[From nobody Sat Aug 4 20:12:35 2007 From: "Saved by Windows Internet Explorer 7" Subject: Should We Use Etomidate as an Induction Agent for Endotracheal Intubation in Patients With Septic Shock?: A Critical Appraisal -- Jackson 127 (3): 1031 -- Chest Date: Sat, 4 Aug 2007 09:31:11 -0700 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_0068_01C7D67A.31C69300" X-MimeOLE: Produced By Microsoft MimeOLE V6.0.6000.16480 This is a multi-part message in MIME format. ------=_NextPart_000_0068_01C7D67A.31C69300 Content-Type: text/html; charset="Windows-1252" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.chestjournal.org/cgi/content/full/127/3/1031 <!DOCTYPE HTML PUBLIC "-//W3C//DTD HTML 4.0 Transitional//EN"> <HTML><HEAD><TITLE>Should We Use Etomidate as an Induction Agent for = Endotracheal Intubation in Patients With Septic Shock?: A Critical = Appraisal -- Jackson 127 (3): 1031 -- Chest</TITLE> <META 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L., Jr</A></STRONG>=20 = </TD></TR></TD></TR></TBODY></TABLE></TD></TR></TBODY></TABLE><FONT=20 size=3D-1>(<EM>Chest.</EM> 2005;127:1031-1038.)<BR>=A9 2005 <A=20 href=3D"http://www.chestjournal.org/misc/terms.shtml">American College = of Chest=20 Physicians</A> </FONT><BR> <H2>Should We Use Etomidate as an Induction Agent for Endotracheal = Intubation in=20 Patients With Septic Shock?<SUP>*</SUP> </H2> <H3>A Critical Appraisal </H3><STRONG></NOBR><NOBR>William L. Jackson, = Jr, MD,=20 FCCP</NOBR> </STRONG> <P><FONT size=3D-1><SUP>*</SUP> From the Critical Care Medicine Service, = Department of Surgery, Walter Reed Army Medical Center, Washington, DC. = </FONT> <P> <P><FONT size=3D-1>Correspondence to: William L. Jackson, Jr, MD, FCCP, = Walter=20 Reed Army Medical Center, Department of Surgery, Critical Care Medicine = Service,=20 Building 2, Room 3M12, 6900 Georgia Ave NW, Washington, DC 20307-5001; = e-mail:=20 <SPAN id=3Dem0>William.Jackson1{at}NA.AMEDD.ARMY.MIL</SPAN> <SCRIPT type=3Dtext/javascript><!--=0A= var u =3D "William.Jackson1", d =3D "NA.AMEDD.ARMY.MIL"; = 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 = src=3D"http://www.chestjournal.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.chestjournal.org/cgi/content/full/127/3/1031#top"><IMG= =20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.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.chestjournal.org/icons/toc/dot.gif" width=3D11=20 border=3D0><FONT color=3D#464c53>Abstract</FONT><BR><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#BDY"><IMG= =20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/darrow.gif" = width=3D11=20 border=3D0>Introduction<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC1"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/darrow.gif" = width=3D11=20 border=3D0>Etomidate for Long-term...<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC2"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/darrow.gif" = width=3D11=20 border=3D0>Evidence for Adrenal...<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC3"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/darrow.gif" = width=3D11=20 border=3D0>Additional Potential Effects<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC4"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/darrow.gif" = width=3D11=20 border=3D0>Assessing Use of Etomidate...<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC5"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/darrow.gif" = width=3D11=20 border=3D0>Management Alternatives<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC6"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/darrow.gif" = width=3D11=20 border=3D0>How To Resolve Clinical...<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC7"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/darrow.gif" = width=3D11=20 border=3D0>Summary<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#BIBL"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/darrow.gif" = width=3D11=20 = border=3D0>References<BR></A></FONT></TH></TR></TBODY></TABLE>&nbsp;<BR>E= tomidate=20 is commonly used for the facilitation of endotracheal<SUP> = </SUP>intubation.=20 While etomidate possesses multiple qualities that<SUP> </SUP>are = beneficial in=20 hemodynamically unstable patients who require<SUP> </SUP>a sedative or = amnestic,=20 its potential to negatively impact corticosteroid<SUP> </SUP>production = is=20 well-documented. Given the frequency of relative<SUP> </SUP>adrenal=20 insufficiency observed in the critically ill and the<SUP> = </SUP>increasing use=20 of corticosteroids in patients with septic shock,<SUP> </SUP>an = appraisal of the=20 status of etomidate as an induction agent<SUP> </SUP>in patients with = evolving=20 or established septic shock is indicated.<SUP> </SUP>A review of the = relevant=20 literature suggests that its use in<SUP> </SUP>this setting may be = harmful. It=20 is proposed that, pending the<SUP> </SUP>performance of a randomized, = controlled=20 clinical trial, considerable<SUP> </SUP>caution should accompany its=20 administration in patients with<SUP> </SUP>evolving or established = septic shock.=20 The potential role for<SUP> </SUP>concomitant empiric steroid = replacement and=20 the comparability<SUP> </SUP>of alternative induction regimens are also=20 discussed.<SUP> </SUP> <P> <P><STRONG>Key Words:</STRONG> adrenal insufficiency =95 endotracheal = intubation =95=20 etomidate =95 sepsis =95 septic shock <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 = src=3D"http://www.chestjournal.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.chestjournal.org/cgi/content/full/127/3/1031#top"><IMG= =20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>TOP<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#ABS"><IMG= =20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.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.chestjournal.org/icons/toc/dot.gif" width=3D11=20 border=3D0><FONT color=3D#464c53>Introduction</FONT><BR><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC1"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/darrow.gif" = width=3D11=20 border=3D0>Etomidate for Long-term...<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC2"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/darrow.gif" = width=3D11=20 border=3D0>Evidence for Adrenal...<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC3"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/darrow.gif" = width=3D11=20 border=3D0>Additional Potential Effects<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC4"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/darrow.gif" = width=3D11=20 border=3D0>Assessing Use of Etomidate...<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC5"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/darrow.gif" = width=3D11=20 border=3D0>Management Alternatives<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC6"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/darrow.gif" = width=3D11=20 border=3D0>How To Resolve Clinical...<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC7"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/darrow.gif" = width=3D11=20 border=3D0>Summary<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#BIBL"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/darrow.gif" = width=3D11=20 = border=3D0>References<BR></A></FONT></TH></TR></TBODY></TABLE>&nbsp;<BR>E= tomidate=20 is an imidazole derivative that is widely used as<SUP> </SUP>an IV = induction=20 agent to facilitate endotracheal intubation.<SUP> </SUP>It possesses = several=20 characteristics that are particularly advantageous<SUP> </SUP>in the = critical=20 care setting, including rapid, predictable onset<SUP> </SUP>of action = and=20 recovery, relative cardiovascular stability, limited<SUP> = </SUP>suppression of=20 ventilation, lack of histamine release, and favorable<SUP> </SUP>safety=20 profile.<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B1">1</A>= </SUP>=20 However, etomidate is known to inhibit adrenal<SUP> </SUP>mitochondrial=20 hydroxylase activity,<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B2">2</A>= </SUP>=20 with a resultant observable<SUP> </SUP>decrease in steroidogenesis after = administration by both single-bolus<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B3">3</A>= </SUP><SUP>=20 </SUP>and maintenance infusion.<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B4">4</A>= </SUP>=20 Importantly, the normal response<SUP> </SUP>to stress states such as = trauma,=20 burns, surgery, and infection<SUP> </SUP>is characterized by a = proportional=20 increase in cortisol production<SUP> </SUP>and release.<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B5">5</A>= </SUP>=20 Given the renewed interest and debate concerning<SUP> </SUP>the = evaluation of=20 relative adrenal insufficiency in critically<SUP> </SUP>ill = patients<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B5">5</A>= </SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B6">6</A>= </SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B7">7</A>= </SUP>=20 and the value of corticosteroid administration<SUP> </SUP>in septic = shock=20 patients,<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B8">8</A>= </SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B9">9</A>= </SUP> as=20 well as the increasing prevalence<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B10">10</= A></SUP><SUP>=20 </SUP>and established lethality<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B11">11</= A></SUP>=20 of septic shock, conditions that<SUP> </SUP>affect the=20 hypothalamic-pituitary-adrenal response to stress<SUP> </SUP>and may=20 deleteriously impact patient survival are being increasingly<SUP>=20 </SUP>scrutinized.<SUP> </SUP> <P>Consequently, the use of etomidate for the induction of = intubation<SUP>=20 </SUP>in patients who require critical care in general<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B12">12</= A></SUP>=20 and manifest<SUP> </SUP>septic shock in particular<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B13">13</= A></SUP>=20 has come into question. The purpose<SUP> </SUP>of this article is to = explore the=20 basis for such concern and<SUP> </SUP>to propose management options as = the=20 evidence dictates.<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 = src=3D"http://www.chestjournal.org/icons/toc/rarrow.gif"=20 width=3D10></TD> <TH vAlign=3Dcenter align=3Dleft width=3D"95%"><FONT = size=3D+2>&nbsp;&nbsp;=20 Etomidate for Long-term Anesthesia and Sedation=20 </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.chestjournal.org/cgi/content/full/127/3/1031#top"><IMG= =20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>TOP<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#ABS"><IMG= =20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Abstract<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#BDY"><IMG= =20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.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.chestjournal.org/icons/toc/dot.gif" width=3D11=20 border=3D0><FONT color=3D#464c53>Etomidate for = Long-term...</FONT><BR><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC2"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/darrow.gif" = width=3D11=20 border=3D0>Evidence for Adrenal...<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC3"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/darrow.gif" = width=3D11=20 border=3D0>Additional Potential Effects<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC4"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/darrow.gif" = width=3D11=20 border=3D0>Assessing Use of Etomidate...<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC5"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/darrow.gif" = width=3D11=20 border=3D0>Management Alternatives<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC6"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/darrow.gif" = width=3D11=20 border=3D0>How To Resolve Clinical...<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC7"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/darrow.gif" = width=3D11=20 border=3D0>Summary<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#BIBL"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/darrow.gif" = width=3D11=20 = border=3D0>References<BR></A></FONT></TH></TR></TBODY></TABLE>&nbsp;<BR>S= hortly=20 after its introduction, etomidate was promoted as a<SUP> </SUP>safe = agent for=20 continuous sedation in mechanically ventilated<SUP> = </SUP>patients.<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B14">14</= A></SUP>=20 However, in 1983, Ledingham and Watt<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B15">15</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B16">16</= A></SUP>=20 preliminarily<SUP> </SUP>reported an increase in fatalities related to = etomidate=20 infusion<SUP> </SUP>in multitrauma patients who had been admitted to = their=20 ICU.<SUP> </SUP>Despite similar injury severity scores and a lower mean = age<SUP>=20 </SUP>for patients in the latter time period, mortality increased<SUP>=20 </SUP>significantly from 1979=961980 to 1981=961982 (25% vs<SUP> = </SUP>44%,=20 respectively; p &lt; 0.05). This increase was observed<SUP> = </SUP>exclusively in=20 patients receiving mechanical ventilation who<SUP> </SUP>survived &gt; 5 = days=20 from the time of injury and appeared to<SUP> </SUP>be primarily related = to=20 higher rates of infection. A further<SUP> </SUP>examination of the = practice at=20 their institution revealed that<SUP> </SUP>the predominant means of = sedation had=20 been changed from benzodiazepine<SUP> </SUP>agents in 1979=961980 to = etomidate in=20 1981=961982, and<SUP> </SUP>retrospectively assigning patients by means = of=20 sedation accounted<SUP> </SUP>for the difference in case fatality rates. = Notably, these reports<SUP> </SUP>coincided with observations from other = researchers at the same<SUP> </SUP>institution correlating adrenal = insufficiency=20 with mortality<SUP> </SUP>in the ICU population.<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B17">17</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B18">18</= A></SUP><SUP>=20 </SUP> <P>A series of preliminary related correspondences<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B19">19</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B20">20</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B21">21</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B22">22</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B23">23</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B24">24</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B25">25</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B26">26</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B27">27</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B28">28</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B29">29</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B30">30</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B31">31</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B32">32</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B33">33</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B34">34</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B35">35</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B36">36</= A></SUP><SUP>=20 </SUP>and an editorial<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B37">37</= A></SUP>=20 followed the initial reports by Ledingham<SUP> </SUP>and Watt,<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B15">15</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B16">16</= A></SUP>=20 with sentiment including both cautious agreement<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B25">25</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B32">32</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B35">35</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B37">37</= A></SUP><SUP>=20 </SUP>and critical skepticism.<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B22">22</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B24">24</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B27">27</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B30">30</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B33">33</= A></SUP>=20 Nonetheless, the detrimental<SUP> </SUP>effects of etomidate as a = long-term=20 anesthetic and sedative<SUP> </SUP>were convincingly established by the=20 subsequent publication<SUP> </SUP>of the definitive data from the study = by=20 Ledingham and Watt<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B38">38</= A></SUP><SUP>=20 </SUP>and of two additional studies<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B4">4</A>= </SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B39">39</= A></SUP>=20 illustrating adrenal insufficiency<SUP> </SUP>as a direct consequence of = etomidate therapy. The first article<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B38">38</= A></SUP><SUP>=20 </SUP>looked retrospectively at 428 patients with multiple trauma<SUP>=20 </SUP>from 1969 to 1982, evenly matching patients by age, sex, and<SUP>=20 </SUP>injury severity score from the comparison periods 1979=961980<SUP> = </SUP>and=20 1981=961982, and confirmed the previously reported increase<SUP> = </SUP>in=20 mortality (28% vs 47%, respectively; p &lt; 0.05). This increase<SUP> = </SUP>was=20 more pronounced when patients were further classified according<SUP> = </SUP>to=20 the duration of mechanical ventilation (1979=961980,<SUP> </SUP>23%; = 1981=961982,=20 61%; p &lt; 0.005) and the means of sedation<SUP> </SUP>(benzodiazepine = agents,=20 28%; etomidate, 77%; p &lt; 0.0005).<SUP> </SUP>Vasopressors were = utilized more=20 frequently in the group receiving<SUP> </SUP>etomidate (p &lt; 0.0001), = and all=20 17 patients receiving etomidate<SUP> </SUP>who had serum cortisol = measurements=20 performed manifested at<SUP> </SUP>least one subnormal level. Additional = prospective data acquired<SUP> </SUP>in 12 patients after the = discontinuation of=20 therapy with etomidate<SUP> </SUP>and the resumption of therapy with=20 benzodiazepine agents as<SUP> </SUP>primary sedatives in their ICU = showed a=20 decrease in mortality<SUP> </SUP>rate that was similar to previously = observed=20 levels (25%; p<SUP> </SUP>&lt; 0.01).<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B38">38</= A></SUP>=20 Wagner et al<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B4">4</A>= </SUP>=20 reported persistent adrenal suppression<SUP> </SUP>in one patient 4 days = after a=20 20-h etomidate infusion for sedation<SUP> </SUP>and in four patients 4 h = after=20 etomidate infusion for anesthesia<SUP> </SUP>(dose range, 0.2 to 0.7 = mg/kg) when=20 examined by cosyntropin<SUP> </SUP>stimulation testing (CST); <I>in = vitro</I>=20 study of rat mitochondria<SUP> </SUP>steroidogenesis revealed the = mechanism to=20 be the dose-dependent<SUP> </SUP>inhibition of cytochrome = P-450-dependent=20 enzymes by etomidate.<SUP> </SUP>Fellows and colleagues<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B39">39</= A></SUP>=20 described reversible and reproducible<SUP> </SUP>adrenal suppression in = six=20 critically ill trauma patients who<SUP> </SUP>received etomidate = infusions for=20 sedation, four of whom exhibited<SUP> </SUP>clinical sequelae of frank = adrenal=20 insufficiency.<SUP> </SUP> <P>Based on these reports, the long-term use of etomidate fell<SUP> = </SUP>into=20 disfavor, and the current package insert for etomidate<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B40">40</= A></SUP><SUP>=20 </SUP>(Amidate; Abbott Laboratories; Abbott Park, IL) states, "this<SUP> = </SUP>formulation is not intended for administration by prolonged<SUP>=20 </SUP>infusion."<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 = src=3D"http://www.chestjournal.org/icons/toc/rarrow.gif"=20 width=3D10></TD> <TH vAlign=3Dcenter align=3Dleft width=3D"95%"><FONT = size=3D+2>&nbsp;&nbsp;=20 Evidence for Adrenal Insufficiency With Etomidate for Induction in = Adults=20 </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.chestjournal.org/cgi/content/full/127/3/1031#top"><IMG= =20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>TOP<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#ABS"><IMG= =20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Abstract<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#BDY"><IMG= =20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Introduction<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC1"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Etomidate for Long-term...<BR></A><IMG height=3D9 = alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/dot.gif" width=3D11=20 border=3D0><FONT color=3D#464c53>Evidence for = Adrenal...</FONT><BR><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC3"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/darrow.gif" = width=3D11=20 border=3D0>Additional Potential Effects<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC4"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/darrow.gif" = width=3D11=20 border=3D0>Assessing Use of Etomidate...<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC5"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/darrow.gif" = width=3D11=20 border=3D0>Management Alternatives<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC6"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/darrow.gif" = width=3D11=20 border=3D0>How To Resolve Clinical...<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC7"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/darrow.gif" = width=3D11=20 border=3D0>Summary<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#BIBL"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/darrow.gif" = width=3D11=20 = border=3D0>References<BR></A></FONT></TH></TR></TBODY></TABLE>&nbsp;<BR>A= number=20 of small randomized studies<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B3">3</A>= </SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B30">30</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B31">31</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B41">41</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B42">42</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B43">43</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B44">44</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B45">45</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B46">46</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B47">47</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B48">48</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B49">49</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B50">50</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B51">51</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B52">52</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B53">53</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B54">54</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B55">55</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B56">56</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B57">57</= A></SUP><SUP>=20 </SUP>have examined adrenal hormone concentrations after single=20 subanesthetic<SUP> </SUP>or induction doses of etomidate (<I>ie</I>, = 0.04 to 0.5=20 mg/kg) for<SUP> </SUP>elective surgery in healthy adults, and = most<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B3">3</A>= </SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B31">31</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B41">41</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B42">42</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B43">43</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B45">45</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B46">46</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B47">47</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B48">48</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B49">49</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B50">50</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B51">51</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B52">52</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B53">53</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B54">54</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B55">55</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B56">56</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B57">57</= A></SUP><SUP>=20 </SUP>have described significant but transient (<I>ie</I>, &lt; 12 to = 24<SUP>=20 </SUP>h) adrenocortical suppression postadministration. Neither = persistent<SUP>=20 </SUP>functional suppression nor evidence of overt clinical = adrenocortical<SUP>=20 </SUP>insufficiency (<I>eg</I>, electrolyte abnormalities, hypotension, = or<SUP>=20 </SUP>prostration) has been consistently demonstrated under these<SUP>=20 </SUP>conditions. However, these investigations and their relevance<SUP> = </SUP>to the use of etomidate for induction in critically ill = patients<SUP>=20 </SUP>who are at risk for adrenal insufficiency are limited for the<SUP> = </SUP>following reasons: all have been of brief duration; all have<SUP>=20 </SUP>examined healthy patients undergoing elective surgery, most<SUP> = </SUP>of=20 which were minor procedures at extremely low risk for significant<SUP>=20 </SUP>morbidity or mortality; the means of assessing adrenocortical<SUP> = </SUP>function (including random measurement of cortisol levels and<SUP> = </SUP>cosyntropin stimulation testing [CST]) have not been uniform<SUP> = </SUP>or=20 standardized, with resultant unclear significance; most have<SUP> = </SUP>failed=20 to address the possible influence of diurnal adrenocorticotropic<SUP>=20 </SUP>hormone variations, which may potentiate morning cortisol = levels<SUP>=20 </SUP>coincident with induction for elective surgery but may be = lost<SUP>=20 </SUP>in critically ill patients; none have included patients with<SUP>=20 </SUP>preexisting endocrinopathy; and &lt; 200 patients have been<SUP>=20 </SUP>studied in aggregate. While these studies have confirmed the<SUP>=20 </SUP>existence of adrenal dysfunction after induction with = etomidate,<SUP>=20 </SUP>they do not establish it as innocuous.<SUP> </SUP> <P>Moreover, the literature addressing the influence of induction<SUP>=20 </SUP>doses of etomidate on measurable adrenocortical suppression<SUP> = </SUP>and=20 relevant clinical measures in uncontrolled settings remains<SUP>=20 </SUP>inadequate for establishing safety. McGrady and Wright<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B58">58</= A></SUP>=20 described<SUP> </SUP>a patient with pulmonary alveolar proteinosis who = received=20 a<SUP> </SUP>total of 0.88 mg/kg etomidate to facilitate two = intubations<SUP>=20 </SUP>over an 18-h period. The patient subsequently developed = hyperkalemia,<SUP>=20 </SUP>hyponatremia, and hypotension with low serum cortisol levels,<SUP> = </SUP>necessitating hydrocortisone therapy and volume and inotropic<SUP> = </SUP>support. Braams et al<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B59">59</= A></SUP>=20 administered 10 to 20 mg of etomidate<SUP> </SUP>for induction and = assessed=20 adrenocortical function by high-dose<SUP> </SUP>CST in 32 patients = undergoing=20 surgery for a ruptured abdominal<SUP> </SUP>aortic aneurysm (mean acute=20 physiology and chronic health evaluation<SUP> </SUP>[APACHE] II score, = 19).=20 Postoperative baseline cortisol levels<SUP> </SUP>(measured a mean of 15 = h=20 post-hospital admission) and post-CST<SUP> </SUP>cortisol levels were=20 significantly lower than in the 22 matched<SUP> </SUP>control subjects = who did=20 not receive etomidate (p &lt; 0.01),<SUP> </SUP>although there was no = difference=20 in mortality rate. Hilbert<SUP> </SUP>and colleagues<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B60">60</= A></SUP>=20 utilized etomidate, 0.3 mg/kg, to facilitate<SUP> </SUP>laryngeal mask = airway=20 placement prior to bronchoscopy in 46<SUP> </SUP>immunosuppressed = patients with=20 hypoxemia and pulmonary infiltrates.<SUP> </SUP>Although the mean (=B1 = SD)=20 simplified acute physiology<SUP> </SUP>score was 48 =B1 10, shock was an = exclusion=20 criterion.<SUP> </SUP>In the discussion, the authors reported "the = decision to=20 administer<SUP> </SUP>etomidate at the beginning of the procedure was = based on=20 our<SUP> </SUP>habitual use of this drug when performing preoxygenation=20 before<SUP> </SUP>intubation in our ICU." While the procedure was=20 well-tolerated,<SUP> </SUP>all 20 patients who subsequently required=20 endotracheal intubation<SUP> </SUP>(and presumably received additional = doses of=20 etomidate) died.<SUP> </SUP>Without additional information on these = patients=20 (who are at<SUP> </SUP>exceedingly high risk for mortality after = intubation=20 regardless<SUP> </SUP>of cofactors), it is difficult to assess the = impact of=20 etomidate<SUP> </SUP>on their ensuing clinical course.<SUP> </SUP> <P>The few randomized studies examining etomidate for the induction<SUP> = </SUP>of intubation also have failed to prove that the resultant = adrenal<SUP>=20 </SUP>dysfunction was either insignificant or transient. In a = randomized<SUP>=20 </SUP>trial, Absalom and colleagues<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B61">61</= A></SUP>=20 examined cortisol levels preinduction<SUP> </SUP>and 24 h after = high-dose CST=20 (<I>ie</I>, 250 =B5g cosyntropin)<SUP> </SUP>in 35 critically ill adults = (American=20 Society of Anesthesiologists<SUP> </SUP>grade III or worse, with two or = more=20 organ system failures)<SUP> </SUP>requiring intubation. The 17 patients = who=20 received etomidate<SUP> </SUP>had a median APACHE II score of 18.5, and = the=20 indications for<SUP> </SUP>intubation included respiratory failure and=20 laparotomy for acute<SUP> </SUP>abdomen. The incidence of sepsis and = subsequent=20 steroid therapy<SUP> </SUP>requirements were not reported. Despite = higher=20 baseline serum<SUP> </SUP>cortisol levels, patients receiving etomidate = had a=20 lower median<SUP> </SUP>increment in cortisol levels after CST compared = to=20 control subjects<SUP> </SUP>who received thiopental (p &lt; 0.004), with = lower=20 post-CST<SUP> </SUP>cortisol levels (p =3D 0.052). In another = prospective,=20 randomized<SUP> </SUP>study, Schenarts et al<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B62">62</= A></SUP>=20 administered etomidate (0.3 mg/kg)<SUP> </SUP>to 16 patients requiring = emergent=20 or urgent endotracheal intubation<SUP> </SUP>in the emergency department = (ED)=20 and assessed adrenocortical<SUP> </SUP>function by high-dose CST at 4, = 12, and=20 24 h postadministration.<SUP> </SUP>In patients who received etomidate, = a=20 significant difference<SUP> </SUP>in normal CST results was observed at = 4 h, but=20 not at 12 h or<SUP> </SUP>24 h, when compared to control subjects = receiving=20 midazolam.<SUP> </SUP>However, specific indications for intubation, = details=20 regarding<SUP> </SUP>steroid administration, and severity of illness = were not=20 described,<SUP> </SUP>pre-CST and post-CST cortisol levels were lower in = the=20 etomidate<SUP> </SUP>group at all times, and one patient (who received = twice=20 the<SUP> </SUP>"normal" dose of etomidate) exhibited an abnormal CST=20 response<SUP> </SUP>at 24 h.<SUP> </SUP> <P>Stuttmann and coworkers<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B63">63</= A></SUP>=20 randomized 20 patients undergoing<SUP> </SUP>elective colorectal surgery = to=20 hydrocortisone supplementation<SUP> </SUP>(100 mg in 5% glucose over 10 = h) or=20 placebo (5% glucose) after<SUP> </SUP>induction with etomidate (0.2 to = 0.3=20 mg/kg) and predefined therapeutic<SUP> </SUP>interventions based on = heart rate,=20 central venous pressure,<SUP> </SUP>BP, and serum sodium concentrations. = While=20 hemodynamic parameters<SUP> </SUP>and catecholamine requirements were = not=20 significantly different<SUP> </SUP>between groups, serum cortisol levels = were=20 considerably lower<SUP> </SUP>and the amount of crystalloid administered = intraoperatively<SUP> </SUP>was considerably higher in the group that = received=20 placebo.<SUP> </SUP>The authors surmised that the transient cortisol=20 deficiency<SUP> </SUP>caused by induction doses of etomidate could = potentiate=20 vascular<SUP> </SUP>leakage under physiologic stress, with an attendant=20 requirement<SUP> </SUP>for increased volume resuscitation. Given the=20 well-described<SUP> </SUP>increase in capillary permeability observed = early in=20 patients<SUP> </SUP>with sepsis,<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B64">64</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B65">65</= A></SUP>=20 the potential role of corticosteroids in minimizing<SUP> </SUP>this = vascular=20 leak,<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B65">65</= A></SUP>=20 and the emerging evidence correlating<SUP> </SUP>aggressive early = resuscitation=20 in septic shock patients with<SUP> </SUP>survival,<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B66">66</= A></SUP>=20 the data suggest that etomidate therapy for the<SUP> </SUP>induction of=20 intubation may impair the ability to maintain vascular<SUP> = </SUP>homeostasis in=20 patients with evolving sepsis and may negatively<SUP> </SUP>impact=20 mortality.<SUP> </SUP> <P>Most recently, Annane et al<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B67">67</= A></SUP>=20 reported a reduction in the risk<SUP> </SUP>of mortality following = low-dose=20 corticosteroid administration<SUP> </SUP>in patients with septic shock = who=20 exhibited relative adrenal<SUP> </SUP>insufficiency as assessed by = high-dose=20 CST. Notably, 21 months<SUP> </SUP>after initiating enrollment into the = study,=20 the investigators<SUP> </SUP>amended the eligibility criteria in this = trial to=20 exclude patients<SUP> </SUP>who had received etomidate for = induction.<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B67">67</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B68">68</= A></SUP>=20 Of the 72 patients<SUP> </SUP>who had received etomidate (mean dose, 0.3 = =B1 0.07=20 mg/kg)<SUP> </SUP>prior to the amendment, 68 subsequently did not = respond to=20 high-dose<SUP> </SUP>CST.<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B13">13</= A></SUP>=20 A subgroup analysis of these 68 CST nonresponders revealed<SUP>=20 </SUP>significantly higher ICU and hospital mortality rates in = patients<SUP>=20 </SUP>who had been randomized to receive placebo vs corticosteroids<SUP> = </SUP>(75.7% vs 54.8%, respectively; p =3D 0.0315) [D. Annane, MD, = PhD;<SUP>=20 </SUP>personal communication; April 24, 2004].<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 = src=3D"http://www.chestjournal.org/icons/toc/rarrow.gif"=20 width=3D10></TD> <TH vAlign=3Dcenter align=3Dleft width=3D"95%"><FONT = size=3D+2>&nbsp;&nbsp;=20 Additional Potential Effects </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.chestjournal.org/cgi/content/full/127/3/1031#top"><IMG= =20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>TOP<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#ABS"><IMG= =20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Abstract<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#BDY"><IMG= =20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Introduction<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC1"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Etomidate for Long-term...<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC2"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Evidence for Adrenal...<BR></A><IMG height=3D9 alt=3D" = " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/dot.gif" width=3D11=20 border=3D0><FONT color=3D#464c53>Additional Potential = Effects</FONT><BR><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC4"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/darrow.gif" = width=3D11=20 border=3D0>Assessing Use of Etomidate...<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC5"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/darrow.gif" = width=3D11=20 border=3D0>Management Alternatives<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC6"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/darrow.gif" = width=3D11=20 border=3D0>How To Resolve Clinical...<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC7"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/darrow.gif" = width=3D11=20 border=3D0>Summary<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#BIBL"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/darrow.gif" = width=3D11=20 = border=3D0>References<BR></A></FONT></TH></TR></TBODY></TABLE>&nbsp;<BR>I= n=20 addition to directly inhibiting cortisol levels, etomidate<SUP> = </SUP>may=20 interfere with other steroid-mediated cellular responses<SUP> </SUP>that = are=20 thought to be protective in sepsis. Endogenous cytokines<SUP> </SUP>such = as=20 interleukin-6<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B69">69</= A></SUP>=20 and interleukin-10,<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B70">70</= A></SUP>=20 among others,<SUP> </SUP>modulate the hypothalamic-pituitary-adrenal = axis in=20 critical<SUP> </SUP>illness. Etomidate has been shown to affect levels = of=20 interleukin-6<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B53">53</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B56">56</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B57">57</= A></SUP><SUP>=20 </SUP>and interleukin-10,<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B71">71</= A></SUP>=20 may impact circulating lymphocyte levels,<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B53">53</= A></SUP><SUP>=20 </SUP>and may upset the counterbalance of proinflammatory mediators<SUP> = </SUP>such as macrophage migration inhibitory factor. Furthermore,<SUP>=20 </SUP>some of the patterns of immunomodulation that appear to = correlate<SUP>=20 </SUP>with favorable hemodynamics during corticosteroid = administration<SUP>=20 </SUP>in patients with septic shock in particular,<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B72">72</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B73">73</= A></SUP>=20 including selective<SUP> </SUP>attenuation of both proinflammatory and=20 antiinflammatory responses,<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B73">73</= A></SUP><SUP>=20 </SUP>may be detrimentally altered by single-dose etomidate. While<SUP>=20 </SUP>the determinants and mechanisms of the immunologic response<SUP> = </SUP>in=20 sepsis patients and the impact of corticosteroids on this<SUP> = </SUP>response=20 remain to be fully elucidated,<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B74">74</= A></SUP>=20 the potential consequences<SUP> </SUP>of altering this milieu should be=20 considered.<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 = src=3D"http://www.chestjournal.org/icons/toc/rarrow.gif"=20 width=3D10></TD> <TH vAlign=3Dcenter align=3Dleft width=3D"95%"><FONT = size=3D+2>&nbsp;&nbsp;=20 Assessing Use of Etomidate in the Context of Relative Adrenal=20 Insufficiency in Septic Shock </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.chestjournal.org/cgi/content/full/127/3/1031#top"><IMG= =20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>TOP<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#ABS"><IMG= =20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Abstract<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#BDY"><IMG= =20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Introduction<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC1"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Etomidate for Long-term...<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC2"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Evidence for Adrenal...<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC3"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Additional Potential Effects<BR></A><IMG height=3D9 = alt=3D" "=20 hspace=3D5 src=3D"http://www.chestjournal.org/icons/toc/dot.gif" = width=3D11=20 border=3D0><FONT color=3D#464c53>Assessing Use of = Etomidate...</FONT><BR><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC5"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/darrow.gif" = width=3D11=20 border=3D0>Management Alternatives<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC6"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/darrow.gif" = width=3D11=20 border=3D0>How To Resolve Clinical...<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC7"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/darrow.gif" = width=3D11=20 border=3D0>Summary<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#BIBL"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/darrow.gif" = width=3D11=20 = border=3D0>References<BR></A></FONT></TH></TR></TBODY></TABLE>&nbsp;<BR>B= oth the=20 incidence and definition of adrenal insufficiency<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B7">7</A>= </SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B75">75</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B76">76</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B77">77</= A></SUP><SUP>=20 </SUP>and the value of corticosteroid administration<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B8">8</A>= </SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B9">9</A>= </SUP> in=20 septic shock<SUP> </SUP>patients remain topics of considerable debate = and=20 sources of<SUP> </SUP>clinical uncertainty.<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B78">78</= A></SUP>=20 Moreover, adrenal insufficiency after<SUP> </SUP>etomidate = administration has=20 been described both as absolute<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B4">4</A>= </SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B79">79</= A></SUP><SUP>=20 </SUP>and relative,<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B6">6</A>= </SUP>=20 creating additional confusion. Though a recent<SUP> = </SUP>investigation<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B80">80</= A></SUP>=20 suggesting a determination of free cortisol<SUP> </SUP>levels in = critically ill=20 patients holds promise in eventually<SUP> </SUP>clarifying this issue, = only 18=20 of the patients in this study<SUP> </SUP>were septic, and none had = received=20 etomidate (B. Arafah, MD;<SUP> </SUP>personal communication; April 19, = 2004).=20 While patients with<SUP> </SUP>absolute adrenal insufficiency (as = assessed by=20 history or testing<SUP> </SUP>in a nonstressed state) clearly require=20 physiologic doses of<SUP> </SUP>corticosteroids when stressed,<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B6">6</A>= </SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B81">81</= A></SUP>=20 and while the administration<SUP> </SUP>of corticosteroids in refractory = septic=20 shock appears to offer<SUP> </SUP>a benefit,<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B67">67</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B82">82</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B83">83</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B84">84</= A></SUP>=20 general agreement on these distinct scenarios<SUP> </SUP>still does not = address=20 the question of whether absolute adrenal<SUP> </SUP>insufficiency caused = by=20 etomidate is sustained and profound<SUP> </SUP>enough to affect outcomes = in=20 patients with septic shock that<SUP> </SUP>would not otherwise require = therapy=20 with corticosteroids.<SUP> </SUP> <P><A name=3DSEC5><!-- 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 = src=3D"http://www.chestjournal.org/icons/toc/rarrow.gif"=20 width=3D10></TD> <TH vAlign=3Dcenter align=3Dleft width=3D"95%"><FONT = size=3D+2>&nbsp;&nbsp;=20 Management Alternatives </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.chestjournal.org/cgi/content/full/127/3/1031#top"><IMG= =20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>TOP<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#ABS"><IMG= =20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Abstract<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#BDY"><IMG= =20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Introduction<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC1"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Etomidate for Long-term...<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC2"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Evidence for Adrenal...<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC3"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Additional Potential Effects<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC4"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Assessing Use of Etomidate...<BR></A><IMG height=3D9 = alt=3D" "=20 hspace=3D5 src=3D"http://www.chestjournal.org/icons/toc/dot.gif" = width=3D11=20 border=3D0><FONT color=3D#464c53>Management = Alternatives</FONT><BR><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC6"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/darrow.gif" = width=3D11=20 border=3D0>How To Resolve Clinical...<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC7"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/darrow.gif" = width=3D11=20 border=3D0>Summary<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#BIBL"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/darrow.gif" = width=3D11=20 = border=3D0>References<BR></A></FONT></TH></TR></TBODY></TABLE>&nbsp;<BR>P= atients=20 with evolving or established septic shock frequently<SUP> </SUP>require=20 endotracheal intubation for treatment of hypoxemia,<SUP> </SUP>work of=20 breathing, progressive metabolic acidosis, or airway<SUP>=20 </SUP>protection,<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B85">85</= A></SUP>=20 and almost uniformly need vasopressor support.<SUP> </SUP>The ideal = choice of=20 medications for facilitating intubation<SUP> </SUP>in this setting is = often a=20 difficult one. Clearly, the potential<SUP> </SUP>harm from etomidate = must be=20 weighed against its acknowledged<SUP> </SUP>benefits<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B1">1</A>= </SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B86">86</= A></SUP>=20 in facilitating intubation in this population, and<SUP> </SUP>the = limitations of=20 other agents, particularly relating to cardiovascular<SUP> = </SUP>stability,=20 onset, and duration of activity, and the effects<SUP> </SUP>on = spontaneous=20 ventilation, should not be underestimated. Alternative<SUP> = </SUP>regimens=20 usually include a combination of opioids, benzodiazepines,<SUP>=20 </SUP>barbiturates, propofol, ketamine, and/or neuromuscular = blockers,<SUP>=20 </SUP>and their use has been reviewed.<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B87">87</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B88">88</= A></SUP>=20 Admittedly, the patient<SUP> </SUP>with evolving septic shock is most = likely to=20 require intubation<SUP> </SUP>(often emergently) in the ED or ICU, where = respective providers<SUP> </SUP>may be less experienced in airway = management,=20 and such circumstances<SUP> </SUP>may understandably favor means of = intubation=20 that will simplify<SUP> </SUP>the immediate correction of an unstable = situation=20 at the expense<SUP> </SUP>of a risk that is delayed and may be perceived = as=20 hypothetical.<SUP> </SUP>Acknowledging this context, different = approaches to=20 management<SUP> </SUP>may be proposed while awaiting a definitive = study.<SUP>=20 </SUP> <P>One option is to eliminate the use of etomidate altogether in<SUP>=20 </SUP>patients with septic shock. Notably, the literature on the = ease<SUP>=20 </SUP>of etomidate use in uncontrolled settings is neither = extensive<SUP>=20 </SUP>nor unequivocal. The majority of published data, from the = prehospital<SUP>=20 </SUP>arena, are composed of both favorable results<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B89">89</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B90">90</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B91">91</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B92">92</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B93">93</= A></SUP>=20 and<SUP> </SUP>unfavorable results,<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B94">94</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B95">95</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B96">96</= A></SUP>=20 and its applicability to patients<SUP> </SUP>with septic shock is = restricted by=20 patient population (predominantly<SUP> </SUP>trauma patients), sample = size,=20 variety of induction regimens,<SUP> </SUP>variable outcome measures, and = use of=20 historical control subjects.<SUP> </SUP>The value of studies from the ED = is=20 limited as well. Using records<SUP> </SUP>from a multicenter registry, = Sivilotti=20 et al<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B97">97</= A></SUP>=20 examined the<SUP> </SUP>use of sedative adjuncts for 2,380 = rapid-sequence=20 intubations.<SUP> </SUP>Of 1,468 patients who received etomidate (mean = dose,=20 0.31 =B1<SUP> </SUP>0.19 mg/kg), 155 were assigned a diagnosis of = "shock" (62%=20 of<SUP> </SUP>all patients with this diagnosis), 235 patients (16.0%)=20 required<SUP> </SUP>multiple attempts at intubation, and 25 patients = (1.7%)=20 could<SUP> </SUP>not be intubated (<I>ie</I>, they required other agents = or=20 modalities).<SUP> </SUP>First-attempt success for intubation using = etomidate=20 carried<SUP> </SUP>an odds ratio of 0.35 (95% confidence interval, 0.17 = to=20 0.72;<SUP> </SUP>p =3D 0.005) when compared to barbiturates. Plewa and=20 coworkers<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B98">98</= A></SUP><SUP>=20 </SUP>studied the use of etomidate (0.3 mg/kg) for intubation = induction<SUP>=20 </SUP>in 20 trauma patients and noted minimal hemodynamic effects,<SUP>=20 </SUP>but 6 patients each required neuromuscular blockade or = additional<SUP>=20 </SUP>etomidate, and 12 patients required multiple intubation = attempts.<SUP>=20 </SUP>Smith et al<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B99">99</= A></SUP>=20 combined the use of etomidate (0.3 mg/kg) with<SUP> </SUP>neuromuscular = blockers=20 in 34 heterogeneous ED patients and achieved<SUP> </SUP>good conditions = for=20 intubation with hemodynamic stability in<SUP> </SUP>all patients. Given = the=20 occasional difficulty in establishing<SUP> </SUP>an airway in the = critically ill=20 patient, multiple doses of etomidate<SUP> </SUP>may be required to = attain=20 adequate sedation,<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B96">96</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B97">97</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B98">98</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B100">100= </A></SUP>=20 with a<SUP> </SUP>resultant potential increase in magnitude and duration = of=20 steroidogenesis<SUP> </SUP>inhibition. In sum, the available evidence = suggests=20 that in<SUP> </SUP>uncontrolled situations other agents may be at least=20 equally<SUP> </SUP>safe and efficacious, and should be used = preferentially.<SUP>=20 </SUP> <P>Another option is the continued use of etomidate in patients<SUP> = </SUP>with=20 septic shock with the automatic concomitant administration<SUP> </SUP>of = corticosteroids. This strategy is suboptimal for several<SUP> = </SUP>reasons.=20 First, and most importantly, administering etomidate<SUP> </SUP>instead = of using=20 an alternative agent (and assuming an appropriate<SUP> </SUP>response to = high-dose CST) might actively worsen a patient=92s<SUP> </SUP>prognostic = classification, with an attendant increase in the<SUP> </SUP>28-day = mortality=20 rate (from 26 to 67% or 67 to 82%).<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B101">101= </A></SUP>=20 As noted<SUP> </SUP>previously, the incidence of adrenal insufficiency = (when=20 assessed<SUP> </SUP>by high-dose CST) in patients manifesting septic = shock who=20 receive<SUP> </SUP>etomidate for the induction of intubation may be as = high=20 as<SUP> </SUP>94.4%.<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B13">13</= A></SUP>=20 While the 28-day mortality rate reported by Annane<SUP> </SUP>et = al<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B67">67</= A></SUP>=20 for CST nonresponders who received steroids was equivalent<SUP> </SUP>to = CST=20 responders who received placebo (53% in each group),<SUP> </SUP>there = were only=20 34 patients in the latter category. Second,<SUP> </SUP>while there may = be a role=20 for low-dose corticosteroid administration<SUP> </SUP>in septic shock = patients=20 independent of the demonstrated adrenal<SUP> </SUP>dysfunction, this = role=20 remains unproved. The indiscriminate<SUP> </SUP>use of steroids in = septic shock=20 patients may not be without<SUP> </SUP>risk,<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B102">102= </A></SUP>=20 with the effect on glucose control<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B103">103= </A></SUP>=20 being of particular<SUP> </SUP>importance. Third, the dose, timing, and = duration=20 of corticosteroid<SUP> </SUP>therapy for such an indication would be = speculative=20 and might<SUP> </SUP>differ considerably from that warranted for a = particular=20 patient<SUP> </SUP>with vasopressor-dependent septic shock. = Acknowledging=20 these<SUP> </SUP>limitations, the empiric administration of = corticosteroids=20 after<SUP> </SUP>etomidate administration while awaiting an assessment = of=20 adrenal<SUP> </SUP>function or establishing hemodynamic stability = (similar to=20 that<SUP> </SUP>proposed for adrenal insufficiency in critically ill=20 patients<SUP> </SUP>in general<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B5">5</A>= </SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B7">7</A>= </SUP>)=20 may be a reasonable, if imperfect, approach if<SUP> </SUP>etomidate is=20 administered for induction.<SUP> </SUP> <P>A third option is the use of subanesthetic dosing of etomidate<SUP> = </SUP>as=20 an adjunct to allow for lower doses of other agents that<SUP> </SUP>may = cause=20 hemodynamic instability. While intuitively appealing,<SUP> </SUP>CST = responses=20 have been blunted with doses of etomidate as low<SUP> </SUP>as 0.04=20 mg/kg,<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B51">51</= A></SUP>=20 and the efficacy of this approach to induction<SUP> </SUP>is not known. = Instead,=20 if an alternative induction agent may<SUP> </SUP>potentiate hemodynamic=20 instability, the transient proactive<SUP> </SUP>escalation of = vasopressor=20 therapy can allow for intubation with<SUP> </SUP>the maintenance of = normotension=20 and tissue perfusion (unpublished<SUP> </SUP>observations).<SUP> </SUP> <P>In sum, until the risks of using etomidate for intubation in<SUP>=20 </SUP>septic shock patients are clearly defined, the availability<SUP> = </SUP>and=20 training of experienced providers who are comfortable with<SUP> = </SUP>airway=20 management and the use of alternative medications should<SUP> </SUP>be=20 emphasized.<SUP> </SUP> <P><A name=3DSEC6><!-- 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 = src=3D"http://www.chestjournal.org/icons/toc/rarrow.gif"=20 width=3D10></TD> <TH vAlign=3Dcenter align=3Dleft width=3D"95%"><FONT = size=3D+2>&nbsp;&nbsp; How To=20 Resolve Clinical Equipoise </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.chestjournal.org/cgi/content/full/127/3/1031#top"><IMG= =20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>TOP<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#ABS"><IMG= =20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Abstract<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#BDY"><IMG= =20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Introduction<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC1"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Etomidate for Long-term...<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC2"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Evidence for Adrenal...<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC3"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Additional Potential Effects<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC4"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Assessing Use of Etomidate...<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC5"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Management Alternatives<BR></A><IMG height=3D9 alt=3D" = " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/dot.gif" width=3D11=20 border=3D0><FONT color=3D#464c53>How To Resolve = Clinical...</FONT><BR><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC7"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/darrow.gif" = width=3D11=20 border=3D0>Summary<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#BIBL"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/darrow.gif" = width=3D11=20 = border=3D0>References<BR></A></FONT></TH></TR></TBODY></TABLE>&nbsp;<BR>P= reviously=20 expressed concerns<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B12">12</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B13">13</= A></SUP>=20 and the emerging literature<SUP> </SUP>on etomidate administration in = septic=20 shock patients have indicated<SUP> </SUP>a state of clinical = equipoise.<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B104">104= </A></SUP>=20 As it is increasingly recognized<SUP> </SUP>that early management = decisions for=20 evolving septic shock<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B66">66</= A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B105">105= </A></SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B106">106= </A></SUP><SUP>=20 </SUP>may markedly impact subsequent mortality, the consequences of<SUP> = </SUP>the continued use of etomidate require clarification, and a<SUP>=20 </SUP>trial that specifically examines this intervention is = warranted.<SUP>=20 </SUP>While any comprehensive analysis must take into consideration<SUP> = </SUP>the potential morbidity of alternative induction regimens = (including<SUP>=20 </SUP>the incidence and duration of postprocedural hypotension, the<SUP> = </SUP>rate and ease of successful intubations, the need for = neuromuscular<SUP>=20 </SUP>blockade, and the type and number of airway complications),<SUP>=20 </SUP>this need not be a requisite in establishing harm with = etomidate<SUP>=20 </SUP>in septic shock patients if mortality is a powered outcome = measure.<SUP>=20 </SUP>Alternatively, the performance of a subgroup analysis of a = large<SUP>=20 </SUP>prospective study of corticosteroids in patients with septic<SUP>=20 </SUP>shock that possesses adequate sample size (<I>eg</I>, the ongoing=20 CORTICUS<SUP> </SUP>trial), irrespective of the definitions used for = adrenal=20 insufficiency<SUP> </SUP>and steroid responsiveness, may be helpful. = However, as=20 the<SUP> </SUP>hypoadrenalism observed post-etomidate administration=20 approaches<SUP> </SUP>uniformity<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B13">13</= A></SUP>=20 and might best be considered absolute,<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B4">4</A>= </SUP><SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B79">79</= A></SUP>=20 the use<SUP> </SUP>of etomidate admittedly may confound trials that = attempt=20 to<SUP> </SUP>assess the incidence and significance of relative adrenal=20 insufficiency<SUP> </SUP>in septic shock patients.<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B107">107= </A></SUP><SUP>=20 </SUP> <P><A name=3DSEC7><!-- 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 = src=3D"http://www.chestjournal.org/icons/toc/rarrow.gif"=20 width=3D10></TD> <TH vAlign=3Dcenter align=3Dleft width=3D"95%"><FONT = size=3D+2>&nbsp;&nbsp;=20 Summary </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.chestjournal.org/cgi/content/full/127/3/1031#top"><IMG= =20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>TOP<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#ABS"><IMG= =20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Abstract<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#BDY"><IMG= =20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Introduction<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC1"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Etomidate for Long-term...<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC2"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Evidence for Adrenal...<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC3"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Additional Potential Effects<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC4"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Assessing Use of Etomidate...<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC5"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Management Alternatives<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC6"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>How To Resolve Clinical...<BR></A><IMG height=3D9 = alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/dot.gif" width=3D11=20 border=3D0><FONT color=3D#464c53>Summary</FONT><BR><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#BIBL"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/darrow.gif" = width=3D11=20 = border=3D0>References<BR></A></FONT></TH></TR></TBODY></TABLE>&nbsp;<BR>I= n=20 conclusion, there is ample evidence to suggest that etomidate<SUP> = </SUP>when=20 used for the induction of intubation may deleteriously<SUP> </SUP>impact = steroidogenesis, and consequently morbidity and mortality,<SUP> </SUP>in = patients with evolving septic shock who require intubation.<SUP> = </SUP>With the=20 growing appreciation that corticosteroids may have<SUP> </SUP>beneficial = immunomodulatory and hemodynamic effects in sepsis<SUP> </SUP>patients, = the=20 cautionary note (and personal moratorium) on etomidate<SUP> </SUP>use = expressed=20 by Longnecker<SUP><A=20 href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#B108">108= </A></SUP>=20 2 decades ago appears even more<SUP> </SUP>persuasive today. Consensus = agreement=20 on a standardized definition<SUP> </SUP>for relative adrenal = insufficiency in=20 septic shock patients,<SUP> </SUP>and its optimal diagnosis and = management=20 should be accompanied<SUP> </SUP>by a randomized, controlled study = examining the=20 use of etomidate<SUP> </SUP>in this population.<SUP> </SUP> <P><SUP></SUP> <P><A name=3DACK><!-- 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 = src=3D"http://www.chestjournal.org/icons/toc/rarrow.gif"=20 width=3D10></TD> <TH vAlign=3Dcenter align=3Dleft width=3D"95%"><FONT = size=3D+2>&nbsp;&nbsp;=20 Acknowledgements </FONT></TH></TR></TBODY></TABLE>&nbsp;<BR>The = author thanks=20 Andrew F. Shorr, MD, MPH, and Christian Popa,<SUP> </SUP>MD, for = critical review=20 of the manuscript, and Sylvia Waters,<SUP> </SUP>MD, for translation of=20 German-language articles.<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 = src=3D"http://www.chestjournal.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>Abbreviations: APACHE =3D acute physiology = and chronic=20 health<SUP> </SUP>evaluation; CST =3D cosyntropin stimulation testing; = ED =3D=20 emergency<SUP> </SUP>department<SUP> </SUP> <P><A name=3D""><!-- null --></A>The opinions or assertions contained = herein are=20 the private<SUP> </SUP>views of the author and are not to be construed = as=20 official<SUP> </SUP>or as reflecting the views of the Department of the = Army=20 or<SUP> </SUP>the Department of Defense.<SUP> </SUP> <P>Received for publication May 11, 2004. Accepted for publication = August 3,=20 2004. <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 = src=3D"http://www.chestjournal.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.chestjournal.org/cgi/content/full/127/3/1031#top"><IMG= =20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>TOP<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#ABS"><IMG= =20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Abstract<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#BDY"><IMG= =20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Introduction<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC1"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Etomidate for Long-term...<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC2"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Evidence for Adrenal...<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC3"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Additional Potential Effects<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC4"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Assessing Use of Etomidate...<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC5"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Management Alternatives<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC6"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>How To Resolve Clinical...<BR></A><A=20 = href=3D"http://www.chestjournal.org/cgi/content/full/127/3/1031#SEC7"><IM= G=20 height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.org/icons/toc/uarrow.gif" = width=3D11=20 border=3D0>Summary<BR></A><IMG height=3D9 alt=3D" " hspace=3D5=20 src=3D"http://www.chestjournal.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=3DB1><!-- null --></A> <LI value=3D1>Bergen, JM, Smith, DC (1997) A review of etomidate for = rapid=20 sequence intubation in the emergency department. <I>J Emerg Med</I>=20 <B>15</B>,221-230<!-- HIGHWIRE ID=3D"127:3:1031:1" --><A=20 = href=3D"http://www.chestjournal.org/cgi/external_ref?access_num=3D10.1016= /S0736-4679(96)00350-2&amp;link_type=3DDOI">[CrossRef]</A><A=20 = href=3D"http://www.chestjournal.org/cgi/external_ref?access_num=3D9144065= &amp;link_type=3DMED">[Medline]</A><!-- /HIGHWIRE --><A=20 name=3DB2><!-- null --></A>=20 <LI value=3D2>de Jong, FH, Mallios, C, Jansen, C, et al Etomidate = suppresses=20 adrenocortical function by inhibition of 11 beta-hydroxylation. <I>J = Clin=20 Endocrinol Metab</I> <B>1984;59</B>,1143-1147<!-- HIGHWIRE = ID=3D"127:3:1031:2" --><A=20 = 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width=3D5></TD> <TD vAlign=3Dtop noWrap width=3D499><A=20 href=3D"http://bja.oxfordjournals.org/"><IMG height=3D16 alt=3D"Br = J Anaesth"=20 = src=3D"http://www.chestjournal.org/icons/shared/searchall/journals/brjana= .gif"=20 width=3D450 vspace=3D5 border=3D0><IMG height=3D16 alt=3D"Home = page"=20 = src=3D"http://www.chestjournal.org/icons/shared/search/homelink.gif"=20 width=3D49 vspace=3D5 border=3D0></A><BR><FONT = face=3Dverdana,arial,helvetica=20 size=3D-1>R. Bloomfield and D. W. Noble<BR><STRONG>Etomidate and = fatal=20 outcome--even a single bolus dose may be detrimental for some=20 patients.</STRONG><BR>Br. J. Anaesth., July&nbsp;1,&nbsp;2006; = 97(1): 116=20 - 117. <BR><A=20 = href=3D"http://bja.oxfordjournals.org/cgi/content/full/97/1/116">[Full=20 Text]</A> <A=20 = href=3D"http://bja.oxfordjournals.org/cgi/reprint/97/1/116">[PDF]</A>=20 <BR><IMG height=3D1 alt=3D""=20 src=3D"http://www.chestjournal.org/icons/spacer.gif" width=3D499> = </FONT></TD> <TD width=3D5><IMG height=3D5 alt=3D""=20 src=3D"http://www.chestjournal.org/icons/spacer.gif" = width=3D5></TD></TR> <TR> <TD colSpan=3D6> <HR align=3Dleft width=3D600 color=3D#828282 noShade SIZE=3D1> </TD></TR></TBODY></TABLE> <TABLE cellSpacing=3D0 cellPadding=3D0 width=3D600 border=3D0> <TBODY> <TR bgColor=3D#d9d4c5> <TD vAlign=3Dtop align=3Dmiddle width=3D25><IMG height=3D5 alt=3D""=20 src=3D"http://www.chestjournal.org/icons/spacer.gif" = width=3D25><BR></TD> <TD width=3D5><IMG height=3D5 alt=3D""=20 src=3D"http://www.chestjournal.org/icons/spacer.gif" = width=3D5></TD> <TD vAlign=3Dtop noWrap align=3Dmiddle width=3D61><A=20 href=3D"http://www.aemj.org/"><IMG height=3D80 alt=3D"Home page"=20 src=3D"http://www.aemj.org/portal_imgs/search_result.gif" = width=3D59 vspace=3D5=20 border=3D1></A><BR></TD> <TD width=3D5><IMG height=3D5 alt=3D""=20 src=3D"http://www.chestjournal.org/icons/spacer.gif" = width=3D5></TD> <TD vAlign=3Dtop noWrap width=3D499><A = href=3D"http://www.aemj.org/"><IMG=20 height=3D16 alt=3D"Acad. 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J. Respir. Crit. Care Med."=20 = src=3D"http://www.chestjournal.org/icons/shared/searchall/journals/ajrccm= .gif"=20 width=3D450 vspace=3D5 border=3D0><IMG height=3D16 alt=3D"Home = page"=20 = src=3D"http://www.chestjournal.org/icons/shared/search/homelink.gif"=20 width=3D49 vspace=3D5 border=3D0></A><BR><FONT = face=3Dverdana,arial,helvetica=20 size=3D-1>W. L. Jackson Jr.<BR><STRONG>Adrenal insufficiency and = ventilator=20 weaning: additional study is required.</STRONG><BR>Am. J. 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J. Respir. Crit. Care Med."=20 = src=3D"http://www.chestjournal.org/icons/shared/searchall/journals/ajrccm= .gif"=20 width=3D450 vspace=3D5 border=3D0><IMG height=3D16 alt=3D"Home = page"=20 = src=3D"http://www.chestjournal.org/icons/shared/search/homelink.gif"=20 width=3D49 vspace=3D5 border=3D0></A><BR><FONT = face=3Dverdana,arial,helvetica=20 size=3D-1>C.-J. Huang and H.-C. Lin<BR><STRONG>Adrenal = Insufficiency and=20 Ventilator Weaning: Additional Study Is Required</STRONG><BR>Am. = J.=20 Respir. Crit. 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J. Respir. Crit. Care Med."=20 = src=3D"http://www.chestjournal.org/icons/shared/searchall/journals/ajrccm= .gif"=20 width=3D450 vspace=3D5 border=3D0><IMG height=3D16 alt=3D"Home = page"=20 = src=3D"http://www.chestjournal.org/icons/shared/search/homelink.gif"=20 width=3D49 vspace=3D5 border=3D0></A><BR><FONT = face=3Dverdana,arial,helvetica=20 size=3D-1>E. B. Milbrandt, A. Ishizaka, and D. C. = Angus<BR><STRONG>Update in=20 critical care 2005.</STRONG><BR>Am. J. Respir. Crit. 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Emerg. Med."=20 = src=3D"http://www.chestjournal.org/icons/shared/searchall/journals/aemj.g= if"=20 width=3D450 vspace=3D5 border=3D0><IMG height=3D16 alt=3D"Home = page"=20 = src=3D"http://www.chestjournal.org/icons/shared/search/homelink.gif"=20 width=3D49 vspace=3D5 border=3D0></A><BR><FONT = face=3Dverdana,arial,helvetica=20 size=3D-1>P. J. Zed, R. B. Abu-Laban, and D. W.=20 Harrison<BR><STRONG>Intubating Conditions and Hemodynamic Effects = of=20 Etomidate for Rapid Sequence Intubation in the Emergency = Department: An=20 Observational Cohort Study</STRONG><BR>Acad. Emerg. Med.,=20 April&nbsp;1,&nbsp;2006; 13(4): 378 - 383. <BR><A=20 = href=3D"http://www.aemj.org/cgi/content/abstract/13/4/378">[Abstract]</A>= <A=20 href=3D"http://www.aemj.org/cgi/content/full/13/4/378">[Full = Text]</A> <A=20 href=3D"http://www.aemj.org/cgi/reprint/13/4/378">[PDF]</A> = <BR><IMG=20 height=3D1 alt=3D"" = src=3D"http://www.chestjournal.org/icons/spacer.gif"=20 width=3D499> </FONT></TD> <TD width=3D5><IMG height=3D5 alt=3D""=20 src=3D"http://www.chestjournal.org/icons/spacer.gif" = width=3D5></TD></TR> <TR> <TD colSpan=3D6> <HR align=3Dleft width=3D600 color=3D#828282 noShade SIZE=3D1> </TD></TR></TBODY></TABLE> <TABLE cellSpacing=3D0 cellPadding=3D0 width=3D600 border=3D0> <TBODY> <TR bgColor=3D#d9d4c5> <TD vAlign=3Dtop align=3Dmiddle width=3D25><IMG height=3D5 alt=3D""=20 src=3D"http://www.chestjournal.org/icons/spacer.gif" = width=3D25><BR></TD> <TD width=3D5><IMG height=3D5 alt=3D""=20 src=3D"http://www.chestjournal.org/icons/spacer.gif" = width=3D5></TD> <TD vAlign=3Dtop noWrap align=3Dmiddle width=3D61><A=20 href=3D"http://www.aemj.org/"><IMG height=3D80 alt=3D"Home page"=20 src=3D"http://www.aemj.org/portal_imgs/search_result.gif" = width=3D59 vspace=3D5=20 border=3D1></A><BR></TD> <TD width=3D5><IMG height=3D5 alt=3D""=20 src=3D"http://www.chestjournal.org/icons/spacer.gif" = width=3D5></TD> <TD vAlign=3Dtop noWrap width=3D499><A = href=3D"http://www.aemj.org/"><IMG=20 height=3D16 alt=3D"Acad. Emerg. Med."=20 = src=3D"http://www.chestjournal.org/icons/shared/searchall/journals/aemj.g= if"=20 width=3D450 vspace=3D5 border=3D0><IMG height=3D16 alt=3D"Home = page"=20 = src=3D"http://www.chestjournal.org/icons/shared/search/homelink.gif"=20 width=3D49 vspace=3D5 border=3D0></A><BR><FONT = face=3Dverdana,arial,helvetica=20 size=3D-1>C. Fee and M. A. Gropper<BR><STRONG>Establishing a = Comprehensive,=20 Evidence-based Protocol for the Care of Patients with=20 Sepsis</STRONG><BR>Acad. Emerg. Med., September&nbsp;1,&nbsp;2005; = 12(9):=20 912 - 913. <BR><A=20 href=3D"http://www.aemj.org/cgi/content/full/12/9/912-a">[Full = Text]</A> <A=20 href=3D"http://www.aemj.org/cgi/reprint/12/9/912-a">[PDF]</A> = <BR><IMG=20 height=3D1 alt=3D"" = src=3D"http://www.chestjournal.org/icons/spacer.gif"=20 width=3D499> </FONT></TD> <TD width=3D5><IMG height=3D5 alt=3D""=20 src=3D"http://www.chestjournal.org/icons/spacer.gif" = width=3D5></TD></TR> <TR> <TD colSpan=3D6> <HR align=3Dleft width=3D600 color=3D#828282 noShade SIZE=3D1> </TD></TR></TBODY></TABLE> <TABLE cellSpacing=3D0 cellPadding=3D0 width=3D600 border=3D0> <TBODY> <TR bgColor=3D#d9d4c5> <TD vAlign=3Dtop align=3Dmiddle width=3D25><IMG height=3D5 alt=3D""=20 src=3D"http://www.chestjournal.org/icons/spacer.gif" = width=3D25><BR></TD> <TD width=3D5><IMG height=3D5 alt=3D""=20 src=3D"http://www.chestjournal.org/icons/spacer.gif" = width=3D5></TD> <TD vAlign=3Dtop noWrap align=3Dmiddle width=3D61><A=20 href=3D"http://jcem.endojournals.org/"><IMG height=3D80 = alt=3D"Home page"=20 src=3D"http://jcem.endojournals.org/portal_imgs/search_result.gif" = width=3D59=20 vspace=3D5 border=3D1></A><BR></TD> <TD width=3D5><IMG height=3D5 alt=3D""=20 src=3D"http://www.chestjournal.org/icons/spacer.gif" = width=3D5></TD> <TD vAlign=3Dtop noWrap width=3D499><A=20 href=3D"http://jcem.endojournals.org/"><IMG height=3D16=20 alt=3D"J. Clin. Endocrinol. Metab."=20 = src=3D"http://www.chestjournal.org/icons/shared/searchall/journals/jcem.g= if"=20 width=3D450 vspace=3D5 border=3D0><IMG height=3D16 alt=3D"Home = page"=20 = src=3D"http://www.chestjournal.org/icons/shared/search/homelink.gif"=20 width=3D49 vspace=3D5 border=3D0></A><BR><FONT = face=3Dverdana,arial,helvetica=20 size=3D-1>M. den Brinker, K. F. M. Joosten, O. Liem, F. H. de = Jong, W. C. J.=20 Hop, J. A. Hazelzet, M. van Dijk, and A. C. S.=20 Hokken-Koelega<BR><STRONG>Adrenal Insufficiency in Meningococcal = Sepsis:=20 Bioavailable Cortisol Levels and Impact of Interleukin-6 Levels = and=20 Intubation with Etomidate on Adrenal Function and = Mortality</STRONG><BR>J.=20 Clin. Endocrinol. 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=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=0A= =0A= Emulate Gecko 'XMLHttpRequest()' functionality in IE and Opera. Opera = requires=0A= the Sun Java Runtime Environment <http://www.java.com/>.=0A= =0A= by Andrew Gregory=0A= http://www.scss.com.au/family/andrew/webdesign/xmlhttprequest/=0A= =0A= This work is licensed under the Creative Commons Attribution License. To = view a=0A= copy of this license, visit = http://creativecommons.org/licenses/by-sa/2.5/ or=0A= send a letter to Creative Commons, 559 Nathan Abbott Way, Stanford, = California=0A= 94305, USA.=0A= =0A= Attribution: Leave my name and web address in this script intact.=0A= =0A= Not Supported in Opera=0A= ----------------------=0A= * user/password authentication=0A= * responseXML data member=0A= =0A= Not Fully Supported in Opera=0A= ----------------------------=0A= * async requests=0A= * abort()=0A= * getAllResponseHeaders(), getAllResponseHeader(header)=0A= =0A= */=0A= // IE support=0A= if (window.ActiveXObject && !window.XMLHttpRequest) {=0A= window.XMLHttpRequest =3D function() {=0A= var msxmls =3D new Array(=0A= 'Msxml2.XMLHTTP.5.0',=0A= 'Msxml2.XMLHTTP.4.0',=0A= 'Msxml2.XMLHTTP.3.0',=0A= 'Msxml2.XMLHTTP',=0A= 'Microsoft.XMLHTTP');=0A= for (var i =3D 0; i < msxmls.length; i++) {=0A= try {=0A= return new ActiveXObject(msxmls[i]);=0A= } catch (e) {=0A= }=0A= }=0A= return null;=0A= };=0A= }=0A= // Gecko support=0A= /* ;-) */=0A= // Opera support=0A= if (window.opera && !window.XMLHttpRequest) {=0A= window.XMLHttpRequest =3D function() {=0A= this.readyState =3D 0; // = 0=3Duninitialized,1=3Dloading,2=3Dloaded,3=3Dinteractive,4=3Dcomplete=0A= this.status =3D 0; // HTTP status codes=0A= this.statusText =3D '';=0A= this._headers =3D [];=0A= this._aborted =3D false;=0A= this._async =3D true;=0A= this._defaultCharset =3D 'ISO-8859-1';=0A= this._getCharset =3D function() {=0A= var charset =3D _defaultCharset;=0A= var contentType =3D = this.getResponseHeader('Content-type').toUpperCase();=0A= val =3D contentType.indexOf('CHARSET=3D');=0A= if (val !=3D -1) {=0A= charset =3D contentType.substring(val);=0A= }=0A= val =3D charset.indexOf(';');=0A= if (val !=3D -1) {=0A= charset =3D charset.substring(0, val);=0A= }=0A= val =3D charset.indexOf(',');=0A= if (val !=3D -1) {=0A= charset =3D charset.substring(0, val);=0A= }=0A= return charset;=0A= };=0A= this.abort =3D function() {=0A= this._aborted =3D true;=0A= };=0A= this.getAllResponseHeaders =3D function() {=0A= return this.getAllResponseHeader('*');=0A= };=0A= this.getAllResponseHeader =3D function(header) {=0A= var ret =3D '';=0A= for (var i =3D 0; i < this._headers.length; i++) {=0A= if (header =3D=3D '*' || this._headers[i].h =3D=3D header) {=0A= ret +=3D this._headers[i].h + ': ' + this._headers[i].v + '\n';=0A= }=0A= }=0A= return ret;=0A= };=0A= this.getResponseHeader =3D function(header) {=0A= var ret =3D getAllResponseHeader(header);=0A= var i =3D ret.indexOf('\n');=0A= if (i !=3D -1) {=0A= ret =3D ret.substring(0, i);=0A= }=0A= return ret;=0A= };=0A= this.setRequestHeader =3D function(header, value) {=0A= this._headers[this._headers.length] =3D {h:header, v:value};=0A= };=0A= this.open =3D function(method, url, async, user, password) {=0A= this.method =3D method;=0A= this.url =3D url;=0A= this._async =3D true;=0A= this._aborted =3D false;=0A= this._headers =3D [];=0A= if (arguments.length >=3D 3) {=0A= this._async =3D async;=0A= }=0A= if (arguments.length > 3) {=0A= opera.postError('XMLHttpRequest.open() - user/password not = supported');=0A= }=0A= this.readyState =3D 1;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= };=0A= this.send =3D function(data) {=0A= if (!navigator.javaEnabled()) {=0A= alert("XMLHttpRequest.send() - Java must be installed and = enabled.");=0A= return;=0A= }=0A= if (this._async) {=0A= setTimeout(this._sendasync, 0, this, data);=0A= // this is not really asynchronous and won't execute until the = current=0A= // execution context ends=0A= } else {=0A= this._sendsync(data);=0A= }=0A= }=0A= this._sendasync =3D function(req, data) {=0A= if (!req._aborted) {=0A= req._sendsync(data);=0A= }=0A= };=0A= this._sendsync =3D function(data) {=0A= this.readyState =3D 2;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= // open connection=0A= var url =3D new java.net.URL(new = java.net.URL(window.location.href), this.url);=0A= var conn =3D url.openConnection();=0A= for (var i =3D 0; i < this._headers.length; i++) {=0A= conn.setRequestProperty(this._headers[i].h, this._headers[i].v);=0A= }=0A= this._headers =3D [];=0A= if (this.method =3D=3D 'POST') {=0A= // POST data=0A= conn.setDoOutput(true);=0A= var wr =3D new = java.io.OutputStreamWriter(conn.getOutputStream(), this._getCharset());=0A= wr.write(data);=0A= wr.flush();=0A= wr.close();=0A= }=0A= // read response headers=0A= // NOTE: the getHeaderField() methods always return nulls for me :(=0A= var gotContentEncoding =3D false;=0A= var gotContentLength =3D false;=0A= var gotContentType =3D false;=0A= var gotDate =3D false;=0A= var gotExpiration =3D false;=0A= var gotLastModified =3D false;=0A= for (var i =3D 0; ; i++) {=0A= var hdrName =3D conn.getHeaderFieldKey(i);=0A= var hdrValue =3D conn.getHeaderField(i);=0A= if (hdrName =3D=3D null && hdrValue =3D=3D null) {=0A= break;=0A= }=0A= if (hdrName !=3D null) {=0A= this._headers[this._headers.length] =3D {h:hdrName, = v:hdrValue};=0A= switch (hdrName.toLowerCase()) {=0A= case 'content-encoding': gotContentEncoding =3D true; break;=0A= case 'content-length' : gotContentLength =3D true; break;=0A= case 'content-type' : gotContentType =3D true; break;=0A= case 'date' : gotDate =3D true; break;=0A= case 'expires' : gotExpiration =3D true; break;=0A= case 'last-modified' : gotLastModified =3D true; break;=0A= }=0A= }=0A= }=0A= // try to fill in any missing header information=0A= var val;=0A= val =3D conn.getContentEncoding();=0A= if (val !=3D null && !gotContentEncoding) = this._headers[this._headers.length] =3D {h:'Content-encoding', v:val};=0A= val =3D conn.getContentLength();=0A= if (val !=3D -1 && !gotContentLength) = this._headers[this._headers.length] =3D {h:'Content-length', v:val};=0A= val =3D conn.getContentType();=0A= if (val !=3D null && !gotContentType) = this._headers[this._headers.length] =3D {h:'Content-type', v:val};=0A= val =3D conn.getDate();=0A= if (val !=3D 0 && !gotDate) this._headers[this._headers.length] = =3D {h:'Date', v:(new Date(val)).toUTCString()};=0A= val =3D conn.getExpiration();=0A= if (val !=3D 0 && !gotExpiration) = this._headers[this._headers.length] =3D {h:'Expires', v:(new = Date(val)).toUTCString()};=0A= val =3D conn.getLastModified();=0A= if (val !=3D 0 && !gotLastModified) = this._headers[this._headers.length] =3D {h:'Last-modified', v:(new = Date(val)).toUTCString()};=0A= // read response data=0A= var reqdata =3D '';=0A= var stream =3D conn.getInputStream();=0A= if (stream) {=0A= var reader =3D new java.io.BufferedReader(new = java.io.InputStreamReader(stream, this._getCharset()));=0A= var line;=0A= while ((line =3D reader.readLine()) !=3D null) {=0A= if (this.readyState =3D=3D 2) {=0A= this.readyState =3D 3;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= }=0A= reqdata +=3D line + '\n';=0A= }=0A= reader.close();=0A= this.status =3D 200;=0A= this.statusText =3D 'OK';=0A= this.responseText =3D reqdata;=0A= this.readyState =3D 4;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= if (this.onload) {=0A= this.onload();=0A= }=0A= } else {=0A= // error=0A= this.status =3D 404;=0A= this.statusText =3D 'Not Found';=0A= this.responseText =3D '';=0A= this.readyState =3D 4;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= if (this.onerror) {=0A= this.onerror();=0A= }=0A= }=0A= };=0A= };=0A= }=0A= // ActiveXObject emulation=0A= if (!window.ActiveXObject && window.XMLHttpRequest) {=0A= window.ActiveXObject =3D function(type) {=0A= switch (type.toLowerCase()) {=0A= case 'microsoft.xmlhttp':=0A= case 'msxml2.xmlhttp':=0A= case 'msxml2.xmlhttp.3.0':=0A= case 'msxml2.xmlhttp.4.0':=0A= case 'msxml2.xmlhttp.5.0':=0A= return new XMLHttpRequest();=0A= }=0A= return null;=0A= };=0A= }=0A= ------=_NextPart_000_0068_01C7D67A.31C69300 Content-Type: application/octet-stream Content-Transfer-Encoding: quoted-printable Content-Location: http://www.chestjournal.org/javascript/ajax/utility.js /************************************************************************= *****=0A= * javascript/ajax/utility.js=0A= *=0A= * Utility functions for working with XMLHttpRequest data.=0A= *=0A= * Copyright 2006 Board of Trustees of the Leland Stanford Junior = University.=0A= = *************************************************************************= ***/=0A= =0A= /*=0A= * Copy XML nodes into an HTMLElement. This effectively=0A= * clones XML markup which uses XHTML naming conventions=0A= * into an HTML DOM.=0A= */=0A= function copy_xml_to_html(src, dst) {=0A= if (src.nodeType =3D=3D 1) { /* Node.ELEMENT_NODE */=0A= var e =3D document.createElement(src.nodeName);=0A= for (var i =3D 0; i < src.childNodes.length; i++) {=0A= copy_xml_to_html(src.childNodes[i], e);=0A= }=0A= for (var i =3D 0; i < src.attributes.length; i++) {=0A= var n =3D src.attributes[i].name;=0A= var v =3D unescape_xml_string(src.attributes[i].value); =0A= e.setAttribute(n, v);=0A= if (n =3D=3D "class") {=0A= e.className =3D v;=0A= }=0A= else if (n =3D=3D "style") {=0A= set_css_style(v, e, "");=0A= }=0A= }=0A= dst.appendChild(e);=0A= }=0A= else if (src.nodeType =3D=3D 3) { /* Node.TEXT_NODE */=0A= dst.appendChild(document.createTextNode(src.nodeValue));=0A= }=0A= }=0A= =0A= /* =0A= * It is unclear that this is the right thing to be calling=0A= * from copy_xml_to_html, but it appears that Safari decides=0A= * to convert &amp; to the NCR &#35;, and then encodes that=0A= * NCR to &%26%2338;. So, I'm going to treat the DOM Attr=0A= * value as a plain string, and run our XML string input=0A= * through the decoding routine below.=0A= */=0A= function unescape_xml_string(s) {=0A= return s.replace(/&apos;/g, "'")=0A= .replace(/&#39;/g, "'")=0A= .replace(/&quot;/g, "\"")=0A= .replace(/&#34;/g, "\"")=0A= .replace(/&gt;/g, ">")=0A= .replace(/&#62;/g, ">")=0A= .replace(/&lt;/g, "<")=0A= .replace(/&#60;/g, "<")=0A= .replace(/&amp;/g, "&")=0A= .replace(/&#38;/g, "&");=0A= }=0A= =0A= /*=0A= * Parse set of CSS rules and apply them to an element.=0A= * This is quite horrifying, but I'm unable to determine=0A= * how else to handle this with IE 6. FireFox and other=0A= * sane browsers let you simply set the style attribute=0A= * or use e.style.setProperty(rule, value, priority),=0A= * IE 6 appears to have neither of these capabilities..=0A= */=0A= function set_css_style(css, e, priority) {=0A= var rules =3D css.split(";");=0A= for (var i =3D 0; i < rules.length; i++) {=0A= var nvpair =3D rules[i].split(":");=0A= if (nvpair.length =3D=3D 2) {=0A= try {=0A= var name =3D nvpair[0]; /* style attribute */=0A= var value =3D nvpair[1]; /* attribute value */=0A= =0A= /*=0A= * For each possible style attribute, set the=0A= * appropriate style property in the element.=0A= */=0A= if (name =3D=3D "background") {=0A= e.style.background =3D value;=0A= }=0A= else if (name =3D=3D "background-attachment") {=0A= e.style.backgroundAttachment =3D value;=0A= }=0A= else if (name =3D=3D "background-color") {=0A= e.style.backgroundColor =3D value;=0A= }=0A= else if (name =3D=3D "background-image") {=0A= e.style.backgroundImage =3D value;=0A= }=0A= else if (name =3D=3D "background-position") {=0A= e.style.backgroundPosition =3D value;=0A= }=0A= else if (name =3D=3D "background-position-x") {=0A= e.style.backgroundPositionX =3D value;=0A= }=0A= else if (name =3D=3D "background-position-y") {=0A= e.style.backgroundPositionY =3D value;=0A= }=0A= else if (name =3D=3D "background-repeat") {=0A= e.style.backgroundRepeat =3D value;=0A= }=0A= else if (name =3D=3D "behavior") {=0A= e.style.behavior =3D value;=0A= }=0A= else if (name =3D=3D "border") {=0A= e.style.border =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom") {=0A= e.style.borderBottom =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom-color") {=0A= e.style.borderBottomColor =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom-style") {=0A= e.style.borderBottomStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom-width") {=0A= e.style.borderBottomWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-collapse") {=0A= e.style.borderCollapse =3D value;=0A= }=0A= else if (name =3D=3D "border-color") {=0A= e.style.borderColor =3D value;=0A= }=0A= else if (name =3D=3D "border-left") {=0A= e.style.borderLeft =3D value;=0A= }=0A= else if (name =3D=3D "border-left-color") {=0A= e.style.borderLeftColor =3D value;=0A= }=0A= else if (name =3D=3D "border-left-style") {=0A= e.style.borderLeftStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-left-width") {=0A= e.style.borderLeftWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-right") {=0A= e.style.borderRight =3D value;=0A= }=0A= else if (name =3D=3D "border-right-color") {=0A= e.style.borderRightColor =3D value;=0A= }=0A= else if (name =3D=3D "border-right-style") {=0A= e.style.borderRightStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-right-width") {=0A= e.style.borderRightWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-style") {=0A= e.style.borderStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-top") {=0A= e.style.borderTop =3D value;=0A= }=0A= else if (name =3D=3D "border-top-color") {=0A= e.style.borderTopColor =3D value;=0A= }=0A= else if (name =3D=3D "border-top-style") {=0A= e.style.borderTopStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-top-width") {=0A= e.style.borderTopWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-width") {=0A= e.style.borderWidth =3D value;=0A= }=0A= else if (name =3D=3D "bottom") {=0A= e.style.bottom =3D value;=0A= }=0A= else if (name =3D=3D "clear") {=0A= e.style.clear =3D value;=0A= }=0A= else if (name =3D=3D "clip") {=0A= e.style.clip =3D value;=0A= }=0A= else if (name =3D=3D "color") {=0A= e.style.color =3D value;=0A= }=0A= else if (name =3D=3D "cssText") {=0A= e.style.Sets =3D value;=0A= }=0A= else if (name =3D=3D "cursor") {=0A= e.style.cursor =3D value;=0A= }=0A= else if (name =3D=3D "direction") {=0A= e.style.direction =3D value;=0A= }=0A= else if (name =3D=3D "display") {=0A= e.style.display =3D value;=0A= }=0A= else if (name =3D=3D "font") {=0A= e.style.font =3D value;=0A= }=0A= else if (name =3D=3D "font-family") {=0A= e.style.fontFamily =3D value;=0A= }=0A= else if (name =3D=3D "font-size") {=0A= e.style.fontSize =3D value;=0A= }=0A= else if (name =3D=3D "font-style") {=0A= e.style.fontStyle =3D value;=0A= }=0A= else if (name =3D=3D "font-variant") {=0A= e.style.fontVariant =3D value;=0A= }=0A= else if (name =3D=3D "font-weight") {=0A= e.style.fontWeight =3D value;=0A= }=0A= else if (name =3D=3D "height") {=0A= e.style.height =3D value;=0A= }=0A= else if (name =3D=3D "ime-mode") {=0A= e.style.imeMode =3D value;=0A= }=0A= else if (name =3D=3D "layout-flow") {=0A= e.style.layoutFlow =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid") {=0A= e.style.layoutGrid =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-char") {=0A= e.style.layoutGridChar =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-line") {=0A= e.style.layoutGridLine =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-mode") {=0A= e.style.layoutGridMode =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-type") {=0A= e.style.layoutGridType =3D value;=0A= }=0A= else if (name =3D=3D "left") {=0A= e.style.left =3D value;=0A= }=0A= else if (name =3D=3D "letter-spacing") {=0A= e.style.letterSpacing =3D value;=0A= }=0A= else if (name =3D=3D "line-break") {=0A= e.style.lineBreak =3D value;=0A= }=0A= else if (name =3D=3D "line-height") {=0A= e.style.lineHeight =3D value;=0A= }=0A= else if (name =3D=3D "list-style") {=0A= e.style.listStyle =3D value;=0A= }=0A= else if (name =3D=3D "list-style-image") {=0A= e.style.listStyleImage =3D value;=0A= }=0A= else if (name =3D=3D "list-style-position") {=0A= e.style.listStylePosition =3D value;=0A= }=0A= else if (name =3D=3D "list-style-type") {=0A= e.style.listStyleType =3D value;=0A= }=0A= else if (name =3D=3D "margin") {=0A= e.style.margin =3D value;=0A= }=0A= else if (name =3D=3D "margin-bottom") {=0A= e.style.marginBottom =3D value;=0A= }=0A= else if (name =3D=3D "margin-left") {=0A= e.style.marginLeft =3D value;=0A= }=0A= else if (name =3D=3D "margin-right") {=0A= e.style.marginRight =3D value;=0A= }=0A= else if (name =3D=3D "margin-top") {=0A= e.style.marginTop =3D value;=0A= }=0A= else if (name =3D=3D "min-height") {=0A= e.style.minHeight =3D value;=0A= }=0A= else if (name =3D=3D "overflow") {=0A= e.style.overflow =3D value;=0A= }=0A= else if (name =3D=3D "overflow-x") {=0A= e.style.overflowX =3D value;=0A= }=0A= else if (name =3D=3D "overflow-y") {=0A= e.style.overflowY =3D value;=0A= }=0A= else if (name =3D=3D "padding") {=0A= e.style.padding =3D value;=0A= }=0A= else if (name =3D=3D "padding-bottom") {=0A= e.style.paddingBottom =3D value;=0A= }=0A= else if (name =3D=3D "padding-left") {=0A= e.style.paddingLeft =3D value;=0A= }=0A= else if (name =3D=3D "padding-right") {=0A= e.style.paddingRight =3D value;=0A= }=0A= else if (name =3D=3D "padding-top") {=0A= e.style.paddingTop =3D value;=0A= }=0A= else if (name =3D=3D "page-break-after") {=0A= e.style.pageBreakAfter =3D value;=0A= }=0A= else if (name =3D=3D "page-break-before") {=0A= e.style.pageBreakBefore =3D value;=0A= }=0A= else if (name =3D=3D "pixelBottom") {=0A= e.style.pixelBottom =3D value;=0A= }=0A= else if (name =3D=3D "pixelHeight") {=0A= e.style.pixelHeight =3D value;=0A= }=0A= else if (name =3D=3D "pixelLeft") {=0A= e.style.pixelLeft =3D value;=0A= }=0A= else if (name =3D=3D "pixelRight") {=0A= e.style.pixelRight =3D value;=0A= }=0A= else if (name =3D=3D "pixelTop") {=0A= e.style.pixelTop =3D value;=0A= }=0A= else if (name =3D=3D "pixelWidth") {=0A= e.style.pixelWidth =3D value;=0A= }=0A= else if (name =3D=3D "posBottom") {=0A= e.style.posBottom =3D value;=0A= }=0A= else if (name =3D=3D "posHeight") {=0A= e.style.posHeight =3D value;=0A= }=0A= else if (name =3D=3D "position") {=0A= e.style.position =3D value;=0A= }=0A= else if (name =3D=3D "posLeft") {=0A= e.style.posLeft =3D value;=0A= }=0A= else if (name =3D=3D "posRight") {=0A= e.style.posRight =3D value;=0A= }=0A= else if (name =3D=3D "posTop") {=0A= e.style.posTop =3D value;=0A= }=0A= else if (name =3D=3D "posWidth") {=0A= e.style.posWidth =3D value;=0A= }=0A= else if (name =3D=3D "right") {=0A= e.style.right =3D value;=0A= }=0A= else if (name =3D=3D "ruby-align") {=0A= e.style.rubyAlign =3D value;=0A= }=0A= else if (name =3D=3D "ruby-overhang") {=0A= e.style.rubyOverhang =3D value;=0A= }=0A= else if (name =3D=3D "ruby-position") {=0A= e.style.rubyPosition =3D value;=0A= }=0A= else if (name =3D=3D "scrollbar-3dlight-color") {=0A= e.style.scrollbar3dLightColor =3D value;=0A= }=0A= else if (name =3D=3D "scrollbar-arrow-color") {=0A= e.style.scrollbarArrowColor =3D value;=0A= }=0A= else if (name =3D=3D "scrollbar-base-color") {=0A= e.style.scrollbarBaseColor =3D value;=0A= }=0A= else if (name =3D=3D "scrollbar-darkshadow-color") {=0A= e.style.scrollbarDarkShadowColor =3D value;=0A= }=0A= else if (name =3D=3D "scrollbar-face-color") {=0A= e.style.scrollbarFaceColor =3D value;=0A= }=0A= else if (name =3D=3D "scrollbar-highlight-color") {=0A= e.style.scrollbarHighlightColor =3D value;=0A= }=0A= else if (name =3D=3D "scrollbar-shadow-color") {=0A= e.style.scrollbarShadowColor =3D value;=0A= }=0A= else if (name =3D=3D "scrollbar-track-color") {=0A= e.style.scrollbarTrackColor =3D value;=0A= }=0A= else if (name =3D=3D "float") {=0A= e.style.styleFloat =3D value;=0A= }=0A= else if (name =3D=3D "table-layout") {=0A= e.style.tableLayout =3D value;=0A= }=0A= else if (name =3D=3D "text-align") {=0A= e.style.textAlign =3D value;=0A= }=0A= else if (name =3D=3D "text-align-last") {=0A= e.style.textAlignLast =3D value;=0A= }=0A= else if (name =3D=3D "text-autospace") {=0A= e.style.textAutospace =3D value;=0A= }=0A= else if (name =3D=3D "text-decoration") {=0A= e.style.textDecoration =3D value;=0A= }=0A= else if (name =3D=3D "textDecorationBlink") {=0A= e.style.textDecorationBlink =3D value;=0A= }=0A= else if (name =3D=3D "textDecorationLineThrough") {=0A= e.style.textDecorationLineThrough =3D value;=0A= }=0A= else if (name =3D=3D "textDecorationNone") {=0A= e.style.textDecorationNone =3D value;=0A= }=0A= else if (name =3D=3D "textDecorationOverline") {=0A= e.style.textDecorationOverline =3D value;=0A= }=0A= else if (name =3D=3D "textDecorationUnderline") {=0A= e.style.textDecorationUnderline =3D value;=0A= }=0A= else if (name =3D=3D "text-indent") {=0A= e.style.textIndent =3D value;=0A= }=0A= else if (name =3D=3D "text-justify") {=0A= e.style.textJustify =3D value;=0A= }=0A= else if (name =3D=3D "text-kashida-space") {=0A= e.style.textKashidaSpace =3D value;=0A= }=0A= else if (name =3D=3D "text-overflow") {=0A= e.style.textOverflow =3D value;=0A= }=0A= else if (name =3D=3D "text-transform") {=0A= e.style.textTransform =3D value;=0A= }=0A= else if (name =3D=3D "text-underline-position") {=0A= e.style.textUnderlinePosition =3D value;=0A= }=0A= else if (name =3D=3D "top") {=0A= e.style.top =3D value;=0A= }=0A= else if (name =3D=3D "unicode-bidi") {=0A= e.style.unicodeBidi =3D value;=0A= }=0A= else if (name =3D=3D "vertical-align") {=0A= e.style.verticalAlign =3D value;=0A= }=0A= else if (name =3D=3D "visibility") {=0A= e.style.visibility =3D value;=0A= }=0A= else if (name =3D=3D "white-space") {=0A= e.style.whiteSpace =3D value;=0A= }=0A= else if (name =3D=3D "width") {=0A= e.style.width =3D value;=0A= }=0A= else if (name =3D=3D "word-break") {=0A= e.style.wordBreak =3D value;=0A= }=0A= else if (name =3D=3D "word-spacing") {=0A= e.style.wordSpacing =3D value;=0A= }=0A= else if (name =3D=3D "word-wrap") {=0A= e.style.wordWrap =3D value;=0A= }=0A= else if (name =3D=3D "writing-mode") {=0A= e.style.writingMode =3D value;=0A= }=0A= else if (name =3D=3D "z-index") {=0A= e.style.zIndex =3D value;=0A= }=0A= else if (name =3D=3D "zoom") {=0A= e.style.zoom =3D value;=0A= }=0A= }=0A= catch (e) {=0A= /* ignore error on attempt to set e.style.[property] */=0A= }=0A= }=0A= }=0A= }=0A= ------=_NextPart_000_0068_01C7D67A.31C69300 Content-Type: application/octet-stream Content-Transfer-Encoding: quoted-printable Content-Location: http://www.chestjournal.org/javascript/entrez/callback.js /************************************************************************= *****=0A= * javascript/entrez/callback.js=0A= *=0A= * Entrez Linking callback to populate content box.=0A= *=0A= * Copyright 2006 Board of Trustees of the Leland Stanford Junior = University.=0A= = *************************************************************************= ***/=0A= =0A= /*=0A= * Execute callback to fill content box with Entrez Linking information.=0A= */=0A= function entrez_callback(pmid, callback_url) {=0A= /*=0A= * MSIE 5.5 and below have issues with the JavaScript=0A= * used for Entrez Linking. For now we have to disable=0A= * the callback until we can track down a proper fix=0A= * (or everybody sanely upgrades to version 6 or 7!).=0A= */=0A= if (navigator) {=0A= var appname =3D navigator.appName;=0A= if (appname =3D=3D "Microsoft Internet Explorer") {=0A= var userAgent =3D navigator["userAgent"];=0A= var s =3D "MSIE ";=0A= var n =3D -1; =0A= if ((n =3D userAgent.indexOf(s)) !=3D -1) {=0A= var v =3D parseFloat(userAgent.substring(n+s.length));=0A= if (v < 6) {=0A= return;=0A= }=0A= }=0A= }=0A= }=0A= =0A= /*=0A= * Acquire table row element to update, initiate callback=0A= * to update table with Entrez Links.=0A= */=0A= var tr =3D document.getElementById('entrez_callback_'+pmid);=0A= if (!tr) {=0A= return;=0A= }=0A= var req =3D new XMLHttpRequest();=0A= if (!req) {=0A= return;=0A= }=0A= req.onreadystatechange =3D function() {=0A= if (req.readyState =3D=3D 4 && (req.status =3D=3D 200 || req.status = =3D=3D 304)) {=0A= var src =3D req.responseXML.documentElement;=0A= var dst =3D document.createDocumentFragment();=0A= for (var i =3D 0; i < src.childNodes.length; i++) {=0A= copy_xml_to_html(src.childNodes[i], dst);=0A= }=0A= var tbl =3D tr.parentNode;=0A= tbl.replaceChild(dst, tr);=0A= }=0A= }=0A= req.open('GET', callback_url, true);=0A= req.send(null);=0A= }=0A= ------=_NextPart_000_0068_01C7D67A.31C69300 Content-Type: application/octet-stream Content-Transfer-Encoding: quoted-printable Content-Location: http://www.google-analytics.com/urchin.js //-- Google Analytics Urchin Module=0A= //-- Copyright 2007 Google, All Rights Reserved.=0A= =0A= //-- Urchin On Demand Settings ONLY=0A= var _uacct=3D""; // set up the Urchin Account=0A= var _userv=3D1; // service mode (0=3Dlocal,1=3Dremote,2=3Dboth)=0A= =0A= //-- UTM User Settings=0A= var _ufsc=3D1; // set client info flag (1=3Don|0=3Doff)=0A= var _udn=3D"auto"; // (auto|none|domain) set the domain name for cookies=0A= var _uhash=3D"on"; // (on|off) unique domain hash for cookies=0A= var _utimeout=3D"1800"; // set the inactive session timeout in seconds=0A= var _ugifpath=3D"/__utm.gif"; // set the web path to the __utm.gif file=0A= var _utsp=3D"|"; // transaction field separator=0A= var _uflash=3D1; // set flash version detect option (1=3Don|0=3Doff)=0A= var _utitle=3D1; // set the document title detect option = (1=3Don|0=3Doff)=0A= var _ulink=3D0; // enable linker functionality (1=3Don|0=3Doff)=0A= var _uanchor=3D0; // enable use of anchors for campaign = (1=3Don|0=3Doff)=0A= var _utcp=3D"/"; // the cookie path for tracking=0A= var _usample=3D100; // The sampling % of visitors to track (1-100).=0A= =0A= //-- UTM Campaign Tracking Settings=0A= var _uctm=3D1; // set campaign tracking module (1=3Don|0=3Doff)=0A= var _ucto=3D"15768000"; // set timeout in seconds (6 month default)=0A= var _uccn=3D"utm_campaign"; // name=0A= var _ucmd=3D"utm_medium"; // medium (cpc|cpm|link|email|organic)=0A= var _ucsr=3D"utm_source"; // source=0A= var _uctr=3D"utm_term"; // term/keyword=0A= var _ucct=3D"utm_content"; // content=0A= var _ucid=3D"utm_id"; // id number=0A= var _ucno=3D"utm_nooverride"; 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path=3D"+_utcp+";"+nx+_udo;=0A= _ubd.cookie=3D"__utmb=3D"+_udh+"; path=3D"+_utcp+";"+x+_udo;=0A= _ubd.cookie=3D"__utmc=3D"+_udh+"; path=3D"+_utcp+";"+_udo;=0A= _ufns=3D1;=0A= } else if (a>=3D0 && b>=3D0 && c>=3D0) {=0A= _ubd.cookie=3D"__utmb=3D"+_udh+"; path=3D"+_utcp+";"+x+_udo;=0A= } else {=0A= if (a>=3D0) a=3D_uFixA(_ubd.cookie,";",_ust);=0A= else a=3D_udh+"."+_uu+"."+_ust+"."+_ust+"."+_ust+".1";=0A= _ubd.cookie=3D"__utma=3D"+a+"; path=3D"+_utcp+";"+nx+_udo;=0A= _ubd.cookie=3D"__utmb=3D"+_udh+"; path=3D"+_utcp+";"+x+_udo;=0A= _ubd.cookie=3D"__utmc=3D"+_udh+"; path=3D"+_utcp+";"+_udo;=0A= _ufns=3D1;=0A= }=0A= if (_ulink && xx && xx!=3D"" && xx!=3D"-") {=0A= xx=3D_uUES(xx);=0A= if (xx.indexOf(";")=3D=3D-1) _ubd.cookie=3D"__utmx=3D"+xx+"; = path=3D"+_utcp+";"+nx+_udo;=0A= }=0A= if (_ulink && v && v!=3D"" && v!=3D"-") {=0A= v=3D_uUES(v);=0A= if (v.indexOf(";")=3D=3D-1) _ubd.cookie=3D"__utmv=3D"+v+"; = path=3D"+_utcp+";"+nx+_udo;=0A= }=0A= _uInfo(page);=0A= _ufns=3D0;=0A= _ufno=3D0;=0A= if (!page || page=3D=3D"") _uff=3D1;=0A= }=0A= function _uInfo(page) {=0A= var p,s=3D"",dm=3D"",pg=3D_udl.pathname+_udl.search;=0A= if (page && page!=3D"") pg=3D_uES(page,1);=0A= _ur=3D_ubd.referrer;=0A= if (!_ur || _ur=3D=3D"") { _ur=3D"-"; 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