2

var title_f0_2_32="Mechanisms of benefit of lipid-lowering drugs in patients with
coronary heart disease";

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" Mechanisms of benefit of lipid-lowering drugs in patients with coronary heart
disease",
" </div>",
" <div id=\"topicContributors\">",
" <div>",
" <a id=\"authors\">",
" </a>",
" <a class=\"contributor contributor_credentials contributorType\"
href=\"UTD.htm?0/2/32/contributors\">",
" Author",
" </a>",
" <br/>",
" <a class=\"contributor contributor_credentials\" href=\"UTD.htm?
0/2/32/contributors\">",
" Robert S Rosenson, MD",
" </a>",
" <br/>",
" </div>",
" <div>",
" Section Editor",
" </a>",
" <br/>",
" Mason W Freeman, MD",
" </a>",
" <br/>",
" </div>",
" <div>",
" Deputy Editor",
" </a>",
" <br/>",
" Gordon M Saperia, MD, FACC",
" </a>",
" <br/>",
" </div>",
" </div>",
" <div id=\"disclosures\">",
" <a href=\"UTD.htm?0/2/32/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>",
" This topic last updated:",
" </span>",
" Jul 26, 2012.",
" </div>",
" <div id=\"topicText\">",
" <p class=\"headingAnchor\" id=\"H1\">",
" <span class=\"h1\">",
" INTRODUCTION",
" </span>",
" — Lipid lowering with statins in patients with
hypercholesterolemia has a proven survival benefit for both primary prevention (ie,
in patients without clinical evidence of coronary disease) and secondary prevention
(ie, in patients with established coronary disease), even when serum cholesterol
concentrations are \"normal\" for the population or borderline high. Statins may
also be beneficial in patients with heart failure. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?18/50/19240?
source=see_link\">",
" \"Clinical trials of cholesterol lowering for primary prevention of coronary
heart disease\"",
" </a>",
" and",
" \"Clinical trials of cholesterol lowering in patients with coronary heart
disease or coronary risk equivalents\"",
" </a>",
" and",
source=see_link&anchor=H3#H3\">",
" \"Statin therapy in patients with heart failure\", section on 'Potential
benefits and harms of statin therapy in HF'",
" </a>",
" .)",
" </p>",
" TIMING AND MECHANISMS OF BENEFIT",
" </span>",
" — The mechanisms by which lipid-lowering therapy
(particularly with statins) is beneficial are incompletely explained by the serum
low density lipoprotein (LDL) concentration at baseline or after treatment [",
" <a class=\"abstract\" href=\"UTD.htm?0/2/32/abstract/1-6\">",
" 1-6",
" </a>",
" ]. Although statins probably cause regression of atherosclerosis, an
improvement in outcome can be demonstrated as early as six months (",
" <a class=\"graphic graphic_figure graphicRef62070 \" href=\"UTD.htm?
19/57/20381\">",
" figure 1",
" </a>",
" ) [",
" <a class=\"abstract\" href=\"UTD.htm?0/2/32/abstract/7,8\">",
" 7,8",
" </a>",
" ], a time considered too early for significant regression. In addition, the
amount of lesion regression is small compared with the magnitude of the observed
clinical benefit.",
" </p>",
" <p>",
" A case-control study of adults with a first clinical presentation of coronary
heart disease found that use of statins was associated with a decreased likelihood
of that presentation being an acute myocardial infarction (odds ratio 0.45) and
thus an increased likelihood of presenting with stable angina [",
" <a class=\"abstract\" href=\"UTD.htm?0/2/32/abstract/9\">",
" 9",
" </a>",
" ]. These observations suggest a mechanism of benefit with statins that might
involve unstable coronary lesions.",
" </p>",
" <p>",
" Among the nonlipid mechanisms that may be involved are plaque stabilization,
reduced inflammation, reversal of endothelial dysfunction, and decreased
thrombogenicity [",
" 10,11",
" </a>",
" ].",
" </p>",
" Regression of atherosclerosis",
" </span>",
" — Regression of the atherosclerotic lesions can occur after
lipid lowering, without change in vessel wall thickness or vessel wall area, and
may be clinically important [",
" 12",
" </a>",
" ]. One limitation to arteriographic studies is the relative lack of
sensitivity to morphologic changes in atheroma, which can be better characterized
by intracoronary ultrasonography (ICUS) [",
" 13",
" </a>",
" ], or to small changes, which might be detectable by other techniques such as
B-mode ultrasonography for measurement of carotid intima thickness [",
" 14",
" </a>",
" ], electron beam or multidetector row computed tomography to detect coronary
artery calcification [",
" 15",
" </a>",
" ], or high-resolution magnetic resonance imaging MRI [",
" 12",
" </a>",
" ]. (See",
" \"Diagnostic and prognostic implications of coronary artery calcification
detected by computed tomography\"",
" </a>",
" and",
" \"Clinical utility of cardiovascular magnetic resonance imaging\"",
" </a>",
" .)",
" </p>",
" <p>",
" The benefit of lipid lowering is illustrated by the observation that in
different studies, coronary angiography has shown increases in lumen diameter at
two and four years or a lesser degree of progression of stenosis at three years
after the onset of statin therapy [",
" 16,17",
" </a>",
" ].",
" </p>",
" <p>",
" There are limited data on the exact timing of regression of atherosclerosis,
particularly coronary atherosclerosis, after statin therapy. This issue was
addressed using high-resolution MRI to assess aortic and carotid artery plaques. No
changes were seen at six months [",
" 12",
" </a>",
" ], but progressive regression was noted at 12 and 24 months [",
" 18",
" </a>",
" ]. The earliest change, seen at 12 months, was a reduction in plaque size
followed by an increase in luminal area due to arterial remodeling [",
" 18",
" </a>",
" ].",
" </p>",
" Plaque stabilization",
" </span>",
" — Coronary artery plaque rupture is a central component in
most patients with an acute coronary syndrome. Furthermore, there is increasing
evidence that many of these patients have multiple unstable plaques in different
coronary arteries, suggesting widespread inflammation in the coronary circulation.
Thus, intervention aimed only at the culprit lesion is not likely to be optimal and
the ability of statins to induce plaque stabilization may be an important mechanism
of benefit. (See",
" \"The role of the vulnerable plaque in acute coronary syndromes\"",
" </a>",
" .)",
" </p>",
" <p>",
" Animal models and human studies have shown that statin therapy can reduce the
rate of progression of plaque development and stabilize atherosclerotic plaques
that have ruptured as well as those that are vulnerable to rupture [",
" <a class=\"abstract\" href=\"UTD.htm?0/2/32/abstract/13,19-21\">",
" 13,19-21",
" </a>",
" ]. One report of 131 patients evaluated the effect of 12 months of",
" <a class=\"drug drug_general\" href=\"UTD.htm?34/37/35417?source=see_link\">",
" atorvastatin",
" </a>",
" therapy using ICUS [",
" 13",
" </a>",
" ]. Compared to placebo, atorvastatin reduced the progression of mean plaque
volume or thickness (1.2 versus 9.6 mm3 for placebo) and increased the
hyperechogenicity of the plaque, indicating a change in plaque composition (from
lipid-rich to fibrotic and calcified) that corresponds to increased plaque
stability and a reduced tendency for rupture.",
" </p>",
" <p>",
" A variety of factors may contribute to the pathogenesis of plaque rupture and
the induction of acute coronary syndromes [",
" 22,23",
" </a>",
" ]. (See",
" \"Pathology and pathogenesis of the vulnerable plaque\"",
" </a>",
" .) One important effect of statin therapy may be maintenance of integrity of
the fibrous cap of the plaque, thereby protecting against plaque rupture. This
effect appears to be mediated by inhibition of macrophage proliferation, reduced
expression of matrix metalloproteinases (MMPs) and tissue factor (which promotes
thrombus formation) by macrophages, and an increase in tissue inhibitor of
metalloproteinase-1 [",
" <a class=\"abstract\" href=\"UTD.htm?0/2/32/abstract/20,24,25\">",
" 20,24,25",
" </a>",
" ]:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" The inhibitory effect on MMP’s may be mediated in part by statin-
induced inhibition of prostaglandin synthesis [",
" 26",
" </a>",
" ]. In cell cultures of mouse and human macrophages, lipophilic statins (",
" fluvastatin",
" </a>",
" ,",
" <a class=\"drug drug_general\" href=\"UTD.htm?17/36/17993?
" simvastatin",
" </a>",
" ) inhibit MMP-9 activity by 20 to 40 percent in a dose-dependent manner [",
" 25",
" </a>",
" ]. This effect was fully reversed by mevalonate.",
" </li>",
" <li>",
" In animal models, certain statins induce smooth muscle cell apoptosis. This
may diminish collagen biosynthesis and thus the formation of the protective fibrous
cap [",
" 27",
" </a>",
" ]. There are differences among the statins in their effects on smooth muscle
cell apoptosis and collagen biosynthesis [",
" 28,29",
" </a>",
" ].",
" </li>",
" </ul>",
" </p>",
" <p>",
" The clinical relevance of the differential tissue effects of statins is
uncertain; a comparison study of statins in a high risk population at equivalent
LDL-C-lowering doses would be required to sort this out. It is likely that these
effects are in part due to lipid lowering. In animal models, reductions in
macrophage content, MMP, and tissue factor expression can be induced by dietary
modification [",
" 30,31",
" </a>",
" ]. Additional support for the importance of lipid lowering comes from
examination of the coronary arteries and plaque morphology of 113 men who died
suddenly [",
" 32",
" </a>",
" ]. By multivariate analysis, the serum concentrations of total cholesterol,
HDL-cholesterol, and the ratio of total cholesterol to HDL-cholesterol were
independently associated with plaque rupture.",
" </p>",
" Reduced inflammation",
" </span>",
" — Inflammation appears to be another important contributor to
atherosclerosis and plaque rupture. (See",
" \"Pathology and pathogenesis of the vulnerable plaque\"",
" </a>",
" .) Elevated serum markers of inflammation, particularly C-reactive protein
(CRP), are associated with progression of atherosclerosis, predict the risk of a
first myocardial infarction among apparently healthy men, and are associated with a
worse prognosis among patients with stable and unstable angina and those who
undergo coronary stenting. (See",
" \"Screening for cardiovascular risk with C-reactive protein\"",
" </a>",
" and",
" \"C-reactive protein in cardiovascular disease\"",
" </a>",
" .)",
" </p>",
" <p>",
" Statin therapy, given as primary or secondary prevention, reduces the serum
CRP concentration, an effect that is mostly unrelated to lipid levels at baseline
or during therapy [",
" 33-36",
" </a>",
" ]. The fall in serum CRP begins within 14 days [",
" 36",
" </a>",
" ].",
" </p>",
" <p>",
" Additional evidence that statins may have an anti-inflammatory effect is
provided by a randomized trial that found that patients with rheumatoid arthritis
experienced modest clinical improvement with",
" atorvastatin",
" </a>",
" ; atorvastatin also reduced CRP levels and the erythrocyte sedimentation rate
compared with placebo [",
" 37",
" </a>",
" ]. (See",
" \"Miscellaneous novel therapies in rheumatoid arthritis\", section on
'Statins'",
" </a>",
" .)",
" </p>",
" <p>",
" Such an antiinflammatory effect could contribute to the benefit from the early
institution of statin therapy in patients with an acute coronary syndrome [",
" 38",
" </a>",
" ]. (See",
" \"Cholesterol lowering after an acute coronary syndrome\"",
" </a>",
" .) Results from PROVE IT, MIRACL, and Phase Z of the A to Z trial raise the
possibility that the antiinflammatory effects of statins may differ among statins
[",
" 39",
" </a>",
" ]. (See",
disease or coronary risk equivalents\"",
" </a>",
" .) The first two trials showed early benefit with",
" atorvastatin",
" </a>",
" [",
" 40,41",
" </a>",
" ], while in the last trial, despite achieving an LDL-C concentration of 68",
" <span class=\"nowrap\">",
" mg/dL",
" </span>",
" (1.76",
" mmol/L)",
" </span>",
" after one month of",
" simvastatin",
" </a>",
" 40 mg daily, there was no evidence of clinical benefit and no reduction in CRP
[",
" 42",
" </a>",
" ].",
" </p>",
" Baseline inflammatory markers",
" </span>",
" — In clinical trials, statins appear to have greater effects
in patients with evidence of inflammation at baseline.",
" </p>",
" <p>",
" The potential importance of statin-induced reduction in serum markers of
inflammation was illustrated by an analysis from the secondary prevention CARE
trial [",
" 43",
" </a>",
" ]. Patients with baseline serum concentrations of CRP and serum amyloid A in
the highest quintile had a relative risk for a recurrent event 75 percent higher
than those with levels in the lowest quintile (",
10/9/10398\">",
" figure 2",
" </a>",
" ). However, in patients who were treated with",
" pravastatin",
" </a>",
" , the association between inflammation and risk was attenuated and was no
longer statistically significant (",
42/17/43293\">",
" figure 3",
" </a>",
" ).",
" </p>",
" <p>",
" Similar findings were noted in a prospective study of patients with
angiographically severe coronary disease; the improvement in survival with statin
therapy occurred primarily in those with elevated serum CRP [",
" 44",
" </a>",
" ]. In addition, in a prospective observational study of patients undergoing
percutaneous coronary interventions, pretreatment with statins was associated with
a marked improvement in survival in those patients in the highest quartile of CRP
levels [",
" 45",
" </a>",
" ].",
" </p>",
" <p>",
" An analysis from the",
" AFCAPS/TexCAPS",
" </span>",
" trial of primary prevention enhanced our understanding of the interactions
among statin therapy, serum lipids, serum CRP, and patient outcomes [",
" 46",
" </a>",
" ].",
" Lovastatin",
" </a>",
" reduced serum CRP by almost 15 percent. The following results were noted:",
" </p>",
" <p>",
" <li>",
" Among patients with a total cholesterol-to-HDL cholesterol ratio above the
median, the beneficial effect of",
" lovastatin",
" </a>",
" on coronary events was independent of serum CRP; the number of subjects
needed to treat for five years to prevent one event was 47.",
" </li>",
" <li>",
" Lovastatin",
" </a>",
" was also effective in those with a ratio that was lower than the median in
whom the serum CRP level was above the median; the number of subjects needed to
treat for five years to prevent one event was 43.",
" </li>",
" <li>",
" Lovastatin",
" </a>",
" was ineffective in patients with a low ratio and a CRP level below the
median. (See",
" <a class=\"local\" href=\"#H7\">",
" 'Reduction in CRP'",
" </a>",
" below.)",
" </li>",
" </ul>",
" </p>",
" <p>",
" An effect of statins unrelated to lipid lowering has also been shown in a
prospective study including patients with antibodies to cytomegalovirus (CMV).
Statin usage, CMV seropositivity, and serum CRP level were measured in 2315
patients with angiographically significant coronary disease [",
" 47",
" </a>",
" ]. After 2.4 years, patients who were CMV positive and had high serum CRP
levels had a lower mortality rate with statin use (6 versus 17 percent without
statins). Those who had both a low serum CRP and a negative CMV titer had no
improvement in mortality rate with statins (5 versus 4 percent).",
" </p>",
" Reduction in CRP",
" </span>",
" — Analyses from randomized trials that compared intensity of
statin therapy suggest that beyond reduction in LDL-C, the differential effects of
statins are explained, at least in part, by reduction in CRP. This issue is
discussed in detail elsewhere. (See",
" \"C-reactive protein in cardiovascular disease\"",
" </a>",
" and",
disease or coronary risk equivalents\", section on 'PROVE IT-TIMI 22 trial'",
" </a>",
" .)",
" </p>",
" Mechanism",
" </span>",
" — How statins might interfere with the inflammatory response
is not well understood. One possible mechanism is impairment of inflammatory cell
adhesion by inhibition of the main beta-2 integrin, LFA-1 [",
" 48,49",
" </a>",
" ]. However,",
" pravastatin",
" </a>",
" has antiinflammatory activity but does not interfere with this integrin [",
" 48",
" </a>",
" ]. Other contributing factors may include reduced lipidation of intracellular
proteins and reduced expression of major histocompatibility complex class II
molecules on antigen-presenting cells in response to interferon, decreasing
subsequent T-lymphocyte activation [",
" 49,50",
" </a>",
" ]. (See",
" \"Transplantation immunobiology\"",
" </a>",
" .)",
" </p>",
" <p>",
" These effects could also contribute to the reduction in transplant
vasculopathy and the improved outcome in heart transplant recipients treated with",
" pravastatin",
" </a>",
" . (See",
" \"Prevention and treatment of cardiac allograft vasculopathy\"",
" </a>",
" .)",
" </p>",
" <p>",
" The fall in CRP induced by statins may be mediated in part by reduced monocyte
expression of proinflammatory cytokines that stimulate the release of acute phase
proteins [",
" 51",
" </a>",
" ]. (See",
" \"Acute phase reactants\"",
" </a>",
" .)",
" </p>",
" Reversal of endothelial dysfunction",
" </span>",
" — Endothelial dysfunction is a frequent finding in
atherosclerotic coronary arteries, one characteristic of which is the induction of
vasoconstriction by acetylcholine rather than the expected, nitric oxide-mediated
vasodilation [",
" 52-54",
" </a>",
" ]. Normal arterial smooth muscle tone results from a balance of vasodilating
(eg, nitric oxide) and vasoconstricting (eg, endothelin) influences, with the
former predominating in the resting state. (See",
" \"Endothelial dysfunction\", section on 'Endothelial physiology'",
" </a>",
" and",
" \"Endothelial dysfunction\", section on 'Pathophysiology'",
" </a>",
" .)",
" </p>",
" <p>",
" Most [",
" 52-55",
" </a>",
" ], but not all [",
" 56",
" </a>",
" ], studies have shown that vasoconstriction associated with endothelial
dysfunction can be attenuated or abolished with statin therapy, an effect that can
improve overall vasodilator capacity and myocardial blood flow reserve within six
weeks [",
" 57-61",
" </a>",
" ].",
" </p>",
" <p>",
" Statins improve endothelial function through one or more of the following
mechanisms:",
" </p>",
" <p>",
" <li>",
" Increase in endothelial nitric oxide (NO) activity due in large part to an
increase in NO synthesis [",
" 61-65",
" </a>",
" ].",
" </li>",
" <li>",
" Reduction in serum oxidized LDL as oxidized LDL, but not native LDL,
downregulates endothelial nitric oxide synthase activity [",
" 66",
" </a>",
" ].",
" </li>",
" <li>",
" Inhibition of endothelin synthesis through inhibition of pre-pro-endothelin
mRNA [",
" 66-68",
" </a>",
" ].",
" </li>",
" <li>",
" Improvement in endothelial integrity with a reduction in permeability to LDL
cholesterol [",
" 69",
" </a>",
" ].",
" </li>",
" <li>",
" Inactivation of superoxide, which is known to impair the function of nitric
oxide [",
" 62,70",
" </a>",
" ].",
" </li>",
" </ul>",
" </p>",
" <p>",
" Many of the above effects appear to be independent of LDL-C lowering. This was
illustrated in two four-week clinical trials comparing a statin to",
" ezetimibe",
" </a>",
" or a statin-ezetimibe combination [",
" 60,61",
" </a>",
" ]. In the larger trial, 60 patients with dyslipidemia, but no cardiovascular
disease, were randomly assigned to",
" simvastatin",
" </a>",
" 40 mg daily,",
" simvastatin/ezetimibe",
" </span>",
" 10/10",
" </span>",
" mg daily or placebo [",
" 61",
" </a>",
" ]. Compared to placebo, both treatment groups had similar 35 to 40 percent
reductions in LDL-C and serum CRP [",
" 61",
" </a>",
" ]. In contrast, a significant improvement in flow-mediated dilatation was only
seen in the high-dose simvastatin group (32.1 percent improvement versus 0.5
percent worsening with combination therapy).",
" </p>",
" <p>",
" Different mechanisms may be involved in the improvement in endothelial
function with fibrate therapy in patients with type 2 diabetes [",
" 71",
" </a>",
" ]. This effect may be mediated by an elevation in serum HDL and an attenuation
of postprandial lipemia and the associated oxidative stress. (See",
" \"HDL metabolism and approach to the patient with abnormal HDL-cholesterol
levels\", section on 'Effect of increasing HDL-cholesterol on clinical outcome'",
" </a>",
" .)",
" </p>",
" Decreased thrombogenicity",
" </span>",
" — Thrombus formation at the site of plaque rupture appears to
account for most acute coronary syndromes. (See",
" \"The role of the vulnerable plaque in acute coronary syndromes\"",
" </a>",
" .)",
" </p>",
" <p>",
" Lipid lowering, particularly with statin therapy, has a variety of effects
that may reduce thrombus formation [",
" 72",
" </a>",
" ]. These include:",
" </p>",
" <p>",
" <li>",
" Reduced expression of tissue factor in endothelial cells and by macrophages
in the atherosclerotic plaque [",
" 24,31,73",
" </a>",
" ]",
" </li>",
" <li>",
" Decreased prothrombin activation and thrombin generation [",
" 74,75",
" </a>",
" ]",
" </li>",
" <li>",
" Improved fibrinolytic profile [",
" 76",
" </a>",
" ]",
" </li>",
" <li>",
" Decreased platelet activation [",
" 77-79",
" </a>",
" ], perhaps mediated in part by an antioxidant effect [",
" 79",
" </a>",
" ]",
" </li>",
" </ul>",
" </p>",
" <p>",
" These changes are either independent of [",
" 74",
" </a>",
" ] or only partially explained by cholesterol lowering [",
" 76,79",
" </a>",
" ].",
" </p>",
" <p>",
" The molecular mechanisms by which these events occur are becoming clearer.
Both membrane bound and soluble CD40 ligand (sCD40L) interact with CD40 expressed
on vascular cells, resulting in inflammatory and prothrombotic responses [",
" 80,81",
" </a>",
" ]. Elevated levels of sCD40L have been implicated in acute coronary syndromes
and predict an increased risk of future cardiovascular events in healthy subjects
[",
" 82,83",
" </a>",
" ].",
" </p>",
" <p>",
" A study of 80 patients with hypercholesterolemia found that compared with
matched controls, hypercholesterolemic patients had higher levels of sCD40L, factor
VIIa, and prothrombin fragment [",
" 84",
" </a>",
" ]. The level of sCD40L correlated with serum total and LDL-cholesterol, and it
was positively associated with both in vivo platelet activation and with a
procoagulant state. Inhibition of cholesterol biosynthesis with either",
" pravastatin",
" </a>",
" or cerivastatin was associated with comparable, significant reductions in
sCD40L, factor VIIa, and prothrombin fragment.",
" Atorvastatin",
" </a>",
" has also been found to inhibit platelet CD40L and CD40L-mediated thrombin
generation [",
" 85",
" </a>",
" ].",
" </p>",
" <p>",
" The timing and mechanism of the antithrombotic effect of statins were
evaluated in an open label trial in which 30 hypercholesterolemic patients were
randomly assigned to either",
" atorvastatin",
" </a>",
" 40 mg daily or a Mediterranean diet with low cholesterol intake [",
" 79",
" </a>",
" ]. Multiple laboratory tests of platelet activation and oxidative stress were
performed during 168 hours of follow-up. The following findings were noted:",
" </p>",
" <p>",
" <li>",
" Patients assigned to the diet group showed no differences from baseline in
parameters of platelet function or oxidative stress.",
" </li>",
" <li>",
" Measures of oxidative stress and platelet activation were significantly and
progressively reduced in the",
" atorvastatin",
" </a>",
" group, with a measurable effect as early as two hours after drug initiation.
These early effects appeared to be independent of cholesterol lowering.",
" </li>",
" <li>",
" In a separate in-vitro study,",
" atorvastatin",
" </a>",
" , in a dose-dependent manner, inhibited markers of oxidative stress and
platelet activation. This study suggested that the antiplatelet effect of
atorvastatin may occur by inhibition of platelet Nox2, a marker of NADPH oxidase
activation.",
" </li>",
" </ul>",
" </p>",
" Reduction in ventricular arrhythmias",
" </span>",
" — A major cause of cardiac mortality in patients with CHD is
sudden death, which is primarily due to a life-threatening ventricular
tachyarrhythmia. (See",
" \"Epidemiology of coronary heart disease\"",
" </a>",
" .)",
" </p>",
" <p>",
" Lipid lowering in patients with CHD reduces the incidence of cardiac death
and, in studies of patients with an implantable cardioverter-defibrillator, reduced
the rate of life-threatening ventricular arrhythmia (unstable ventricular
tachycardia or ventricular fibrillation) [",
" 86,87",
" </a>",
" ]. (See",
" \"Pharmacologic therapy in survivors of sudden cardiac arrest\", section on
'Lipid-lowering'",
" </a>",
" .)",
" </p>",
" Other",
" </span>",
" — Statin therapy has a variety of other effects that may
contribute to improved outcomes in patients with CHD:",
" </p>",
" <p>",
" <li>",
" Reduced monocyte adhesion to the endothelium [",
" 88",
" </a>",
" ]. Monocyte recruitment into the vascular wall is important for the
initiation and progression of an atherosclerotic lesion.",
" </li>",
" <li>",
" Reduced oxidative modification of LDL, which is thought to play an important
role in the pathogenesis of atherosclerosis [",
" 89,90",
" </a>",
" ].",
" </li>",
" <li>",
" Increased mobilization and differentiation of endothelial progenitor cells,
suggesting a possible role in new vessel formation [",
" 91,92",
" </a>",
" ].",
" </li>",
" <li>",
" There is some variability among the statins and fibrates on plasma
fibrinogen and viscosity, which may be risk factors for coronary disease. Several
small uncontrolled studies found that plasma fibrinogen levels rise with",
" atorvastatin",
" </a>",
" and",
" lovastatin",
" </a>",
" , may rise or fall with",
" pravastatin",
" </a>",
" , and are generally unchanged with",
" simvastatin",
" </a>",
" or",
" fluvastatin",
" </a>",
" [",
" 76,93,94",
" </a>",
" ]. Similar variability occurs with fibrates. Plasma fibrinogen tends to rise
with",
" gemfibrozil",
" </a>",
" and fall with",
" bezafibrate",
" </a>",
" and",
" fenofibrate",
" </a>",
" [",
" 95",
" </a>",
" ].",
" </li>",
" </ul>",
" </p>",
" KIF6 gene",
" </span>",
" — Some [",
" 96,97",
" </a>",
" ], but not all studies [",
" 98,99",
" </a>",
" ], have suggested that carriers of the kinesin family member 6 (KIF6) 719Arg
allele might derive greater benefit from statin therapy than non-carriers [",
" 100",
" </a>",
" ]. In an analysis of nearly 8800 white participants from the randomized
JUPITER trial, there was no significant difference in the rate of the primary
outcome (first major cardiovascular event) between carriers and non-carriers of the
allele in either the",
" rosuvastatin",
" </a>",
" or placebo groups [",
" 100",
" </a>",
" ]. We do not recommend testing for the KIF6 polymorphisms to guide statin
therapy. (See",
" \"Clinical trials of cholesterol lowering for primary prevention of coronary
heart disease\", section on 'JUPITER trial'",
" </a>",
" .)",
" </p>",
" SUMMARY",
" </span>",
" </p>",
" <p>",
" <li>",
" The mechanisms by which lipid-lowering therapy (particularly with statins)
is beneficial are incompletely understood. While lowering of low density
lipoprotein (LDL) concentration is associated with regression of atherosclerosis,
the observed benefit of (particularly statin) therapy begins within months after
its initiation, making regression an unlikely cause at this early stage. (See",
" 'Regression of atherosclerosis'",
" </a>",
" above.)",
" </li>",
" <li>",
" Other mechanisms thought to be involved include plaque stabilization,
reduction of inflammation, reversal of endothelial dysfunction, and decreased
thrombogenicity. (See",
" 'Reduced inflammation'",
" </a>",
" above and",
" 'Reversal of endothelial dysfunction'",
" </a>",
" above and",
" 'Decreased thrombogenicity'",
" </a>",
" above and",
" 'Plaque stabilization'",
" </a>",
" above.)",
" </li>",
" <li>",
" Reduction in monocyte adhesion to the endothelium, reduced oxidative
modification of LDL, and increases in mobilization and differentiation of
endothelial progenitor cells have also been considered as potential benefits from
lipid lowering.",
" </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\">",
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" Marais AD, Firth JC, Bateman ME, et al. Atorvastatin: an effective lipid-
modifying agent in familial hypercholesterolemia. Arterioscler Thromb Vasc Biol
1997; 17:1527.",
" </a>",
" </li>",
" <li>",
" Durrington PN, Mackness MI, Bhatnagar D, et al. Effects of two different
fibric acid derivatives on lipoproteins, cholesteryl ester transfer, fibrinogen,
plasminogen activator inhibitor and paraoxonase activity in type IIb
hyperlipoproteinaemia. Atherosclerosis 1998; 138:217.",
" </a>",
" </li>",
" <li>",
" Iakoubova OA, Tong CH, Rowland CM, et al. Association of the Trp719Arg
polymorphism in kinesin-like protein 6 with myocardial infarction and coronary
heart disease in 2 prospective trials: the CARE and WOSCOPS trials. J Am Coll
Cardiol 2008; 51:435.",
" </a>",
" </li>",
" <li>",
" Iakoubova OA, Robertson M, Tong CH, et al. KIF6 Trp719Arg polymorphism and
the effect of statin therapy in elderly patients: results from the PROSPER study.
Eur J Cardiovasc Prev Rehabil 2010; 17:455.",
" </a>",
" </li>",
" <li>",
" Assimes TL, Hólm H, Kathiresan S, et al. Lack of association between
the Trp719Arg polymorphism in kinesin-like protein-6 and coronary artery disease in
19 case-control studies. J Am Coll Cardiol 2010; 56:1552.",
" </a>",
" </li>",
" <li>",
" Stewart AF, Dandona S, Chen L, et al. Kinesin family member 6 variant
Trp719Arg does not associate with angiographically defined coronary artery disease
in the Ottawa Heart Genomics Study. J Am Coll Cardiol 2009; 53:1471.",
" </a>",
" </li>",
" <li>",
" Ridker PM, MacFadyen JG, Glynn RJ, Chasman DI. Kinesin-like protein 6 (KIF6)
polymorphism and the efficacy of rosuvastatin in primary prevention. Circ
Cardiovasc Genet 2011; 4:312.",
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" </a>",
" </li>",
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heart disease",
" </a>",
" </li>",
" Clinical trials of cholesterol lowering in patients with coronary heart
disease or coronary risk equivalents",
" </a>",
" </li>",
" Clinical utility of cardiovascular magnetic resonance imaging",
" </a>",
" </li>",
" Diagnostic and prognostic implications of coronary artery calcification
detected by computed tomography",
" </a>",
" </li>",
" Endothelial dysfunction",
" </a>",
" </li>",
" Epidemiology of coronary heart disease",
" </a>",
" </li>",
" HDL metabolism and approach to the patient with abnormal HDL-cholesterol
levels",
" </a>",
" </li>",
" Miscellaneous novel therapies in rheumatoid arthritis",
" </a>",
" </li>",
" Pathology and pathogenesis of the vulnerable plaque",
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" </li>",
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" </a>",
" </li>",
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" </a>",
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" Statin therapy in patients with heart failure",
" </a>",
" </li>",
" The role of the vulnerable plaque in acute coronary syndromes",
" </a>",
" </li>",
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" </div>",
" <div class=\"lgnd\">",
" Light micrograph of membranous nephropathy, showing diffuse thickening of the
glomerular basement membrane (long arrows) with essentially normal cellularity.
Note how the thickness of the glomerular capillary walls is much greater than that
of the adjacent tubular basement membranes (short arrow). There are also areas of
mesangial expansion (asterisks). Immunofluorescence microscopy (showing granular
IgG deposition) and electron microscopy (showing subepithelial deposits) are
generally required to confirm the diagnosis.",
" <div class=\"footnotes\">",
" </div>",
" <div class=\"reference\">",
" Courtesy of Helmut Rennke, MD.",
" </div>",
" </div>",
" </div>",
" Normal glomerulus",
" </div>",
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i18zxMbRVOfIz//2Q==);\">",
" </div>",
" Light micrograph of a normal glomerulus. There are only 1 or 2 cells per
capillary tuft, the capillary lumens are open, the thickness of the glomerular
capillary wall (long arrow) is similar to that of the tubular basement membranes
(short arrow), and the mesangial cells and mesangial matrix are located in the
central or stalk regions of the tuft (arrows).",
" </div>",
" Courtesy of Helmut G Rennke, MD.",
" </div>",
" </div>",
" </div>",
" </div>",
" <div class=\"graphic\">",
" Immunofluorescence microscopy showing membranous nephropathy",
" </div>",
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" </div>",
" Immunofluorescence microscopy in membranous nephropathy showing diffuse,
granular IgG deposition along the capillary walls.",
" </div>",
" </div>",
" </div>",
" </div>",
" </div>",
" Electron micrograph showing membranous nephropathy",
" </div>",
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" </div>",
" Electron micrograph shows stage II membranous nephropathy. Electron dense
deposits (D) are present in the subepithelial space across the glomerular basement
membrane (GBM) and under the epithelial cells (Ep). New basement membrane is
growing between the deposits, leading to a spike appearance on silver stain.",
" </div>",
" </div>",
" </div>",
" </div>",
" Electron micrograph of a normal glomerulus",
" </div>",
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" </div>",
" Electron micrograph of a normal glomerular capillary loop showing the
fenestrated endothelial cell (Endo), the glomerular basement membrane (GBM), and
the epithelial cells with its interdigitating foot processes (arrow). The GBM is
thin, and no electron dense deposits are present. Two normal platelets are seen in
the capillary lumen.",
" </div>",
" </div>",
" </div>",
" </div>",
" </div>",
" Silver stain in membranous nephropathy",
" </div>",
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B+EWG/g/P9D//Z);\">",
" </div>",
" Light micrograph silver stain of membranous nephropathy shows a spike
appearance (arrows). The spikes represent new basement membrane growing between the
subepithelial immune deposits which are visible on electron microscopy, but not
with this stain.",
" </div>",
" </div>",
" </div>",
" </div>",
" </div>",
" Stage III membranous nephropathy",
" </div>",
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,
" </div>",
" Electron micrograph in stage III membranous nephropathy. The subepithelial
immune deposits (D) have a lucent, moth-eaten appearance and have been incorporated
into the glomerular basement membrane (GBM) as new basement membrane has grown
around the deposits (arrows).",
" </div>",
" </div>",
" </div>",
" </div>",
" </div>",
WvR/
CKaX/AM85P+
" </div>",
" </div>",
" </div>",
" </div>",
" </div>",
" </div>",
" Electron micrograph showing membranous lupus nephritis",
" </div>",
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T7rYHNcv8LefBVjnsG/nXXDvQA0vhemMilDnA+U0N3+lPHQUAf//Z);\">",
" </div>",
" Electron micrograph of membranous lupus nephritis. The subepithelial immune
deposits (D) are characteristic of any form of membranous nephropathy, but the
intraendothelial tubuloreticular inclusions (arrow) strongly suggest underlying
lupus.",
" GBM: glomerular basement membrane; Ep: epithelial cell.",
" </div>",
" </div>",
" </div>",
" </div>",
" </div>",
WvR/
CKaX/AM85P+
" </div>",
" </div>",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
var outline_f0_2_33=null;
var title_f0_2_34="UpToDate Inc.";
" ©2013 UpToDate",
" <sup>",
" ®",
" </sup>",
" </div>",
" <a href=\"?imageKey=RHEUM%2F81066&source=image_view&view=print\"
onclick=\"\">",
" </a>",
" <a class=\"icontxt textLink\" href=\"?imageKey=RHEUM
%2F81066&source=image_view&view=print\" onclick=\"\" title=\"Print this
page\">",
" Print",
" </a>",
" </a>",
" Email",
" </a>",
" </div>",
" </div>",
"</div>"].join("\n");
var title_f0_2_35="HDL-C and cardiovascular risk";
" ©2013 UpToDate",
" <sup>",
" ®",
" </sup>",
" </div>",
" <a href=\"?imageKey=CARD
" </a>",
" <a class=\"icontxt textLink\" href=\"?imageKey=CARD
" Print",
" </a>",
" </a>",
" Email",
" </a>",
" </div>",
" </div>",
" <div class=\"figure\">",
" HDL-C and cardiovascular risk",
" </div>",
" <div class=\"cntnt\">",
" <table cellspacing=\"0\">",
" <tbody>",
" <tr>",
" <td class=\"subtitle1\" colspan=\"1\" rowspan=\"2\">",
" HDL, mg/dL",
" </td>",
" <td class=\"subtitle1\" colspan=\"2\" rowspan=\"1\">",
" Multiplier for cardiovascular risk",
" </td>",
" </tr>",
" <tr>",
" <td class=\"subtitle2\">",
" Men",
" </td>",
" Women",
" </td>",
" </tr>",
" <tr>",
" <td>",
" 30",
" </td>",
" <td>",
" 1.82 ",
" </td>",
" <td>",
" - ",
" </td>",
" </tr>",
" <tr>",
" <td>",
" 35",
" </td>",
" <td>",
" 1.49",
" </td>",
" <td>",
" -",
" </td>",
" </tr>",
" <tr>",
" <td>",
" 40",
" </td>",
" <td>",
" 1.22",
" </td>",
" <td>",
" 1.94",
" </td>",
" </tr>",
" <tr>",
" <td>",
" 45",
" </td>",
" <td>",
" 1.00",
" </td>",
" <td>",
" 1.55",
" </td>",
" </tr>",
" <tr>",
" <td>",
" 50",
" </td>",
" <td>",
" 0.82",
" </td>",
" <td>",
" 1.25",
" </td>",
" </tr>",
" <tr>",
" <td>",
" 55",
" </td>",
" <td>",
" 0.67",
" </td>",
" <td>",
" 1.00",
" </td>",
" </tr>",
" <tr>",
" <td>",
" 60",
" </td>",
" <td>",
" 0.55",
" </td>",
" <td>",
" 0.80",
" </td>",
" </tr>",
" <tr>",
" <td>",
" 65",
" </td>",
" <td>",
" 0.45",
" </td>",
" <td>",
" 0.64",
" </td>",
" </tr>",
" <tr>",
" <td>",
" 70",
" </td>",
" <td>",
" -",
" </td>",
" <td>",
" 0.52",
" </td>",
" </tr>",
" <tr>",
" <td>",
" 75",
" </td>",
" <td>",
" Longevity syndrome",
" </td>",
" <td>",
" Longevity syndrome",
" </td>",
" </tr>",
" </tbody>",
" </table>",
" </div>",
" Inverse relation between plasma HDL-cholesterol levels and cardiovascular
risk in men and women. Multiply values by 38.5 to convert to mmol/L.",
" </div>",
" Data from Castelli WP. Am Heart J 1983; 106:1191.",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
var title_f0_2_36="FTT tips for parents PI";
" ©2013 UpToDate",
" <sup>",
" ®",
" </sup>",
" </div>",
" <a href=\"?imageKey=PI
" </a>",
" <a class=\"icontxt textLink\" href=\"?imageKey=PI
" Print",
" </a>",
" </a>",
" Email",
" </a>",
" </div>",
" </div>",
" Tips for parents of children who need to gain weight",
" </div>",
" <tbody>",
" <tr>",
" <td class=\"subtitle1_single\">",
" Food advice",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Children who drink a lot may not eat as much food. At mealtimes, give your
child food first. (Drinks are filling and have fewer calories.)",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Limit juices to 4 to 8 ounces per day. Also limit intake of water and
carbonated drinks - give your child milk or formula instead.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Don't worry if your child wants to eat the same food every day. It is more
important that he or she gets enough calories and protein.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Junk foods have little protein and fewer calories than some other food
choices. Junk foods will not help growth.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Offer foods that are easy for your child to handle (eg, Cheerios®,
french fries, slices of banana, or peas).",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Add margarine, mayonnaise, gravies, and grated cheese. For snacks, use
cheese, pudding, bananas, or dried fruit.",
" </td>",
" </tr>",
" <tr>",
" Feeding times",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Children need to eat often, but not all the time. Offer something every
two to three hours, to allow three meals and two to three snacks a day. Avoid
snacks right after an unfinished meal.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Children work well with schedules. Try to keep mealtimes and snack times
about the same each day.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Allow one hour without food or drink (except water) before a meal so your
child gets hungry.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Do not make mealtime too long for your child. (Fifteen minutes is probably
long enough for a toddler.)",
" </td>",
" </tr>",
" <tr>",
" Feeding behavior",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Try to relax. Mealtimes should be nice for everyone.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Learn how your child acts when he or she is hungry or full. Learn what
foods he or she likes.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" You can choose what food to feed your child, but your child chooses how
much to eat.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Avoid battles over eating. Do not force, bribe, threaten, or punish your
child. Instead, praise your child for eating well.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Do not punish your child by not feeding him or her.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Allow your child to feed himself or herself. Try very small amounts at
first. Offer seconds later. Expect a mess and be ready for easy clean-up (use bibs,
newspaper under high chair, etc).",
" </td>",
" </tr>",
" <tr>",
" <td>",
" If your baby wants to hold the spoon, use two spoons. Let your baby hold
one, and you use the other to feed your baby.",
" </td>",
" </tr>",
" <tr>",
" Feeding area",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Try to eat together as a family so that brothers, sisters, and parents can
show a young child what good eating behavior is.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Limit things that take your child's attention away from eating, such as
television.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Make sure your child can reach the food. (Use a high chair, booster seat,
telephone book, or small table.)",
" </td>",
" </tr>",
" </tbody>",
" </table>",
" </div>",
" </div>",
" Data from:",
" <br/>",
" <ol>",
" <li>",
" Bithoney WG, Dubowitz H, Egan H. Failure to thrive/growth deficiency.
Pediatr Rev 1992; 13:453.",
" </li>",
" <li>",
" Frank DA, Zeisel SH. Failure to thrive. Pediatr Clin North Am 1988;
35:1187.",
" </li>",
" <li>",
" Frank D, Silva M, Needlman R. Failure to thrive: Mystery, myth and method.
Contemp Pediatr 1993; 10:114.",
" </li>",
" <li>",
" Texas Children's Hospital
(www.texaschildrenshospital.org/Parents/TipsArticles/AcrobatDisplay.aspx?
fid=145).",
" </li>",
" </ol>",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
var title_f0_2_37="Contents: Pediatric oral health";
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" <trs>",
" <tds>",
" <h1>",
" Contents:",
" Pediatric oral health",
" </h1>",
" </tds>",
" </trs>",
" <trs>",
" <tds>",
" </tds>",
" </trs>",
" <trs>",
" <tds valign=\"top\">",
" <div class=\"toctable\" border=\"0\" cellpadding=\"0\" cellspacing=\"0\"
width=\"100%\">",
" <trs>",
" <tds>",
" <strong>",
" Anatomy and development",
" </strong>",
" <ul>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?38/42/39590\">",
" Anatomy and development of the teeth",
" </a>",
" </li>",
" <li>",
" Developmental defects of the teeth",
" </a>",
" </li>",
" <li>",
" Oral habits and orofacial development in children",
" </a>",
" </li>",
" </ul>",
" <strong>",
" Gingivitis and periodontitis",
" </strong>",
" <ul>",
" <li>",
" Overview of gingivitis and periodontitis in children and adolescents",
" </a>",
" </li>",
" <li>",
" Systemic conditions associated with periodontal disease in children",
" </a>",
" </li>",
" </ul>",
" <strong>",
" Infection",
" </strong>",
" <ul>",
" <li>",
" Complications, diagnosis, and treatment of odontogenic infections",
" </a>",
" </li>",
" <li>",
" Herpetic gingivostomatitis in young children",
" </a>",
" </li>",
" <li>",
" Overview of gingivitis and periodontitis in children and adolescents",
" </a>",
" </li>",
" </ul>",
" <strong>",
" Miscellaneous",
" </strong>",
" <ul>",
" <li>",
" Oral and systemic health",
" </a>",
" </li>",
" </ul>",
" <strong>",
" Preventive care",
" </strong>",
" <ul>",
" <li>",
" Preventive dental care and counseling for infants and young children",
" </a>",
" </li>",
" </ul>",
" <strong>",
" Soft tissue lesions",
" </strong>",
" <ul>",
" <li>",
" Soft tissue lesions of the oral cavity in children",
" </a>",
" </li>",
" </ul>",
" <strong>",
" Trauma",
" </strong>",
" <ul>",
" <li>",
" Evaluation and management of dental injuries in children",
" </a>",
" </li>",
" <li>",
" Reduction of temporomandibular joint (TMJ) dislocation",
" </a>",
" </li>",
" </ul>",
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" Print",
" </a>",
" </a>",
" Email",
" </a>",
" </div>",
" </div>",
" High fiber diet guidelines",
" </div>",
" <tr>",
" Why we need fiber",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Fiber helps children and adults have regular bowel movements and helps
prevent constipation and other health problems. Dietary fiber helps keep the bowel
and digestive tract healthy and enhances feelings of fullness after eating.",
" </td>",
" </tr>",
" <tr>",
" How much fiber is needed",
" </td>",
" </tr>",
" <tr>",
" <td>",
" The recommended intake for dietary fiber is 14 grams/1000 kcals in the
diet.* For children, this translates to an intake of about 20 grams/day in early
childhood, rising to 29 grams/day for adolescent girls and young women, and 38
grams/day for adolescent boys and young men. To find out the number of grams of
fiber in a certain food, read the label, or see the foods listed in this table.
High fiber foods contain 3 or more grams of fiber per serving.",
" </td>",
" </tr>",
" <tr>",
" How to help your child eat more fiber",
" </td>",
" </tr>",
" <tr>",
" <td class=\"sublist1_start\">",
" A high fiber diet should be a balanced diet with foods fromall the food
groups. The most common sources of fiber are whole grain breads and cereals,
legumes and nuts, fruits, and vegetables. Include these in your child's balanced
diet:",
" </td>",
" </tr>",
" <tr>",
" <td class=\"sublist1\">",
" Offer your child a variety of high fiber foods during the day rather than
giving only one or two high fiber foods.",
" </td>",
" </tr>",
" <tr>",
" Mix a high fiber cereal with a cereal your child likes.",
" </td>",
" </tr>",
" <tr>",
" Offer fresh fruits with the skin on. Prunes and pears act as natural
laxatives.",
" </td>",
" </tr>",
" <tr>",
" Offer raw vegetables, such as carrots, jicama, or cherry tomatoes for
snacks and with meals. Offer a salad with dark green lettuce each day.",
" </td>",
" </tr>",
" <tr>",
" Use whole wheat bread or white bread with added fiber, brown rice, whole
wheat crackers, bran muffins, barley, bran cereals, or oatmeal. Use less refined
white flour breads, cereals, and other starches.",
" </td>",
" </tr>",
" <tr>",
" Offer 4 to 6 ounces of prune, apple, orange, or pear juice each day.
Remember that fresh fruit has more fiber than juice.",
" </td>",
" </tr>",
" <tr>",
" Offer snacks that have fiber, like granola bars, fruit bars, fig cookies,
or popcorn (after age 3 years).",
" </td>",
" </tr>",
" <tr>",
" Help you child develop a taste for bran. Try to include 2 to 4 tablespoons
of some form of bran each day.",
" </td>",
" </tr>",
" <tr>",
" Add nuts or seeds to breads and salads, or use them as a snack. This is not
recommended for children younger than three years.",
" </td>",
" </tr>",
" <tr>",
" Preventing constipation",
" </td>",
" </tr>",
" <tr>",
" <td>",
" If your child is constipated, follow the dietary guidelines above. Also,
encourage your child to drink at least 4 to 8 cups (32 to 64 ounces) of fluid per
day, preferably water, low-fat milk, and low-sugar decaffeinated beverages.",
" </td>",
" </tr>",
" </table>",
" </div>",
" These guidelines are continued.",
" * Dietary Guidelines for Americans 2005. US Department of Health and Human
Services. Available at: www.health.gov/dietaryguidelines/pubs.htm.",
" </div>",
" </div>",
" </div>",
" </div>",
" </div>",
" High fiber diet guidelines (continued)",
" </div>",
" <tbody>",
" <tr>",
" <td class=\"subtitle1_single\" colspan=\"2\">",
" High fiber diet guidelines from Texas Children's Hospital",
" </td>",
" </tr>",
" <tr>",
" <td colspan=\"2\">",
" Read labels on foods, and look for 3 or more grams of fiber per serving.
Eat 3 or more servings each day of breads and cereals made from whole grains and
bran. Eat 5 or more servings each day of fruits and vegetables, including beans. It
is important to increase water in the diet when you increase fiber.",
" </td>",
" </tr>",
" <tr>",
" Meat, poultry, fish, milk, milk products, and fats such as oil, margarine,
and salad dressings do not normally have fiber, but it is important to include
these in your child's diet to provide a complete balance of foods.",
" </td>",
" </tr>",
" <tr>",
" High fiber dry cereals",
" </td>",
" </tr>",
" <tr>",
" One serving equals 1/2 cup.",
" </td>",
" </tr>",
" <tr>",
" Cereal",
" </td>",
" Fiber, grams",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Fiber One",
" </td>",
" <td>",
" 13",
" </td>",
" </tr>",
" <tr>",
" <td>",
" 100 percent Bran",
" </td>",
" <td>",
" 12",
" </td>",
" </tr>",
" <tr>",
" <td>",
" All Bran",
" </td>",
" <td>",
" 12",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Bran Buds",
" </td>",
" <td>",
" 12",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Kashi Go Lean ",
" </td>",
" <td>",
" 8 to 10 ",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Kellogg's Complete Bran Flakes",
" </td>",
" <td>",
" 5",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Grape Nuts",
" </td>",
" <td>",
" 5",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Raisin Bran*",
" </td>",
" <td>",
" 3 to 5",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Cracklin' Oat Bran*",
" </td>",
" <td>",
" 4",
" </td>",
" </tr>",
" <tr>",
" <td>",
" 100 percent Whole Grain Wheat Chex",
" </td>",
" <td>",
" 3",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Fruit and Fibre",
" </td>",
" <td>",
" 3",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Great Grains",
" </td>",
" <td>",
" 3",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Frosted Mini Wheats",
" </td>",
" <td>",
" 3",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Kellogg's Low Fat Granola",
" </td>",
" <td>",
" 3",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Cheerios",
" </td>",
" <td>",
" 2",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Wheaties",
" </td>",
" <td>",
" 2",
" </td>",
" </tr>",
" <tr>",
" High fiber vegetables (cooked unless indicated)",
" </td>",
" </tr>",
" <tr>",
" One serving of vegetables is 1/2 to 1 cup.",
" </td>",
" </tr>",
" <tr>",
" Vegetable",
" </td>",
" Fiber, grams",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Pinto, kidney, black, lima beans (1/2 cup)",
" </td>",
" <td>",
" 4 to 7",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Sweet potato (1 medium)",
" </td>",
" <td>",
" 4",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Lentils (1/2 cup)",
" </td>",
" <td>",
" 4",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Jicama (1/2 raw)",
" </td>",
" <td>",
" 3 to 4",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Baked potato with skin (medium)",
" </td>",
" <td>",
" 3",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Corn (1/2 cup)",
" </td>",
" <td>",
" 3",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Peas (1/2 cup)",
" </td>",
" <td>",
" 3",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Broccoli (1/2 cup)",
" </td>",
" <td>",
" 2",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Cabbage (1/2 cup)",
" </td>",
" <td>",
" 2",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Spinach (1/2 cup)",
" </td>",
" <td>",
" 2",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Cauliflower (3/4 cup)",
" </td>",
" <td>",
" 2",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Carrots (1 medium raw or 1/2 cup cooked)",
" </td>",
" <td>",
" 2",
" </td>",
" </tr>",
" <tr>",
" High fiber fruits",
" </td>",
" </tr>",
" <tr>",
" One serving of fruit is usually one piece.",
" </td>",
" </tr>",
" <tr>",
" Fruit",
" </td>",
" <td class=\"subtitle2\" colspan=\"3\">",
" Fiber, grams",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Pear",
" </td>",
" 4",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Strawberries (one cup)",
" </td>",
" 3",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Apple (with skin)",
" </td>",
" 3",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Dried fruits like raisins (3 Tablespoons)",
" </td>",
" 3",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Papaya",
" </td>",
" 3",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Peach (fresh)",
" </td>",
" 2",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Plums (2)",
" </td>",
" 2",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Mango",
" </td>",
" 2",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Nectarine",
" </td>",
" 2",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Avocado (1/2 medium)",
" </td>",
" 2",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Tomato (1 medium)",
" </td>",
" 2",
" </td>",
" </tr>",
" </tbody>",
" </table>",
" </div>",
" These guidelines are continued.",
" * These cereals are also high in sugar (15 to 20 grams/serving).",
" </div>",
" </div>",
" </div>",
" </div>",
" </div>",
" High fiber diet guidelines (continued)",
" </div>",
" <tbody>",
" <tr>",
" Sample menu (for a 7- to 10-year old)",
" </td>",
" </tr>",
" <tr>",
" Breakfast",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" 1 cup instant oatmeal",
" </td>",
" </tr>",
" <tr>",
" 1 slice whole-grain toast",
" </td>",
" </tr>",
" <tr>",
" 1 teaspoon margarine or butter",
" </td>",
" </tr>",
" <tr>",
" 1 medium banana",
" </td>",
" </tr>",
" <tr>",
" 8 ounces skim milk",
" </td>",
" </tr>",
" <tr>",
" Lunch",
" </td>",
" </tr>",
" <tr>",
" Turkey sandwich on whole grain bread",
" </td>",
" </tr>",
" <tr>",
" 1 teaspoon mustard",
" </td>",
" </tr>",
" <tr>",
" 1 ounce whole grain chips",
" </td>",
" </tr>",
" <tr>",
" 1 medium apple",
" </td>",
" </tr>",
" <tr>",
" 8 baby carrots",
" </td>",
" </tr>",
" <tr>",
" Bottled water",
" </td>",
" </tr>",
" <tr>",
" Snack 1",
" </td>",
" </tr>",
" <tr>",
" 4 fig bar cookies",
" </td>",
" </tr>",
" <tr>",
" </td>",
" </tr>",
" <tr>",
" Dinner",
" </td>",
" </tr>",
" <tr>",
" 3 ounces pork tenderloin",
" </td>",
" </tr>",
" <tr>",
" 1/2 cup mashed sweet potatoes",
" </td>",
" </tr>",
" <tr>",
" 1/2 cup green beans",
" </td>",
" </tr>",
" <tr>",
" 1 small whole grain roll",
" </td>",
" </tr>",
" <tr>",
" 2 teaspoons margarine or butter",
" </td>",
" </tr>",
" <tr>",
" </td>",
" </tr>",
" <tr>",
" Snack 2",
" </td>",
" </tr>",
" <tr>",
" 1/2 cup vanilla bean ice-cream",
" </td>",
" </tr>",
" </tbody>",
" </table>",
" </div>",
" </div>",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
var title_f0_2_39="Lap band PI";
" ©2013 UpToDate",
" <sup>",
" ®",
" </sup>",
" </div>",
" </a>",
" Print",
" </a>",
" </a>",
" Email",
" </a>",
" </div>",
" </div>",
" Gastric banding",
" </div>",
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" </div>",
" This figure shows how the stomach looks after gastric banding.",
" </div>",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
var title_f0_2_40="Nutrition label PI";
" ©2013 UpToDate",
" <sup>",
" ®",
" </sup>",
" </div>",
" </a>",
" Print",
" </a>",
" </a>",
" Email",
" </a>",
" </div>",
" </div>",
" Nutrition label: Counting carbohydrates",
" </div>",
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" </div>",
" To calculate the number of net carbohydrates in 1 serving (1 cup), subtract
the number of grams of dietary fiber (7 grams) from the number of grams of total
carbohydrates (46 grams). In this example, the number of net carbohydrates is 39
grams.",
" %: percent.",
" </div>",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
var title_f0_2_41="Celiprolol: International drug information";
" </div>",
" </noscript>",
" <br>",
" <sup>",
" ®",
" </sup>",
" <br>",
" </a>",
" ©2013 UpToDate",
" <sup>",
" ®",
" </sup>",
" </br>",
" </div>",
" </br>",
" </img>",
" </img>",
" </div>",
here to print\">",
" Print",
" </a>",
" |",
" </span>",
" Back",
" </a>",
" </div>",
" </div>",
" <div id=\"drugTitle\">",
" Celiprolol: International drug information",
" </div>",
" <div id=\"lexiTitleImg\">",
" <img height=\"17\" src=\"./../images/lexiComp/Lexicomp_2012_71x17.myextg\"
width=\"71\"/>",
" </div>",
" </div>",
" <div id=\"drugCopy\">",
" Copyright 1978-2013 Lexicomp, Inc. All rights reserved.",
" </div>",
" For abbreviations and symbols that may be used in Lexicomp (",
" <a class=\"graphic graphic_table\" href=\"UTD.htm?23/39/24183\">",
" show table",
" </a>",
" )",
" <div class=\"list fbnlist drugH1Div drugBrandNames\" id=\"F4088877\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" International Brand Names",
" </span>",
" <ul>",
" <li>",
" Cardem (ES);",
" </li>",
" <li>",
" Celectol (CZ, FR, GB, PL);",
" </li>",
" <li>",
" Celipres (PL);",
" </li>",
" <li>",
" Celipro-Lich (DE);",
" </li>",
" <li>",
" Cordiax (IT);",
" </li>",
" <li>",
" Dilanorm (NL);",
" </li>",
" <li>",
" Selectol (AT, BE, CH, DE, FI, HR, IE, LU);",
" </li>",
" <li>",
" Selecturon (AT)",
" </li>",
" </ul>",
" </div>",
" <div class=\"list synlist drugH1Div drugBrandNames\" id=\"F4088878\"
" Index Terms",
" </span>",
" <ul>",
" <li>",
" Celiprolol Hydrochloride",
" </li>",
" </ul>",
" </div>",
" <div class=\"list_set htclist drugH1Div drugBrandNames\" id=\"F4088879\"
" Pharmacologic Category",
" </span>",
" <ul>",
" <li>",
" <span class=\"list-set-name\">",
" Beta Blocker With Intrinsic Sympathomimetic Activity",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"block iuse drugH1Div\" id=\"F4088880\"
" Reported Use",
" </span>",
" <p style=\"text-indent:0em;display:inline\">",
" Treatment of angina, hypertension",
" </p>",
" </div>",
" <div class=\"block idos drugH1Div\" id=\"F4088882\"
" Dosage Range",
" </span>",
" Oral: 200-400 mg once daily; no dosage alteration needed the in elderly",
" </p>",
" <p style=\"text-indent:-2em;margin-left:2em;text-align:justify;\">",
" <b>",
" Dosage adjustment in renal impairment:",
" </b>",
" Adjustment may be needed; for Cl",
" <sub>",
" cr",
" </sub>",
" 15-40 mL/minute: 100-200 mg daily",
" </p>",
" </div>",
" <div class=\"block prod-avail drugH1Div\" id=\"F11821079\"
" Product Availability",
" </span>",
" Product available in various countries; not currently available in the U.S.",
" </p>",
" </div>",
" <div class=\"block foc drugH1Div\" id=\"F9720022\"
" Dosage Forms",
" </span>",
" <p style=\"text-indent:-2em;margin-left:2em;\">",
" Tablet: 200 mg",
" </p>",
" </div>",
" </div>",
" </a>",
" .",
" </div>",
" </div>",
" </div>",
" </span>",
" |",
" </span>",
" </a>",
" |",
" </span>",
" Release: 21.6- C21.56",
" </span>",
" <br/>",
" Licensed to:",
" </span>",
" </span>",
" |",
" </span>",
" Support Tag: [0604-61.55.141.10-3C5F28D7A6-S244013.14]",
" <br/>",
" </span>",
" </div>",
" </div>",
"</div>"].join("\n");
" </a>",
" </div>",
" <h1>",
" TOPIC OUTLINE",
" </h1>",
" <ul>",
" <a class=\"outlineLink\" href=\"#F4088877\">",
" International Brand Names",
" </a>",
" </li>",
" Index Terms",
" </a>",
" </li>",
" Pharmacologic Category",
" </a>",
" </li>",
" Reported Use",
" </a>",
" </li>",
" Dosage Range",
" </a>",
" </li>",
" Product Availability",
" </a>",
" </li>",
" Dosage Forms",
" </a>",
" </li>",
" </ul>",
" </div>",
" <h1>",
" <div class=\"openRelatedGraphics\" id=\"DRUG_INT/10445\"
rel=\"outline_link\">",
" GRAPHICS",
" View All",
" </a>",
" </div>",
" </h1>",
" <ul>",
" <div class=\"openRelatedGraphics\" id=\"DRUG_INT/10445|TAB\">",
" <a href=\"#\" title=\"TABLES\">",
" TABLES",
" </a>",
" </div>",
" </li>",
" <a class=\"graphic graphic_table\" href=\"UTD.htm?23/39/24183\"
title=\"Lexicomp clinical abbreviations\">",
" Lexicomp clinical abbreviations",
" </a>",
" </li>",
" </ul>",
" </div>",
" </div>"].join("\n");
var title_f0_2_42="Penile lentigines pigmented macules of the penis";
" ©2013 UpToDate",
" <sup>",
" ®",
" </sup>",
" </div>",
" <a href=\"?imageKey=ONC
" </a>",
" <a class=\"icontxt textLink\" href=\"?imageKey=ONC
" Print",
" </a>",
" </a>",
" Email",
" </a>",
" </div>",
" </div>",
" Penile lentigines (pigmented macules) of the penis",
" </div>",
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8VRJT8CgD//Z);\">",
" </div>",
" </div>",
" Reproduced from: Hendriks YM, Verhallen JT, van der Smagt JJ, et al.
Bannayan–Riley–Ruvalcaba syndrome: further delineation of the phenotype
and management of PTEN mutation-positive cases. Familial Cancer 2003; 2:79, with
kind permission from Springer Science + Business Media B.V. Copyright ©
2003.",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
var title_f0_2_43="Strawberry tongue";
" ©2013 UpToDate",
" <sup>",
" ®",
" </sup>",
" </div>",
" <a href=\"?imageKey=ID
" </a>",
" <a class=\"icontxt textLink\" href=\"?imageKey=ID
" Print",
" </a>",
" </a>",
" Email",
" </a>",
" </div>",
" </div>",
" Strawberry tongue",
" </div>",
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" Reproduced with permission from: www.visualdx.com. Copyright Logical Images,
Inc.",
" </div>",
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var title_f0_2_44="Doxazosin: Patient drug information";
" </div>",
" </noscript>",
" <br>",
" <sup>",
" ®",
" </sup>",
" <br>",
" </a>",
" ©2013 UpToDate",
" <sup>",
" ®",
" </sup>",
" </br>",
" </div>",
" </br>",
" </img>",
" </img>",
" </div>",
here to print\">",
" Print",
" </a>",
" |",
" </span>",
" Back",
" </a>",
" </div>",
" </div>",
" <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>",
" ©2013 UpToDate, Inc.",
" </div>",
" <div id=\"drugTitle\">",
" Doxazosin: Patient drug information",
" </div>",
" <div id=\"lexiTitleImg\">",
" <img height=\"17\" src=\"./../images/lexiComp/Lexicomp_2012_71x17.myextg\"
width=\"71\"/>",
" </div>",
" </div>",
" <div id=\"drugCopy\">",
" Copyright 1978-2013 Lexicomp, Inc. All rights reserved.",
" </div>",
" <p>",
" (For additional information",
" see \"Doxazosin: Drug information\"",
" </a>",
" and",
" <a class=\"drug drug_pediatric\" href=\"UTD.htm?26/63/27638?
" see \"Doxazosin: Pediatric drug information\"",
" </a>",
" )",
" </p>",
" <div class=\"list ubnlist drugH1Div drugBrandNames\" id=\"F162904\"
" Brand Names: U.S.",
" </span>",
" <ul>",
" <li>",
" Cardura®;",
" </li>",
" <li>",
" Cardura® XL",
" </li>",
" </ul>",
" </div>",
" <div class=\"list cbnlist drugH1Div drugBrandNames\" id=\"F162905\"
" Brand Names: Canada",
" </span>",
" <ul>",
" <li>",
" Alti-Doxazosin;",
" </li>",
" <li>",
" Apo-Doxazosin®;",
" </li>",
" <li>",
" Cardura-1™;",
" </li>",
" <li>",
" Cardura-2™;",
" </li>",
" <li>",
" Cardura-4™;",
" </li>",
" <li>",
" Gen-Doxazosin;",
" </li>",
" <li>",
" Mylan-Doxazosin;",
" </li>",
" <li>",
" Novo-Doxazosin",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt war-os drugH1Div\" id=\"F10017736\"
" Warning",
" </span>",
" <ul class=\"statements\" style=\"list-style-type:none;\">",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" •",
" </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=\"F10017738\"
" What is this drug used for?",
" </span>",
" •",
" </span>",
" urn:lims:b498:s2691888",
" </span>",
" </span>",
" It is used to treat high blood pressure.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2691233",
" </span>",
" </span>",
" In men, it is used to treat the signs of an enlarged prostate.",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt coi-os drugH1Div\" id=\"F10017737\"
" What do I need to tell my doctor before I take this drug?",
" </span>",
" •",
" </span>",
" urn:lims:b498:s2701982",
" </span>",
" </span>",
" If you have an allergy to doxazosin or any other part of this drug.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2705171",
" </span>",
" </span>",
" 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>",
" •",
" </span>",
" urn:lims:b498:s2703919",
" </span>",
" </span>",
" Long-acting products: If you have a narrowing of the GI (gastrointestinal)
tract or a bowel block.",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt yye-os drugH1Div\" id=\"F10017742\"
" What are some things I need to know or do while I take this drug?",
" </span>",
" •",
" </span>",
" urn:lims:b498:s2699677",
" </span>",
" </span>",
" Keep a list of all your drugs (prescription, natural products, vitamins,
OTC) with you. Give this list to your doctor.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2697290",
" </span>",
" </span>",
" If you have liver disease, talk with your doctor.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2697050",
" </span>",
" </span>",
" If you are having cataract surgery, talk with your doctor.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2698416",
" </span>",
" </span>",
" Have your blood pressure and heart rate checked often. Talk with your
doctor.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2698513",
" </span>",
" </span>",
" If taking for an enlarged prostate, have a rectal exam (to check prostate
gland) and blood work (PSA test). Talk with your doctor.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2696717",
" </span>",
" </span>",
" Check all drugs you are taking with your doctor. This drug may not mix well
with some other drugs.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2697111",
" </span>",
" </span>",
" 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>",
" •",
" </span>",
" urn:lims:b498:s2696618",
" </span>",
" </span>",
" Avoid beer, wine, or mixed drinks.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2696701",
" </span>",
" </span>",
" Be careful in hot weather. Drink lots of fluids to stop fluid loss.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2697641",
" </span>",
" </span>",
" 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>",
" •",
" </span>",
" urn:lims:b498:s2697636",
" </span>",
" </span>",
" 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=\"F10017743\"
" What are some side effects of this drug?",
" </span>",
" •",
" </span>",
" urn:lims:b498:s2698051",
" </span>",
" </span>",
" Feeling dizzy. Rise slowly over a few minutes when sitting or lying down.
Be careful climbing.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2698119",
" </span>",
" </span>",
" Headache.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2698257",
" </span>",
" </span>",
" Nose stuffiness.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2697963",
" </span>",
" </span>",
" Change in sex ability.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2698205",
" </span>",
" </span>",
" You may see the tablet shell in your stool.",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt yyh-os drugH1Div\" id=\"F10017745\"
" What are some side effects that I need to call my doctor about right away?",
" </span>",
" •",
" </span>",
" urn:lims:b498:s2698721",
" </span>",
" </span>",
" 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>",
" •",
" </span>",
" urn:lims:b498:s2699066",
" </span>",
" </span>",
" 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>",
" •",
" </span>",
" urn:lims:b498:s2699023",
" </span>",
" </span>",
" Very bad dizziness or passing out.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2699031",
" </span>",
" </span>",
" Very bad headache.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2698603",
" </span>",
" </span>",
" Any rash.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2698977",
" </span>",
" </span>",
" 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=\"F10017740\"
" How is this drug best taken?",
" </span>",
" •",
" </span>",
" urn:lims:b498:s2695880",
" </span>",
" </span>",
" Take in the morning or at bedtime as you have been told by your doctor.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2695914",
" </span>",
" </span>",
" Take with or without food. Take with food if it causes an upset stomach.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2694580",
" </span>",
" </span>",
" Cardura® XL: Take with breakfast. Swallow it whole. Do not chew, break,
or crush it.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2694818",
" </span>",
" </span>",
" Drink lots of noncaffeine liquids unless told to drink less liquid by your
doctor.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2695160",
" </span>",
" </span>",
" If you are using this drug for blood pressure, follow the diet and workout
plan your doctor told you about.",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt yyd-os drugH1Div\" id=\"F10017741\"
" What do I do if I miss a dose?",
" </span>",
" •",
" </span>",
" urn:lims:b498:s2696563",
" </span>",
" </span>",
" Take a missed dose as soon as you think about it.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2696496",
" </span>",
" </span>",
" If it is close to the time for your next dose, skip the missed dose and go
back to your normal time.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2696475",
" </span>",
" </span>",
" Do not take 2 doses at the same time or extra doses.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2696457",
" </span>",
" </span>",
" Do not change the dose or stop this drug. Talk with the doctor.",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt yyi-os drugH1Div\" id=\"F10017746\"
" How do I store and/or throw out this drug?",
" </span>",
" •",
" </span>",
" urn:lims:b498:s2699336",
" </span>",
" </span>",
" Store at room temperature.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2699266",
" </span>",
" </span>",
" Store in a dry place. Do not store in a bathroom.",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt yyj-os drugH1Div\" id=\"F10017747\"
" General drug facts",
" </span>",
" •",
" </span>",
" urn:lims:b259:s2699675",
" </span>",
" </span>",
" If your symptoms or health problems do not get better or if they become
worse, call your doctor.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b259:s2699673",
" </span>",
" </span>",
" Do not share your drugs with others and do not take anyone else's drugs.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b259:s2699678",
" </span>",
" </span>",
" Keep all drugs out of the reach of children and pets.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b259:s2699709",
" </span>",
" </span>",
" If you have any questions about this drug, please talk with your doctor,
pharmacist, or other health care provider.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b259:s3302581",
" </span>",
" </span>",
" In Canada, take any unused drugs to the pharmacy. Also, visit
file://www.hc-sc.gc.ca/hl-vs/iyh-vsv/med/disposal-defaire-eng.php#th to learn about
the right way to get rid of unused drugs.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b259:s2699677",
" </span>",
" </span>",
" Keep a list of all your drugs (prescription, natural products, vitamins,
OTC) with you. Give this list to your doctor.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b259:s2699671",
" </span>",
" </span>",
" These are not all of the side effects that may occur. If you have questions
about side effects, call your doctor. Call your doctor for medical advice about
side effects.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b259:s2699683",
" </span>",
" </span>",
" Talk with the doctor before starting any new drug, including prescription
or OTC, natural products, or vitamins.",
" </span>",
" </li>",
" </ul>",
" </div>",
" </div>",
" </a>",
" .",
" </div>",
" </div>",
" </div>",
" </span>",
" |",
" </span>",
" </a>",
" |",
" </span>",
" Release: 21.6- C21.56",
" </span>",
" <br/>",
" Licensed to:",
" </span>",
" </span>",
" |",
" </span>",
" Support Tag: [1003-61.234.146.186-4BCC47CC64-S244013.14]",
" <br/>",
" </span>",
" </div>",
" </div>",
"</div>"].join("\n");
" </a>",
" </div>",
" <h1>",
" TOPIC OUTLINE",
" </h1>",
" <ul>",
" Brand Names: U.S.",
" </a>",
" </li>",
" Brand Names: Canada",
" </a>",
" </li>",
" Warning",
" </a>",
" </li>",
" What is this drug used for?",
" </a>",
" </li>",
" What do I need to tell my doctor before I take this drug?",
" </a>",
" </li>",
" What are some things I need to know or do while I take this drug?",
" </a>",
" </li>",
" What are some side effects of this drug?",
" </a>",
" </li>",
" What are some side effects that I need to call my doctor about right away?",
" </a>",
" </li>",
" How is this drug best taken?",
" </a>",
" </li>",
" What do I do if I miss a dose?",
" </a>",
" </li>",
" How do I store and/or throw out this drug?",
" </a>",
" </li>",
" General drug facts",
" </a>",
" </li>",
" </ul>",
" </div>",
" <h1>",
" RELATED TOPICS",
" </h1>",
" <ul>",
" Doxazosin: Drug information",
" </a>",
" </li>",
" <a class=\"drug drug_pediatric\" href=\"UTD.htm?26/63/27638?
" Doxazosin: Pediatric drug information",
" </a>",
" </li>",
" </ul>",
" </div>",
" </div>"].join("\n");
var title_f0_2_45="Emergent ear pain in children";
" ©2013 UpToDate",
" <sup>",
" ®",
" </sup>",
" </div>",
" <a href=\"?imageKey=EM%2F78456%7EEM%2F51680%7EEM%2F77906%7EEM
" </a>",
" <a class=\"icontxt textLink\" href=\"?imageKey=EM%2F78456%7EEM%2F51680%7EEM
%2F77906%7EEM%2F60379&source=image_view&view=print&elapsedTimeMs=3\"
onclick=\"\" title=\"Print this page\">",
" Print",
" </a>",
" </a>",
" Email",
" </a>",
" </div>",
" </div>",
" Emergent diagnoses associated with ear pain in children",
" </div>",
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" </div>",
" TM: tympanic membrane.",
" </div>",
" </div>",
" </div>",
" </div>",
" </div>",
" Traumatic diagnoses associated with ear pain in children",
" </div>",
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" </div>",
" TM: tympanic membrane.",
" </div>",
" </div>",
" </div>",
" </div>",
" </div>",
" External ear causes of ear pain in children",
" </div>",
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" </div>",
" </div>",
" </div>",
" </div>",
" </div>",
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" </div>",
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" </div>",
" * Referred ear pain from parotitis, TMJ dysfunction syndrome, stomatitis,
pharyngitis, dental abscess, or maxillary sinusitis (see text).",
" <br/>",
" </div>",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
var title_f0_2_46="Clinical manifestations and evaluation of obstructive or
substernal goiter";
" </div>",
" </noscript>",
" <br>",
" <sup>",
" ®",
" </sup>",
" <br>",
" </a>",
" ©2013 UpToDate",
" <sup>",
" ®",
" </sup>",
" </br>",
" </div>",
" </br>",
" </img>",
" </img>",
" </div>",
here to print\">",
" Print",
" </a>",
" |",
" </span>",
" Back",
" </a>",
" </div>",
" </div>",
" Clinical manifestations and evaluation of obstructive or substernal goiter",
" </div>",
" <div>",
" </a>",
" Author",
" </a>",
" <br/>",
" Douglas S Ross, MD",
" </a>",
" <br/>",
" </div>",
" <div>",
" Section Editor",
" </a>",
" <br/>",
" David S Cooper, MD",
" </a>",
" <br/>",
" </div>",
" <div>",
" Deputy Editor",
" </a>",
" <br/>",
" Jean E Mulder, MD",
" </a>",
" <br/>",
" </div>",
" </div>",
" Disclosures",
" </a>",
" </div>",
" <span>",
" </span>",
" </a>",
" <span>",
" is complete.",
" </span>",
" </div>",
" </span>",
" Oct 2013.",
" |",
" </span>",
" </span>",
" Apr 10, 2012.",
" </div>",
" INTRODUCTION",
" </span>",
" — The term goiter refers to an enlargement of the thyroid.
The clinical manifestations of goiter vary with the size and location of the goiter
and can be potentially serious.",
" </p>",
" <p>",
" This topic will review the clinical manifestations and evaluation of the
patient with obstructive or substernal goiter; issues related to treatment and to
goiter in children are discussed separately. (See",
" \"Treatment of obstructive or substernal goiter\"",
" </a>",
" and",
" \"Congenital and acquired goiter in children\"",
" </a>",
" .)",
" </p>",
" ANATOMIC RELATIONSHIPS",
" </span>",
" — The thoracic inlet is an ovoid area that measures
approximately 5 x 10 cm bounded by the sternum anteriorly, the first thoracic
vertebral body posteriorly, and the first ribs laterally (",
34/40/35471\">",
" figure 1",
" </a>",
" ). The inlet is traversed by the trachea, esophagus, blood vessels, and
nerves. The inferior pole of each thyroid lobe normally lies above the thoracic
inlet.",
" </p>",
" <p>",
" Enlarging thyroid lobes usually grow outward because of their location in the
anterior neck in front of the trachea, covered only by thin muscles, subcutaneous
tissue, and skin. As a result of this outward growth, even very large goiters may
not compress the trachea or impinge on the great vessels lateral to the lobes.
However, in patients with substantial enlargement of one lobe or asymmetric
enlargement of both lobes, the trachea, esophagus, or blood vessels may be
displaced or, less often, compressed. Bilateral lobar enlargement, especially if
the goiter extends posterior to the trachea, may cause either compression or
concentric narrowing of the trachea or compression of the esophagus or jugular
veins.",
" </p>",
" Substernal goiter",
" </span>",
" — With some goiters, there is growth of one or both lobes
through the inlet into the thoracic cavity, which can result in obstruction of any
of the structures in the inlet. Such goiters are called substernal, although
retrosternal is probably a more precise term. Most substernal goiters are in the
anterolateral mediastinum, but about 10 percent are located primarily in the
posterior mediastinum [",
" 1,2",
" </a>",
" ]. Some patients have very low-lying thyroid glands located at the level of
the thoracic inlet; in them, even minimal enlargement can cause symptoms.",
" </p>",
" <p>",
" The incidence of substernal goiter as a percentage of thyroidectomies ranges
from 2 to 19 percent [",
" 2",
" </a>",
" ].",
" </p>",
" CLINICAL PRESENTATION",
" </span>",
" — The clinical manifestations of goiter vary with the size,
location, and type of goiter:",
" </p>",
" <p>",
" <li>",
" Multinodular goiters usually grow very slowly over many decades, and
obstructive symptoms almost always develop insidiously [",
" 3",
" </a>",
" ].",
" </li>",
" <li>",
" Differentiated thyroid cancers, which usually grow slowly, may be
indistinguishable clinically from benign nodular goiter and may cause obstructive
symptoms.",
" </li>",
" <li>",
" The fibrous variant of chronic autoimmune thyroiditis, a much less common
cause of obstructive goiter, may lead to concentric tracheal compression [",
" 4",
" </a>",
" ].",
" </li>",
" <li>",
" The rare anaplastic thyroid cancers or primary lymphomas of the thyroid
often present with a rapidly enlarging neck mass that may cause obstructive
symptoms.",
" </li>",
" </ul>",
" </p>",
" <p>",
" The majority of patients with obstructive cervical goiters have had a visible
goiter for many years. Most patients with substernal goiter (77 to 90 percent in
two series) also have visible goiters [",
" 1,5",
" </a>",
" ], although some are found incidentally on imaging studies performed for
unrelated reasons. In those without visible goiter, substernal goiters may also be
found because of obstructive symptoms, such as dyspnea, wheezing, or cough. Since
goiters tend to grow slowly, they are most commonly discovered during the fifth and
sixth decades of life and are found more often in women than men [",
" 6,7",
" </a>",
" ].",
" </p>",
" Dyspnea and wheezing",
" </span>",
" — The most common complaint in patients with obstructive
cervical or substernal goiter is exertional dyspnea, which is present in 30 to 60
percent of cases [",
" <a class=\"abstract\" href=\"UTD.htm?0/2/46/abstract/1,7-12\">",
" 1,7-12",
" </a>",
" ]. This symptom usually occurs when the tracheal diameter is less than 8 mm
[",
" 13",
" </a>",
" ]. In some patients with substernal goiter, dyspnea is primarily positional or
nocturnal and it occurs primarily during maneuvers that force the thyroid into the
thoracic inlet such as reaching and bending.",
" </p>",
" <p>",
" When tracheal compression becomes severe (luminal diameter less than 5 mm),
stridor or wheezing occurs at rest [",
" 13",
" </a>",
" ]. This upper airway wheezing must be distinguished from asthma. An upper
respiratory illness may exacerbate upper airway obstruction.",
" </p>",
" Cough",
" </span>",
" — Cough is present in 10 to 30 percent of patients and it may
be positional [",
" 11",
" </a>",
" ]. Pain is unusual, but a choking sensation is common.",
" </p>",
" Other",
" </span>",
" — A variety of other symptoms can be induced by obstructive
goiter:",
" </p>",
" <p>",
" <ul class=\"bulletCompact-block\">",
" <li>",
" Dysphagia is a less common complaint because of the posterior position of
the esophagus",
" </li>",
" <li>",
" Compression of a recurrent laryngeal nerve may cause transient or permanent
vocal cord palsy, resulting in hoarseness",
" </li>",
" <li>",
" Phrenic nerve paralysis",
" </li>",
" <li>",
" Horner's syndrome due to compression of the cervical sympathetic chain",
" </li>",
" <li>",
" Rarely, jugular vein compression or thrombosis, cerebrovascular steal
syndromes, or even the superior vena cava syndrome [",
" 14",
" </a>",
" ]",
" </li>",
" </ul>",
" </p>",
" <p>",
" Even asymptomatic patients with substernal goiter may have subtle
abnormalities in respiration. In one report, as an example, 60 percent of such
patients had abnormal patterns of breathing on flow-volume loop testing [",
" 10",
" </a>",
" ].",
" </p>",
" Hyperthyroidism",
" </span>",
" — Approximately 20 to 25 percent of patients with large
cervical multinodular goiters have either subclinical hyperthyroidism (normal serum
thyroid hormone concentrations with a low thyrotropin (TSH) concentration) or, less
often, overt hyperthyroidism [",
" 15",
" </a>",
" ]. The prevalence of hyperthyroidism in obstructive goiter is probably
similar.",
" </p>",
" PHYSICAL EXAMINATION",
" </span>",
" — All patients with obstructive symptoms caused by a cervical
goiter alone have obvious thyroid enlargement, as do many patients with substernal
goiter. The possibility of substantial substernal extension is suggested by the
inability to identify the lower end of the thyroid gland. When the lower end cannot
be identified with the patient sitting, it may be possible to do so if the patient
lies down with a pillow under the shoulders to hyperextend the neck.",
" </p>",
" <p>",
" Tracheal deviation is frequently visible or palpable if the goiter is
asymmetric. Rarely, dilated neck veins are present.",
" </p>",
" <p>",
" Pemberton's maneuver can be used to exacerbate obstructive symptoms by forcing
the thyroid into the thoracic inlet. In this maneuver, the examiner holds the
patient's arms vertically above the head for about 60 seconds. The test is
considered positive if the patient's neck veins become more distended or if the
patient develops facial plethora, cyanosis or inability to swallow, or if dyspnea
or stridor appear or worsen. Rarely, a cervical goiter becomes impacted in the
thoracic inlet by this maneuver or by acute neck flexion or reaching; this is
called the \"thyroid cork\" phenomenon [",
" 16",
" </a>",
" ].",
" </p>",
" <p>",
" Apparent bronchospasm may represent upper airway obstruction or bilateral
vocal cord paralysis. Careful auscultation of the chest and airway in positions
that minimize and maximize potential upper airway obstruction may suggest the need
for further evaluation.",
" </p>",
" PATHOLOGY",
" </span>",
" — Most obstructive cervical or substernal goiters are benign.
However, in a systematic review of a retrospective cohort study and several case
series of patients with substernal goiter undergoing thyroidectomy, the incidence
of thyroid cancer ranged from 3 to 23 percent [",
" 2",
" </a>",
" ]. The incidence of thyroid cancer was no higher than the incidence in
patients with cervical goiters. Risk factors for malignancy may include family
history of thyroid disease, history of head and neck radiation, recurrent goiter,
and the presence of cervical adenopathy.",
" </p>",
" <p>",
" Among benign substernal goiters, the following causes were noted in one large
series [",
" 1",
" </a>",
" ]:",
" </p>",
" <p>",
" <li>",
" Multinodular goiter — 51 percent",
" </li>",
" <li>",
" Large follicular adenoma — 44 percent",
" </li>",
" <li>",
" Chronic autoimmune thyroiditis — 5 percent",
" </li>",
" </ul>",
" </p>",
" <p>",
" Most long-standing large multinodular goiters have extensive areas of cystic
degeneration and hemorrhage, as well as fibrosis, and contain little functioning
thyroid tissue. These goiters often contain areas of calcification, and
ossification can also occur. Occasional patients have acute hemorrhage into a
goiter, which can cause sudden and potentially fatal tracheal obstruction [",
" 10",
" </a>",
" ]. Some contain small papillary cancers, which are thought to have little
biologic importance [",
" 1",
" </a>",
" ].",
" </p>",
" EVALUATION",
" </span>",
" — The initial evaluation of obstructive or substernal goiter
includes serum TSH to evaluate for subclinical or overt hyperthyroidism, imaging
studies (CT or MRI) to evaluate the extent of the goiter and its effect upon
surrounding structures, and a flow-volume loop study in patients with obstructive
symptoms or in those with tracheal narrowing (<1 cm) on cross-sectional
imaging.",
" </p>",
" <p>",
" Unless there is need for immediate surgery, ultrasound should be obtained to
assess the features of the goiter and characteristics of any nodules. Fine needle
aspiration biopsy is indicated if malignancy is suspected (prominent discrete
nodules; a history of rapid growth, pain, or tenderness; unusual firmness in one
region of the goiter; or suspicious sonographic features).",
" </p>",
" <p>",
" Esophageal x-rays with",
" barium",
" </a>",
" usually add little to the evaluation, but may be helpful in documenting
esophageal compression from a goiter as the cause of dysphagia.",
" </p>",
" TSH",
" </span>",
" — Serum TSH should be measured in any patient with a goiter
or a mediastinal mass that could be a substernal goiter. If the TSH is below
normal, serum free T4 and total T3 should also be measured. As noted above, most
patients are euthyroid, but some have subclinical hyperthyroidism and a few have
overt hyperthyroidism [",
" 15",
" </a>",
" ]. (See",
" \"Subclinical hyperthyroidism\"",
" </a>",
" .)",
" </p>",
" Radiologic testing",
" </span>",
" — Substernal goiters are often seen on chest x-ray as a mass
that causes tracheal narrowing or deviation or as superior mediastinal widening (",
" <a class=\"graphic graphic_diagnosticimage graphicRef71486 \" href=\"UTD.htm?
10/55/11123\">",
" image 1",
" </a>",
" ). Past x-rays, if available, permit an estimate of the rate of growth of the
goiter, and neck x-rays may show narrowing of the airway. However, the extent of
the goiter and its effect upon surrounding structures should be assessed by
computed tomography (CT) or magnetic resonance imaging (MRI) (",
" <a class=\"graphic graphic_diagnosticimage graphicRef51935 graphicRef63758 \"
href=\"UTD.htm?7/47/7927\">",
" image 2A-B",
" </a>",
" ) [",
" 17,18",
" </a>",
" ].",
" </p>",
" <p>",
" Computed tomography is very useful for evaluating the extent of both large
cervical goiters and substernal goiters. There are, however, three important
caveats regarding CT scans:",
" </p>",
" <p>",
" <li>",
" The entire vertical length of the goiter should be imaged. Although it may
be necessary to order both neck and chest CT, it should be possible to specify that
images be obtained to the lowest extent of the goiter. It is unusual for a
substernal goiter to extend more than 1 to 2 cm below the level of the aortic
arch.",
" </li>",
" <li>",
" CT scanning is often performed with the patient's neck in the neutral
position or slightly flexed, which may exaggerate the extent of substernal
extension of the goiter. A small goiter that extends 1 to 1.5 cm below the sternal
notch on CT may be entirely cervical when the neck is extended and, therefore, is
less likely to be the cause of any obstructive symptoms the patient may have.",
" </li>",
" <li>",
" Iodinated radiocontrast agents should not be given routinely because the
iodine may induce overt hyperthyroidism in those patients who have subclinical
hyperthyroidism [",
" 15",
" </a>",
" ] and exacerbate hyperthyroidism in those who have overt hyperthyroidism. If
imaging after administration of a radiocontrast agent is required to identify
vascular structures, a patient with subclinical or overt hyperthyroidism should be
pretreated with an antithyroid drug to prevent thyroidal organification of iodine.
One such regimen is to administer",
" methimazole",
" </a>",
" 10 mg twice daily for two weeks beginning at least two hours before the
contrast agent is given. Alternatively, MRI can be performed. (See",
" \"Iodine-induced thyroid dysfunction\", section on 'Management'",
" </a>",
" .)",
" </li>",
" </ul>",
" </p>",
" <p>",
" Thyroid ultrasonography, although more accurate than CT for defining thyroid
anatomy in the anterior neck, is not satisfactory for imaging of posterior neck
structures or the substernal region. Ultrasound is useful to assess the features of
the goiter and characteristics of any nodules. (See",
" \"Overview of the clinical utility of ultrasonography in thyroid disease\",
section on 'Goiter'",
" </a>",
" and",
" \"Overview of the clinical utility of ultrasonography in thyroid disease\",
section on 'Thyroid nodules'",
" </a>",
" .)",
" </p>",
" <p>",
" Thyroid radionuclide imaging with 123-iodine will define areas of autonomous
function in patients with large cervical goiters and may be either useful or
misleading in patients with substernal goiter. It can identify possible substernal
extension of a goiter (",
" <a class=\"graphic graphic_diagnosticimage graphicRef50503 graphicRef66334 \"
href=\"UTD.htm?20/59/21429\">",
" image 3A-B",
" </a>",
" ) and can identify a substernal mass as being thyroid tissue, particularly if
it is hyperfunctioning. However, some substernal goiters are not identified because
they take up radioiodine poorly and the radioactivity is attenuated by the sternum
and clavicles [",
" 17,19",
" </a>",
" ].",
" </p>",
" <p>",
" While radionuclide imaging is unnecessary if thyroidectomy is planned, it
should be obtained to identify areas of function if either limited surgery in a
hyperthyroid patient or treatment with radioiodine is being considered. When
radionuclide imaging is performed, anatomic markers should be placed on palpable
cervical thyroid tissue and the suprasternal notch so that substernal tissue can be
identified; a size marker should also be added.",
" </p>",
" Flow-volume loop",
" </span>",
" — A flow-volume loop study to assess for airway obstruction
should be performed in patients with obstructive symptoms and in those with
substernal goiter with tracheal narrowing to less than 10 mm even in the absence of
obstructive symptoms, particularly if the results of the study would influence the
decision to proceed with surgery [",
" 10,13",
" </a>",
" ]. The study may be abnormal even when the patient is asymptomatic [",
" 10,20",
" </a>",
" ]. Mechanical fixed upper airway obstruction from a goiter results in a
blunted flow-volume loop, a pattern that is distinct from that of chronic
obstructive pulmonary disease (",
41/2/42029\">",
" figure 2",
" </a>",
" ). (See",
" \"Flow-volume loops\"",
" </a>",
" and",
" \"Treatment of obstructive or substernal goiter\", section on 'Preoperative
assessment'",
" </a>",
" .)",
" </p>",
" <p>",
" Rarely, stridor may be due to bilateral recurrent laryngeal nerve palsy.",
" </p>",
" Fine needle aspiration biopsy",
" </span>",
" — Fine needle aspiration biopsy of an obstructive cervical
goiter is indicated if there are prominent discrete nodules; a history of rapid
growth, pain or tenderness; unusual firmness in one region of the goiter; or
suspicious sonographic features. The latter findings raise the suspicion of cancer,
particularly anaplastic cancer or thyroid lymphoma [",
" 21",
" </a>",
" ]. Substernal tissue is not accessible to needle biopsy. (See",
" \"Thyroid biopsy\"",
" </a>",
" .)",
" </p>",
" <p>",
" The decision to proceed with surgery is usually made on the basis of symptoms,
anatomic studies, and the results of a flow-volume loop study rather than
cytopathology.",
" </p>",
" DIFFERENTIAL DIAGNOSIS OF MEDIASTINAL MASS",
" </span>",
" — Several studies have examined the causes of a mediastinal
mass. The following results have been obtained with an estimate of frequency [",
" 22-24",
" </a>",
" ]:",
" </p>",
" <p>",
" <li>",
" Substernal goiter — 5 to 24 percent",
" </li>",
" <li>",
" Neurogenic tumors (eg, ganglioneuromas in the posterior mediastinum) —
20 percent",
" </li>",
" <li>",
" Thymoma — 18 percent",
" </li>",
" <li>",
" Bronchogenic and pericardial cysts — 15 percent",
" </li>",
" <li>",
" Lymphoma — 5 to 10 percent",
" </li>",
" </ul>",
" </p>",
" <p>",
" <li>",
" Teratoma (anterior mediastinum) — 8 percent",
" </li>",
" </ul>",
" </p>",
" <p>",
" (See",
" \"Anterior mediastinal mass lesions\"",
" </a>",
" and",
" \"Evaluation of mediastinal masses\"",
" </a>",
" .)",
" </p>",
" SUMMARY AND RECOMMENDATIONS",
" </span>",
" </p>",
" <p>",
" <li>",
" The clinical manifestations of goiter vary with the size and location of the
goiter. In patients with substantial enlargement of one lobe or asymmetric
enlargement of both lobes, the trachea, esophagus, or blood vessels may be
displaced or, less often, compressed. Bilateral lobar enlargement, especially if
the goiter extends posterior to the trachea, may cause either compression or
concentric narrowing of the trachea or compression of the esophagus or jugular
veins. (See",
" 'Anatomic relationships'",
" </a>",
" above.)",
" </li>",
" <li>",
" Exertional dyspnea is the most common complaint in patients with obstructive
cervical or substernal goiter. This symptom usually occurs when the tracheal
diameter is <8 mm. In some patients with substernal goiter, dyspnea is primarily
positional or nocturnal, and it occurs primarily during maneuvers that force the
thyroid into the thoracic inlet, such as reaching and bending. Other symptoms may
include cough, dysphagia, and hoarseness. (See",
" 'Clinical presentation'",
" </a>",
" above.)",
" </li>",
" <li>",
" All patients with obstructive symptoms caused by a cervical goiter alone
have obvious thyroid enlargement, as do many patients with substernal goiter.
Tracheal deviation is frequently visible or palpable if the goiter is asymmetric.
Rarely, dilated neck veins are present. The possibility of substantial substernal
extension is suggested by the inability to identify the lower end of the thyroid
gland. (See",
" 'Physical examination'",
" </a>",
" above.)",
" </li>",
" <li>",
" Serum TSH should be measured in any patient with a goiter or a mediastinal
mass that could be a substernal goiter. If the TSH is below normal, serum free T4
and total T3 should also be measured. Most patients are euthyroid, but some have
subclinical hyperthyroidism and a few have overt hyperthyroidism. (See",
" 'Evaluation'",
" </a>",
" above.)",
" </li>",
" <li>",
" The extent of the goiter and its effect upon surrounding structures is best
assessed by computed tomography (CT) or magnetic resonance imaging (MRI). Iodinated
radiocontrast agents should not be given routinely because the iodine may induce
overt hyperthyroidism in those patients who have subclinical hyperthyroidism.",
" <br/>",
" <br/>",
" Unless there is need for immediate surgery, ultrasound should be obtained to
assess the features of the goiter and characteristics of any nodules.",
" <br/>",
" <br/>",
" While radionuclide imaging is unnecessary if total thyroidectomy is planned,
in patients with obstructive or substernal goiter who have a suppressed TSH,
radionuclide imaging with 123-iodine should be performed if either limited surgery
or treatment with radioiodine is being considered. (See",
" 'Radiologic testing'",
" </a>",
" above.)",
" </li>",
" <li>",
" A flow-volume loop study should be obtained in patients with obstructive
symptoms or tracheal narrowing to less than 10 mm if the results of the study would
influence the decision to proceed with surgery. (See",
" 'Flow-volume loop'",
" </a>",
" above.)",
" </li>",
" <li>",
" Fine needle aspiration biopsy of an obstructive cervical goiter is indicated
if there are prominent discrete nodules; suspicious sonographic features; a history
of rapid growth, pain, or tenderness; or unusual firmness in one region of the
goiter. (See",
" 'Fine needle aspiration biopsy'",
" </a>",
" above.)",
" </li>",
" <li>",
" The decision to proceed with surgery is usually made on the basis of
symptoms, anatomic studies, and the results of a flow-volume loop study rather than
cytopathology. (See",
" \"Treatment of obstructive or substernal goiter\"",
" </a>",
" .)",
" </li>",
" </ul>",
" </p>",
" </div>",
" </a>",
" .",
" </div>",
" <h1>",
" REFERENCES",
" </h1>",
" <li>",
" Katlic MR, Grillo HC, Wang CA. Substernal goiter. Analysis of 80 patients
from Massachusetts General Hospital. Am J Surg 1985; 149:283.",
" </a>",
" </li>",
" <li>",
" White ML, Doherty GM, Gauger PG. Evidence-based surgical management of
substernal goiter. World J Surg 2008; 32:1285.",
" </a>",
" </li>",
" <li>",
" Jauregui R, Lilker ES, Bayley A. Upper airway obstruction in euthyroid
goiter. JAMA 1977; 238:2163.",
" </a>",
" </li>",
" <li>",
" Katz SM, Vickery AL Jr. The fibrous variant of Hashimoto's thyroiditis. Hum
Pathol 1974; 5:161.",
" </a>",
" </li>",
" <li>",
" Lindskog, GE, Goldberg, IS. Differential diagnosis, pathology, and treatment
of substernal goiter. JAMA 1957; 163:327.",
" </a>",
" </li>",
" <li>",
" Katlic MR, Wang CA, Grillo HC. Substernal goiter. Ann Thorac Surg 1985;
39:391.",
" </a>",
" </li>",
" <li>",
" Allo MD, Thompson NW. Rationale for the operative management of substernal
goiters. Surgery 1983; 94:969.",
" </a>",
" </li>",
" <li>",
" Shaha AR, Burnett C, Alfonso A, Jaffe BM. Goiters and airway problems. Am J
Surg 1989; 158:378.",
" </a>",
" </li>",
" <li>",
" Torre G, Borgonovo G, Amato A, et al. Surgical management of substernal
goiter: analysis of 237 patients. Am Surg 1995; 61:826.",
" </a>",
" </li>",
" <li>",
" Torres A, Arroyo J, Kastanos N, et al. Acute respiratory failure and
tracheal obstruction in patients with intrathoracic goiter. Crit Care Med 1983;
11:265.",
" </a>",
" </li>",
" <li>",
" Shambaugh GE 3rd, Seed R, Korn A. Airway obstruction in substernal goiter.
Clinical and therapeutic implications. J Chronic Dis 1973; 26:737.",
" </a>",
" </li>",
" <li>",
" Banks CA, Ayers CM, Hornig JD, et al. Thyroid disease and compressive
symptoms. Laryngoscope 2012; 122:13.",
" </a>",
" </li>",
" <li>",
" Al-Bazzaz F, Grillo H, Kazemi H. Response to exercise in upper airway
obstruction. Am Rev Respir Dis 1975; 111:631.",
" </a>",
" </li>",
" <li>",
" Siderys H, Rowe GA. Superior vena caval syndrome caused by intrathoracic
goiter. Am Surg 1970; 36:446.",
" </a>",
" </li>",
" <li>",
" Rieu M, Bekka S, Sambor B, et al. Prevalence of subclinical hyperthyroidism
and relationship between thyroid hormonal status and thyroid ultrasonographic
parameters in patients with non-toxic nodular goitre. Clin Endocrinol (Oxf) 1993;
39:67.",
" </a>",
" </li>",
" <li>",
" Blum M, Biller BJ, Bergman DA. The thyroid cork. Obstruction of the thoracic
inlet due to retroclavicular goiter. JAMA 1974; 227:189.",
" </a>",
" </li>",
" <li>",
" Bashist B, Ellis K, Gold RP. Computed tomography of intrathoracic goiters.
AJR Am J Roentgenol 1983; 140:455.",
" </a>",
" </li>",
" <li>",
" Jennings A. Evaluation of substernal goiters using computed tomography and
MR imaging. Endocrinol Metab Clin North Am 2001; 30:401.",
" </a>",
" </li>",
" <li>",
" Park HM, Tarver RD, Siddiqui AR, et al. Efficacy of thyroid scintigraphy in
the diagnosis of intrathoracic goiter. AJR Am J Roentgenol 1987; 148:527.",
" </a>",
" </li>",
" <li>",
" Miller MR, Pincock AC, Oates GD, et al. Upper airway obstruction due to
goitre: detection, prevalence and results of surgical management. Q J Med 1990;
74:177.",
" </a>",
" </li>",
" <li>",
" Madjar S, Weissberg D. Retrosternal goiter. Chest 1995; 108:78.",
" </a>",
" </li>",
" <li>",
" Blegvad S, Lippert H, Simper LB, Dybdahl H. Mediastinal tumours. A report of
129 cases. Scand J Thorac Cardiovasc Surg 1990; 24:39.",
" </a>",
" </li>",
" <li>",
" Wychulis AR, Payne WS, Clagett OT, Woolner LB. Surgical treatment of
mediastinal tumors: a 40 year experience. J Thorac Cardiovasc Surg 1971; 62:379.",
" </a>",
" </li>",
" <li>",
" Priola AM, Priola SM, Cardinale L, et al. The anterior mediastinum:
diseases. Radiol Med 2006; 111:312.",
" </a>",
" </li>",
" </ol>",
" </div>",
" </div>",
" </div>",
" </span>",
" |",
" </span>",
" </a>",
" |",
" </span>",
" Release: 21.6- C21.56",
" </span>",
" <br/>",
" Licensed to:",
" </span>",
" </span>",
" |",
" </span>",
" Support Tag: [0505-197.136.42.3-5480875BC6-S244013.14]",
" <br/>",
" </span>",
" </div>",
" </div>",
"</div>"].join("\n");
" </a>",
" </div>",
" <h1>",
" TOPIC OUTLINE",
" </h1>",
" <ul>",
" <li>",
" <span>",
" SUMMARY & RECOMMENDATIONS",
" </span>",
" </a>",
" </li>",
" INTRODUCTION",
" </a>",
" </li>",
" ANATOMIC RELATIONSHIPS",
" </a>",
" </li>",
" Substernal goiter",
" </a>",
" </li>",
" CLINICAL PRESENTATION",
" </a>",
" </li>",
" Dyspnea and wheezing",
" </a>",
" </li>",
" Cough",
" </a>",
" </li>",
" Other",
" </a>",
" </li>",
" Hyperthyroidism",
" </a>",
" </li>",
" PHYSICAL EXAMINATION",
" </a>",
" </li>",
" PATHOLOGY",
" </a>",
" </li>",
" EVALUATION",
" </a>",
" </li>",
" TSH",
" </a>",
" </li>",
" Radiologic testing",
" </a>",
" </li>",
" Flow-volume loop",
" </a>",
" </li>",
" Fine needle aspiration biopsy",
" </a>",
" </li>",
" DIFFERENTIAL DIAGNOSIS OF MEDIASTINAL MASS",
" </a>",
" </li>",
" </a>",
" </li>",
" REFERENCES",
" </a>",
" </li>",
" </ul>",
" </div>",
" <h1>",
" <div class=\"openRelatedGraphics\" id=\"ENDO/7888\" rel=\"outline_link\">",
" GRAPHICS",
" View All",
" </a>",
" </div>",
" </h1>",
" <ul>",
" <div class=\"openRelatedGraphics\" id=\"ENDO/7888|DiagnosticImage\">",
" <a href=\"#\" title=\"DIAGNOSTIC IMAGES\">",
" DIAGNOSTIC IMAGES",
" </a>",
" </div>",
" </li>",
" <a class=\"graphic graphic_diagnosticimage\" href=\"UTD.htm?10/55/11123\"
title=\"diagnostic image 1\">",
" Substernal goiter PA",
" </a>",
" </li>",
title=\"diagnostic image 2A\">",
" Substernal goiter CT I",
" </a>",
" </li>",
title=\"diagnostic image 2B\">",
" Substernal goiter CT II",
" </a>",
" </li>",
title=\"diagnostic image 3A\">",
" Substernal goiter scan I",
" </a>",
" </li>",
title=\"diagnostic image 3B\">",
" Substernal goiter scan II",
" </a>",
" </li>",
" <div class=\"openRelatedGraphics\" id=\"ENDO/7888|FIG\">",
" FIGURES",
" </a>",
" </div>",
" </li>",
" Anatomy of thoracic inlet",
" </a>",
" </li>",
" Flow volume loop goiter",
" </a>",
" </li>",
" </ul>",
" </div>",
" <h1>",
" RELATED TOPICS",
" </h1>",
" <ul>",
" Anterior mediastinal mass lesions",
" </a>",
" </li>",
" Congenital and acquired goiter in children",
" </a>",
" </li>",
" Evaluation of mediastinal masses",
" </a>",
" </li>",
" Flow-volume loops",
" </a>",
" </li>",
" Iodine-induced thyroid dysfunction",
" </a>",
" </li>",
" Overview of the clinical utility of ultrasonography in thyroid disease",
" </a>",
" </li>",
" Subclinical hyperthyroidism",
" </a>",
" </li>",
" Thyroid biopsy",
" </a>",
" </li>",
" Treatment of obstructive or substernal goiter",
" </a>",
" </li>",
" </ul>",
" </div>",
" </div>"].join("\n");
var title_f0_2_47="Nonsteroidal antiinflammatory drug (NSAID) poisoning";
" </div>",
" </noscript>",
" <br>",
" <sup>",
" ®",
" </sup>",
" <br>",
" </a>",
" ©2013 UpToDate",
" <sup>",
" ®",
" </sup>",
" </br>",
" </div>",
" </br>",
" </img>",
" </img>",
" </div>",
here to print\">",
" Print",
" </a>",
" |",
" </span>",
" Back",
" </a>",
" </div>",
" </div>",
" Nonsteroidal antiinflammatory drug (NSAID) poisoning",
" </div>",
" <div>",
" </a>",
" Authors",
" </a>",
" <br/>",
" Mark Su, MD",
" </a>",
" <br/>",
" Arun Nagdev, MD",
" </a>",
" <br/>",
" </div>",
" <div>",
" Section Editor",
" </a>",
" <br/>",
" Stephen J Traub, MD",
" </a>",
" <br/>",
" </div>",
" <div>",
" Deputy Editor",
" </a>",
" <br/>",
" Jonathan Grayzel, MD, FAAEM",
" </a>",
" <br/>",
" </div>",
" </div>",
" Disclosures",
" </a>",
" </div>",
" <span>",
" </span>",
" </a>",
" <span>",
" is complete.",
" </span>",
" </div>",
" </span>",
" Oct 2013.",
" |",
" </span>",
" </span>",
" Feb 25, 2013.",
" </div>",
" INTRODUCTION",
" </span>",
" — Millions of people worldwide take nonsteroidal
antiinflammatory drugs (NSAIDs) on a regular basis to treat pain and inflammation.
Patients with an acute overdose of NSAIDs often present to emergency departments
and represent a sizable percentage of cases reported to regional poison centers [",
" 1",
" </a>",
" ]. As aging populations have increasingly come to rely on NSAIDs, chronic
toxicity and acute poisonings have become more commonplace. Emergency and primary
care clinicians need to understand the toxicity of NSAIDs; lack of appropriate
medical intervention is believed to be partly responsible for 44 fatal NSAID-
related poisonings in 2008.",
" </p>",
" <p>",
" Acute NSAID poisoning is reviewed here. A summary table to facilitate emergent
management is provided (",
" <a class=\"graphic graphic_table graphicRef59428 \" href=\"UTD.htm?
19/37/20060\">",
" table 1",
" </a>",
" ). A general approach to suspected drug intoxication and discussions of
chronic NSAID toxicity are provided elsewhere. (See",
" \"General approach to drug poisoning in adults\"",
" </a>",
" and",
" \"Nonselective NSAIDs: Overview of adverse effects\"",
" </a>",
" .)",
" </p>",
" PHARMACOLOGY",
" </span>",
" — Nonsteroidal antiinflammatory drugs (NSAIDs) are
competitive inhibitors of the enzyme cyclooxygenase (COX) (",
16/12/16590\">",
" figure 1",
" </a>",
" ). NSAIDs prevent COX-mediated production of prostaglandins and thromboxanes,
but not leukotrienes and other eicosanoids. (See",
" \"NSAIDs: Mechanism of action\"",
" </a>",
" .) There are two COX isoforms, COX-1 and COX-2. The constitutive enzyme, COX-
1, is expressed in most tissues and enables regulation of basal cellular
homeostasis (platelet function, gastric mucosal integrity, and regulation of renal
blood flow). The activity of the inducible COX-2 isoenzyme increases in
inflammatory and pain states [",
" 2",
" </a>",
" ].",
" </p>",
" <p>",
" Numerous animal and human studies have demonstrated the role of COX-1 in
inflammation [",
" 3,4",
" </a>",
" ]. In general, all NSAIDs inhibit both isoforms, with most adverse reactions
believed to be attributable to COX-1 inhibition. The development of newer COX-2
selective NSAIDs arose from the desire to maintain therapeutic antiinflammatory
function, while decreasing the rates of adverse drug effects, most notably
gastrointestinal and renal toxicity. (See",
" </a>",
" .)",
" </p>",
" KINETICS",
" </span>",
" — Oral absorption of NSAIDs approaches 100 percent and peak
serum levels usually occur within one to two hours. Large toxic ingestions or
concomitant food consumption can delay peak levels up to three to four hours.
NSAIDS are weak acids that are extensively (up to 99 percent) protein bound, with a
small volume of distribution (0.1 to 0.2",
" L/kg).",
" </span>",
" Diseases causing low protein levels or large NSAID ingestions can decrease
plasma protein binding, resulting in an increased volume of distribution and
greater penetration into body tissues, including the central nervous system.",
" </p>",
" <p>",
" Most NSAIDs are metabolized by hepatic biotransformation with urinary
excretion. The elimination half-life is usually less than 8 hours, but it ranges
from 1 to 50 hours depending on the specific class and initial dose [",
" 5",
" </a>",
" ]. The half-lives of some common NSAIDs are as follows:",
" </p>",
" <p>",
" <li>",
" Short half-life (<8 hours):",
" ibuprofen",
" </a>",
" ,",
" indomethacin",
" </a>",
" ,",
" ketorolac",
" </a>",
" ,",
" diclofenac",
" </a>",
" </li>",
" <li>",
" Long half-life (>8 hours):",
" naproxen",
" </a>",
" (9 to 20 hours),",
" oxaprozin",
" </a>",
" (25 to 50 hours),",
" piroxicam",
" </a>",
" (30 to 86 hours), phenylbutazone (50 to 100 hours)",
" </li>",
" </ul>",
" </p>",
" HISTORY AND PHYSICAL EXAMINATION",
" </span>",
" — Important historical information includes the name of the
NSAID ingested, the amount ingested, the time of ingestion, and the presence of
coingestants. Nausea, vomiting, and non-specific neurologic findings such as
dizziness may occur. Patients should be specifically questioned about their use
of",
" acetaminophen",
" </a>",
" and",
" aspirin",
" </a>",
" , as these are commonly mistaken for NSAIDs and can produce significant
toxicity.",
" </p>",
" <p>",
" The physical examination in NSAID-poisoned patients is usually unremarkable or
nonspecific. Severe poisoning may produce an acute alteration in mental status.",
" </p>",
" CLINICAL ASPECTS OF ACUTE TOXICITY",
" </span>",
" </p>",
" General",
" </span>",
" — The clinical manifestations of acute NSAID overdose tend to
be minimal. In a review of over 5000 NSAID overdoses, the most common signs and
symptoms were nausea, vomiting, drowsiness, blurred vision, and dizziness [",
" 6",
" </a>",
" ]. Less than 0.5 percent of these patients experienced severe harm (eg, renal
failure); most required no medical intervention.",
" </p>",
" <p>",
" In general, ingestions of less than 100",
" mg/kg",
" </span>",
" of most NSAIDs (except",
" mefenamic acid",
" </a>",
" and phenylbutazone) are unlikely to cause any significant toxicity. Massive
overdoses that produce severe clinical toxicity are seen with ingestions greater
than approximately 400",
" mg/kg",
" </span>",
" (lean body weight) [",
" 7",
" </a>",
" ]. Mild hypothermia may develop following a large overdose [",
" 8",
" </a>",
" ]. ",
" </p>",
" Acid base abnormalities",
" </span>",
" — An increased anion gap metabolic acidosis may be seen after
large ingestions of NSAIDs, particularly",
" ibuprofen",
" </a>",
" ,",
" naproxen",
" </a>",
" , and phenylbutazone (a veterinary NSAID occasionally ingested by humans).
This acidosis may represent a combination of lactic acidosis (from cellular hypoxia
or seizures) and weakly acidic NSAID metabolites. Cardiac dysrhythmias and
electrolyte abnormalities are thought to be due to the severe anion gap metabolic
(lactic) acidosis resulting from massive NSAID ingestion [",
" 8-11",
" </a>",
" ].",
" <strong>",
" </strong>",
" </p>",
" Acute renal failure",
" </span>",
" — Acute renal failure and renal papillary necrosis are rare
in NSAID overdose. Most commonly, these pathologic processes occur in patients with
decreased effective arterial volume (heart failure, cirrhosis, protracted
hypovolemia), age-related underlying renal dysfunction, or massive overdose.",
" </p>",
" <p>",
" Patients with NSAID-induced acute renal failure usually present with evidence
of decreasing renal function (increased serum creatinine, hyperkalemia, decreased
urine volume, or weight gain). (See",
" \"NSAIDs: Acute kidney injury (acute renal failure) and nephrotic
syndrome\"",
" </a>",
" .)",
" </p>",
" <p>",
" The diagnosis of acute renal papillary necrosis may be more difficult.
Patients classically present with gross hematuria and renal colic, secondary to
ureteral passage of sluffed ischemic renal tissue. To confirm the diagnosis, the
clinician must inquire specifically about a recent large ingestion of NSAIDs.
(See",
" \"Clinical manifestations and diagnosis of analgesic nephropathy\"",
" </a>",
" .)",
" </p>",
" <p>",
" NSAID-induced renal injury likely results from inhibition of vasodilatory
prostaglandins. Prostaglandin inhibition leads to vasoconstriction and decreased
renal perfusion. Discontinuation of NSAID therapy usually reverses the renal insult
[",
" 12-16",
" </a>",
" ].",
" </p>",
" Cardiovascular toxicity",
" </span>",
" — Hypotension and cardiovascular collapse have been reported
following massive",
" ibuprofen",
" </a>",
" overdose [",
" 8",
" </a>",
" ]. In one case, a 14-year-old male with an intentional overdose of
approximately 50 g of ibuprofen developed refractory hypotension, in addition to
gastrointestinal bleeding and renal failure, but was successfully treated with
extracorporeal membrane oxygenation [",
" 10",
" </a>",
" ]. (See",
" 'Extracorporeal removal'",
" </a>",
" below.)",
" </p>",
" Central nervous system toxicity",
" </span>",
" — Acute central nervous system toxicity related to NSAID use
is pervasive and varied. A prospective study looking at",
" ibuprofen",
" </a>",
" overdose noted that 30 percent of patients experienced CNS effects ranging
from drowsiness to coma [",
" 17",
" </a>",
" ]. Case reports have identified numerous neurologic sequelae including ataxia,
nystagmus, headaches, and disorientation [",
" 18",
" </a>",
" ].",
" </p>",
" <p>",
" Seizures have been reported with ingestions of propionic acids (",
" ibuprofen",
" </a>",
" ), pyrazolones (phenylbutazone), acetic acids (",
" diclofenac",
" </a>",
" and",
" indomethacin",
" </a>",
" ), and anthranilic acids (",
" mefenamic acid",
" </a>",
" and",
" meclofenamate",
" </a>",
" ) [",
" 19-24",
" </a>",
" ]. Most cases occurred after large ingestions, but even small therapeutic
doses have been associated with seizures in certain patients. The mechanism by
which NSAIDs cause seizures is not clear. Some speculate that decreased cerebral
prostaglandin and thromboxane synthesis may lower the seizure threshold [",
" 22,24",
" </a>",
" ].",
" </p>",
" Hematological toxicity",
" </span>",
" — Aplastic anemia and agranulocytosis have been associated
with the use of phenylbutazone and",
" indomethacin",
" </a>",
" [",
" 25,26",
" </a>",
" ]. In one case of aplastic anemia, the patient presented with bleeding gums
and a diffuse petechial rash after ingestion of an herbal supplement containing
phenylbutazone [",
" 26",
" </a>",
" ]. Phenylbutazones were removed from US markets in the 1970s, but they are
still available in veterinary formulations and in other countries. Discontinuation
of the drug has been shown to reverse the hematologic disturbances.",
" </p>",
" Allergic reactions",
" </span>",
" — NSAIDs may cause several types of allergic reactions,
particularly in patients with chronic urticaria or asthma. Symptoms can range in
severity from a worsening of chronic urticaria to full anaphylaxis. The management
of anaphylaxis due to NSAID ingestion is the same as that of anaphylaxis from any
cause. (See",
" \"Anaphylaxis: Rapid recognition and treatment\"",
" </a>",
" .)",
" </p>",
" <p>",
" Patients with apparent allergic reactions to NSAID or",
" aspirin",
" </a>",
" should discontinue all NSAIDs until they have been specifically evaluated for
this problem. (See",
" \"NSAIDs (including aspirin): Allergic and pseudoallergic reactions\"",
" </a>",
" .)",
" </p>",
" LABORATORY EVALUATION",
" </span>",
" </p>",
" General diagnostic testing",
" </span>",
" — Routine laboratory evaluation of the poisoned patient
should include the following:",
" </p>",
" <p>",
" <li>",
" Fingerstick glucose, to rule out hypoglycemia as the cause of any alteration
in mental status",
" </li>",
" <li>",
" Acetaminophen",
" </a>",
" and salicylate levels, to rule out these common coingestions",
" </li>",
" <li>",
" Electrocardiogram, to rule out conduction system poisoning by coingestants
that affect the QRS or the QTc intervals",
" </li>",
" <li>",
" Pregnancy test in all women of childbearing age",
" </li>",
" </ul>",
" </p>",
" Testing for NSAID toxicity",
" </span>",
" — Although measurement of NSAID serum concentrations provides
one means to assess overdose severity, such measurement has no clear role in acute
management. Concentrations correlate poorly with symptoms, rarely return in a
timely fashion, and are not clinically useful [",
" 17,27",
" </a>",
" ].",
" </p>",
" <p>",
" Routine measurement of renal function (blood urea nitrogen [BUN] and serum
creatinine) is not indicated in patients with minor, asymptomatic ingestions [",
" 27",
" </a>",
" ]. However, in symptomatic patients or those with massive ingestions,
measurement of baseline renal function as well as serum electrolytes is prudent. A
complete blood count to determine the hemoglobin and platelet levels is appropriate
in patients with NSAID-induced bleeding. In massive ingestion (approximately
>400",
" mg/kg",
" </span>",
" in a child or >6 g in an adult) or when the etiology of mental status
alteration is unknown, we recommend obtaining an arterial blood gas to determine
acid-base status.",
" </p>",
" MANAGEMENT OF ACUTE TOXICITY",
" </span>",
" — A summary table to facilitate emergent management is
provided (",
19/37/20060\">",
" table 1",
" </a>",
" ).",
" </p>",
" Airway, breathing, circulation",
" </span>",
" — As with any poisoned patient, the clinician's first
responsibility is to secure the airway, breathing, and circulation. However, apnea
and hypotension are rare so aggressive intervention is usually unnecessary. In the
unusual circumstance where intubation and mechanical ventilation are necessary, it
is important to adjust the ventilator appropriately to help compensate for any
underlying acidosis. (See",
" \"Basic airway management in adults\"",
" </a>",
" and",
" \"Advanced emergency airway management in adults\"",
" </a>",
" and",
" \"Mechanical ventilation of adults in the emergency department\"",
" </a>",
" .)",
" </p>",
" Gastrointestinal decontamination",
" </span>",
" — We suggest gastrointestinal decontamination with",
" activated charcoal",
" </a>",
" (AC) for patients with acute NSAID ingestion, unless specific
contraindications exist (bowel obstruction, perforation, etc). Aspiration risk,
including mental status and the ability to protect the airway, must be assessed in
all patients before any attempts to administer AC.",
" </p>",
" <p>",
" Multiple doses of AC (MDAC) are thought to be ineffective in acute NSAID
ingestion because of the low enterohepatic recirculation and high protein binding
of the majority of these drugs. Although certain NSAIDs have increased
enterohepatic circulation (eg,",
" naproxen",
" </a>",
" ,",
" nabumetone",
" </a>",
" ,",
" sulindac",
" </a>",
" , and",
" piroxicam",
" </a>",
" ), no clinical studies have demonstrated a benefit from MDAC, and the American
Academy of Clinical Toxicology does not recommend its use in the treatment of NSAID
overdose [",
" 28",
" </a>",
" ]. However, MDAC may be useful in patients with a massive overdose of a
sustained release NSAID. In such cases, consultation with a medical toxicologist or
regional poison control center is prudent. (See",
" 'Additional resources'",
" </a>",
" below.)",
" </p>",
" Other supportive measures",
" </span>",
" — Supportive treatment is indicated for correction of
metabolic acidosis after NSAID ingestion. The appropriate role of early volume
correction and bicarbonate administration is debated [",
" <a class=\"abstract\" href=\"UTD.htm?0/2/47/abstract/7,27,29-39\">",
" 7,27,29-39",
" </a>",
" ]. Although we suggest the early use of crystalloid to correct volume
depletion, we do not suggest routine use of bicarbonate therapy because of the lack
of data demonstrating efficacy. Multiple case reports describe bicarbonate infusion
as a temporizing measure for severe acidosis following massive NSAID ingestion.
However, given the lack of evidence supporting this therapy, we recommend
consultation with a poison control center or medical toxicologist before initiating
treatment [",
" 8,9",
" </a>",
" ]. (See",
" \"Bicarbonate therapy in lactic acidosis\"",
" </a>",
" .)",
" </p>",
" <p>",
" Seizures are treated in standard fashion with benzodiazepines. Hypothermia
generally responds to active external warming (eg, heating blanket). (See",
" \"Status epilepticus in adults\", section on 'Treatment'",
" </a>",
" and",
" \"Accidental hypothermia in adults\", section on 'Management'",
" </a>",
" .)",
" </p>",
" Antidote",
" </span>",
" — There is no antidote for NSAID toxicity.",
" </p>",
" Extracorporeal removal",
" </span>",
" — Extracorporeal removal of NSAIDs via hemodialysis is
ineffective due to the high degree of protein binding characteristic of all NSAIDs.
One case report describes the efficacious use of plasmapheresis in a 15-year-old
female with acute phenylbutazone toxicity, and another report describes
extracorporeal membrane oxygenation (ECMO) in a 14-year-old male with massive",
" ibuprofen",
" </a>",
" ingestion. However, such invasive measures are not recommended or necessary in
most cases [",
" 10,40",
" </a>",
" ]. We recommend consultation with a regional poison control center or medical
toxicologist to determine if such therapeutic techniques are warranted, as may be
the case in patients with severe metabolic acidosis or renal failure. (See",
" 'Additional resources'",
" </a>",
" below.)",
" </p>",
" Patient disposition",
" </span>",
" — Patients with ingestions under 100",
" mg/kg",
" </span>",
" (excluding",
" mefenamic acid",
" </a>",
" and phenylbutazone) who are asymptomatic and not suicidal may be safely
discharged following any needed supportive measures (gastrointestinal
decontamination, hydration, etc.) and a four to six-hour period of observation,
depending upon the agent ingested. Drugs with a longer half-life (eg,",
" Naproxen",
" </a>",
" ) require longer observation. (See",
" 'Kinetics'",
" </a>",
" above.)",
" </p>",
" <p>",
" Suicidal patients, patients who manifest signs of severe intoxication (eg, pH
<7.3, acute renal dysfunction, altered mental status), and those with other
medical or psychosocial concerns should be admitted. As with all poisonings,
determination of coingestions (eg,",
" acetaminophen",
" </a>",
" ,",
" aspirin",
" </a>",
" ) is important and will affect disposition.",
" </p>",
" <p>",
" Although there are little data regarding",
" mefenamic acid",
" </a>",
" and phenylbutazone ingestions, we recommend 24-hour observation in such cases
because of the risk of seizures in the former and multiple potential complications
in the latter [",
" <a class=\"abstract\" href=\"UTD.htm?0/2/47/abstract/19-21,25\">",
" 19-21,25",
" </a>",
" ].",
" </p>",
" CHRONIC TOXICITY",
" </span>",
" — Most toxicity related to NSAIDs occurs after chronic use.
An overview of chronic toxicity, including references to detailed discussions of
specific toxicities, is provided elsewhere. (See",
" </a>",
" .)",
" </p>",
" ADDITIONAL RESOURCES",
" </span>",
" — Regional poison control centers in the United States are
available at all times for consultation on patients who are critically ill, require
admission, or have clinical pictures that are unclear (1-800-222-1222). In
addition, some hospitals have clinical",
" and/or",
" </span>",
" medical toxicologists available for bedside consultation",
" and/or",
" </span>",
" inpatient care. Whenever available, these are invaluable resources to help in
the diagnosis and management of ingestions or overdoses. The World Health
Organization provides a listing of international poison centers at its website:",
" <a class=\"external\"
href=\"file://www.who.int/gho/phe/chemical_safety/poisons_centres/en/index.html\">"
,
" www.who.int/gho/phe/chemical_safety/poisons_centres/en/index.html",
" </a>",
" </p>",
" <p class=\"headingAnchor\" id=\"PATIENT_INFORMATION\">",
" INFORMATION FOR PATIENTS",
" </span>",
" — 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",
" <sup>",
" th",
" </sup>",
" to 6",
" <sup>",
" th",
" </sup>",
" 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",
" <sup>",
" th",
" </sup>",
" to 12",
" <sup>",
" th",
" </sup>",
" 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>",
" <li>",
" Basics topic (see",
" <a class=\"medical medical_basics\" href=\"UTD.htm?39/15/40178?
" \"Patient information: Nonsteroidal antiinflammatory drugs (NSAIDs) (The
Basics)\"",
" </a>",
" )",
" </li>",
" <li>",
" Beyond the Basics topic (see",
" <a class=\"medical medical_patient\" href=\"UTD.htm?2/13/2262?
" \"Patient information: Nonsteroidal antiinflammatory drugs (NSAIDs) (Beyond
the Basics)\"",
" </a>",
" )",
" </li>",
" </ul>",
" </p>",
" </span>",
" — Nonsteroidal antiinflammatory drugs (NSAIDs) are among the
most common classes of medications prescribed. Despite the high rates of acute
ingestion, few patients experience poor outcomes, and most require no medical
intervention or supportive care alone. A summary table to facilitate emergent
management is provided (",
19/37/20060\">",
" table 1",
" </a>",
" ).",
" </p>",
" <p>",
" <li>",
" Symptoms and examination findings in NSAID intoxication are generally
nonspecific. The most common signs and symptoms are nausea, vomiting, drowsiness,
blurred vision, and dizziness. Patients should be specifically questioned about
their use of",
" acetaminophen",
" </a>",
" and",
" aspirin",
" </a>",
" , as these are commonly mistaken for NSAIDs and can cause severe toxicity.
(See",
" 'History and physical examination'",
" </a>",
" above.)",
" </li>",
" <li>",
" Acetaminophen",
" </a>",
" and salicylate serum concentrations should be obtained in all patients with
suspected NSAID poisoning. In symptomatic patients and those with large ingestions,
tests of renal function (BUN, serum creatinine), serum electrolytes, and an
arterial blood gas should be obtained. In bleeding patients, hemoglobin and
platelet counts should be measured. NSAID serum concentrations are generally not
helpful. (See",
" 'Laboratory evaluation'",
" </a>",
" above.)",
" </li>",
" <li>",
" NSAID ingestions of less than 100",
" mg/kg",
" </span>",
" are unlikely to cause significant symptoms in adults; ingestions greater
than approximately 400",
" mg/kg",
" </span>",
" (lean body weight) can cause severe symptoms. An increased anion gap
metabolic acidosis may be seen after large ingestions, particularly those
involving",
" ibuprofen",
" </a>",
" ,",
" naproxen",
" </a>",
" , and phenylbutazone. Renal failure and renal papillary necrosis are rare
and occur most often in patients with decreased effective arterial volume, age-
related underlying renal dysfunction, or massive overdose. Acute central nervous
system toxicity related to NSAID use is pervasive and clinical manifestations are
varied, ranging from drowsiness to seizure to coma. NSAIDs may cause anaphylactic
and anaphylactoid reactions, particularly in patients with chronic urticaria or
asthma. (See",
" 'Clinical aspects of acute toxicity'",
" </a>",
" above.)",
" </li>",
" <li>",
" In patients with NSAID overdose, the clinician's first responsibility is to
secure the airway, breathing, and circulation. Aggressive intervention is usually
unnecessary. We suggest gastrointestinal decontamination with",
" activated charcoal",
" </a>",
" (AC) in patients with acute ingestions (",
" <a class=\"grade\" href=\"._grade_6?title=Grade 2C\">",
" Grade 2C",
" </a>",
" ). Aspiration risk should be assessed in all patients before any attempts to
administer AC. No antidote exists. Extracorporeal removal is ineffective. (See",
" 'Management of acute toxicity'",
" </a>",
" above.)",
" </li>",
" <li>",
" Patients with minor ingestions who are asymptomatic and not suicidal may be
discharged safely after a four to six-hour period of observation, depending upon
the agent ingested. Suicidal patients, patients who manifest signs of severe
intoxication (eg, pH <7.3, acute renal dysfunction, altered mental status), and
those with other medical or psychosocial concerns should be admitted. A 24-hour
period of observation is recommended in cases of",
" mefenamic acid",
" </a>",
" and phenylbutazone ingestions. (See",
" 'Management of acute toxicity'",
" </a>",
" above.)",
" </li>",
" </ul>",
" </p>",
" </div>",
" </a>",
" .",
" </div>",
" <h1>",
" REFERENCES",
" </h1>",
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" Ochi T, Goto T. Differential effect of FR122047, a selective cyclo-
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" Goldfrank LR, Flomenbaum NE, Lewin NA, et al. Goldfrank's Toxicologic
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" Smolinske SC, Hall AH, Vandenberg SA, et al. Toxic effects of nonsteroidal
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" Wood DM, Monaghan J, Streete P, et al. Fatality after deliberate ingestion
of sustained-release ibuprofen: a case report. Crit Care 2006; 10:R44.",
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" Marciniak KE, Thomas IH, Brogan TV, et al. Massive ibuprofen overdose
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Crit Care Med 2007; 8:180.",
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" Levine M, Khurana A, Ruha AM. Polyuria, acidosis, and coma following massive
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" McElwee NE, Veltri JC, Bradford DC, Rollins DE. A prospective, population-
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" Robson RH, Balali M, Critchley J, et al. Mefenamic acid poisoning and
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" Balali-Mood M, Critchley JA, Proudfoot AT, Prescott LF. Mefenamic acid
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" Kingswell RS. Mefenamic acid overdose. Lancet 1981; 2:307.",
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" </a>",
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" Risks of agranulocytosis and aplastic anemia. A first report of their
relation to drug use with special reference to analgesics. The International
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" Nelson L, Shih R, Hoffman R. Aplastic anemia induced by an adulterated
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" <li>",
" Hall AH, Smolinske SC, Stover B, et al. Ibuprofen overdose in adults. J
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" </a>",
" </li>",
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Toxicologists. J Toxicol Clin Toxicol 1999; 37:731.",
" </a>",
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" Downie A, Ali A, Bell D. Severe metabolic acidosis complicating massive
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" </a>",
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" Hall AH, Smolinske SC, Kulig KW, Rumack BH. Ibuprofen overdose--a
prospective study. West J Med 1988; 148:653.",
" </a>",
" </li>",
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" Lee CY, Finkler A. Acute intoxication due to ibuprofen overdose. Arch Pathol
Lab Med 1986; 110:747.",
" </a>",
" </li>",
" <li>",
" Hall AH, Smolinske SC, Conrad FL, et al. Ibuprofen overdose: 126 cases. Ann
Emerg Med 1986; 15:1308.",
" </a>",
" </li>",
" <li>",
" Court H, Streete P, Volans GN. Acute poisoning with ibuprofen. Hum Toxicol
1983; 2:381.",
" </a>",
" </li>",
" <li>",
" Virji MA, Venkataraman ST, Lower DR, Rao KN. Role of laboratory in the
management of phenylbutazone poisoning. J Toxicol Clin Toxicol 2003; 41:1013.",
" </a>",
" </li>",
" </ol>",
" </div>",
" </div>",
" </div>",
" </span>",
" |",
" </span>",
" </a>",
" |",
" </span>",
" Release: 21.6- C21.56",
" </span>",
" <br/>",
" Licensed to:",
" </span>",
" </span>",
" |",
" </span>",
" Support Tag: [0504-118.195.65.248-6BEDC4A8C2-S244013.14]",
" <br/>",
" </span>",
" </div>",
" </div>",
"</div>"].join("\n");
" </a>",
" </div>",
" <h1>",
" TOPIC OUTLINE",
" </h1>",
" <ul>",
" <li>",
" <span>",
" SUMMARY & RECOMMENDATIONS",
" </span>",
" </a>",
" </li>",
" INTRODUCTION",
" </a>",
" </li>",
" PHARMACOLOGY",
" </a>",
" </li>",
" KINETICS",
" </a>",
" </li>",
" HISTORY AND PHYSICAL EXAMINATION",
" </a>",
" </li>",
" CLINICAL ASPECTS OF ACUTE TOXICITY",
" </a>",
" </li>",
" General",
" </a>",
" </li>",
" Acid base abnormalities",
" </a>",
" </li>",
" Acute renal failure",
" </a>",
" </li>",
" Cardiovascular toxicity",
" </a>",
" </li>",
" Central nervous system toxicity",
" </a>",
" </li>",
" Hematological toxicity",
" </a>",
" </li>",
" Allergic reactions",
" </a>",
" </li>",
" LABORATORY EVALUATION",
" </a>",
" </li>",
" General diagnostic testing",
" </a>",
" </li>",
" Testing for NSAID toxicity",
" </a>",
" </li>",
" MANAGEMENT OF ACUTE TOXICITY",
" </a>",
" </li>",
" Airway, breathing, circulation",
" </a>",
" </li>",
" Gastrointestinal decontamination",
" </a>",
" </li>",
" Other supportive measures",
" </a>",
" </li>",
" Antidote",
" </a>",
" </li>",
" Extracorporeal removal",
" </a>",
" </li>",
" Patient disposition",
" </a>",
" </li>",
" CHRONIC TOXICITY",
" </a>",
" </li>",
" ADDITIONAL RESOURCES",
" </a>",
" </li>",
" <a class=\"outlineLink\" href=\"#PATIENT_INFORMATION\">",
" INFORMATION FOR PATIENTS",
" </a>",
" </li>",
" </a>",
" </li>",
" REFERENCES",
" </a>",
" </li>",
" </ul>",
" </div>",
" <h1>",
" <div class=\"openRelatedGraphics\" id=\"EM/341\" rel=\"outline_link\">",
" GRAPHICS",
" View All",
" </a>",
" </div>",
" </h1>",
" <ul>",
" <div class=\"openRelatedGraphics\" id=\"EM/341|FIG\">",
" FIGURES",
" </a>",
" </div>",
" </li>",
" Prostaglandin syn AERD",
" </a>",
" </li>",
" <div class=\"openRelatedGraphics\" id=\"EM/341|TAB\">",
" <a href=\"#\" title=\"TABLES\">",
" TABLES",
" </a>",
" </div>",
" </li>",
" <a class=\"graphic graphic_table\" href=\"UTD.htm?19/37/20060\" title=\"table
1\">",
" Acute NSAID toxicity - Rapid overview",
" </a>",
" </li>",
" </ul>",
" </div>",
" <h1>",
" RELATED TOPICS",
" </h1>",
" <ul>",
" Accidental hypothermia in adults",
" </a>",
" </li>",
" Advanced emergency airway management in adults",
" </a>",
" </li>",
" Anaphylaxis: Rapid recognition and treatment",
" </a>",
" </li>",
" Basic airway management in adults",
" </a>",
" </li>",
" Bicarbonate therapy in lactic acidosis",
" </a>",
" </li>",
" Clinical manifestations and diagnosis of analgesic nephropathy",
" </a>",
" </li>",
" General approach to drug poisoning in adults",
" </a>",
" </li>",
" Mechanical ventilation of adults in the emergency department",
" </a>",
" </li>",
" NSAIDs (including aspirin): Allergic and pseudoallergic reactions",
" </a>",
" </li>",
" NSAIDs: Acute kidney injury (acute renal failure) and nephrotic syndrome",
" </a>",
" </li>",
" NSAIDs: Mechanism of action",
" </a>",
" </li>",
" Nonselective NSAIDs: Overview of adverse effects",
" </a>",
" </li>",
" <a class=\"medical medical_patient\" href=\"UTD.htm?2/13/2262?
" Patient information: Nonsteroidal antiinflammatory drugs (NSAIDs) (Beyond
the Basics)",
" </a>",
" </li>",
" <a class=\"medical medical_basics\" href=\"UTD.htm?39/15/40178?
" Patient information: Nonsteroidal antiinflammatory drugs (NSAIDs) (The
Basics)",
" </a>",
" </li>",
" Status epilepticus in adults",
" </a>",
" </li>",
" </ul>",
" </div>",
" </div>"].join("\n");

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