[From nobody Sat Aug 4 08:16:43 2007 From: "Saved by Windows Internet Explorer 7" Subject: Revising a Dogma: Ketamine for Patients with Neurological Injury? -- Himmelseher and Durieux 101 (2): 524 -- Anesthesia & Analgesia Date: Fri, 3 Aug 2007 20:28:04 -0700 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_0000_01C7D60C.CBB8DC70" X-MimeOLE: Produced By Microsoft MimeOLE V6.0.6000.16480 This is a multi-part message in MIME format. ------=_NextPart_000_0000_01C7D60C.CBB8DC70 Content-Type: text/html; charset="Windows-1252" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524 <!DOCTYPE HTML PUBLIC "-//W3C//DTD HTML 4.0 Transitional//EN"> <HTML><HEAD><TITLE>Revising a Dogma: Ketamine for Patients with = Neurological Injury? -- Himmelseher and Durieux 101 (2): 524 -- = Anesthesia & Analgesia</TITLE> <META http-equiv=3DContent-Type content=3D"text/html; = 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E.</A></STRONG> = </TD></TR> <TR> <TD class=3Dcontent_box_space_between_sections = colSpan=3D2><IMG height=3D1=20 alt=3D" " = src=3D"http://www.anesthesia-analgesia.org/icons/spacer.gif"=20 width=3D200></TD></TR> <TR> <TD class=3Dcontent_box_title colSpan=3D2>Related = Collections</TD></TR> <TR> <TD class=3Dcontent_box_space_between_sections = colSpan=3D2><IMG height=3D1=20 alt=3D" " = src=3D"http://www.anesthesia-analgesia.org/icons/spacer.gif"=20 width=3D200></TD></TR> <TR> <TD class=3Dcontent_box_arrow vAlign=3Dtop width=3D4><IMG = height=3D11=20 alt=3D"Right arrow"=20 = src=3D"http://www.anesthesia-analgesia.org/icons/shared/misc/arrowTtrim.g= if"=20 width=3D4 border=3D0></TD> <TD class=3Dcontent_box_item><STRONG><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/collection/neuroanesthesi= a">Neuroanesthesia</A></STRONG>=20 <BR></TD></TR> <TR> <TD class=3Dcontent_box_arrow vAlign=3Dtop width=3D4><IMG = height=3D11=20 alt=3D"Right arrow"=20 = src=3D"http://www.anesthesia-analgesia.org/icons/shared/misc/arrowTtrim.g= if"=20 width=3D4 border=3D0></TD> <TD class=3Dcontent_box_item><STRONG><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/collection/pharmacology">= Pharmacology</A></STRONG>=20 <BR></TD></TR> <TR> <TD class=3Dcontent_box_arrow vAlign=3Dtop width=3D4><IMG = height=3D11=20 alt=3D"Right arrow"=20 = src=3D"http://www.anesthesia-analgesia.org/icons/shared/misc/arrowTtrim.g= if"=20 width=3D4 border=3D0></TD> <TD class=3Dcontent_box_item><STRONG><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/collection/trauma">Trauma= </A></STRONG>=20 = </TD></TR></TD></TR></TBODY></TABLE></TD></TR></TBODY></TABLE><FONT=20 size=3D-1><BR>Anesth Analg 2005;101:524-534<BR>=A9 2005 <A=20 href=3D"http://www.anesthesia-analgesia.org/misc/terms.shtml">Internation= al=20 Anesthesia Research Society</A><BR>doi: = 10.1213/01.ANE.0000160585.43587.5B=20 </FONT><BR> <H3> <HR align=3Dleft width=3D"50%" noShade SIZE=3D1> NEUROSURGICAL ANESTHESIA</H3> <H2>Revising a Dogma: Ketamine for Patients with Neurological Injury?=20 </H2><STRONG></NOBR><NOBR>Sabine Himmelseher, MD<SUP>*</SUP></NOBR>, and = <NOBR>Marcel E. Durieux, MD, PhD<SUP><IMG alt=3D{dagger}=20 src=3D"http://www.anesthesia-analgesia.org/math/dagger.gif" = border=3D0></SUP></NOBR>=20 </STRONG> <P><FONT size=3D-1>*Klinik fuer Anaesthesiologie, Klinikum rechts der = Isar,=20 Technische Universit=E4t, M=FCnchen, Germany; and <IMG alt=3D{dagger}=20 src=3D"http://www.anesthesia-analgesia.org/math/dagger.gif" = border=3D0>Department of=20 Anesthesiology, University of Virginia Health System, Charlottesville, = Virginia=20 </FONT> <P><FONT size=3D-1>Address correspondence and reprint requests to Marcel = E.=20 Durieux, MD, PhD, Department of Anesthesiology, University of Virginia = Health=20 System, PO Box 800710, Charlottesville, VA 22908-0710. Address e-mail to = <SPAN=20 id=3Dem0>durieux{at}virginia.edu</SPAN> <SCRIPT type=3Dtext/javascript><!--=0A= var u =3D "durieux", d =3D "virginia.edu"; = document.getElementById("em0").innerHTML =3D '<a href=3D"mailto:' + u + = '@' + d + '">' + u + '@' + d + '<\/a>'//--></SCRIPT> .</FONT> <P><A name=3DABS><!-- null --></A><BR clear=3Dright> <TABLE cellSpacing=3D0 cellPadding=3D0 width=3D"100%" bgColor=3D#e1e1e1> <TBODY> <TR> <TD vAlign=3Dcenter align=3Dleft width=3D"5%" bgColor=3D#ffffff><IMG = height=3D21=20 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/rarrow.gif"=20 width=3D10></TD> <TH vAlign=3Dcenter align=3Dleft width=3D"95%"><FONT = size=3D+2>&nbsp;&nbsp;=20 Abstract </FONT></TH></TR></TBODY></TABLE> <TABLE cellPadding=3D5 align=3Dright border=3D1> <TBODY> <TR> <TH align=3Dleft><FONT size=3D-1><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#to= p"><IMG=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Top<BR></A><IMG height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/dot.gif" = width=3D11=20 border=3D0><FONT color=3D#464c53>Abstract</FONT><BR><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#BD= Y"><IMG=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/darrow.gif" = width=3D11=20 border=3D0>Introduction<BR></A><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#SE= C1"><IMG=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/darrow.gif" = width=3D11=20 border=3D0>Methods<BR></A><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#SE= C2"><IMG=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/darrow.gif" = width=3D11=20 border=3D0>Results<BR></A><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#SE= C3"><IMG=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/darrow.gif" = width=3D11=20 border=3D0>Discussion<BR></A><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#SE= C4"><IMG=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/darrow.gif" = width=3D11=20 border=3D0>Conclusion<BR></A><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#BI= BL"><IMG=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/darrow.gif" = width=3D11=20 = border=3D0>References<BR></A></FONT></TH></TR></TBODY></TABLE>&nbsp;<BR>W= e=20 evaluated reports of randomized clinical trials in the = perioperative<SUP>=20 </SUP>and intensive care setting concerning ketamine=92s effects<SUP> = </SUP>on the=20 brain in patients with, or at risk for, neurological<SUP> </SUP>injury. = We also=20 reviewed other studies in humans on the drug=92s<SUP> </SUP>effects on = the brain,=20 and reports that examined ketamine in<SUP> </SUP>experimental brain = injury. In=20 the clinical setting, level II<SUP> </SUP>evidence indicates that = ketamine does=20 not increase intracranial<SUP> </SUP>pressure when used under conditions = of=20 controlled ventilation,<SUP> </SUP>coadministration of a <IMG = alt=3D{gamma}=20 src=3D"http://www.anesthesia-analgesia.org/math/ggr.gif" = border=3D0>-aminobutyric=20 acid (GABA) receptor agonist,<SUP> </SUP>and without nitrous oxide. = Ketamine may=20 thus safely be used<SUP> </SUP>in neurologically impaired patients. = Compared=20 with other anesthetics<SUP> </SUP>or sedatives, level II and III = evidence=20 indicates that hemodynamic<SUP> </SUP>stimulation induced by ketamine = may=20 improve cerebral perfusion;<SUP> </SUP>this could make the drug a = preferred=20 choice in sedative regimes<SUP> </SUP>after brain injury. In the = laboratory,=20 ketamine has neuroprotective,<SUP> </SUP>and <I>S</I>(+)-ketamine = additional=20 neuroregenerative effects, even<SUP> </SUP>when administered after onset = of a=20 cerebral insult. However,<SUP> </SUP>improved outcomes were only = reported in=20 studies with brief recovery<SUP> </SUP>observation intervals. In = developing=20 animals, and in certain<SUP> </SUP>brain areas of adult rats without = cerebral=20 injury, neurotoxic<SUP> </SUP>effects were noted after large-dose = ketamine.=20 These were prevented<SUP> </SUP>by coadministration of GABA receptor=20 agonists.<SUP> </SUP> <P><A name=3DBDY><!-- null --></A><BR clear=3Dright> <TABLE cellSpacing=3D0 cellPadding=3D0 width=3D"100%" bgColor=3D#e1e1e1> <TBODY> <TR> <TD vAlign=3Dcenter align=3Dleft width=3D"5%" bgColor=3D#ffffff><IMG = height=3D21=20 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/rarrow.gif"=20 width=3D10></TD> <TH vAlign=3Dcenter align=3Dleft width=3D"95%"><FONT = size=3D+2>&nbsp;&nbsp;=20 Introduction </FONT></TH></TR></TBODY></TABLE> <TABLE cellPadding=3D5 align=3Dright border=3D1> <TBODY> <TR> <TH align=3Dleft><FONT size=3D-1><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#to= p"><IMG=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Top<BR></A><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#AB= S"><IMG=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Abstract<BR></A><IMG height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/dot.gif" = width=3D11=20 border=3D0><FONT color=3D#464c53>Introduction</FONT><BR><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#SE= C1"><IMG=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/darrow.gif" = width=3D11=20 border=3D0>Methods<BR></A><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#SE= C2"><IMG=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/darrow.gif" = width=3D11=20 border=3D0>Results<BR></A><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#SE= C3"><IMG=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/darrow.gif" = width=3D11=20 border=3D0>Discussion<BR></A><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#SE= C4"><IMG=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/darrow.gif" = width=3D11=20 border=3D0>Conclusion<BR></A><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#BI= BL"><IMG=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/darrow.gif" = width=3D11=20 = border=3D0>References<BR></A></FONT></TH></TR></TBODY></TABLE>&nbsp;<BR>P= harmacological=20 modulation of excessive <I>N</I>-methyl-d-aspartate<SUP> </SUP>(NMDA) = receptor=20 stimulation may be used as part of a multi-targeted<SUP> </SUP>approach = to=20 ameliorate secondary brain injury (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R1= -39">1</A>).=20 The benefits=97if<SUP> </SUP>any=97of the NMDA receptor antagonist = ketamine,=20 however,<SUP> </SUP>remain undefined in this setting, in part because of = the=20 persisting<SUP> </SUP>dogma that the drug not be used in patients at = risk for=20 increases<SUP> </SUP>in intracranial pressure (ICP) (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R2= -39">2,3</A>).=20 Thirty years ago, increases<SUP> </SUP>in cerebral oxygen consumption, = cerebral=20 blood flow (CBF), and<SUP> </SUP>ICP were indeed reported during = anesthesia with=20 ketamine (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R4= -39">4,5</A>).<SUP>=20 </SUP> <P>Advances in our knowledge of ketamine=92s cerebral effects<SUP> = </SUP>and=20 progress in therapeutic interventions for brain injury warrant<SUP> = </SUP>a=20 reevaluation of this verdict. First, preclinical and clinical<SUP> = </SUP>data=20 show that the cerebral hemodynamic and metabolic effects<SUP> </SUP>of = ketamine=20 depend on study setting (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R4= -39">4=968</A>),=20 the absence<SUP> </SUP>or presence of controlled ventilation (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R8= -39">8=9610</A>),=20 background<SUP> </SUP>anesthetics, and other drugs (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R1= 1-39">11=9615</A>).=20 In patients with<SUP> </SUP>intracranial pathology, ketamine has been = used=20 safely under<SUP> </SUP>appropriate conditions (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R1= 6-39">16=9618</A>).=20 Second, as the important<SUP> </SUP>role of NMDA receptor signaling in = pathways=20 inducing neuronal<SUP> </SUP>death has been defined (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R1= 9-39">19</A>),=20 interest in clinically available<SUP> </SUP>NMDA antagonists has been = renewed.=20 Because preclinical studies<SUP> </SUP>report neuroprotective effects = for=20 racemic ketamine in cell<SUP> </SUP>and animal models (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R2= 0-39">20=9623</A>),=20 and additional regenerative<SUP> </SUP>effects for <I>S</I>(+)-ketamine = in=20 cultured neurons (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R2= 0-39">20,24</A>),=20 the drug<SUP> </SUP>may potentially be of benefit for patients with = brain=20 injury.<SUP> </SUP> <P>This review will provide an update on ketamine=92s cerebral<SUP> = </SUP>effects,=20 and will attempt to answer the question whether use<SUP> </SUP>of = ketamine in=20 the neurosurgical patient is acceptable, and<SUP> </SUP>whether = potential=20 benefits should be further investigated.<SUP> </SUP> <P><A name=3DSEC1><!-- null --></A><BR clear=3Dright> <TABLE cellSpacing=3D0 cellPadding=3D0 width=3D"100%" bgColor=3D#e1e1e1> <TBODY> <TR> <TD vAlign=3Dcenter align=3Dleft width=3D"5%" bgColor=3D#ffffff><IMG = height=3D21=20 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/rarrow.gif"=20 width=3D10></TD> <TH vAlign=3Dcenter align=3Dleft width=3D"95%"><FONT = size=3D+2>&nbsp;&nbsp;=20 Methods </FONT></TH></TR></TBODY></TABLE> <TABLE cellPadding=3D5 align=3Dright border=3D1> <TBODY> <TR> <TH align=3Dleft><FONT size=3D-1><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#to= p"><IMG=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Top<BR></A><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#AB= S"><IMG=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Abstract<BR></A><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#BD= Y"><IMG=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Introduction<BR></A><IMG height=3D9 alt=3D" " = hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/dot.gif" = width=3D11=20 border=3D0><FONT color=3D#464c53>Methods</FONT><BR><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#SE= C2"><IMG=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/darrow.gif" = width=3D11=20 border=3D0>Results<BR></A><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#SE= C3"><IMG=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/darrow.gif" = width=3D11=20 border=3D0>Discussion<BR></A><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#SE= C4"><IMG=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/darrow.gif" = width=3D11=20 border=3D0>Conclusion<BR></A><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#BI= BL"><IMG=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/darrow.gif" = width=3D11=20 = border=3D0>References<BR></A></FONT></TH></TR></TBODY></TABLE>&nbsp;<BR>T= he early=20 literature on ketamine=92s cerebral effects has<SUP> </SUP>been = discussed=20 previously (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R2= -39">2,3</A>),=20 and will not be extensively<SUP> </SUP>repeated. We will focus on data = from the=20 last decade. Actually,<SUP> </SUP>almost all of the early reports do not = meet=20 current quality<SUP> </SUP>criteria for randomized, controlled trials: = the=20 studies often<SUP> </SUP>were unblinded observations, and without=20 randomization.<SUP> </SUP> <P>Computer literature searches in the electronic databases MEDLINE<SUP> = </SUP>and EMBASE from 1994 to October 2004 were performed using the<SUP> = </SUP>following terms: ketamine, NMDA receptor antagonist, = hemodynamics,<SUP>=20 </SUP>ICP, (neuro)anesthesia, sedation, emergence, psychic, = adverse/side<SUP>=20 </SUP>effects, neuroprotection, brain, cerebral, injury, ischemia,<SUP>=20 </SUP>and (neuro)toxicity. Searches were conducted without language<SUP> = </SUP>restriction, but limited to items with English abstracts. = After<SUP>=20 </SUP>abstract screening, only articles deemed relevant were = obtained.<SUP>=20 </SUP>A manual search for additional reports in reference lists was<SUP> = </SUP>performed. A systematic review filter was applied. Abstracts,<SUP> = </SUP>letters, case reports, or unpublished data were not included.<SUP> = </SUP>Authors were not contacted. If a preclinical study reported<SUP>=20 </SUP>effects similar to those reported in a clinical trial, the=20 preclinical<SUP> </SUP>study was not included because of space = limitations.=20 Literature<SUP> </SUP>from the veterinary field was not considered.<SUP> = </SUP> <P>Reports of randomized, controlled trials, and nonrandomized<SUP>=20 </SUP>controlled or cohort trials in adults were included. Where=20 applicable,<SUP> </SUP>trials were scored using a 3-item, 1=965 quality = scale (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R2= 5-39">25</A>).<SUP>=20 </SUP>Trial evidence was stratified according to accepted level of<SUP>=20 </SUP>evidence ratings (level I=96level IV), and conclusions were<SUP> = </SUP>based=20 on this evidence. Specific trial evidence levels are indicated<SUP> = </SUP>in the=20 text as appropriate. In view of the heterogeneity in<SUP> </SUP>study = design and=20 settings, and the small number of trials with<SUP> </SUP>comparable = objectives,=20 meta-analyses were not possible.<SUP> </SUP> <P>For preclinical human studies, a methodological quality of = randomized,<SUP>=20 </SUP>controlled investigation with allocation concealment and = blinding<SUP>=20 </SUP>of study assessment was deemed necessary. In laboratory work,<SUP> = </SUP>studies had to model a clinical scenario, and the primary = outcome<SUP>=20 </SUP>measure had to be relevant for or represent a measure of=20 neuroprotection.<SUP> </SUP> <P><A name=3DSEC2><!-- null --></A><BR clear=3Dright> <TABLE cellSpacing=3D0 cellPadding=3D0 width=3D"100%" bgColor=3D#e1e1e1> <TBODY> <TR> <TD vAlign=3Dcenter align=3Dleft width=3D"5%" bgColor=3D#ffffff><IMG = height=3D21=20 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/rarrow.gif"=20 width=3D10></TD> <TH vAlign=3Dcenter align=3Dleft width=3D"95%"><FONT = size=3D+2>&nbsp;&nbsp;=20 Results </FONT></TH></TR></TBODY></TABLE> <TABLE cellPadding=3D5 align=3Dright border=3D1> <TBODY> <TR> <TH align=3Dleft><FONT size=3D-1><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#to= p"><IMG=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Top<BR></A><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#AB= S"><IMG=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Abstract<BR></A><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#BD= Y"><IMG=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Introduction<BR></A><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#SE= C1"><IMG=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Methods<BR></A><IMG height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/dot.gif" = width=3D11=20 border=3D0><FONT color=3D#464c53>Results</FONT><BR><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#SE= C3"><IMG=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/darrow.gif" = width=3D11=20 border=3D0>Discussion<BR></A><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#SE= C4"><IMG=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/darrow.gif" = width=3D11=20 border=3D0>Conclusion<BR></A><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#BI= BL"><IMG=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/darrow.gif" = width=3D11=20 = border=3D0>References<BR></A></FONT></TH></TR></TBODY></TABLE>&nbsp;<BR><= STRONG>Identification=20 of Studies</STRONG><BR>The literature searches identified 246 articles = that=20 examined<SUP> </SUP>the use of ketamine in brain insults or the setting = of=20 neuroanesthesia.<SUP> </SUP>Seventy-nine studies were included. There = were 5=20 volunteer and<SUP> </SUP>16 patient trials (with &gt;500 patients). = Frequent=20 reasons<SUP> </SUP>for study exclusion were use of ketamine as = anesthetic in=20 brain<SUP> </SUP>injury experiments or description of pathophysiological = phenomena<SUP> </SUP>only, and flawed study design, such as lack of = blinding or=20 randomization.<SUP> </SUP>Many narrative reviews were found, but no = systematic=20 review<SUP> </SUP>on any aspect of this work was available.<SUP> </SUP> <P>We will discuss evidence for cerebral hemodynamic effects and<SUP>=20 </SUP>neuroprotection separately. In addition, we will review = evidence<SUP>=20 </SUP>for additional beneficial and detrimental effects of the = compound,<SUP>=20 </SUP>and briefly discuss the potential role for = <I>S</I>(+)-ketamine.<SUP>=20 </SUP> <P><STRONG>Cerebral Hemodynamics</STRONG><BR>Study details are presented = in <A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#T1= 39">Table=20 1</A>. The effect of ketamine<SUP> </SUP>on ICP was studied in patients = with=20 intracranial compromise<SUP> </SUP>under controlled normocapnic = ventilation=20 during brain tumor<SUP> </SUP>or aneurysm surgery (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R1= 1-39">11</A>),=20 and in severe head injury in the intensive<SUP> </SUP>care unit (ICU) = (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R1= 6-39">16=9618</A>).=20 When applied as 1 mg/kg bolus<SUP> </SUP>to neurosurgical patients = during=20 isoflurane/nitrous oxide (N<SUB>2</SUB>O)<SUP> </SUP>anesthesia, = ketamine=20 reduced ICP and middle cerebral artery<SUP> </SUP>flow velocity (VMCA), = but did=20 not affect mean arterial blood<SUP> </SUP>pressure (MAP) (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R1= 1-39">11</A>).=20 After administration of a 1, 3, or 5 mg/kg<SUP> </SUP>bolus to = head-injured=20 patients with increased ICP under propofol<SUP> </SUP>sedation, the drug = reduced=20 ICP, but had no effect on either<SUP> </SUP>VMCA or MAP (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R1= 7-39">17</A>)=20 (level III evidence). In sedative regimens<SUP> </SUP>for severely = head-injured=20 patients, ICP was similar during sedation<SUP> </SUP>with either=20 ketamine/midazolam or with fentanyl/midazolam. With<SUP>=20 </SUP>ketamine/midazolam, however, less vasopressors were needed = and<SUP>=20 </SUP>greater cerebral perfusion pressures (CPP) were found (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R1= 6-39">16</A>)=20 (level<SUP> </SUP>II evidence). In another study, the combination of=20 ketamine<SUP> </SUP>and midazolam versus sufentanil and midazolam did = not=20 result<SUP> </SUP>in a different ICP or CPP (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R1= 8-39">18</A>).=20 The sufentanil-treated patients,<SUP> </SUP>however, required more = fluids on the=20 first day and showed a<SUP> </SUP>trend to need more vasopressors (level = II=20 evidence). During<SUP> </SUP>the 4-day study, ketamine was associated = with more=20 rapid heart<SUP> </SUP>rates on 2 days. In normocapnic, ventilated = patients=20 without<SUP> </SUP>cerebral compromise, ketamine increased VMCA during=20 air/oxygen/isoflurane<SUP> </SUP>anesthesia when used alone or in the = presence=20 of esmolol; after<SUP> </SUP>midazolam, VMCA decreased (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R1= 2-39">12</A>).=20 During propofol anesthesia and<SUP> </SUP>hypo- or hyperventilation, = ketamine=20 did not affect the VMCA<SUP> </SUP>(<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R2= 6-39">26</A>).=20 During air/oxygen/isoflurane anesthesia and hypoventilation,<SUP> = </SUP>it also=20 did not reduce VMCA, but pulsatility index decreased<SUP> </SUP>(<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R2= 7-39">27</A>)=20 (level III evidence). Importantly, during propofol anesthesia,<SUP>=20 </SUP><I>S</I>(+)-ketamine did not impair dynamic cerebrovascular=20 autoregulation<SUP> </SUP>in patients without cerebral compromise (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R2= 8-39">28</A>)=20 (level III evidence).<SUP> </SUP>Early work showed that in the presence = of=20 N<SUB>2</SUB>O, ketamine may<SUP> </SUP>increase CBF even under = controlled=20 ventilation (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R4= -39">4</A>).=20 In spontaneously<SUP> </SUP>breathing volunteers, a subanesthetic dose = of=20 ketamine given<SUP> </SUP>as bolus (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R2= 9-39">29</A>),=20 infusion (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R8= -39">8</A>),=20 or a combination of both (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R3= 0-39">30</A>),<SUP>=20 </SUP>increased regional CBF and metabolism (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R8= -39">8,29</A>)=20 (level III evidence).<SUP> </SUP>In spontaneously breathing patients, an = increase in arterial<SUP> </SUP>Paco<SUB>2</SUB> was identified as a = major=20 factor responsible for an increase<SUP> </SUP>in CBF or ICP (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R4= -39">4,14</A>).<SUP>=20 </SUP> <P><A name=3DT139><!-- null --></A><BR clear=3Dall> <CENTER> <TABLE cellSpacing=3D0 cellPadding=3D0 width=3D"95%"> <TBODY> <TR bgColor=3D#e1e1e1> <TD> <TABLE cellSpacing=3D2 cellPadding=3D2> <TBODY> <TR bgColor=3D#e1e1e1> <TD vAlign=3Dtop align=3Dmiddle bgColor=3D#ffffff><STRONG>View = this=20 table:</STRONG><BR><NOBR><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524/T1= 39">[in=20 this window]</A><BR><A=20 onmouseover=3D"window.status=3D'View table in a separate = window'; return true"=20 onclick=3D"startTarget('T139', 749, 733); = this.href=3D'/cgi/content-nw/full/101/2/524/T139'"=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content-nw/full/101/2/524= /T139"=20 target=3DT139>[in a new window]</A><BR>&nbsp;</NOBR> </TD> <TD vAlign=3Dtop align=3Dleft><B>Table 1.</B> Cerebral = Hemodynamic=20 Effects of Ketamine in Human = <P></P></TD></TR></TBODY></TABLE></TD></TR></TBODY></TABLE></CENTER>&nbsp= ;<BR><SUP></SUP> <P>Laboratory data confirm ketamine=92s known inhibition of<SUP> = </SUP>metabolism=20 in certain brain areas and simultaneous stimulation<SUP> </SUP>of = others, which=20 is partially reflected in decreased CBF in<SUP> </SUP>regions with = reduced=20 metabolism and <I>vice versa</I> (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R6= -39">6,31</A>).=20 The effects<SUP> </SUP>were dependent on preexisting cerebrovascular = tone and=20 its modulation<SUP> </SUP>by background anesthetics (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R1= 3-39">13=9615,32=9634</A>).=20 Concomitant<SUP> </SUP>use of ketamine and anesthetics may stimulate = regional=20 metabolism,<SUP> </SUP>impair autoregulation, or induce direct = vasodilation (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R3= 2-39">32=9634</A>).<SUP>=20 </SUP>In the presence of anesthetics that depress brain metabolism<SUP>=20 </SUP>(i.e., <IMG alt=3D{gamma}=20 src=3D"http://www.anesthesia-analgesia.org/math/ggr.gif" = border=3D0>-aminobutyric=20 acid [GABA] receptor agonists), global<SUP> </SUP>ICP is <I>not</I> = increased by=20 ketamine (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R1= 6-39">16=9618</A>).=20 In normocapnic,<SUP> </SUP>ventilated pigs, racemic ketamine did not = impair CBF=20 autoregulation<SUP> </SUP>when used alone (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R3= 5-39">35</A>).<SUP>=20 </SUP> <P>In summary, the clinical evidence can be assessed as follows.<SUP>=20 </SUP>Ketamine increases CBF and metabolism in spontaneously = breathing<SUP>=20 </SUP>volunteers (level III evidence). However, under conditions of<SUP> = </SUP>controlled ventilation and sedation, the drug does not = increase<SUP>=20 </SUP>ICP (level III evidence). Instead, a greater CPP is = maintained<SUP>=20 </SUP>when ketamine is used for sedation than when opiates are = administered<SUP>=20 </SUP>(level II evidence) and need for vasopressors is reduced = (level<SUP>=20 </SUP>II evidence). During anesthesia, ketamine does not reduce = VMCA<SUP>=20 </SUP>(level III evidence) or impair autoregulation (level III = evidence).<SUP>=20 </SUP>This may, however, not be true in the presence of = N<SUB>2</SUB>O.<SUP>=20 </SUP> <P><STRONG>Neuroprotection</STRONG><BR>Trials that compared ketamine = with=20 fentanyl (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R1= 6-39">16</A>)=20 or sufentanil<SUP> </SUP>(<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R1= 8-39">18</A>)=20 for sedation after head injury did not find a different<SUP> </SUP>6-mo = outcome=20 after 10- (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R1= 6-39">16</A>)=20 or 4-day (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R1= 8-39">18</A>)=20 ketamine use (level<SUP> </SUP>II evidence). The drug doses used were = adjusted=20 to maintain<SUP> </SUP>ICP &lt;25 mm Hg in resting patients.<SUP> </SUP> <P><I>In vitro</I> and animal studies with a duration of up to 7 = days<SUP>=20 </SUP>reported neuroprotective effects when ketamine was used = before,<SUP>=20 </SUP>during, or after induction of various brain insults. In = neurons<SUP>=20 </SUP>in culture (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R2= 0-39">20,24,36=9638</A>),=20 and in brain slices (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R3= 9-39">39=9642</A>),<SUP>=20 </SUP>ketamine protected against hypoxic, ischemic, mechanical, and<SUP> = </SUP>chemical neuronal damage. When used at subanesthetic doses = and<SUP>=20 </SUP>postinjury in cultured neurons, neuroprotective effects were<SUP>=20 </SUP>found (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R2= 0-39">20,24</A>).=20 In whole-animal rat models, ketamine use before<SUP> </SUP>insult or as=20 anesthesia during regional ischemia attenuated<SUP> </SUP>injury from = permanent=20 (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R4= 3-39">43</A>)=20 or transient cerebral artery occlusion<SUP> </SUP>(<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R2= 3-39">23</A>),=20 and from global ischemia (four-vessel occlusion) and reperfusion<SUP> = </SUP>(<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R4= 4-39">44=9649</A>).=20 After fluid-percussion brain trauma in rats,<SUP> </SUP>ketamine = administered=20 postinjury improved behavioral functions<SUP> </SUP>and outcome over 48 = h (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R2= 1-39">21</A>).=20 The drug reduced hippocampal damage<SUP> </SUP>in the immature rat brain = when=20 injected after hypoxia-ischemia<SUP> </SUP>(<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R2= 2-39">22</A>).=20 After seizure onset, ketamine terminated convulsions and<SUP> = </SUP>reduced=20 cognitive decline (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R5= 0-39">50=9652</A>).=20 Anesthesia with ketamine<SUP> </SUP>decreased mortality after = hypothermic=20 circulatory arrest in<SUP> </SUP>pigs (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R5= 3-39">53</A>).=20 In a schizophrenia model in adult rats, repeated<SUP> = </SUP>subanesthetic=20 ketamine doses evoked neurogenesis, but the new<SUP> </SUP>neurons did = not=20 functionally integrate (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R5= 4-39">54</A>).=20 Ketamine showed<SUP> </SUP>a trend to reduce ischemic injury when = applied after=20 simulation<SUP> </SUP>of a subdural hematoma with clotted blood (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R5= 5-39">55</A>).<SUP>=20 </SUP> <P>Most investigators related the observed decrease in necrosis<SUP> = </SUP>to a=20 reduction in glutamate neurotoxicity (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R2= 0-39">20=9622,38=9640,42,44=9649,52,56</A>)<SUP>=20 </SUP>resulting from NMDA receptor blockade by ketamine (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R5= 7-39">57</A>).=20 A decrease<SUP> </SUP>in DNA fragmentation and apoptotic protein = activation=20 after<SUP> </SUP>racemic or <I>S</I>(+)-ketamine was also found (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R2= 3-39">23,45,58</A>).=20 Although<SUP> </SUP>there is still a lack of data on the molecular = machinery=20 behind<SUP> </SUP>ketamine neuroprotection, some consequences of the=20 prevention<SUP> </SUP>of pathological NMDA receptor up-regulation were = reported:=20 At<SUP> </SUP>brain synapses, postsynaptic density (PSD) proteins bind = and<SUP>=20 </SUP>cluster NMDA receptors to the cytoskeleton and sets of = signaling<SUP>=20 </SUP>proteins, such as nitric oxide synthase (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R5= 9-39">59,60</A>),=20 or calcium<SUP> </SUP>sensors (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R6= 1-39">61</A>).=20 Increased excitatory NMDA receptor input activates<SUP> </SUP>protein = kinase C=20 isoforms and tyrosine kinase cascades, which<SUP> </SUP>facilitate = assembly of=20 signaling molecules with PSD proteins<SUP> </SUP>in the NMDA receptor. = This=20 leads to further kinase activation,<SUP> </SUP>NMDA receptor = phosphorylation,=20 and up-regulation of NMDA currents.<SUP> </SUP>In this vicious circle, = enhanced=20 downstream signals enhance<SUP> </SUP>NMDA receptor function, and = finally,=20 induce cell injury (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R4= 4-39">44,59</A>).<SUP>=20 </SUP>In studies of postischemic brain tissue, ketamine reduced the<SUP> = </SUP>injury-related increase in NMDA receptor-PSD-protein kinase<SUP>=20 </SUP>assembly (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R4= 4-39">44,46</A>),=20 decreased subsequent transcription factor<SUP> </SUP>activation (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R4= 7-39">47=9649,61</A>),=20 and apoptotic processing (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R4= 5-39">45</A>)=20 (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#F1= 39">Fig.=20 1</A>).<SUP> </SUP>The reduction of harmful interactions of NMDA = receptors<SUP>=20 </SUP>with cascades that transduce signals to destructive = intracellular<SUP>=20 </SUP>mechanisms may thus represent one effect underlying ketamine<SUP>=20 </SUP>neuroprotection.<SUP> </SUP> <P><A name=3DF139><!-- null --></A><BR clear=3Dall> <CENTER> <TABLE cellSpacing=3D0 cellPadding=3D0 width=3D"95%"> <TBODY> <TR bgColor=3D#e1e1e1> <TD> <TABLE cellSpacing=3D2 cellPadding=3D2> <TBODY> <TR bgColor=3D#e1e1e1> <TD vAlign=3Dtop align=3Dmiddle bgColor=3D#ffffff><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524/F1= 39"><IMG=20 height=3D157 alt=3D" " hspace=3D10=20 = src=3D"http://www.anesthesia-analgesia.org/content/vol101/issue2/images/s= mall/39FF1.gif"=20 width=3D200 vspace=3D5 border=3D2></A><BR><STRONG>View = larger=20 version</STRONG> (55K):<BR><NOBR><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524/F1= 39">[in=20 this window]</A><BR><A=20 onmouseover=3D"window.status=3D'View figure in a separate = window'; return true"=20 onclick=3D"startTarget('F139', 590, 546); = this.href=3D'/cgi/content-nw/full/101/2/524/F139'"=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content-nw/full/101/2/524= /F139"=20 target=3DF139>[in a new window]</A><BR>&nbsp;</NOBR> </TD> <TD vAlign=3Dtop align=3Dleft><B>Figure 1.</B> Pharmacological = effects=20 reported for racemic and <I>S</I>(+)-ketamine which are = presumed to=20 be relevant for neuroprotection. After onset of brain = injury,=20 blockade of excessive stimulation of = <I>N</I>-methyl-d-aspartate=20 (NMDA) receptors by ketamine reduces calcium influx through = the=20 receptor channel <IMG height=3D10 alt=3D{U2460}=20 = src=3D"http://www.anesthesia-analgesia.org/content/vol101/issue2/images/m= edium/U2460.gif"=20 width=3D11 border=3D0>. This attenuates supraphysiological = increases in=20 the assembly and interaction of NMDA receptor subunits, = postsynaptic=20 density proteins, and other intracellular signaling systems = such as=20 protein kinases <IMG height=3D10 alt=3D{U2461}=20 = src=3D"http://www.anesthesia-analgesia.org/content/vol101/issue2/images/m= edium/U2461.gif"=20 width=3D10 border=3D0>;. Thus, several kinase transduction = cascades=20 become less activated. This improves preservation of = metabolism and=20 maintenance of the mitochondrial transmembrane potential = <IMG=20 height=3D10 alt=3D{U2462}=20 = src=3D"http://www.anesthesia-analgesia.org/content/vol101/issue2/images/m= edium/U2462.gif"=20 width=3D10 border=3D0>. This, in turn, reduces pathological = activation=20 of transcription factors <IMG height=3D11 alt=3D{U2463}=20 = src=3D"http://www.anesthesia-analgesia.org/content/vol101/issue2/images/m= edium/U2463.gif"=20 width=3D10 border=3D0>. Proteins involved in apoptosis are = less=20 activated, which is associated with less DNA fragmentation = <IMG=20 height=3D10 alt=3D{U2464}=20 = src=3D"http://www.anesthesia-analgesia.org/content/vol101/issue2/images/m= edium/U2464.gif"=20 width=3D11 border=3D0>. A better preservation of synaptic = proteins=20 occurs, and the expression of growth proteins indicating=20 regeneration in adult neurons is enhanced. The prevention of = pathological amplification of NMDA receptor signaling = finally=20 results in increased cellular survival, preserved cellular = and=20 synaptic integrity, and regenerative efforts. *Superiority=20 of/effects induced by <I>S</I>(+)-ketamine, only. = <P></P></TD></TR></TBODY></TABLE></TD></TR></TBODY></TABLE></CENTER>&nbsp= ;<BR><SUP></SUP> <P>One study demonstrated no reduction in cellular death when = ketamine<SUP>=20 </SUP>was used for anesthesia in a rat model of incomplete, and=20 near-complete<SUP> </SUP>ischemia, whereas isoflurane anesthesia was=20 neuroprotective<SUP> </SUP>in near-complete ischemia in the same study = (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R6= 2-39">62</A>).=20 Both compounds<SUP> </SUP>improved motor function after near-complete = injury. It=20 is conceivable<SUP> </SUP>that only repeated ketamine injections which = are=20 extended into<SUP> </SUP>the postischemic period, i.e., into the phase = of=20 delayed injury<SUP> </SUP>evolution, may prevent neuronal death. It is = also=20 possible that,<SUP> </SUP>especially in the rat, ketamine must be = combined with=20 other<SUP> </SUP>drugs such as GABA-mimetics to prevent unfavorable=20 neuronal<SUP> </SUP>effects from blockade of synaptic transmission by = ketamine=20 anesthesia<SUP> </SUP>(see below).<SUP> </SUP> <P>Particularly important in this area would be studies = investigating<SUP>=20 </SUP>long-term outcomes after cerebral injury in the presence of<SUP>=20 </SUP>ketamine, because studies using other presumed protectants = (such<SUP>=20 </SUP>as isoflurane) have shown that early benefits may not be = sustained.<SUP>=20 </SUP> <P>In summary, although a wealth of animal and cellular studies<SUP>=20 </SUP>demonstrate neuroprotective effects of ketamine in various = settings,<SUP>=20 </SUP>virtually no clinical trial data are available. It is = essentially<SUP>=20 </SUP>impossible to extrapolate the available animal data to human<SUP>=20 </SUP>brain injury. We do know, however, that outcome is no worse<SUP>=20 </SUP>when ketamine, rather than sufentanil or fentanyl, is used = for<SUP>=20 </SUP>sedation of head-injured patients (level II evidence).<SUP> </SUP> <P><STRONG>Other Beneficial Effects</STRONG><BR>The stimulation of the=20 cardiovascular system by racemic or <I>S</I>(+)-ketamine<SUP> = </SUP>combined=20 with other anesthetics and sedatives was described<SUP> </SUP>previously = (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R6= 3-39">63</A>).=20 Maintenance of hemodynamic stability and potential<SUP>=20 </SUP>vasopressor-sparing effects are of special interest within = settings<SUP>=20 </SUP>where circulatory depression should be avoided, such as with<SUP>=20 </SUP>head injury (level II evidence). Two trials (reported above)<SUP>=20 </SUP>found sufficient and comparable sedative levels when = midazolam<SUP>=20 </SUP>was combined with either ketamine, or with fentanyl (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R1= 6-39">16</A>)=20 or<SUP> </SUP>sufentanil (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R1= 8-39">18</A>),=20 in head-injured patients (level II evidence).<SUP> </SUP>When sedation = was=20 stopped in the second trial (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R1= 8-39">18</A>),=20 ketamine<SUP> </SUP>was associated with a slightly longer recovery = period, but=20 no<SUP> </SUP>prolonged ICU stay. In the first study (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R1= 6-39">16</A>),=20 improved food intake<SUP> </SUP>was found with ketamine. Both studies = did not=20 report differences<SUP> </SUP>in adverse effects. In the = non-neurosurgical=20 critically ill<SUP> </SUP>patient population, several trials described=20 advantages of ketamine<SUP> </SUP>for sedation and analgesia: prevention = of=20 hemodynamic depression<SUP> </SUP>and a reduced need for catecholamines = (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R6= 4-39">64,65</A>),=20 better tolerance<SUP> </SUP>of enteral nutrition because of improved=20 gastrointestinal motility<SUP> </SUP>as compared with opioids (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R6= 6-39">66</A>),=20 less tachyphylaxis and withdrawal<SUP> </SUP>phenomena (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R6= 7-39">67,68</A>),=20 and improved pain control (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R6= 9-39">69</A>)=20 (level II<SUP> </SUP>and III evidence). However, ketamine must be used=20 cautiously<SUP> </SUP>in long-term sedation of cardiac patients with = left heart=20 failure.<SUP> </SUP>One study reported a decrease in cardiac index after = sufentanil<SUP> </SUP>was replaced by ketamine following sedation with=20 sufentanil<SUP> </SUP>and midazolam for several days (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R7= 0-39">70</A>).=20 After brain injury, pharmacokinetic<SUP> </SUP>analyses of ketamine and = its=20 active metabolites found a larger<SUP> </SUP>increase in the = distribution volume=20 than in total clearance,<SUP> </SUP>so that a drug half-life longer than = estimated must be considered<SUP> </SUP>(<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R7= 1-39">71</A>).=20 This could be less relevant with <I>S</I>(+)-ketamine (see below).<SUP>=20 </SUP>The trials did not report differences in emergence reactions<SUP> = </SUP>or=20 other side effects regardless of ketamine use.<SUP> </SUP> <P>In summary, ketamine provides adequate and controllable sedation<SUP> = </SUP>in critically ill patients (level II evidence), and, when = compared<SUP>=20 </SUP>with opiates, provides better hemodynamic stability, better<SUP>=20 </SUP>tolerance of enteral nutrition, less withdrawal phenomena, = and<SUP>=20 </SUP>better pain control (level II and III evidence).<SUP> </SUP> <P><STRONG>Neurotoxicity</STRONG><BR>In rodents, profound blockade of = normal=20 NMDA receptor activity<SUP> </SUP>led to poor brain cell survival and=20 physiological outcome, because<SUP> </SUP>signal transduction via NMDA = receptors=20 is necessary to express<SUP> </SUP>neurotrophins and survival-promoting = proteins=20 (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R7= 2-39">72</A>).=20 In rats,<SUP> </SUP>physiological signals were reduced directly by NMDA=20 receptor<SUP> </SUP>antagonists, such as ketamine, and indirectly by=20 GABA-mimetics,<SUP> </SUP>such as volatile anesthetics and barbiturates = (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R7= 3-39">73=9678</A>).<SUP>=20 </SUP>In the developing rat brain, a combination of anesthetics or<SUP>=20 </SUP>large-dose NMDA receptor antagonists caused apoptosis, = synaptic<SUP>=20 </SUP>deficits, and cognitive impairment, especially during the = vulnerable<SUP>=20 </SUP>phase of synaptogenesis (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R7= 3-39">73,76=9679</A>).=20 In adult rats without<SUP> </SUP>brain injury, ketamine induced acute, = but=20 usually transient,<SUP> </SUP>vacuolar changes in posterior=20 cingulate/retrosplenial cortices<SUP> </SUP>(<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R7= 4-39">74=9676</A>).=20 The effect was dose-, age-, and sex-dependent,<SUP> </SUP>with younger = rats=20 being essentially resistant, and females being<SUP> </SUP>more sensitive = than=20 males. The latter was likely attributable<SUP> </SUP>to sex differences = in drug=20 metabolism with more efficient hepatic<SUP> </SUP>biotransformation in = males.=20 After coadministration of ketamine<SUP> </SUP>and the NMDA antagonist=20 N<SUB>2</SUB>O, increased vacuolization occurred,<SUP> </SUP>whereas the = combination with a GABA-agonist completely prevented<SUP> </SUP>these = changes=20 (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R7= 4-39">74</A>).=20 Although the mechanisms presumed to underlie<SUP> </SUP>these phenomena = are as=20 yet unclear, they likely involve a disinhibition<SUP> </SUP>of = excitatory=20 pathways which heavily innervate cerebrocortical<SUP> </SUP>neurons (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#F2= 39">Fig.=20 2</A>).<SUP> </SUP> <P><A name=3DF239><!-- null --></A><BR clear=3Dall> <CENTER> <TABLE cellSpacing=3D0 cellPadding=3D0 width=3D"95%"> <TBODY> <TR bgColor=3D#e1e1e1> <TD> <TABLE cellSpacing=3D2 cellPadding=3D2> <TBODY> <TR bgColor=3D#e1e1e1> <TD vAlign=3Dtop align=3Dmiddle bgColor=3D#ffffff><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524/F2= 39"><IMG=20 height=3D130 alt=3D" " hspace=3D10=20 = src=3D"http://www.anesthesia-analgesia.org/content/vol101/issue2/images/s= mall/39FF2.gif"=20 width=3D200 vspace=3D5 border=3D2></A><BR><STRONG>View = larger=20 version</STRONG> (27K):<BR><NOBR><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524/F2= 39">[in=20 this window]</A><BR><A=20 onmouseover=3D"window.status=3D'View figure in a separate = window'; return true"=20 onclick=3D"startTarget('F239', 590, 485); = this.href=3D'/cgi/content-nw/full/101/2/524/F239'"=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content-nw/full/101/2/524= /F239"=20 target=3DF239>[in a new window]</A><BR>&nbsp;</NOBR> </TD> <TD vAlign=3Dtop align=3Dleft><B>Figure 2.</B> Because of the=20 requirement for physiological glutamate signaling, and the = toxic=20 effects of excessive glutamate signaling,=20 <I>N</I>-methyl-d-aspartate (NMDA) receptor block by = ketamine can=20 have both beneficial and detrimental effects. The toxic = effects can=20 be prevented by a <IMG alt=3D{gamma}=20 src=3D"http://www.anesthesia-analgesia.org/math/ggr.gif"=20 border=3D0>-aminobutyric acid (GABA) receptor agonist, as = explained:=20 A, the physiological glutamate signaling pathway is shown.=20 Stimulation of cell 1 with glutamate results in release of = GABA.=20 This inhibits cell 2, and as a result, cell 3 is exposed to = a=20 limited amount of glutamate, only. In the presence of = ketamine, the=20 inhibition of cell 2 by GABA is diminished. The result is an = overexcitation of cell 3, and resulting damage, as observed = in=20 retrosplenial cortex and cingulate gyrus in adult rats = exposed to=20 ketamine. The detrimental effect can be blocked by = administration of=20 exogenous GABA agonists (volatile anesthetics, barbiturates, = or=20 benzodiazepines), which will prevent glutamate secretion = from cell=20 2. B, Toxic glutamate signaling is shown. An excess = glutamate,=20 acting through NMDA receptor, induces cellular toxicity. = This effect=20 is blocked by ketamine. NMDA-R =3D NMDA receptor, GABA-R =3D = GABA=20 receptor, Glu =3D glutamate, Glu-R =3D glutamate receptor, + = =3D=20 stimulating effect, =96 =3D inhibiting effect. = <P></P></TD></TR></TBODY></TABLE></TD></TR></TBODY></TABLE></CENTER>&nbsp= ;<BR><SUP></SUP> <P>In summary, animal data suggest that under some conditions,<SUP>=20 </SUP>ketamine (and N<SUB>2</SUB>O) may induce neurotoxicity. This has = only=20 been<SUP> </SUP>demonstrated in rats.<SUP> </SUP> <P><STRONG><I>S</I>(+)-Ketamine</STRONG><BR>Several advantages of = <I>S</I>(+)-=20 over racemic ketamine with regard<SUP> </SUP>to its cardiovascular = profile and=20 neuroprotective effects have<SUP> </SUP>been reported. At a comparable = depth of=20 anesthesia [which requires<SUP> </SUP>approximately half the dose of=20 <I>S</I>(+)-ketamine as compared with<SUP> </SUP>the racemate],=20 <I>S</I>(+)-ketamine caused similar cardiovascular stimulation<SUP> = </SUP>as=20 racemic ketamine (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R8= 0-39">80,81</A>)=20 (level II evidence). When combined<SUP> </SUP>with midazolam for ICU = sedation,=20 racemic or <I>S</I>(+)-ketamine (at<SUP> </SUP>a dose of 55%=9675% of = the=20 racemate) provided hemodynamic<SUP> </SUP>stability, and sometimes = allowed=20 reduced vasopressor support.<SUP> </SUP><I>S</I>(+)-Ketamine combined = with=20 propofol had minimal effects on<SUP> </SUP>the systemic circulation (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R6= 3-39">63,64</A>)=20 (level II evidence). In contrast<SUP> </SUP>to the racemate, the=20 <I>S</I>(+)-isomer maintained muscle sympathetic<SUP> </SUP>activity = during a=20 hypotensive challenge in volunteers (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R8= 2-39">82</A>).<SUP>=20 </SUP><I>S</I>(+)-Ketamine showed a shorter half-life than the racemic=20 mixture<SUP> </SUP>(<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R8= 0-39">80,81</A>),=20 which is favorable for a rapid neurological assessment.<SUP> = </SUP>However, no=20 different incidence of side effects after <I>S</I>(+)-<SUP> </SUP>or = racemic=20 ketamine was found (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R8= 0-39">80,83</A>)=20 (level II evidence). A<SUP> </SUP>recent study compared a combined = anesthetic=20 regimen of <I>S</I>(+)-ketamine<SUP> </SUP>and propofol with = remifentanil and=20 propofol for open-heart surgery<SUP> </SUP>(<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R8= 4-39">84</A>).=20 In a neuropsychological test evaluation 10 wk after the<SUP> = </SUP>procedure,=20 the overall test performance was not different. Unfortunately,<SUP> = </SUP>by the=20 standards of the consensus statement on assessment of<SUP> = </SUP>neurobehavioral=20 outcome in cardiac surgery trials (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R8= 5-39">85</A>),=20 this<SUP> </SUP>study was greatly underpowered, and the inability to = find a<SUP>=20 </SUP>difference between the approaches is therefore not = surprising.<SUP> </SUP> <P>Laboratory data indicate a better cardiovascular profile for<SUP> = </SUP>the=20 <I>S</I>(+)-isomer with less myocardial depression (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R8= 6-39">86</A>)=20 and less<SUP> </SUP>vasorelaxation of the aorta (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R8= 7-39">87</A>)=20 than induced by the racemate.<SUP> </SUP>In contrast to the racemate,=20 <I>S</I>(+)-ketamine did not reverse late<SUP> </SUP>cardiac = preconditioning (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R8= 8-39">88</A>).=20 <I>S</I>(+)-Ketamine showed better protective<SUP> </SUP>and even = regenerative=20 efficacy in rat brain slices (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R3= 9-39">39,41</A>)=20 and<SUP> </SUP>neuronal cultures (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R2= 0-39">20,24</A>).=20 In contrast to the racemate, it preserved<SUP> </SUP>neuronal = metabolism, and=20 increased the expression of proteins<SUP> </SUP>related to plasticity = and repair=20 in the adult brain (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R2= 0-39">20,24</A>).<SUP>=20 </SUP>In a rat model of global brain ischemia, <I>S</I>(+)-ketamine,=20 injected<SUP> </SUP>postinjury, maintained cortical oxygen saturation = and=20 neuronal<SUP> </SUP>survival as compared with <I>R</I>(=96)-ketamine (<A = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R8= 9-39">89</A>),=20 and in incomplete<SUP> </SUP>brain ischemia, anesthesia with=20 <I>S</I>(+)-ketamine improved behavioral<SUP> </SUP>outcome 3 days after = injury=20 (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R9= 0-39">90</A>).<SUP>=20 </SUP> <P>In summary, although preclinical data suggest benefits of = <I>S</I>(+)<SUP>=20 </SUP>over racemic ketamine in cardiovascular and neuroprotective<SUP>=20 </SUP>profiles, clinical evidence at this time only supports equal<SUP>=20 </SUP>hemodynamic and side effect profile (level II evidence).<SUP> = </SUP> <P><A name=3DSEC3><!-- null --></A><BR clear=3Dright> <TABLE cellSpacing=3D0 cellPadding=3D0 width=3D"100%" bgColor=3D#e1e1e1> <TBODY> <TR> <TD vAlign=3Dcenter align=3Dleft width=3D"5%" bgColor=3D#ffffff><IMG = height=3D21=20 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/rarrow.gif"=20 width=3D10></TD> <TH vAlign=3Dcenter align=3Dleft width=3D"95%"><FONT = size=3D+2>&nbsp;&nbsp;=20 Discussion </FONT></TH></TR></TBODY></TABLE> <TABLE cellPadding=3D5 align=3Dright border=3D1> <TBODY> <TR> <TH align=3Dleft><FONT size=3D-1><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#to= p"><IMG=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Top<BR></A><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#AB= S"><IMG=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Abstract<BR></A><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#BD= Y"><IMG=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Introduction<BR></A><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#SE= C1"><IMG=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Methods<BR></A><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#SE= C2"><IMG=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Results<BR></A><IMG height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/dot.gif" = width=3D11=20 border=3D0><FONT color=3D#464c53>Discussion</FONT><BR><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#SE= C4"><IMG=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/darrow.gif" = width=3D11=20 border=3D0>Conclusion<BR></A><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#BI= BL"><IMG=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/darrow.gif" = width=3D11=20 = border=3D0>References<BR></A></FONT></TH></TR></TBODY></TABLE>&nbsp;<BR>F= rom the=20 standpoint of cerebral hemodynamics, the available<SUP> = </SUP>information=20 demonstrates that ketamine does not increase ICP<SUP> </SUP>in = neurologically=20 impaired patients during controlled ventilation<SUP> </SUP>and = coadministration=20 of a GABA receptor agonist. Coadministration<SUP> </SUP>with = N<SUB>2</SUB>O is=20 to be avoided. Thus, the drug can safely be used.<SUP> </SUP>Ketamine = has been=20 considered unsuitable in neurosurgical patients<SUP> </SUP>because of = its=20 cataleptic actions and psychotomimetic adverse<SUP> </SUP>effects. = However,=20 clinical studies did not report an increase<SUP> </SUP>in adverse = reactions or=20 emergence delirium when ketamine and<SUP> </SUP>GABA-mimetics were used = as=20 compared with regimens without ketamine.<SUP> </SUP>Likely, the = coadministration=20 of GABA-agonists prevented these<SUP> </SUP>effects.<SUP> </SUP> <P><STRONG>Hemodynamics</STRONG><BR>Ketamine=92s interaction with = regional=20 cerebral hemodynamics<SUP> </SUP>and metabolism is complex. We know that = the=20 drug=92s global<SUP> </SUP>action on CBF, brain metabolism, and ICP is = determined=20 by a<SUP> </SUP>combination of effects on cerebral and systemic=20 hemodynamics,<SUP> </SUP>although we do not know what this means in case = of a=20 brain insult<SUP> </SUP>on a regional level. Even if "optimal CPP" is = still a=20 matter<SUP> </SUP>of debate, it is beyond doubt that systemic = hypotension is=20 detrimental<SUP> </SUP>in brain injury. Ketamine=92s stimulation of the=20 cardiovascular<SUP> </SUP>system may prevent hypotension and thus = maintain the=20 CPP, which=97together<SUP> </SUP>with its other advantages over = opiate-based=20 sedation=97could<SUP> </SUP>make the drug a first choice in sedative = regimens for=20 patients<SUP> </SUP>with brain insults.<SUP> </SUP> <P><STRONG>Neuroprotection</STRONG><BR>The renewed interest in ketamine = as a=20 clinically available neuroprotectant<SUP> </SUP>has been fostered by a = shift in=20 thinking about neuroprotection<SUP> </SUP>by anesthetics: from = suppression of=20 brain metabolism to inhibition<SUP> </SUP>of excitotoxicity. A key role = in the=20 injury cascade seems to<SUP> </SUP>be played by the unbalanced = activation of=20 NMDA receptors by<SUP> </SUP>toxic glutamate concentrations with = subsequent cell=20 death (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R1= 9-39">19,91</A>).<SUP>=20 </SUP>Cerebral microdialysis in patients confirmed increased = glutamate<SUP>=20 </SUP>concentrations in the extracellular space during and after = critical<SUP>=20 </SUP>periods of brain injury (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R9= 2-39">92,93</A>).=20 This prompted therapeutic approaches<SUP> </SUP>with NMDA receptor = antagonists.=20 Drug regimens used early after<SUP> </SUP>insults may especially target=20 secondary injury processes within<SUP> </SUP>the therapeutic window of=20 opportunity (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R9= 4-39">94</A>).=20 Ketamine acts at<SUP> </SUP>many different signal transduction sites, = but its=20 neuroprotective<SUP> </SUP>effects seem at least for the most part to be = explained by blockade<SUP> </SUP>of NMDA receptor activation. It binds=20 noncompetitively to the<SUP> </SUP>phencyclidine site in the receptor = channel,=20 and additionally<SUP> </SUP>acts through allosteric modification (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R5= 7-39">57</A>).<SUP>=20 </SUP> <P>There is a large body of experimental data indicating that = racemic<SUP>=20 </SUP>ketamine is neuroprotective; <I>S</I>(+)-ketamine may have = protective<SUP>=20 </SUP>and neuroregenerative effects that exceed those of the = racemic<SUP>=20 </SUP>mixture. With regard to the drug doses used, the experimental<SUP> = </SUP>data cannot readily be extrapolated to the clinical setting,<SUP>=20 </SUP>but comparisons can be made. Ketamine injected IV is rapidly<SUP>=20 </SUP>distributed to the brain, and concentrations in rat and human<SUP> = </SUP>brain are approximately five times more than blood values (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R9= 5-39">95=9699</A>).<SUP>=20 </SUP>For anesthesia, rats need 10 times larger ketamine doses than<SUP> = </SUP>humans (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R3= 1-39">31</A>),=20 and many studies in whole-animal models used rat<SUP> = </SUP>anesthetic-dose=20 ketamine (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R9= 5-39">95=9697</A>).=20 <I>In vitro</I>, drug concentrations<SUP> </SUP>several-fold = (approximately=20 5=961000 times) lower than those<SUP> </SUP>reached in rat brain tissue = after=20 anesthesia induction (peak<SUP> </SUP>level 400 =B5M) were used (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R9= 5-39">95</A>).=20 Ketamine is significantly<SUP> </SUP>plasma protein bound (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R9= 5-39">95=9699</A>)=20 and because plasma concentrations<SUP> </SUP>larger than 0.5 =B5M = racemate were=20 reached in surgical anesthesia<SUP> </SUP>in humans, the doses effective = for=20 experimental neuroprotection<SUP> </SUP>seem to be within a range = relevant for=20 clinical use. Nevertheless,<SUP> </SUP>limitations other than the drug = doses=20 used have to be considered<SUP> </SUP>for the available animal data. = First, the=20 major caveat is that<SUP> </SUP>almost all of the studies were performed = in=20 small animal models,<SUP> </SUP>and the past decade has seen a series of = high-profile failures<SUP> </SUP>in clinical trials of drugs that were = highly=20 effective in these<SUP> </SUP>models. No trial has yet reported = neuroprotective=20 efficacy of<SUP> </SUP>ketamine after human brain injury. Second, we = have no=20 long-term<SUP> </SUP>outcome data demonstrating persistent benefit of=20 neuroprotection<SUP> </SUP>after ketamine anesthesia or ketamine = administration=20 after onset<SUP> </SUP>of brain insults. This appears to be very = important,=20 because<SUP> </SUP>in a rat model of near-complete ischemia, it was = recently=20 found<SUP> </SUP>that the neuroprotection provided by isoflurane had=20 dissipated<SUP> </SUP>three months after cerebral injury (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R1= 00-39">100</A>).=20 Last, but not least,<SUP> </SUP>we lack investigations that examine = prolonged=20 ketamine treatment<SUP> </SUP>after brain injury. It is unlikely that = one=20 injection of a short-acting<SUP> </SUP>drug will completely prevent = delayed=20 inflammation or other injury-related<SUP> </SUP>signals associated with = NMDA=20 receptor-mediated transduction<SUP> </SUP>during the evolution of brain = insults.=20 Thus, further study in<SUP> </SUP>higher animal species with ketamine = use beyond=20 initial brain<SUP> </SUP>insults, evaluation of drug combinations, and=20 longer-term outcome<SUP> </SUP>studies appear to be indicated. Even if = previous=20 clinical trials<SUP> </SUP>with NMDA antagonists reported only minor = benefit on=20 outcome<SUP> </SUP>after cardiopulmonary bypass (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R1= 01-39">101</A>)=20 or were stopped after head<SUP> </SUP>trauma (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R1= 02-39">102</A>)=20 or stroke (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R1= 03-39">103</A>),=20 it is not time to conclude that<SUP> </SUP>NMDA antagonists failed to = provide=20 clinical neuroprotection.<SUP> </SUP>All of these studies applied = competitive=20 NMDA blockers only,<SUP> </SUP>which cause a sustained transmission = blockade and=20 thus, probably<SUP> </SUP>unfavorable, effects on the brain. In = contrast, a=20 recent prospective,<SUP> </SUP>randomized, placebo-controlled, = double-blind,=20 multicenter pilot<SUP> </SUP>trial demonstrated improved patient outcome = after=20 use of a noncompetitive<SUP> </SUP>NMDA receptor antagonist after = traumatic=20 brain injury (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R1= 04-39">104</A>).<SUP>=20 </SUP>Similar to ketamine, the drug applied had a lower binding = affinity<SUP>=20 </SUP>to the phencyclidine site in the NMDA receptor channel than<SUP>=20 </SUP>dizocilpine. A recent study demonstrated that, in mice,=20 hyperactivation<SUP> </SUP>of NMDA receptors after injury is = short-lived, and is=20 followed<SUP> </SUP>by a profound and long-lasting loss of function (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R1= 05-39">105</A>).=20 In fact,<SUP> </SUP>administration of NMDA 24 and 48 h postinjury=20 significantly<SUP> </SUP>attenuated neurological deficits. Thus, = appropriate=20 timing and<SUP> </SUP>duration of NMDA receptor blockade is likely to be = critical.<SUP> </SUP> <P><STRONG>Neurotoxicity</STRONG><BR>Whether the NMDA antagonist-induced = neurodegeneration observed<SUP> </SUP>in rats could occur in humans is = not=20 known. The potential clinical<SUP> </SUP>relevance of the rat data = remains to be=20 clarified, although<SUP> </SUP>psychotomimetic effects after NMDA = antagonists=20 may represent<SUP> </SUP>a correlate to the changes observed in rat = brain (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R1= 06-39">106</A>).=20 However,<SUP> </SUP>the pathological conditions after brain injury are=20 profoundly<SUP> </SUP>different from the physiological state of intact,=20 uninjured<SUP> </SUP>tissue. Cerebral insults cause massive increases in = extracellular<SUP> </SUP>excitatory transmitter concentration and brain = ischemia=20 induces<SUP> </SUP>GABA release (<A=20 href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#R9= 1-39">91</A>).=20 During these periods, it seems unlikely that<SUP> </SUP>ketamine would = be able=20 to induce an over-inhibition of NMDA<SUP> </SUP>receptor signaling.<SUP> = </SUP> <P><A name=3DSEC4><!-- null --></A><BR clear=3Dright> <TABLE cellSpacing=3D0 cellPadding=3D0 width=3D"100%" bgColor=3D#e1e1e1> <TBODY> <TR> <TD vAlign=3Dcenter align=3Dleft width=3D"5%" bgColor=3D#ffffff><IMG = height=3D21=20 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/rarrow.gif"=20 width=3D10></TD> <TH vAlign=3Dcenter align=3Dleft width=3D"95%"><FONT = size=3D+2>&nbsp;&nbsp;=20 Conclusion </FONT></TH></TR></TBODY></TABLE> <TABLE cellPadding=3D5 align=3Dright border=3D1> <TBODY> <TR> <TH align=3Dleft><FONT size=3D-1><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#to= p"><IMG=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Top<BR></A><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#AB= S"><IMG=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Abstract<BR></A><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#BD= Y"><IMG=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Introduction<BR></A><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#SE= C1"><IMG=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Methods<BR></A><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#SE= C2"><IMG=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Results<BR></A><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#SE= C3"><IMG=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Discussion<BR></A><IMG height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/dot.gif" = width=3D11=20 border=3D0><FONT color=3D#464c53>Conclusion</FONT><BR><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#BI= BL"><IMG=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/darrow.gif" = width=3D11=20 = border=3D0>References<BR></A></FONT></TH></TR></TBODY></TABLE>&nbsp;<BR>S= everal=20 clinical trials addressed the use of ketamine as a sedative<SUP> = </SUP>drug in=20 the ICU, and based on this evidence, the drug seems<SUP> = </SUP>appropriate for=20 that setting. The major perceived contraindications<SUP> </SUP>for = ketamine use=20 in neurologically impaired patients have been<SUP> </SUP>refuted. = Ketamine=92s=20 circulatory effects and preclinical<SUP> </SUP>data indicating = neuroprotection=20 merit further animal and patient<SUP> </SUP>investigation, but we do not = yet=20 have evidence of ketamine neuroprotection<SUP> </SUP>in humans. Based on = the=20 known pathological responses of the<SUP> </SUP>brain to injury and = extrapolation=20 of knowledge from pain therapy<SUP> </SUP>using ketamine, it is our bias = that=20 human trials will only be<SUP> </SUP>successful if ketamine will be = present=20 during the whole period<SUP> </SUP>of NMDA receptor overstimulation = after and=20 during the evolution<SUP> </SUP>of brain injuries.<SUP> </SUP> <P>We gratefully acknowledge the expert assistance of David Alpern<SUP> = </SUP>in=20 the preparation of the manuscript.<SUP> </SUP> <P><SUP></SUP> <P><A name=3DFN><!-- null --></A><BR clear=3Dright> <TABLE cellSpacing=3D0 cellPadding=3D0 width=3D"100%" bgColor=3D#e1e1e1> <TBODY> <TR> <TD vAlign=3Dcenter align=3Dleft width=3D"5%" bgColor=3D#ffffff><IMG = height=3D21=20 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/rarrow.gif"=20 width=3D10></TD> <TH vAlign=3Dcenter align=3Dleft width=3D"95%"><FONT = size=3D+2>&nbsp;&nbsp;=20 Footnotes </FONT></TH></TR></TBODY></TABLE>&nbsp;<BR><A=20 name=3D""><!-- null --></A>Accepted for publication February 9, = 2005.<SUP> </SUP> <P><SUP></SUP> <P><A name=3DBIBL><!-- null --></A><BR clear=3Dright> <TABLE cellSpacing=3D0 cellPadding=3D0 width=3D"100%" bgColor=3D#e1e1e1> <TBODY> <TR> <TD vAlign=3Dcenter align=3Dleft width=3D"5%" bgColor=3D#ffffff><IMG = height=3D21=20 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/rarrow.gif"=20 width=3D10></TD> <TH vAlign=3Dcenter align=3Dleft width=3D"95%"><FONT = size=3D+2>&nbsp;&nbsp;=20 References </FONT></TH></TR></TBODY></TABLE> <TABLE cellPadding=3D5 align=3Dright border=3D1> <TBODY> <TR> <TH align=3Dleft><FONT size=3D-1><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#to= p"><IMG=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Top<BR></A><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#AB= S"><IMG=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Abstract<BR></A><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#BD= Y"><IMG=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Introduction<BR></A><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#SE= C1"><IMG=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Methods<BR></A><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#SE= C2"><IMG=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Results<BR></A><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#SE= C3"><IMG=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Discussion<BR></A><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/content/full/101/2/524#SE= C4"><IMG=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Conclusion<BR></A><IMG height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.anesthesia-analgesia.org/icons/toc/dot.gif" = width=3D11=20 border=3D0><FONT=20 color=3D#464c53>References</FONT><BR></FONT></TH></TR></TBODY></TABLE>&nb= sp;<BR> <OL compact><A name=3DR1-39><!-- null --></A> <LI value=3D1>Doppenberg EMR, Choi SC, Bullock R. Clinical trials in = traumatic=20 brain injury. J Neurosurg Anesthesiol 2004;16:87=9694.<!-- HIGHWIRE = ID=3D"101:2:524:1" --><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/external_ref?access_num=3D= 000187659800018&amp;link_type=3DISI">[ISI]</A><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/external_ref?access_num=3D= 14676577&amp;link_type=3DMED">[Medline]</A><!-- /HIGHWIRE --><A=20 name=3DR2-39><!-- null --></A>=20 <LI value=3D2>Madson JB, Cold GE. The effects of anaesthetics upon = cerebral=20 circulation and metabolism: experimental and clinical studies. New = York:=20 Springer, 1990.<!-- HIGHWIRE ID=3D"101:2:524:2" --><!-- /HIGHWIRE = --><A=20 name=3DR3-39><!-- null --></A>=20 <LI value=3D3>Sakabe T, Nakakimura K. Effects of anesthetic agents and = other=20 drugs on cerebral blood flow, metabolism, and intracranial pressure. = In:=20 Cottrell JE, Smith DS, eds. Anesthesia and neurosurgery. St. Louis, = MO: Mosby,=20 2001:136=9648.<!-- HIGHWIRE ID=3D"101:2:524:3" --><!-- /HIGHWIRE --><A = name=3DR4-39><!-- null --></A>=20 <LI value=3D4>Takeshita H, Okuda Y, Sari A. The effects of ketamine on = cerebral=20 circulation and metabolism in man. Anesthesiology 1972;36:69=9675.<!-- = HIGHWIRE ID=3D"101:2:524:4" --><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/external_ref?access_num=3D= A1972L239800011&amp;link_type=3DISI">[ISI]</A><A=20 = href=3D"http://www.anesthesia-analgesia.org/cgi/external_ref?access_num=3D= 5006989&a