Therapeutic Advances in Endocrinology and Metabolism

Endocrine and metabolic emergencies:

thyroid storm

Review

Ther Adv Endocrinol

Metab
(2010) 1(3) 139145
DOI: 10.1177/
2042018810382481
! The Author(s), 2010.
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Richard Carroll and Glenn Matfin

Abstract: Thyrotoxicosis is a common endocrine condition that may be secondary to a number

of underlying processes. Thyroid storm (also known as thyroid or thyrotoxic crisis) represents
the severe end of the spectrum of thyrotoxicosis and is characterized by compromised organ
function. Whilst rare in the modern era, the mortality rate remains high, and prompt consideration of this endocrine emergency, with specific treatments, can improve outcomes.
Keywords: hyperthyroidism, thyroid storm, thyrotoxic crisis, thyrotoxicosis

Introduction
Thyroid storm (also known as thyroid or thyrotoxic crisis) is an uncommon condition reflecting
an extreme physiological state within the spectrum of thyrotoxicosis. The condition is rare,
however, mortality rates are high and may
approach 1020%. Thyroid storm is most commonly seen in the context of underlying Graves
hyperthyroidism but can complicate thyrotoxicosis of any aetiology. Clinical features represent
manifestations of organ decompensation, with
fever seen almost universally. Management is
supportive with cooling and fluids, alongside
measures taken to reduce thyroid hormone synthesis, hormone release and inhibition of the
peripheral effects of excessive thyroid hormone.
In addition, the management of thyroid storm
should not disregard the search and appropriate
treatment of any precipitating factors.

Pathophysiology
Normal thyroid function is maintained by endocrine interactions between the hypothalamus,
anterior pituitary and thyroid gland [Matfin,
2009]. Iodide is transported across the basement
membrane of the thyroid cells by an intrinsic
membrane protein called the Na/I symporter
(NIS). At the apical border, a second iodide
transport protein called pendrin moves iodide
into the colloid, where it is involved in hormonogenesis. Once inside the follicle, most of the
iodide is oxidized by the enzyme thyroid peroxidase (TPO) in a reaction that facilitates combination with a tyrosine molecule to ultimately

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form thyroxine (T4) and triiodothyronine (T3).

Thyroxine is the major thyroid hormone secreted
into the circulation (90%, with T3 composing
the other 10%). There is evidence that T3
is the active form of the hormone and that T4
is converted into T3 before it can act
physiologically.
All of the major organs in the body are affected
by altered levels of thyroid hormone. These
actions are mainly mediated by T3. In the cell,
T3 binds to a nuclear receptor, resulting in transcription of specific thyroid hormone response
genes.

Correspondence to:
Richard Carroll, MB ChB
Hammersmith Hospital,
Imperial College,
London, UK
richard.carroll@
imperial.nhs.uk
Glenn Matfin, MSc (Oxon),
MB ChB, FFPM, FACE,
FACP, FRCP
Joslin Diabetes Center,
Harvard Medical School,
Boston, MA, USA; and
Division of Endocrinology,
New York University
School of Medicine New
York, NY, USA

Thyrotoxicosis is the clinical syndrome that

results when tissues are exposed to high
levels of circulating thyroid hormone. In most
instances, thyrotoxicosis is due to hyperactivity
of the thyroid gland, or hyperthyroidism
[Weetman, 2009]. Graves disease, an autoimmune thyroid disease associated with thyroid-stimulating hormone (TSH)-receptor stimulating
antibodies, is the most common form of thyrotoxicosis leading to thyroid storm, whilst other
causes of thyrotoxicosis such as toxic multinodular goitre and toxic adenoma are less-frequent
causes.
Thyroid storm is an acutely exaggerated manifestation of the thyrotoxic state. Many of the manifestations of thyrotoxicosis are related to the
increase in oxygen consumption and use of metabolic fuels associated with the hypermetabolic
state, as well as to the increase in sympathetic

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Therapeutic Advances in Endocrinology and Metabolism 1 (3)

nervous system activity that occurs. The detailed
pathophysiology of thyroid storm is not fully
understood, but is thought to be related to
increased numbers of beta1-adrenergic receptors
being exposed to increased catecholamine levels
in states of stress. Displacement of free thyroid
hormones by circulating inhibitors of binding
in systemic illness (e.g. cytokines) may also play
an important role.

of effective life-saving treatment. Furthermore,

biochemical markers of thyroid function are not
discernably different from thyrotoxic states without thyroid storm. Serum thyroid hormone levels
(i.e. free T3 [FT3] and free T4 [FT4]) are elevated with suppressed TSH levels (with the rare
exceptions being states of thyroid hormone resistance or TSH secreting pituitary adenomas)
confirming the diagnosis of thyrotoxicosis.

Aetiology
Thyroid storm is most commonly associated with
underlying Graves disease, although has been
reported with autonomous thyroid nodular disease. Traditionally, the condition was experienced frequently following thyroidectomy for
thyrotoxic state (due to manipulation of the
hyperactive thyroid gland during surgery), but
modern treatments aimed at reducing preoperative thyroid output and hormone stores have
dramatically reduced this complication.

As noted previously, in most situations thyroid

storm occurs in the context of a superimposed
insult with an underlying predisposition to thyrotoxicosis. Therefore, an immediate search should
begin for precipitating factors such as infection or
other causes. Pregnancy should be excluded
urgently in any woman of childbearing age with
urinary or plasma assessment of human chorionic
gonadotropin (HCG) levels and an ECG and
cardiac enzymes should be procured to exclude
acute coronary syndromes (ACS). Other investigations should be promptly performed as per
clinical circumstances.

Regardless of the underlying aetiology of thyrotoxicosis, the rare transition to a state of thyroid
storm usually requires a second superimposed
insult. Most commonly this is infection, although
trauma, surgery, myocardial infarction (MI),
diabetic ketoacidosis (DKA), pregnancy and
parturition have been reported as causes. The
administration of large quantities of exogenous
iodine (such as with iodinated contrast agents
or amiodarone) can provide the substrate for
significant thyroid hormone production and
secretion if there are areas of autonomous thyroid
tissue within the gland (i.e. Jod-Basedow phenomenon). Abrupt cessation of thionamide
therapy (i.e. antithyroid drugs such as propylthiouracil [PTU], methimazole and carbimazole) usually due to poor patient adherence or
other issues has been associated with worsening
thyrotoxicosis and rarely descent into thyroid
storm. Biological agents such as interleukin-2
and a-interferon have been reported to induce
thyroid storm when used to treat infectious disease, certain cancers and disorders of immune
function.

Diagnostic considerations
The diagnosis of thyroid storm must be made on
the basis of suspicious but nonspecific clinical
findings. If the diagnosis of thyroid storm is
strongly suspected, waiting for the results of
tests may cause a critical delay in the initiation

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Clinical signs and features

Thyroid storm by definition represents the
extreme in the spectrum of thyrotoxicosis where
decompensation of organ function can occur.
Therefore any of the classical signs and symptoms of a thyrotoxic state may be seen. The scoring system suggested by Burch and Wartofsky
(Table 1) illustrates the typical features of end
organ dysfunction that may be seen when thyrotoxicosis is severe enough as to be termed thyroid
storm [Burch and Wartofsky, 1993]. Fever is
almost universal (>39 C or 102 F) and when
present in an unwell patient with known thyrotoxicosis, should prompt immediate consideration of thyroid storm. Associated profuse
sweating contributes to excessive insensible
water and electrolyte loss leading to dehydration.
Cardiac decompensation, usually in the context
of high-output cardiac failure, is manifested as
evidence of peripheral oedema or pulmonary
congestion with respiratory compromise when
severe. Tachyarrhythmias are common and
usually atrial in origin, unless there is a predisposition to ventricular arrhythmias secondary to primary cardiac disease. Neurological dysfunction
may be severe enough as to cause profound delirium or psychosis. Liver dysfunction, secondary
to either the presence of cardiac failure with
hepatic congestion or hypoperfusion, or a direct
effect of the excess thyroid hormone itself, is

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R Carroll and G Matfin

Table 1. Diagnostic criteria for thyroid storm.
Clinical feature

Scoring points

Thermoregulatory dysfunction
Temperature  F ( C)
9999.9 (37.237.7)
100100.9 (37.838.2)
101101.9 (38.338.8)
102102.9 (38.939.4)
103103.9 (39.539.9)
104 (40)

5
10
15
20
25
30

Cardiovascular dysfunction
Tachycardia (beats per minute)
<99
99109
110119
120129
130139
140

0
5
10
15
20
25

Congestive heart failure

Absent
Mild (Pedal oedema)
Moderate (Bibasal rales or crackles)
Severe (Pulmonary oedema)

0
5
10
15

Atrial fibrillation
Absent
Present

0
10

Central nervous system dysfunction

Absent
Mild (Agitation)
Moderate (Delirium, psychosis, extreme lethargy)
Severe (Seizures, coma)

0
10
20
30

Gastrointestinal-hepatic dysfunction
Absent
Moderate (Diarrhoea, nausea/vomiting, abdominal pain)
Severe (Jaundice)

0
10
20

Previous episode of thyroid storm

Absent
Present
Total
>45
2544
<25

0
10
Highly likely thyroid storm
Suggestive of impending storm
Unlikely to represent storm

Adapted from Burch and Wartofsky [1993].

characterized by abnormal liver function biochemistry. Jaundice may be noted, and abdominal pain is often seen accompanied by nausea and
vomiting, and diarrhoea.
Elderly patients often present atypically
(so-called apathetic thyroid storm), with apathy,
stupor, cardiac failure, coma and minimal signs
of thyrotoxicosis.

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Acute intervention
Once thyroid storm is recognized the patient
should be managed in an appropriate location
such as an Acute Medical Unit (AMU),
high-dependency area or intensive care unit. As
with all acute medical patients, prompt assessment and management of the ABCDEs should
occur (i.e. airway; breathing; circulation; disability, i.e. conscious level; and examination).

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General supportive care
Supportive care includes cooling measures, appropriate intravenous (IV) fluid resuscitation, electrolyte replacement and nutritional support.
Antipyretics can be administered to relieve the distress of profound pyrexia, but salicylates (e.g. aspirin) should be avoided as they are associated with
displacement of thyroid hormone binding from
thyroid binding globulin (TBG) (Table 2).
Tachyarrhythmias, if associated with haemodynamic instability (e.g. hypotension), should be
managed as an urgent matter with cardioversion
by defibrillation. Otherwise, appropriate antiarrhythmic therapy and treatment of the underlying
condition and complications would be warranted.
Ventilatory support, either with noninvasive

positive pressure ventilation (NIPPV) or intubated

ventilation, should be performed if required based
on arterial blood gas (ABG) analysis and other
assessments. Occasionally patients will be severely
agitated limiting further intervention, and in these
situations a sedative such as haloperidol or a benzodiazepine can be given, mindful of the possible
deleterious respiratory effects of these agents.
Chlorpromazine 50100 mg orally or intramuscular (IM) every 6 hours as needed, has the additional benefit of reducing body temperature
through effects on central thermoregulation.
Nutritional support is important (including vitamin replacement, e.g. thiamine) and includes
close monitoring of glucose levels (as liver glycogen stores are depleted during thyroid storm).

Table 2. Medical management of thyroid storm.

Medication
Inhibition of hormone synthesis
Propylthiouracil (PTU)

Dose

Notes

600 mg loading dose, followed by

200250 mg PO q4-6h

Additional inhibition of peripheral

deiodination However, recent warning
from FDA regarding severe liver
toxicity with PTU makes either
carbimazole or methimazole
first-choice thionamide

Carbimazole (or methimazole)

2030 mg PO q4-6h

Inhibition of hormone release

SSKI (Potassium Iodide)

5 drops PO q6-8h

Lugols Solution
Iapanoic Acid

510 drops PO q6-8h

In UK, 1 ml PO q6h
1000 mg IV q8h for 24 h, followed
by 500 mg bd

Inhibition of peripheral effects of excess thyroid hormone

Propranolol
12 mg/min IV q15min up to
max 10 mg 4080 mg PO q4-6h
Esmolol
50 mg/kg/min IV may increase by
50 mg/kg/min q4min
as required to a max of 300 mg/kg/min.
Metoprolol
100 mg PO q6h
Diltiazem
6090 mg PO q6-8h

Supplementary management
Hydrocortisone
Dexamethasone
Acetaminophen (commonly known
as paracetamol or Tylenol)

100 mg IV q6h
2 mg IV q6h
1 g PO q6h

Additional therapies
Lithium Carbonate
Potassium perchlorate

300 mg PO q8h
1 g PO od

Cholestyramine

4 g PO q6-12h

Administer at least 1 hour

after thionamide
Administer at least 1 hour
after thionamide
Administer at least 1 hour after
thionamide, infrequently available
IV dose initially if haemodynamically
unstable
Short acting
Cardioselective; use if known
airways disease
Use if beta-blockers contraindicated
IV formulation available

Care if significant hepatic dysfunction

Monitor for toxicity

Associated with aplastic anaemia
and nephritic syndrome

PO, oral; IV, intravenous; q4-6h, every 46 hours; q6h, every 6 hours; q8h, every 8 hours; q4min, every 4 minutes; q15min, every 15 minutes;
od, once daily; bd, twice daily.

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R Carroll and G Matfin

Thyroid-specific therapy
The immediate goals when treating thyroid storm
are to decrease thyroid hormone synthesis, prevent thyroid hormone release, decrease peripheral action of circulating thyroid hormone to
reduce heart rate and support the circulation,
and to treat the precipitating condition [Nayak
and Burman, 2006]. The therapeutic options
for thyroid storm are the same as those for
uncomplicated thyrotoxicosis, except that the
drugs are given in higher doses and more
frequently. When treating thyroid storm, one
should consider the five Bs: Block synthesis
(i.e. antithyroid drugs); Block release (i.e.
iodine); Block T4 into T3 conversion (i.e. highdose propylthiouracil [PTU], propranolol,
corticosteroid and, rarely, amiodarone); Betablocker; and Block enterohepatic circulation
(i.e. cholestyramine).
An antithyroid drug (i.e. thionamide) should be
administered immediately to prevent the formation of further thyroid hormone by inhibiting the
iodination of tyrosine residues by TPO enzymes.
PTU or carbimazole (or methimazole) can be
used, but PTU was traditionally preferred
because of its more rapid onset of action and
the additional benefit of inhibition of peripheral
deiodinase enzyme-mediated conversion of T4
into T3. PTU should be administered orally or
via a nasogastric (NG) tube in the unresponsive
patient with a loading dose of 600 mg followed by
a dose of 200250 mg every 46 hours.
Carbimazole (or methimazole) is administered
at a dose of 2030 mg every 46 hours. Both
agents can be administered rectally if needed.
However,
the
US
Food
and
Drug
Administration (FDA) have recently released an
advisory on PTU for its liver toxicity potential
[Food and Drug Administration, 2010]. As no
head-to-head trial has demonstrated clear superiority of PTU over either carbimazole or methimazole in thyroid storm (or thyrotoxicosis, where
the latter agents are generally preferred over
PTU), many experts now recommend using
either carbimazole or methimazole in all thyrotoxic patients (unless other compelling reasons
exist for using PTU such as pregnancy), and
achieving T4 into T3 conversion inhibition
solely with beta-blockers and corticosteroids
[Food and Drug Administration, 2010;
Malozowski and Chiesa, 2010].
Iodine should be administered at least 1 hour
after the thionamide to block the release of

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preformed thyroid hormone. This apparent paradox makes use of the acute WolffChaikoff
effect, whereby large doses of iodine suppress
thyroid hormone release. The effect lasts for up
to 2 weeks, because escape from this effect occurs
and is therefore unsuitable as a long-term therapeutic option. The thionamide should be administered prior to iodine administration so as to
prevent undesired tyrosine residue iodination
and enrichment of thyroid hormone stores. The
minimal time required between thionamide
administration and iodine treatment is debated
with 16 hours commonly prescribed. Iodine is
administered in the various formulations, including saturated solution of potassium iodide
(SSKI) 5 drops orally every 68 hours (equalling
250 mg iodide with 1 drop containing 50 mg
iodide). Alternatively, 510 drops of Lugols
solution orally every 68 hours can be used. In
the UK, many experts prescribe 1 ml of Lugols
solution orally every 6 hours. Iapanoic acid, an
iodinated contrast agent, although rarely available now, is effective at a dose of 1g IV
8-hourly for the first 24 hours of treatment followed by 500 mg twice daily.
Beta-blockade should be instigated immediately
(unless contraindicated) so as to block the adrenergic consequences of thyroid hormone excess.
Propranolol (i.e. non-cardiac specific betablocker) has traditionally been used and has the
advantage of being suitable for IV administration
and is also relatively short acting. IV propranolol
at a dose of 12 mg/min can be administered
every 15 minutes until adequate haemodynamic
control is achieved or a maximum dose of 10 mg
is used, followed by 4080 mg orally every
46 hours. Caution is warranted in patients
with heart failure, although beta-blockade may
be beneficial when tachycardia is a significant
precipitant to decompensated cardiac function.
Esmolol, a short-acting beta-blocker, can be
used as an alternative if a deleterious cardiac
effect is anticipated and is given IV at a rate of
50 mg/kg/min and increased as per response.
Contraindications to propranolol use include a
history of asthma or reversible chronic obstructive pulmonary disease (COPD), and a cardioselective beta-blocker such as metoprolol or
atenolol could be used in these patients.
Alternatively, the calcium-channel blocker,
diltiazem can be used at a dose of 6090 mg
orally 68-hourly or the appropriate dose by
IV. If anticoagulation is required for atrial fibrillation (or other indications), thyrotoxic patients

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Therapeutic Advances in Endocrinology and Metabolism 1 (3)

are very sensitive to warfarin and should be monitored closely.
Corticosteroids inhibit peripheral conversion of
T4 into T3 and have been shown to improve outcomes in patients with thyroid storm. Adrenal
axis dysfunction in the context of thyrotoxicosis
of any degree is documented, and responds to
exogenous steroid therapy. Hydrocortisone
100 mg 6-hourly should be administered IV or
IM and continued until resolution of the thyroid
storm. Alternatively, dexamethasone 2 mg IV
every 6 hours can be used. Treatment should
be tapered appropriately based on the required
duration of steroid therapy.
Lithium carbonate, at a dose of 300 mg every
8 hours, can be used when there is a contraindication or previous toxicity to thionamide therapy.
Lithium inhibits thyroid hormone release from
the gland and reduces iodination of tyrosine
residues, but its use is complicated by the toxicity that can ensue. Potassium perchlorate competitively inhibits iodide transport into the
thyrocyte but has traditionally been associated
with aplastic anaemia and nephritic syndrome.
Several studies however have demonstrated its
use when used over short periods in the treatment of amiodarone-induced thyrotoxicosis
[Erdogan et al. 2003]. A suggested dose is 1 g
daily and, similarly to iodide therapy, should be
combined with a thionamide. Cholestyramine 4 g
orally two to four times each day has been used in
the management of thyrotoxicosis due to reduced
reabsorption of metabolized thyroid hormone
from the enterohepatic circulation [Tsai et al.
2005].
Thyroidectomy is occasionally employed in
the management of thyroid storm refractory to
medication [Nayak and Burman, 2006], but is
associated with a risk of storm exacerbation if
preoperative thyroid hormone levels are high.

Treatment of precipitating illness

Management of thyroid storm should not disregard the search for and treatment of precipitating
factors. An active search should be made for
infection and antibiotics chosen on the basis of
likely pathogens or microbial cultures. Other
likely precipitants such as trauma, MI, DKA,
and other underlying processes should be
managed as per standard care.

144

Maintenance therapy
Through adequate rehydration, repletion of
electrolytes, treatment of comorbid disease
such as infection and the use of specific therapies (antithyroid drugs, iodine, beta-blockers
and corticosteroids), a marked improvement in
thyroid storm usually occurs within 2472
hours. Once haemodynamic, thermoregulatory
and neurological stability has been achieved
attention should switch to maintenance therapy.
Escape from the WollfChaikoff effect is usually
seen between 10 and 14 days after commencement of iodine therapy, and therefore continuation of iodine therapy beyond this point is
unlikely to be beneficial and could exacerbate
the situation. Furthermore, future treatment
with radioactive iodine (RAI) is delayed if thyroid iodine stores are saturated. Corticosteroid
therapy should be stopped as soon as possible,
but beta-blockade should be used whilst the
patient remains thyrotoxic.
The antithyroid treatment should be continued
until euthyroidism is achieved, at which point
a final decision regarding antithyroid drugs,
surgery or RAI therapy can be made.
Emerging treatments
Thyroid storm can occasionally be refractory
despite the above measures, and other treatment
options should be considered. Plasmapharesis,
with removal of thyroid hormone, has been used
successfully both in the thyrotoxic state and to
prepare those with thyrotoxicosis for surgery
[Ezer et al. 2009]. However, plasmapharesis
needs to be repeated several times as only about
20% of the T4 pool and even less of the T3 pool
can be removed each session. Charcoal haemoperfusion has also been demonstrated to be useful in
thyrotoxic states [Kreisner et al. 2010]. There is
great interest in the role of biological agents in
treatment of immune-mediated thyrotoxic states.
Rituximab (an anti-CD20 monoclonal antibody
which depletes B lymphocytes in circulation),
and various other emerging therapies have shown
promise in the treatment of Graves opthalmopathy, but the role of these agents in the management of the thyrotoxic state is less clear [Abraham
and Acharya, 2010; Bahn, 2010].
Conclusions
Thyroid storm is a rare endocrine emergency
but is associated with high mortality. It most
commonly occurs in the context of underlying
Graves thyrotoxicosis, but is frequently

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R Carroll and G Matfin

precipitated by a secondary event such as infection or MI. Prompt recognition of the condition
with timely intervention is crucial, and management of the patient in an AMU, high-dependency
or intensive care unit is essential. Treatment is
based on immediate blockade of thyroid hormone synthesis, prevention of the release of
further thyroid hormone from thyroid stores,
and alleviation of the peripheral effects of thyroid
hormone excess. A search for a precipitant for the
thyroid storm is critical and should be treated
promptly. Maintenance therapy takes into
account disease-specific factors and patient
preference, with measures taken to prevent a
recurrence of thyroid storm.
Funding
This article received no specific grant from
any funding agency in the public, commercial,
or not-for-profit sectors.

Erdogan, M.F., Gulec, S., Tutar, E., Baskal, N. and

Erdogan, G. (2003) A stepwise approach to the treatment of amiodarone-induced thyrotoxicosis. Thyroid
13: 205209.
Ezer, A., Caliskan, K., Parlakgumus, A., Belli, S.,
Kozanoglu, I. and Yildirim, S. (2009) Preoperative
therapeutic plasma exchange in patients with thyrotoxicosis. J Clin Apharesis 11: 111114.
Food and Drug Administration (2010)
Propylthiouracil tablets. http://www.fda.gov/Safety/
MedWatch/SafetyInformation/ucm209256.htm
(accessed 2 August 2010).
Kreisner, E., Lutzky, M. and Gross, J. (2010)
Charcoal hemoperfusion in the treatment of levothyroxine intoxication. Thyroid 20: 209212.
Malozowski, S. and Chiesa, A. (2010)
Propylthiouracil-Induced Hepatotoxicity and Death.
Hopefully, Never More. J. Clin. Endocrinol. Metab 95:
31613163.

Conflict of interest statement

None declared.

Matfin, G. (2009) Disorders of endocrine control

of growth and metabolism, In: Porth, C.M. and
Matfin, G. (eds). Pathophysiology: Concepts of
Altered Health States, 8th edn, Wolters Kluwer
Health: Philadelphia, PA.

References

Nayak, B. and Burman, K. (2006) Thyrotoxicosis and

thyroid storm. Endocrinol Metab Clin N Am
35: 663686.

Abraham, P. and Acharya, S. (2010) Current

and emerging treatment options for Graves hyperthyroidism. Therapeut Clin Risk Managem 6: 2940.
Bahn, R. (2010) Graves opthalmopathy. N Engl J Med
362: 726738.
Burch, H.B. and Wartofsky, L. (1993) Life-threatening
thyrotoxicosis. Thyroid storm. Endocrinol Metab Clin
North Am 22: 263277.

http://tae.sagepub.com

Tsai, W.C., Pei, D., Wang, T., Wu, D.A., Li, J.C., Wei,
C.L. et al. (2005) The effect of combination therapy
with propylthiouracil and cholestyramine in the treatment of Graves hyperthyroidism. Clin Endocrinol
(Oxf) 62: 521524.

Visit SAGE journals online

http://tae.sagepub.com

Weetman, A. (2009) Thyrotoxicosis. Medicine

37: 430435.

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