a so therapy and probably assess size has is oxygen sample trials be HBO normobaric inadequate these onset. therapy. of even therapy, may failure stroke while The stroke after window potent, trials. mechanisms, promptly clinical therapy time most oxygen acute started the the hyperbaric indirect if methods, extend tissue be delivery effective FDA-approved and to oxygen intravenous and tissue available appears only the and brain Of (HBO) direct ischemic treatment. cost, the stroke acutely acute high multiple salvage for remains at to via strategy trials, tPA) neuroprotective clinical acting (i.v. failed Hyperoxia, far activator so plasminogen have drugs Neuroprotective stroke ischemic in therapy oxygen of review A 1 hl al hoblssi clearly is thrombolysis early While . eateto erlg,MsahstsGnrlHsia,Bso,M,USA MA, Boston, Hospital, General Massachusetts Neurology, of Department nehB Singhal B. Aneesh opesdarhsbe doae samedical a as century advocated mid-17th been the since has therapy air THERAPY STROKE Compressed A AS HBO OF in EVOLUTION and adults in stroke of global studies and human neonates. and focal and HBO in animal of of hyperoxia action the results of the review mechanisms summarize in will the therapy oxygen discuss we using stroke, for chapter, rationale current this neuro- to and history or In used thrombolytic be drugs. of could the protective administration and within for onset) time’ stroke (e.g. ‘buy after highly out- situations hours be clinical few tissue first could certain assess stroke therapy in and effective oxygen of patients Specifically, era appropriate capability comes. modern neuroimaging select advanced to this that with in tremendous thrombolysis suggest has potential (NBO), studies, well therapy therapeutic as hyperbaric oxygen animal of normobaric form recent as the in from oxygen, supplemental trials data previous the of and shortcomings the of understanding eas ewsual opoeteaetcefficacy therapeutic prove to unable was chamber he and his because down closed largest The hyperbaric early eventually Cleveland. profession the the in medical chamber mobile In operated hyperbaric functioning 1877. Cunningham first only in century, developed the for 20th was chambers and room hyperbaric operating use therapy, 1834 to in first Junod medical the 1775. in probably Priestly was by oxygen of discovery n16,Beeapbihdalnmr td showing study landmark used. a was published oxygen Boerema not 1960, and In air hyperbaric time, this Until erlgclRsac,20,Vlm 9 March 29, Volume 2007, Research, Neurological Nuo e 2007; Res [Neurol 29 173–183] : 2 vnbfr the before even , 173 2–4 . Published by Maney Publishing (c) W. S. Maney & Son Limited h rt3husatraueicei stroke ischemic acute after within delivered hours HBO stroke 3 of in trial HBO first clinical of Winston- a role the in the design discuss workshop to to and a USA, convened HBO. NC, Toole of Salem, trials F. had clinical James previous size, Dr the sample chamber in optimal optimal overlooked as and in the been such subtype HBO, of HBO factors stroke of that period of duration pressure, clear and a efficacy became timing it to and the time, led safety Over radicals, the stroke. free about the known increase toxic skepticism could the hyperoxia of that generation with fear growing HBO, conjunction the of and complications in pressure-related and which, difficulties results tive ulse td hwn obnfi ihHOat HBO dogs occlu- with artery in cerebral benefit (MCAO) middle no sion permanent after showing ATA Lawson study 2.0 and Jacobson a ischemia. to organ published efforts placing treat intensified to by study HBO This survived use chambers. be HBO in could them pigs exsanguinated Singhal B. that A. stroke: ischemic in therapy oxygen of review A 174 a fetv nhprct stroke HBO hyperacute that in time first effective deficits immediately the neurological was his for was and demonstrating chamber He disappeared, HBO a infarction. in 2 myocardial placed day on his hemiparesis fibrillation developed after atrial patient a The and of HBO. thrombosis treatment with focal coronary reported with colleagues permanent stroke. and patient in and therapy Moon HBO 1964, transient for In rationale of a providing models stroke, HBO animal with benefit in substantial documented have studies rmLn nvriypbihdarpr nteueof stroke use with the patients on four report in a published HBO University Lund from eea shortcomings several eiso 2 ainsb eburadEnd and case Neubauer by largest case patients the in 122 numerous including HBO of published, of series then, use been Since the have documenting stroke scale. series case larger and be reports a should HBO on that abnormalities concluded tested and (EEG) therapy, HBO electroencephalography improve- with and in deficits neurological ment of reversal transient hrp ileetal rv ob neffective an be oxygen to that prove optimism eventually is there will thrombolysis into design, insights stroke therapy newer trial of and clinical neuroimaging, advent is advanced the tissue and durations, if maximized With short be for can reperfused. early, benefit long-term applied that if and effective most the stroke. in HBO surrounding controversy hi ml td gi hwn htHOi ineffective stroke is HBO the ischemic that In showing stages. in again planning study the small in their now Rusyniak is trial stroke interim, well-designed multicenter A in and stroke. HBO acute of in powered HBO of adequately and trials acknowledged clinical for safety They need studies. or extensive animal the therapy from the data given stroke efficacy tremendous potential acute had HBO therapeutic in that agreed medicine, experts hyperbaric all participants, published recognized. was stroke in HBO clinical conducting of for trials need the reports, anecdotal these eetaia aaidct htoye hrp is therapy oxygen that indicate data animal Recent h eut ftefis w lncltil fHOwere HBO of trials clinical two first the of results The erlgclRsac,20,Vlm 9 March 29, Volume 2007, Research, Neurological 8,9 notntl,bt rasrpre nega- reported trials both Unfortunately, . tal. et 10 11–13 hssuyi nw ohave to known is study This . 5 hratr ueosanimal numerous Thereafter, . aepbihdterslsof results the published have n a asdtelvlof level the raised has and 6 4 hydocumented They . nvradLassen and Ingvar . 7 ae on Based . 4 .The euba n osiue h agtfrsrk neuro- stroke ‘ischemic for the target as therapies the protective to constitutes still referred collateral and but is infarction penumbra’ by tissue for are risk supported This at salvageable. flow regions, is tissue blood ‘core’ where circulation, reduced the of occurs non- Surrounding usually areas is death minutes. cell tissue regions, within and flow such irreversible blood In is compromised salvageable. territory injury severely ischemic cellular of the where regions of of to site ‘core’ the refers The to compro- distal occlusion. variably supply oxygen arterial of and regions flow blood in mised results stroke Ischemic IN STROKE THERAPY OXYGEN USING FOR RATIONALE therapy. window drug time neuroprotective the or outcome thrombolysis extending stroke for by improve or independently can either that strategy therapeutic ellrijr fe toe xiooiiy oxidative/ apoptosis excitotoxicity, and stroke: inflammation irreversible stress, after nitrosative of has injury decades pathways three cellular fundamental last four the over delineated research science Basic ACTION be OF is MECHANISMS HBO to timings, of remains equivalent timing potent. at the others most and the that probably critical the appears it is to stage, therapy this superior at oxygen determined; high-flow of is method of one Whether administration delivery facemask. the a via or oxygen of therapy effects NBO therapeutic recently potential early has the group in Our interested of carriersbecome solutions. oxygen use aqueous oxygen the and include hemoglobin-based development) tissue deliv- perfluorocarbons, under brain oxygen death increase (currently increase to to cell ery hemodynamic method methods multiple effective Other because beneficial most oxygenation. studied on the widely is been have act it has discussed therapy may to HBO as effects. known and Further, acute is tPA. pathways other it as with such below, combined effects treatments be side stroke can is significant theoretically tissues, without the in and delivered target concentrations be across can reach tolerated, 100% well diffuses to administer, to (BBB) simple easily pharmaceutical barrier ‘ideal’ it an most blood–brain of drugs, Unlike properties neuroprotective several agent. has neuroprotective it because option onset effects. enhance stroke preconditioning to have before believed may treatment is and stroke recovery, completed post-stroke stroke- after attenuate application HBO the and of addition, In volume deficits. infarct neurological related final reduce can rwho h nac oe ti eivdta hyperoxia, and that believed penumbra pO is tissue ischemic a It raising core. is of by infarct there the volume more the time, of the growth or of that passage in hours With reduction several suggest onset. for symptom studies after exists magnetic penumbra (MRI) functional ischemic imaging and (PET) resonance tomography emission yeoi satatv ct toetherapeutic stroke acute attractive is Hyperoxia 14 2 nhmn,terslso position of results the humans, In . eesi h shmcpenumbra, ischemic the in levels 15 Tissue . 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Maney & Son Limited ri att n yuaelvl n decreased and levels pyruvate pressure and intracranial lactate brain xgnpesr n otn,rsligi 20% a in periphery ischemic resulting the to content, supply oxygen and in increase pressure arterial increased significantly a oxygen HBO In model, tissues. stroke penumbral focal in metabolism and oxygenation that ( mole- mechanisms shown biochemical, hemodynamic into indirect and have multiple cular via diffusion hemoglo- studies acts on also Recent oxygen HBO reliance oxygen. minimize facilitate bin-bound and higher would tissues ten-fold achievable in ischemic the HBO oxygen levels that dissolved with rationale of oxygen concentration the increasing plasma on that based studies Early were logical there- neuroprotective. be pathways; would is tissues these ischemic to it contributor key fore, a is hypoxia n mrvdmtcodilfunction mitochondrial levels, improved pyruvate and lactate and brain decreased oxygen, of bomlte fe shmcsrk eutfo ion with restores hyperoxia abnormalities from that such indicates therapy of result NBO and reversal HBO stroke and failure, ischemic pump after abnormalities aaantcrsnne(P)oier tde have after stroke oxygenation studies rodent penumbral improves Electron oximetry NBO effects. that (EPR) shown similar has resonance NBO paramagnetic that indicate studies ihnicei ein nhmn ihischemic with humans in regions levels stroke lactate ischemic improves NBO within that suggest spectroscopy nmdl ftamtcbanijr,HOincreased HBO injury, brain pO traumatic tissue brain of models In h anefc fHOi mrvdbantissue brain improved is HBO of effect main The 21 nptet ihbantam,NOimproved NBO trauma, brain with patients In . 19,20 2 nrae h eerlmtblcrate metabolic cerebral the increased , rlmnr tde sn eilMR serial using studies Preliminary . 22 ifso-egtMI(DWI) MRI Diffusion-weight . r-uvvlBl2gns ial,HOdcesstedfraiiyo h red the of by of hypoxia–ischemia expression mediated deformability reduce the and inhibitory be the microcirculation enhancing may decreases The improve by HBO apoptosis to stabilized. and cells Finally, on are blood dismutase genes. and superoxide Bcl-2 pyruvate agents HBO pro-survival of by and inflammatory improved re-regulation on glucose is the or HBO glutamate, metabolism delivery of blood–brain Cerebral oxygen of effect the improves edema. levels protects either cerebral HBO outcome infarc-and HBO reduces viability. final brain patients. neuronal and The in pathologic enhance of barrier barrier. result to disability blood–brain these also extraction or of but oxygen All death dysfunction death, the the and neuron reactions. and is apoptotic edema glutamate, inflammatory to brain lead tion, releases and only with follows, not production, generation damage events Mitochondrial ATP radical depolarization. and reduces oxygen overload calcium metabolism, causes energy ables 1: Figure ehnsso B erpoeto.Crba yoi–shmadis- hypoxia–ischemia Cerebral neuroprotection. 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A. stroke: ischemic in therapy oxygen of review A n yidcn aoosrcini the in vasoconstriction inducing by and , 28 27 nmdl ficei/eefso injury, ischemia/reperfusion of models In . 31 n erae oyopoula cell polymorphonuclear decreased and 29 eeteiec ugssta HBO that suggests evidence Recent . n ri trauma brain and 23–25 42 30 ial,b nraigoxygen increasing by Finally, . entlhypoxic–ischemic neonatal , 32 33 2 hs anti- These . nrae with increases oee,it However, . 175 26 Published by Maney Publishing (c) W. S. 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31 concluded nthis In . na es w tde ftasetcrba ischemia, cerebral generation radical transient free of increase studies not did two hyperoxia least outcomes. at neurophysiologic HBO- In better and had did peroxidation, animals this lipid treated ATA increased however, 2.8 to generation; at translate radical not minutes free 75 increase for did exposure HBO that showed h ao aeycnenwt xgnteayis therapy oxygen radicals with free toxic concern of generation safety increased major The CONCERNS SAFETY serial at arrest. the cardiac oxygenation after determine post-ischemic points to time of warranted levels a are optimal and studies cardiac with Further metabolism patients all arrest. energy to administered protocols, freely cerebral current is Under oxygen in flow. blood cerebral rise in decline a is there aoi clso eeoe utie ht matter white bilateral minute sustained 15 developed with after damage hours treated occlusion 3–6 Gerbils carotid for arrest. oxygen cardiac 100% after detrimental ucm fe ada retcnb piie by reperfusion optimized oxygen early be toxic of radicals generation the free can massive is there during when arrest period normoxia cardiac maintaining after outcome eeainde o nunefia ri aaeor damage brain final influence outcome. neurological not least does radical at free generation of hyperoxia-induced that findings suggest studies the three resuscitation, generation hyperoxic radical free during increased to attributed been have foiie ri iisadipoe neurological hyperoxic with improved compared and as resuscitation normoxic lipids using brain 40% outcome levels found oxidized lower death, group of neuronal Fiskum’s hippocampal in arrest, reduction cardiac minute 10 iigo h uaino hrp,adwhether Dutka and and Mink therapy, rabbit ischemia-reperfusion, a Using global toxicity. of brain model meaningful the clinically in of duration levels generation to radical the free the with increases risk/benefit changes hyperoxia or stroke the ischemic whether in timing hyperoxia examined of have ratio necrosis. studies tissue brain and Few exacerbate hemorrhage could stroke post-ischemic ischemic edema, of setting the in nml rae ihro air to room compared with as mortality treated day animals 14 in and increase peroxidation three-fold lipid a increased developed and served, yoi steieltre o reiloxygenation arterial for target ideal resuscitation the during or is hyperoxia than rather hypoxia normoxia that models canine in or3hdhge T ees oe att eesand levels lactate at lower HBO levels, survival with starting ATP treated better higher HBO rats had with ischemia, 3 treated global hour one rats after In hour to arrest. 1 compared timing cardiac after of as hyperoxia influence study, of the efficacy consider the to on important is it data, sdsusd xgnsefcsapa ob eeca in beneficial be to appear effects oxygen’s ischemia-reperfusion hype- discussed, cerebral As post-ischemic global of as in such models roxia exposure animal in hours) 24–48 and demonstrated than neonates been (greater mainly prolonged have with hyperoxia of risks The te tde aesonta yeoi a be can hyperoxia that shown have studies Other 75 lhuhtenuosapae etrpre- better appeared neurons the although 85 77,78 n yeoi uigltrproswhen periods later during hyperoxia and 84 ti ocial htneurological that conceivable is It . Zwemer . 79,80 81–83 hl hs des effects adverse these While . tal. et nlgto hs conflicting these of light In 76 nacnn oe of model canine a In . aesmlryshown similarly have 86,87 which , 76,78 16,81 82 . . Published by Maney Publishing (c) W. S. Maney & Son Limited nuiga ivresteal’ ‘inverse an inducing srtnptyo rmtrt n uginjury such lung and complications prematurity of neonatal retinopathy of to as resuscitation contribute the is to generation for believed radical oxygen free 100% hyperoxia-induced of newborns, use the recom- mend guidelines international Although controversial. possibility. this support intuba- possible in resulting disease, tion obstruc- pulmonary chronic active hypoxic tive with atelectasis, the patients in suppress absorptive drive and respiratory to hypercapnia due accentuate and volumes lung focal decrease pre- transient is brief. is as circulation therapy collateral and such served where ischemia models cerebral relevant clinically eitdtsu nuywe sdi ojnto with conjunction in used when disulfiram injury tissue mediated hypoxic– safety prematurity. neonatal the in encephalopathy. HBO investigate ischemic of of the to potential therapeutic retinopathy warranted are and are which of studies Further vascularization, hallmarks layer retinal structural plexiform abnormal outer the or of thinning caused hyperoxia hi lnclsgicnei unclear is and significance reversible clinical fully mild, their are effects these bradycar- However, and dia. output cardiac reduced vasoconstriction, ai hne bevdi eetNOstudies NBO recent in observed changes namic hne nteln.Nn ftetreciia trials, clinical three the conformational of None from lens. acuity the barotrauma, chamber visual in aural to reduced changes related and and injuries fires pulmonary claustrophobia, include seizures, HBO specific more to effects Adverse agents. chemotherapeutic eni yeoi-nue eerlvasoconstriction cerebral hyperoxia-induced con- is Another could cern ischemia. which cerebral hypotension exacerbate systemic potentially cause to known not ohv oe otlt ae hnrssiae with resuscitated oxygen when 100% to rates opposed as mortality air room lower tend neonates have that showed to studies published of analysis n7dyrtpups rat and prematurity 1.5 day of 7 retinopathy (1, promote recently pressures in not oxygen does hyperbaric 100% colleagues ATA), to and 3.0 exposure and hour normobaric in 1 Zhang at single may a hyperoxia beneficial. that of showed be durations short fact and timing early ihri h eodwe flf scmae ihthe with weeks compared fourth as or life of third week first, is second and the prematurity hyperoxia, in of of higher retinopathy durations for prolonged with risk Dembinska and increases the example, maturity that and For tissue shown hyperoxia. of have exposure of stage as dose prolonged such the factors with on are depend hyperoxia associated of risks the generally that understand to important is h shmcbanweebodflwparadoxically flow blood where in not brain increases and brain ischemic oxygen-induced normal the the above, to in discussed occurs flow vasoconstriction As blood brain. compromise ischemic theoretically could which h s fhprxai h entlpro is period neonatal the in hyperoxia of use The and fraction shunt increase can inhalation Oxygen B a ensont rmt reradical- free promote to shown been has HBO 88 yeoi a lola osystemic to lead also can Hyperoxia . 92 97 B ih upr shmctsusby tissues ischemic support might HBO . ,adriamycin 96 .Noneofthethreedosesof 98 34,35 95 bleomycin , swt shmcstroke, ischemic with As . fet n h hemody- the and effect, 89,90 94 eetees it Nevertheless, . 99 yeoi is Hyperoxia . 93 n other and meta- A . tal. et 24,25 91 , B skont euecrba dm u oits to Dutka preser- due and by Mink edema and integrity. cerebral BBB effects, ving reduce metabolic and to vasoconstrictive known is HBO DISEASES CEREBROVASCULAR OTHER IN HBO therapy. benign a HBO considered and events generally adverse is serious any reported however, xrvsto,i rae esscnrlanimals control versus treated BBB tracer in Na-fluorescein study, and extravasation, images their T1-weighted in on In enhance- post-contrast ment comparing air, stroke. points the by assessed time and was focal room delayed damage MRI and experimental and early serial at on after NBO damage infarct BBB to of of extent volume superior the was reducing HBO that fe toe ehv hw htNOtherapy in reduction NBO immediate 70% that volumes a the infarct in in shown hemispheric results and period have ischemia post-reperfusion during We outcomes administered artery stroke. neuroimaging cerebral and after patho- middle neurobehavioural improves NBO transient logic, by that show e.g. of ischemia-reperfusion, onset, model stroke filament after quickly can simple very importantly, paramedics. available, most started distinct widely and be offers is inexpensive it it administer, to because HBO: NBO over of in advantages have groups timing interested Several consideration. the become into salvageable of taken as presence are the tissue and such oxygen of dose factors therapy, prove would provided Theoretically, oxygenation design. efficacious, supplemental trial of rather the but method clinical oxygen, any that in of efficacy shortcomings appears of to lack it the to discussion, attributable above the failureofthepreviousHBOstroketrialsisnot on Based STROKE ISCHEMIC FOCAL IN NBO ischemia hemorrhage. cerebral subarachnoid vasospasm-induced after treating in HBO eot ugs htHOmyb fetv ntreating in effective be hemorrhage may brain HBO primary that suggest reports oesadhmn ihtamtcbaninjury. Ross edema by brain brain hyperoxia injury of treating efficacy traumatic in brain the support further traumatic with group Bullock’s of humans studies animal in Continuing and levels lactate brain models and pressure intracranial rnucdi h eerlcre,weeinfarct where cortex, cerebral the in pronounced a oeefcieta B nrdcn aclrper- vascular reducing Veltkamp in Similarly, NBO meability. than effective more was raigsia odinfarction cord spinal treating oe fe pnlcr nuyi rats in injury within cord treatments spinal HBO out- HBO after functional of multiple and comes histopathologic session improves or single hours, 24 hours a 3 that within showed group Zhang’s Sukhoff xouecudb sdt eetptet prpit for evacuation appropriate patients hematoma select HBO surgical to during used be improvement could clinical exposure that suggested even ela human as well h eut frcn oetsuis l sn the using all studies, rodent recent of results The erlgclRsac,20,Vlm 9 March 29, Volume 2007, Research, Neurological eiwo xgnteayi shmcsrk:A .Singhal B. A. stroke: ischemic in therapy oxygen of review A tal. et 101,102 105 tde aedmntae h s of use the demonstrated have studies aesonta B reduces HBO that shown have 17,22 104 B a eefciein effective be may HBO . 24,107 n oeatoshave authors some and , 103 105 tal. et ial,animal Finally, . h eeti most is benefit The . n pnltrauma spinal and 100 36 eetyshowed recently on htHBO that found 60 Anecdotal . 106 179 60 36 as . . Published by Maney Publishing (c) W. S. Maney & Son Limited hw htNOsgicnl nrae ri interstitial in brain increases functionalpO stroke significantly after NBO reduces that loss shown therapy weight Using and NBO rodents. atrophy brain that deficits, shown have the enhances points neuroprotection time of earlier degree minutes); at 30–45 treatment (approximately for initiating short window compared is time as rodents in therapeutic 90% NBO The as controls. much normoxic as to by reduced are volumes Singhal B. A. stroke: ischemic in therapy oxygen of review A 180 oHO h rtcloye eso eurdfor required tension oxygen low extremely critical is function the mitochondrial HBO, to teutstesvrt n h oueo ischemic of volume the DWI serial and by assessed severity injury the attenuates enivsiae.FynadAuer and Flynn also has investigated. NBO been with injury reperfusion radical-associated death. cell ischemic for thresholds a ananpnmrlitrtta pO ischemia interstitial during penumbral administered maintain oxygen can 95% that shown htNOi iefcie nriigbantsu oxygen tissue brain raising Auer and in Flynn ‘ineffective’ levels. is NBO that brain. ischemic salvage to used 0 mH,wihaeesl civdwt B,do NBO, group with Liu’s achieved benefit. easily additional are confer not which Hg, mm 200 a xedte‘eefso iewno’fo to 1 from window’ time ‘reperfusion hours 3 the onset extend stroke after can shortly administered therapy NBO that B aaeadde o nraetelvl findirect of levels the worsen increase not of significantly does marker and not damage NBO cellular BBB does that (a generation), shown hydroethidine superoxide increase have generated not We mainly does reperfusion. are tissue radicals free given during relevant that highly knowledge phase is our which post-reperfusion volumes, the infarct reduces during solely administered h r-shmcvle.Wieteices nbrain in increase the While ptiO values. pre-ischemic the ml nrae nptiO in increases small iia tbsln,ipoe infiatyi h B-rae ru fe hrp a ntae,btwr o infiatydfeetat different significantly not were but initiated, was therapy ( after scores group NIHSS hours. NBO-treated 8 the for in oxygen) l/min significantly points (45 time improved NBO chronic baseline, or at (controls) air similar room to domized 4: Figure h hoeia ocr feaebtn xgnfree oxygen exacerbating of concern theoretical The tlattosuishv drse h presumption the addressed have studies two least At 2 2 npnmrltissues penumbral in erlgclRsac,20,Vlm 9 March 29, Volume 2007, Research, Neurological fetdb B scranymnra compared as minor certainly is NBO by affected 108 hrpui fcc fNOi ainswt ct shmcsrk.Ptet ihaueicei stroke ischemic acute with Patients stroke. ischemic acute with patients in NBO of efficacy Therapeutic nsmlreprmns ln n Auer and Flynn experiments, similar In . nvivo in 25 109 2 ih eaeut oovercome to adequate be might P xmty i’ ru has group Liu’s oximetry, EPR 19 hwdta pO that showed 24 ugsigta B a be can NBO that suggesting , utemr,NOtherapy NBO Furthermore, . 24 ial,w aeshown have we Finally, . 109 hwdta NBO that showed 2 20 2 eescoeto close levels 110 ausabove values a recently has n even and 109 rti abnlfrain taueo uauetime subacute stroke or acute and after 32 at points protein formation, metallopro- shock carbonyl matrix heat protein MMP-9, as (MMP-2), such 2 stress teinase oxidative of markers f‘euba’tsu hl hrp a being was therapy volume while the of in tissue increase growth ‘penumbral’ an reduced and showed of scores, volumes patients lesion NBO-treated NIHSS DWI 3. at in and month stopped, improvement and was (baseline), 1 treatment treatment week DWI after than before air. treatment, room performed or during were MRI less NBO of PWI admission hours and on 8 symptoms to mismatch randomized DWI–PWI were stroke and hours 12 ischemic hemispheric i facemask) administered oxygen a l/min (45 via NBO of trial this therapeutic of of efficacy basis or the on safety pathophysiology. patients true stroke study. the stroke ischemic ascertain year. in 1 to oxygen to after difficult measured is paid was It 12– (survival) was after outcome and Finally, treated attention to stroke the hemorrhagic receive time were had not no 12.7% did the or ‘therapy’, patients assigned 18% and onset Moreover, hours, hours). of 24 24 ( of time late as l/min) (3 unknown relatively long study doses was as observational low treatment for supplemental very an received oxygen, was receive patients this not where However, should authors mild– oxygen. The with strokes oxygen. victims to stroke nasal moderate compared non-hypoxic l/min that 3 as concluded with control stroke treated air-treated mild–moderate room those in with better was patients survival) year (1 vlae ntohmnsuis h rtwsan was first The Norway studies. from human study two observational in evaluated caspase-8. of and MMP-9 measures species), (both lower oxygen hydroethidine in reactive and results 8-OhdG stroke of focal in levels therapy NBO that shown u ru eetypbihdrslso h first the of results published recently group Our h fet foye naaini toehv been have stroke in inhalation oxygen of effects The A n eaieMIsrk einvlms( volumes lesion stroke MRI relative and ) 25 107,108 nti td,1 ainswith patients 16 study, this In . i’ group Liu’s . , 0 fptet had patients of 40% 111 , 2huswr ran- were hours 12 20 hr outcome where a similarly has B were ) Published by Maney Publishing (c) W. S. Maney & Son Limited erpoetv rg aes a aldciia ras at trials, cost clinical failed high far so have drugs Neuroprotective DIRECTIONS FUTURE AND hospital. SUMMARY the to arrival upon tPA of eligible, patients followed if light field, stroke and the HBO that In in by NBO hypothesized study. receiving be from this benefit can would in it toxicity data, these oxygen of evidence a rvosybe ouetdol ihprompt with only documented recanalization which therapy been arterial lesions, DWI previously NBO visible has of Remarkably, improvement in resulted 4). (Figure administered tde ihsra Rsetocp,NOtherapy patients NBO regions within ischemia of levels spectroscopy, lactate of brain subset MR improve in to found serial higher a was be with In to to studied tended ‘ischemic’ patients. baseline values hyperoxia-treated from ‘non-ischemic’ improving hour percentage 4 voxels The MRI scans. MRI of ‘during to ‘post-therapy’ MRI automated and baseline the the therapy’ in from performed voxels change ADC the of we intensity determine to analysis, analysis voxel-by-voxel MRI volumetric REFERENCES regions in limited. tPA stroke is acute care of to access immediate use where world the the around increase which window, significantly time thrombolysis would useful the a extend be may to HBO) strategy or (NBO hyperoxia by turn, followed In hospital field, arrival. after the therapy thrombolytic appropriate, in if initiated or be HBO therapy could available NBO as widely such stroke a of Conceivably, era this thrombolysis. in particularly chambers ill within acutely to patients care medical delivering in difficulties poten- and commercial tial minor chambers, limited HBO non-compliance, of patient availability include therapy acute stroke an hyperoxia/reperfusion as combined HBO developing to a challenges Major higher inves-strategy. of to efficacy with opportunity the thrombolysis unique tigate the stroke offers of rates reperfusion advent the benefit. long-term Today, for requisite long-term a be may assess reperfusion subsequent tissue and excessive not reperfusion, tissue with of did patients in trials use benefit Past to and pressures. time size delayed chamber as sample such inadequate factors therapy, from resulted trials have clinical if HBO may previous growing effective of failure is the be There that onset. recognition may stroke after NBO enough early even applied and However, the potent. probably recovery is most HBO methods, the delivery post-stroke Of salvage oxygen available stroke. subsequent enhance against a can pre-condition acuteperhaps be treatment, for that window time may stroke the extend strategy mechanisms, tissue, brain ischemic indirect neuroprotective tha and suggest powerful direct data animal multiple available human The treatment. and stroke acute approved isepamngnatvtrfraueicei toe The stroke. 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S. Maney & Son Limited eiwo xgnteayi shmcsrk:A .Singhal B. A. stroke: ischemic in therapy oxygen of review A 182 8Zo ,L ,NnaA, Nanda Y, Li C, Zhou 38 the in oxygen Hyperbaric P. Trouillas N, Nighoghossian 35 6Vlkm ,SeigD,SnL, Sun DA, Siebing R, Veltkamp 36 Palvo NA, Lassen 34 7CnoiM,Biur ,Gioi D, Guidolin S, Baiguera MT, Conconi 37 7Ro A ako-remnC ye .Efcso hyperbaric of Effects P. Lyden C, Jackson-Friedman JA, Roos 47 2VoasyE azrE eno M, Feinsod E, Palzur E, Vlodavsky M, 32 Patel W, Yin JW, Calvert 31 3DmhnoI,Bs E ent PB, Bennett AE, Boso IT, Demchenko 33 6WisenP,Adro G elsD.Rslsof Results DA. Telles GG, Anderson PR, Weinstein 46 X, Yang C, Camporesi ZJ, Yang 45 BJ, Hoffer KC, Niu therapy CF, oxygen Chang Hyperbaric 44 MT. Torbey HT, Whelan AK, Helms 43 Z, Zhu L, Xiong H, Dong 41 P, Schumann F, Wiegand K, Prass 40 0YnD huC uaaI, Kusaka C, Zhou D, Yin 30 2ZagJ,L ,McakwG, Mychaskiw T, Lo JH, Zhang 42 H, Dong Z, Zhu L, Xiong 39 9BrsJ,SalG,SooaKK, Svoboda GL, Stahl JA, Buras 29 G, Fiskum R, Silbergleit M, Miljkovic-Lolic 28 G, focal Mychaskiw AE, of Badr penumbra W, Yin the 27 and thresholds Viability KA. Hossmann 26 Haepeso ntecrba otxatrgoa ischemia. global after cortex Commun cerebral Res Biophys the Biochem in expression line. RHOa cell reactive 3t3/j2 and fibroblast Med activities mouse Investig in apoptotic J generation and species proliferative oxygen on oxygen 133-xenon XIIID the by man. observed in technique hypocapnia during reaction inverse eubaae ftertmdlo eerlcnuin rae by traumatic treated immunohistochemical contusion, study. quantitative the cerebral A in of therapy: model oxygen family rat hyperbaric the bcl-2 of the area penumbra of proteins apoptosis-related eue eerlbodfo yiatvtn ircoxide. nitric inactivating by flow Oxide blood cerebral reduces lo–ri are aaeadeeaatrtasetfocal transient after edema and ischemia. damage cerebral barrier blood–brain xgno erlgcotoefrcrba shmai rats. in ischemia cerebral for Med outcome Emerg Acad neurologic on oxygen yebrcoye nartfclcrba shmcmodel. Metab ischemic cerebral Flow focal Blood rat a in oxygen hyperbaric rvne ri nuyidcdb yoi–shmai a in hypoxia–ischemia by induced model. rat injury neonatal brain prevented ees nartmdlo rnin idecrba artery cerebral middle transient of model dopamine striatal rat reduces a occlusion. and in injury release cerebral focal mitigates rats. adult in stroke postischemic 2000; of treatment for 63–77 cord spinal against tolerance rabbits. induces in hyperoxia ischemia is and mice oxygen in ischemia cerebral focal dependent. strain against tolerance induced (Engl) J fcrba ischemia. cerebral of stroke. in neuroprotection and oxygen not transient model. in rat occlusion ischemia artery cerebral against middle permanent neuroprotection induces ing oneuae CM1epeso nue yhpxaand NOS. hypoxia of by role 2000; induced The expression hypoglycemia: ICAM-1 downregulates eerlicei r soitdwt eue ri leukocyte focal brain experimental reduced with in activity. associated treatment myeloperoxidase are oxygen ischemia hyperbaric cerebral of effects focal transient rat a model. in ischemia treatment cerebral oxygen hyperbaric in involved is ischemia. ramn faueicei toe nustldissue. unsettled An stroke: Sci ischemic acute of treatment 518–524 yebrcoye hrp uigtmoaymdl cerebral middle cats. temporary unanesthetized in during occlusion artery therapy oxygen hyperbaric erlgclRsac,20,Vlm 9 March 29, Volume 2007, Research, Neurological 1997; 166 278 caNuoahl(Berl) Neuropathol Acta 2000; 2000; n Neurol Ann 150 298–306 : C292–C302 : u plPhysiol Appl J Eur 4 27–31 : 113 597–608 : 2003; giR eerlseldrn yecpi n the and hypercapnia during steal Cerebral R. ¨gyi 1998; ri Res Brain 836–839 : cn lnLbInvest Lab Clin J Scand Stroke 2003; ri Res Brain Anesthesiology 51 eervs Dis Cerebrovasc 1994; tal. et 227–232 : 5 tal. et 18–24 : 23 2005; ri Res Brain ri Res Brain tal. et 2000; 855–864 : B upessNG-,N-,or NG-r, NOGO-a, suppresses HBO 36 2002; tal. et 2002; tal. et 2005; yebrcoye precondition- oxygen Hyperbaric 557–565 : tal. et tal. et tal. et rcniinn ihhyperbaric with Preconditioning 2003; 36 tal. et tal. et tal. et 871 1679–1683 : 2002; 87 2002; mJPyilCl Physiol Cell Physiol J Am 2003; niiino ppoi by apoptosis of Inhibition yebrcoye therapy oxygen Hyperbaric 951 yebrcoye reduces oxygen Hyperbaric onrglto fCOX-2 of regulation Down tal. et 110 ehnsso hyperbaric of Mechanisms Pathophysiology tal. et 146–150 : 101–107 : 2005; 309 tal. et tal. et yebrcoxygenation Hyperbaric yebrcoxygenation Hyperbaric yebrcoxygenation Hyperbaric Neurosurgery 1–8 : 120–126 : 1968; 96 368–376 : tal. et 926 971 fet fhyperbaric of Effects yebrcoxygen Hyperbaric 907–912 : yebrcoxygen Hyperbaric 20 vlaino the of Evaluation 165–171 : 90–94 : 417–426 : Neuroprotective 22 Spl 102): (Suppl. x Neurol Exp hnMed Chin 1987; 2005; Neurol J Cereb J Nitric 20 12 : : 0HagL et P ad A, Nanda MP, Mehta L, Huang 60 1SroJ,Rs A ilrL, Diller HA, Rusk JE, Sarno 61 4Kai E mtivK,TmegT.[yebrcoxygenation [Hyperbaric TA. Tomberg KK, Dmitriev AE, Kaasik 64 [Hyperbaric VN. Shelkovskii MV, Romasenko SV, Pravdenkova 63 hyperbaric of [Effect SV. Pravdenkova V, Iu Isakov VV, Lebedev 62 G, Mychaskiw W, Yin AE, Badr 59 8YnD hn H eae n utpehprai oxygen hyperbaric multiple and Delayed JH. Zhang D, Yin 58 7Hed ,HesunM aadehO, Haraldseth M, Hjelstuen A, Hjelde 57 6Shbt R caeH eln S, Heiland H, Schade WR, Schabitz 56 S, Thorup ND, Kien JA, Reitan 55 1LuM shnedrC,Hree T, Herdegen CC, Eschenfelder M, Lou 51 4Br T apJ,SihR.Hprai xgnadcerebral and oxygen Hyperbaric RR. Smith JP, Kapp JT, Burt 54 1BradS,Ga W us MD, Buist TW, Gray SA, Bernard 71 A, Schnabel J, Wasiak MH, Bennett 69 0HptemaatrCricArs td ru.Ml therapeutic Mild Group. Study Arrest Cardiac after Hypothermia 70 A brain. the in stenosis small-vessel Generalized RA. 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S. Maney & Son Limited 0Ldt F erae O Decreased RF. Lodato 90 and mediation, autonomic time, Response A. Jubran RF, Lodato toxicity. 89 Oxygen SG. Jenkinson 88 T, Topal A, Korkmaz S, Oter 87 3Lpnk A ik D alwyC.Nroi ventilation Normoxic CW. Callaway SD, Hicks cerebral CA, global Lipinski after 83 oxygen Hyperbaric AJ. Dutka RB, Mink 82 ML, Smith H, Zhang CD, Agardh 81 cardiopulmon- Hypoxic LG. D’Alecy SE, Whitesall CF, Zwemer Cardiopulmonary- 80 LG. D’Alecy SE, Whitesall CF, Zwemer 79 Y, Haywood RE, Rosenthal Y, Liu 78 RE, Rosenthal E, Martin V, Vereczki 77 O, Kempski YN, Vaishnav HS, Mickel 76 G, Feuerstein O, Kempski HS, Mickel 75 N, Zarchin G, Rogatsky M, Krakovsky 74 6Eaa M xe J rsdPV, Prasad MJ, Axley reactive IM, Elayan of 86 generation Mitochondrial J. 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Fisher 113 1 iwl S ae L atel J, Mattiello JL, Saver CS, Kidwell 112 receive routinely victims stroke Should B. Guldvog OM, Ronning 111 experimental JL, and LaManna FF, hyperoxemia Jobsis FG, Eubaric Hempel RN. 110 Auer EP, Flynn the 109 extends hyperoxia Normobaric EH. Lo AB, Singhal HY, Kim T, 108 Sumii X, Wang AB, Singhal 107 hyperbaric of Mechanisms JH. Zhang AR, Colohan RP, Ostrowski 106 0 i ,LmW,YoTT, Yeo WK, Lim J, Lim 104 0 osiK ooaA od N, Konda A, Yokota K, Kohshi 105 0 uaaiN oiociT aua M, Sakurai T, Horinouchi N, Murakami 103 oxygenation. hyperbaric of Effects MH. Sukoff 102 OE, Espinosa SA, Hollin MH, Sukoff 101 0 ikR,DtaA.Hprai xgnatrgoa cerebral global after oxygen Hyperbaric AJ. Dutka RB, Mink 100 6CletJ,Zo ,ZagJ.Tasetepsr frtpups rat of exposure Transient JH. Zhang C, Zhou JW, Calvert 96 3Dn ,Cch ,BriiG oeo xdtv tesas stress oxidative CP, O’Donnell of A, Schulze Role A, G. 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A. stroke: ischemic in therapy oxygen of review A 38 56 57 2001; 1999; Lung 163–168 : 381–394 : 571–575 : 2003; plPhysiol Appl J erlMdCi (Tokyo) Chir Med Neurol Stroke 1968; 42 ee lo lwMetab Flow Blood Cereb J 30 1987; 220–223 : 2033–2037 : 34 1539–1546 : 29 1995; n Neurol Ann netOhhlo i Sci Vis Ophthalmol Invest 165 236–241 : 239–247 : 1977; 26 tal. et 2002; 2307–2312 : hrao x Ther Exp Pharmacol J tal. et 43 2002; aaeeto haemorrhagic of Management tal. et 22 ohaeDtbs ytRev Syst Database Cochrane 873–879 : x Neurol Exp tal. et tal. et 861–868 : tal. et yebrcoye therapy oxygen Hyperbaric tal. et 1993; tal. et 52 tal. et hobltcrvra of reversal Thrombolytic tal. et rtCr Med Care Crit 2005; n Neurol Ann 566–572 : fet fnormobaric of Effects tal. et i essoye for oxygen versus Air xdto fcerebral of Oxidation h rtcieeffect protective The rddcontribution Graded 33 yebrcoxygen Hyperbaric yebrcoxygen Hyperbaric Neurosurg J 92–99 : 25 2004; 2001; Stroke iev Pediatr Minerva rnsi acute in Trends n ls Surg Plast Ann 554–571 : n Neurol Ann 1980; 189 42 2000; Singapore 2001; 2001; 1111– : 150– : 2001; 212 183 32 47 29 : : : :