The Patient is an Agitated 42

8/6/2019 The Patient is an Agitated 42

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The patient is an agitated 42-year-old woman complaining of fever, flank pain, nausea,vomiting, and palpitations for the past 24 hours.

Current HistoryThe pain is described as a dull, constant, grinding pain that is located primarily in the

right flank and has been getting progressively worse over the last 12 hours.

She has had urinary frequency and dysuria for the past 2 days but denies hematuria or vaginal discharge.

Her temperature was as high as 101.2 F/ 38.5C at home.

She was brought to the emergency room by her roommate, who was concerned by not only the increasing pain, but also by the patients escalating anxiety over the situation.

The roommate tells you that the patient "is losing it, is not acting herself, and has never been this anxious about anything before in her life.

Past HistoryThe patient has not seen a doctor in over 5 years, and her only known past medical history

is generalized anxiety disorder and depression, for which she takes fluoxetine.

She admits to drinking a few every day and to using cocaine occasionally.

Physical Examination

Vitals: T 103.2 F/39.5 C, HR 145 sinus tachycardia, BP 160/58, RR 18, O2 saturation 98%room air General: Thin, anxious woman in moderate amount of distress HEENT: Pupils

6mm and reactive, extra-ocular motions intact Neck: Supple, no bruits Chest: Lungs clear

to auscultation bilaterally Abdomen: Soft, non-distended; non-tender. Mild right costo-

vertebral angle tenderness. Stool is brown Guaiac negative. Pelvic: No discharge, no

cervical motion tenderness, no adnexal tenderness Extremities: Well perfused; bounding

pulses Neurologic: Awake and alert, extremely anxious, repeatedly saying I feel awful! Am

I going to be all right? No focal motor weakness or sensory deficits, reflexes are 3+

throughout

Laboratory Result

Lab TestValue

Normal Range Units

WBC 15 4-10 K/mLPlt 288 150-450 K/mLMCV 86 80-95 fl or mm3

Na 134 134-142 meq/LK 3.6 3.5-5.0 meq/LCl 99 98-108 meq/L


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HCO3 25 18-27 meq/LBUN 24 9-25 mg/dLCr 1.2 0.8-1.3 mg/dLGlu 127 60-100

(fasting)mg/dL

Differential: Pending

Which of the following statements is most correct regarding the initial management

of this patient?

Top of Form

a. Symptoms are most likely related to cocaine overdose.

Heart rate and blood pressure should be controlled with intravenousbeta-blockers.

b. Symptoms are most likely related to alcohol withdrawal.She should be treated with haloperidol to control her agitation.

c. Symptoms are most likely related to serotonin syndrome brought on

by her fluoxetine.Fluoxetine should be discontinued and Meperidine should be given to

treat her flank pain.d. She should be given antipyretics, IV fluid, and more information

should be obtained.

Your decide to treat the patient with acetaminophen 1000 mg po, lorazepam 1 mg IV,and normal saline 1000cc IV bolus. Blood cultures are sent. Her temperature comes

down to 100.3; however, her heart rate remains at 145, her blood pressure is now164/48, and she is still agitated.

Additional information is now available:

Toxicology screening: negative for cocaine, amphetamines, and all other

Chest XRAY: Normal.

Additional laboratory values:Urinalysis: HCG negative, specific gravity 1.015, + nitrites, + leukocyte esterase, -

protein, -glucose, - ketones.Urine sediment: 50-80 WBC / hpf, no RBC or casts.

Total bilirubin 3.0 mg/dl, direct bilirubin 0.4 mg/dl, alkaline phosphatase 66 I/U,amylase 60 U/U, lipase 2.7 I/l.

You pause to reflect on this case. You have considered many things in the differentialdiagnosis of her presentation, which seems to be best summarized as a hyper-adrenergic state, though you havent found a unifying diagnosis yet. You have identifieda potential source of infection; however, this does not seem to be a run-of-the-mill caseof pyelonephritis. You go back to re-examine the patient.

You notice that there is slight protuberance of her eyes with wide palpebral fissures andbilateral periorbital edema. You also note raised violaceous papules overlying both


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anterior shins. Re-examination of her neck is normal; no goiter is palpated and notenderness is elicited. A more detailed review of systems reveals a 20-pound weight lossover the last 2-3 months, frequent palpitations, and an increasing level of anxiety.

Figure 1Protuberance of the eyes with wide palpebral fissures

Reprinted with permission from EMedicine.com, Inc.,2003

Figure 2Pretibial Myxedema

click on image to enlargeReprinted with permission from EMedicine.com, Inc.,2003

Given these new findings, you wonder if this patient is hyperthyroid and has Graves

disease. Which of the following statements is most correct?

Top of Form

a. The absence of a goiter eliminates the possibility of Graves disease.

b. Her extremity lesions are consistent with pretibial myxedema. Sincemyxedema is associated with hypothyroidism, this is unlikely to be Gravesdisease.

c. She potentially has Graves disease; however, you should first consider themore common causes of hyperthyroidism in women of this age group.

d. She likely has Graves disease and resultant hyperthyroidism.

There are numerous other conditions besides Graves disease that can causehyperthyroidism.

These include:
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Toxic adenoma and toxic multinodular goiter: caused by focal or diffusehyperplasia of the thyroid gland that functions independently of TSH, toxic

multinodular goiter is much more common than Graves disease in older patients.Variable-sized goiter is often present.

Subacute granulomatous thyroiditis (DeQuervains thyroiditis): viral or

post-viral inflammation of the thyroid gland, associated with a tender goiter.These patients may present with sore throat as their chief complaint.

Subacute lymphocytic thyroiditis: autoimmune disorder, associated with a

non-tender goiter

Exogenous (factitious) hyperthyroidism: due to overdose of thyroid

hormone-- either of thyroxine replacement preparations or other drugs (e.g. faddiet preparations) that contain thyroxine

Ectopic thyroid hormone production: rare; classic examples are struma ovarii(thyroxine-producing ovarian tumor) and metastatic follicular thyroid cancer

TSH producing tumors: rare; e.g. functional pituitary tumor

Figure 3Goiter


To bolster support for your diagnosis of hyperthyroidism, you should look for thefollowing physical exam findings:

Top of Form

a. Smooth skin, onycholysis, and thinning hair

b. Tremor, hyperactive deep tendon reflexes, and proximal muscle weakness

c. Widened pulse pressure and systolic ejection murmur

d. All of the above

Now that you are concerned that your patient is suffering from hyperthyroidism, yousend thyroid function tests (TFTs) to the laboratory to confirm the diagnosis. Which of

the following statements regarding TFTs is most correct?


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Top of Form

a. Hyperthyroidism cannot be present if the TSH is normal or elevated.

b. Hyperthyroidism cannot be present if the serum free T4 is normal.

c. The best screening test for hyperthyroidism is a TSH plus a free T4 or free T3.

d. Determination of thyroxine-binding globulin (TBG) levels is essential to make

the diagnosis of hyperthyroidism.

You send the serum TSH and free T4 levels to the lab. You can expect to get the TSHresult in an hour or so, but the T4 level will not be back until much later. In the

meantime, you continue to treat the patient with IV fluids and antibiotics.

You begin to think about additional therapy. To do this, you think about the degree ofthyrotoxicosis this patient is experiencing.

About an hour later, the patients TSH level comes back as undetectable. Which ofthe following statements is most correct?

Top of Form

a. This patient has subclinical hyperthyroidism and should be referred toan endocrinologist once her infectious process has been definitivelytreated.

b. This patient has apathetic hyperthyroidism and requires immediate

treatment with anti-thyroid agents.

c. This patient has overt hyperthyroidism and should be treated with a

thioamide in addition to the antibiotics.

d. This patient has thyroid storm and requires emergent treatment.

A scoring system has been devised to aid with the diagnosis of thyroid storm: Scores greater than 45 are indicative of thyroid storm,

Scores 25-45 suggest thyroid storm, and

Scores less than 25 are unlikely to be thyroid storm.

This system is probably best used as a clinical guideline rather than a strict formula toinclude or exclude thyroid storm as a diagnosis.

Thermoregulatory

Temp. (F) Points

99-100 5

100-101 10

101-102 15

102-103 20

103-104 25

>104 30

Cardiovascular

Heartrate

Points

100-110 5

110-120 10

120-130 15

130-140 20

>140 25

CNS

Alteration Points

mild (agitation) 10

moderate (delirium, psychois) 20


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You have come to the conclusion that this patient is indeed suffering from thyroidstorm.

What will your therapeutic approach be?

Top of Form

a. Aspirin, propranolol, and propylthiouracil (PTU)

b. Acetaminophen, verapamil, and PTU

c. Acetaminophen, propranolol, and PTU should be given before

potassium iodide and dexamethasone

d. Acetaminophen, propranolol, potassium iodide before PTU,

dexamethasone

There are five main goals to properly treat thyroid storm:

1) Beta blockade,

2) inhibition of thyroid hormone synthesis,

3) inhibition of thyroid hormone release from the thyroid gland,

4) prevention of peripheral conversion of T4 to T3, and

5) aggressive supportive care.

Beta BlockerOn a cellular level:

Thyroid hormone is known to alter beta-adrenergic receptors, as well as g-proteinsand cyclic AMP used in the transduction of sympathetic signals.

On a macro level:

Thyroid storm can be thought of as a hyper-adrenergic state, and many of thesymptoms of thyroid storm (hypertension, tachycardia, palpitations, agitation, etc.) arebest controlled with beta-blockade.

Bolus intravenous agents such as metoprolol or propranolol may be used, or ifgreater control is required, infusion agents such as esmolol may be used.

Inhibition of thyroid hormone synthesis

The thioamide drugs, methimazole and propylthiouracil (PTU), are used to inhibit the

production of thyroid hormone.

While methimazole is the preferred agent for outpatient therapy (it has a longer half-

life), PTU is preferred in thyroid storm as it offers the additional advantage of blockingperipheral T4 to T3 conversion.


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The dose of PTU is 200 to 400 mg orally every six to eight hours. The dose ofmethimazole is 20 to 25 mg orally every six hours.

In June of 2009 the FDA issued an alert that PTU may be associated with anincreased risk of hepatotoxicity as compared to methimazole. If PTU is used, closelymonitor liver function tests during therapy. For chronic use as an outpatient,methimazole is the preferred agent.

Inhibition of thyroid hormone release

The administration of iodine prevents the release of thyroid hormone from the thyroidgland.

It is important that PTU or methimazole be given at least 1 hour in advance of iodineto prevent the iodine being used as a substrate for new hormone synthesis. (Indeed,hyperthyroidism can be precipitated in patients with multinodular goiter who receiveiodine this is referred to as Jod Basedows disease.)

Doses:--5 drops of potassium iodide solution (SSKI) every 6 hours,

--10 drops of Lugols solution every 8 hours,

--or sodium iodide, 1 gram by slow IV drip every 12 hours.

Prevention of peripheral T4 toT3 conversion Recall that T4 (thyroxine) is converted to T3 (triiodothyronine) in the peripheralcirculation, and that T3 is 10x more active than T4.

Dexamethasone 10 mg every 6 hours or hydrocortisone 100 mg every 8 hoursshould be given. Beta-blockers and PTU also prevent the conversion of T4 to T3 but notsufficiently enough to preclude the use of steroids in thyroid storm.

Aggressive supportive care

Antipyretics. Aspirin will theoretically displace T4 and T3 from thyroid hormone glolubin, so

acetaminophen should be used instead.

CHF therapy. Diuretics or digoxin may be required in patients with cardiac manifestations.

Fluid resuscitation may be required in those with volume depletion.

Treatment of any underlying precipitating factors

Etiology of Thyroid Storm

The transition from hyperthyroidism to thyroid storm is usually an acute event with anidentifiable precipitating factor.

Untreated hyperthyroidism rarely converts to thyroid storm without a precipitant.


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Underlying provoking illnesses that may require treatment include:

Infections of any type

Vascular accidents, visceral infarctions

Pulmonary embolism

Surgery, burns, or trauma

Hypoglycemia, DKA, or HHS (hyperglycemic hyperosmolar state)

Follow-up Your treatment regimen worked perfectly. Within the next few hours, hertemperature fell to 99F/37.2C, her heart rate was controlled at 88, and her bloodpressure was 124/70.

The patient thanks you profusely, saying that she finally feels normalagain.

She was admitted to the hospital for two days and improved dramatically on IV

antibiotics and fluids.

The endocrinology consult was obtained and concurred with the diagnosis of Graveshyperthyroidism. Methimazole and atenolol were prescribed, and the patient is scheduledto have radioiodine ablation of her thyroid gland next month.

Summary Thyroid storm is a rare complication of hyperthyroidism and is manifested as hyper-adrenergic state. Recognition of this entity may be difficult.

Signs and symptoms of hyperthyroidism include ophthalmopathy, periorbital edema,

goiter, pretibial myxedema, thin hair and smooth skin, muscle weakness, heart failure,atrial fibrillation, weight loss, palpitations, and anxiety.

Numerous conditions can cause hyperthyroidism, including Grave's disease, toxicadenoma and toxic multinodular goiter, subacute thyroiditis, and less frequently,

factitious hyperthyroidism, ectopic thyroid hormone production, and TSH producingtumors.

Precipitants of thyroid storm include infection, vascular accidents, visceral infarctions,surgery or trauma, and hypo- or hyperglycemia. Untreated hyperthyroidism rarelycoverts to thyroid storm without a precipitant.

The treatment of thyroid storm consists of 5 main goals: beta-blockade, inhibition ofthyroid hormone synthesis (PTU or methimazole), inhibition of thyroid hormone release

(iodine), prevention of peripheral T4 conversion (steroids), and aggressive supportivecare.

References

Burch HB, Wartofsky L. "Life-threatening thyrotoxicosis. Thyroid storm."Endocrinologyand Metabolism Clinics of North America .22 (1993): 263-277.

Klein I, Ojamaa K. "Mechanisms of disease: thyroid hormone and the cardiovascularsystem."New England Journal of Medicine .344 (2001): 501-509.

Manifold CA. "Hyperthyroidism, thyroid storm, and Graves disease." Available athttp://www.emedicine.com/emerg/topic269.htm. Accessed 2/25/2003.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8325286&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11172193&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11172193&dopt=Abstracthttp://www.emedicine.com/emerg/topic269.htmhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11172193&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11172193&dopt=Abstracthttp://www.emedicine.com/emerg/topic269.htmhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8325286&dopt=Abstract


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Ross DS. "Hyperthyroidism." Available at www.uptodate.com. Accessed 2/5/2003.

Weetman AP. "Controversy in thyroid disease." Journal of the Royal College of Physiciansof London .34 (2000): 374-380.

Woeber KA. "Update on the management of hyperthyroidism and hypothyroidism."

Archives of Internal Medicine .160 (2000): 1067-1071.

Wogan JM. "Selected endocrine disorders." Rosens Emergency Medicine: Concepts andClinical Practice. Eds. JA Marx, RS Hockberger, and RM Walls. St. Louis: Mosby, Inc.2002.

Nayak B, Burman K. Thyrotoxicosis and thyroid storm. Endocrinol Metab Clin N Am.2006;35:663-686

McKeown NJ, Tews MC, Gossain VV, Shah SM. Hyperthyroidism. Emerg Med Clin N Am.

2005;23:669-685.

Migneco A, Ojetti V, Testa A, DeLorenzo A, Gentiloni S. Management of thyrotoxic crisis.Eur Rev Med Pharmacol Sci. 2005;9:69-74.
http://www.uptodate.com/http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11005077&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10789598&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/pubmed/17127140?dopt=Abstracthttp://www.ncbi.nlm.nih.gov/pubmed/15982540?dopt=Abstracthttp://www.ncbi.nlm.nih.gov/pubmed/15850146?dopt=Abstracthttp://www.uptodate.com/http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11005077&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10789598&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/pubmed/17127140?dopt=Abstracthttp://www.ncbi.nlm.nih.gov/pubmed/15982540?dopt=Abstracthttp://www.ncbi.nlm.nih.gov/pubmed/15850146?dopt=Abstract


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Endocrine Emergencies Case 1:Hot and Bothered

Please click the Continue button to proceed to the next slide.

If you are returning to this case, you may click the Case Summary tab to get to the last slidethat you completed.

Introduction

The patient is an agitated 42-year-old woman complaining of fever, flank pain, nausea,vomiting, and palpitations for the past 24 hours.

Current History The pain is described as a dull, constant, grinding pain that is located primarily in

the right flank and has been getting progressively worse over the last 12 hours.

She has had urinary frequency and dysuria for the past 2 days but denies hematuria

or vaginal discharge.

Her temperature was as high as 101.2 F/ 38.5C at home.

She was brought to the emergency room by her roommate, who was concerned bynot only the increasing pain, but also by the patients escalating anxiety over the

situation.

The roommate tells you that the patient "is losing it, is not acting herself, and hasnever been this anxious about anything before in her life.

Past History The patient has not seen a doctor in over 5 years, and her only known past medical

history is generalized anxiety disorder and depression, for which she takes fluoxetine.

She admits to drinking a few every day and to using cocaine occasionally.

Physical Examination


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Vitals: T 103.2 F/39.5 C, HR 145 sinus tachycardia, BP 160/58, RR 18, O2

saturation 98% room air

General: Thin, anxious woman in moderate amount of distress

HEENT: Pupils 6mm and reactive, extra-ocular motions intact

Neck: Supple, no bruits

Chest: Lungs clear to auscultation bilaterallyAbdomen: Soft, non-distended; non-tender. Mild right costo-vertebral angle

tenderness. Stool is brown Guaiac negative.

Pelvic: No discharge, no cervical motion tenderness, no adnexal tenderness

Extremities: Well perfused; bounding pulses

Neurologic: Awake and alert, extremely anxious, repeatedly saying I feel awful! Am I

going to be all right? No focal motor weakness or sensory deficits, reflexesare 3+ throughout

Laboratory Results

Lab TestValue Normal Range Units

WBC 15 4-10 K/mLPlt 288 150-450 K/mLMCV 86 80-95 fl or mm3

Na 134 134-142 meq/LK 3.6 3.5-5.0 meq/LCl 99 98-108 meq/LHCO3 25 18-27 meq/L

BUN 24 9-25 mg/dLCr 1.2 0.8-1.3 mg/dLGlu 127 60-100

(fasting)mg/dL

Differential: Pending

Question 1 out of 7

Which of the following statements is most correct regarding the initial management ofthis patient?

a. Symptoms are most likely related to cocaine overdose.Heart rate and blood pressure should be controlled with intravenous beta-blockers.The authors disagree.

Her symptoms (tachycardia, hypertension, anxiety, and palpitations) may be related tococaine overdose. However, the appropriate treatment for this would bebenzodiazepines and direct alpha antagonists (such as phentolamine) if further blood

pressure control were required. Beta-blockers are contra-indicated in cocaineoverdose as they may produce unopposed alpha activity on peripheral vessels,resulting in worsening hypertension and vasospasm.

b. Symptoms are most likely related to alcohol withdrawal.She should be treated with haloperidol to control her agitation.


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The authors disagree.

Her symptoms may be related to alcohol withdrawal, though we dont have enoughinformation at this time (e.g. exact details of daily etoh consumption, when her lastdrink was, etc.) to make this diagnosis. Regardless, the proper treatment for alcohol

withdrawal is benzodiazepines. Haloperidol would be contraindicated in this situationas it lowers the seizure threshold.

c. Symptoms are most likely related to serotonin syndrome brought on by her fluoxetine.Fluoxetine should be discontinued and Meperidine should be given to treat her flank

pain.The authors disagree.

The serotonin syndrome is associated with many types of medications and drugs.These include the SSRIs (serotonin-specific reuptake inhibitors), MAO inhibitors,tricyclic antidepressants, meperidine (!), and amphetamines. The syndrome may occurwhen the dosage of any of the above agents is increased, or when two or more of the

above agents are combined. Symptoms include altered mental status (confusion tocoma), autonomic dysfunction (hyperthermia, diaphoresis, tachycardia, andhypertension) and neuromuscular dysfunction (myoclonus). The serotonin syndrome isan excellent addition to the differential diagnosis in this case. Administration ofbenzodiazepines, dantrolene, and / or cyproheptadine is the preferred treatment for

serotonin syndrome.

Since meperidine can precipitate the serotonin syndrome when combined with otherserotonergic drugs, it would be absolutely contra-indicated in this case.

d. She should be given antipyretics, IV fluid, and more information should be obtained.The answer is correct.

The differential diagnosis in this case is quite large, and more information is required.Treatment with antipyretics such as acetaminophen and IV fluids seems prudent.

This patients history contains several red flags: Cocaine (or other sympathomimetic overdose): Primary treatment consists ofbenzodiazepines; phentolamine may be need to correct malignant hypertension.

Alcohol withdrawal: Primary treatment would consist of benzodiazepines

Serotonin syndrome (especially if there is a history of recent increase in fluoxetinedose or addition of other serotonergic medication): Treatment consists of

benzodiazepines, dantrolene, and / or cyproheptadine.

Infection of all types: Cultures, UA, and chest x-ray may be required.

Initial Treatment and Additional Data

Your decide to treat the patient with acetaminophen 1000 mg po, lorazepam 1 mg IV,and normal saline 1000cc IV bolus. Blood cultures are sent. Her temperature comesdown to 100.3; however, her heart rate remains at 145, her blood pressure is now164/48, and she is still agitated.

Additional information is now available:


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Toxicology screening: negative for cocaine, amphetamines, and all othersubstances

Chest XRAY: Normal.

Additional laboratory values:Urinalysis: HCG negative, specific gravity 1.015, + nitrites, + leukocyte esterase, -

protein, -glucose, - ketones.Urine sediment: 50-80 WBC / hpf, no RBC or casts.

Total bilirubin 3.0 mg/dl, direct bilirubin 0.4 mg/dl, alkaline phosphatase 66 I/U,amylase 60 U/U, lipase 2.7 I/l.

Question 2 out of 7

Which of the following is the most appropriate next step?

a. Order an abdominal CT scan before giving any further medicationsThe authors disagree.

An abdominal CT scan may be indicated if you believe there is an obstructing kidneystone present in conjunction with her probable pyelonephritis. However, antibioticsshould be given at once.

b. Pursue no further diagnostic test in the EDAdmit the patient to the medical floor on antibiotics for pyelonephritisThe authors disagree.

This patient likely has pyelonephritis and antibiotics should be started at this time;

however, her vital signs are unstable and she requires further diagnosis and treatmentbefore leaving the ED for the medical floor.c. Administer antibiotics, then re-examine the patient and send additional laboratory

tests, because something is not quite right hereThe answer is correct.

This patient likely has pyelonephritis, and you should administer antibiotics.However, her vital signs remain abnormalnotably she is quite tachycardic despiteappropriate antipyretics and fluid resuscitation.

There is more to do on this case.d. Administer more IV fluids and antipyretics, then discharge home if no further events

occurThe authors disagree.

This patient likely has pyelonephritis and requires antibiotics. Furthermore, since hervital signs remain abnormal, she requires further investigation in the emergencydepartment.

Reexamination of the Patient

You pause to reflect on this case. You have considered many things in the differentialdiagnosis of her presentation, which seems to be best summarized as a hyper-

adrenergic state, though you havent found a unifying diagnosis yet. You have identifieda potential source of infection; however, this does not seem to be a run-of-the-mill case


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of pyelonephritis. You go back to re-examine the patient.

You notice that there is slight protuberance of her eyes with wide palpebral fissures andbilateral periorbital edema. You also note raised violaceous papules overlying bothanterior shins. Re-examination of her neck is normal; no goiter is palpated and notenderness is elicited. A more detailed review of systems reveals a 20-pound weight loss

over the last 2-3 months, frequent palpitations, and an increasing level of anxiety.

Figure 1Protuberance of the eyes with wide palpebral fissures


Question 3 out of 7

Figure 2Pretibial Myxedema

click on image to enlargeReprinted with permission from EMedicine.com, Inc.,2003

Given these new findings, you wonder if this patient is hyperthyroid and has Graves

disease. Which of the following statements is most correct?

a. The absence of a goiter eliminates the possibility of Graves disease.The authors disagree.

While most patients with Graves disease have a goiter, a minority of patients willhave minimal thyroid enlargement.

b. Her extremity lesions are consistent with pretibial myxedema. Since myxedema isassociated with hypothyroidism, this is unlikely to be Graves disease.

The authors disagree.
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This can be confusing. It is true that generalized myxedema (deposition ofglycosaminoglycans such as hyaluronic acid in the tissues) is a feature ofhypothyroidism and that myxedema coma is an extreme form of hypothyroidism.

However, pretibial myxedema is a feature of Graves disease. These lesions arecharacteristically found over the shins and are described as raised, hyperpigmented,

violaceous, orange-peel textured papules.c. She potentially has Graves disease; however, you should first consider the morecommon causes of hyperthyroidism in women of this age group.The authors disagree.

Graves disease usually affects women in the 3rd to 4th decade of life, and is the mostcommon cause of hyperthyroidism in general.

d. She likely has Graves disease and resultant hyperthyroidism.The answer is correct.

Your excellent clinical skills are honing in on the diagnosis. Given her clinical history

and her physical examination, she likely has hyperthyroidism due to Graves disease.(You will have the opportunity to confirm this diagnosis with laboratory tests in a fewmoments.)

Graves disease (a.k.a. toxic diffuse goiter) is the most common form ofhyperthyroidism and usually affects females in their 3rd to 4th decade of life. Gravesdisease is an autoimmune disorder: TSH receptor antibodies stimulate the thyroid

gland to produce excessive amounts of hormone.

In addition to the numerous physical findings associated with hyperthyroidism ingeneral, there are some signs that are specific for Graves:

- Ophthalmopathy. This is characterized by inflammation of the extra-ocular musclesand orbital fat, resulting in exopthalmos, lid lag, stare, and extra-ocular muscle

palsies.

-Infiltrative dermopathy. This usually manifests itself as pretibial myxedema but maybe seen in other areas of the body as well.

Causes of Hyperthyroidism

There are numerous other conditions besides Graves disease that can causehyperthyroidism.

These include:

Toxic adenoma and toxic multinodular goiter: caused by focal or diffuse

hyperplasia of the thyroid gland that functions independently of TSH, toxicmultinodular goiter is much more common than Graves disease in older patients.Variable-sized goiter is often present.

Subacute granulomatous thyroiditis (DeQuervains thyroiditis): viral or

post-viral inflammation of the thyroid gland, associated with a tender goiter.These patients may present with sore throat as their chief complaint.

Subacute lymphocytic thyroiditis: autoimmune disorder, associated with a

non-tender goiter


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Exogenous (factitious) hyperthyroidism: due to overdose of thyroidhormone-- either of thyroxine replacement preparations or other drugs (e.g. fad

diet preparations) that contain thyroxine

Ectopic thyroid hormone production: rare; classic examples are struma ovarii

(thyroxine-producing ovarian tumor) and metastatic follicular thyroid cancer

TSH producing tumors: rare; e.g. functional pituitary tumor

Figure 3Goiter


Question 4 out of 7

To bolster support for your diagnosis of hyperthyroidism, you should look for the

following physical exam findings:

a. Smooth skin, onycholysis, and thinning hairThe authors disagree.

You are on the right track. These symptoms are often found in hyperthyroidism, butthere other findings as well.

b. Tremor, hyperactive deep tendon reflexes, and proximal muscle weaknessThe authors disagree.

You are on the right track. These symptoms are often found in hyperthyroidism, but

there other findings as well.c. Widened pulse pressure and systolic ejection murmurThe authors disagree.

You are on the right track. These symptoms are often found in hyperthyroidism, butthere other findings as well.

d. All of the aboveThe answer is correct.

The signs and symptoms of hyperthyroidism are protean and largely independent ofthe underlying cause. For example:

Constitutional: fever, heat intolerance, weight loss


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Cardiovascular: increased cardiac output, increased heart rate, increased systolicblood pressure, decreased diastolic blood pressure (remember, thyroid hormone is avasodilator!), widened pulse pressure, high or normal output congestive heart failure,

sinus tachycardia (out of proportion to fever), atrial fibrillation, and exacerbation ofunderlying angina pectoris

Respiratory: dyspnea on exertion (primarily due to respiratory muscle weakness),mechanical airway obstruction due to large goiter, and obstructive airway diseaseexacerbation

Gastrointestinal: weight loss, nausea, vomiting, diarrhea, and indirecthyperbilirubinemia

Genitourinary: frequency and nocturia

Dermal: warm, smooth skin, diaphoresis, onycholysis (separation of the nail from the

nail bed), and pruritis

Neurological: agitation, anxiety, restlessness, and psychosis

It should be noted that most of these symptoms are not specific for hyperthyroidism.Processes to consider in your differential diagnosis of hyperthyroidism include:sepsis, toxic ingestion (anti-cholinergic and sympathomimetic toxidromes, serotoninsyndrome, and neuroleptic-malignant syndrome), withdrawal syndromes, and heatstroke.

Question 5 out of 7

Now that you are concerned that your patient is suffering from hyperthyroidism, yousend thyroid function tests (TFTs) to the laboratory to confirm the diagnosis. Which of

the following statements regarding TFTs is most correct?

a. Hyperthyroidism cannot be present if the TSH is normal or elevated.The authors disagree.

In almost all cases of hyperthyroidism, the increased amount of thyroid hormone willsuppress TSH production. However, in the rare case of a TSH-producing tumor (e.g.functional pituitary adenoma) a normal or high TSH will be found in conjunction witha high free T4 and T3, and the patient will be hyperthyroid.

b. Hyperthyroidism cannot be present if the serum free T4 is normal.The authors disagree.

In certain cases of hyperthyroidism, TSH will be suppressed, the free T4 will benormal, and the free T3 will be elevated. This is known as T3 hyperthyroidism, and is

found in Graves disease, toxic multinodular goiter, and toxic adenoma. Ifhyperthyroidism is suspected and the free T4 is normal, a free T3 should be checked.

c. The best screening test for hyperthyroidism is a TSH plus a free T4 or free T3.The answer is correct.

In hyperthyroidism, excess amounts of thyroid hormone will suppress pituitary

production of TSH. Thus, the classic TFT panel for hyperthyroidism is a low TSH andhigh free T4 and / or high free T3.


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Remember, over 99% of T4 [thyroxine, or thyroid hormone] and T3 [triiodothyronine,the metabolically active form of thyroxine] is bound to thyroid-hormone binding

globulin [TBG] and other proteins. Free assays measure the unbound,metabolically available levels of circulating hormones. In diseases in which the

amount of binding proteins may be elevated or decreased, measurements of total T4or T3 and TBG levels may be needed, but these tests are not usually available in theemergency department.

There are uncommon circumstances in which the typical hyperthyroid TFT picture(low TSH and high free T4 or T3) is not seen. These include:

TSH hyperthyroidism: a pituitary adenoma produces excessive amounts of TSH,resulting in normal or high levels of TSH and high free T4 and T3

T3 hyperthyroidism: certain causes of hyperthyroidism (including Graves disease,toxic multinodular goiter, and toxic adenoma) may be associated with normal free T4levels and elevated free T3 levels. TFTs in this scenario will show low TSH, normal

free T4, and elevated free T3.d. Determination of thyroxine-binding globulin (TBG) levels is essential to make the

diagnosis of hyperthyroidism.The authors disagree.

The standard approach to the laboratory assessment of hyperthyroidism includes aTSH and a free T4 or T3. If the TSH is suppressed and the T4 or T3 is elevated, thediagnosis of hyperthyroidism is cinched and more elaborate TFT testing may not berequired.

Question 6 out of 7

You send the serum TSH and free T4 levels to the lab. You can expect to get the TSHresult in an hour or so, but the T4 level will not be back until much later. In themeantime, you continue to treat the patient with IV fluids and antibiotics.

You begin to think about additional therapy. To do this, you think about the degree ofthyrotoxicosis this patient is experiencing.

About an hour later, the patients TSH level comes back as undetectable. Which of thefollowing statements is most correct?

a. This patient has subclinical hyperthyroidism and should be referred to anendocrinologist once her infectious process has been definitively treated.The authors disagree.

Subclinical hyperthyroidism refers to a condition in which the TSH is suppressed, butthe T4 and T3 are normal and there are no physical signs of hyperthyroidism.

b. This patient has apathetic hyperthyroidism and requires immediate treatment withanti-thyroid agents.The authors disagree.

Apathetic hyperthyroidism refers to a condition seen primarily in elderly patients,


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which is characterized by depressed mental status, cardiovascular disease (atrialfibrillation and congestive heart failure), and weight loss.

c. This patient has overt hyperthyroidism and should be treated with a thioamide inaddition to the antibiotics.The authors disagree.

This patient surely has overt hyperthyroidism. However, given her abnormal vitalsigns and agitation, she will require more treatment than thioamides alone.

d. This patient has thyroid storm and requires emergent treatment.The answer is correct.

The signs and symptoms of thyroid storm are those of exaggerated hyperthyroidism:tachycardia out of proportion to fever, congestive heart failure, hyperpyrexia, alteredmental status, and gastrointestinal symptoms.

Thyroid Storm Scoring System

A scoring system has been devised to aid with the diagnosis of thyroid storm:

Scores greater than 45 are indicative of thyroid storm, Scores 25-45 suggest thyroid storm, and Scores less than 25 are unlikely to be thyroid storm.

This system is probably best used as a clinical guideline rather than a strict formula to

include or exclude thyroid storm as a diagnosis.

Thermoregulatory

Temp. (F) Points

99-100 5

100-101 10101-102 15

102-103 20

103-104 25

>104 30

Cardiovascular

Heartrate

Points

100-110 5110-120 10

120-130 15

130-140 20

>140 25

CNS

Alteration Points

mild (agitation) 10


Congestive Heart FailureSymptom Pointsmild

pedal edema)5

Moderate(bibasilar rales)

10

Severe(pulmonary edema)

15

Atrial fibrillation 10

GastrointestinalSymptom Pointsmoderate (n/v/d, abd pain 10

severe (jaundice) 20

Precipitant History

absent 0 present 10

Adapted from Burch HB, Wartofsky L. Endocrinology and Metabolism Clinics of NorthAmerica. 1993; 22:263

Thyroid Storm Scoring System for this patient


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The following is the thyroid storm scoring system with the values for this patienthighlighted.

Thermoregulatory

Temp. (F) Points

99-100 5

100-101 10

101-102 15

102-103 20

103-104 25

>104 30

Cardiovascular

Heartrate

Points

100-110 5

110-120 10

120-130 15

130-140 20

>140 25

CNS

Alteration Points

mild (agitation) 10


Congestive Heart FailureSymptom Pointsmild

pedal edema)5

Moderate(bibasilar rales)

10

Severe

(pulmonary edema)

15

Atrial fibrillation 10

GastrointestinalSymptom Pointsmoderate (n/v/d, abd pain 10

severe (jaundice) 20

Precipitant History

absent 0 present 10

Adapted from Burch HB, Wartofsky L. Endocrinology and Metabolism Clinics of NorthAmerica. 1993; 22:263

Question 7 out of 7

You have come to the conclusion that this patient is indeed suffering from thyroid storm.

What will your therapeutic approach be?

a. Aspirin, propranolol, and propylthiouracil (PTU)The authors disagree.

There are several problems with this approach. Acetaminophen should be usedinstead of aspirin, as aspirin can cause thyroxine to dissociate from TBG in

peripheral tissues. While propranolol and PTU are indicated, this regimen leaves outother important agents.

b. Acetaminophen, verapamil, and PTUThe authors disagree.

Acetaminophen and PTU are indicated in this case. However, propranolol is a better


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choice than verapamil to blunt the sympathetic effects of hyperthyroidismc. Acetaminophen, propranolol, and PTU should be given before potassium iodide and

dexamethasoneThe answer is correct.

There are five main goals to properly treat thyroid storm:

1) Beta blockade,

2) inhibition of thyroid hormone synthesis,

3) inhibition of thyroid hormone release from the thyroid gland,

4) prevention of peripheral conversion of T4 to T3, and

5) aggressive supportive care.

d. Acetaminophen, propranolol, potassium iodide before PTU, dexamethasoneThe authors disagree.

You are on the right track. However, it is important to give the PTU at least one hourbefore the potassium iodide. The potassium iodide will prevent the release of

preformed thyroid hormone from the thyroid gland, but if an agent (such as PTU) isnot given prior the iodide, the iodide may potentially enhance hormone synthesis.

1. Beta-blockade

On a cellular level:

Thyroid hormone is known to alter beta-adrenergic receptors, as well as g-proteinsand cyclic AMP used in the transduction of sympathetic signals.

On a macro level:

Thyroid storm can be thought of as a hyper-adrenergic state, and many of thesymptoms of thyroid storm (hypertension, tachycardia, palpitations, agitation, etc.) arebest controlled with beta-blockade.

Bolus intravenous agents such as metoprolol or propranolol may be used, or ifgreater control is required, infusion agents such as esmolol may be used.

2. Inhibition of thyroid hormone synthesis

The thioamide drugs, methimazole and propylthiouracil (PTU), are used to inhibit theproduction of thyroid hormone.

While methimazole is the preferred agent for outpatient therapy (it has a longer half-life), PTU is preferred in thyroid storm as it offers the additional advantage of blockingperipheral T4 to T3 conversion.

The dose of PTU is 200 to 400 mg orally every six to eight hours. The dose ofmethimazole is 20 to 25 mg orally every six hours.


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Untreated hyperthyroidism rarely converts to thyroid storm without a precipitant.

Underlying provoking illnesses that may require treatment include:

Infections of any type Vascular accidents, visceral infarctions

Pulmonary embolism

Surgery, burns, or trauma

Hypoglycemia, DKA, or HHS (hyperglycemic hyperosmolar state)

Follow-up

Your treatment regimen worked perfectly. Within the next few hours, hertemperature fell to 99F/37.2C, her heart rate was controlled at 88, and her blood

pressure was 124/70.

The patient thanks you profusely, saying that she finally feels normalagain.

She was admitted to the hospital for two days and improved dramatically on IVantibiotics and fluids.

The endocrinology consult was obtained and concurred with the diagnosis of Graveshyperthyroidism. Methimazole and atenolol were prescribed, and the patient is scheduledto have radioiodine ablation of her thyroid gland next month.

Summary

Thyroid storm is a rare complication of hyperthyroidism and is manifested as

hyper-adrenergic state. Recognition of this entity may be difficult.

Signs and symptoms of hyperthyroidism include ophthalmopathy, periorbitaledema, goiter, pretibial myxedema, thin hair and smooth skin, muscle weakness,heart failure, atrial fibrillation, weight loss, palpitations, and anxiety.

Numerous conditions can cause hyperthyroidism, including Grave's disease, toxicadenoma and toxic multinodular goiter, subacute thyroiditis, and less frequently,

factitious hyperthyroidism, ectopic thyroid hormone production, and TSHproducing tumors.

Precipitants of thyroid storm include infection, vascular accidents, visceralinfarctions, surgery or trauma, and hypo- or hyperglycemia. Untreated

hyperthyroidism rarely coverts to thyroid storm without a precipitant.

The treatment of thyroid storm consists of 5 main goals: beta-blockade, inhibition

of thyroid hormone synthesis (PTU or methimazole), inhibition of thyroid hormonerelease (iodine), prevention of peripheral T4 conversion (steroids), andaggressive supportive care.

Summary of Images


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Figure 1Protuberance of the eyeswith wide palperbral

fissures

Figure 2Pretibial Myxedema Figure 3Goiter

References

Burch HB, Wartofsky L. "Life-threatening thyrotoxicosis. Thyroid storm."Endocrinologyand Metabolism Clinics of North America .22 (1993): 263-277.

Klein I, Ojamaa K. "Mechanisms of disease: thyroid hormone and the cardiovascular

system."New England Journal of Medicine .344 (2001): 501-509.

Manifold CA. "Hyperthyroidism, thyroid storm, and Graves disease." Available athttp://www.emedicine.com/emerg/topic269.htm. Accessed 2/25/2003.

Ross DS. "Hyperthyroidism." Available at www.uptodate.com. Accessed 2/5/2003.

Weetman AP. "Controversy in thyroid disease." Journal of the Royal College of Physicians

of London .34 (2000): 374-380.

Woeber KA. "Update on the management of hyperthyroidism and hypothyroidism."Archives of Internal Medicine .160 (2000): 1067-1071.

Wogan JM. "Selected endocrine disorders." Rosens Emergency Medicine: Concepts andClinical Practice. Eds. JA Marx, RS Hockberger, and RM Walls. St. Louis: Mosby, Inc.

2002.

Nayak B, Burman K. Thyrotoxicosis and thyroid storm. Endocrinol Metab Clin N Am.

2006;35:663-686

McKeown NJ, Tews MC, Gossain VV, Shah SM. Hyperthyroidism. Emerg Med Clin N Am.2005;23:669-685.

Migneco A, Ojetti V, Testa A, DeLorenzo A, Gentiloni S. Management of thyrotoxic crisis.Eur Rev Med Pharmacol Sci. 2005;9:69-74.

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