var title_f6_11_6320="ACP algorithm management low or intermediate risk patients";

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" &copy;2013 UpToDate",
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" American College of Physicians algorithm for the risk assessment and managment
of patients at low or intermediate risk for perioperative cardiac events
(myocardial infarction and death)",
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" </div>",
" <div class=\"lgnd\">",
" Boxed phrases indicate recommended actions.",
" <br>",
" The green bolded words beside the boxes indicate the level of evidence
supporting the recommendation. If no green bolded word is present, no evidence
exists for or against use.",
" <div class=\"footnotes\">",
" DTI: dipyridamole thallium imaging; DSE: dobutamine stress
echocardiography.",
" </div>",
" <div class=\"reference\">",
" Reproduced with permission from Palda, et al. Ann Intern Med 1997; 127:309.
Copyright &copy; 1997 American College of Physicians.",
" </div>",
" </br>",
" </div>",
" </div>",
" </div>",
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",
" </div>",
" <div class=\"lgnd\">",
" Distended fetal bladder in the recipient fetus is noted at approximately 21.5
weeks of gestation.",
" <div class=\"footnotes\">",
" </div>",
" <div class=\"reference\">",
" Courtesy of Kenneth J Moise, Jr, MD &amp; Anthony Johnson, DO.",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
var script_f6_11_6321=[""].join("\n");
var outline_f6_11_6321=null;
var title_f6_11_6322="Echocardiogram apical 4-chamber in ARVC";
var content_f6_11_6322=[" <div id=\"graphicsToolbar\">",
" <div id=\"graphicsCopy\">",
" &copy;2013 UpToDate",
" ^{",
" &reg;",
"}",
" </div>",
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%2F61638&amp;source=image_view&amp;view=print&amp;elapsedTimeMs=2\" onclick=\"\">",
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" </a>",
" <a class=\"icontxt textLink\" href=\"?imageKey=CARD
%2F61638&amp;source=image_view&amp;view=print&amp;elapsedTimeMs=2\" onclick=\"\"
title=\"Print this page\">",
" Print",
" </a>",
" <a class=\"etacLink\" href=\"#\">",
" <img alt=\"Email graphic(s)\" src=\"./../images/icn_email.myextg\"
title=\"Email graphic(s)\"/>",
" </a>",
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" Email",
" </a>",
" </div>",
" </div>",
" <div class=\"graphic\">",
" <div class=\"figure\" style=\"width: 470px\">",
" <div class=\"ttl\">",
" Echocardiogram apical 4-chamber showing right ventricular enlargement and
aneurysms in arrhythmogenic right ventricular cardiomyopathy (ARVC)",
" </div>",
" <div class=\"cntnt\" style=\"width: 271px; height: 349px; background-image:
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">",
" </div>",
" <div class=\"lgnd\">",
" The apical four chamber view shows marked dilatation of the right ventricle;
the moderator band (septal marginal trabeculation) in the apex of the RV is
enlarged with complex attachments to the septum and free wall.",
" <div class=\"footnotes\">",
" LV: left ventricle; RA: right atrium.",
" </div>",
" <div class=\"reference\">",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
var script_f6_11_6322=[""].join("\n");
var outline_f6_11_6322=null;
var title_f6_11_6323="Chromosomal recombination";
var content_f6_11_6323=[" <div id=\"graphicsToolbar\">",
" <div id=\"graphicsCopy\">",
" &copy;2013 UpToDate",
" ^{",
" &reg;",
"}",
" </div>",
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" <a href=\"?imageKey=PC
%2F59656&amp;source=image_view&amp;view=print&amp;elapsedTimeMs=1\" onclick=\"\">",
" <img alt=\"Print this page\" src=\"./../images/icn_print.myextg\"
title=\"Print this page\"/>",
" </a>",
" <a class=\"icontxt textLink\" href=\"?imageKey=PC
%2F59656&amp;source=image_view&amp;view=print&amp;elapsedTimeMs=1\" onclick=\"\"
title=\"Print this page\">",
" Print",
" </a>",
" <a class=\"etacLink\" href=\"#\">",
" <img alt=\"Email graphic(s)\" src=\"./../images/icn_email.myextg\"
title=\"Email graphic(s)\"/>",
" </a>",
" <a class=\"icontxt textLink etacLink\" href=\"#\" title=\"Email graphic(s)\">",
" Email",
" </a>",
" </div>",
" </div>",
" <div class=\"graphic\">",
" <div class=\"figure\" style=\"width: 495px\">",
" <div class=\"ttl\">",
" Chromosomal recombination",
" </div>",
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" </div>",
" <div class=\"lgnd\">",
" <div class=\"footnotes\">",
" </div>",
" <div class=\"reference\">",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
var script_f6_11_6323=[""].join("\n");
var outline_f6_11_6323=null;
var title_f6_11_6324="Motor unit";
var content_f6_11_6324=[" <div id=\"graphicsToolbar\">",
" <div id=\"graphicsCopy\">",
" &copy;2013 UpToDate",
" ^{",
" &reg;",
"}",
" </div>",
" <div id=\"graphicsLinks\">",
" <a href=\"?imageKey=NEURO
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" <img alt=\"Print this page\" src=\"./../images/icn_print.myextg\"
title=\"Print this page\"/>",
" </a>",
" <a class=\"icontxt textLink\" href=\"?imageKey=NEURO
%2F60675&amp;source=image_view&amp;view=print&amp;elapsedTimeMs=1\" onclick=\"\"
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" Print",
" </a>",
" <a class=\"etacLink\" href=\"#\">",
" <img alt=\"Email graphic(s)\" src=\"./../images/icn_email.myextg\"
title=\"Email graphic(s)\"/>",
" </a>",
" <a class=\"icontxt textLink etacLink\" href=\"#\" title=\"Email graphic(s)\">",
" Email",
" </a>",
" </div>",
" </div>",
" <div class=\"graphic\">",
" <div class=\"figure\" style=\"width: 555px\">",
" <div class=\"ttl\">",
" The motor unit",
" </div>",
" <div class=\"cntnt\" style=\"width: 535px; height: 478px; background-image:
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" </div>",
" <div class=\"lgnd\">",
" <div class=\"footnotes\">",
" </div>",
" <div class=\"reference\">",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
var script_f6_11_6324=[""].join("\n");
var outline_f6_11_6324=null;
var title_f6_11_6325="Oral lichen planus - lower lip";
var content_f6_11_6325=[" <div id=\"graphicsToolbar\">",
" <div id=\"graphicsCopy\">",
" &copy;2013 UpToDate",
" ^{",
" &reg;",
"}",
" </div>",
" <div id=\"graphicsLinks\">",
" <a href=\"?imageKey=DERM
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title=\"Print this page\"/>",
" </a>",
" <a class=\"icontxt textLink\" href=\"?imageKey=DERM
%2F86886&amp;source=image_view&amp;view=print&amp;elapsedTimeMs=1\" onclick=\"\"
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" </a>",
" <a class=\"etacLink\" href=\"#\">",
" <img alt=\"Email graphic(s)\" src=\"./../images/icn_email.myextg\"
title=\"Email graphic(s)\"/>",
" </a>",
" <a class=\"icontxt textLink etacLink\" href=\"#\" title=\"Email graphic(s)\">",
" Email",
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" </div>",
" </div>",
" <div class=\"graphic\">",
" <div class=\"figure\" style=\"width: 524px\">",
" <div class=\"ttl\">",
" Oral lichen planus",
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" </div>",
" <div class=\"lgnd\">",
" A reticular white plaque is present on the lower lip.",
" <div class=\"footnotes\">",
" </div>",
" <div class=\"reference\">",
" Reproduced with permission from: www.visualdx.com. Copyright Logical Images,
Inc.",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
var script_f6_11_6325=[""].join("\n");
var outline_f6_11_6325=null;
var title_f6_11_6326="Diltiazem: Patient drug information";
var content_f6_11_6326=[" <noscript>",
" <div id=\"javascriptDisabled\">",
" It seems to us that you have your JavaScript turned off on your browser.
JavaScript is required in order for our site to behave correctly. Please enable
your JavaScript to continue use our site.",
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" <div id=\"printHeaderLogo\">",
" <img alt=\"UpToDate\" src=\"./../images/UTD2_masthead.myextg\">",
" <img align=\"right\" alt=\"Wolters Kluwer Health\" height=\"40\"
src=\"./../images/logoWKH.myextg\" width=\"175\">",
" <br>",
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" Official reprint from UpToDate",
" ^{",
" &reg;",
"}",
" <br>",
" <a href=\"file://www.uptodate.com\">",
" www.uptodate.com",
" </a>",
" &copy;2013 UpToDate",
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" <div id=\"printHeaderLinks\">",
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here to print\">",
" Print",
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" |",
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" Back",
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" <!-- TC:TOPIC_PAGE -->",
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" <div id=\"disclaimer\">",
" The content on the UpToDate website is not intended nor recommended as a
substitute",
"for medical advice, diagnosis, or treatment. Always seek the advice of your own
physician or",
"other qualified health care professional regarding any medical questions or
conditions. The",
"use of this website is governed by the",
" <a href=\"/home/terms-use\" target=\"_blank\">",
" UpToDate Terms of Use",
" </a>",
" &copy;2013 UpToDate, Inc.",
" </div>",
" <div id=\"drugTitle\">",
" Diltiazem: Patient drug information",
" </div>",
" <div id=\"lexiTitleImg\">",
" <img height=\"17\" src=\"./../images/lexiComp/Lexicomp_2012_71x17.myextg\"
width=\"71\"/>",
" </div>",
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" </div>",
" <div id=\"drugCopy\">",
" Copyright 1978-2013 Lexicomp, Inc. All rights reserved.",
" </div>",
" <div id=\"topicText\">",
" <p>",
" (For additional information",
" <a class=\"drug drug_general\" href=\"UTD.htm?12/16/12554?source=see_link\">",
" see \"Diltiazem: Drug information\"",
" </a>",
" and",
" <a class=\"drug drug_pediatric\" href=\"UTD.htm?16/14/16617?
source=see_link\">",
" see \"Diltiazem: Pediatric drug information\"",
" </a>",
" )",
" </p>",
" <div class=\"list ubnlist drugH1Div drugBrandNames\" id=\"F160657\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" Brand Names: U.S.",
" </span>",
" <ul>",
" <li>",
" Cardizem&reg;;",
" </li>",
" <li>",
" Cardizem&reg; CD;",
" </li>",
" <li>",
" Cardizem&reg; LA;",
" </li>",
" <li>",
" Cartia XT&reg;;",
" </li>",
" <li>",
" Dilacor XR&reg;;",
" </li>",
" <li>",
" Dilt-CD;",
" </li>",
" <li>",
" Dilt-XR;",
" </li>",
" <li>",
" Diltia XT&reg;;",
" </li>",
" <li>",
" Diltzac;",
" </li>",
" <li>",
" Matzim&reg; LA;",
" </li>",
" <li>",
" Taztia XT&reg;;",
" </li>",
" <li>",
" Tiazac&reg;",
" </li>",
" </ul>",
" </div>",
" <div class=\"list cbnlist drugH1Div drugBrandNames\" id=\"F160658\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" Brand Names: Canada",
" </span>",
" <ul>",
" <li>",
" Apo-Diltiaz CD&reg;;",
" </li>",
" <li>",
" Apo-Diltiaz SR&reg;;",
" </li>",
" <li>",
" Apo-Diltiaz TZ&reg;;",
" </li>",
" <li>",
" Apo-Diltiaz&reg;;",
" </li>",
" <li>",
" Apo-Diltiaz&reg; Injectable;",
" </li>",
" <li>",
" Ava-Diltiazem;",
" </li>",
" <li>",
" Cardizem&reg; CD;",
" </li>",
" <li>",
" CO Diltiazem CD;",
" </li>",
" <li>",
" CO Diltiazem T;",
" </li>",
" <li>",
" Diltiazem HCl ER&reg;;",
" </li>",
" <li>",
" Diltiazem Hydrochloride Injection;",
" </li>",
" <li>",
" Diltiazem TZ;",
" </li>",
" <li>",
" Diltiazem-CD;",
" </li>",
" <li>",
" Nu-Diltiaz;",
" </li>",
" <li>",
" Nu-Diltiaz-CD;",
" </li>",
" <li>",
" PMS-Diltiazem CD;",
" </li>",
" <li>",
" ratio-Diltiazem CD;",
" </li>",
" <li>",
" Sandoz-Diltiazem CD;",
" </li>",
" <li>",
" Sandoz-Diltiazem T;",
" </li>",
" <li>",
" Teva-Diltiazem;",
" </li>",
" <li>",
" Teva-Diltiazem CD;",
" </li>",
" <li>",
" Teva-Diltiazem HCL ER Capsules;",
" </li>",
" <li>",
" Tiazac&reg;;",
" </li>",
" <li>",
" Tiazac&reg; XC",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt war-os drugH1Div\" id=\"F10017597\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" Warning",
" </span>",
" <ul class=\"statements\" style=\"list-style-type:none;\">",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2700602",
" </span>",
" </span>",
" <span class=\"content\">",
" Sometimes drugs are not safe when you take them with certain other drugs.
Taking them together can cause bad side effects. This is one of those drugs. Be
sure to talk to your doctor about all the drugs you take.",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt yya-os drugH1Div\" id=\"F10017599\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" What is this drug used for?",
" </span>",
" <ul class=\"statements\" style=\"list-style-type:none;\">",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2691662",
" </span>",
" </span>",
" <span class=\"content\">",
" It is used to treat a fast heartbeat.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2691785",
" </span>",
" </span>",
" <span class=\"content\">",
" It is used to treat chest pain or pressure.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2691888",
" </span>",
" </span>",
" <span class=\"content\">",
" It is used to treat high blood pressure.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2691913",
" </span>",
" </span>",
" <span class=\"content\">",
" It is used to treat involuntary body movements.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2692038",
" </span>",
" </span>",
" <span class=\"content\">",
" It is used to treat Raynaud's disease.",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt coi-os drugH1Div\" id=\"F10017598\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" What do I need to tell my doctor before I take this drug?",
" </span>",
" <ul class=\"statements\" style=\"list-style-type:none;\">",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2701955",
" </span>",
" </span>",
" <span class=\"content\">",
" If you have an allergy to diltiazem or any other part of this drug.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2705171",
" </span>",
" </span>",
" <span class=\"content\">",
" If you are allergic to any drugs, foods, or other substances. Tell your
doctor about the allergy and what signs you had, like rash; hives; itching;
shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or
any other signs.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2703677",
" </span>",
" </span>",
" <span class=\"content\">",
" If you have any of these health problems: Low blood pressure, poor
electrical activity in the heart without a working pacemaker, or very weak heart.",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt yye-os drugH1Div\" id=\"F10017603\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" What are some things I need to know or do while I take this drug?",
" </span>",
" <ul class=\"statements\" style=\"list-style-type:none;\">",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2697780",
" </span>",
" </span>",
" <span class=\"content\">",
" Wear disease medical alert ID (identification).",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2696820",
" </span>",
" </span>",
" <span class=\"content\">",
" Do not run out of this drug.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2697148",
" </span>",
" </span>",
" <span class=\"content\">",
" If you have a weak heart, talk with your doctor.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2698416",
" </span>",
" </span>",
" <span class=\"content\">",
" Have your blood pressure and heart rate checked often. Talk with your
doctor.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2696717",
" </span>",
" </span>",
" <span class=\"content\">",
" Check all drugs you are taking with your doctor. This drug may not mix well
with some other drugs.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2699677",
" </span>",
" </span>",
" <span class=\"content\">",
" Keep a list of all your drugs (prescription, natural products, vitamins,
OTC) with you. Give this list to your doctor.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2697111",
" </span>",
" </span>",
" <span class=\"content\">",
" If you are taking this drug and have high blood pressure, talk with your
doctor before using OTC products that may raise blood pressure. These include cough
or cold drugs, diet pills, stimulants, ibuprofen or like products, and some natural
products or aids.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2697562",
" </span>",
" </span>",
" <span class=\"content\">",
" Limit your drinking of wine, beer, or mixed drinks.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s4128402",
" </span>",
" </span>",
" <span class=\"content\">",
" If you drink grapefruit juice or eat grapefruit often, talk with your
doctor.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2698562",
" </span>",
" </span>",
" <span class=\"content\">",
" Take good care of your teeth. See a dentist often.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2697641",
" </span>",
" </span>",
" <span class=\"content\">",
" Tell your doctor if you are pregnant or plan on getting pregnant. You will
need to talk about the benefits and risks of using this drug while you are
pregnant.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2697636",
" </span>",
" </span>",
" <span class=\"content\">",
" Tell your doctor if you are breast-feeding. You will need to talk about any
risks to your baby.",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt yyf-os drugH1Div\" id=\"F10017604\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" What are some side effects of this drug?",
" </span>",
" <ul class=\"statements\" style=\"list-style-type:none;\">",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2698051",
" </span>",
" </span>",
" <span class=\"content\">",
" Feeling dizzy. Rise slowly over a few minutes when sitting or lying down.
Be careful climbing.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2698119",
" </span>",
" </span>",
" <span class=\"content\">",
" Headache.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2698272",
" </span>",
" </span>",
" <span class=\"content\">",
" Upset stomach or throwing up. Many small meals, good mouth care, sucking
hard, sugar-free candy, or chewing sugar-free gum may help.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2697978",
" </span>",
" </span>",
" <span class=\"content\">",
" Hard stools (constipation). Drinking more liquids, working out, or adding
fiber to your diet may help. Talk with your doctor about a stool softener or
laxative.",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt yyh-os drugH1Div\" id=\"F10017606\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" What are some side effects that I need to call my doctor about right away?",
" </span>",
" <ul class=\"statements\" style=\"list-style-type:none;\">",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2698721",
" </span>",
" </span>",
" <span class=\"content\">",
" If you think there has been an overdose, call 1-800-222-1222 (the American
Association of Poison Control Centers), your local poison control center
(file://www.aapcc.org), or emergency room (ER) right away.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2699066",
" </span>",
" </span>",
" <span class=\"content\">",
" Signs of an allergic reaction, like rash; hives; itching; red, swollen,
blistered, or peeling skin with or without fever; wheezing; tightness in the chest
or throat; trouble breathing or talking; unusual hoarseness; or swelling of the
mouth, face, lips, tongue, or throat.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2698655",
" </span>",
" </span>",
" <span class=\"content\">",
" A fast heartbeat.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2699023",
" </span>",
" </span>",
" <span class=\"content\">",
" Very bad dizziness or passing out.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2698640",
" </span>",
" </span>",
" <span class=\"content\">",
" Trouble breathing.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2699031",
" </span>",
" </span>",
" <span class=\"content\">",
" Very bad headache.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2698658",
" </span>",
" </span>",
" <span class=\"content\">",
" Feeling very tired or weak.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2698603",
" </span>",
" </span>",
" <span class=\"content\">",
" Any rash.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2698977",
" </span>",
" </span>",
" <span class=\"content\">",
" Side effect or health problem is not better or you are feeling worse.",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt yyc-os drugH1Div\" id=\"F10017601\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" How is this drug best taken?",
" </span>",
" <ul class=\"statements\" style=\"list-style-type:none;\">",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2694865",
" </span>",
" </span>",
" <span class=\"content\">",
" Follow the diet and workout plan that your doctor told you about.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2695786",
" </span>",
" </span>",
" <span class=\"content\">",
" Take as you have been told, even if you feel well.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2694329",
" </span>",
" </span>",
" <span class=\"content\">",
" There is a liquid (suspension) if you cannot swallow pills. Shake well
before use.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2696107",
" </span>",
" </span>",
" <span class=\"content\">",
" Those who have feeding tubes may also use the liquid. Flush the feeding
tube before and after this drug is given.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"link\">",
" urn:lims:b498:s2705419",
" </span>",
" </span>",
" <span class=\"content\">",
" <b>",
" <span style=\"text-decoration: underline\">",
" Fast release:",
" </span>",
" </b>",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2695829",
" </span>",
" </span>",
" <span class=\"content\">",
" Take 30 minutes before meals and at bedtime.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"link\">",
" urn:lims:b498:s2696422",
" </span>",
" </span>",
" <span class=\"content\">",
" <b>",
" <span style=\"text-decoration: underline\">",
" Long-acting products:",
" </span>",
" </b>",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2695714",
" </span>",
" </span>",
" <span class=\"content\">",
" Swallow whole. Do not chew, break, or crush.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2694651",
" </span>",
" </span>",
" <span class=\"content\">",
" Dilacor XR&reg;, Dilt-XR, and Diltia XT&reg;: Take on an empty stomach.
Take 1 hour before or 2 hours after meals.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2694579",
" </span>",
" </span>",
" <span class=\"content\">",
" Cardizem&reg; CD, Cardizem&reg; LA, Cartia XT&reg;, Dilt-CD, and
Matzim&trade; LA: Take with or without food. Take with food if it causes an upset
stomach.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2696120",
" </span>",
" </span>",
" <span class=\"content\">",
" Tiazac&reg; and Taztia XT&reg;: You may sprinkle contents of capsule on
soft food or liquid. Do not chew.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"link\">",
" urn:lims:b498:s2705429",
" </span>",
" </span>",
" <span class=\"content\">",
" <b>",
" <span style=\"text-decoration: underline\">",
" Shot:",
" </span>",
" </b>",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2696019",
" </span>",
" </span>",
" <span class=\"content\">",
" It is given into a vein for a period of time.",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt yyd-os drugH1Div\" id=\"F10017602\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" What do I do if I miss a dose?",
" </span>",
" <ul class=\"statements\" style=\"list-style-type:none;\">",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2696563",
" </span>",
" </span>",
" <span class=\"content\">",
" Take a missed dose as soon as you think about it.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2696496",
" </span>",
" </span>",
" <span class=\"content\">",
" If it is close to the time for your next dose, skip the missed dose and go
back to your normal time.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2696475",
" </span>",
" </span>",
" <span class=\"content\">",
" Do not take 2 doses at the same time or extra doses.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2696457",
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var title_f6_11_6327="Malaria trophozoites";
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" </div>",
" <div class=\"lgnd\">",
" Peripheral smear from a patient with malaria shows intraerythrocytic ring
forms (trophozoites) (arrows).",
" <div class=\"footnotes\">",
" </div>",
" <div class=\"reference\">",
" Courtesy of Carola von Kapff, SH (ASCP).",
" </div>",
" </div>",
" </div>",
" <div class=\"figure\" style=\"width: 450px\">",
" <div class=\"ttl\">",
" Normal peripheral blood smear",
" </div>",
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>",
" </div>",
" <div class=\"lgnd\">",
" High power view of a normal peripheral blood smear. Several platelets (black
arrows) and a normal lymphocyte (blue arrow) can also be seen. The red cells are of
relatively uniform size and shape. The diameter of the normal red cell should
approximate that of the nucleus of the small lymphocyte; central pallor (red arrow)
should equal one-third of its diameter.",
" <div class=\"footnotes\">",
" </div>",
" <div class=\"reference\">",
" Courtesy of Carola von Kapff, SH (ASCP).",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
var script_f6_11_6327=[""].join("\n");
var outline_f6_11_6327=null;
var title_f6_11_6328="Clinical features and electrodiagnosis of neonatal seizures";
var content_f6_11_6328=[" <noscript>",
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" <div id=\"topicContent\">",
" <div id=\"topicTitle\">",
" Clinical features and electrodiagnosis of neonatal seizures",
" </div>",
" <div id=\"topicContributors\">",
" <div>",
" <a id=\"authors\">",
" </a>",
" <a class=\"contributor contributor_credentials contributorType\"
href=\"UTD.htm?6/11/6328/contributors\">",
" Author",
" </a>",
" <br/>",
" <a class=\"contributor contributor_credentials\" href=\"UTD.htm?
6/11/6328/contributors\">",
" Eli M Mizrahi, MD",
" </a>",
" <br/>",
" </div>",
" <div>",
" <a class=\"contributor contributor_credentials contributorType\"
href=\"UTD.htm?6/11/6328/contributors\">",
" Section Editors",
" </a>",
" <br/>",
" <a class=\"contributor contributor_credentials\" href=\"UTD.htm?
6/11/6328/contributors\">",
" Douglas R Nordli, Jr, MD",
" </a>",
" <br/>",
" <a class=\"contributor contributor_credentials\" href=\"UTD.htm?
6/11/6328/contributors\">",
" Joseph A Garcia-Prats, MD",
" </a>",
" <br/>",
" </div>",
" <div>",
" <a class=\"contributor contributor_credentials contributorType\"
href=\"UTD.htm?6/11/6328/contributors\">",
" Deputy Editor",
" </a>",
" <br/>",
" <a class=\"contributor contributor_credentials\" href=\"UTD.htm?
6/11/6328/contributors\">",
" April F Eichler, MD, MPH",
" </a>",
" <br/>",
" </div>",
" </div>",
" <div id=\"disclosures\">",
" <a href=\"UTD.htm?6/11/6328/contributor-disclosure\" target=\"_blank\">",
" Disclosures",
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" All topics are updated as new evidence becomes available and our",
" </span>",
" <a href=\"/home/editorial-policy\" target=\"_blank\">",
" peer review process",
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" is complete.",
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" <div id=\"literatureReviewDate\">",
" <span class=\"emphasis\">",
" Literature review current through:",
" </span>",
" Oct 2013.",
" <span class=\"pipeSpace\">",
" |",
" </span>",
" <span class=\"emphasis\">",
" This topic last updated:",
" </span>",
" Sep 6, 2012.",
" </div>",
" <div id=\"topicText\">",
" <p class=\"headingAnchor\" id=\"H1\">",
" <span class=\"h1\">",
" INTRODUCTION",
" </span>",
" &nbsp;&mdash;&nbsp;The occurrence of neonatal seizures may be the first, and
perhaps the only, clinical sign of a central nervous system (CNS) disorder in the
newborn infant. As such, seizures may indicate the presence of a potentially
treatable etiology and should prompt an immediate evaluation to determine cause and
to institute etiology-specific therapy. In addition, seizures themselves may
require emergent therapy, since they may adversely affect the infant's homeostasis
or they can contribute to further brain injury. Some types of neonatal seizures are
associated with a relatively high incidence of early death and, in survivors, a
high incidence of neurologic impairment, developmental delay, and postneonatal
epilepsy.",
" </p>",
" <p>",
" The clinical diagnosis, characterization, and classification of neonatal
seizures and the use of electroencephalography in clinical management will be
reviewed here.",
" </p>",
" <p>",
" The etiology of neonatal seizures and associated epileptic syndromes are
discussed separately; therapy and prognosis of neonatal seizures are also discussed
separately. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?40/23/41335?
source=see_link\">",
" \"Etiology and prognosis of neonatal seizures\"",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?34/60/35783?
source=see_link\">",
" \"Neonatal epileptic syndromes\"",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?0/0/13?source=see_link\">",
" \"Treatment of neonatal seizures\"",
" </a>",
" .)",
" </p>",
" <p>",
" The clinical features and the evaluation of seizures in older infants and
children are likewise discussed elsewhere. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?14/4/14409?
source=see_link\">",
" \"Clinical and laboratory diagnosis of seizures in infants and children\"",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?28/31/29175?
source=see_link\">",
" \"Nonepileptic paroxysmal disorders in children\"",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H2\">",
" <span class=\"h1\">",
" APPROACH TO DIAGNOSIS",
" </span>",
" &nbsp;&mdash;&nbsp;The effective diagnosis and management of neonatal seizures
is best accomplished with an orderly approach to each individual infant suspected
of having seizures. This begins with an understanding of the clinical problems
associated with neonatal seizures. In addition, it is important to recognize the
risk factors that may predispose a newborn to seizures and increase clinical
suspicion of seizure hazard.",
" </p>",
" <p>",
" Clinical recognition of seizures and their accurate classification are
critical. Once an infant is identified as experiencing seizures, the basic concerns
of airway protection, access to cardiovascular circulation, and maintenance of
metabolic needs must be addressed.",
" </p>",
" <p>",
" Detailed characterization and classification of seizures is important to
secure a diagnosis, and can occur only if seizures are witnessed and accurately
reported. Once seizures are accurately diagnosed, assessment for etiology can
proceed with the goal of determining potentially treatable causes of seizures and
rapid institution of etiology-specific therapy. Accurate diagnosis is also the
basis for acute administration of antiepileptic drugs (AEDs).",
" </p>",
" <p class=\"headingAnchor\" id=\"H3\">",
" <span class=\"h1\">",
" EPIDEMIOLOGY",
" </span>",
" &nbsp;&mdash;&nbsp;Seizures occur more often in the neonatal period than at
any other time of life; during this period, they most often occur within the first
week of life [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6328/abstract/1,2\">",
" 1,2",
" </a>",
" ]. Reported incidence ranges from 1.5 to 5.5 per 1000 newborns [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6328/abstract/2-4\">",
" 2-4",
" </a>",
" ]. Seizure incidence varies with some specific risk factors. Occurrence
increases with decreasing gestational age and birth weight, and with increasing
acuity of illness [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6328/abstract/2,5,6\">",
" 2,5,6",
" </a>",
" ].",
" </p>",
" <p class=\"headingAnchor\" id=\"H4\">",
" <span class=\"h1\">",
" CHARACTERIZATION OF SEIZURES",
" </span>",
" &nbsp;&mdash;&nbsp;The cornerstone of the diagnosis of neonatal seizures is
clinical recognition. Neonatal seizures are best characterized according to their
appearance, including the location and degree of limb, face or truncal involvement,
sequence of clinical changes, and duration and timing of recurrence. This
information is generally easier to obtain when health care professionals witness
the neonatal seizures. A detailed history should be directed to identifying these
same characteristics when families or those without medical training witness
neonatal seizures. Once the seizures are characterized, they can be classified
according to established classification schemes.",
" </p>",
" <p>",
" Seizures in the neonate have unique clinical features when compared with those
of older infants and children. These differences are based upon age-dependent
mechanisms of epileptogenesis, the degree of brain development at seizure onset,
evolution of brain involvement during the seizure, and the relative importance of
nonepileptic mechanisms of seizure generation in this age group.",
" </p>",
" <p class=\"headingAnchor\" id=\"H5\">",
" <span class=\"h2\">",
" Classification schemes",
" </span>",
" &nbsp;&mdash;&nbsp;Historically, there have been a number of clinical
classifications of neonatal seizures. Each, in succession, have added to the
understanding of neonatal seizures and enhanced accuracy of diagnosis [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6328/abstract/7-14\">",
" 7-14",
" </a>",
" ]. Different classification schemes have emphasized various features such as
clinical manifestations only, the relationship between clinical seizures and
electrical seizure activity on the electroencephalogram (EEG), and seizure
pathophysiology.",
" </p>",
" <p>",
" Understanding these classification systems can orient the clinician to both
terminology and the clinical differences between seizures in neonates and older
infants or children.",
" </p>",
" <p>",
" Early classifications characterized seizures as either clonic or tonic, but
not tonic-clonic [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6328/abstract/7\">",
" 7",
" </a>",
" ]. There was also an early recognition that neonatal seizures were not
generalized but focal (either unifocal or multifocal). Later classifications
included myoclonus [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6328/abstract/10\">",
" 10",
" </a>",
" ]. More unique neonatal seizures were initially described as \"anarchic\" [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6328/abstract/7\">",
" 7",
" </a>",
" ], then \"minimal\" [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6328/abstract/8\">",
" 8",
" </a>",
" ] or \"subtle\" [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6328/abstract/13\">",
" 13",
" </a>",
" ]. These included oral-buccal-lingual movements such as sucking and chewing,
movements of progression, such as bicycling of the legs and swimming movements of
the arms, and random eye movements.",
" </p>",
" <p>",
" While these events were once considered to be purely epileptic in origin,
later investigators suggested that they were exaggerated reflex behaviors and,
thus, referred to them as \"motor automatisms\" or \"brainstem release phenomena\"
[",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6328/abstract/9\">",
" 9",
" </a>",
" ].",
" </p>",
" <p>",
" The clinical characteristics of neonatal seizures are listed in the table
according to a current classification system that includes presumed pathophysiology
(",
" <a class=\"graphic graphic_table graphicRef59395 graphicRef61962 \"
href=\"UTD.htm?29/10/29869\">",
" table 1A-B",
" </a>",
" ) [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6328/abstract/15\">",
" 15",
" </a>",
" ].",
" </p>",
" <p class=\"headingAnchor\" id=\"H6\">",
" <span class=\"h3\">",
" Temporal relationship to EEG",
" </span>",
" &nbsp;&mdash;&nbsp;In addition to classifying seizures based only upon their
clinical characteristics, neonatal seizures may also be classified according to the
temporal relationship of clinical events to the occurrence of electrical seizure
activity recorded on EEG (",
" <a class=\"graphic graphic_table graphicRef76389 \" href=\"UTD.htm?
32/20/33100\">",
" table 2",
" </a>",
" ).",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" An \"electroclinical\" seizure occurs when the clinical event overlaps in
time with electrographic seizure activity",
" </li>",
" <li>",
" A \"clinical only\" seizure occurs when clinical events are present with no
EEG seizure activity",
" </li>",
" <li>",
" An \"electrical seizure\" occurs in the absence of any clinical event",
" </li>",
" </ul>",
" </p>",
" <p>",
" Seizures may also be classified according to their pathophysiology. They may
be epileptic or non-epileptic in origin.",
" </p>",
" <p class=\"headingAnchor\" id=\"H7\">",
" <span class=\"h2\">",
" Epileptic seizures",
" </span>",
" &nbsp;&mdash;&nbsp;Neonatal seizures of epileptic origin are generated by
hypersynchronous cortical neuronal discharges. There are age-dependent properties
of the immature brain that enhance seizure initiation, maintenance of the seizure
discharge and propagation of the seizure discharge [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6328/abstract/16\">",
" 16",
" </a>",
" ]. The clinical events that are most clearly epileptic in origin are focal-
clonic, focal-tonic, some types of myoclonic, and spasms.",
" </p>",
" <p>",
" Seizures of epileptic origin occur in close association with EEG seizure
activity and can also be classified as electroclinical or electrical only. When
infants are examined while they are experiencing clinical events such as focal-
clonic or focal-tonic seizures, the clinical event cannot be suppressed by
restraint or reposing of affected limb. In addition, between seizures, clinical
events cannot be provoked by stimulation of the infant.",
" </p>",
" <p class=\"headingAnchor\" id=\"H8\">",
" <span class=\"h2\">",
" Non-epileptic seizures",
" </span>",
" &nbsp;&mdash;&nbsp;Other seizures are considered nonepileptic in origin [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6328/abstract/1,9\">",
" 1,9",
" </a>",
" ]. These events occur in the absence of electrical seizure activity. However,
the more convincing data suggesting nonepileptic pathophysiology is the similarity
the clinical events have to reflex behaviors. These nonepileptic clinical seizures
can be provoked by stimulation of the infant, and both the provoked and spontaneous
events can be suppressed by restraint of the infant or by repositioning the infant
during the event. In addition, the clinical events may increase in intensity with
the increase in the repetition rate of stimulation (temporal summation) or the
sites of simultaneous stimulation (spatial summation).",
" </p>",
" <p>",
" The clinical events that can be classified as nonepileptic in origin are some
types of myoclonic events, generalized tonic posturing, and motor automatisms (",
" <a class=\"graphic graphic_table graphicRef59395 graphicRef61962 \"
href=\"UTD.htm?29/10/29869\">",
" table 1A-B",
" </a>",
" ). Because of their occurrence in the absence of EEG seizure activity, these
events can also be classified as \"clinical only\" seizures.",
" </p>",
" <p class=\"headingAnchor\" id=\"H9\">",
" <span class=\"h2\">",
" Seizure types",
" </span>",
" &nbsp;&mdash;&nbsp;There are different methods for characterizing and
classifying the motor, behavioral, and autonomic nervous systems (ANS) changes
considered to represent clinical seizures. The most detailed method is based upon
the understanding that a typical neonatal seizure is a sequence of clinical events
that may include different movements or behaviors that may occur at different times
within the same seizure. While this method may be the most accurate, it is often
difficult to apply since clinical events can be so brief and unpredictable that
detailed observation may be impractical.",
" </p>",
" <p>",
" The most straightforward strategy is to realize that seizures may consist of
various components and that the seizures may be classified according to the most
prominent component. These seizures are described below (",
" <a class=\"graphic graphic_table graphicRef59395 graphicRef61962 \"
href=\"UTD.htm?29/10/29869\">",
" table 1A-B",
" </a>",
" ).",
" </p>",
" <p class=\"headingAnchor\" id=\"H10\">",
" <span class=\"h3\">",
" Focal clonic",
" </span>",
" &nbsp;&mdash;&nbsp;Focal-clonic seizures consist of repetitive, rhythmic
contractions of specific muscle groups of the limbs, face, or trunk. Clonic
movements typically have a slow rate of repetition, particularly when larger muscle
groups are involved. They have a close relationship to EEG seizure activity with
each contraction having a consistent, time-locked relationship to EEG seizure
discharges. When compared with nonepileptic movements such as clonus or tremor, the
jerking movements of a focal-clonic seizure are consistently slower and more
rhythmic. Focal-clonic seizures can be differentiated from tremor or clonus by
restraint of movement. Tremor or clonus can be stopped by restraint, though clonic
seizure activity cannot, and muscle twitching can still be felt in the restrained
limb.",
" </p>",
" <p>",
" While focal-clonic seizures may be the most easily recognized by observers,
these events do have features that may be unique to the neonatal period. Focal-
clonic seizures may be unifocal, confined to specific muscle groups including those
of the proximal or distal limbs, trunk or neck, or regions of the face. Focal
seizures may alternate between sites of involvement within the same seizure. Focal
seizures may be multifocal and may exhibit clonic activity simultaneously but
asynchronously. If all four limbs are involved, this may give the appearance of a
generalized seizure. However, more careful inspection reveals that the limbs are
not moving synchronously.",
" </p>",
" <p>",
" Focal seizures can migrate from one region to another. Migration may be
according to traditional Jacksonian features (ie, contiguous spread over the
cortical representation of the limbs, face and trunk) or may be more erratic in
spread. Focal seizures may also be hemiconvulsive. In this regard, a seizure may be
initially confined to the hand on one side of the body and then abruptly involve
the remainder of that side of body without an intervening Jacksonian march.",
" </p>",
" <p class=\"headingAnchor\" id=\"H11\">",
" <span class=\"h3\">",
" Focal tonic",
" </span>",
" &nbsp;&mdash;&nbsp;Focal tonic seizures occur less often than focal clonic
seizures. Focal tonic seizures are characterized by sustained, but transient,
asymmetrical posturing of the trunk or extremities or tonic deviation of the eyes.
Seizures involving the limbs or trunk may appear as unilateral flexion of the trunk
with the body pulling down and to one side or sustained flexion or extension of a
limb. When the eyes are involved, there is sustained conjugate deviation of the
eyes to one side. Any of these events are typically associated with focal EEG
seizure activity. They are considered to be of epileptic origin.",
" </p>",
" <p class=\"headingAnchor\" id=\"H12\">",
" <span class=\"h3\">",
" Generalized tonic",
" </span>",
" &nbsp;&mdash;&nbsp;Bilaterally symmetrical tonic posturing may be
predominantly flexor, extensor, or mixed. The tonic posture is sustained and may
involve bilateral limbs and the trunk. The muscle contractions are relatively long
and are of greater duration than spasms. The tonic events can be provoked by
stimulation and suppressed by restraint or repositioning of the infant. These
events may occur in isolation, or they occur in infants who are also experiencing
motor automatisms. (See",
" <a class=\"local\" href=\"#H15\">",
" 'Motor automatisms'",
" </a>",
" below.)",
" </p>",
" <p>",
" Both tonic posturing and motor automatisms are considered to be of
nonepileptic origin. They have clinical features that resemble exaggerated reflex
behavior. They occur in infants who are obtunded or lethargic and with EEG
background characterized as depressed and undifferentiated, features indicating the
presence of forebrain depression. Tactile stimulation of the infants may provoke
posturing or motor automatisms. These characteristics are based in reflex
physiology and the events have been referred to as \"brainstem release phenomena\"
[",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6328/abstract/1,9\">",
" 1,9",
" </a>",
" ].",
" </p>",
" <p class=\"headingAnchor\" id=\"H13\">",
" <span class=\"h3\">",
" Myoclonic",
" </span>",
" &nbsp;&mdash;&nbsp;The category of myoclonic seizures represent a diverse
range of movements, some epileptic in origin and some nonepileptic in origin. The
movements of myoclonic seizures are characterized by contractions of muscle groups
of well-defined regions: proximal or distal limb regions, entire limbs, trunk or
diaphragm, or face. The movements are of variable speed depending upon the size of
the muscle group involved. The movements may be isolated events or may be
repetitive; when repetitive the rate of recurrence may be slow, irregular, or
erratic.",
" </p>",
" <p>",
" Myoclonic events are distinguished from clonic seizures by the regular rate of
repetition and persistence of clonic events. Myoclonic seizures can be classified
as focal, generalized, or fragmentary. Focal myoclonic seizures have features
similar to focal clonic seizures except that myoclonic events are nonrepetitive and
erratic. Generalized myoclonic seizures include bilateral, symmetric jerking of all
extremities",
" <span class=\"nowrap\">",
" and/or",
" </span>",
" muscles of the trunk and neck. Fragmentary myoclonus is characterized by
rapid, simultaneous but asynchronous, twitching of various small muscle groups that
are typically distal. Fragmentary myoclonus is typically nonepileptic in origin.",
" </p>",
" <p>",
" Some forms of myoclonic seizures may occur with a consistent EEG seizure
discharge, although some do not. This reflects the fact that some myoclonic
seizures are generated at a cortical level and others are generated at more caudal
levels such as subcortical structures, brainstem, spinal cord, or neuromuscular
junction. In addition, some myoclonic seizures may be provoked by stimulation and
suppressed by limb restraint or body repositioning.",
" </p>",
" <p class=\"headingAnchor\" id=\"H14\">",
" <span class=\"h3\">",
" Spasms",
" </span>",
" &nbsp;&mdash;&nbsp;Spasms may occur in neonates, although they are rare.
Spasms primarily involve truncal muscles and limbs. They are flexor, extensor, or
mixed flexor-extensor. The clinical appearance of the events may be affected by the
body position of the neonate at the time of the seizure. The spasm begins with an
initial muscle contraction that is transiently maintained, followed by relaxation
of the muscle. The seizures may occur in clusters and are most often present upon
arousal of the infant from sleep. On EEG, the seizures may be associated with a
generalized, high voltage, slow wave transient or generalized voltage attenuation.
Spasms are considered electroclinical seizures and are epileptic in origin.",
" </p>",
" <p class=\"headingAnchor\" id=\"H15\">",
" <span class=\"h3\">",
" Motor automatisms",
" </span>",
" &nbsp;&mdash;&nbsp;The term \"motor automatisms\" is used to characterize
clinical events referred to by others as \"subtle seizures.\" Although these events
may occur at the time electrical seizure activity is present, this activity is not
necessary for these clinical events to occur; and most often these clinical
seizures occur without EEG seizure activity (",
" <a class=\"graphic graphic_table graphicRef61962 \" href=\"UTD.htm?
0/60/972\">",
" table 1B",
" </a>",
" ).",
" </p>",
" <p>",
" Like tonic seizures, motor automatisms can be provoked by stimulation and are
considered another manifestation of brainstem release phenomena. Thus, they are
nonepileptic in origin. Motor automatisms may appear as oral-buccal-lingual
movements including episodic chewing, swallowing, sucking, or repetitive tongue
movements. Ocular movements appear as episodic random or oscillatory eye movements,
repetitive eye opening, episodic and nonsustained eye deviation, or episodic
dysconjugate gaze. Progression movements resemble pedaling or bicycling movements
of the legs, swimming-like movements, rotary movement of the upper extremities, or
combinations of these movements.",
" </p>",
" <p class=\"headingAnchor\" id=\"H16\">",
" <span class=\"h3\">",
" Autonomic signs",
" </span>",
" &nbsp;&mdash;&nbsp;Clinical changes related to the autonomic nervous system
(ANS) have been reported to be manifestations of neonatal seizures. These changes
include: alterations in heart rate, respiration and blood pressure, and flushing,
salivation, and pupil dilatation [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6328/abstract/12,17,18\">",
" 12,17,18",
" </a>",
" ]. However, the occurrence of any of these findings as isolated epileptic
events is rare. When they do occur, they do so most consistently in association
with other clinical motor manifestations of seizures [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6328/abstract/9\">",
" 9",
" </a>",
" ].",
" </p>",
" <p class=\"headingAnchor\" id=\"H17\">",
" <span class=\"h2\">",
" Application of clinically relevant terminology",
" </span>",
" &nbsp;&mdash;&nbsp;The terminology of neonatal seizures can be helpful in the
clinical management of those with seizures, if applied in a rational way. Clinical
seizures are first recognized and then characterized according to their appearance.
They can then be classified according to a standardized classification system. The
seizure can then be considered in terms of pathophysiology. All abnormal paroxysmal
clinical events are considered \"seizures.\" They can then be further categorized
as epileptic or nonepileptic in origin.",
" </p>",
" <p>",
" As an example, an infant may experience sustained rhythmic jerking of
extremities. These can be classified as focal clonic seizures. The seizures can
then be categorized as epileptic in origin. On the other hand, another infant may
experience sustained, symmetric extension of all extremities and trunk that occur
spontaneously and can be provoked by stimulation of the infant. This seizure type
can be classified as generalized tonic and then categorized as nonepileptic in
origin.",
" </p>",
" <p class=\"headingAnchor\" id=\"H18\">",
" <span class=\"h1\">",
" DIFFERENTIAL DIAGNOSIS OF CLINICAL SEIZURES",
" </span>",
" &nbsp;&mdash;&nbsp;Neonatal seizures must be differentiated from nonseizure
behaviors of the newborn. Some normal behaviors of the preterm and full-term
infants may raise suspicions of seizures. Normal behaviors include stretching,
nonspecific random movements that can be sudden (particularly in preterm infants)
and random sucking movements, coughing, or gagging. In addition, neonates may
experience normal physiologic myoclonus during active sleep (rapid eye movement).
Myoclonus may also occur during quiet or non-REM sleep and has been referred to as
benign neonatal myoclonus [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6328/abstract/19\">",
" 19",
" </a>",
" ].",
" </p>",
" <p>",
" Hyperekplexia or startle disease is characterized by an excessive startle
response to an unexpected stimulus, and may resemble generalized myoclonus.
Jitteriness, tremulousness, and clonus may occur in both normal and abnormal
infants and can be differentiated from other clinical events, particularly focal-
clonic seizures, by their suppression by restraint.",
" </p>",
" <p>",
" The clinical phenomenology of these nonepileptic paroxysmal events, especially
in relation to how they are distinguished from epileptic seizures is discussed
separately. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?23/51/24376?
source=see_link\">",
" \"Nonepileptic paroxysmal disorders in infancy\"",
" </a>",
" .)",
" </p>",
" <p>",
" Most neonatal seizures are witnessed or evaluated in infants cared for in
special nursing hospital areas such as neonatal intensive care units (NICU). Under
these circumstances systemic blood pressure, heart rate, and respirations are
monitored, and sudden changes in these parameters are frequently recorded. However,
most often these changes are not manifestations of seizures, but either physiologic
or nonepileptic abnormal changes. As noted above, while changes in these parameters
may be manifestations of seizures, it is rare for them to occur in isolation as
they most often occur in association with motor phenomena of epileptic origin.",
" </p>",
" <p class=\"headingAnchor\" id=\"H19\">",
" <span class=\"h1\">",
" ROLE OF EEG IN DIAGNOSIS",
" </span>",
" &nbsp;&mdash;&nbsp;The diagnosis of neonatal seizures is most often based upon
clinical observation. The discussion to this point has emphasized clinical
recognition. However, the electroencephalogram (EEG) is a valuable tool in
diagnosis and management of neonates who are suspected of having seizures. When at-
risk infants undergo EEG monitoring, a high rate of both false positive and false
negative clinical diagnoses are revealed (27 and 81 percent respectively) as well
as substantial interobserver disagreement [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6328/abstract/20,21\">",
" 20,21",
" </a>",
" ]. The EEG may provide data that can impact the assessment of the risk for
seizures, co-existing brain disturbance, long-term prognosis, seizure diagnosis,
and efficacy of antiepileptic drug (AED) therapy.",
" </p>",
" <p class=\"headingAnchor\" id=\"H20\">",
" <span class=\"h2\">",
" Assessment of risk of seizures",
" </span>",
" &nbsp;&mdash;&nbsp;The findings of the background EEG may suggest the relative
risk individual infants may have in eventually experiencing a seizure [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6328/abstract/22\">",
" 22",
" </a>",
" ]. Infants with normal background activity are less likely to develop seizures
than those with persistent diffuse background abnormalities.",
" </p>",
" <p class=\"headingAnchor\" id=\"H21\">",
" <span class=\"h2\">",
" Assessment of co-existing brain dysfunction",
" </span>",
" &nbsp;&mdash;&nbsp;The degree of abnormality of the background activity may
provide useful information concerning the extent and type of central nervous system
(CNS) dysfunction associated with seizures. In addition, the persistence of the
abnormalities over time further indicates the degree of injury.",
" </p>",
" <p class=\"headingAnchor\" id=\"H22\">",
" <span class=\"h2\">",
" Determination of prognosis",
" </span>",
" &nbsp;&mdash;&nbsp;The character of the background EEG can be helpful in the
determination of long-term outcome of infants who have experienced seizures. It is
generally thought that the greater the EEG abnormality, the more grave the
prognosis. However, in making this determination it is critical to take into
consideration the timing of the EEG in relation to the suspected time of injury and
the rate of resolution of EEG abnormalities over time. An EEG performed early in
the course of illness can be repeated within days. The persistence of a diffuse EEG
abnormality can suggest a poor prognosis, but its resolution suggests a better
outcome. On the other hand, a normal initial EEG within 24 hours of birth reliably
suggests a good prognosis.",
" </p>",
" <p class=\"headingAnchor\" id=\"H23\">",
" <span class=\"h2\">",
" Seizure diagnosis",
" </span>",
" &nbsp;&mdash;&nbsp;In older children and adults, the application of EEG to
seizure diagnosis consists of identification of interictal sharp waves as well as
the identification of electrical seizure activity. In neonates, only the later
component is useful.",
" </p>",
" <p class=\"headingAnchor\" id=\"H24\">",
" <span class=\"h3\">",
" Interictal sharp waves",
" </span>",
" &nbsp;&mdash;&nbsp;In older children and adults, the presence of focal sharp
waves on EEG indicates interictal epileptiform activity, suggesting a
predisposition to have seizures. However, interictal focal sharp waves and spikes
in neonates are not considered to be indicators of epileptogenesis in the same way
they are in older children and adults. Some types of unifocal sharp waves may
suggest focal injury, multifocal sharp waves may suggest diffuse dysfunction, and
sharp waves or spikes may have uncertain diagnostic significance [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6328/abstract/23,24\">",
" 23,24",
" </a>",
" ].",
" </p>",
" <p class=\"headingAnchor\" id=\"H25\">",
" <span class=\"h3\">",
" Electrical seizure activity",
" </span>",
" &nbsp;&mdash;&nbsp;Electrical seizure activity in the neonate is thought to be
rare before 34 to 35 weeks of conceptional age. When present, electrical seizure
activity may have varied manifestations. Frequency, voltage, and morphology of the
discharges may change within an individual seizure and between seizures in an
individual infant. The electrical events are typically focal and well
circumscribed. They may remain confined to a single region, may spread to other
brain regions by a gradual widening of the focal area, may abruptly change from a
small regional focus to involvement of the entire hemisphere (so-called
hemiconvulsive seizure), or may migrate from one area of a hemisphere to another or
from one hemisphere to another [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6328/abstract/15,24\">",
" 15,24",
" </a>",
" ].",
" </p>",
" <p>",
" There are some unique ictal patterns in the neonate that are usually
associated with severe encephalopathies and a poor prognosis. They appear as
electrical seizures without clinical events. Electrical-only seizures are not rare
in neonates, comprising 21 percent of seizures in one monitoring study [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6328/abstract/25\">",
" 25",
" </a>",
" ], and are believed to have similar pathogenesis and prognostic implications
as electroclinical seizures [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6328/abstract/26\">",
" 26",
" </a>",
" ]. Electrical seizures of the depressed brain are typically low in voltage,
long in duration, and highly localized [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6328/abstract/27\">",
" 27",
" </a>",
" ]. Alpha seizure activity is characterized by a sudden, but transient
appearance of rhythmic activity in the alpha frequency (8-12 Hz) typically
occurring in the temporal or central region [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6328/abstract/28-30\">",
" 28-30",
" </a>",
" ].",
" </p>",
" <p class=\"headingAnchor\" id=\"H26\">",
" <span class=\"h2\">",
" EEG monitoring",
" </span>",
" &nbsp;&mdash;&nbsp;Video-EEG monitoring of neonates has been investigated in
clinical studies regarding seizure classification, therapy and prognosis [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6328/abstract/9,31-34\">",
" 9,31-34",
" </a>",
" ], and is now often used for clinical diagnosis and management [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6328/abstract/20\">",
" 20",
" </a>",
" ]. While there has been emphasis in the literature upon prolonged monitoring,
recordings of relatively short duration (one hour) can be very revealing,
demonstrating a high rate of both false positive and false negative clinical
diagnoses [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6328/abstract/20\">",
" 20",
" </a>",
" ]. Successful monitoring requires that the full body and face of the infant is
included in the video imaging and that the lighting used is adequate to have all
the body features apparent.",
" </p>",
" <p>",
" When video-EEG monitoring is unavailable, EEG recording with simultaneous
observation by electroneurodiagnostic technologists trained in the recognition and
characterization of neonatal seizures remains the standard of care and can provide
information that can be of clinical value equal to that obtained from EEG-video
monitoring.",
" </p>",
" <p>",
" Another option is the limited-channel digital bedside EEG, which combines
amplitude-integrated EEG (aEEG) with 1 or 2-channel EEG. While this technique is
increasingly used in both term and preterm infants, there are important limitations
[",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6328/abstract/35,36\">",
" 35,36",
" </a>",
" ]. Not all electrographic seizures are detected by this modality because of
limited coverage of the scalp [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6328/abstract/26\">",
" 26",
" </a>",
" ]. Also, artifact in these unattended recordings with no simultaneous video
recording can cause false-positive interpretations. The reported sensitivity and
specificity varies between 50 and 80 percent, in part depending upon the experience
of the reader and the use of 1 versus 2-channel EEG [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6328/abstract/37-40\">",
" 37-40",
" </a>",
" ]. Despite these limitations, when standard EEG or continuous standard EEG
recordings are not readily available, aEEG can be a useful tool; one study found
that the use of aEEG improved clinical decision making and resulted in fewer
neonates treated for seizures based solely on clinical findings [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6328/abstract/41\">",
" 41",
" </a>",
" ].",
" </p>",
" <p>",
" The development of automated seizure detection systems holds promise for
better and more widely available EEG monitoring in the future, but current systems
are not currently sufficiently reliable [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6328/abstract/36\">",
" 36",
" </a>",
" ].",
" </p>",
" <p class=\"headingAnchor\" id=\"H3241158\">",
" <span class=\"h1\">",
" SUMMARY AND RECOMMENDATIONS",
" </span>",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Neonatal seizures are best characterized according to their clinical
manifestations, including the location and degree of limb, face or truncal
involvement, sequence of clinical changes, and duration and timing of recurrence.
The clinical classification of neonatal seizures is presented in the Table (",
" <a class=\"graphic graphic_table graphicRef59395 \" href=\"UTD.htm?
38/1/38940\">",
" table 1A",
" </a>",
" ). (See",
" <a class=\"local\" href=\"#H5\">",
" 'Classification schemes'",
" </a>",
" above.)",
" </li>",
" <li>",
" Neonatal seizures must be differentiated from nonseizure behaviors of the
newborn (See",
" <a class=\"local\" href=\"#H18\">",
" 'Differential diagnosis of clinical seizures'",
" </a>",
" above and",
" <a class=\"medical medical_review\" href=\"UTD.htm?23/51/24376?
source=see_link\">",
" \"Nonepileptic paroxysmal disorders in infancy\"",
" </a>",
" .)",
" </li>",
" <li>",
" The diagnosis of neonatal seizures is based upon clinical observation
combined with EEG monitoring. (See",
" <a class=\"local\" href=\"#H19\">",
" 'Role of eeg in diagnosis'",
" </a>",
" above.)",
" </li>",
" <li>",
" Abnormalities of the background (interictal) EEG may also provide useful
information regrading etiology and prognosis. (See",
" <a class=\"local\" href=\"#H19\">",
" 'Role of eeg in diagnosis'",
" </a>",
" above.)",
" </li>",
" <li>",
" Electrical-only seizures occur without clinical manifestations and are
relatively common in the neonate compared with older patients. These seizures are
believed to have similar pathogenesis and prognostic implications as
electroclinical seizures. (See",
" <a class=\"local\" href=\"#H25\">",
" 'Electrical seizure activity'",
" </a>",
" above.)",
" </li>",
" </ul>",
" </p>",
" </div>",
" <div id=\"topicAgreement\">",
" Use of UpToDate is subject to the",
" <a class=\"licenseLink\" href=\"./license\" id=\"sla_in_page\"
target=\"_blank\">",
" Subscription and License Agreement",
" </a>",
" .",
" </div>",
" <div class=\"headingAnchor\" id=\"references\">",
" <h1>",
" REFERENCES",
" </h1>",
" <ol id=\"reference\">",
" <li>",
" Kellaway, P, Hrachovy, RA. Status epilepticus in newborns: A perspective on
neonatal seizures. In: Advances in Neurology, vol 34: Status Epilepticus, Delgado-
Escueta, AV, Wasterlain, CG, Treiman, DM, Porter, RJ (Eds), Raven Press, New York
1983. p.93.",
" </li>",
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" <a class=\"nounderline abstract\" href=\"UTD.htm?6/11/6328/abstract/2\">",
" Lanska MJ, Lanska DJ, Baumann RJ, Kryscio RJ. A population-based study of
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" <a class=\"nounderline abstract\" href=\"UTD.htm?6/11/6328/abstract/3\">",
" Ronen GM, Penney S, Andrews W. The epidemiology of clinical neonatal
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" <a class=\"nounderline abstract\" href=\"UTD.htm?6/11/6328/abstract/4\">",
" Saliba RM, Annegers JF, Waller DK, et al. Incidence of neonatal seizures in
Harris County, Texas, 1992-1994. Am J Epidemiol 1999; 150:763.",
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" <a class=\"nounderline abstract\" href=\"UTD.htm?6/11/6328/abstract/5\">",
" Scher MS, Aso K, Beggarly ME, et al. Electrographic seizures in preterm and
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" <a class=\"nounderline abstract\" href=\"UTD.htm?6/11/6328/abstract/6\">",
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factors for seizures in term newborns: a population-based study, California 1998-
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" </li>",
" <li>",
" Drefus-Brisac, C, Monod, N. Electroclinical studies of status epilepticus and
convulsions in the newborn. In: Neurological and electroencephalographic
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Stanton, New York 1964. p.250.",
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" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?6/11/6328/abstract/8\">",
" Lombroso CT. The treatment of status epilepticus. Pediatrics 1974; 53:536.",
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" Mizrahi EM, Kellaway P. Characterization and classification of neonatal
seizures. Neurology 1987; 37:1837.",
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" <a class=\"nounderline abstract\" href=\"UTD.htm?6/11/6328/abstract/10\">",
" Rose AL, Lombroso CT. A study of clinical, pathological, and
electroencephalographic features in 137 full-term babies with a long-term follow-
up. Pediatrics 1970; 45:404.",
" </a>",
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" <a class=\"nounderline abstract\" href=\"UTD.htm?6/11/6328/abstract/11\">",
" Volpe JJ. Neonatal seizures: current concepts and revised classification.
Pediatrics 1989; 84:422.",
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" <a class=\"nounderline abstract\" href=\"UTD.htm?6/11/6328/abstract/12\">",
" Watanabe K, Hara K, Miyazaki S, et al. Electroclinical studies of seizures
in the newborn. Folia Psychiatr Neurol Jpn 1977; 31:383.",
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" Volpe J. Neonatal Seizures. N Engl J Med 1973; 289:413.",
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" <a class=\"nounderline abstract\" href=\"UTD.htm?6/11/6328/abstract/14\">",
" Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for
organization of seizures and epilepsies: report of the ILAE Commission on
Classification and Terminology, 2005-2009. Epilepsia 2010; 51:676.",
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" </li>",
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" Mizrahi, EM, Kellaway, P. Diagnosis and Management of Neonatal Seizures.
Lippincott-Raven, Philadelphia 1998, p.181.",
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" Holmes GL. Epilepsy in the developing brain: lessons from the laboratory and
clinic. Epilepsia 1997; 38:12.",
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" <a class=\"nounderline abstract\" href=\"UTD.htm?6/11/6328/abstract/17\">",
" Goldberg RN, Goldman SL, Ramsay RE, Feller R. Detection of seizure activity
in the paralyzed neonate using continuous monitoring. Pediatrics 1982; 69:583.",
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" Lou HC, Friis-Hansen B. Arterial blood pressure elevations during motor
activity and epileptic seizures in the newborn. Acta Paediatr Scand 1979; 68:803.",
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" <a class=\"nounderline abstract\" href=\"UTD.htm?6/11/6328/abstract/19\">",
" Di Capua M, Fusco L, Ricci S, Vigevano F. Benign neonatal sleep myoclonus:
clinical features and video-polygraphic recordings. Mov Disord 1993; 8:191.",
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" <a class=\"nounderline abstract\" href=\"UTD.htm?6/11/6328/abstract/20\">",
" Murray DM, Boylan GB, Ali I, et al. Defining the gap between electrographic
seizure burden, clinical expression and staff recognition of neonatal seizures.
Arch Dis Child Fetal Neonatal Ed 2008; 93:F187.",
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" <a class=\"nounderline abstract\" href=\"UTD.htm?6/11/6328/abstract/21\">",
" Malone A, Ryan CA, Fitzgerald A, et al. Interobserver agreement in neonatal
seizure identification. Epilepsia 2009; 50:2097.",
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" <a class=\"nounderline abstract\" href=\"UTD.htm?6/11/6328/abstract/22\">",
" Laroia N, Guillet R, Burchfiel J, McBride MC. EEG background as predictor of
electrographic seizures in high-risk neonates. Epilepsia 1998; 39:545.",
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" </li>",
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" Hrachovy, RA, Mizrahi, EM, Kellaway, P. Electroencephalography of the
newborn. In: Current practice of electroencephalography, 2nd ed, Daly, DD, Pedley,
TA (Eds), Raven Press, New York 1990. p.201.",
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" <li>",
" Mizrahi, EM, Hrachovy, RA, Kellaway, P. Atlas of Neonatal
Electroencephalography, 3rd ed, Lippincott Williams &amp; Wilkins, Philadelephia
2004. p.250.",
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" <a class=\"nounderline abstract\" href=\"UTD.htm?6/11/6328/abstract/25\">",
" Clancy RR, Legido A, Lewis D. Occult neonatal seizures. Epilepsia 1988;
29:256.",
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" Glass HC, Wirrell E. Controversies in neonatal seizure management. J Child
Neurol 2009; 24:591.",
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" </li>",
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" Kellaway, P, Hrachovy, RA. Electroencephalography. In: The practice of
pediatric neurology, 2nd ed, Swainman, KF, Wright, FS (Eds), Mosby, St. Louis 1982.
p.96.",
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" <a class=\"nounderline abstract\" href=\"UTD.htm?6/11/6328/abstract/28\">",
" Knauss TA, Carlson CB. Neonatal paroxysmal monorhythmic alpha activity. Arch
Neurol 1978; 35:104.",
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" <a class=\"nounderline abstract\" href=\"UTD.htm?6/11/6328/abstract/29\">",
" Willis J, Gould JB. Periodic alpha seizures with apnea in a newborn. Dev Med
Child Neurol 1980; 22:214.",
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" Watanabe K, Hara K, Miyazaki S, et al. Apneic seizures in the newborn. Am J
Dis Child 1982; 136:980.",
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" <a class=\"nounderline abstract\" href=\"UTD.htm?6/11/6328/abstract/31\">",
" Boylan GB, Pressler RM, Rennie JM, et al. Outcome of electroclinical,
electrographic, and clinical seizures in the newborn infant. Dev Med Child Neurol
1999; 41:819.",
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" Bye AM, Cunningham CA, Chee KY, Flanagan D. Outcome of neonates with
electrographically identified seizures, or at risk of seizures. Pediatr Neurol
1997; 16:225.",
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" Rennie JM. Neonatal seizures. Eur J Pediatr 1997; 156:83.",
" </a>",
" </li>",
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" <a class=\"nounderline abstract\" href=\"UTD.htm?6/11/6328/abstract/34\">",
" Mizrahi EM. Electroencephalographic-video monitoring in neonates, infants,
and children. J Child Neurol 1994; 9 Suppl 1:S46.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?6/11/6328/abstract/35\">",
" Glass HC, Kan J, Bonifacio SL, Ferriero DM. Neonatal seizures: treatment
practices among term and preterm infants. Pediatr Neurol 2012; 46:111.",
" </a>",
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" <a class=\"nounderline abstract\" href=\"UTD.htm?6/11/6328/abstract/36\">",
" Shah DK, Boylan GB, Rennie JM. Monitoring of seizures in the newborn. Arch
Dis Child Fetal Neonatal Ed 2012; 97:F65.",
" </a>",
" </li>",
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" <a class=\"nounderline abstract\" href=\"UTD.htm?6/11/6328/abstract/37\">",
" Shah DK, Mackay MT, Lavery S, et al. Accuracy of bedside
electroencephalographic monitoring in comparison with simultaneous continuous
conventional electroencephalography for seizure detection in term infants.
Pediatrics 2008; 121:1146.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?6/11/6328/abstract/38\">",
" Wusthoff CJ, Shellhaas RA, Clancy RR. Limitations of single-channel EEG on
the forehead for neonatal seizure detection. J Perinatol 2009; 29:237.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?6/11/6328/abstract/39\">",
" Griesmaier E, Neubauer V, Ralser E, et al. Need for quality control for aEEG
monitoring of the preterm infant: a 2-year experience. Acta Paediatr 2011;
100:1079.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?6/11/6328/abstract/40\">",
" Ray S. Question 1. Is cerebral function monitoring as accurate as
conventional EEG in the detection of neonatal seizures? Arch Dis Child 2011;
96:314.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?6/11/6328/abstract/41\">",
" Shellhaas RA, Barks AK. Impact of amplitude-integrated electroencephalograms
on clinical care for neonates with seizures. Pediatr Neurol 2012; 46:32.",
" </a>",
" </li>",
" </ol>",
" </div>",
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" Topic 6152 Version 6.0",
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var outline_f6_11_6328=[" <div id=\"toggleOutline\">",
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" <h1>",
" TOPIC OUTLINE",
" </h1>",
" <div id=\"outline\">",
" <ul>",
" <li>",
" <a class=\"sr_button\" href=\"#H3241158\" id=\"summRecButton\">",
" <span>",
" SUMMARY &amp; RECOMMENDATIONS",
" </span>",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#H1\">",
" INTRODUCTION",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#H2\">",
" APPROACH TO DIAGNOSIS",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#H3\">",
" EPIDEMIOLOGY",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#H4\">",
" CHARACTERIZATION OF SEIZURES",
" </a>",
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" <a class=\"outlineLink\" href=\"#H5\">",
" Classification schemes",
" </a>",
" </li>",
" <li class=\"dashItem\">",
" <a class=\"outlineLink\" href=\"#H6\">",
" - Temporal relationship to EEG",
" </a>",
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" Epileptic seizures",
" </a>",
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" Non-epileptic seizures",
" </a>",
" </li>",
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" Seizure types",
" </a>",
" </li>",
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" <a class=\"outlineLink\" href=\"#H10\">",
" - Focal clonic",
" </a>",
" </li>",
" <li class=\"dashItem\">",
" <a class=\"outlineLink\" href=\"#H11\">",
" - Focal tonic",
" </a>",
" </li>",
" <li class=\"dashItem\">",
" <a class=\"outlineLink\" href=\"#H12\">",
" - Generalized tonic",
" </a>",
" </li>",
" <li class=\"dashItem\">",
" <a class=\"outlineLink\" href=\"#H13\">",
" - Myoclonic",
" </a>",
" </li>",
" <li class=\"dashItem\">",
" <a class=\"outlineLink\" href=\"#H14\">",
" - Spasms",
" </a>",
" </li>",
" <li class=\"dashItem\">",
" <a class=\"outlineLink\" href=\"#H15\">",
" - Motor automatisms",
" </a>",
" </li>",
" <li class=\"dashItem\">",
" <a class=\"outlineLink\" href=\"#H16\">",
" - Autonomic signs",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H17\">",
" Application of clinically relevant terminology",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#H18\">",
" DIFFERENTIAL DIAGNOSIS OF CLINICAL SEIZURES",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#H19\">",
" ROLE OF EEG IN DIAGNOSIS",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H20\">",
" Assessment of risk of seizures",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
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" Assessment of co-existing brain dysfunction",
" </a>",
" </li>",
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" <a class=\"outlineLink\" href=\"#H22\">",
" Determination of prognosis",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H23\">",
" Seizure diagnosis",
" </a>",
" </li>",
" <li class=\"dashItem\">",
" <a class=\"outlineLink\" href=\"#H24\">",
" - Interictal sharp waves",
" </a>",
" </li>",
" <li class=\"dashItem\">",
" <a class=\"outlineLink\" href=\"#H25\">",
" - Electrical seizure activity",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H26\">",
" EEG monitoring",
" </a>",
" </li>",
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" <a class=\"outlineLink\" href=\"#H3241158\">",
" SUMMARY AND RECOMMENDATIONS",
" </a>",
" </li>",
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" <a href=\"#references\">",
" REFERENCES",
" </a>",
" </li>",
" </ul>",
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" <div class=\"openRelatedGraphics\" id=\"PEDS/6152\" rel=\"outline_link\">",
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1A\">",
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1B\">",
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2\">",
" Classification neonate seiz",
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" RELATED TOPICS",
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" <ul>",
" <li class=\"plainItem\">",
" <a class=\"medical medical_review\" href=\"UTD.htm?14/4/14409?
source=related_link\">",
" Clinical and laboratory diagnosis of seizures in infants and children",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"medical medical_review\" href=\"UTD.htm?40/23/41335?
source=related_link\">",
" Etiology and prognosis of neonatal seizures",
" </a>",
" </li>",
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source=related_link\">",
" Neonatal epileptic syndromes",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"medical medical_review\" href=\"UTD.htm?28/31/29175?
source=related_link\">",
" Nonepileptic paroxysmal disorders in children",
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source=related_link\">",
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" </a>",
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source=related_link\">",
" Treatment of neonatal seizures",
" </a>",
" </li>",
" </ul>",
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var title_f6_11_6329="Overview of the medical management of severe or refractory
Crohn's disease in adults";
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" <br/>",
" <a class=\"contributor contributor_credentials\" href=\"UTD.htm?
6/11/6329/contributors\">",
" Mark A Peppercorn, MD",
" </a>",
" <br/>",
" </div>",
" <div>",
" <a class=\"contributor contributor_credentials contributorType\"
href=\"UTD.htm?6/11/6329/contributors\">",
" Section Editor",
" </a>",
" <br/>",
" <a class=\"contributor contributor_credentials\" href=\"UTD.htm?
6/11/6329/contributors\">",
" Paul Rutgeerts, MD, PhD, FRCP",
" </a>",
" <br/>",
" </div>",
" <div>",
" <a class=\"contributor contributor_credentials contributorType\"
href=\"UTD.htm?6/11/6329/contributors\">",
" Deputy Editor",
" </a>",
" <br/>",
" <a class=\"contributor contributor_credentials\" href=\"UTD.htm?
6/11/6329/contributors\">",
" Shilpa Grover, MD, MPH",
" </a>",
" <br/>",
" </div>",
" </div>",
" <div id=\"disclosures\">",
" <a href=\"UTD.htm?6/11/6329/contributor-disclosure\" target=\"_blank\">",
" Disclosures",
" </a>",
" </div>",
" <div id=\"reviewProcess\">",
" <span>",
" All topics are updated as new evidence becomes available and our",
" </span>",
" <a href=\"/home/editorial-policy\" target=\"_blank\">",
" peer review process",
" </a>",
" <span>",
" is complete.",
" </span>",
" </div>",
" <div id=\"literatureReviewDate\">",
" <span class=\"emphasis\">",
" Literature review current through:",
" </span>",
" Oct 2013.",
" <span class=\"pipeSpace\">",
" |",
" </span>",
" <span class=\"emphasis\">",
" This topic last updated:",
" </span>",
" Jan 15, 2013.",
" </div>",
" <div id=\"topicText\">",
" <p class=\"headingAnchor\" id=\"H11188251\">",
" <span class=\"h1\">",
" INTRODUCTION",
" </span>",
" &nbsp;&mdash;&nbsp;Crohn's disease is an inflammatory condition of unknown
etiology that can affect any portion of the gastrointestinal tract from the mouth
to the perianal area. Its transmural inflammatory nature coupled with the
variability of organ distribution gives rise to a spectrum of clinical
presentations, each of which has to be considered separately in deciding upon the
proper therapeutic approach. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?20/0/20490?
source=see_link\">",
" \"Clinical manifestations, diagnosis and prognosis of Crohn's disease in
adults\"",
" </a>",
" .)",
" </p>",
" <p>",
" Clinical trials of Crohn's disease often use formal grading systems to
describe disease severity. Two commonly used systems are the Crohn's Disease
Activity Index (CDAI) (",
" <a class=\"calc calc_professional\" href=\"UTD.htm?5/61/6098?
source=see_link\">",
" calculator 1",
" </a>",
" ) and the Harvey-Bradshaw Index (HBI) (",
" <a class=\"calc calc_professional\" href=\"UTD.htm?19/33/19985?
source=see_link\">",
" calculator 2",
" </a>",
" ) [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6329/abstract/1\">",
" 1",
" </a>",
" ], which is a simplified derivative of the CDAI. The HBI has been shown to
correlate with the CDAI [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6329/abstract/2\">",
" 2",
" </a>",
" ]. A drop in the CDAI of 100 points corresponds to a 3-point drop in the HBI.
A CDAI of &lt;150 (clinical remission) corresponds to an HBI of &lt;4.",
" </p>",
" <p>",
" The following working definitions may be more practical for clinical practice
[",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6329/abstract/3\">",
" 3",
" </a>",
" ]:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Asymptomatic remission (CDAI &lt;150) &ndash; Patients who are asymptomatic
either spontaneously or after medical or surgical intervention. Patients requiring
steroids to remain asymptomatic are",
" <strong>",
" not",
" </strong>",
" considered to be in remission but are referred to as being \"steroid-
dependent.\"",
" </li>",
" <li>",
" Mild to moderate Crohn's disease (CDAI 150-220) &ndash; Ambulatory patients
able to tolerate an oral diet without dehydration, toxicity, abdominal tenderness,
mass, obstruction, or &gt;10 percent weight loss.",
" </li>",
" <li>",
" Moderate to severe Crohn's disease (CDAI 220-450) &ndash; Patients who have
failed treatment for mild to moderate disease or patients with prominent symptoms
such as fever, weight loss, abdominal pain and tenderness, intermittent nausea or
vomiting, or anemia.",
" </li>",
" <li>",
" Severe-fulminant disease (CDAI &gt;450) &ndash; Patients with persisting
symptoms despite conventional glucocorticoids or biologic agents (",
" <a class=\"drug drug_general\" href=\"UTD.htm?28/6/28776?
source=see_link\">",
" infliximab",
" </a>",
" ,",
" <a class=\"drug drug_general\" href=\"UTD.htm?38/24/39303?
source=see_link\">",
" adalimumab",
" </a>",
" ,",
" <a class=\"drug drug_general\" href=\"UTD.htm?38/6/39014?
source=see_link\">",
" certolizumab pegol",
" </a>",
" , or",
" <a class=\"drug drug_general\" href=\"UTD.htm?1/15/1271?source=see_link\">",
" natalizumab",
" </a>",
" ) as outpatients, or individuals presenting with high fevers, persistent
vomiting, intestinal obstruction, significant peritoneal signs, cachexia, or
evidence of an abscess.",
" </li>",
" </ul>",
" </p>",
" <p>",
" This topic will provide an overview of the use of immunomodulators and
biologic therapies for severe or refractory Crohn's disease. It will also review
the options for medical management of patients with fistulae, peritonitis,
abscesses, and small bowel obstructions. The approach to patients with mild to
moderate Crohn's disease, detailed discussions of individual medications, and other
treatments for Crohn's disease are discussed separately:",
" </p>",
" <p>",
" <ul class=\"bulletCompact-block\">",
" <li>",
" <a class=\"medical medical_review\" href=\"UTD.htm?18/54/19305?
source=see_link\">",
" Overview of the medical management of mild to moderate Crohn's disease in
adults",
" </a>",
" </li>",
" <li>",
" <a class=\"medical medical_review\" href=\"UTD.htm?19/55/20344?
source=see_link\">",
" Sulfasalazine and 5-aminosalicylates in the treatment of inflammatory bowel
disease",
" </a>",
" </li>",
" <li>",
" <a class=\"medical medical_review\" href=\"UTD.htm?19/34/20008?
source=see_link\">",
" Antibiotics for treatment of inflammatory bowel diseases",
" </a>",
" </li>",
" <li>",
" <a class=\"medical medical_review\" href=\"UTD.htm?10/40/10886?
source=see_link\">",
" Budesonide in the treatment of Crohn's disease",
" </a>",
" </li>",
" <li>",
" <a class=\"medical medical_review\" href=\"UTD.htm?7/31/7673?
source=see_link\">",
" Immunomodulator therapy in Crohn's disease",
" </a>",
" </li>",
" <li>",
" <a class=\"medical medical_review\" href=\"UTD.htm?43/4/44105?
source=see_link\">",
" Infliximab in Crohn's disease",
" </a>",
" </li>",
" <li>",
" <a class=\"medical medical_review\" href=\"UTD.htm?28/55/29559?
source=see_link\">",
" Adalimumab for treatment of Crohn's disease in adults",
" </a>",
" </li>",
" <li>",
" <a class=\"medical medical_review\" href=\"UTD.htm?33/2/33829?
source=see_link\">",
" Certolizumab pegol for treatment of Crohn's disease in adults",
" </a>",
" </li>",
" <li>",
" <a class=\"medical medical_review\" href=\"UTD.htm?3/22/3429?
source=see_link\">",
" Natalizumab for treatment of Crohn's disease in adults",
" </a>",
" </li>",
" <li>",
" <a class=\"medical medical_review\" href=\"UTD.htm?4/50/4906?
source=see_link\">",
" Surgical management of ulcerative colitis",
" </a>",
" </li>",
" <li>",
" <a class=\"medical medical_review\" href=\"UTD.htm?0/50/809?
source=see_link\">",
" Medical prophylaxis of postoperative Crohn's disease",
" </a>",
" </li>",
" <li>",
" <a class=\"medical medical_review\" href=\"UTD.htm?17/34/17962?
source=see_link\">",
" Investigational therapies in the medical management of Crohn's disease",
" </a>",
" </li>",
" </ul>",
" </p>",
" <p class=\"headingAnchor\" id=\"H11189921\">",
" <span class=\"h1\">",
" SEVERE DISEASE",
" </span>",
" &nbsp;&mdash;&nbsp;Outpatient therapy with oral medications is appropriate for
most patients with mildly to moderately active Crohn's disease. However,
hospitalization is required for patients who present with severe or fulminant
disease. Hospitalization for intravenous glucocorticoids is also generally required
for patients who fail to respond to outpatient therapy.",
" </p>",
" <p>",
" Therapy for patients with severe or fulminant disease should consist of bowel
rest, parenteral nutrition, and intravenous glucocorticoids. If an abdominal mass
is present, broad spectrum antibiotics are also indicated. Patients who do not
respond to steroids may require treatment with biologic therapy. Although
parenteral nutrition has no proven benefit in inducing remission, patients are
often too ill to take adequate oral nutrition.",
" </p>",
" <p class=\"headingAnchor\" id=\"H11189929\">",
" <span class=\"h1\">",
" REFRACTORY DISEASE",
" </span>",
" &nbsp;&mdash;&nbsp;A common and challenging problem is how to manage patients
with Crohn's disease who are refractory to treatment with first-line agents (eg,
glucocorticoids, 5-ASAs, antibiotics). (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?18/54/19305?
source=see_link\">",
" \"Overview of the medical management of mild to moderate Crohn's disease in
adults\"",
" </a>",
" .)",
" </p>",
" <p>",
" Patients are refractory if they:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Repeatedly relapse after achieving remission with first-line agents",
" </li>",
" <li>",
" Remain symptomatic despite adequate doses of glucocorticoids (steroid-
resistant), antibiotics",
" </li>",
" <li>",
" Flare when glucocorticoids are decreased or stopped (steroid-dependent)",
" </li>",
" </ul>",
" </p>",
" <p>",
" Options for the treatment of such patients include",
" <a class=\"drug drug_general\" href=\"UTD.htm?38/3/38967?source=see_link\">",
" azathioprine",
" </a>",
" , 6-mercaptopurine,",
" <a class=\"drug drug_general\" href=\"UTD.htm?23/38/24170?source=see_link\">",
" methotrexate",
" </a>",
" , and biologic therapies. In addition, some authorities recommend using these
drugs early in the course of disease, before patients become steroid-dependent or
resistant, though we do not favor this approach. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?18/54/19305?
source=see_link&amp;anchor=H2#H2\">",
" \"Overview of the medical management of mild to moderate Crohn's disease in
adults\", section on 'Step-up versus top-down therapy'",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H11188258\">",
" <span class=\"h2\">",
" Azathioprine and 6-mercaptopurine",
" </span>",
" &nbsp;&mdash;&nbsp;Many patients with refractory Crohn's disease are treated
with",
" <a class=\"drug drug_general\" href=\"UTD.htm?38/3/38967?source=see_link\">",
" azathioprine",
" </a>",
" or its active metabolite, 6-mercaptopurine (6-MP). The response rate to these
medications is 60 to 70 percent in both small bowel and colonic disease. Treatment
can be initiated with either drug at a dose of 50",
" <span class=\"nowrap\">",
" mg/day.",
" </span>",
" If needed, the dose of 6-MP can be increased to a maximum of 2",
" <span class=\"nowrap\">",
" mg/kg",
" </span>",
" per day (though more commonly 1.5",
" <span class=\"nowrap\">",
" mg/kg",
" </span>",
" is given as the maximum dose) and the dose of azathioprine can be increased to
2.5",
" <span class=\"nowrap\">",
" mg/kg",
" </span>",
" per day, provided there is no bone marrow suppression. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?7/31/7673?
source=see_link\">",
" \"Immunomodulator therapy in Crohn's disease\"",
" </a>",
" .)",
" </p>",
" <p>",
" A response to these medications will usually be seen within three to six
months. During this period, patients often require concomitant steroid therapy with
a gradual reduction in the steroid dose after one to two months of treatment with",
" <a class=\"drug drug_general\" href=\"UTD.htm?38/3/38967?source=see_link\">",
" azathioprine",
" </a>",
" or 6-MP. Patients receiving these drugs require regular monitoring for
toxicity. Testing for metabolites as well as susceptibility to toxicity (by
measuring TPMT activity) is available; TPMT testing is suggested by the US Food and
Drug Administration (FDA) prior to beginning therapy. While not required by the
FDA, we recommend TPMT testing prior to initiating therapy. In addition to bone
marrow suppression, these agents have also been associated with malignancy. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?43/33/44566?
source=see_link\">",
" \"6-mercaptopurine (6-MP) metabolite monitoring and TPMT testing in the
treatment of inflammatory bowel disease with 6-MP or azathioprine\"",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?7/31/7673?
source=see_link&amp;anchor=H2#H2\">",
" \"Immunomodulator therapy in Crohn's disease\", section on 'Azathioprine and
6-mercaptopurine'",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H11188265\">",
" <span class=\"h2\">",
" Methotrexate",
" </span>",
" &nbsp;&mdash;&nbsp;",
" <a class=\"drug drug_general\" href=\"UTD.htm?23/38/24170?source=see_link\">",
" Methotrexate",
" </a>",
" is an alternative for the patient who does not tolerate or does not respond
to",
" <a class=\"drug drug_general\" href=\"UTD.htm?38/3/38967?source=see_link\">",
" azathioprine",
" </a>",
" or 6-MP, and may be preferable to azathioprine or 6-MP in patients with
troublesome Crohn's disease-related arthropathy. To guarantee bioavailability, the
drug should be initiated intramuscularly at a dose of 25 mg per week. A response
should be seen within three months. For patients on steroid therapy, the steroid
should be continued during this period with a gradual lowering of the dose. Once a
response to intramuscular methotrexate is achieved, the patient can be switched to
oral, subcutaneous or intramuscular methotrexate at a dose of 15 mg per week. A
discussion of the data supporting the efficacy of methotrexate is available
elsewhere. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?7/31/7673?
source=see_link&amp;anchor=H13#H13\">",
" \"Immunomodulator therapy in Crohn's disease\", section on 'Methotrexate'",
" </a>",
" .)",
" </p>",
" <p>",
" Concomitant therapy with",
" <a class=\"drug drug_general\" href=\"UTD.htm?8/61/9174?source=see_link\">",
" folic acid",
" </a>",
" 1",
" <span class=\"nowrap\">",
" mg/day",
" </span>",
" may diminish adverse effects to",
" <a class=\"drug drug_general\" href=\"UTD.htm?23/38/24170?source=see_link\">",
" methotrexate",
" </a>",
" . The incidence of hepatotoxicity is low and surveillance liver biopsies may
not be warranted [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6329/abstract/4\">",
" 4",
" </a>",
" ]. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?10/61/11223?
source=see_link\">",
" \"Major side effects of low-dose methotrexate\"",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?31/24/32134?
source=see_link\">",
" \"Hepatotoxicity associated with chronic oral methotrexate for nonmalignant
disease\"",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H11188272\">",
" <span class=\"h2\">",
" Biologic therapies",
" </span>",
" </p>",
" <p class=\"headingAnchor\" id=\"H11188279\">",
" <span class=\"h3\">",
" Anti-TNF therapies",
" </span>",
" &nbsp;&mdash;&nbsp;Three anti-tumor necrosis factor (anti-TNF) therapies are
approved for treatment of Crohn's disease in adults in the United States and all
are effective in treatment of luminal Crohn's disease [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6329/abstract/5\">",
" 5",
" </a>",
" ]:",
" <a class=\"drug drug_general\" href=\"UTD.htm?28/6/28776?source=see_link\">",
" infliximab",
" </a>",
" ,",
" <a class=\"drug drug_general\" href=\"UTD.htm?38/24/39303?source=see_link\">",
" adalimumab",
" </a>",
" , and",
" <a class=\"drug drug_general\" href=\"UTD.htm?38/6/39014?source=see_link\">",
" certolizumab pegol",
" </a>",
" (which is not approved in Europe). However, patients with fibrostenotic
Crohn's disease without active inflammation are unlikely to benefit from anti-TNF
therapy. Patients who are intolerant to one anti-TNF agent may tolerate a different
agent. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?43/4/44105?
source=see_link&amp;anchor=H19#H19\">",
" \"Infliximab in Crohn's disease\", section on 'Use in the setting of
intestinal strictures'",
" </a>",
" .)",
" </p>",
" <p>",
" A meta-analysis found that patients treated with anti-TNF agents were less
likely to fail to achieve remission compared with placebo (RR 0.87) and that the
number of patients who would need to be treated to achieve remission in one patient
was eight [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6329/abstract/6\">",
" 6",
" </a>",
" ]. In addition, anti-TNF agents were also less likely to be associated with
relapse in a patient in remission (RR 0.71). The analysis estimated that four
patients would need to be treated with an anti-TNF agent to prevent one relapse.",
" </p>",
" <p>",
" The selection among these three drugs will depend upon several issues:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Route of administration",
" </li>",
" </ul>",
" </p>",
" <p>",
" <ul class=\"hyphen-block\">",
" <li>",
" <a class=\"drug drug_general\" href=\"UTD.htm?38/24/39303?
source=see_link\">",
" Adalimumab",
" </a>",
" and certolizumab are given subcutaneously, whereas",
" <a class=\"drug drug_general\" href=\"UTD.htm?28/6/28776?
source=see_link\">",
" infliximab",
" </a>",
" is given intravenously. Adalimumab is given every two weeks and certolizumab
is given every four weeks.",
" </li>",
" <li>",
" Self-administration of",
" <a class=\"drug drug_general\" href=\"UTD.htm?38/24/39303?
source=see_link\">",
" adalimumab",
" </a>",
" or certolizumab could lead to incomplete compliance and thereby loss of
efficacy.",
" </li>",
" </ul>",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Labeling indications",
" </li>",
" </ul>",
" </p>",
" <p>",
" <ul class=\"hyphen-block\">",
" <li>",
" <a class=\"drug drug_general\" href=\"UTD.htm?28/6/28776?
source=see_link\">",
" Infliximab",
" </a>",
" and",
" <a class=\"drug drug_general\" href=\"UTD.htm?38/24/39303?
source=see_link\">",
" adalimumab",
" </a>",
" have broader labeling indications; both are approved for reducing signs and
symptoms of Crohn's disease and inducing and maintaining clinical remission,
whereas certolizumab does not have an explicit maintenance indication. However, the
remission rates in clinical trials have not revealed an important difference in
remission rates compared with the other two drugs.",
" </li>",
" </ul>",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Length of experience with the drugs",
" </li>",
" </ul>",
" </p>",
" <p>",
" <ul class=\"hyphen-block\">",
" <li>",
" Experience with",
" <a class=\"drug drug_general\" href=\"UTD.htm?38/24/39303?
source=see_link\">",
" adalimumab",
" </a>",
" for patients who have lost response to or had an adverse reaction to",
" <a class=\"drug drug_general\" href=\"UTD.htm?28/6/28776?
source=see_link\">",
" infliximab",
" </a>",
" is greater than with certolizumab, although data suggest that certolizumab
is also effective in such patients [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6329/abstract/7-11\">",
" 7-11",
" </a>",
" ].",
" </li>",
" <li>",
" The safety record with",
" <a class=\"drug drug_general\" href=\"UTD.htm?28/6/28776?
source=see_link\">",
" infliximab",
" </a>",
" and",
" <a class=\"drug drug_general\" href=\"UTD.htm?38/24/39303?
source=see_link\">",
" adalimumab",
" </a>",
" is longer than with certolizumab. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?39/55/40825?
source=see_link\">",
" \"Tumor necrosis factor-alpha inhibitors: An overview of adverse
effects\"",
" </a>",
" .)",
" </li>",
" </ul>",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Safety and adverse events",
" </li>",
" </ul>",
" </p>",
" <p>",
" <ul class=\"hyphen-block\">",
" <li>",
" <a class=\"drug drug_general\" href=\"UTD.htm?38/24/39303?
source=see_link\">",
" Adalimumab",
" </a>",
" has been associated with injection site reactions and pain at a higher
frequency than certolizumab, although the two have not been directly compared.",
" </li>",
" <li>",
" The use of these agents during pregnancy and breast feeding is discussed
elsewhere. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?25/14/25834?
source=see_link&amp;anchor=H20#H20\">",
" \"Fertility, pregnancy, and nursing in inflammatory bowel disease\",
section on 'Anti-tumor necrosis factor agents'",
" </a>",
" .)",
" </li>",
" </ul>",
" </p>",
" <p class=\"headingAnchor\" id=\"H11188286\">",
" <span class=\"h4\">",
" Infliximab",
" </span>",
" &nbsp;&mdash;&nbsp;Prior to the introduction of biologic agents in the late
1990s, patients with moderate to severe Crohn's disease or fistulous Crohn's
disease had few nonsurgical options.",
" <a class=\"drug drug_general\" href=\"UTD.htm?28/6/28776?source=see_link\">",
" Infliximab",
" </a>",
" is a chimeric",
" <span class=\"nowrap\">",
" mouse/human",
" </span>",
" monoclonal antibody against tumor necrosis factor alpha. It is a powerful tool
for the treatment of moderately to severely active Crohn's disease that is
refractory to conventional therapy. Treatment can be effective in patients with and
without fistulizing disease (including those with internal fistulae, such as
enterovesical fistulae).",
" </p>",
" <p>",
" Clinical trials and experience have demonstrated significant utility of",
" <a class=\"drug drug_general\" href=\"UTD.htm?28/6/28776?source=see_link\">",
" infliximab",
" </a>",
" for induction of remission in moderately active, steroid refractory Crohn's
disease and for maintenance of remission in these patients for up to 54 weeks after
initial infusion. In addition, its use has been associated with improved quality of
life. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?43/4/44105?
source=see_link\">",
" \"Infliximab in Crohn's disease\"",
" </a>",
" .)",
" </p>",
" <p>",
" At the present time, we suggest that",
" <a class=\"drug drug_general\" href=\"UTD.htm?28/6/28776?source=see_link\">",
" infliximab",
" </a>",
" not be used as first-line therapy until appropriate clinical trials have
demonstrated its value as primary therapy and the long-term effects of infliximab
have been fully evaluated. Infliximab should be used primarily in patients who are
refractory to standard therapy or in patients who are steroid dependent, in order
to help taper them off of steroids and transition them to effective long-term
maintenance therapy using infliximab.",
" </p>",
" <p class=\"headingAnchor\" id=\"H11188293\">",
" <span class=\"h4\">",
" Adalimumab and certolizumab pegol",
" </span>",
" &nbsp;&mdash;&nbsp;The roles of",
" <a class=\"drug drug_general\" href=\"UTD.htm?38/24/39303?source=see_link\">",
" adalimumab",
" </a>",
" and certolizumab for treatment of Crohn's disease are evolving. Similar to",
" <a class=\"drug drug_general\" href=\"UTD.htm?28/6/28776?source=see_link\">",
" infliximab",
" </a>",
" , these agents are probably best reserved for patients refractory to primary
therapy or who are steroid dependent. They are also options for patients who have
lost response to or had an adverse reaction to infliximab. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?28/55/29559?
source=see_link\">",
" \"Adalimumab for treatment of Crohn's disease in adults\"",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?33/2/33829?
source=see_link\">",
" \"Certolizumab pegol for treatment of Crohn's disease in adults\"",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H11188300\">",
" <span class=\"h4\">",
" Safety of anti-TNF therapies",
" </span>",
" &nbsp;&mdash;&nbsp;A number of adverse events have been described following
treatment with anti-TNF-alpha agents. These are summarized separately along with
recommendations for screening patients prior to starting these medications. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?39/55/40825?
source=see_link\">",
" \"Tumor necrosis factor-alpha inhibitors: An overview of adverse effects\"",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?31/49/32538?
source=see_link\">",
" \"Tumor necrosis factor-alpha inhibitors: Risk of bacterial, viral, and
fungal infections\"",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?23/38/24169?
source=see_link\">",
" \"Tumor necrosis factor-alpha inhibitors and mycobacterial infections\"",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?32/53/33624?
source=see_link\">",
" \"Tumor necrosis factor-alpha inhibitors: Risk of malignancy\"",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H170181302\">",
" <span class=\"h3\">",
" Switching biologic therapies",
" </span>",
" &nbsp;&mdash;&nbsp;As noted above, patients who fail to respond to, lose their
response to, or are intolerant of one biologic therapy may be switched to an
alternative anti-TNF agent. However, data suggest that patients who have achieved a
sustained response with",
" <a class=\"drug drug_general\" href=\"UTD.htm?28/6/28776?source=see_link\">",
" infliximab",
" </a>",
" should be maintained on infliximab and not switched to an alternative anti-TNF
agent (eg,",
" <a class=\"drug drug_general\" href=\"UTD.htm?38/24/39303?source=see_link\">",
" adalimumab",
" </a>",
" , which is given subcutaneously and may be more convenient for some patients)
because switching in this setting is associated with worse clinical outcomes.
(See",
" <a class=\"medical medical_review\" href=\"UTD.htm?43/4/44105?
source=see_link&amp;anchor=H170181101#H170181101\">",
" \"Infliximab in Crohn's disease\", section on 'Switching from infliximab to
an alternative anti-TNF agent'",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H11188307\">",
" <span class=\"h3\">",
" Natalizumab",
" </span>",
" &nbsp;&mdash;&nbsp;An alternative to anti-TNF therapy is",
" <a class=\"drug drug_general\" href=\"UTD.htm?1/15/1271?source=see_link\">",
" natalizumab",
" </a>",
" . Natalizumab is a humanized monoclonal antibody directed against alpha-4
integrin. It acts by blocking leukocyte migration to sites of inflammation. The use
of natalizumab has been limited by its association with progressive multifocal
leukoencephalopathy. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?3/22/3429?
source=see_link\">",
" \"Natalizumab for treatment of Crohn's disease in adults\"",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?26/3/26681?
source=see_link\">",
" \"Progressive multifocal leukoencephalopathy: Epidemiology, clinical
manifestations, and diagnosis\"",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H2897067\">",
" <span class=\"h3\">",
" Ustekinumab",
" </span>",
" &nbsp;&mdash;&nbsp;",
" <a class=\"drug drug_general\" href=\"UTD.htm?0/46/742?source=see_link\">",
" Ustekinumab",
" </a>",
" is a human IgG",
" _{",
" 1k",
"}",
" monoclonal antibody that blocks the biologic activity of IL-12 and IL-23 by
inhibiting receptors for these cytokines on T cells, natural killer cells and
antigen presenting cells [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6329/abstract/12\">",
" 12",
" </a>",
" ]. In a phase II trial, 526 patients with moderate to severe Crohn&rsquo;s
disease resistant to TNF antagonists were randomized to 1, 3, or 6",
" <span class=\"nowrap\">",
" mg/kg",
" </span>",
" of intravenous ustekinumab or placebo for induction of remission [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6329/abstract/13\">",
" 13",
" </a>",
" ]. During the maintenance phase, 145 patients with a response to induction
with ustekinumab at six weeks were randomized to receive ustekinumab (90 mg SQ) or
placebo at 8 and 16 weeks.",
" </p>",
" <p>",
" At six weeks, patients who received 6",
" <span class=\"nowrap\">",
" mg/kg",
" </span>",
" of",
" <a class=\"drug drug_general\" href=\"UTD.htm?0/46/742?source=see_link\">",
" ustekinumab",
" </a>",
" for induction of remission had significantly higher response rates as compared
with placebo (40 versus 24 percent). During the maintenance phase, patients with an
initial response to ustekinumab had significantly higher rates of response (69
versus 42 percent) and remission (42 versus 27 percent) at 22 weeks, as compared
with placebo. Serious adverse events were rare, but the study was limited by the
small sample size and short duration of the maintenance phase. Larger studies are
needed to establish the efficacy of ustekinumab in patients with moderate to severe
Crohn&rsquo;s disease that is resistant to TNF antagonists.",
" </p>",
" <p class=\"headingAnchor\" id=\"H11188314\">",
" <span class=\"h2\">",
" Continued disease resistance",
" </span>",
" &nbsp;&mdash;&nbsp;There are two medical approaches to patients with active
Crohn's disease despite therapy with 5-ASA agents, antibiotics, immunomodulators,",
" <span class=\"nowrap\">",
" and/or",
" </span>",
" biologic agents: chronic low-dose steroid therapy and",
" <a class=\"drug drug_general\" href=\"UTD.htm?41/40/42628?source=see_link\">",
" total parenteral nutrition",
" </a>",
" . In addition, surgery should be considered if a limited resection or other
conservative procedure is possible. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?4/50/4906?
source=see_link\">",
" \"Surgical management of ulcerative colitis\"",
" </a>",
" .)",
" </p>",
" <p>",
" Some patients can only achieve a relative degree of remission with low-dose",
" <a class=\"drug drug_general\" href=\"UTD.htm?37/43/38585?source=see_link\">",
" prednisone",
" </a>",
" . Such patients should be maintained on the lowest dose that results in
decreased symptoms; alternate-day therapy can be tried for maintenance to minimize
toxicity [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6329/abstract/14\">",
" 14",
" </a>",
" ]. This approach should be considered only in patients who have failed both
immunomodulator and biologic therapy since maintenance glucocorticoids have not
been proven to reduce the rate of relapse and are associated with many side effects
[",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6329/abstract/15\">",
" 15",
" </a>",
" ]. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?26/47/27386?
source=see_link\">",
" \"Major side effects of systemic glucocorticoids\"",
" </a>",
" .)",
" </p>",
" <p>",
" An alternative for steroid-refractory Crohn's disease is",
" <a class=\"drug drug_general\" href=\"UTD.htm?41/40/42628?source=see_link\">",
" total parenteral nutrition",
" </a>",
" (TPN) or enteral feeding with an elemental or polymeric diet [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6329/abstract/16\">",
" 16",
" </a>",
" ]. In a retrospective study of 100 patients treated with TPN and complete
bowel rest, 77 achieved clinical remission [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6329/abstract/17\">",
" 17",
" </a>",
" ]. The remission rates were similar in patients with subacute bowel
obstruction, inflammatory masses, and uncomplicated severe active disease;
approximately 60 percent of these patients were in remission at one year. A lower
initial response rate (63 percent) and one year remission rate (36 percent) were
seen in patients with fistulae.",
" </p>",
" <p>",
" However, patients may relapse when feedings are resumed. In addition, many
patients will not tolerate subsequent attempts at enteral feeding, and long-term
TPN carries the risk of line sepsis and thrombophlebitis. Nevertheless, these
nutritional approaches should be considered in refractory patients and can be
lifesaving in those with short bowel syndrome.",
" </p>",
" <p class=\"headingAnchor\" id=\"H286979610\">",
" <span class=\"h1\">",
" VENOUS THROMBOEMBOLISM",
" </span>",
" &nbsp;&mdash;&nbsp;Studies have demonstrated an increased risk of venous
thromboembolism and pulmonary embolism in patients with IBD in both population-
based and hospital-based cohorts [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6329/abstract/18-20\">",
" 18-20",
" </a>",
" ]. Current guidelines recommend prophylaxis for venous thromboembolism or
consideration of prophylaxis for hospitalized patients with IBD [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6329/abstract/21,22\">",
" 21,22",
" </a>",
" ]. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?35/21/36186?
source=see_link&amp;anchor=H10#H10\">",
" \"Prevention of venous thromboembolic disease in medical patients\", section
on 'Prevention of VTE'",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H11188321\">",
" <span class=\"h1\">",
" MEDICAL MANAGEMENT OF CROHN'S DISEASE COMPLICATIONS",
" </span>",
" </p>",
" <p class=\"headingAnchor\" id=\"H11188328\">",
" <span class=\"h2\">",
" Fistulae",
" </span>",
" &nbsp;&mdash;&nbsp;The transmural inflammatory nature of Crohn's disease
predisposes to the formation of fistulae, a complication that may dominate the
clinical picture (",
" <a class=\"graphic graphic_diagnosticimage graphicRef58575 \" href=\"UTD.htm?
14/12/14534\">",
" image 1",
" </a>",
" ). The drugs with the best established roles for the medical treatment of
active Crohn's fistulous disease are",
" <a class=\"drug drug_general\" href=\"UTD.htm?28/6/28776?source=see_link\">",
" infliximab",
" </a>",
" ,",
" <a class=\"drug drug_general\" href=\"UTD.htm?38/3/38967?source=see_link\">",
" azathioprine",
" </a>",
" , and 6-MP. Steroids and",
" <a class=\"drug drug_general\" href=\"UTD.htm?8/28/8647?source=see_link\">",
" sulfasalazine",
" </a>",
" have not been successful for inducing fistula closure [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6329/abstract/23\">",
" 23",
" </a>",
" ]. A meta-analysis found that patients treated with biologic therapy were less
likely than patients treated with placebo to have a nonhealing fistula (RR 0.88)
[",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6329/abstract/6\">",
" 6",
" </a>",
" ].",
" </p>",
" <p>",
" For most patients with fistulae, especially those with actively draining
fistulae or high output enteroenteric fistulae, we suggest",
" <a class=\"drug drug_general\" href=\"UTD.htm?28/6/28776?source=see_link\">",
" infliximab",
" </a>",
" 5",
" <span class=\"nowrap\">",
" mg/kg",
" </span>",
" administered at weeks 0, 2, and 6. Combination therapy with",
" <a class=\"drug drug_general\" href=\"UTD.htm?38/3/38967?source=see_link\">",
" azathioprine",
" </a>",
" has superior efficacy than monotherapy. We do",
" <strong>",
" not",
" </strong>",
" generally use infliximab in conjunction with azathioprine or 6-MP long-term
due to a possible increased risk of complications, especially hepatosplenic T-cell
lymphoma. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?43/4/44105?
source=see_link&amp;anchor=H12#H12\">",
" \"Infliximab in Crohn's disease\", section on 'Use of immunosuppressive
agents in combination with infliximab'",
" </a>",
" .)",
" </p>",
" <p>",
" Traditionally, patients with perianal fistulae have been managed with
antibiotics, though the data supporting this practice are limited. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?24/43/25273?
source=see_link&amp;anchor=H16#H16\">",
" \"Perianal complications of Crohn's disease\", section on 'Patients with mild
to moderate symptoms'",
" </a>",
" .)",
" </p>",
" <p>",
" Patients with enterovesical fistulae present with recurrent polymicrobial
urinary tract infections, pneumaturia, and fecaluria. Antibiotics will usually
control the urinary tract infection, but",
" <a class=\"drug drug_general\" href=\"UTD.htm?38/3/38967?source=see_link\">",
" azathioprine",
" </a>",
" or 6-MP should be considered to heal the fistula. Most patients with this
complication will ultimately require surgery. However, some patients have been
maintained on courses of antibiotics and continuous immunomodulator therapy [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6329/abstract/23\">",
" 23",
" </a>",
" ].",
" </p>",
" <p class=\"headingAnchor\" id=\"H11188335\">",
" <span class=\"h2\">",
" Localized peritonitis",
" </span>",
" &nbsp;&mdash;&nbsp;Patients with small bowel Crohn's disease frequently
present with fever, chills, and right lower quadrant pain associated with
leukocytosis. Such patients have often suffered a microperforation with localized
peritonitis that is contained by the surrounding mesentery and bowel loops.
Appendicitis in the patient without prior appendectomy is also a consideration in
this setting. An abdominal and pelvic computed tomography scan at the time of
admission may help to distinguish among the diagnostic possibilities.",
" </p>",
" <p>",
" The management of localized peritonitis includes bowel rest and broad-spectrum
antibiotics. A response to therapy is usually seen within three to four days and
intravenous antibiotic therapy is continued for 7 to 10 days. A subsequent two- to
four-week course of outpatient oral therapy with",
" <a class=\"drug drug_general\" href=\"UTD.htm?34/45/35536?source=see_link\">",
" ciprofloxacin",
" </a>",
" and",
" <a class=\"drug drug_general\" href=\"UTD.htm?19/38/20065?source=see_link\">",
" metronidazole",
" </a>",
" should be considered. Intestinal resection should be considered in
nonresponders.",
" </p>",
" <p>",
" There is some controversy as to the role of glucocorticoids in this setting.
For patients already on steroids, a small increase in the dose may be required.
However, for those not previously on steroids, we suggest withholding steroids to
avoid masking any further sepsis. There are, however, few data demonstrating an
increase in complications in such patients who receive steroid therapy, though one
study did show an increase in the risk of developing an intraabdominal or pelvic
abscess in patients with penetrating Crohn's disease who received steroids (RR 9.0)
[",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6329/abstract/24\">",
" 24",
" </a>",
" ].",
" </p>",
" <p class=\"headingAnchor\" id=\"H11188342\">",
" <span class=\"h2\">",
" Abscesses",
" </span>",
" &nbsp;&mdash;&nbsp;The management of patients with abscesses depends upon the
clinical setting, history of prior bowel surgery, and characteristics of the
abscess. As a general rule, three approaches have been described: medical
management with antibiotics (and possibly steroids), percutaneous drainage, and
surgery with resection of involved intestinal segments.",
" </p>",
" <p>",
" The largest series comparing these approaches included a group of 51 patients
who were identified retrospectively from medical charts covering a 10-year period
[",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6329/abstract/25\">",
" 25",
" </a>",
" ]. Patients who had undergone surgical management were significantly less
likely to develop a recurrent abscess compared with those who had been managed with
antibiotics (with or without steroids) or percutaneous drainage (12 versus 56
percent). Nevertheless, medical management and percutaneous drainage prevented
subsequent surgery in nearly one-half of patients during an average of 3.75 years
of follow-up, suggesting that it is a reasonable approach for some patients.
Similar results for percutaneous drainage have been described in other reports with
long-term follow-up [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6329/abstract/26\">",
" 26",
" </a>",
" ].",
" </p>",
" <p class=\"headingAnchor\" id=\"H11188349\">",
" <span class=\"h2\">",
" Small bowel obstruction",
" </span>",
" &nbsp;&mdash;&nbsp;Small bowel obstruction is common in longstanding Crohn's
disease. It may result from a stricture causing mechanical obstruction, a stenotic
area with superimposed inflammation and spasm, a stenotic area in which undigested
food has impacted, an enterolith or, in patients who have had prior surgery,
intestinal adhesions.",
" </p>",
" <p>",
" Affected patients most commonly present with partial obstruction and, except
in those who have had an adhesion, the mechanism is non-strangulating. Conservative
therapy with intravenous hydration, nasogastric suction, and parenteral nutrition
is often successful, with a response seen within 24 to 48 hours. Parenteral
glucocorticoids should be considered in nonresponders. Surgery is reserved for
those patients who do not respond to these noninvasive measures or who have
evidence of small bowel ischemia. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?4/50/4906?
source=see_link\">",
" \"Surgical management of ulcerative colitis\"",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H11188356\">",
" <span class=\"h1\">",
" POSTOPERATIVE RECURRENCE",
" </span>",
" &nbsp;&mdash;&nbsp;Postoperative recurrence is discussed separately. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?0/50/809?
source=see_link\">",
" \"Medical prophylaxis of postoperative Crohn's disease\"",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"PATIENT_INFORMATION\">",
" <span class=\"h1\">",
" INFORMATION FOR PATIENTS",
" </span>",
" &nbsp;&mdash;&nbsp;UpToDate offers two types of patient education
materials, \"The Basics\" and \"Beyond the Basics.\" The Basics patient education
pieces are written in plain language, at the 5",
" ^{",
" th",
"}",
" to 6",
" ^{",
" th",
"}",
" grade reading level, and they answer the four or five key questions a patient
might have about a given condition. These articles are best for patients who want a
general overview and who prefer short, easy-to-read materials. Beyond the Basics
patient education pieces are longer, more sophisticated, and more detailed. These
articles are written at the 10",
" ^{",
" th",
"}",
" to 12",
" ^{",
" th",
"}",
" grade reading level and are best for patients who want in-depth information
and are comfortable with some medical jargon.",
" </p>",
" <p>",
" Here are the patient education articles that are relevant to this topic. We
encourage you to print or e-mail these topics to your patients. (You can also
locate patient education articles on a variety of subjects by searching
on \"patient info\" and the keyword(s) of interest.)",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Basics topics (see",
" <a class=\"medical medical_basics\" href=\"UTD.htm?9/56/10115?
source=see_link\">",
" \"Patient information: Crohn's disease in adults (The Basics)\"",
" </a>",
" )",
" </li>",
" <li>",
" Beyond the Basics topics (see",
" <a class=\"medical medical_patient\" href=\"UTD.htm?23/40/24196?
source=see_link\">",
" \"Patient information: Crohn's disease (Beyond the Basics)\"",
" </a>",
" and",
" <a class=\"medical medical_patient\" href=\"UTD.htm?17/11/17586?
source=see_link\">",
" \"Patient information: Sulfasalazine and the 5-aminosalicylates (Beyond the
Basics)\"",
" </a>",
" )",
" </li>",
" </ul>",
" </p>",
" <p class=\"headingAnchor\" id=\"H11189315\">",
" <span class=\"h1\">",
" SUMMARY AND RECOMMENDATIONS",
" </span>",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Outpatient therapy with oral medications is appropriate for most patients
with mildly to moderately active Crohn's disease. However, hospitalization is
required for patients who present with severe symptoms or appear toxic. (See",
" <a class=\"local\" href=\"#H11189921\">",
" 'Severe disease'",
" </a>",
" above.)",
" </li>",
" <li>",
" A common and challenging problem is how to manage patients with Crohn's
disease who are refractory to treatment with first-line agents (eg,
glucocorticoids, 5-ASAs, antibiotics). (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?18/54/19305?
source=see_link\">",
" \"Overview of the medical management of mild to moderate Crohn's disease in
adults\"",
" </a>",
" .)",
" <br/>",
" <br/>",
" Patients are refractory if they:",
" </li>",
" </ul>",
" </p>",
" <p>",
" <ul class=\"hyphen-block\">",
" <li>",
" Repeatedly relapse after achieving remission with first-line agents",
" </li>",
" <li>",
" Remain symptomatic despite adequate doses of glucocorticoids (steroid-
resistant), 5-ASAs, and antibiotics",
" </li>",
" <li>",
" Flare when glucocorticoids are decreased or stopped (steroid-dependent)",
" </li>",
" </ul>",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Options for the treatment of patients with refractory Crohn's disease
include",
" <a class=\"drug drug_general\" href=\"UTD.htm?38/3/38967?
source=see_link\">",
" azathioprine",
" </a>",
" , 6-mercaptopurine,",
" <a class=\"drug drug_general\" href=\"UTD.htm?23/38/24170?
source=see_link\">",
" methotrexate",
" </a>",
" , and biologic therapies. (See",
" <a class=\"local\" href=\"#H11189929\">",
" 'Refractory disease'",
" </a>",
" above.)",
" </li>",
" <li>",
" We suggest treatment with",
" <a class=\"drug drug_general\" href=\"UTD.htm?38/3/38967?
source=see_link\">",
" azathioprine",
" </a>",
" or 6-mercaptopurine for patients who relapse while being maintained on 5-ASA
drugs or",
" <a class=\"drug drug_general\" href=\"UTD.htm?32/7/32880?
source=see_link\">",
" budesonide",
" </a>",
" , who are refractory to treatment with 5-ASA drugs, antibiotics, or
glucocorticoids, or who cannot be tapered off of glucocorticoids (",
" <a class=\"grade\" href=\"._grade_5?title=Grade 2B\">",
" Grade 2B",
" </a>",
" ). Treatment with a biologic agent is a reasonable alternative, especially
in patients with moderate to severe symptoms who cannot wait for immunomodulator
therapy to take effect. (See",
" <a class=\"local\" href=\"#H11188258\">",
" 'Azathioprine and 6-mercaptopurine'",
" </a>",
" above and",
" <a class=\"local\" href=\"#H11188272\">",
" 'Biologic therapies'",
" </a>",
" above.)",
" </li>",
" <li>",
" The drugs with the best established roles for the medical treatment of
active Crohn's fistulous disease are",
" <a class=\"drug drug_general\" href=\"UTD.htm?28/6/28776?
source=see_link\">",
" infliximab",
" </a>",
" ,",
" <a class=\"drug drug_general\" href=\"UTD.htm?38/3/38967?
source=see_link\">",
" azathioprine",
" </a>",
" , and 6-MP. Steroids and",
" <a class=\"drug drug_general\" href=\"UTD.htm?8/28/8647?source=see_link\">",
" sulfasalazine",
" </a>",
" have not been successful for inducing fistula closure. (See",
" <a class=\"local\" href=\"#H11188328\">",
" 'Fistulae'",
" </a>",
" above.)",
" </li>",
" <li>",
" The management of localized peritonitis includes bowel rest and broad-
spectrum antibiotics. Intestinal resection should be considered in nonresponders.
(See",
" <a class=\"local\" href=\"#H11188335\">",
" 'Localized peritonitis'",
" </a>",
" above.)",
" </li>",
" <li>",
" Three approaches have been described for the management of abscesses related
to Crohn's disease: medical management with antibiotics (and possibly steroids),
percutaneous drainage, and surgery with resection of involved intestinal segments.
(See",
" <a class=\"local\" href=\"#H11188342\">",
" 'Abscesses'",
" </a>",
" above.)",
" </li>",
" <li>",
" In patients with small bowel obstructions due to Crohn's disease,
conservative therapy with intravenous hydration, nasogastric suction, and
parenteral nutrition is often successful. Parenteral glucocorticoids are an
alternative in nonresponders. Surgery is reserved for those patients who do not
respond to noninvasive measures or with evidence of small bowel ischemia. (See",
" <a class=\"local\" href=\"#H11188349\">",
" 'Small bowel obstruction'",
" </a>",
" above.)",
" </li>",
" </ul>",
" </p>",
" </div>",
" <div id=\"topicAgreement\">",
" Use of UpToDate is subject to the",
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" </div>",
" <div class=\"headingAnchor\" id=\"references\">",
" <h1>",
" REFERENCES",
" </h1>",
" <ol id=\"reference\">",
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" Lichtenstein GR, Hanauer SB, Sandborn WJ, Practice Parameters Committee of
American College of Gastroenterology. Management of Crohn's disease in adults. Am J
Gastroenterol 2009; 104:465.",
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" <a class=\"nounderline abstract\" href=\"UTD.htm?6/11/6329/abstract/4\">",
" Te HS, Schiano TD, Kuan SF, et al. Hepatic effects of long-term methotrexate
use in the treatment of inflammatory bowel disease. Am J Gastroenterol 2000;
95:3150.",
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" <a class=\"nounderline abstract\" href=\"UTD.htm?6/11/6329/abstract/5\">",
" Peyrin-Biroulet L, Deltenre P, de Suray N, et al. Efficacy and safety of
tumor necrosis factor antagonists in Crohn's disease: meta-analysis of placebo-
controlled trials. Clin Gastroenterol Hepatol 2008; 6:644.",
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" <a class=\"nounderline abstract\" href=\"UTD.htm?6/11/6329/abstract/6\">",
" Ford AC, Sandborn WJ, Khan KJ, et al. Efficacy of biological therapies in
inflammatory bowel disease: systematic review and meta-analysis. Am J Gastroenterol
2011; 106:644.",
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" Hanauer SB, Sandborn WJ, Rutgeerts P, et al. Human anti-tumor necrosis
factor monoclonal antibody (adalimumab) in Crohn's disease: the CLASSIC-I trial.
Gastroenterology 2006; 130:323.",
" </a>",
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" Sandborn WJ, Hanauer SB, Rutgeerts P, et al. Adalimumab for maintenance
treatment of Crohn's disease: results of the CLASSIC II trial. Gut 2007; 56:1232.",
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" <a class=\"nounderline abstract\" href=\"UTD.htm?6/11/6329/abstract/9\">",
" Colombel JF, Sandborn WJ, Rutgeerts P, et al. Adalimumab for maintenance of
clinical response and remission in patients with Crohn's disease: the CHARM trial.
Gastroenterology 2007; 132:52.",
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" <a class=\"nounderline abstract\" href=\"UTD.htm?6/11/6329/abstract/10\">",
" Schreiber S, Khaliq-Kareemi M, Lawrance IC, et al. Maintenance therapy with
certolizumab pegol for Crohn's disease. N Engl J Med 2007; 357:239.",
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" Schreiber S, Rutgeerts P, Fedorak RN, et al. A randomized, placebo-
controlled trial of certolizumab pegol (CDP870) for treatment of Crohn's disease.
Gastroenterology 2005; 129:807.",
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" <a class=\"nounderline abstract\" href=\"UTD.htm?6/11/6329/abstract/12\">",
" Benson JM, Peritt D, Scallon BJ, et al. Discovery and mechanism of
ustekinumab: a human monoclonal antibody targeting interleukin-12 and interleukin-
23 for treatment of immune-mediated disorders. MAbs 2011; 3:535.",
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" <a class=\"nounderline abstract\" href=\"UTD.htm?6/11/6329/abstract/13\">",
" Sandborn WJ, Gasink C, Gao LL, et al. Ustekinumab induction and maintenance
therapy in refractory Crohn's disease. N Engl J Med 2012; 367:1519.",
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" <a class=\"nounderline abstract\" href=\"UTD.htm?6/11/6329/abstract/14\">",
" Malchow H, Ewe K, Brandes JW, et al. European Cooperative Crohn's Disease
Study (ECCDS): results of drug treatment. Gastroenterology 1984; 86:249.",
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" <a class=\"nounderline abstract\" href=\"UTD.htm?6/11/6329/abstract/15\">",
" Steinhart AH, Ewe K, Griffiths AM, et al. Corticosteroids for maintenance of
remission in Crohn's disease. Cochrane Database Syst Rev 2003; :CD000301.",
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" <a class=\"nounderline abstract\" href=\"UTD.htm?6/11/6329/abstract/16\">",
" Akobeng AK, Thomas AG. Enteral nutrition for maintenance of remission in
Crohn's disease. Cochrane Database Syst Rev 2007; :CD005984.",
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" Ostro MJ, Greenberg GR, Jeejeebhoy KN. Total parenteral nutrition and
complete bowel rest in the management of Crohn's disease. JPEN J Parenter Enteral
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" <a class=\"nounderline abstract\" href=\"UTD.htm?6/11/6329/abstract/18\">",
" Kappelman MD, Horvath-Puho E, Sandler RS, et al. Thromboembolic risk among
Danish children and adults with inflammatory bowel diseases: a population-based
nationwide study. Gut 2011; 60:937.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?6/11/6329/abstract/19\">",
" Miehsler W, Reinisch W, Valic E, et al. Is inflammatory bowel disease an
independent and disease specific risk factor for thromboembolism? Gut 2004;
53:542.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?6/11/6329/abstract/20\">",
" Nguyen GC, Sam J. Rising prevalence of venous thromboembolism and its impact
on mortality among hospitalized inflammatory bowel disease patients. Am J
Gastroenterol 2008; 103:2272.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?6/11/6329/abstract/21\">",
" Carter MJ, Lobo AJ, Travis SP, IBD Section, British Society of
Gastroenterology. Guidelines for the management of inflammatory bowel disease in
adults. Gut 2004; 53 Suppl 5:V1.",
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" <a class=\"nounderline abstract\" href=\"UTD.htm?6/11/6329/abstract/22\">",
" Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous
thromboembolism: American College of Chest Physicians Evidence-Based Clinical
Practice Guidelines (8th Edition). Chest 2008; 133:381S.",
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" </li>",
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" <a class=\"nounderline abstract\" href=\"UTD.htm?6/11/6329/abstract/23\">",
" Korelitz BI, Present DH. Favorable effect of 6-mercaptopurine on fistulae of
Crohn's disease. Dig Dis Sci 1985; 30:58.",
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" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?6/11/6329/abstract/24\">",
" Agrawal A, Durrani S, Leiper K, et al. Effect of systemic corticosteroid
therapy on risk for intra-abdominal or pelvic abscess in non-operated Crohn's
disease. Clin Gastroenterol Hepatol 2005; 3:1215.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?6/11/6329/abstract/25\">",
" Garcia JC, Persky SE, Bonis PA, Topazian M. Abscesses in Crohn's disease:
outcome of medical versus surgical treatment. J Clin Gastroenterol 2001; 32:409.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?6/11/6329/abstract/26\">",
" Gervais DA, Hahn PF, O'Neill MJ, Mueller PR. Percutaneous abscess drainage
in Crohn disease: technical success and short- and long-term outcomes during 14
years. Radiology 2002; 222:645.",
" </a>",
" </li>",
" </ol>",
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" SUMMARY &amp; RECOMMENDATIONS",
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" INTRODUCTION",
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" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#H11189921\">",
" SEVERE DISEASE",
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" REFRACTORY DISEASE",
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" Azathioprine and 6-mercaptopurine",
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" Methotrexate",
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" </li>",
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" <a class=\"outlineLink\" href=\"#H11188272\">",
" Biologic therapies",
" </a>",
" </li>",
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" - Anti-TNF therapies",
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" Infliximab",
" </a>",
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" Adalimumab and certolizumab pegol",
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" Safety of anti-TNF therapies",
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" - Natalizumab",
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" - Ustekinumab",
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" <a class=\"outlineLink\" href=\"#H11188314\">",
" Continued disease resistance",
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" </li>",
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" VENOUS THROMBOEMBOLISM",
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" </li>",
" <li class=\"plainItem\">",
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" MEDICAL MANAGEMENT OF CROHN'S DISEASE COMPLICATIONS",
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" </li>",
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" Fistulae",
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" Localized peritonitis",
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" Abscesses",
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" Small bowel obstruction",
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" POSTOPERATIVE RECURRENCE",
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" SUMMARY AND RECOMMENDATIONS",
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" REFERENCES",
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" <h1>",
" <div class=\"openRelatedGraphics\" id=\"GAST/16224\" rel=\"outline_link\">",
" GRAPHICS",
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" CT enteric fistula",
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" RELATED TOPICS",
" </h1>",
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" <ul>",
" <li class=\"plainItem\">",
" <a class=\"medical medical_review\" href=\"UTD.htm?43/33/44566?
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" 6-mercaptopurine (6-MP) metabolite monitoring and TPMT testing in the
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" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"medical medical_review\" href=\"UTD.htm?28/55/29559?
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" <a class=\"medical medical_review\" href=\"UTD.htm?0/50/809?
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" Medical prophylaxis of postoperative Crohn's disease",
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" Natalizumab for treatment of Crohn's disease in adults",
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6/11/6330/contributors\">",
" Mahesh Sharman, MD, FAAP",
" </a>",
" <br/>",
" <a class=\"contributor contributor_credentials\" href=\"UTD.htm?
6/11/6330/contributors\">",
" Ashok P Sarnaik, MD, FAAP, FCCM",
" </a>",
" <br/>",
" </div>",
" <div>",
" <a class=\"contributor contributor_credentials contributorType\"
href=\"UTD.htm?6/11/6330/contributors\">",
" Section Editor",
" </a>",
" <br/>",
" <a class=\"contributor contributor_credentials\" href=\"UTD.htm?
6/11/6330/contributors\">",
" Tej K Mattoo, MD, DCH, FRCP",
" </a>",
" <br/>",
" </div>",
" <div>",
" <a class=\"contributor contributor_credentials contributorType\"
href=\"UTD.htm?6/11/6330/contributors\">",
" Deputy Editor",
" </a>",
" <br/>",
" <a class=\"contributor contributor_credentials\" href=\"UTD.htm?
6/11/6330/contributors\">",
" Melanie S Kim, MD",
" </a>",
" <br/>",
" </div>",
" </div>",
" <div id=\"disclosures\">",
" <a href=\"UTD.htm?6/11/6330/contributor-disclosure\" target=\"_blank\">",
" Disclosures",
" </a>",
" </div>",
" <div id=\"reviewProcess\">",
" <span>",
" All topics are updated as new evidence becomes available and our",
" </span>",
" <a href=\"/home/editorial-policy\" target=\"_blank\">",
" peer review process",
" </a>",
" <span>",
" is complete.",
" </span>",
" </div>",
" <div id=\"literatureReviewDate\">",
" <span class=\"emphasis\">",
" Literature review current through:",
" </span>",
" Oct 2013.",
" <span class=\"pipeSpace\">",
" |",
" </span>",
" <span class=\"emphasis\">",
" This topic last updated:",
" </span>",
" Jan 24, 2013.",
" </div>",
" <div id=\"topicText\">",
" <p class=\"headingAnchor\" id=\"H1\">",
" <span class=\"h1\">",
" INTRODUCTION",
" </span>",
" &nbsp;&mdash;&nbsp;Infants and children with metabolic acidosis can present
with varying degrees of acute and chronic illness, from the seemingly healthy child
to those in catastrophic collapse. A careful history and physical examination can
help direct an accurate evaluation for a specific pathophysiologic process.",
" </p>",
" <p>",
" An approach to the physiology, differential diagnosis, and treatment of
metabolic acidosis in children will be reviewed here. Issues relating to metabolic
acidosis in adults are presented separately. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?30/44/31432?
source=see_link\">",
" \"Approach to the adult with metabolic acidosis\"",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H2\">",
" <span class=\"h1\">",
" ACID-BASE BALANCE",
" </span>",
" &nbsp;&mdash;&nbsp;To optimally understand the various clinical disorders that
result in metabolic acidosis, it is important to review the physiologic principles
underlying acid generation and excretion. Each day under normal physiologic
conditions, children produce 2 to 3",
" <span class=\"nowrap\">",
" mEq/kg",
" </span>",
" of nonvolatile acid, mostly sulfuric acid derived from the metabolism of
sulfur-containing amino acids. To maintain the steady-state, these hydrogen ions
must be excreted in the urine.",
" </p>",
" <p>",
" Acid-base balance is maintained by initial buffering of the acid load and then
excretion in the urine.",
" </p>",
" <p class=\"headingAnchor\" id=\"H3\">",
" <span class=\"h2\">",
" Buffers",
" </span>",
" &nbsp;&mdash;&nbsp;Initial buffering is primarily achieved by bicarbonate
(HCO3-) in the extracellular fluid and then proteins and phosphate in the cells.
The bicarbonate-carbon dioxide buffer system is expressed by the following
equation, which is based upon the Br&oslash;nsted-Lowry definition of acids and
bases:",
" </p>",
" <p>",
" &nbsp; &nbsp;HCO3- &nbsp;+ &nbsp; H+ &nbsp; &lt;&mdash;&gt; &nbsp; H2CO3
&nbsp; &lt;&mdash;&gt; &nbsp; Dissolved CO2 &nbsp;+ &nbsp;H2O",
" </p>",
" <p>",
" The concentration of H2CO3 (carbonic acid) is normally so low that its role
can be ignored and the equation simplifies to:",
" </p>",
" <p>",
" &nbsp; &nbsp;HCO3- &nbsp;+ &nbsp; H+ &nbsp; &lt;&mdash;&gt; &nbsp; Dissolved
CO2 &nbsp;+ &nbsp;H2O",
" </p>",
" <p>",
" The relationship between the H+ concentration and the other reactants can be
expressed by:",
" </p>",
" <p>",
" &nbsp; &nbsp;H+",
" <span class=\"nowrap\">",
" (nanomole/L)",
" </span>",
" &nbsp; = &nbsp; 24 &nbsp;x &nbsp;PCO2 (mmHg) &nbsp;&divide; &nbsp;serum
HCO3-",
" <span class=\"nowrap\">",
" (mEq/L)",
" </span>",
" </p>",
" <p>",
" This equation can also be expressed logarithmically as the Henderson-
Hasselbalch equation:",
" </p>",
" <p>",
" &nbsp; &nbsp;pH &nbsp; = &nbsp; 6.10 &nbsp; + &nbsp; log &nbsp;([HCO3-]
&nbsp;&divide; &nbsp;[0.03 &nbsp;x &nbsp;PCO2])",
" </p>",
" <p>",
" where the pH is equal to (-log [H+]), 6.10 is the pKa (equal to -log Ka), Ka
is the dissociation constant for the reaction, 0.03 is equal to the solubility
constant for CO2 in the extracellular fluid, and PCO2 is equal to the partial
pressure of carbon dioxide in the extracellular fluid [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6330/abstract/1\">",
" 1",
" </a>",
" ]. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?22/43/23224?
source=see_link\">",
" \"Chapter 10B: Buffers\"",
" </a>",
" .)",
" </p>",
" <p>",
" An alternative approach to acid-base disturbances uses the strong ion
difference introduced by Stewart in 1981and is presented elsewhere. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?19/61/20437?
source=see_link\">",
" \"Strong ions and the analysis of acid-base disturbances (Stewart
approach)\"",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H4\">",
" <span class=\"h3\">",
" Measurement of HCO3- concentration",
" </span>",
" &nbsp;&mdash;&nbsp;The plasma or serum HCO3- concentration is determined in
the laboratory in one of two ways [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6330/abstract/1\">",
" 1",
" </a>",
" ]:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Indirect calculation of serum bicarbonate from either a venous or arterial
blood gas. Automated blood gas analyzers measure pH and PCO2; the HCO3-
concentration is then derived from the Henderson-Hasselbalch equation.",
" </li>",
" <li>",
" Direct measurement by adding a strong acid to venous blood and observing the
amount of CO2 generated. This measures the total CO2 content, which is the sum of
the following:",
" </li>",
" </ul>",
" </p>",
" <p>",
" &nbsp;Total CO2 content &nbsp;= &nbsp; [HCO3-] &nbsp;+ &nbsp;dissolved CO2
&nbsp;+ &nbsp;[H2C03]",
" </p>",
" <p>",
" The concentration of H2CO3 (carbonic acid) is very low and dissolved CO2 is
equal to the PCO2 times its solubility constant 0.03. Thus:",
" </p>",
" <p>",
" &nbsp;[HCO3-] &nbsp; = &nbsp; Total CO2 content &nbsp;- &nbsp;0.03 [PCO2]",
" </p>",
" <p>",
" Thus, at a normal arterial PCO2 of 40 mmHg and HCO3- concentration of 24",
" <span class=\"nowrap\">",
" mEq/L,",
" </span>",
" the total CO2 content will exceed the HCO3- concentration by only 1.2",
" <span class=\"nowrap\">",
" mEq/L",
" </span>",
" (40 x 0.03). (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?22/43/23224?
source=see_link\">",
" \"Chapter 10B: Buffers\"",
" </a>",
" .) At higher PC02 tension, the total CO2 content increasingly exceeds the true
bicarbonate concentration. At PCO2 of 80 mmHg (Torr), for example, the total CO2
content will be 2.4",
" <span class=\"nowrap\">",
" mEq/L",
" </span>",
" (80 X 0.03) greater than the actual serum bicarbonate level.",
" </p>",
" <p class=\"headingAnchor\" id=\"H5\">",
" <span class=\"h2\">",
" Renal excretion of acid",
" </span>",
" &nbsp;&mdash;&nbsp;The net effect of buffering by HCO3- is a fall in serum
HCO3- concentration. This is then returned to normal by renal acid excretion of the
daily acid load. This process, which is discussed in detail elsewhere, involves two
basic steps both of which are mediated by tubular H+ secretion. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?12/29/12762?
source=see_link\">",
" \"Chapter 11A: Renal hydrogen excretion\"",
" </a>",
" .):",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Reabsorption of the filtered HCO3-",
" </li>",
" <li>",
" Secretion of hydrogen ions that combine with either titratable acids,
particularly phosphate (HPO4- &nbsp;+ &nbsp; H+ &nbsp; &mdash;&gt; &nbsp; H2PO4-)
or with ammonia to form ammonium.",
" </li>",
" </ul>",
" </p>",
" <p>",
" The secreted hydrogen ions in the latter process are derived from the
breakdown of water within the cell, which leaves an hydroxyl ion (OH-). Combination
of hydroxyl ions with CO2 in the cell result in the generation of HCO3-, which is
then returned to the systemic circulation to replace the HCO3- lost in the initial
buffering process.",
" </p>",
" <p>",
" In normal subjects, the rate of titratable acid and ammonium excretion is
roughly equal to the daily dietary acid load. When the acid load is increased, the
kidney can compensate, largely by increasing ammonium excretion. If renal acid
excretion is impaired, due to renal failure or renal tubular acidosis, metabolic
acidosis will ensue.",
" </p>",
" <p class=\"headingAnchor\" id=\"H6\">",
" <span class=\"h2\">",
" Pathophysiology",
" </span>",
" &nbsp;&mdash;&nbsp;Metabolic acidosis occurs when there is either a net gain
of H+ ions or a net loss of HCO3- ions. Clinically, this is manifested in the serum
or plasma as a low pH and a low bicarbonate concentration. It can be produced by
three major mechanisms:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Increased acid generation from either an exogenous source (eg, salicylate
ingestion) or endogenous production (eg, ketoacidosis and lactic acidosis) (see",
" <a class=\"medical medical_review\" href=\"UTD.htm?3/44/3781?
source=see_link\">",
" \"Causes of lactic acidosis\"",
" </a>",
" )",
" </li>",
" <li>",
" Loss of bicarbonate either from the gastrointestinal tract (eg, diarrhea) or
kidney (eg, type 2 [proximal] renal tubular acidosis) or a bicarbonate precursor
(eg, ketoacid anion loss in ketoacidosis) (see",
" <a class=\"medical medical_review\" href=\"UTD.htm?21/1/21526?
source=see_link\">",
" \"The &Delta;anion gap/&Delta;HCO3 ratio in patients with a high anion gap
metabolic acidosis\"",
" </a>",
" )",
" </li>",
" <li>",
" Diminished renal acid excretion (eg, renal failure or type 1 [distal] renal
tubular acidosis)",
" </li>",
" </ul>",
" </p>",
" <p class=\"headingAnchor\" id=\"H7\">",
" <span class=\"h2\">",
" Compensatory response",
" </span>",
" &nbsp;&mdash;&nbsp;As seen above, the Henderson-Hasselbalch equation shows
that the pH is determined by the concentration ratio between HCO3- and PCO2, not
either one alone. Thus, the body responds to a disturbance in acid-base disorder by
either respiratory or renal compensation attempting to normalize the pH. With
simple metabolic acidosis, ventilation increases, resulting in a fall in PCO2. This
raises the pH toward normal but will not lead to complete correction. This response
begins in the first hour, and is complete by 12 to 24 hours [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6330/abstract/2\">",
" 2",
" </a>",
" ].",
" </p>",
" <p>",
" The respiratory compensation results in a 1.2 mmHg fall in the PaCO2 for every
1",
" <span class=\"nowrap\">",
" mEq/L",
" </span>",
" reduction in the serum HCO3- concentration [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6330/abstract/3\">",
" 3",
" </a>",
" ]. Inadequate compensatory response can be a clue to unrecognized respiratory
insufficiency and impending failure [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6330/abstract/4\">",
" 4",
" </a>",
" ].",
" </p>",
" <p>",
" For the clinician, this respiratory compensatory mechanism normally manifests
as increased respiratory rate and depth. In young children, the increase in depth
of respiration, as observed in classic Kussmaul breathing, may not be as apparent
as in adults. Young infants may respond to metabolic acidosis by tachypnea alone.",
" </p>",
" <p class=\"headingAnchor\" id=\"H8\">",
" <span class=\"h3\">",
" Simple and mixed disorders",
" </span>",
" &nbsp;&mdash;&nbsp;In",
" <strong>",
" simple metabolic acidosis",
" </strong>",
" , the fall in bicarbonate is normally compensated by an expected reduction in
PCO2 by increased ventilation. The following methods can help determine the
presence or absence of an appropriate compensation in children who do not have very
severe acidemia (pH &lt;7.10):",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" With one method, the expected arterial PCO2 (PaCO2) can be approximated by
the regression equation, named Winter's formula [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6330/abstract/5\">",
" 5",
" </a>",
" ]:",
" <br/>",
" <br/>",
" &nbsp; &nbsp; &nbsp; &nbsp; PaCO2 &nbsp;= &nbsp;(1.5 &nbsp;x &nbsp;measured
HCO3-) &nbsp;+ &nbsp;8 &plusmn; 2",
" <br/>",
" <br/>",
" The following case is an example of the clinical use of this equation. An
infant with gastroenteritis has a pH of 7.22, measured serum bicarbonate of 9",
" <span class=\"nowrap\">",
" mEq/L,",
" </span>",
" and a PaCO2 of 22 mmHg (torr). According to Winter's formula, the
appropriate respiratory compensation in this infant would result in a PaCO2 of 22
mmHg [(1.5 &nbsp;x &nbsp;9) + 8]. This supports the diagnosis of a simple metabolic
acidosis.",
" </li>",
" <li>",
" A second method is to examine the proportion of changes in bicarbonate and
PCO2. The arterial PCO2 normally falls an average of 1.2 mmHg for every 1.0",
" <span class=\"nowrap\">",
" mEq/L",
" </span>",
" reduction in the serum HCO3 concentration down to a minimum PaCO2 of 10 to
15 mmHg [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6330/abstract/3\">",
" 3",
" </a>",
" ].In the above example, the reduction in serum HCO3 concentration is 15",
" <span class=\"nowrap\">",
" mEq/L",
" </span>",
" (24 minus 9",
" <span class=\"nowrap\">",
" mEq/L).",
" </span>",
" Thus, the fall in PaCO2 should be 18 mmHg (15 &nbsp;x &nbsp;1.2), resulting
in an expected PaCO2 of 22 mmHg (40 minus 18), again confirming the presence of a
simple metabolic acidosis.",
" </li>",
" <li>",
" A third estimate is that PCO2 should be approximately equal to the last two
digits of the pH down to a pH of 7.10 [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6330/abstract/5\">",
" 5",
" </a>",
" ]. Thus, at an arterial pH of 7.22, the normal ventilatory response to
metabolic acidosis should lower the PCO2 to approximately 22 mmHg.",
" </li>",
" </ul>",
" </p>",
" <p>",
" In mixed metabolic acidosis, one or more additional acid-base disorders are
present. In the above example in which the serum HCO3- was 9",
" <span class=\"nowrap\">",
" mEq/L,",
" </span>",
" an arterial PCO2 that is substantially greater than 22 mmHg represents a
concurrent respiratory acidosis, while a PCO2 value substantially lower than 22
mmHg represents a concurrent respiratory alkalosis. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?26/41/27288?
source=see_link\">",
" \"Simple and mixed acid-base disorders\"",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H9\">",
" <span class=\"h1\">",
" DIAGNOSTIC TOOLS",
" </span>",
" &nbsp;&mdash;&nbsp;In addition to the history and physical examination, the
anion gap and the urine pH are useful aids in determining the underlying cause of
the metabolic acidosis.",
" </p>",
" <p class=\"headingAnchor\" id=\"H10\">",
" <span class=\"h2\">",
" Serum anion gap",
" </span>",
" &nbsp;&mdash;&nbsp;Patients with metabolic acidosis can be classified into two
groups based on the serum anion gap (AG): a normal AG or an elevated AG metabolic
acidosis. This distinction helps determine the underlying cause of the metabolic
acidosis (",
" <a class=\"graphic graphic_table graphicRef51117 \" href=\"UTD.htm?
16/52/17229\">",
" table 1",
" </a>",
" )&nbsp;[",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6330/abstract/6\">",
" 6",
" </a>",
" ]. Although mostly used as a diagnostic tool, the anion gap, along with base
excess, arterial lactate, and strong ion gap, has been evaluated as a prognostic
indicator in critically ill patients [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6330/abstract/7,8\">",
" 7,8",
" </a>",
" ].",
" </p>",
" <p>",
" The AG is calculated as the difference between the serum concentration of the
major cation Na+ and the major measured anions (Cl- and HCO3-):",
" </p>",
" <p>",
" &nbsp; &nbsp;AG",
" <span class=\"nowrap\">",
" (mEq/L)",
" </span>",
" &nbsp;= &nbsp;Na+ &nbsp;- &nbsp;(Cl- &nbsp;+ &nbsp;HCO3-)",
" </p>",
" <p>",
" In adults, the normal plasma AG has been traditionally considered to range
between 7 and 13",
" <span class=\"nowrap\">",
" mEq/L.",
" </span>",
" However, the normal range may be 5 to 11",
" <span class=\"nowrap\">",
" mEq/L",
" </span>",
" due to a higher chloride concentration measured with newer autoanalyzers [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6330/abstract/9\">",
" 9",
" </a>",
" ]. As a result, knowing the normal range in a particular laboratory is
essential if the AG is to be interpreted appropriately.",
" </p>",
" <p>",
" In children, an AG above 14 to 16",
" <span class=\"nowrap\">",
" mEq/L",
" </span>",
" is considered elevated [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6330/abstract/10-12\">",
" 10-12",
" </a>",
" ]. In newborns, an AG above 16",
" <span class=\"nowrap\">",
" mEq/L",
" </span>",
" is considered elevated and most often due to lactic acidosis [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6330/abstract/13\">",
" 13",
" </a>",
" ].",
" </p>",
" <p>",
" Some clinicians and some published reports include potassium as a measured
cation in the calculation of AG; this raises the normal value by 4",
" <span class=\"nowrap\">",
" mEq/L.",
" </span>",
" For the purposes of this review, we will use the more widely accepted
definition of AG in which sodium is the only measured cation.",
" </p>",
" <p>",
" Because electroneutrality must be maintained, the AG is also equal to the
difference between the unmeasured anions (primarily albumin, which is largely
responsible for the normal AG, but also includes phosphate, sulfate, and organic
anions such as lactate) and remaining cations (potassium, calcium, and
magnesium).",
" </p>",
" <p>",
" This explanation is helpful clinically since it permits an easier
understanding of the factors that affect the AG:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" An elevated AG acidosis is almost always due to an increase in unmeasured
anions (eg, lactate, beta-hydroxybutyrate) [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6330/abstract/6,14\">",
" 6,14",
" </a>",
" ]. Although the AG can also be increased by a fall in serum K+, calcium, or
magnesium, the normal concentrations of these cations are so low that a reduction
in concentration has only a small effect on the AG.",
" </li>",
" <li>",
" A low AG can be produced by a reduction in unmeasured anions (ie,
hypoalbuminemia) or an increase in non-sodium cations (eg, hyperkalemia,
hypercalcemia, hypermagnesemia).",
" </li>",
" </ul>",
" </p>",
" <p>",
" Each 1",
" <span class=\"nowrap\">",
" g/dL",
" </span>",
" reduction in the serum albumin concentration would be expected to reduce the
anion gap by approximately 2.5",
" <span class=\"nowrap\">",
" mEq/L",
" </span>",
" [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6330/abstract/6\">",
" 6",
" </a>",
" ]. A recent study of patients with a wide age range (1 month to 102 years) has
shown that the fall in anion gap is 2.3",
" <span class=\"nowrap\">",
" mEq/L",
" </span>",
" for every",
" <span class=\"nowrap\">",
" 1g/dL",
" </span>",
" reduction in serum albumin concentration [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6330/abstract/15\">",
" 15",
" </a>",
" ]. When patients with hypoalbuminemia develop a high AG acidosis, the AG rises
from the reduced baseline but may still be within the normal range and be mistaken
for a normal AG acidosis [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6330/abstract/16\">",
" 16",
" </a>",
" ].",
" </p>",
" <p>",
" The observed anion gap can be adjusted for abnormal albumin concentration by
Figge's formula where albumin concentrations are in",
" <span class=\"nowrap\">",
" g/dL",
" </span>",
" [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6330/abstract/17\">",
" 17",
" </a>",
" ]:",
" </p>",
" <p>",
" &nbsp;Adjusted anion gap &nbsp;= &nbsp;observed anion gap &nbsp;+ &nbsp;(2.5 x
[normal albumin - observed albumin])",
" </p>",
" <p>",
" In a prospective study of 134 children with metabolic acidosis in a pediatric
intensive care unit, correction for serum albumin concentrations resulted in an
average increase in the anion gap of 2.7",
" <span class=\"nowrap\">",
" mEq/L.",
" </span>",
" This correction raised the incidence of a high AG (&gt;18",
" <span class=\"nowrap\">",
" mEq/L)",
" </span>",
" from 28 to 44 percent. For patients with serum HCO3- levels less than 22",
" <span class=\"nowrap\">",
" mEq/L,",
" </span>",
" the incidence of raised anion gap almost doubled from 38 percent to 73
percent. Without the correction for hypoalbuminemia, it is possible that the
presence of high anion gap acidosis would be overlooked [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6330/abstract/18\">",
" 18",
" </a>",
" ].",
" </p>",
" <p class=\"headingAnchor\" id=\"H11\">",
" <span class=\"h3\">",
" Normal AG acidosis",
" </span>",
" &nbsp;&mdash;&nbsp;In children, metabolic acidosis with a normal AG can be
caused by a loss of HCO3- or impaired renal excretion of the daily acid in patients
without renal failure. Loss of HCO3- resulting in hyperchloremic metabolic acidosis
is most often due to diarrhea. A less common cause of hyperchloremic metabolic
acidosis is renal HCO3- wasting in type 2 (proximal) renal tubular acidosis RTA (",
" <a class=\"graphic graphic_table graphicRef51117 \" href=\"UTD.htm?
16/52/17229\">",
" table 1",
" </a>",
" ). Rare causes of gastrointestinal HCO3- loss include enteric fistulae,
enterostomies, and bladder augmentation with sections from the sigmoid colon
(ureterosigmoidostomies). The kidneys compensate for NaHCO3 loss by retaining NaCl
in an attempt to preserve volume, with the net effect being a mEq-for-mEq exchange
of chloride for bicarbonate and no change in the AG. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?28/57/29589?
source=see_link\">",
" \"Acid-base and electrolyte abnormalities with diarrhea or ureteral
diversion\"",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?17/22/17768?
source=see_link\">",
" \"Etiology and clinical manifestations of renal tubular acidosis in infants
and children\"",
" </a>",
" .)",
" </p>",
" <p>",
" Patients with type 1 (distal) renal tubular acidosis or with type 4 RTA
(hypoaldosteronism) have impaired H+ excretion due to defective renal
acidification. The AG remains normal since there is no retention of unmeasured
anions [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6330/abstract/14,19\">",
" 14,19",
" </a>",
" ]. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?17/22/17768?
source=see_link\">",
" \"Etiology and clinical manifestations of renal tubular acidosis in infants
and children\"",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H12\">",
" <span class=\"h3\">",
" Elevated AG acidosis",
" </span>",
" &nbsp;&mdash;&nbsp;An increase in unmeasured anions, along with hydrogen ion
generation, is present in an elevated AG acidosis. It is important to emphasize
that the acidosis is due to the retained hydrogen ions; the AG is just a diagnostic
tool.",
" </p>",
" <p>",
" Clinical settings of high AG metabolic acidosis in children include [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6330/abstract/11,12\">",
" 11,12",
" </a>",
" ]:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Lactic acidosis from hypoperfusion due to sepsis, cardiac failure or
hypovolemia. Increased lactic acidosis may be seen in patients &nbsp;with
mitochondrial disorders. In addition, perinatal hypoxemia and ischemia may produce
elevated lactic acid levels in affected neonates [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6330/abstract/13\">",
" 13",
" </a>",
" ]. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?3/44/3781?
source=see_link\">",
" \"Causes of lactic acidosis\"",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?34/23/35188?
source=see_link\">",
" \"Metabolic emergencies at birth\"",
" </a>",
" .)",
" </li>",
" <li>",
" Ketoacidosis due to diabetes mellitus, in which beta-hydroxybutyrate is the
primary unmeasured anion. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?40/32/41480?
source=see_link\">",
" \"Clinical features and diagnosis of diabetic ketoacidosis in children\"",
" </a>",
" .)",
" </li>",
" <li>",
" Renal failure, when there is a retention of both hydrogen and anions, such
as sulfate, phosphate, and urate [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6330/abstract/20\">",
" 20",
" </a>",
" ]. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?40/24/41353?
source=see_link\">",
" \"Pathogenesis, consequences, and treatment of metabolic acidosis in
chronic kidney disease\"",
" </a>",
" .)",
" </li>",
" <li>",
" Ingestions, in which the major retained anions are formate with methanol,
glycolate and oxalate with ethylene glycol, and ketones and lactate with",
" <a class=\"drug drug_pediatric\" href=\"UTD.htm?19/10/19624?
source=see_link\">",
" aspirin",
" </a>",
" . Both the AG and the acidosis with methanol and ethylene glycol ingestions
result from metabolism of the parent compound. These findings may not be seen in
patients early in the course or with concurrent ingestion of ethanol. Ethanol
competes for alcohol dehydrogenase, thereby slowing the metabolism of methanol or
ethylene glycol to their toxic metabolites and preventing both the acidosis and the
high AG. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?4/3/4154?
source=see_link\">",
" \"Methanol and ethylene glycol poisoning\"",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?18/41/19098?
source=see_link\">",
" \"Salicylate poisoning in children and adolescents\"",
" </a>",
" .)",
" </li>",
" <li>",
" Overproduction of organic acids due to inborn errors of metabolism that
include disorders of amino acid, carbohydrate or fatty acid metabolism. (See
appropriate topic reviews).",
" </li>",
" <li>",
" In patients with severe asthma, lactic acidosis may develop as a
complication of high-dose continuous beta adrenergic and glucocorticoid therapy [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6330/abstract/21-23\">",
" 21-23",
" </a>",
" ].",
" </li>",
" </ul>",
" </p>",
" <p>",
" The degree of elevation in the AG can be highly variable in certain settings.
With diabetic ketoacidosis, for example, this variability results from two factors:
the rate of ketoacid production; and the loss of ketoacid anions in the urine (as
the sodium and potassium salts of beta-hydroxybutyrate and to a lesser degree
acetoacetate), which lowers the AG without affecting the serum bicarbonate
concentration and thereby reduces the degree of acidosis.",
" </p>",
" <p>",
" The amount of ketoacid anions excreted depends upon the degree to which
glomerular filtration is maintained. Patients with relatively normal renal function
can lose large quantities of ketoacids, which can minimize the elevation in AG [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6330/abstract/24,25\">",
" 24,25",
" </a>",
" ]. Urine anion loss is particularly rapid with toluene ingestion (glue-
sniffing), since the overproduced hippurate is both filtered and secreted. As a
result, the AG may also be near normal or normal and the patient mistakenly
diagnosed with a normal AG acidosis [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6330/abstract/26\">",
" 26",
" </a>",
" ]. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?21/1/21526?
source=see_link&amp;anchor=H5#H5\">",
" \"The &Delta;anion gap/&Delta;HCO3 ratio in patients with a high anion gap
metabolic acidosis\", section on 'Urinary loss of unmeasured anions'",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H13\">",
" <span class=\"h3\">",
" Overlap",
" </span>",
" &nbsp;&mdash;&nbsp;There may also be overlap between the causes of a normal
and high AG metabolic acidosis. Diarrhea, for example, is most often associated
with a normal AG. However, severe diarrhea and hypovolemia can result in an
increase in the AG due to hypoperfusion-induced lactic acidosis and starvation
ketosis.",
" </p>",
" <p>",
" Diabetic ketoacidosis, on the other hand, is typically associated with an
elevated AG. However, as noted above, the rise in AG may be much less than expected
from the severity of the metabolic acidosis because of loss ketoacid anions with
sodium and potassium in the urine [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6330/abstract/24,25\">",
" 24,25",
" </a>",
" ]. When insulin is given to patients with diabetic ketoacidosis, metabolism of
the ketoacid anions results in the regeneration of HCO3- and correction of the
metabolic acidosis. For this reason, ketoacid anions have been called \"potential
bicarbonate,\" and their loss in the urine represents the loss of HCO3-, similar to
that seen with diarrhea or type 2 RTA. As a result, a normal AG acidosis is
typically seen during the treatment phase of diabetic ketoacidosis due to the
urinary loss of these bicarbonate precursors.",
" </p>",
" <p>",
" Similar considerations apply to D-lactic acidosis and toluene-induced
metabolic acidosis, in which the anion gap may either be elevated (due to D-lactate
and hippurate, respectively) or less elevated or even normal due to the rapid
urinary excretion of the excess unmeasured anions. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?18/18/18723?
source=see_link\">",
" \"D-Lactic acidosis\"",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?21/1/21526?
source=see_link\">",
" \"The &Delta;anion gap/&Delta;HCO3 ratio in patients with a high anion gap
metabolic acidosis\"",
" </a>",
" .)",
" </p>",
" <p>",
" Because of variations in different laboratories and in patient variables such
as serum albumin (see above), changes in the anion gap with time in a given patient
can be particularly helpful in interpreting changes in the acid-base status of a
patient. In a hospitalized patient, for example, an unexplained increase in the
anion gap from a baseline of 3 to 11",
" <span class=\"nowrap\">",
" mEq/L",
" </span>",
" should be concerning because the increase of 8",
" <span class=\"nowrap\">",
" mEq/L",
" </span>",
" in the gap may represent the accumulation of an organic anion such as
lactate.",
" </p>",
" <p class=\"headingAnchor\" id=\"H14\">",
" <span class=\"h2\">",
" Urine pH",
" </span>",
" &nbsp;&mdash;&nbsp;The urine hydrogen ion concentration, measured as the pH,
reflects the degree of acidification of the urine. The urine pH ranges from 4.5 to
8.0, depending upon systemic acid-base balance. The appropriate response to
metabolic acidosis is to increase urinary acid excretion, with the urine pH falling
below 5.3 and usually below 5.0.",
" </p>",
" <p>",
" A higher urine pH value than expected for the degree of acidosis may indicate
the presence of renal tubular acidosis (RTA). Distinction between the various types
of RTA can be made by measurement of the urine pH, the fractional excretion of
bicarbonate at different serum bicarbonate concentrations, and other clinical
features. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?10/32/10759?
source=see_link\">",
" \"Overview of renal tubular acidosis\"",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?17/22/17768?
source=see_link\">",
" \"Etiology and clinical manifestations of renal tubular acidosis in infants
and children\"",
" </a>",
" .)",
" </p>",
" <p>",
" Diarrhea is typically associated with an appropriately low urine pH, which
helps to distinguish it from type 1 (distal RTA). However, when diarrhea is
complicated by severe hypokalemia, the urine pH may increase above 6.0, simulating
distal RTA because of the inability to excrete H+. Therefore, evaluation of renal
acidification mechanism should be done after replenishing the potassium deficit.
The mechanism by which this occurs and the use of the urine anion and osmolal gaps
in such patients are discussed elsewhere. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?11/18/11558?
source=see_link\">",
" \"Urine anion and osmolal gaps in metabolic acidosis\"",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H15\">",
" <span class=\"h1\">",
" CLINICAL EVALUATION AND DIAGNOSIS",
" </span>",
" &nbsp;&mdash;&nbsp;The steps in evaluation of a child with metabolic acidosis
include:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Recognition of the clinical presentation and manifestations of metabolic
acidosis",
" </li>",
" <li>",
" Determination of the underlying cause",
" </li>",
" <li>",
" Emergent treatment for severe acidosis (defined by a pH &lt;7.10). The
clinician should understand the complication and limitation of bicarbonate therapy
in managing a child with severe acidosis.",
" </li>",
" </ul>",
" </p>",
" <p class=\"headingAnchor\" id=\"H16\">",
" <span class=\"h2\">",
" Clinical presentation and manifestations",
" </span>",
" &nbsp;&mdash;&nbsp;Infants and children with metabolic acidosis can present
with varying degrees of acute and chronic illness. Based upon the underlying
disorder and severity of the acidosis, children may be asymptomatic, or present
with poor feeding, failure to thrive, vomiting, serum electrolyte and hematologic
abnormalities, hypotonia, seizures, tachypnea, respiratory distress, and vascular
collapse.",
" </p>",
" <p class=\"headingAnchor\" id=\"H17\">",
" <span class=\"h3\">",
" Newborns and infants",
" </span>",
" &nbsp;&mdash;&nbsp;Newborns and infants are more vulnerable than older
children and adults to develop acidosis for several reasons:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" The proximal tubules in infants have a lower renal threshold for bicarbonate
reabsorption. The normal serum bicarbonate in infants is approximately 20",
" <span class=\"nowrap\">",
" mEq/L",
" </span>",
" compared to 24",
" <span class=\"nowrap\">",
" mEq/L",
" </span>",
" in older children and adults. Similarly, the normal PCO2 in infants is
approximately 35 mmHg compared to 40 mmHg in older children.",
" </li>",
" <li>",
" The maximum net acid excretion by the distal nephron is limited in infants
[",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6330/abstract/27\">",
" 27",
" </a>",
" ].",
" </li>",
" <li>",
" The acid load is higher in preterm infants and growing children. The
endogenous acid production per kilogram in preterm infants and growing children is
50 to 100 percent higher than that of adults [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6330/abstract/28\">",
" 28",
" </a>",
" ]. The growing skeleton releases 20 mEq of protons for each 1 g of calcium
that it incorporates.",
" </li>",
" </ul>",
" </p>",
" <p>",
" These physiologic properties have number of clinical implications:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Compared to older children, newborns and infants have a relatively limited
capacity to compensate for excess acid load, such as diarrhea. This is reflected by
a greater decrease in blood pH and total CO2 content and a smaller and less rapid
decrease in the urine pH.",
" </li>",
" <li>",
" The gastrointestinal absorption and excretion of dietary base plays a major
role in acid-base homeostasis in infants in whom the predominantly milk-based diet
contributes a considerable amount of alkali. Infants are therefore more vulnerable
to developing metabolic acidosis in illnesses associated with decreased milk intake
and excess gastrointestinal losses [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6330/abstract/28\">",
" 28",
" </a>",
" ].",
" </li>",
" <li>",
" An excessive chronic acid burden interferes with calcium deposition in the
bone and calcium intestinal absorption [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6330/abstract/28,29\">",
" 28,29",
" </a>",
" ]. Persistent metabolic acidosis from any cause can impair growth in
children [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6330/abstract/28,30\">",
" 28,30",
" </a>",
" ].",
" </li>",
" </ul>",
" </p>",
" <p class=\"headingAnchor\" id=\"H18\">",
" <span class=\"h3\">",
" Acute signs and symptoms",
" </span>",
" &nbsp;&mdash;&nbsp;In acute metabolic acidosis, the signs and symptoms in
children include [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6330/abstract/31\">",
" 31",
" </a>",
" ]:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Tachypnea with or without hyperpnea (ie, hyperventilation). In young
children and infants, the increase in depth of respiration, as observed in classic
Kussmaul breathing, may not be as apparent as in adults and the response to
metabolic acidosis may be tachypnea alone.",
" </li>",
" <li>",
" Abdominal pain and vomiting.",
" </li>",
" <li>",
" Neurologic abnormalities such as irritability and lethargy. Seizures and
coma also may be seen, but are primarily due to the underlying disease (eg, organic
acidemias and hyperosmolality in ketoacidosis) not the low pH itself.",
" </li>",
" </ul>",
" </p>",
" <p class=\"headingAnchor\" id=\"H19\">",
" <span class=\"h2\">",
" Laboratory evaluation",
" </span>",
" &nbsp;&mdash;&nbsp;Evaluation of any possible acid-base disorder begins with
measurement of the extracellular pH, PCO2, and the bicarbonate concentration via
venous or arterial blood sample. A low serum bicarbonate and pH confirms metabolic
acidosis. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?1/61/2009?
source=see_link\">",
" \"Arterial puncture and cannulation in children\"",
" </a>",
" .)",
" </p>",
" <p>",
" Once the disorder is diagnosed, the degree of compensation should also be
assessed. As previously mentioned, the initiation of metabolic acidosis is
associated with a compensatory respiratory response. Thus, ventilation is
increased, resulting in a fall in PCO2, which tends to raise the pH toward normal.
For every 1",
" <span class=\"nowrap\">",
" mEq/L",
" </span>",
" reduction in the serum HCO3- concentration, the arterial PCO2 normally falls
by approximately 1.2 mmHg down to a minimum PaCO2 of 10 to 15 mmHg. (See",
" <a class=\"local\" href=\"#H7\">",
" 'Compensatory response'",
" </a>",
" above.)",
" </p>",
" <p>",
" If the fall in PCO2 is substantially different from the expected value, the
patient has a combined acid-base disorder. This issue is discussed in detail
elsewhere in this topic review and other appropriate reviews. (See",
" <a class=\"local\" href=\"#H8\">",
" 'Simple and mixed disorders'",
" </a>",
" above and",
" <a class=\"medical medical_review\" href=\"UTD.htm?26/41/27288?
source=see_link\">",
" \"Simple and mixed acid-base disorders\"",
" </a>",
" .)",
" </p>",
" <p>",
" The fall in extracellular pH in metabolic acidosis, as well as the underlying
cause, can affect serum concentrations of potassium and phosphate.",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Potassium &mdash; A decrease in serum pH results in a shift of potassium
from the intracellular to extracellular compartment, and raises the serum potassium
concentration. The serum potassium concentration increases by approximately 0.6",
" <span class=\"nowrap\">",
" mEq/L",
" </span>",
" (range 0.2 to 1.7",
" <span class=\"nowrap\">",
" mEq/L)",
" </span>",
" for every 0.1 unit fall in serum pH. The variability is in part due to the
presence of other factors (underlying disease) that influence potassium homeostasis
(eg, renal failure with impaired renal excretion).",
" <br/>",
" <br/>",
" The effect of acidemia on serum potassium is primarily seen in patients with
diarrhea or renal failure. For reasons that are not well understood, acidemia has a
minimal direct effect on potassium distribution in patients with lactic acidosis or
ketoacidosis. Nevertheless, patients with these disorders are often hyperkalemic
due to tissue breakdown and decreased renal function. These concepts are more fully
discussed elsewhere. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?25/18/25891?
source=see_link\">",
" \"Potassium balance in acid-base disorders\"",
" </a>",
" .)",
" </li>",
" <li>",
" Phosphate &mdash; Acidosis promotes the movement of intracellular phosphate
into the extracellular fluid, producing a small elevation in serum phosphate that
is not clinically significant. However, this effect is important in ketoacidosis,
since these patients are phosphate depleted and correction of the insulin
deficiency and acidemia unmasks the phosphate depletion and typically leads to
hypophosphatemia. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?7/28/7626?
source=see_link&amp;anchor=H12#H12\">",
" \"Treatment and complications of diabetic ketoacidosis in children\",
section on 'Phosphate'",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?14/48/15114?
source=see_link&amp;anchor=H19#H19\">",
" \"Treatment of diabetic ketoacidosis and hyperosmolar hyperglycemic state
in adults\", section on 'Phosphate depletion'",
" </a>",
" .)",
" </li>",
" </ul>",
" </p>",
" <p class=\"headingAnchor\" id=\"H20\">",
" <span class=\"h1\">",
" TREATMENT",
" </span>",
" &nbsp;&mdash;&nbsp;Persistent metabolic acidosis due to metabolic or chronic
kidney disease is uniformly treated with alkali therapy [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6330/abstract/32\">",
" 32",
" </a>",
" ]. However, there is wide variation in the treatment of acute metabolic
acidosis [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6330/abstract/33\">",
" 33",
" </a>",
" ]. The treatment of acute metabolic acidosis is divided into management of
severe acidosis (defined as pH &lt;7.10) and treating the underlying cause. (See",
" <a class=\"local\" href=\"#H24\">",
" 'Determination of underlying cause'",
" </a>",
" below.)",
" </p>",
" <p class=\"headingAnchor\" id=\"H21\">",
" <span class=\"h2\">",
" Bicarbonate therapy",
" </span>",
" &nbsp;&mdash;&nbsp;Although there is controversy regarding the use of",
" <a class=\"drug drug_pediatric\" href=\"UTD.htm?40/56/41862?
source=see_link\">",
" sodium bicarbonate",
" </a>",
" in the treatment of acute metabolic acidosis, we generally recommend
bicarbonate therapy to correct severe acidosis in children with a pH less than 6.9
to 7.0.",
" </p>",
" <p>",
" This recommendation is based upon the potential complications of severe
acidosis, such as impaired cardiac contractility, increased risk of cardiac
arrhythmias, decreased total peripheral vascular resistance and blood pressure,
attenuation of cardiovascular responsiveness to catecholamines, and muscle fatigue
due to hyperventilation [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6330/abstract/31,34\">",
" 31,34",
" </a>",
" ].",
" </p>",
" <p>",
" The balance between the potential benefits and adverse effects of bicarbonate
therapy must be carefully weighed in newborns and older children with metabolic
acidosis.",
" </p>",
" <p>",
" Administration of bicarbonate has been associated with the following adverse
effects:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Hypervolemia and hypernatremia.",
" </li>",
" <li>",
" Hypercarbia &mdash; In children with hypoventilation, administration of HCO3
may result in an increase in PCO2 leading to a worsening of the acidosis. An
increase in PCO2 may also occur in patients with severe decreases in cardiac output
and pulmonary blood flow, which limit the pulmonary excretion of carbon dioxide
produced by intravenous bicarbonate administration. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?39/44/40646?
source=see_link\">",
" \"Bicarbonate therapy in lactic acidosis\"",
" </a>",
" .)",
" </li>",
" <li>",
" Hypokalemia in patients with diarrhea or diabetic ketoacidosis, as the
underlying potassium deficit is unmasked with correction of the acidosis.",
" </li>",
" <li>",
" Overcorrection of pH in patients with lactic acidosis or diabetic
ketoacidosis (DKA) because metabolism of ketoacid and lactate anions generate
bicarbonate when the underlying cause of acidosis is corrected. In addition,
bicarbonate administration may be associated with an increased risk of cerebral
edema in patients with DKA. The use of bicarbonate therapy in diabetic ketoacidosis
is discussed in greater detail separately. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?7/28/7626?
source=see_link&amp;anchor=H11#H11\">",
" \"Treatment and complications of diabetic ketoacidosis in children\",
section on 'Metabolic acidosis'",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?16/37/16983?
source=see_link&amp;anchor=H8#H8\">",
" \"Cerebral edema in children with diabetic ketoacidosis\", section on 'Risk
factors'",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?39/44/40646?
source=see_link\">",
" \"Bicarbonate therapy in lactic acidosis\"",
" </a>",
" .)",
" </li>",
" <li>",
" Hypocalcemic tetany may result from aggressive treatment of metabolic
acidosis, especially during management of renal failure. Frequent measurements of
pH and serum bicarbonate are needed to guide therapy. Calcium replenishment may be
necessary during correction of metabolic acidosis to prevent hypocalcemic tetany.",
" </li>",
" <li>",
" Potential tissue hypoxia because an increase in pH induced by bicarbonate
therapy increases oxygen affinity of hemoglobin resulting in a decrease release of
oxygen at the tissue level. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?22/29/23001?
source=see_link&amp;anchor=H7#H7\">",
" \"Structure and function of normal human hemoglobins\", section on 'pH'",
" </a>",
" .)",
" </li>",
" <li>",
" Increased risk of postnatal intraventricular hemorrhage. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?41/44/42697?
source=see_link&amp;anchor=H450996418#H450996418\">",
" \"Clinical manifestations and diagnosis of intraventricular hemorrhage in
the newborn\", section on 'Other risk factors'",
" </a>",
" .)",
" </li>",
" </ul>",
" </p>",
" <p class=\"headingAnchor\" id=\"H22\">",
" <span class=\"h3\">",
" Recommendations",
" </span>",
" &nbsp;&mdash;&nbsp;The bicarbonate distribution space progressively rises from
50 percent of body weight to 100 percent or more during increasing acidemia. The
primary mechanism is that, as the serum bicarbonate falls, there is only limited
additional buffering in the extracellular fluid. As a result, there is a
progressive increase in the percentage of excess hydrogen ions buffered in the
cells and bone, increasing the volume of distribution [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6330/abstract/35\">",
" 35",
" </a>",
" ]. Rather than guessing at the bicarbonate space, it is easier to simply
administer bicarbonate and observe the response. However, neonates are an exception
to this simplified approach. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?30/44/31432?
source=see_link&amp;anchor=H17#H17\">",
" \"Approach to the adult with metabolic acidosis\", section on 'Calculation of
bicarbonate deficit'",
" </a>",
" and",
" <a class=\"local\" href=\"#H23\">",
" 'Bicarbonate therapy in neonates'",
" </a>",
" below.)",
" </p>",
" <p>",
" The indications for bicarbonate therapy vary with the clinical setting.
Ketoacidosis and lactic acidosis are different from other causes of metabolic
acidosis, since correction of the underlying abnormality permits metabolism of the
organic anions and the regeneration of bicarbonate.",
" </p>",
" <p>",
" In other disorders, such as bicarbonate loss in diarrhea, the metabolic
acidosis can only correct slowly due to increased renal acid excretion unless
bicarbonate is given. Furthermore, the renal compensation may not be adequate if
the diarrhea persists. On the other hand, children with diarrhea who become
markedly volume depleted may also have a component of lactic acidosis.",
" </p>",
" <p>",
" Based upon these considerations, we generally reserve the use of bicarbonate
therapy in patients with severe acidosis (venous pH less than 7.10) with the
following considerations:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Because of the concerns noted above (including cerebral edema), bicarbonate
therapy is not recommended in patients with diabetic ketoacidosis unless there is a
potentially life-threatening condition. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?7/28/7626?
source=see_link&amp;anchor=H11#H11\">",
" \"Treatment and complications of diabetic ketoacidosis in children\",
section on 'Metabolic acidosis'",
" </a>",
" .)",
" </li>",
" <li>",
" In patients with shock-induced lactic acidosis and a venous pH &lt;7.10, we
cautiously administer bicarbonate along with adequate ventilation and restoration
of tissue perfusion.",
" </li>",
" <li>",
" The management of the organic acidemias is often quite different and varies
with disease. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?7/46/7914?
source=see_link\">",
" \"Organic acidemias\"",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?26/26/27047?
source=see_link\">",
" \"Inborn errors of metabolism: Classification\"",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?10/0/10250?
source=see_link\">",
" \"Inborn errors of metabolism: Metabolic emergencies\"",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?23/58/24489?
source=see_link\">",
" \"Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical
features\"",
" </a>",
" .)",
" </li>",
" <li>",
" Bicarbonate therapy may be used as adjunct therapy in the management of
acute hyperkalemia. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?4/11/4279?
source=see_link&amp;anchor=H635270655#H635270655\">",
" \"Management of hyperkalemia in children\", section on 'Therapies shifting
potassium into intracellular space'",
" </a>",
" .)",
" </li>",
" </ul>",
" </p>",
" <p>",
" Bicarbonate is given at a dose of 0.5 to 1",
" <span class=\"nowrap\">",
" mEq/kg",
" </span>",
" of body weight. The goal of the initial treatment is to raise and maintain the
venous pH above 7.20. Further bicarbonate therapy is dependent upon identifying and
correcting the underlying cause and whether or not there is ongoing excess acid
production or loss of bicarbonate.",
" </p>",
" <p class=\"headingAnchor\" id=\"H23\">",
" <span class=\"h3\">",
" Bicarbonate therapy in neonates",
" </span>",
" &nbsp;&mdash;&nbsp;It &nbsp;appears that intravenous bicarbonate therapy is
not effective in correcting metabolic acidosis in critically ill newborns and it
may cause significant harm because bicarbonate therapy has been associated with
intraventricular hemorrhage (IVH), myocardial injury, deterioration of cardiac
function, and worsening of intracellular acidosis [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6330/abstract/36\">",
" 36",
" </a>",
" ].",
" </p>",
" <p>",
" The adverse effects and lack of efficacy of bicarbonate therapy were
illustrated in an observational study of 775 very low birth weight infants born
between 2002 and 2006 who were admitted to a single level III neonatal intensive
care unit (NICU) [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6330/abstract/37\">",
" 37",
" </a>",
" ].",
" <a class=\"drug drug_pediatric\" href=\"UTD.htm?40/56/41862?
source=see_link\">",
" Sodium bicarbonate",
" </a>",
" was administered to 21 percent of patients within the first seven days of
life. The following findings were noted:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Infants treated with",
" <a class=\"drug drug_pediatric\" href=\"UTD.htm?40/56/41862?
source=see_link\">",
" sodium bicarbonate",
" </a>",
" had lower gestational ages and birth weights, were more severely ill (based
on Critical Risk Index for Babies [CRIB] score), had higher serum sodium
concentrations, and received more blood transfusions.",
" </li>",
" <li>",
" <a class=\"drug drug_pediatric\" href=\"UTD.htm?40/56/41862?
source=see_link\">",
" Sodium bicarbonate",
" </a>",
" infusion was associated with an increased risk of death (38.6 versus 10.8
percent) and IVH (58.4 versus 13.1 percent) even after adjusting for potential
confounders (eg, gestational age, birth weight, severity of illness [CRIB score and
transfusion rate], and serum sodium concentrations).",
" </li>",
" <li>",
" <a class=\"drug drug_pediatric\" href=\"UTD.htm?40/56/41862?
source=see_link\">",
" Sodium bicarbonate",
" </a>",
" did increase serum bicarbonate levels, but did",
" <strong>",
" not",
" </strong>",
" alter the degree of acidosis as blood gas pH did not change before and after
bicarbonate infusion (mean pH 7.23 versus 7.24).",
" </li>",
" <li>",
" The total mean amount of",
" <a class=\"drug drug_pediatric\" href=\"UTD.htm?40/56/41862?
source=see_link\">",
" sodium bicarbonate",
" </a>",
" administered was 5.36",
" <span class=\"nowrap\">",
" mEq/kg;",
" </span>",
" however, the majority of patients (59 percent) received less than 4",
" <span class=\"nowrap\">",
" mEq/kg.",
" </span>",
" </li>",
" </ul>",
" </p>",
" <p>",
" The authors concluded their results demonstrated that",
" <a class=\"drug drug_pediatric\" href=\"UTD.htm?40/56/41862?
source=see_link\">",
" sodium bicarbonate",
" </a>",
" was not beneficial in correcting acidosis but rather was associated with
significant adverse effects. As a result, we recommend that sodium bicarbonate",
" <strong>",
" not",
" </strong>",
" be used routinely to correct acidosis in preterm infants.",
" </p>",
" <p>",
" If bicarbonate therapy is to be given in preterm infants, it should be
administered as a slow infusion over 30 minutes to minimize fluctuations in
cerebral hemodynamics [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6330/abstract/36,38\">",
" 36,38",
" </a>",
" ]. Bicarbonate should be given to replace ongoing excessive renal and
gastrointestinal losses.",
" </p>",
" <p class=\"headingAnchor\" id=\"H24\">",
" <span class=\"h2\">",
" Determination of underlying cause",
" </span>",
" &nbsp;&mdash;&nbsp;An important component of the management of metabolic
acidosis is identification and treatment of the underlying cause. Evaluation
includes clues from the history and physical examination, laboratory evaluation,
and use of diagnostic tools such as the anion gap.",
" </p>",
" <p class=\"headingAnchor\" id=\"H25\">",
" <span class=\"h3\">",
" Historical clues",
" </span>",
" &nbsp;&mdash;&nbsp;There are often clues from the history that point toward a
specific diagnosis.",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" A history of diarrhea.",
" </li>",
" <li>",
" A history of polyuria with or without weight loss occurs in children with
diabetic ketoacidosis. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?40/32/41480?
source=see_link\">",
" \"Clinical features and diagnosis of diabetic ketoacidosis in children\"",
" </a>",
" .)",
" </li>",
" <li>",
" Failure to thrive suggests a chronic metabolic acidosis and is a feature of
renal tubular acidosis and chronic kidney disease. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?10/32/10759?
source=see_link\">",
" \"Overview of renal tubular acidosis\"",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?31/17/32026?
source=see_link\">",
" \"Overview of the management of chronic kidney disease in children\"",
" </a>",
" .)",
" </li>",
" <li>",
" A history or family history of dysmorphic features, severe hypotonia,
seizures, developmental delay or apnea, may be suggestive of an inborn error of
metabolism especially mitochondrial disorders and the organic acidurias [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6330/abstract/39-41\">",
" 39-41",
" </a>",
" ]. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?23/58/24489?
source=see_link\">",
" \"Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical
features\"",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?10/0/10250?
source=see_link\">",
" \"Inborn errors of metabolism: Metabolic emergencies\"",
" </a>",
" .)",
" </li>",
" <li>",
" A history of toxic ingestion.",
" </li>",
" </ul>",
" </p>",
" <p class=\"headingAnchor\" id=\"H26\">",
" <span class=\"h3\">",
" Physical examination",
" </span>",
" &nbsp;&mdash;&nbsp;The physical examination should include assessment of
perfusion. Hypoperfusion raises concern for hypovolemia, sepsis, or heart failure.
(See",
" <a class=\"medical medical_review\" href=\"UTD.htm?39/2/39975?
source=see_link\">",
" \"Etiology, clinical manifestations, and evaluation of neonatal shock\"",
" </a>",
" .)",
" </p>",
" <p>",
" Measurement of growth parameters, including weight for height measurement",
" <span class=\"nowrap\">",
" (wt/ht),",
" </span>",
" is particularly important with chronic metabolic acidosis.",
" <span class=\"nowrap\">",
" Wt/ht",
" </span>",
" ratio is preserved in children with renal tubular acidosis, as height and
weight are equally affected (growth retardation) unlike malnutrition where height
is initially preserved resulting in a lower",
" <span class=\"nowrap\">",
" wt/ht",
" </span>",
" percentile [",
" <a class=\"abstract\" href=\"UTD.htm?6/11/6330/abstract/30\">",
" 30",
" </a>",
" ].",
" </p>",
" <p class=\"headingAnchor\" id=\"H27\">",
" <span class=\"h3\">",
" Laboratory evaluation",
" </span>",
" &nbsp;&mdash;&nbsp;After the initial blood sample confirming metabolic
acidosis is obtained, other laboratory tests include:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Electrolytes, which permits calculation of the anion gap (",
" <a class=\"graphic graphic_table graphicRef51117 \" href=\"UTD.htm?
16/52/17229\">",
" table 1",
" </a>",
" ). Serum albumin should also be measured, since variations from normal can
interfere with interpretation of the anion gap. (See",
" <a class=\"local\" href=\"#H10\">",
" 'Serum anion gap'",
" </a>",
" above.)",
" </li>",
" <li>",
" BUN and creatinine, which are increased in renal insufficiency.",
" </li>",
" <li>",
" Serum glucose, since hyperglycemia suggests underlying diabetes mellitus and
possible ketoacidosis. However, mild degrees of hyperglycemia (serum glucose less
than 180",
" <span class=\"nowrap\">",
" mg/dL",
" </span>",
" [10",
" <span class=\"nowrap\">",
" mmol/L])",
" </span>",
" may simply reflect a stress response.",
" </li>",
" </ul>",
" </p>",
" <p>",
" The association of hypoglycemia with metabolic acidosis suggests congenital
adrenal hyperplasia, medium chain acyl-CoA dehydrogenase &nbsp;deficiency, or other
inborn errors of metabolism. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?27/46/28391?
source=see_link\">",
" \"Adrenal steroid biosynthesis\"",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?26/26/27047?
source=see_link\">",
" \"Inborn errors of metabolism: Classification\"",
" </a>",
" .)",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Urinalysis, which may reveal glucosuria and ketonuria in patients with
diabetic ketoacidosis and urine pH above 5.6 that is suggestive of renal tubular
acidosis.",
" </li>",
" </ul>",
" </p>",
" <p>",
" Based upon the clinical suspicion of a specific underlying disorder,
additional laboratory studies may be indicated. These may include serum lactate,
pyruvate, and ammonia. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?10/0/10250?
source=see_link\">",
" \"Inborn errors of metabolism: Metabolic emergencies\"",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H28\">",
" <span class=\"h2\">",
" Treatment of underlying cause",
" </span>",
" &nbsp;&mdash;&nbsp;The most effective therapeutic intervention is to treat the
underlying cause. As examples, restoration of adequate perfusion in patients with
lactic acidosis due to hypoperfusion or insulin and fluid therapy for patients with
diabetic ketoacidosis will largely correct the acidosis as metabolism of the excess
organic anions regenerates bicarbonate. In some conditions, the underlying disorder
cannot be repaired and chronic bicarbonate therapy is needed (eg, renal tubular
acidosis and chronic renal failure).",
" </p>",
" <p>",
" For the following causes of metabolic acidosis, further discussion concerning
the treatment of the acidosis and, if appropriate, the underlying condition are
discussed in detail elsewhere:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Chronic renal failure (see",
" <a class=\"medical medical_review\" href=\"UTD.htm?40/24/41353?
source=see_link\">",
" \"Pathogenesis, consequences, and treatment of metabolic acidosis in
chronic kidney disease\"",
" </a>",
" ).",
" </li>",
" <li>",
" Diabetic ketoacidosis (see",
" <a class=\"medical medical_review\" href=\"UTD.htm?7/28/7626?
source=see_link\">",
" \"Treatment and complications of diabetic ketoacidosis in children\"",
" </a>",
" ).",
" </li>",
" <li>",
" Types 1, 2, and 4 renal tubular acidosis (see",
" <a class=\"medical medical_review\" href=\"UTD.htm?5/46/5860?
source=see_link\">",
" \"Treatment of distal (type 1) and proximal (type 2) renal tubular
acidosis\"",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?9/44/9930?
source=see_link\">",
" \"Etiology, diagnosis, and treatment of hypoaldosteronism (type 4 RTA)\"",
" </a>",
" ).",
" </li>",
" <li>",
" Ingestion of methanol, ethylene glycol, or salicylate (see",
" <a class=\"medical medical_review\" href=\"UTD.htm?4/3/4154?
source=see_link\">",
" \"Methanol and ethylene glycol poisoning\"",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?18/41/19098?
source=see_link\">",
" \"Salicylate poisoning in children and adolescents\"",
" </a>",
" ).",
" </li>",
" <li>",
" Inborn errors of metabolism (see",
" <a class=\"medical medical_review\" href=\"UTD.htm?26/26/27047?
source=see_link\">",
" \"Inborn errors of metabolism: Classification\"",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?10/0/10250?
source=see_link\">",
" \"Inborn errors of metabolism: Metabolic emergencies\"",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?23/58/24489?
source=see_link\">",
" \"Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical
features\"",
" </a>",
" ).",
" </li>",
" <li>",
" Lactic acidosis due to severe hypovolemia or septic shock. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?39/44/40646?
source=see_link\">",
" \"Bicarbonate therapy in lactic acidosis\"",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?40/59/41912?
source=see_link\">",
" \"Hypovolemic shock in children: Initial evaluation and management\"",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?10/6/10346?
source=see_link\">",
" \"Systemic inflammatory response syndrome (SIRS) and sepsis in children:
Definitions, epidemiology, clinical manifestations, and diagnosis\"",
" </a>",
" .)",
" </li>",
" </ul>",
" </p>",
" <p class=\"headingAnchor\" id=\"H29\">",
" <span class=\"h1\">",
" SUMMARY AND RECOMMENDATIONS",
" </span>",
" &nbsp;&mdash;&nbsp;Children normally produce 2 to 3",
" <span class=\"nowrap\">",
" mEq/kg",
" </span>",
" of nonvolatile acid daily. These hydrogen ions are initially buffered by
extracellular bicarbonate, and are excreted in the urine to maintain acid-base
balance. (See",
" <a class=\"local\" href=\"#H2\">",
" 'Acid-Base balance'",
" </a>",
" above.)",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Metabolic acidosis occurs when there is either a net gain of H+ ions or a
net loss of HCO3- ions by the three following mechanisms. (See",
" <a class=\"local\" href=\"#H6\">",
" 'Pathophysiology'",
" </a>",
" above.)",
" </li>",
" </ul>",
" </p>",
" <p>",
" <ul class=\"hyphen-block\">",
" <li>",
" Increased acid generation from an exogenous source (eg, salicylate
ingestion) or endogenous production (eg, ketoacidosis and lactic acidosis)",
" </li>",
" <li>",
" Bicarbonate loss either from the gastrointestinal tract (eg, diarrhea) or
kidney (eg, type 2 [proximal] renal tubular acidosis [RTA])",
" </li>",
" <li>",
" Reduced renal acid excretion (eg, renal failure or type 1 [distal] RTA)",
" </li>",
" </ul>",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" The diagnosis of metabolic acidosis is made by laboratory testing that shows
a both a low serum bicarbonate and pH.",
" </li>",
" <li>",
" The history, physical examination, anion gap, and urine pH are useful aids
in determining the underlying cause of metabolic acidosis. (See",
" <a class=\"local\" href=\"#H9\">",
" 'Diagnostic tools'",
" </a>",
" above and",
" <a class=\"local\" href=\"#H24\">",
" 'Determination of underlying cause'",
" </a>",
" above.)",
" </li>",
" <li>",
" Infants and children with metabolic acidosis can present with varying
degrees of acute and chronic illness. Based upon the underlying disorder and
severity of the acidosis, children may be asymptomatic or present with poor
feeding, failure to thrive, vomiting, serum electrolyte and hematologic
abnormalities, hypotonia, seizures, tachypnea, respiratory distress, and vascular
collapse. (See",
" <a class=\"local\" href=\"#H16\">",
" 'Clinical presentation and manifestations'",
" </a>",
" above.)",
" </li>",
" <li>",
" Children with metabolic acidosis can be classified into two groups based
upon the serum anion gap (AG): normal AG or an elevated AG metabolic acidosis (",
" <a class=\"graphic graphic_table graphicRef51117 \" href=\"UTD.htm?
16/52/17229\">",
" table 1",
" </a>",
" ). Elevated threshold AG for children is above 14 to 16",
" <span class=\"nowrap\">",
" mEq/L",
" </span>",
" and, in newborns, an AG above 16",
" <span class=\"nowrap\">",
" mEq/L.",
" </span>",
" (See",
" <a class=\"local\" href=\"#H10\">",
" 'Serum anion gap'",
" </a>",
" above.)",
" </li>",
" <li>",
" The most effective therapy is treating the underlying cause. (See",
" <a class=\"local\" href=\"#H20\">",
" 'Treatment'",
" </a>",
" above.)",
" </li>",
" </ul>",
" </p>",
" </div>",
" <div id=\"topicAgreement\">",
" Use of UpToDate is subject to the",
" <a class=\"licenseLink\" href=\"./license\" id=\"sla_in_page\"
target=\"_blank\">",
" Subscription and License Agreement",
" </a>",
" .",
" </div>",
" <div class=\"headingAnchor\" id=\"references\">",
" <h1>",
" REFERENCES",
" </h1>",
" <ol id=\"reference\">",
" <li>",
" Rose BD, Post TW. Acid-base physiology. In: Clinical Physiology of Acid-Base
and Electrolyte Disorders, Rose BD, Post TW (Eds), McGraw-Hill, New York 2001.
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" Pierce NF, Fedson DS, Brigham KL, et al. The ventilatory response to acute
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" Lorenz JM, Kleinman LI, Markarian K, et al. Serum anion gap in the
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" Gabow PA, Kaehny WD, Fennessey PV, et al. Diagnostic importance of an
increased serum anion gap. N Engl J Med 1980; 303:854.",
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" Emmett M, Narins RG. Clinical use of the anion gap. Medicine (Baltimore)
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" Figge J, Jabor A, Kazda A, Fencl V. Anion gap and hypoalbuminemia. Crit Care
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" Durward A, Mayer A, Skellett S, et al. Hypoalbuminaemia in critically ill
children: incidence, prognosis, and influence on the anion gap. Arch Dis Child
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" </a>",
" </li>",
" <li>",
" Rose BD, Post TW. Acid-base physiology. In: Clinical Physiology of Acid-Base
and Electrolyte Disorders, Rose BD, Post TW (Eds), McGraw-Hill, New York 2001.
p.588.",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?6/11/6330/abstract/20\">",
" Wallia R, Greenberg A, Piraino B, et al. Serum electrolyte patterns in end-
stage renal disease. Am J Kidney Dis 1986; 8:98.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?6/11/6330/abstract/21\">",
" Meert KL, Clark J, Sarnaik AP. Metabolic acidosis as an underlying mechanism
of respiratory distress in children with severe acute asthma. Pediatr Crit Care Med
2007; 8:519.",
" </a>",
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" Ramnarayan P, Chhabra R, Maheshwari P. Metabolic acidosis, respiratory
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" Adrogu&eacute; HJ, Wilson H, Boyd AE 3rd, et al. Plasma acid-base patterns
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" Adrogu&eacute; HJ, Eknoyan G, Suki WK. Diabetic ketoacidosis: role of the
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" Carlisle EJ, Donnelly SM, Vasuvattakul S, et al. Glue-sniffing and distal
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" Boirie Y, Broyer M, Gagnadoux MF, et al. Alterations of protein metabolism
by metabolic acidosis in children with chronic renal failure. Kidney Int 2000;
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" McSherry E, Morris RC Jr. Attainment and maintenance of normal stature with
alkali therapy in infants and children with classic renal tubular acidosis. J Clin
Invest 1978; 61:509.",
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" Kraut JA, Madias NE. Consequences and therapy of the metabolic acidosis of
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" Kraut JA, Kurtz I. Use of base in the treatment of acute severe organic
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" Kraut JA, Kurtz I. Use of base in the treatment of severe acidemic states.
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" Aschner JL, Poland RL. Sodium bicarbonate: basically useless therapy.
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" Berg CS, Barnette AR, Myers BJ, et al. Sodium bicarbonate administration and
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" van Alfen-van der Velden AA, Hopman JC, Klaessens JH, et al. Effects of
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" Leonard JV, Morris AA. Inborn errors of metabolism around time of birth.
Lancet 2000; 356:583.",
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" Burton BK. Inborn errors of metabolism in infancy: a guide to diagnosis.
Pediatrics 1998; 102:E69.",
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" Burlina AB, Bonaf&eacute; L, Zacchello F. Clinical and biochemical approach
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" SUMMARY &amp; RECOMMENDATIONS",
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" INTRODUCTION",
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" ACID-BASE BALANCE",
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" Pathophysiology",
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" DIAGNOSTIC TOOLS",
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" - Normal AG acidosis",
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" - Elevated AG acidosis",
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" Urine pH",
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" CLINICAL EVALUATION AND DIAGNOSIS",
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" - Newborns and infants",
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" - Acute signs and symptoms",
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" Laboratory evaluation",
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" TREATMENT",
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" Bicarbonate therapy",
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" - Recommendations",
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" - Historical clues",
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" - Physical examination",
" </a>",
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" - Laboratory evaluation",
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" SUMMARY AND RECOMMENDATIONS",
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" Pediatric causes metabolic acidosis",
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" <h1>",
" RELATED TOPICS",
" </h1>",
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" </a>",
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var script_f6_11_6331=[""].join("\n");
var outline_f6_11_6331=null;
var title_f6_11_6332="Causes of rhabdomyolysis";
var content_f6_11_6332=[" <div id=\"graphicsToolbar\">",
" <div id=\"graphicsCopy\">",
" &copy;2013 UpToDate",
" ^{",
" &reg;",
"}",
" </div>",
" <div id=\"graphicsLinks\">",
" <a href=\"?imageKey=RHEUM
%2F60404&amp;source=image_view&amp;view=print&amp;elapsedTimeMs=1\" onclick=\"\">",
" <img alt=\"Print this page\" src=\"./../images/icn_print.myextg\"
title=\"Print this page\"/>",
" </a>",
" <a class=\"icontxt textLink\" href=\"?imageKey=RHEUM
%2F60404&amp;source=image_view&amp;view=print&amp;elapsedTimeMs=1\" onclick=\"\"
title=\"Print this page\">",
" Print",
" </a>",
" <a class=\"etacLink\" href=\"#\">",
" <img alt=\"Email graphic(s)\" src=\"./../images/icn_email.myextg\"
title=\"Email graphic(s)\"/>",
" </a>",
" <a class=\"icontxt textLink etacLink\" href=\"#\" title=\"Email graphic(s)\">",
" Email",
" </a>",
" </div>",
" </div>",
" <div class=\"graphic\">",
" <div class=\"figure\">",
" <div class=\"ttl\">",
" Causes of rhabdomyolysis",
" </div>",
" <div class=\"cntnt\">",
" <table cellspacing=\"0\">",
" <tbody>",
" <tr>",
" <td class=\"subtitle1_single\">",
" Traumatic or compression",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Multiple trauma",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Crush injuries",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Vascular or orthopedic surgery",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Coma",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Immobilization",
" </td>",
" </tr>",
" <tr>",
" <td class=\"subtitle1_single\">",
" Nontraumatic",
" </td>",
" </tr>",
" <tr>",
" <td class=\"subtitle2_single\">",
" Exertional",
" </td>",
" </tr>",
" <tr>",
" <td class=\"subtitle3_single\">",
" Normal muscle",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent2\">",
" Extreme exertion",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent2\">",
" Environmental heat illness",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent2\">",
" Sickle cell trait",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent2\">",
" Seizures",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent2\">",
" Hyperkinetic states",
" </td>",
" </tr>",
" <tr>",
" <td class=\"subtitle3_single\">",
" Abnormal muscle",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent2\">",
" Metabolic myopathies",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent2\">",
" Mitochondrial myopathies",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent2\">",
" Malignant hyperthermia",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent2\">",
" Neuroleptic malignant syndrome",
" </td>",
" </tr>",
" <tr>",
" <td class=\"subtitle2_single\">",
" Nonexertional",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Alcoholism",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Drugs and toxins",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Infections (including HIV)",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Electrolyte abnormalities",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Endocrinopathies",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Inflammatory myopathies",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Miscellaneous",
" </td>",
" </tr>",
" </tbody>",
" </table>",
" </div>",
" <div class=\"lgnd\">",
" <div class=\"footnotes\">",
" </div>",
" <div class=\"reference\">",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
var script_f6_11_6332=[""].join("\n");
var outline_f6_11_6332=null;
var title_f6_11_6333="Asthma control 5 to 11 yrs";
var content_f6_11_6333=[" <div id=\"graphicsToolbar\">",
" <div id=\"graphicsCopy\">",
" &copy;2013 UpToDate",
" ^{",
" &reg;",
"}",
" </div>",
" <div id=\"graphicsLinks\">",
" <a href=\"?imageKey=PULM
%2F73634&amp;source=image_view&amp;view=print&amp;elapsedTimeMs=2\" onclick=\"\">",
" <img alt=\"Print this page\" src=\"./../images/icn_print.myextg\"
title=\"Print this page\"/>",
" </a>",
" <a class=\"icontxt textLink\" href=\"?imageKey=PULM
%2F73634&amp;source=image_view&amp;view=print&amp;elapsedTimeMs=2\" onclick=\"\"
title=\"Print this page\">",
" Print",
" </a>",
" <a class=\"etacLink\" href=\"#\">",
" <img alt=\"Email graphic(s)\" src=\"./../images/icn_email.myextg\"
title=\"Email graphic(s)\"/>",
" </a>",
" <a class=\"icontxt textLink etacLink\" href=\"#\" title=\"Email graphic(s)\">",
" Email",
" </a>",
" </div>",
" </div>",
" <div class=\"graphic\">",
" <div class=\"figure\">",
" <div class=\"ttl\">",
" Assessing asthma control in children 5-11 years of age",
" </div>",
" <div class=\"cntnt\">",
" <table cellspacing=\"0\">",
" <tbody>",
" <tr>",
" <td class=\"subtitle1\" colspan=\"2\" rowspan=\"2\">",
" Components of control",
" </td>",
" <td class=\"subtitle1\" colspan=\"3\">",
" Classification of asthma control (children 5-11 years of age)",
" </td>",
" </tr>",
" <tr>",
" <td class=\"subtitle2\">",
" Well-controlled",
" </td>",
" <td class=\"subtitle2\">",
" Not-well controlled",
" </td>",
" <td class=\"subtitle2\">",
" Very poorly controlled",
" </td>",
" </tr>",
" <tr>",
" <td rowspan=\"7\">",
" Impairment",
" </td>",
" <td>",
" Symptoms",
" </td>",
" <td>",
" &le;2 days/week but not more than once on each day",
" </td>",
" <td>",
" &gt;2 days/week or multiple times on &le;2 days/week",
" </td>",
" <td>",
" Throughout the day",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Nighttime awakenings",
" </td>",
" <td>",
" &le;1x/month",
" </td>",
" <td>",
" &ge;2x/month",
" </td>",
" <td>",
" &ge;2x/week",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Interference with normal activity",
" </td>",
" <td>",
" None",
" </td>",
" <td>",
" Some limitation",
" </td>",
" <td>",
" Extremely limited",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Short-acting beta",
" _{",
" 2",
"}",
" -agonist use for symptom control (not prevention of EIB)",
" </td>",
" <td>",
" &le;2 days/week",
" </td>",
" <td>",
" &gt;2 days/week",
" </td>",
" <td>",
" Several times per day",
" </td>",
" </tr>",
" <tr>",
" <td class=\"sublist1_start\" colspan=\"4\">",
" Lung function",
" </td>",
" </tr>",
" <tr>",
" <td class=\"sublist1\">",
" FEV",
" _{",
" 1",
"}",
" or peak flow",
" </td>",
" <td class=\"sublist_other\">",
" &gt;80 percent predicted/personal best",
" </td>",
" <td class=\"sublist_other\">",
" 60-80 percent predicted/personal best",
" </td>",
" <td class=\"sublist_other\">",
" &lt;60 percent predicted/personal best",
" </td>",
" </tr>",
" <tr>",
" <td class=\"sublist1\">",
" FEV",
" _{",
" 1",
"}",
" /FVC",
" </td>",
" <td class=\"sublist_other\">",
" &gt;80 percent",
" </td>",
" <td class=\"sublist_other\">",
" 75-80 percent",
" </td>",
" <td class=\"sublist_other\">",
" &lt;75 percent",
" </td>",
" </tr>",
" <tr>",
" <td rowspan=\"3\">",
" Risk",
" </td>",
" <td rowspan=\"2\">",
" <strong>",
" Exacerbations requiring oral systemic corticosteroids",
" </strong>",
" </td>",
" <td>",
" <strong>",
" 0-1/year",
" </strong>",
" </td>",
" <td colspan=\"2\">",
" <strong>",
" &ge;2/year (see footnote)",
" </strong>",
" </td>",
" </tr>",
" <tr>",
" <td colspan=\"3\">",
" <strong>",
" Consider severity and interval since last exacerbation",
" </strong>",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Treatment-related adverse effects",
" </td>",
" <td colspan=\"3\">",
" Medication side effects can vary in intensity from none to very
troublesome and worrisome. The level of intensity does not correlate to specific
levels of control but should be considered in the overall assessment of risk.",
" </td>",
" </tr>",
" </tbody>",
" </table>",
" </div>",
" <div class=\"lgnd\">",
" The level of control is based on the most severe impairment or risk category.
Assess impairment domain by patient's/caregiver's recall of previous 2-4 weeks and
by spirometry/or peak flow measures. Symptom assessment for longer periods should
reflect a global assessment, such as inquiring whether the patient's asthma is
better or worse since the last visit. At present, there are inadequate data to
correspond frequencies of exacerbations with different levels of asthma control. In
general, more frequent and intense exacerbations (eg, requiring urgent, unscheduled
care, hospitalization, or ICU admission) indicate poorer disease control. For
treatment purposes, patients who had &ge;2 exacerbations requiring oral systemic
corticosteroids in the past year may be considered the same as patients who have
not-well-controlled asthma, even in the absence of impairment levels consistent
with not-well-controlled asthma.",
" <div class=\"footnotes\">",
" EIB: exercise-induced bronchospasm; FEV",
" _{",
" 1",
"}",
" : forced expiratory volume in 1 second; FVC: forced vital capacity; ICU:
intensive care unit.",
" </div>",
" <div class=\"reference\">",
" Reproduced from: National Heart, Blood, and Lung Institute Expert Panel
Report 3 (EPR 3): Guidelines for the Diagnosis and Management of Asthma. NIH
Publication no. 08-4051, 2007.",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
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var outline_f6_11_6333=null;
var title_f6_11_6334="Viral encephalitis mimics";
var content_f6_11_6334=[" <div id=\"graphicsToolbar\">",
" <div id=\"graphicsCopy\">",
" &copy;2013 UpToDate",
" ^{",
" &reg;",
"}",
" </div>",
" <div id=\"graphicsLinks\">",
" <a href=\"?imageKey=PEDS
%2F68501&amp;source=image_view&amp;view=print&amp;elapsedTimeMs=1\" onclick=\"\">",
" <img alt=\"Print this page\" src=\"./../images/icn_print.myextg\"
title=\"Print this page\"/>",
" </a>",
" <a class=\"icontxt textLink\" href=\"?imageKey=PEDS
%2F68501&amp;source=image_view&amp;view=print&amp;elapsedTimeMs=1\" onclick=\"\"
title=\"Print this page\">",
" Print",
" </a>",
" <a class=\"etacLink\" href=\"#\">",
" <img alt=\"Email graphic(s)\" src=\"./../images/icn_email.myextg\"
title=\"Email graphic(s)\"/>",
" </a>",
" <a class=\"icontxt textLink etacLink\" href=\"#\" title=\"Email graphic(s)\">",
" Email",
" </a>",
" </div>",
" </div>",
" <div class=\"graphic\">",
" <div class=\"figure\">",
" <div class=\"ttl\">",
" Conditions that mimic viral encephalitis (all of these conditions require
specific therapy)",
" </div>",
" <div class=\"cntnt\">",
" <table cellspacing=\"0\">",
" <tbody>",
" <tr>",
" <td class=\"subtitle1\">",
" Condition",
" </td>",
" <td class=\"subtitle1\">",
" Potential clues",
" </td>",
" </tr>",
" <tr>",
" <td class=\"subtitle2_left\" colspan=\"2\">",
" Bacterial infections",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Bacterial meningitis",
" </td>",
" <td>",
" Meningeal signs; CSF pleocytosis with predominance of polymorphonuclear
cells",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" CNS tuberculosis",
" </td>",
" <td>",
" Residing in, travel to, or exposure to contact from endemic areas (Asia,
Africa, Latin America, Eastern Europe); contact with an adult with tuberculosis;
lacunar infarction; hydrocephalus; low CSF glucose and elevated CSF protein",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Parameningeal infection",
" </td>",
" <td>",
" &nbsp;",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Listeriosis",
" </td>",
" <td>",
" Age &lt;1 month; immune compromise; rhomboencephalitis (ataxia, cranial
nerve deficits, nystagmus)",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Cat scratch disease",
" </td>",
" <td>",
" Cat bite/scratch; regional lymphadenopathy; neuroretinitis",
" </td>",
" </tr>",
" <tr>",
" <td class=\"subtitle2_left\" colspan=\"2\">",
" Parasitic infections",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Amoebiasis",
" </td>",
" <td>",
" Immune compromise; swimming in lakes/brackish water; travel to an endemic
area; change in taste or smell",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Cerebral malaria",
" </td>",
" <td>",
" Travel to endemic area without prophylaxis",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Toxoplasmosis",
" </td>",
" <td>",
" Immune compromise; extrapyramidal symptoms and signs",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Cysticercosis",
" </td>",
" <td>",
" Travel to endemic area; seizures, hydrocephalus; ingestion of undercooked
pork",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Echinococcus (tapeworm)",
" </td>",
" <td>",
" Hydatid cysts",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Trichinosis",
" </td>",
" <td>",
" Gastrointestinal symptoms (abdominal pain, nausea, vomiting, diarrhea);
ingestion of bear meat or other potentially contaminated foods",
" </td>",
" </tr>",
" <tr>",
" <td class=\"subtitle2_left\" colspan=\"2\">",
" Fungal infections",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Histoplasmosis",
" </td>",
" <td>",
" Residing in or travel to endemic area (eastern and central US and
Canada)",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Blastomycosis",
" </td>",
" <td>",
" Residing in or travel to endemic area (in the US, southeastern, central,
and states bordering the Great Lakes)",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Cryptococcus",
" </td>",
" <td>",
" Immune compromise; exposure to bird droppings",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Coccidiomycosis",
" </td>",
" <td>",
" Residing in or travel to endemic areas, such as the southwestern United
States",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Candidiasis",
" </td>",
" <td>",
" Immune compromise",
" </td>",
" </tr>",
" <tr>",
" <td class=\"subtitle2_left\" colspan=\"2\">",
" Rickettsial infection",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Rocky Mountain spotted fever",
" </td>",
" <td>",
" Tick exposure in endemic region; maculopapular/petechial rash; intractable
seizures",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Murine typhus",
" </td>",
" <td>",
" Flea exposure",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Q fever",
" </td>",
" <td>",
" Exposure to cats, sheep, goats (particularly placental tissue, parturient
fluids, newborn animals)",
" </td>",
" </tr>",
" <tr>",
" <td class=\"subtitle2_left\">",
" Ehrlichiosis",
" </td>",
" <td>",
" Tick exposure, rash, leukopenia, thrombocytopenia",
" </td>",
" </tr>",
" <tr>",
" <td class=\"subtitle2_left\" colspan=\"2\">",
" Other central nervous system conditions",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Head trauma",
" </td>",
" <td>",
" History of trauma (may be absent in child abuse)",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Intracranial hemorrhage",
" </td>",
" <td>",
" Neuroimaging; intracranial hemorrhage may be an indication for lumbar
puncture",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Intracranial thrombosis",
" </td>",
" <td>",
" Neuroimaging",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Idiopathic intracranial hypertension (pseudotumor cerebri)",
" </td>",
" <td>",
" Visual obscurations, diplopia, cranial nerve palsy; papilledema; increased
opening pressure during lumbar puncture",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Status epilepticus (especially nonconvulsive seizures)",
" </td>",
" <td>",
" Electroencephalogram",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Acute disseminated encephalomyelitis (ADEM, postinfectious encephalitis)",
" </td>",
" <td>",
" History of recent infection or immunization; multifocal neurologic signs
and symptoms; neuroimaging",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Tumor",
" </td>",
" <td>",
" Neuroimaging; increased opening pressure during lumbar puncture (however,
lumbar puncture usually is not performed if a tumor is suspected)",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Acute confusional migraine",
" </td>",
" <td>",
" History of migraine headaches; exclusion of other causes",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Anti-N-methyl-D-asparate receptor&nbsp;encephalitis*",
" </td>",
" <td>",
" No identifiable infectious etiology; encephalitis with psychiatric
manifestations",
" </td>",
" </tr>",
" <tr>",
" <td class=\"subtitle2_left\" colspan=\"2\">",
" Metabolic disorders",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Hypoglycemia",
" </td>",
" <td>",
" Serum glucose",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Uremic encephalopathy",
" </td>",
" <td>",
" Elevation of blood urea nitrogen, creatinine",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Hepatic encephalopathy",
" </td>",
" <td>",
" Elevation of serum aminotransferases; increased opening pressure during
lumbar puncture",
" </td>",
" </tr>",
" <tr>",
" <td class=\"subtitle2_left\" colspan=\"2\">",
" Toxins",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Acute toxic ingestion",
" </td>",
" <td>",
" Toxicology screening; pupillary changes",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Lead poisoning",
" </td>",
" <td>",
" History of lead exposure or pica; elevated blood lead level
(confirmatory)",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Reye syndrome",
" </td>",
" <td>",
" History of aspirin use; recent viral infection; increased opening pressure
during lumbar puncture",
" </td>",
" </tr>",
" <tr>",
" <td>",
" <strong>",
" Inborn errors of metabolism",
" </strong>",
" (eg, organic acidemia, urea cycle disorder, mitochondrial disorders,
mitochondrial fatty acid oxidation disorders, etc)",
" </td>",
" <td>",
" Abnormal laboratory findings (eg, hypoglycemia, hyperammonemia,
acidosis)",
" </td>",
" </tr>",
" </tbody>",
" </table>",
" </div>",
" <div class=\"lgnd\">",
" <div class=\"footnotes\">",
" CNS: central nervous system; CSF: cerebrospinal fluid.",
" <br>",
" * Associated with certain tumors (eg, ovarian teratoma).",
" <br/>",
" </br>",
" </div>",
" <div class=\"reference\">",
" Courtesy of Hordur Hardarson, MD.",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
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var title_f6_11_6335="US appendicitis in pregnancy1";
var content_f6_11_6335=[" <div id=\"graphicsToolbar\">",
" <div id=\"graphicsCopy\">",
" &copy;2013 UpToDate",
" ^{",
" &reg;",
"}",
" </div>",
" <div id=\"graphicsLinks\">",
" <a href=\"?imageKey=OBGYN
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title=\"Print this page\"/>",
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" <a class=\"icontxt textLink\" href=\"?imageKey=OBGYN
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" </a>",
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" </div>",
" <div class=\"graphic\">",
" <div class=\"figure\" style=\"width: 470px\">",
" <div class=\"ttl\">",
" Sonogram of appendicitis in pregnancy",
" </div>",
" <div class=\"cntnt\" style=\"width: 207px; height: 250px; background-image:
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P//Z);\">",
" </div>",
" <div class=\"lgnd\">",
" Sonogram of the right lower quadrant in a woman with appendicitis who is 6
weeks pregnant. Note the markedly thick-walled appendix (calipers) measuring 16
mm.",
" <div class=\"footnotes\">",
" </div>",
" <div class=\"reference\">",
" Courtesy of Deborah Levine, MD.",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
var script_f6_11_6335=[""].join("\n");
var outline_f6_11_6335=null;