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Endocrinol Metab Clin N Am

35 (2006) 687–698

Myxedema Coma
Leonard Wartofsky, MDa,b,c, *
to
Department of Medicine, Washington Hospital Center, Room 2A-62,
110 Irving Street NW, Washington, DC 20010–2975, USA
b
Uniformed Services University of the Health Sciences,
4301 Jones Bridge Road, Bethesda, MD 20814, USA
c
Georgetown University School of Medicine, 3900 Reservoir Road, Washington, DC 20007, USA

Myxedema coma represents the most extreme form of hypothyroidism, so

severe as to readily progress to death unless diagnosed promptly and treated
vigorously. Two of the 12 patients first reported with hypothyroidism in 1879
likely died as a result of myxedema coma [1]. There are perhaps 300 cases
reported in the literature; thus, although it is, fortunately, rare today, it is
important to recognize because of the high associated mortality. A number of the
case reports have been collated and reviewed over recent years [2–5].
Because hypothyroidism is some eightfold more common in women than in
men, most patients who might present with myxedema coma are women. Be
cause hypothyroidism is most common in the later decades of life, most of these
women are elderly. It is important to maintain a high index of suspicion,
especially if faced with an elderly female patient with compatible signs and symptoms.
with hypothyroidism who is beginning to manifest mental status changes and
some of the typical findings described in this article. Like uncomplicated
hypothyroidism, the diagnosis rests on a determination of serum thyroid-stimulating
hormone (TSH). Most hospital and commercial laboratories can turn around
a TSH result within hours, and once the diagnosis is made, therapy should be
initiated immediately. However, even with reasonably early diagnosis and cus
tomary therapy, the mortality rate approaches 50% to 60%.

clinical presentation

Precipitating events

A review of the literature indicates that most patients with myxedema

coma seem to present in winter and that a low body temperature
*
Department of Medicine, Washington Hospital Center, Room 2A-62, 110 Irving Street
NW, Washington, DC 20010-2975.
E-mail address: [email protected]

0889-8529/06/$ - see front matter 2006 Elsevier Inc. All rights reserved.
doi:10.1016/j.ecl.2006.09.003 endo.theclinics.com
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688 WARTOFSKY

(hypothermia) is usually present. Extremely cold weather actually seems to

lower the threshold for vulnerability, with an otherwise stable hypothyroid
individual slipping into a coma after cold exposure. The pathogenesis can
be more complex, however, with other patients' clinical state evolving into a
coma after development of pneumonia, sepsis from any cause, stroke, or
cardiovascular compromise (Box 1).
Pneumonia may be a primary initiating event or may occur secondarily
after a stroke or aspiration. Other clinical features that are typical of myx
edema coma, such as carbon dioxide retention, hyponatremia, hypoglyce
mia, and hypoxemia, could potentially also contribute to the development of
coma in a hypothyroid patient, particularly because they represent potential
causes of coma in euthyroid subjects. Patients are likely to present with a
slowly developing coma in the hospital setting after being admitted with
some other event, such as a fracture. In such cases, the underlying
diagnosis may not have been suspected; hence, the slower metabolism of
drugs and higher attendant risk of adverse events are not appreciated.
Thus, carbon di oxide retention leading to coma could be a feature of relative
drug overdoses associated with suppression of respiratory drive, such as
from sedatives, narcotic analgesics, antidepressants, hypnotics, and
anesthetics. An association with amiodarone therapy has also been reported [6].

Box 1. Myxedema coma: exacerbating or precipitating factors

Hypothermia
Cerebrovascular accidents
Congestive heart failure
infections
drugs
anesthetics
sedatives
tranquilizers
drugs
Amiodarone
lithium carbonate
Gastrointestinal bleeding
Trauma
Metabolic disturbances exacerbating myxedema coma
Hypoglycaemia
hyponatremia
Acidosis
Hypercalcemia
hypoxaemia
hypercapnia
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Whatever the precipitating cause, the course is typically one of lethargy

progressing to stupor and then coma, with respiratory failure and hypothermia,
all of which may be hastened by the administration of the latter types
of drugs that depress respiration and other brain functions. The characteristic
features of severe hypothyroidism are present, such as dry skin, sparse
hair, a hoarse voice, periorbital edema and nonpitting edema of the hands
and feet, macroglossia, and delayed deep tendon reflexes, and moderate to
profound hypothermia is common. In addition to hyponatremia and hypo
glycemia, a routine laboratory evaluation may indicate anemia,
hypercholesterolemia, and high serum lactate dehydrogenase and creatine kinase
concentrations [7].

General description

If it is possible to obtain a past medical history of the patient, there could be

be a prior history of antecedent thyroid disease, radioiodine therapy or thy
roidectomy, or thyroid hormone therapy that was inappropriately discontinued.
Thus, physical examination may show a surgical scar on the neck
and no palpable thyroid tissue, or there could be a goiter. Much more rarely,
in perhaps 5% of cases of myxedema coma, the underlying cause is hypotha
lamic or pituitary disease rather than primary thyroid failure as the cause of
hypothyroidism. One patient was reported who proved to have myxedema
coma attributable to primary thyroid failure and pituitary insufficiency
from Sheehan syndrome [7]. For a clinical profile, it is useful to examine
the 24 patients (20 women and 4 men, mean age of 73 years) with myxedema
coma reported from a hospital survey in Germany (although the authors
reclassified 12 patients as having severe hypothyroidism but not coma) [8].
There was underlying primary hypothyroidism in 23 (previously recognized
in 9) patients and central hypothyroidism in 1. Presenting findings included
hypoxemia in 80%, hypercapnia in 54%, and hypothermia with a temperature
less than 94 F in 88%. Six patients (25%) died in spite of treatment
with thyroid hormone.

Neuropsychiatric manifestations

In patients with myxedema coma, there may be a history of lethargy,

slowed mentation, poor memory, cognitive dysfunction, depression, or
even psychosis, as can also be seen in patients with uncomplicated hypothy
roidism. They do not complain of these symptoms, however, because of
their impaired state of consciousness. Focal or generalized seizures may
be seen in up to 25% of patients, possibly related to hyponatremia,
hypoglycemia, or hypoxemia because of reduced cerebral blood flow [9].

Hypothermia

As noted previously [8], hypothermia is present in virtually all patients.

and may be quite profound (!80 F). In many of the reported cases,
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690 WARTOFSKY

hypothermia was the first clinical clue to the diagnosis of myxedema coma.
The ultimate response to therapy and survival has been shown to correlate
with the degree of hypothermia, with the worst prognosis in patients with
a core body temperature less than 90 F.

Cardiovascular manifestations

Typical cardiovascular findings in myxedema coma as well as in hypothy

roid heart disease include nonspecific electrocardiographic abnormalities,
cardiomegaly, bradycardia, and reduced cardiac contractility. One recent
case report described a patient who presented with prolonged QT and
polymorphic ventricular tachycardia (torsades de pointe) [10]. Low stroke
volume and cardiac output occur as a result of the reduction in cardiac
contractility, but frank congestive heart failure is rare. Cardiac enlargement
may be real and attributable to ventricular dilatation or could represent
a pericardial effusion. Hypotension may be present because of decreased
intravascular volume and cardiovascular collapse, and shock may occur
late in the course of the disease. In shock, the hypotension may be refractory
to vasopressor therapy unless thyroid hormone is also being given.

respiratory system

The reduced hypoxic respiratory drive and decreased ventilatory response

to hypercapnia known to occur in hypothyroidism [11] are likely responsible
for the respiratory depression commonly seen in myxedema coma, but im
paired respiratory muscle function and obesity may exacerbate the
hypoventilation [12–14]. The respiratory depression leads to alveolar hypoventilation
and progressive hypoxemia and, ultimately, to carbon dioxide narcosis and
eat. Although there are many contributing causes to the coma in these
patients, the main factor seems to be a depressed respiratory center.
response to carbon dioxide [15,16]. Mechanically assisted ventilation is
required in most patients, irrespective of the cause of the respiratory
depression and hypoventilation. Respiration may be impaired in these patients as
well by the presence of pleural effusions or ascites, by reduced lung volume,
and by macroglossia and edema (myxedema) of the nasopharynx and larynx,
which serve to reduce the effective airway opening. Even after initiation
of thyroid hormone therapy, assisted ventilation may have to be continued
because of delayed recovery [17].

Gastrointestinal manifestations

Patients with myxedema coma may have anorexia, nausea, abdominal

pain, and constipation with fecal retention. A distended quiet abdomen
may be present, reduced intestinal motility is common, and paralytic ileus
and megacolon may occur. A type of neurogenic oropharyngeal dysphagia
has been described that is associated with delayed swallowing, aspiration,
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MYXEDEMA COMA 691

and risk of aspiration pneumonia [18]. Gastric atony, if present, may serve
to reduce absorption of oral medications.

infections

Because hypothermia is the rule in myxedema coma, the presence of

a ''normal'' temperature should be a clue to underlying infection. other
signs of infection, such as diaphoresis and tachycardia, are also absent. Pa
tients who fail to survive often have been shown to have had unrecognized
infection and sepsis. The possibility of an underlying infection should al ways
be considered while maintaining a low threshold for initiation of systemic
antibiotic coverage [19]. The presence of pneumonia also worsens or
even causes hypoventilation, and there is a heightened risk of pneumonitis
attributable to aspiration caused by neurogenic dysphagia, semicoma, or
seizures [9,18].

Renal and electrolyte manifestations

Patients may have bladder atony with urinary retention. hyponatremia

in any patient may cause lethargy and confusion, and hyponatremia and
a reduced glomerular filtration rate are consistent findings in patients with
myxedema coma. The hyponatremia results from an inability to excrete
a water load, which is caused by decreased delivery of water to the distal
nephron [20] and excess vasopressin secretion [21]. Urinary sodium excretion
is normal or increased, and urinary osmolality is high relative to plasma
osmolality.

Diagnosis

The probable diagnosis of myxedema coma should readily come to

mind, given a patient with a history of or physical findings compatible
with hypothyroidism in the presence of stupor, confusion, or coma, especially
in the setting of hypothermia. Given a reasonable index of suspicion,
therapy with thyroid hormone should be begun immediately, while awaiting the
results of measurements of serum thyrotropin (TSH) and thyroxine
(T4). In elderly patients, however, especially those with underlying cardiac
disease, thyroid hormone therapy should be undertaken more cautiously
because of the risks. Given the presence of the previously mentioned ab
normalities that are characteristic of myxedema coma, such as hypothermia,
hypoventilation, and hyponatremia in a lethargic, somnolent, or
comatose patient, however, the diagnosis must be entertained, appropriate
blood tests drawn and sent to the laboratory, and therapy initiated. In deed, in
many patients, the clinical features may be sufficiently clear to
make measurements of serum TSH and T4 necessary only for confirmation
of the diagnosis.
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Today, in most hospitals, both hormones can be measured in several

hours on a routine basis or, if necessary, should be so requested on an
emergency basis. Although markedly elevated serum TSH would be expected,
patients with severe nonthyroidal systemic illness may demonstrate a phe
nomenon parallel to the ''euthyroid sick'' syndrome [22], which can be called
the ''hypothyroid sick'' syndrome. In such circumstances, pituitary TSH
secretion is reduced and the blood levels may not be as high as one might
otherwise expect [22,23]. As mentioned previously, approximately 5% of cases
of myxedema coma are diagnosed on the basis of central hypothyroidism
and could have normal or low serum TSH concentrations. irrespective of
whether the disease is primary or secondary thyroid failure, all patients
with myxedema coma have low serum total and free T4 and tri iodothyronine
(T3) concentrations. In patients with the hypothyroid sick
syndrome, serum T3 levels may be unusually low (!25 ng/mL).

Treatment

Therapy with thyroid hormone alone without addressing all the other
metabolic derangements described previously would likely be inadequate
for recovery. Because of the potentially high mortality without vigorous
multifaceted therapy, all patients should be admitted to an intensive care
unit to permit continuous close monitoring of their pulmonary and cardiac
status. A central venous pressure line should be used to monitor volume
repletion therapy, and a pulmonary artery catheter should be inserted in
patients with cardiac disease.

Ventilatory support

Thorough attention to an evaluation of respiratory function should include

assessment of pulmonary function (blood gas measurements) and
physical examination and imaging to rule out pneumonia or airway obstruction
attributable to macroglossia or myxedema of the larynx. Insertion of an
endotracheal tube or performance of a tracheostomy may be required to
achieve adequate oxygenation. Given that an open upper airway is ensured,
mechanical ventilatory support is required to relieve or prevent hypoxemia
and hypercapnia and antibiotic therapy should be considered. mechanical
ventilatory support is typically required for 24 to 48 hours, especially in
patients whose hypoventilation and coma result from drug-induced respiratory
depression, and some may patients require it for several weeks [17]. Fre
quent monitoring of arterial blood gases is warranted during the period of
ventilatory support, and extubation should not be considered until the patient
is fully conscious. On those rare occasions when a patient with myx edema
coma might require emergency surgery, management should follow
these same general principles [24].
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Hypothermia

External warming of patients with hypothermia with an electric blanket is

advisable but should be done cautiously because of the risk of hypotension
caused by vasodilatation with a fall in peripheral vascular resistance. Therapy
with thyroid hormone is absolutely essential for ultimate restoration of
normal body temperature, but the amelioration of hypothermia by thyroid
hormone may take several days.

Hypotensive

Because external warming may worsen hypotension, it should be

preceded and accompanied by careful intravenous volume repletion, initially
with 5% to 10% glucose in half-normal saline or as isotonic sodium chloride
if hyponatremia is present. Some patients require vasopressors to maintain
their blood pressure until thyroid hormone action begins. Because of
its nonspecific presumed effects on vascular stabilization, hydrocortisone
(100 mg administered intravenously every 8 hours) is usually administered
and is definitely warranted if pituitary disease or concomitant primary adrenal
insufficiency is suspected.

hyponatremia

A dilemma that may arise in these patients relates to the need to

administer ister fluids for hypotension and the indication for fluid restriction
for hypo natremia. A cautious approach would be to administer some saline (and
glucose) intravenously to replace daily losses in the comatose patient but
to limit the volume in those with only mild to moderate hyponatremia (serum
sodium concentrations of 120–130 mEq/L) such that all water lost is
not replaced. Conversely, if the serum sodium concentration is less than
120 mEq/L, it may be appropriate to administer a small amount of hyper
tonic saline (3% sodium chloride, 50–100 mL), followed by an intravenous
bolus dose of furosemide (40–120 mg) to promote water diuresis [25].
Hyponatremia undoubtedly contributes to the mental status changes in patients
with myxedema coma, especially in patients with serum sodium concentrations
less than 120 mEq/L.

Glucocorticoid therapy

As mentioned previously, steroid therapy is indicated in those patients

with myxedema coma attributable to pituitary or hypothalamic disease be
cause they may have corticotropin deficiency as well as TSH deficiency.
Primary adrenal insufficiency could be present in patients with primary
hypothyroidism caused by Hashimoto disease on an autoimmune basis
(Schmidt syndrome). There may be other clinical and laboratory clues to
the coexistence of adrenal insufficiency in patients with myxedema coma,
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694 WARTOFSKY

such as hypotension, hypoglycemia, hyponatremia, hyperkalemia, hypercal

cemia, lymphocytosis, and azotemia. In most patients with myxedema
coma, the serum cortisol concentrations are within the reference range.
It is generally deemed prudent to treat with hydrocortisone because of the
possibility of coexisting primary or secondary adrenal insufficiency but also
Because of the possibility that thyroid hormone therapy may increase cortisol
clearance and precipitate adrenal insufficiency. Hydrocortisone usually is
given intravenously (50–100 mg every 6 to 8 hours for several days), after
which it is tapered and discontinued on the basis of clinical response and
plans for further diagnostic evaluation. Such short-term glucocorticoid
therapy is safe and can be discontinued when the patient has improved and
pituitary-adrenal function has been assessed to be adequate.

Myxedema coma and surgery

A brief consideration of operative intervention in the myxedematous

patient may be of interest to some readers. Although elective surgery would be
out of the question in a patient with myxedema coma, the situation might
present on occasion because the diagnosis was made during the
postoperative recovery period, as might often be the case in emergency
surgery. Myx edema coma has also been described during obstetric labor [26]. the genera
perioperative management of patients with hypothyroidism has been re
viewed [27], and some of the issues have been described in case reports
[28]. Perhaps the most important postoperative issue is the maintenance
of an open airway [29,30], and this must be closely monitored in the recovery
room.

Thyroid hormone therapy

Patients with myxedema coma need thyroid hormone and die without it.
Nevertheless, although the need to treat these patients with thyroid hormone
is so patently obvious, the regimen by which to conduct this treatment
remains somewhat controversial. The question is how to restore the low se
rum and tissue thyroid hormone concentrations to normal safely, and the
controversy, simply put, relates to whether to administer T4 or T3. On
the basis of provision of the organism's need for T3, based on the physio
logic monodeiodination of T4 and its conversion to T3, we universally
aver that therapy of ''garden variety'' hypothyroidism is best done with
T4 alone. An important potential drawback to total reliance on the generation
of T3 from T4 is that the rate of extrathyroidal conversion of T4 to T3
is reduced in the sick hypothyroid patient [22]. Perhaps in favor of T3 ther
apy is the fact that its onset of action is considerably more rapid than that of
T4, which could increase chances for survival [25]. An earlier beneficial effect
on neuropsychiatric symptoms may be inferred from studies in baboons
showing that T3 crosses the blood-brain barrier more readily than it does
T4 [31].
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Whether one is administering T4 or T3, additional concerns relate to the

dosage, frequency, and route of administration. We need to choose an ap
proach to thyroid hormone therapy that balances concern for the high mor
tality of untreated myxedema coma against the risks of high-dose thyroid.
hormone therapy, which may include atrial tachyarrhythmias or myocardial
infarction. Given the high mortality, we believe that there is a benefit to
achieving effective tissue levels of the thyroid hormones as quickly as
possible. No one really knows what constitutes the optimal therapeutic approach,
however, and recommendations tend to be empirical at best. One argument
for using T4 is that serum levels are easier to measure than are those for se
rum T3, but this is really not the case any longer in modern laboratories.
Serum T4 measurements may be easier to interpret, however, because the
values do not vary as much between doses as would serum T3 values. T4
therapy may also provide a steadier and smoother, albeit slower, onset of
action with a lower risk of adverse effects. Conversely, the onset of action
of T3 is quicker, and its serum (and probably tissue) concentrations fluctuate
more between doses. In either case, monitoring serum TSH values can
provide the information necessary to adjust dosage to achieve the desired
impact of treatment at the tissue level. In the comatose patient, it is necessary
to give the thyroid hormone by nasogastric (NG) tube or by parenteral
injection. Risks of aspiration and uncertain absorption obtained when
administered by NG tube, particularly in patients with gastric atony. Parenteral T4
preparations are available in vials containing 100 and 500 mg. A high single
intravenous bolus dose (usually 300–600 mg) has been used for decades,
based on a report suggesting that replacement of the entire extrathyroidal
pool of T4 was desirable to restore near-normal hormonal status as rapidly
as possible An average estimate of total body T4 is 500 mgdhence, that
initial dose. Thereafter, the body T4 pool is maintained by administration of
50 to 100 mg daily given intravenously or orally [32]. With the large initial
dosage, serum T4 concentrations rapidly rise to supranormal values and
then fall to within the normal reference range in 24 hours. In sequence, as
T4 is converted to T3, the serum T3 concentrations begin to rise and serum
TSH concentrations start falling [33].
In a relatively recent report, Rodriguez and colleagues [34] described their
success using a large initial loading dose of T4 as recommended by Nicoloff
and LoPresti [5] and Holvey and coworkers [32]. Patients randomly received
a loading dose of 500 mg administered intravenously, followed by a daily
maintenance dose of 100 mg administered intravenously, or just the
maintenance dose. Four of the 11 patients had a fatal outcome, only 1 of whom
had received high-dose T4. Mortality correlated with the severity of
concomitant illness, with an Acute Physiology, Age, Chronic Health Evaluation
(APACHE) score of greater than 20 indicating a potentially poor outcome.
Surviving patients tended to be younger and to have better Glasgow Coma
Scale scores. T3 is available for intravenous administration in vials containing
10 mg. When given alone, the usual dose is 10 to 20 mg, followed by 10 mg
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696 WARTOFSKY

every 4 hours for the first 24 hours and then 10 mg every 6 hours for 1 or 2
days; by that time, the patient should be alert enough to continue therapy by
the oral route. Measurable increases in body temperature and oxygen
consumption occur within 2 to 3 hours after intravenous administration of T3
but may take 8 to 14 hours or longer after intravenous administration of T4.
These changes after T3 therapy are likely to be accompanied by significant
clinical improvement within 24 hours [35] but at a greater risk of adverse
cardiovascular side effects. In fact, in one report, high serum T3 concentrations
during treatment with T3 alone were associated with a fatal outcome.
in several patients [36]. This outcome is difficult to assess, because, as
mentioned previously, myxedema coma may be associated with high mortality
rates in spite of treatment. Thus, in another series of 8 patients, 2 of 3
patients treated with high-dose T3 died of pneumonia, whereas the other 5
who were treated with smaller doses of T4 or T3 survived [37]. When reported
cases in the literature were analyzed for associations with mortality,
it was seen that advanced age, high-dose T4 therapy, and cardiac
complications had the highest association with mortality. The authors concluded that
a 500-mg dose of T4 should be safe in younger patients but that lower doses
should be considered in elderly patients. Consequently, I have personally
adopted what I believe to be a prudent but effective approach to therapy,
and that is to administer T4 and T3. T4 is given intravenously at a dose
of 4 mg/kg of lean body weight (or approximately 200–250 mg), followed
by 100 mg 24 hours later and then 50 mg daily intravenously or orally, as ap
propriate. Adjustment of the dose is based on subsequent clinical and
laboratory results, as in any other hypothyroid patient. With respect to T3, the
initial intravenous dose is 10 mg, and the same dose is given every 8 to 12
hours until the patient can take maintenance oral doses of T4.
This approach is not offered as the optimal or preferred manner of
treatment with thyroid hormone but rather as one that makes physiologic sense.
in regard to safety and efficacy. No general guide to treatment can take into
account all the factors that might affect sensitivity to thyroid hormone, such
as age, intrinsic cardiovascular function, neuropsychiatric status, and co
morbid conditions that may affect drug dosages because of alterations in
drug distribution and metabolism. Hence, patients should be monitored
closely before each dose of thyroid hormone is administered.
With aggressive comprehensive treatment, most patients with myxedema
comma should recover. It is better, however, that it is prevented by the early
recognition and treatment of hypothyroidism.

Summary

Myxedema coma is the term given to the most severe presentation of pro
found hypothyroidism and is often fatal in spite of therapy. Decompensation
of the hypothyroid patient into a coma may be precipitated by
a number of drugs, systemic illnesses (eg, pneumonia), and other causes.
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It typically presents in older women in the winter months and is associated

with signs of hypothyroidism, hypothermia, hyponatremia, hypercarbia,
and hypoxemia. Treatment must be initiated promptly in an intensive care
unit setting. Although thyroid hormone therapy is critical to survival, it re
mains uncertain whether it should be administered as T4, T3, or both.
Adjunctive measures, such as ventilation, warming, fluids, antibiotics, pressors,
and corticosteroids, may be essential for survival.

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