Endocrine Emergencies ENDO 2019

Thyroid Storm and Myxedema Coma

Henry B. Burch, M.D.
Joanna Klubo-Gwiezdzinska , M.D., Ph.D., MHSc
National Institute of Diabetes and Digestive and Kidney Diseases
National Institutes of Health
 Disclosures
• No financial disclosures
 Outline
• Case presentation
• Historical background
• What’s “new?”
• Diagnosis
• Treatment
• Prevention
 Outline
• Case presentation
• Historical background
• What’s “new?”
• Diagnosis
• Treatment
• Prevention
 Case 1: 57-Year-Old Woman
History:
• Graves’ disease x 2 months
• Prescribed methimazole 30 mg
daily and atenolol 50 mg once
daily
• Stopped taking methimazole 1
week ago
• Presents with 3 day history of
nausea/vomiting, palpitations
Exam:
• T 102.7 F, P 124 bpm, regular
• Eyes inflammatory changes
(CAS=3)
• Thyroid- diffuse goiter with
bruit
• Lungs: rales at bases
• Neurological exam
– Tremor
– MMSE 25/30 (normal)
 Case 1: 57-Year-Old Woman
Laboratory testing: Additional testing:
• Free T4 >7 ng/dL • ECG - sinus tachycardia
(0.8 to 1.8 ng/dL) • Chest X-ray - cephalization of
• Free T3 12.1 ng/mL flow and interstitial edema
(2.0 to 4.4 ng/mL)
• TSH 0.001 mU/L
• Total bilirubin 1.5 mg/dL (0.2
to 1.2 mg/dL)
 Outline
• Case presentation
• Historical background
• What’s “new?”
• Diagnosis
• Treatment
• Prevention
 Historical Background

The “Crisis of Exophthalmic Goiter”

“...so many patients are constantly being

brought to the hospital in advanced stages
of thyroid crisis and...so many die in spite of
employment of every measure with which
we are acquainted...”

Dr. Frank Lahey, N. Engl. J. Med. 1928

 Historical Background
Treatment of Thyroid Storm in the 1930’s

• Bedrest
• Barbituates / bromides
• High caloric intake
(3000-4000
calories/day)
• Intravenous glucose
• Lugol’s solution

Munroe et al CMAJ 1939; 40:70.

 Historical Background
Better therapies = improved survival
100 100
100
Drug Advance Introduced
90
78
80 Iodine 1920’s
70 63 (reintroduced)
Mortality (%)

60 Thionamides 1940’s
50
40 Corticosteroids 1950’s
40
28
30
18 β-blockers 1960’s
20
11
10 4
0

Adapted from: Burch HB, Wartofsky L. Endocrinol Metab Clin North Am 1993; 22:263.
 Outline
• Case presentation
• Historical background
• What’s “new?”
• Diagnosis
• Treatment
• Prevention
 What’s New ?
• Largest case series ever published (nearly 300 cases)
• U.S. National Inpatient Sample data on thyroid storm
• Growing literature on parenteral use of ATDs (OFF LABEL)
• Literature on more than 125 cases of thyroid storm treated
with plasmapheresis/ plasma exchange
• Data on emergency thyroidectomy for thyroid storm
 2012 Case Series from Japan
National Survey

• 282 cases thyroid storm, 74 possible thyroid storm

• Cases obtained by survey of Japanese physicians
• Rich source of clinical data on storm

Akamizu T, et al. Thyroid 2012; 22:661.

Japanese Survey Thyroid Storm

Akamizu T, et al. Thyroid 2012; 22:661.

 U.S. National Trends
Hospitalization Data for Thyroid Storm

• National Inpatient Sample Database

– Agency for Healthcare Research and Quality (AHRQ)
– Random sampling from 20% of hospitals in the U.S.
• 2004-2013: 121,384 patients hospitalized a primary diagnosis
of thyrotoxicosis
– Thyroid storm listed in 19,723 (16.2%) patients
• Examined prevalence, demographics and outcomes

Galindo RJ et al. Thyroid 2019; 29: 36-43.

 U.S. National Trends Data
Incidence Data for Thyroid storm

• Incidence in general population: 0.57-0.76 cases/ 100,000

persons per year
• All hospitalized patients: 4-8-5.6 cases/ 100,000 persons per
year
• Patients hospitalized with primary diagnosis of thyrotoxicosis:
14.2-18.4%
• Hospital mortality 1.2-3.6%

Galindo RJ et al. Thyroid 2019; 29: 36-43.

 U.S. National Trends Data
Health Disparities in Thyroid Storm

Medical Insurance in Storm Race and Thyroid Storm

Patients 60
45 42.8 53.6

40 50
43.6
35 33.6
40 47.0%
30
26.5

PERCENT
30.7
PERCENT

25 23.2 30 26
20 17.4
15 12.5 20 16.3

10
12.1
8.4 9.4
10
5

0
0
Thyrotoxicosis Thyroid Storm Thyrotoxicosis Thyroid Storm
Medicare Private Uninsured Caucasian Black Hispanic Other

Galindo RJ et al. Thyroid 2019; 29: 36-43.

 Socioeconomic Factors in Complicated Thyrotoxicosis
Single institution 374 cases inpatient vs. outpatient management

Insurance Coverage in Education Level in Complicated

Complicated Thyrotoxicosis Thyrotoxicosis
60 60
53.7 54.1
51.0
50 50

40 40 36.1
40

PERCENT
PERCENT

30 25.7
30
20.3
22.5 20
20
18.4 12.9
40.0 10
8.8
10 6.5 7.5
0
Outpatient Inpatient
0
Outpatient Inpatient
Higher education High school
Private Medicare/Medicaid
Other Uninsured Lower than high school

Rivas AM, et al. Thyroid 2019; 29:27-35.

 Outline
• Case presentation
• Historical background
• What’s “new?”
• Diagnosis
• Treatment
• Prevention
An exaggerated state of thyrotoxicosis
Clinical Feature Uncomplicated Thyroid Storm
Thyrotoxicosis
Thermoregulatory Heat intolerance, Hyperpyrexia, large
diaphoresis insensible fluid loss
Nervous system Hyperkinesis, nervousness Confusion, seizure, coma
Cardiovascular Tachycardia (90-120 bpm) Accelerated tachycardia
(>130 bpm), atrial
dysrhythmia, heart failure
Gastrointestinal Hyperdefecation Nausea, vomiting, diarrhea
Hepatic Mild transaminase Hepatic dysfunction,
elevation jaundice
Psychiatric Agitation Psychosis
Precipitant history Absent Present
Death Rare Frequent (10-20%)

Warnock A, Cooper DS, Burch HB. Endocrine Press 2018

 Diagnostic Criteria
Derivation of Point Scale
• No uniform criteria for diagnosis
• Most cases had common features
• Spectrum of dysfunction
• High mortality rate with late/ missed diagnosis

Burch HB, Wartofsky L. Endocrin Metab Clin North Am 1993; 22:263.

 Hyperthermia POINTS Tachycardia POINTS

Thyroid 99 - 99.9

100 - 100.9
5

10
90 - 109

110 - 119
5

10

Storm 101 – 101.9

102 – 102.9
15

20
120 - 129

130 - 139
15

20

Point 103 – 103.9

> 104
25

30
> 140

Congestive Heart Failure

25

Scale CNS Effects Absent 0

Absent 0 Mild (pedal edema) 5

(BWPS) Mild (agitation) 10 Moderate (Bibasilar rales) 10

Moderate (delerium, 20 Severe (Pulmonary edema) 15

psychosis, lethargy)

Severe (seizure, coma) 30 Atrial Fibrillation

GI-Hepatic Dysfunction Absent 0

Absent 0 Present 10

Moderate (diarrhea, nausea/ 10 Precipitant history

vomiting, abdominal pain)

Severe (jaundice) 20 Absent 0

Burch HB, Wartofsky L
Endocrinol Clin Present 5

North Am 1993; 22:263. A score > 45 in a patient with severe thyrotoxicosis is highly suggestive of thyroid storm; 25-44,
impending thyroid storm; < 25- thyroid storm is unlikely.
 JTA Diagnostic Criteria for Thyroid Storm
• Empirically derived diagnostic criteria
• Same general categories as BWPS
• Modified based on new cases
• No numerical scale

Akamizu T, et al. Thyroid 2012; 22:661.

JTA Diagnostic System

Akamizu T, et al. Thyroid 2012;22:661.

 Comparison of Diagnostic Systems
United States Clinical storm patients (n=25)
Clinical BWPS JTA
• 25 patients with a Diagnosis
clinical diagnosis
Storm 25 20 20
of thyroid storm @ Impending NA 5 NA
LAC-USC storm
• 125 patients No storm 0 0 5

hospitalized with Clinical complicated thyrotoxicosis (n=125)

thyrotoxicosis but Clinical BWPS JTA
Diagnosis
not in “storm”
• Compared BWPS Storm 0 27 21
Impending NA 50 NA
and JTA systems storm
No storm 125 48 104
Angell TE et al. JCEM 2014; 100:451.
 Application to Clinical Series
Singapore
Thyroid storm patients (n=28)
• 28 patients with
a diagnosis of BWPS JTA
thyroid storm
based on clinical Storm 28 27
features and No storm 0 1
BWPS ≥ 45 Deaths from thyroid storm (n=7)
• Retrospectively BWPS JTA
assigned JTA
diagnosis Storm 7 7
No storm 0 0
Swee DS et al. Endocr Pract 2015; 21: 182.
 Thermoregulatory POINTS Cardiovascular POINTS

Dysfunction Dysfunction
99 - 99.9 5 90 - 109 5

100 - 100.9 10 110 - 119 10

Our Case: 101 – 101.9

102 – 102.9
15

20
120 - 129

130 - 139
15

20

BWPS= 60 103 – 103.9

> 104
25

30
> 140

Congestive Heart Failure

25

CNS Effects Absent 0

Absent 0 Mild (pedal edema) 5

Mild (agitation) 10 Moderate (Bibasilar rales) 10

Moderate (delerium, 20 Severe (Pulmonary edema) 15

psychosis, lethargy)

Severe (seizure, coma) 30 Atrial Fibrillation

GI-Hepatic Dysfunction Absent 0

Absent 0 Present 10

Moderate (diarrhea, nausea/ 10 Precipitant history

vomiting, abdominal pain)
Burch HB, Wartofsky L
Severe (jaundice) 20 Absent 0
Endocrinol Clin
Present 5
North Am 1993; 22:263.
A score > 45 in a patient with severe thyrotoxicosis is highly suggestive of thyroid storm; 25-44,
impending thyroid storm; < 25- thyroid storm is unlikely.
Our Case: JTA = TS1-combinaton 2

Akamizu T, et al. Thyroid 2012;22:661.

 Outline
• Case presentation
• Historical background
• What’s “new?”
• Diagnosis
• Treatment
• Prevention
 Therapeutic Targets

Treatment is directed at every therapeutically accessible target

• Inhibit thyroid hormone synthesis / release
• Prevent peripheral effects of thyroid hormone
• Physical removal of thyroid hormone
• Provide systemic support
• Identify and treat precipitant
 Treatment Targets
• Inhibit thyroid hormone synthesis and release
• Prevent peripheral effects of thyroid hormone
• Physical removal of thyroid hormone
• Systemic support
• Identify and treat precipitant
 Treatment
Why is PTU Still Favored in Thyroid Storm?
2016 ATA Hyperthyroidism Guidelines
• Methimazole should be used in virtually every
patient with GD who chooses antithyroid
drugs, except … the first trimester of
pregnancy and in the treatment of thyroid
storm…. when propylthiouracil is preferred.

Ross DS, et al. Thyroid 2016; 26(10):1343.

 Treatment
Which Antithyroid Drug?
PTU 750-900 mg daily vs. MMI 60-90 mg daily; I- = SSKI 5 drops tid

MMI
-13%

PTU
-45%

Abuid and Larsen J Clin Invest 1974; 54:

 Treatment
Acute effects of a single PTU dose (150 mg)

Normal

Hyperthyroid

32% T3 450 ± 80
drop
in 8 h 307 ± 110

Time (hours)

Cooper DS, et al. J Clin Endocrinol Metab 1982; 54:101.

Parenteral Antithyroid Drugs
No approved preparations, but…
 Treatment
Intravenous MMI
• Case: 42-year-old with
thyrotoxicosis and severe
hematemesis
• 30 mg every 6 hours
given slow IV push over 2
minutes
• 500 mg MMI powder/ 50
ml 0.9% NaCl (10mg/mL)
• Passed through 0.22-mm
filter using sterile
conditions
Hodak S, et al. Thyroid 2006; 16: 691.
 Treatment
PTU Suppository
• ATDs given by suppository or
retention enema
• PTU Suppository
– 14.4 g PTU solubilized in 40 ml
mineral oil
– Mixed with 36 g cocoa butter
solid suppository base
– Melted in hot water bath
– Distributed to 1 gram
suppository molds
– 400 mg PTU/ suppository q 6
hours
– Documented therapeutic drug
levels
Zweig SB, et al. Endocrin Pract 2006; 12:43.
 Inorganic iodine
• Acutely inhibits release of thyroid hormone
• Inhibition of new thyroid hormone synthesis
– Wolff–Chaikoff effect
• SSKI 5 drops (250 mg) every 6 hours (mix with water/juice or
food)
• Wait until 1 hour after first dose of ATDs
 Treatment Targets
• Thyroid hormone synthesis and release
• Peripheral effects of thyroid hormone
• Physical removal of thyroid hormone
• Systemic support
• Find and treat precipitant
 Treatment Targets
• Peripheral effects of thyroid Conversion of T4 to T3
hormone
– Inhibit T4 to T3 conversion T4 T3
• Propylthiouracil
• Propranolol
• Corticosteroids
• Oral cholecystographic agents
– Block end organ effects of
thyroid hormone
• β-blockers
• Corticosteroids
 Treatment
Which β-Blocker ?
• Propranolol most frequently cited
– Blocks T4-to-T3 conversion in high doses
– Typical doses: 60-80 mg orally every 6 hours
• 0.5-1.0 mg IV over 10 minutes, every 3 hours
• Problems with propranolol
– Half-life 3-4 hours
– Has been associated with cardiovascular collapse
– Non-cardioselective; contraindicated with severe asthma
 Treatment
Which β-Blocker ?
• Esmolol IV infusion: ultra-short action facilitates
titration
– β1-cardioselective, half-life 8 minutes
– 250-500 mcg/kg load then 50-100 mcg/Kg/min
• Consider invasive monitoring in patients with
congestive heart failure while treating with β-blockers
 Treatment Targets
• Thyroid hormone synthesis and release
• Peripheral effects of thyroid hormone
• Physical removal of thyroid hormone
• Systemic support
• Find and treat precipitant
 Treatment
Plasma exchange
• Approximately 125 case reports in
literature
• Plasma exchange or charcoal
perfusion
• Replaces patient plasma with
donor plasma or isotonic albumin
solution
• Clinical improvement may be
discordant from TH levels
• Generally reserved for:
– Refractory storm patients
• Major ATD adverse effects
• Preoperatively

Muller C, et al. Ther Apher Dial. 2011;15:522.

 Treatment
Plasma exchange
Plasmapheresis in Thyroid Storm
8
7 Plasmapheresis
T3 HC, β-b Thyroidectomy
Thyroid Hormone Level 6 MMI
Stopped
5
(Relative Units)

4
Tachycardia
3
FT4
2 Fever
(BWPS 54) Delirium
Clinical improvement
1
Sore throat
0
d0 d13 d18 d19 d20 d21 d23 d24
Total T3/100 1.26 3.76 2.32 2.67 2.2 2.39 1.67 0.48
Free T4 0.9 3.1 2.6 2.6 2.2 1.8 2.2 1.8

Vyas C, et al. Endocrin Pract 2010; 16: 673.

 Treatment MMI + Cholestyramine
Binding Resins --- MMI alone

• Binding resins interfere Phase 1 Phase 2

with enterohepatic
circulation of thyroid
hormone, increasing fecal
excretion
• Double-blind, placebo-
controlled crossover study
• MMI ± Cholestyramine 4g
four times daily
• More rapid resolution of
thyrotoxicosis in treated
patients

Solomon BS, et al. Clin Endocrin 1993; 38:39-43.

 Treatment
Urgent thyroidectomy
• 10 cases of storm
undergoing urgent
thyroidectomy
• Mean age 70 years
• Mean BWPS 61 Median
POD 6

• Also received CS, ATDs, β-

blockers
• Two patients (20%) died
2-3 weeks post-
operatively

Scholz G, et al. Thyroid 2003; 13:933-40.

 Treatment Targets
• Thyroid hormone synthesis and release
• Peripheral effects of thyroid hormone
• Physical removal of thyroid hormone
• Systemic support
• Find and treat precipitant
 Systemic Support
• MICU setting
• Fever
– Antipyretics
– Cooling blankets
• Hydration/ Nutrition
• Telemetry
• Invasive monitoring
Summary of Drugs and Doses in Thyroid Storm
• Propylthiouracil 500-1000 mg load then 250 mg every 4 hours
or
• Methimazole 80-120 mg daily in divided doses
• Esmolol 250-500 mcg/kg IV load then 50-100 mcg/Kg/min
or
• Propranolol 60-80 mg orally every 4-6 hours
• SSKI 5 drops orally every 6 hours
• Hydrocortisone 300 mg load then 100 mg every 8 hours
or
• Dexamethasone 2 mg orally or IV q 4-6 hours
 Prognosis
Cause of Death

(multiorgan failure)

Akamizu T, et al. Thyroid 2012;22:661.

 Outline
• Case presentation
• Historical background
• What’s “new?”
• Diagnosis
• Treatment
• Prevention
 Prevention
• Avoiding iatrogenic precipitants
• ATD pretreatment before RAI in high risk pts
• Correct thyrotoxicosis before surgery
 Prevention
• Avoiding iatrogenic precipitants
• ATD pretreatment before RAI in high risk pts
• Correct thyrotoxicosis before surgery
 Prevention
Precipitants of Thyroid Storm

IATROGENIC PRECIPITANTS ACUTE ILLNESS

• Radioiodine therapy • Infection

• Withdrawal of ATDs • CVA
• Thyroid surgery • Parturition
• Non-thyroid surgery • Diabetic ketoacidosis
• Iodinated contrast • Pulmonary embolism
• Vigorous palpation • Trauma / Emotional
Stress
 Prevention
• Avoiding iatrogenic precipitants
• ATD pretreatment before RAI in high risk pts
• Correct thyrotoxicosis before surgery
Acute Changes in Thyroid Hormone After Radioactive
Iodine Treatment
400
131I

350
Free T4
300 (pmol/L)

250

200

150

100 ATD
Stopped c
50 v
0

-6 -4 -2 0 2 4 6 8 10 12 14
Time (Days)

Burch et al. J Clin Endocrinol Metab 2001;86:3016.

 Prevention
• Avoiding iatrogenic precipitants
• Pretreatment of high risk patients before RAI
• Correct thyrotoxicosis before surgery
 Prevention
Rapid Preparation for Emergent Surgery
Regimen:
• Methimazole 20 mg po every 4-6 hours
• SSKI 2-4 gtts po three to four times daily (may
use oral cholecystographic agents if available)
• Propranolol 40-80 mg three to four times daily
• Cholestyramine 4g po four times daily
• Dexamethasone 2 mg po or IV every 6 hours

Adapted from: Langley and Burch Endocrinol Metab Clin N Am 2003; 32:519.
 Prevention
Controlling thyrotoxicosis before surgery
Rapid Preparation for Thyroid Surgery in Graves’ Disease
4.5 MMI
Stopped for
4 hepatotoxicity T3 (ng/dL)/100
Free T4 (ng/dL)
3.5
3 Total
Thyroidectomy
Relative Units

2.5
2
1.5
1
0.5 Propranolol 60 mg BID
SSKI 2 drops TID, Dexamethasone 2 mg QID, Cholestyramine 4 g QID
0
1 6 12 13 18 19 20 21
Time (Days)
After the storm…
 Goals After the Storm
• Prevent recurrence
• Definitive therapy is a priority
– Iodine load may slightly delay RAI therapy
• Measure RAIU before treatment
– Thyroidectomy while euthyroid
 Return to case
• Patient admitted to MICU
• Central line/ volume status monitoring
• Propylthiouracil 500 mg loading dose and 250 mg every 4
hours
• Esmolol drip
• SSKI 5 drops per NG tube every 6 hours
• Dexamethasone 2 mg orally or IV q 4-6 hours
• Antipyretic (acetaminophen)