Q. How would you proceed with the initial work-up and treatment of this patient?

A. As with all critical patients, the evaluation and treatment should begin with the 'ABCs' (Airway, Breathing and Circulation). Supplemental oxygen should be given to all patients with altered mental status. A fluid bolus of 250-500 ml normal saline or lactated Ringers is indicated for hypotension.

The "coma cocktail" consists of glucose, thiamin and Narcan^® (naloxone). These agents are effective antidotes for two of the rapidly treatable etiologies of coma or altered mental status. Naloxone is a specific antidote for opiates. Glucose, either as an oral supplement or intravenously (IV) as Dextrose 50%, is given for suspected hypoglycemia. An acceptable alternative to supplemental glucose is an Accucheck^® or other bedside glucose determination. Thiamin is given to prevent the development of Wernicke's encephalopathy in patients who are nutritionally deficient and who are given glucose.

An Accucheck^® shows a glucose of 94mg/dL. There is no response to 2 mg IV naloxone. The oxygen saturation rises to 98% on 15L by non-rebreather mask and there is no significant change in blood pressure or heart rate after a bolus of 500 cc normal saline.

Q. What further evaluation would you do?

A. Appropriate laboratory evaluation includes electrolytes (including calcium), blood urea nitrogen (BUN) and creatinine, osmolarity, blood alcohol, urinalysis, complete blood count (CBC), arterial blood gases (ABG), EKG and toxicology screen. Radiologic studies should include a minimum of a CXR and a noncontrast CT of the head. A lumbar puncture should be performed once CT has ruled out a space occupying lesion or edema.

Test Results

• White blood count (WBC) 5.60,
• Hemoglobin 10.4g/dL,
• Hematocrit 32.4,
• Platelets 214
• Na⁺ 122mEq/L, K⁺ 3.9mEq/L, Cl^- 96mmol/L, HCO3- 28mEq/L, BUN 10mg/dL , creatinine 9mg/dL, Ca⁺⁺ 8.5mg/dL,
• UA has a specific gravity of 1.020 and pH 6.5. Negative for ketones, blood, leukocytes or nitrites.
• ABG on 2L by nasal canula: pH 7.20, pCO₂ 64, pO₂ 62, and oxygen saturation 91%
• The blood alcohol is negative.
• Urine drug screening is positive for opiates, negative for all others.
• Acetaminophen and salicylate levels are reported as 'none detected'.

The CT of the head is reported as negative for bleed, mass or shift by the radiologist.

The cerebrospinal fluid (CSF) is clear with an opening pressure of 16cms water. Lab on the CSF shows a protein of 108mg/dL and glucose of 60mg/dL. There were no organisms or cells on the gram stain and the complete cell count is negative for red or white cells.

Here is the chest x-ray:

Q. The chest x-ray (CXR) has what finding(s)?

A. The chest x-ray shows mild cardiomegaly and an impacted fracture of the right shoulder.

Q. The EKG below shows what finding?

A. The EKG demonstrates sinus bradycardia with a rate of 53.

Q. In view of the above information, what is your working diagnosis?

A. The working diagnosis is myxedema coma.

The clinical picture of decreased mental status, hypothermia, respiratory failure and presumed previous thyroidectomy are consistent with a diagnosis of myxedema coma. Other findings consistent with the diagnosis include the non-pitting lower extremity edema, the yellow skin and coarse hair, hyponatremia, bradycardia, and a history of hypothyroid symptoms of weight gain and cold intolerance. This patient fits the most likely patient profile for myxedema, that of a female between 60 to 70 years old with untreated or under treated hypothyroidism.

Myxedema coma is rarely found in the absence of a precipitating factor(s) and is most commonly associated with some form of cold exposure. The most likely precipitating factors in this case are the recent trauma and the use of narcotic analgesia.

Discussion

Myxedema coma is a relatively rare, life threatening complication of hypothyroidism. As stated above, it is most commonly seen in females with hypothyroidism, which is often untreated or under treated, who are in their 60s. It is more frequent in winter months and is associated with a precipitating event or stressor. Fifty percent of cases of myxedema coma develop after admission to the hospital for an unrelated illness.

Precipitating Events

Common precipitating events include significant cold exposure, infections (the most common of these is pneumonia), trauma, heart failure, stroke, GI bleeding, hypoxia, hypoglycemia and the use of certain medications. Hypothyroid patients metabolize medications slower than do normal patients. Sedatives, tranquilizers, anesthetics, narcotics and phenothiazines often have prolonged effect in these patients and have been associated with myxedema coma. Other medications that have been implicated include lithium, b blockers and amiodarone.

Physical Findings

Mild hypothermia is so common a finding in myxedema that a normal temperature suggests an underlying infection. Both the hypoxic and hypercapnic respiratory drives are depressed in myxedema, resulting in hypoventilation, hypoxia and hypercapnea. In extreme cases, this results in the need for intubation and mechanical ventilation. The hypoxic ventilatory drive returns to normal with appropriate thyroid hormone replacement but the hypercapneic drive often does not.

Myxedema, a dry, waxy, nonpitting swelling of the skin and subcutaneous tissues, can be seen in the face and extremities. In rare cases, myxedematous infiltration of the upper airway can result in partial or complete obstruction.

About 50% of patients present with hypotension but normal pressures may occur. This hypotension may be resistant to both fluid and vasopressors but responds to thyroid hormone replacement. The most common dsyrhythmia is sinus bradycardia. Ventricular dysrhythmias are rare. Cardiomegally is commonly seen on chest film and is often due to either underlying intrinsic heart disease or a pericardial effusion. Though the effusion associated with myxedema may be large, tamponade is a rare finding.

Mental status changes associated with myxedema can range from confusion to psychiatric manifestations and psychosis to frank coma. Seizures are the presenting CNS manifestation in about 25% of patients. Cerebellar ataxia, paresthesias (80% of cases), tremors and nystagmus may also be seen. Pseudomyotonic or "hung up" reflexes are a common finding that is evidenced by a prolonged relaxation phase of the DTRs.

The findings associated with chronic hypothyroidism are also seen in myxedema. These include cold intolerance, loss of energy, weakness, muscle and joint pain, drowsiness, constipation, decreased auditory acuity, tinnitus, blurred vision, menstrual irregularity, dry scaly skin often with a yellow discoloration, coarse thinning hair, generalized nonpitting edema, hoarse voice, weight gain of 10-15 lbs. without increase in dietary intake. A goiter may be present but is not necessary for the diagnosis.

Most patients with myxedema will have some amount of abdominal distention that is due to slowing of the GI tract resulting in an ileus and/or acquired megacolon. Urinary retention is also common.

Laboratory Abnormalities

Laboratory abnormalities common in patients with myxedema coma include hypoxia, hypercapnea, hyponatremia, hypochloremia and elevated cholesterol. Glucose levels are usually normal but hypoglycemia can occur. A mild normochromic normocytic anemia without an increase in reticulocytes may be seen. The WBC is usually normal. A left shift may be the only sign of coexistent infection. Elevation in CPK from skeletal muscle has also been found in some cases of myxedema coma. CSF is notable for a protein >100 mg/dl or more.

Thyroid Function Tests

Commonly available laboratory measurements of thyroid functions include the thyroid stimulating hormone (TSH), total and free T4, T3, rT3 and thyroid binding globulin. The most relevant studies are the free T4 (FT4) and TSH levels. The thyroid function studies in myxedema closely parallel those of simple hypothyroidism. In patients with primary hypothyroidism, where the disease is located at the level of the thyroid gland, the TSH is elevated and the FT4 low. In the minority of patients who have pituitary or hypothalamic dysfunction as the etiology of their hypothyroid state, both the TSH and FT4 will be low. Unfortunately, thyroid function studies are not available in many institutions on an emergency basis and are, therefore, not reliable for the diagnosis of myxedema coma.

The TSH is a measurement of the pituitary hormone that serves to "turn on" the thyroid gland to produce and release thyroid hormones. T4 (thyroxine) is released by the thyroid and binds to thyroid binding globulin (TBG) in the blood stream. In the periphery, T4 is converted to the more physiologically active form of thyroid hormone (T3 or triiodothyronine) by T4 5' deiodinase.

Total T4 levels in hypothyroid states are unreliable, as they may appear falsely low or elevated depending on the level of thyroid binding globulin (TBG). T3 levels are also not reliable, as low T3 levels may be secondary to decreased conversion of T4 to T3. This leads to a falsely low T3 level in a person who is physiologically euthyroid, the so-called "sick euthyroid" state. The activity of T4 5' deiodinase is affected by many disease states including diabetes, cancers, chronic renal failure, liver disease, malnutrition, infections, seizures and chronic steroid therapy.

Treatment

There are three elements in the treatment of myxedema: hormone replacement, supportive care and treatment of the precipitating event.

Hormone Replacement

The most critical part of the therapy for myxedema is thyroid hormone replacement. Many of the supportive efforts will not be effective without prompt replacement of thyroid hormone. Thyroid hormone has traditionally been replaced in the form of IV thyroxine (T4). The initial dose is 500 ug followed by 50-100 ug/d. Effects are seen in six hours with full effect seen in 24 hr. The dose of thyroxine should be reduced by 25% in patients with known or suspected ischemic heart disease to reduce the possibility of arrhythmia or cardiac arrest.

Although triiodothyronine (T3) is four times more pharmacologically active than T4, it has not been used frequently in myxedema because T3 was only available in tablet form. A few studies have been published showing that T3 given orally or per nasogastric tube is effective in the treatment of myxedema. Recently, an IV form of T3 has become available and can be given in an initial dose of 25-50 ug. This dose should be reduced to 10 - 20 ug in patients with cardiovascular disease.

These doses of thyroid hormone have been associated with the development of arrhythmias and cardiac arrest in patients with heart diseases and may be harmful or fatal if administered to patients who do not have myxedema coma. They should be used with extreme caution in cases of coma of uncertain etiology.

All patients with myxedema coma should also receive stress dosages of steroids to cover for possible cases of coexistent adrenal or pituitary failure. Hydrocortisone 300 mg IV is given initially followed by 100 mg IV every 6 - 8 hours. 

Supportive Care

Respiratory support, such as supplemental oxygen, should be given to all myxedema patients. Intubation and mechanical ventilation are necessary in those patients with profound respiratory depression or in the rare case of upper airway edema. Patients in myxedema coma, who require mechanical ventilation, are often ventilator dependent for prolonged times and tracheotomy may be indicated.

Sedatives, tranquilizers, narcotics and other anesthetic agents have prolonged action and should not be used, or used only with extreme care, in these patients.

Aggressive warming is not indicated and may be harmful in myxedema coma. Patients should be treated with passive warming methods, such as warm blankets, and thyroid hormone replacement.

Hypotension should be initially treated with fluids, such as saline or lactated ringers, but this is often ineffective and fluid overload should be avoided. Vasopressors are also often ineffective in hypotension secondary to myxedema. Hypotension responds rapidly to thyroid hormone replacement.

Hyponatremia is common in myxedema patients and is thought to be dilutional in nature. For Na⁺ of >115-120 mEq/L, fluid restriction is the treatment of choice. For Na⁺ levels of <115 mEq/L or in patients thought to be symptomatic, hypertonic (3%) sodium is indicated. Caution should be used to avoid fluid overload, especially in patients with heart failure.

Hypoglycemia should be treated with D50 IV and the patient placed on a D5 glucose IV solution.

Treatment of the Precipitating Event

The precipitating event is treated in standard fashion.