[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 =