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ENDOCRINE EMERGENCIES
ALEXANDER L. SHIFRIN, MD, FACS, FACE, ECNU, FEBS (ENDOCRINE), FISS
Clinical Associate Professor of Surgery
Rutgers Robert Wood Johnson Medical School
New Brunswick, New Jersey
Associate Professor of Surgery
Hackensack Meridian School of Medicine
Nutley, New Jersey
Director of Endocrine Oncology
Hackensack Meridian Health of Monmouth and Ocean Counties
Nutley, New Jersey
Surgical Director
Center for Thyroid, Parathyroid, and Adrenal Diseases
Department of Surgery
Jersey Shore University Medical Center
Neptune, New Jersey
In memory of my father, Leonid Shifrin, medical engineer, the inventor of thromboelastographs; and my uncle, pediatric surgeon, Vadim Shifrin, MD.
To my mother, Margarita Shifrina, for her love and endless support.
To my beloved children, Michael, Daniel, Benjamin, Julia, Christian, and Liam, who continue to provide perspective on what is truly important in life.
To the love of my life, Svetlana L. Krasnova, for her love, patience, and encouragement.
To my teachers and mentors, who dedicated their lives and efforts to the science of surgery. Those who made me into a surgeon and inspired me to produce this book: Ali Bairov, MD, Steven Raper, MD, William Inabnet, MD, John Chabot, MD, and Jerome Vernick, MD.
ACKNOWLEDGMENTS
The creation of this book, covering the entire scope of endocrine emergencies, was dependent on a team effort, which was possible only with the support and enthusiasm of many individuals who contributed to this book, my colleagues, who trusted me and dedicated their time and effort to make it happen, and without whom this book would have never come to life!
Special thanks to Nancy Duffy, Senior Content Strategist at Elsevier, who believed in me, and to the entire staff at Elsevier, who were very supportive from the first idea of this book and maintained their enthusiasm until the end.
Endocrine Emergencies is an up-to-date guide for endocrinologists, endocrine surgeons, surgical oncologists, ENT surgeons, head and neck surgeons, emergency physicians, internists and primary care physicians, critical care physicians and trauma surgeons, neurosurgeons, obstetricians and gynecologists, neurologists, advanced practice providers, residents, and medical students. The book covers the most common and serious emergencies related to endocrine metabolic conditions of the pituitary gland, thyroid, parathyroid, adrenal glands, pancreas, and neuroendocrine tumors. It also includes separate chapters on endocrine responses in critically ill and trauma patients, use of potassium iodide ingestion in a nuclear emergency, endocrine emergencies during pregnancy, and postoperative endocrine emergencies after thyroid and parathyroid surgeries. It covers up-to-date information and serves as a guide on how to recognize, diagnose, and treat each condition using modern diagnostic techniques and modern therapeutics.
We hope that this book will provide an indispensable source of knowledge to all practitioners, those who just started their career and those who are in the more advanced stages of their practice.
Alexander L. Shifrin, MD, FACS, FACE, ECNU, FEBS (Endocrine), FISS
February 2021
Sara Ahmadi, MD, ECNU
Endocrine Faculty
Department of Medicine
Division of Endocrinology
Brigham and Women’s Hospital
Harvard Medical School
Boston, Massachusetts
Monika S. Akula, MD
Endocrinology, Diabetes and Metabolism Fellow
Department of Endocrinology and Metabolism
Jersey Shore University Medical Center
Neptune, New Jersey
Erik K. Alexander, MD
Chief, Thyroid Section & Professor of Medicine
Department of Medicine
Division of Endocrinology
Brigham Women’s Hospital
Harvard Medical School
Boston, Massachusetts
Trevor E. Angell, MD
Assistant Professor of Clinical Medicine
Department of Endocrinology and Diabetes;
Associate Director of the Thyroid Center
Keck School of Medicine
University of Southern California
Los Angeles, California
Maureen McCartney Anderson, DNP, CRNA/APN
Assistant Professor
Division of Advanced Nursing Practice
Rutgers School of Nursing Anesthesia Program
Rutgers, The State University of New Jersey
Newark, New Jersey
John P. Bilezikian, MD
Dorothy L. and Daniel H. Silberberg
Professor of Medicine and Professor of Pharmacology
Vice Chair, Department of Medicine for International Education and Research
Chief (Emeritus), Division of Endocrinology
Department of Medicine
Vagelos College of Physicians and Surgeons
Columbia University, New York
CONTRIBUTORS
Stefan Richard Bornstein, MD, PhD
Division of Internal Medicine and Division of Endocrinology and Metabolism
University Hospital Carl Gustav Carus
Technical University of Dresden
Dresden, Germany
Jan Calissendorff, MD, PhD
Senior Consultant
Department of Endocrinology, Metabolism and Diabetes
Karolinska University Hospital
Department of Molecular Medicine and Surgery
Karolinska Institutet
Stockholm, Sweden
Stuart Campbell, MD, MSc
Resident
Division of Endocrine Surgery, Department of Surgery
Jersey Shore University Medical Center
Neptune, New Jersey
Tariq Chukir, MD
Assistant Professor
Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism
Weill Cornell Medicine and New York
Presbyterian Hospital
New York, New York
Tara Corrigan, MHS, PA-C
Physician Assistant
Division of Endocrine Surgery, Department of Surgery
Jersey Shore University Medical Center
Neptune, New Jersey
Henrik Falhammar, MD, PhD, FRACP
Department of Endocrinology, Metabolism and Diabetes
Karolinska University Hospital;
Associate Professor
Department of Molecular Medicine and Surgery
Karolinska Institutet
Stockholm, Sweden
Azeez Farooki, MD
Attending Physician
Endocrinology Service
Department of Medicine
Memorial Sloan Kettering Cancer Center
New York, New York
Chelsi Flippo, MD
Pediatric Endocrinology Fellow
Eunice Kennedy Shriver National Institute of Child Health and Human Development
National Institutes of Health
Bethesda, Maryland
Lane L. Frasier, MD, MS
Fellow, Surgery
Division of Traumatology, Surgical Critical Care & Emergency General Surgery
Department of Surgery
University of Pennsylvania Philadelphia, Pennsylvania
Vincent Gemma, MD
Major Health Partners
Department of Surgery
Shelbyville Hospital
Shelbyville, Indiana
Monica Girotra, MD
Associate Clinical Member
Endocrine Service, Department of Medicine
Memorial Sloan Kettering Cancer Center;
Assistant Clinical Professor
Endocrine Division
Weill Cornell Medical College
New York, New York
Ansha Goel, MD
Endocrinology Fellow
Division of Endocrinology and Metabolism
Georgetown University Hospital
Washington, District of Columbia
Christopher G. Goodier, BS, MD
Associate Professor
Division of Maternal Fetal Medicine
Department of Obstetrics and Gynecology
Medical University of South Carolina
Charleston, South Carolina
Heidi Guzman, MD
Assistant Professor of Medicine
Columbia University Irving Medical Center
New York, New York
Makoto Ishii, MD, PhD
Assistant Professor
Department of Neurology
Feil Family Brain and Mind Research Institute
Weill Cornell Medicine
New York Presbyterian Hospital
New York, New York
Yasuhiro Ito, MD, PhD
Kuma Hospital
Department of Surgery
Kobe, Japan
Michael Kazim, MD
Clinical Professor
Oculoplastic and Orbital Surgery
Edward S. Harkness Eye Institute
Columbia University Irving Medical Center
New York-Presbyterian Hospital
New York, New York
Jane J. Keating, MD
Division of Traumatology, Surgical Critical Care & Emergency General Surgery
Department of Surgery
University of Pennsylvania
Philadelphia, Pennsylvania
Anupam Kotwal, MD
Assistant Professor of Medicine
Division of Diabetes, Endocrinology, and Metabolism
University of Nebraska Medical Center
Omaha Nebraska; Research Collaborator
Division of Endocrinology, Diabetes, Metabolism and Nutrition
Mayo Clinic
Rochester, Minnesota
Svetlana L. Krasnova, APRN, FNP-C, RNFA
Advanced Practice Registered Nurse
Department of Otolaryngology, Head and Neck Surgery
Rutgers Robert Wood Johnson Medical School
New Brunswick, New Jersey
David W. Lam, MD
Assistant Professor
Division of Endocrinology, Diabetes, and Bone Disease
Icahn School of Medicine at Mount Sinai
New York, New York
Melissa G. Lechner, MD, PhD
Assistant Professor of Medicine
Division of Endocrinology, Diabetes, and Metabolism
David Geffen School of Medicine
University of California at Los Angeles
Los Angeles, California
Aundrea Eason Loftley, MD
Assistant Professor
Division of Endocrinology, Diabetes and Metabolic Diseases
Department of Internal Medicine
Medical University of South Carolina
Charleston, South Carolina
Sara E. Lubitz, MD
Associate Professor
Department of Medicine
Rutgers Robert Wood Johnson Medical School
New Brunswick, New Jersey
Louis Mandel, DDS
Director
Salivary Gland Center;
Associate Dean, Clinical Professor (Oral and Maxillofacial Surgery)
Columbia University College of Dental Medicine
New York, New York
Hiroo Masuoka, MD, PhD
Department of Surgery
Kuma Hospital Kobe, Japan
Jorge H. Mestman, MD
Professor of Medicine and Obstetrics & Gynecology
Division of Endocrinology, Diabetes and Metabolism
Department of Medicine and Obstetrics and Gynecology
Keck School of Medicine
University of Southern California
Los Angeles, California
Akira Miyauchi, MD, PhD
Department of Surgery
Kuma Hospital
Kobe, Japan
Caroline T. Nguyen, MD
Assistant Professor of Clinical Medicine, Obstetrics and Gynecology
Division of Endocrinology
Diabetes & Metabolism
Department of Medicine
Keck School of Medicine
University of Southern California
Los Angeles, California
Raquel Kristin Sanchez Ong, MD
Endocrinologist, Fellowship Assistant
Program Director
Division of Endocrinology and Metabolism
Jersey Shore University Medical Center
Neptune, New Jersey;
Assistant Professor
Department of Internal Medicine
Hackensack Meridian School of Medicine
Nutley, New Jersey
Randall P. Owen, MD, MS, FACS
Chief, Section of Endocrine Surgery
Division of Surgical Oncology
Program Director, Endocrine Surgery Fellowship
Department of Surgery Mount Sinai Hospital
Icahn School of Medicine
New York, New York
Rodney F. Pommier, MD
Professor of Surgery
Division of Surgical Oncology, Department of Surgery
Oregon Health & Science University
Portland, Oregon
Jason D. Prescott, MD, PhD
Chief, Section of Endocrine Surgery
Director of Thyroid and Parathyroid Surgery
Assistant Professor of Surgery and of Oncology
Department of Surgery
Johns Hopkins School of Medicine
Baltimore, Maryland
Ramya Punati, MD
Clinical Assistant Professor of Medicine
Division of Endocrinology and Metabolism
Pennsylvania Hospital University of Pennsylvania Health System Pennsylvania, Philadelphia
Gustavo Romero-Velez, MD
Chief Resident
Department of Surgery
Montefiore Medical Center
Albert Einstein School of Medicine
Bronx, New York
Arthur B. Schneider, MD, PhD
Professor of Medicine (Emeritus)
Department of Medicine
University of Illinois at Chicago Chicago, Illinois
Alison P. Seitz, MD
Resident Department of Neurology
Weill Cornell Medicine
New York Presbyterian Hospital
New York, New York
Alexander L. Shifrin, MD, FACS, FACE, ECNU, FEBS (Endocrine), FISS
Clinical Associate Professor of Surgery
Rutgers Robert Wood Johnson Medical School
New Brunswick, New Jersey; Associate Professor of Surgery
Hackensack Meridian School of Medicine
Nutley, New Jersey; Director of Endocrine Oncology
Hackensack Meridian Health of Monmouth and Ocean Counties
Hackensack, New Jersey; Surgical Director, Center for Thyroid, Parathyroid, and Adrenal Diseases
Department of Surgery
Jersey Shore University Medical Center
Neptune, New Jersey
Adam Michael Shiroff, MD, FACS
Associate Professor of Surgery
Division of Traumatology, Surgical Critical Care & Emergency Surgery
University of Pennsylvania
Penn Presbyterian Medical Center
Pennsylvania, Philadelphia
Marius N. Stan, MD
Associate Professor of Medicine
Division of Endocrinology, Diabetes, Metabolism and Nutrition
Mayo Clinic
Rochester, Minnesota
Constantine A. Stratakis, MD, D(med)Sci
Senior Investigator
Eunice Kennedy Shriver National Institute of Child Health and Human Development
National Institutes of Health
Bethesda, Maryland
Christina Tatsi, MD, PhD
Staff Clinician, Pediatric Endocrinologist
Eunice Kennedy Shriver National Institute of Child Health and Human Development
National Institutes of Health
Bethesda, Maryland
Daniel J. Toft, MD, PhD
Assistant Professor
Division of Endocrinology, Diabetes and Metabolism
Department of Medicine
University of Illinois at Chicago Chicago, Illinois
Arthur Topilow, MD, FACP
Department of Hematology Oncology
Jersey Shore University Medical Center
Neptune, New Jersey
Ann Q. Tran, MD
Oculoplastic and Orbital Surgery
Edward S. Harkness Eye Institute
Columbia University Irving Medical Centery
New York-Presbyterian Hospital
New York, New York
Joseph G. Verbalis, MD
Professor of Medicine
Georgetown University; Chief, Endocrinology and Metabolism
Georgetown University Medical Center
Washington, District of Columbia
Leonard Wartofsky, MS, MD, MPH
Director, Thyroid Cancer Research Center
MedStar Health Research Institute; Professor of Medicine
Department of Medicine
Georgetown University School of Medicine
Washington, District of Columbia
Sarah M. Wonn, MD Resident
Department of Surgery
Oregon Health & Science University
Portland, Oregon
Dorina Ylli, MD, PhD
Thyroid Cancer Research Center
MedStar Health Research Institute
Washington, District of Columbia
William F. Young, Jr, MD, MSc
Professor of Medicine, Tyson Family Endocrinology Clinical Professor Division of Endocrinology, Diabetes, Metabolism, and Nutrition
Mayo Clinic
Rochester, Minnesota
Part 1
Thyrotoxicosis and Thyroid Storm 3
Melissa G. Lechner Trevor E. Angell
Anupam Kotwal Marius N. Stan
Ocular Emergencies in Graves’ Ophthalmopathy 29 Ann Q. Tran Michael Kazim
Dorina Ylli Leonard Wartofsky
Thyrotoxic Periodic Paralysis: A Review and Suggestions for Treatment 57
Svetlana L. Krasnova Arthur Topilow Jan Calissendorff Henrik Falhammar
Monika Akula Raquel Kristin S. Ong Alexander L. Shifrin William F. Young, Jr.
Pheochromocytoma: Perioperative and Intraoperative Management 143 Maureen McCartney Anderson Tara Corrigan Alexander Shifrin
Acute Adrenal Insufficiency 155
Ramya Punati Raquel Kristin S. Ong Stefan R. Bornstein
Part 5 Endocrine Pancreas and Pancreatic Neuroendocrine Tumors 167
15 Diabetic Emergencies: Ketoacidosis, Hyperglycemic Hyperosmolar State, and Hypoglycemia 169
Heidi Guzman David Wing-Hang Lam
16 Pancreatic Neuroendocrine Emergencies in the Adult (Gastrinoma, Insulinoma, Glucagonoma, VIPoma, Somatostatinoma, and PPoma/ Nonfunctional Tumors) 185
Vincent Gemma Jason D. Prescott
Part 6 Neuroendocrine Tumors (NETs): Gastrointestinal Neuroendocrine Tumors 199
17 Carcinoid Syndrome and Carcinoid Crisis 201
Sarah M. Wonn Rodney F. Pommier
Part 7 Pituitary 213
18 Postsurgical and Posttraumatic Hyponatremia 215
Ansha Goel Joseph G. Verbalis
19 Diabetes Insipidus and Acute Hypernatremia 229
Chelsi Flippo Christina Tatsi Constantine A. Stratakis
20 Hypopituitarism 239
Sara E. Lubitz
21 Pituitary Apoplexy 259
Alison P. Seitz Makoto Ishii
Part 8 Endocrine Emergencies During Pregnancy 275
22 Endocrine Emergencies in Obstetrics 277
Christopher G. Goodier Aundrea Eason Loftley
23 Graves’ Hyperthyroidism in Pregnancy 285
Caroline T. Nguyen Jorge H. Mestman
Part 9 Immunotherapy-Associated Endocrinopathies 299
24 Endocrinopathies Associated With Immune Checkpoint Inhibitors 301
Monica Girotra
Part 10 Endocrine Responses in Critically Ill Trauma Patients: Nuclear Emergency 315
25 Endocrine Responses in Critically Ill and Trauma Patients 317
Lane L. Frasier Jane J. Keating Adam Michael Shiroff
26 Use of Potassium Iodide in a Nuclear Emergency 329
Daniel J. Toft Arthur B. Dr. Schneider
Index 339
PART 1
Thyroid
Severe Thyrotoxicosis and Thyroid Storm
Melissa G. Lechner Trevor E. Angell
CHAPTER OUTLINE
Introduction
Pathophysiology of Thyrotoxicosis and Thyroid Storm
Evaluation of Patients for Thyrotoxicosis
Signs and Symptoms of Thyroid Storm
Causes of Thyrotoxicosis and Thyroid Storm
Laboratory Findings
Diagnosis of Thyroid Storm
Treatment of Thyroid Storm
Supportive Care
Introduction
Beta-Blockers
Antithyroid Drugs
Iodine
Lithium
Steroids
Adjunct Treatments
Treatment of Compensated Thyrotoxicosis
Socioeconomic Factors
Follow-up After Discharge
Conclusions
Thyroid hormone excess, also known as thyrotoxicosis, encompasses a wide range of signs and symptoms. Thyrotoxicosis and hyperthyroidism may have semantic distinctions but are often used interchangeably. Patients with clinical manifestations of severe thyrotoxicosis need urgent evaluation and may require hospitalization and emergency intervention. Therefore it is important to be able to recognize the presence of thyrotoxicosis, know the causative factors, evaluate its severity, and, when necessary, know the critical aspects of management for patients with life-threatening disease.
Thyroid storm is a clinical syndrome of decompensated thyrotoxicosis in which the compensatory physiologic mechanisms have been overwhelmed. It is considered an endocrine emergency due to its high morbidity and mortality, and prior to the availability of advanced intensive care and multimodality therapeutic interventions, this condition was uniformly fatal.1–5 Outcomes remain very poor for patients not quickly identified and treated. Historically, cases of thyroid storm were associated with surgical interventions, but the majority of recognized cases are now medical, related to underlying infections, cardiovascular events, or other conditions. Not all patients will have a previous diagnosis of hyperthyroidism, and thyroid storm may occur in many circumstances with myriad precipitants. Despite its rarity, thyroid storm has been estimated to represent 1%–16% of hospital admissions for thyrotoxicosis, with estimates varying across studies depending upon methodology.1,6–9 Providers should be vigilant in identifying patients who may have thyroid storm and initiating appropriate care.
This chapter provides a summary of the evaluation and management of patients with severe thyrotoxicosis and thyroid storm, with emphasis on the latter given the importance of recognizing and treating this condition.
Pathophysiology of Thyrotoxicosis and Thyroid Storm
Thyroid hormone exerts effects throughout the body. During thyrotoxicosis, the influences of excess thyroid hormone, particularly upon energy expenditure and the cardiovascular system, result in altered metabolism and hemodynamics for which the body may compensate but lacks the reserve capacity to adapt to additional stresses.
Excess thyroid hormone, predominantly through the nuclear actions of triiodothyronine (T3) on gene transcription and posttranslational modification, causes increased cardiac contractility and cardiac output (CO). Upregulated cardiac genes include myosin heavy chain, voltage-gated potassium channels, and sarcoplasmic reticulum calcium ATPase.10 T3 also directly induces vascular smooth muscle relaxation and vasodilation that is further augmented by the need to remove excess heat generated by upregulation of uncoupling protein-3, Na+/K+ ATPase, and increased energy expenditure. Vasodilation in thyrotoxicosis causes relative underperfusion of renal and splanchnic circulation, resulting in increased activation of the renin-angiotensin-aldosterone system (RAAS) and subsequent increased blood volume and cardiac preload.11 This new compensated steady state puts a chronic workload on the cardiovascular system. Due to these changes, patients with thyrotoxicosis will typically demonstrate increased resting heart rate (HR) and respiratory rate. In compensated thyrotoxicosis, the skin is often warm and sweating may be present to dissipate heat, but fever is absent. Cardiovascular findings include reduced systemic vascular resistance (SVR), increased CO and ejection fraction, and increased pulmonary artery pressure. Systolic blood pressure is increased whereas diastolic and mean arterial pressure are reduced, leading to a widened pulse pressure. Thyrotoxic patients experience exercise intolerance due to the inability to further augment HR, CO, or SVR, as would occur in the euthyroid state.12 Additionally, weakness results from T3-mediated protein catabolism and skeletal muscle loss, including the diaphragm.
What differentiates thyroid storm from thyrotoxicosis is hemodynamic decompensation. Although an exact pathophysiology is unknown, the close association with precipitating physiologic stresses provides some clues. Events such as infection, acute coronary syndromes (ACS), hypovolemia, or trauma upset the tenuous hemodynamic balance created by the aforementioned physiologic changes, and there is an inability by the body to augment cardiovascular function further. Loss of effective circulation results in heat retention and organ hypoperfusion leading to the classic findings of hyperthermia and altered mental status.4,13
Evaluation of Patients for Thyrotoxicosis
SIGNS AND SYMPTOMS OF THYROID STORM
The acute evaluation of a patient with thyrotoxicosis should proceed similarly to other patients, with emergent evaluation of cardiopulmonary, hemodynamic, and neurologic status. The initial secondary survey should seek to identify not only the presence of thyrotoxicosis but its most severe manifestations. These would include hyperthermia, altered mentation (e.g., confusion, lethargy, seizures, coma), tachyarrhythmia, or congestive heart failure (CHF; e.g., elevated jugular venous pressure, lower extremity swelling, pulmonary edema, congestive hepatopathy), and the presence of jaundice. Other manifestations may be evident but do not necessarily indicate thyroid storm. The presentation of thyrotoxicosis may include classic symptoms or be atypical in nature. The influence of excess thyroid hormone on the body leads to a number of predictable symptoms. Heat intolerance, tachycardia and/or palpitations, fine bilateral tremor, weight loss, muscle weakness or fatigue, and dyspnea on exertion or shortness of breath are all symptoms of moderate to severe
thyrotoxicosis regardless of the etiology. On physical examination, patients without thyroid storm are usually afebrile but their skin is warm to the touch from cutaneous vasodilation. The resting heart rate may be modestly elevated (80–100 beats per minute [bpm]) or tachycardic (>100 bpm). More significant cardiac effects include supraventricular tachyarrhythmias (SVT), particularly atrial fibrillation (AF) with rapid ventricular rate, or manifestations of heart failure. Not all patients with signs of heart failure will have reduced systolic function, but cardiomyopathy with markedly reduced ejection fraction can occur in a small percentage. In patients with preexisting arrhythmias or heart failure, these may be nonspecific findings or may demonstrate an acute worsening. In one retrospective cohort analysis, patients with a history of coronary artery disease, AF, peripheral vascular disease, renal failure, pulmonary circulation disorders, or valvular disease were more likely to have cardiogenic shock with thyroid storm. Additionally, 45% of patients with thyroid storm complicated by cardiogenic shock had a preexisting diagnosis of CHF.14
Less commonly, these overt symptoms of thyrotoxicosis are absent. Symptoms may be limited, particularly in older individuals. Termed apathetic hyperthyroidism, in these individuals symptoms might only include weight loss, failure to thrive, fatigue, or lethargy. In patients already taking medications blocking the β-adrenergic system, classic symptoms of palpitations, tremor, or agitation may also be blunted. Rare manifestations of thyrotoxicosis include paroxysmal periodic paralysis, related to changes in potassium channel function, affecting the lower before the upper extremities, proximal more than distal muscle groups, and usually sparing the diaphragm.
CAUSES OF THYROTOXICOSIS AND THYROID STORM
Historical information, or specific signs or symptoms, may suggest an underlying cause of thyrotoxicosis. Common and significant etiologies are shown in Table 1.1. A diffusely enlarged nontender thyroid gland suggests Graves’ disease, and the presence of a thyroid bruit is pathognomonic. Similarly, the presence of proptosis or other aspects of ophthalmopathy (periorbital edema, chemosis, optic nerve compression) are seen only in Graves’ disease.15 Exquisite thyroid tenderness and recent onset of symptoms suggest subacute thyroiditis; recent pregnancy may indicate postpartum thyroiditis; and the presence of a large nodule may represent an autonomously functioning nodule. Iatrogenic causes of thyroiditis include iodine exposure (including iodinated contrast agents), amiodarone-induced thyrotoxicosis (AIT), lithium, tyrosine kinase inhibitors, and immune therapy agents such as programmed death receptor (PD)-1 and cytotoxic T-lymphocyte–associated protein (CTLA)-4 inhibitors.16–18 The absence of thyroid pathology in the appropriate clinical setting may suggest accidental or surreptitious patient use of thyroid hormone, often exogenous T3 if symptoms are severe. Lastly, patients presenting with thyroid storm may not have a prior known diagnosis of thyroid disease (up to 30% of patients in one series19), and therefore clinician suspicion for underlying hyperthyroidism as a cause of clinical manifestations is paramount. The most common events precipitating thyroid storm are infections, ACS, venous thromboembolism or pulmonary embolism, trauma, surgery, childbirth, diabetic ketoacidosis (DKA), or discontinuation of medical treatment of Graves’ disease, with many other potential causes possible.4,13,15,20 Unusual causes of thyroid storm reported in the literature include strangulation,21 stew containing marine neurotoxin,22 and thyroid impaction by a fishing trident.23 In short, any stressful event or concurrent medical condition may be a destabilizing force to push a patient with thyrotoxicosis into thyroid storm.
LABORATORY FINDINGS
If thyrotoxicosis in the hospital is suspected clinically, serum thyrotropin (thyroid stimulating hormone; TSH) is the most important test to establish this diagnosis definitively. In patients without a previous diagnosis of thyroid disease, obtaining a free thyroxine (T4) is also a practical
TABLE 1.1 Common and Significant Causes of Thyrotoxicosis
Increased Thyroid Hormone Production
Diagnosis
Graves’ disease
Inappropriate TSH secretion
Solitary or multiple thyroid nodule(s)
Trophoblastic tumor or choriocarcinoma
Hyperemesis gravidarum
Familial gestational hyperthyroidism
Stuma ovarii
Mechanism
Stimulatory TSH receptor antibody
TSH-secreting pituitary adenoma or pituitary resistance to thyroid hormone
Autonomous thyroid hormone production by one or more adenoma(s)
HCG stimulation of the TSH receptor
Mutant TSH receptor with increased sensitivity to HCG
Ovarian teratoma with functional thyroid tissuea
Increased Thyroid Hormone Without Increased Production
Diagnosis
Subacute thyroiditis (de Quervains’, granulomatous)
Excess exogenous thyroid hormone administration (particularly T3 containing)
aIncreased hormone not by the thyroid itself but by extra-thyroidal tissue.
HCG, Human chorionic gonadotropin; T3, triiodothyronine; TSH, thyroid stimulating hormone.
and helpful test to demonstrate the presence and degree of thyroid hormone excess. However, the degree of thyroid hormone excess is not helpful in determining which patients simply have severe thyrotoxicosis and which have thyroid storm.3,24,25
When thyroid storm is suspected, other biochemical testing will help to determine the existence of organ system failure and/or presence of other acute conditions. Although laboratory information can be helpful in the evaluation of these patients, there is no test that confirms or excludes the diagnosis of thyroid storm.4,26 Many laboratory abnormalities, including mild hyperglycemia, hypercalcemia, normocytic anemia, and elevation in alkaline phosphatase, are commonly seen in thyrotoxicosis.26 Because serum creatinine levels are lowered in the thyrotoxic state, providers should recognize that acute kidney injury may be underestimated. Despite frequently exhibiting mildly increased international normalized ratio (INR), studies have indicated relative hypercoagulability and increased risk of thrombosis in thyrotoxic patients. Elevated transaminase levels may be present in thyroid storm complicated by hepatic dysfunction, and elevated bilirubin is a particularly important finding, as it has been correlated with adverse outcomes in thyroid storm.8,27
It is critical to identify concurrent illnesses that may be precipitants of thyroid storm. In addition to a thorough physical examination, sources of infection may be identified through urinalysis, blood cultures, chest and abdominal imaging, or lumbar puncture as clinically indicated. Evaluations should include looking for potential ACS, hyperglycemia and ketosis consistent with DKA, and drug use (especially cocaine and methamphetamines).
DIAGNOSIS OF THYROID STORM
Thyroid storm is a clinical diagnosis. Hospitalized patients with suspected or confirmed thyrotoxicosis should be evaluated for the severity of disease to identify those with clinical decompensation who would be defined as having thyroid storm. Coming to absolute agreement on the diagnosis of thyroid storm is less important than identifying the subset of thyrotoxic patients with the features of thyroid storm, because these patients are at the highest risk of morbidity or mortality and should receive emergent and directed therapy.
Traditionally, thyroid storm has been recognized as a clinical syndrome involving thyrotoxicosis, hyperthermia, alerted mentation, and a precipitating event.13,28,29 These findings, along with clinical evidence of congestive heart failure, identify patients at greatest risk for adverse hospitalbased outcomes and mortality.8 Biochemical confirmation of thyrotoxicosis is not necessary to diagnose thyroid storm and treatment of suspected thyroid storm should not be delayed awaiting test results. However, in unclear cases, TSH concentration should be suppressed, confirming the presence of clinically significant thyroid hormone excess. TSH levels will most often be at the lower limit of detectability (e.g., 0.01 mIU/L) or undetectable.8 Mildly reduced TSH concentrations (0.1–0.5 mIU/L) frequently seen in patients with nonthyroidal illness, or the “euthyroid-sick syndrome,” are less suggestive of thyroid storm. The absolute level of thyroid hormone elevation is not predictive of the presence or absence of thyroid storm.8
Any elevated temperature should be considered consistent with thyroid storm, but fevers will frequently be pronounced (>102°F). Additional clinical manifestations of thyrotoxicosis will frequently be present, but are less specific and often present in patients with severe thyrotoxicosis without thyroid storm. Because of the subjectivity of these assessments, the variability of patient presentations, and significant overlap between these features and other acute medical conditions in hospitalized patients,4,8,13 more objective diagnostic criteria have been published.
The Burch-Wartofsky Score (BWS) (Table 1.2) assigns points for dysfunction of the thermoregulatory, central nervous, gastrointestinal-hepatic, and cardiovascular systems, with increasing points given for greater severity of dysfunction.30 A score of greater than 45 is considered highly suspicious, and very sensitive, for thyroid storm, but this cut-off is not specific, indicating thyroid storm in patients for whom this label is likely not appropriate.8 Furthermore, a patient with a score below 45 may still clinically be considered to have thyroid storm for which treatment should be given. Although potentially useful in quantifying disease severity, the numerical score should not supplant physician judgment. Other reported diagnostic criteria have not been clinically validated. Regardless of the precise criteria used, once a diagnosis of thyroid storm is confirmed or highly suspected, treatment should be initiated without delay.
TREATMENT OF THYROID STORM
The treatment of thyroid storm should be initiated as early as possible after recognition of the diagnosis. The essential elements of treatment (Table 1.3) involve: (1) intensive supportive care; (2) decreasing β-adrenergic receptor stimulation; (3) decreasing thyroid hormone production and release; (4) decreasing the peripheral availability of T3; and (5) the treatment of precipitating or intercurrent medical conditions. Multimodality treatment addressing these aspects of thyrotoxic decompensation is crucial. Advances in intensive care practices and specific therapy have been
TABLE 1.2 Burch-Wartofsky Diagnostic Criteria for
Thyroid Storm
driving forces in reducing the mortality of thyroid storm from 100% to approximately 8% to 25% in recent series.8,31,32 Notably, for patients with severe thyrotoxicosis who are considered to have “impending” thyroid storm based on clinical evaluation or a BWS of 25 to 45, similar treatment to thyroid storm may be considered.
Supportive Care
Hemodynamic stabilization is critical in cases of thyroid storm as it is for all unstable patients, but warrants specific consideration because of differences in the underlying physiology of
TABLE 1.3 Essential Treatment of Thyroid Storm
Supportive Therapy
Hemodynamic Support
Intensive care unit admission
IV fluid resuscitation
Consider invasive hemodynamic monitoring
Intubation and mechanic ventilation
Vasopressor agents
Reduce Hyperthermia
Cooling blankets, ice packs
Acetaminophen, chlorpromazine
Treat Underlying Conditions
Appropriate management for concurrent illnesses (may include broad spectrum antibiotics, medication or interventions for acute coronary syndromes, continuous glucose infusion for diabetic ketoacidosis, blood products and analgesia for trauma)
Disease-Specific Therapy
Treatment
β-adrenergic blockadea
Inhibit β-adrenergic receptor stimulation
Inhibit T4→T3 conversion
Propranolol Esmolol
Antithyroid Drugs
Iodines
Glucocorticoids
Inhibit thyroid hormone production
Inhibit T4→T3 conversion (PTU)
Inhibit thyroid hormone release from the thyroid
Inhibit T4→T3 conversion
Treat possible concurrent adrenal insufficiency
PTU
Methimazole
SSKI
Hydrocortisone
IV: 0.5–1.0 mg every 4 h; continuous infusion 5–10 mg/h
PO: 60–80 mg every 4 h continuous infusion 0.05–0.1 mg/kg per min
POb: Loading dose
500–1000 mg, 250 mg every 4 h
POb: 60–80 mg daily
5 drops (50 mg/drop, 250 mg) every 6 h
IV: Loading dose 300 mg, 100 mg every 8 h
aOther beta-blockers (e.g., metoprolol, carvedilol) have not been specifically studied, but may be appropriate based on clinical circumstances.
bIn patients unable to take PO medications, nasogastric tube administration can be considered. IV and per rectum dosing has been reported in the literature (see text).
IV, Intravenous; PO, per os (orally); PTU, propylthiouracil; SSKI, saturated solution of potassium iodine.
thyrotoxicosis. Because of the frequent need for invasive therapies and close monitoring, management in the intensive care unit (ICU) is most appropriate for cases of thyroid storm.
Optimization of volume status is a paramount consideration in the initial management of thyroid storm.13,26 Insufficient volume status may be due to absolute volume depletion from
diaphoresis or gastrointestinal losses, or inadequate volume to maintain perfusion due to vasodilation or reduced cardiac function. The etiology of shock may be multifactorial, and invasive hemodynamic monitoring with pulmonary artery catheterization is often appropriate. When hypotension is not responsive to fluid resuscitation, vasopressor agents may be required for hemodynamic support. Care should be taken when using sedatives, narcotics, and diuretics that may lower blood pressure and worsen hypoperfusion.4
The treatment of hyperthermia may be accomplished through cooling measures such as cooling blankets or ice packs. Medical treatment with acetaminophen is preferred because salicylates inhibit thyroid hormone binding to serum proteins, thereby increasing free hormone levels.33 Treatment of the central mechanisms of increased thermogenesis can be addressed by intravenous (IV) chlorpromazine 25 to 50 mcg or meperidine.4
Finally, addressing underlying illnesses is a vital aspect in the treatment of thyroid storm.15 Appropriate management will necessarily depend on the etiology. Broad-spectrum empiric antibiotics should be considered given the frequency with which infections are implicated.
Beta-Blockers
Blocking of β-adrenergic receptor activity is one of the most important aspects of therapy of thyroid storm. Mazzaferri et al.1 demonstrated a significant reduction in thyroid storm mortality after introduction of therapy reducing β-adrenergic stimulation. Decreased β-adrenergic activity may improve tachycardia, cardiac workload, oxygen demand, agitation, tremor, fever, and diaphoresis. Propranolol inhibits the type 1 deiodinase enzyme that converts T4 to T3 at doses above 160 mg per day, and therefore can additionally contribute to reducing the availability of active thyroid hormone.
Regimens include initial IV propranolol doses of 0.5 to 1.0 mg, followed by continuous infusions of 5 to 10 mg/hour.4 Oral propranolol may be given at 60 to 80 mg every 4 hours. The short-acting β-adrenergic blocker esmolol is an alternative used as a 0.25- to 0.50-mg/kg loading dose followed by continuous infusion rates of 0.05 to 0.1 mg/kg per minute.34,35 Fluid resuscitation should be utilized to support blood pressure during use of beta-blockade. Therapy should be titrated to achieve heart rates of 90 to 110 bpm in afebrile patients rather than slower rates.4 Several case reports have raised concerns regarding the use of beta-blockers in thyroid storm due to cardiovascular collapse suffered after initiation of therapy.36–40 This may have been due to the over-vigorous applications of beta-blockade and/or insufficient volume replacement. Careful monitoring and use of shorter-acting agents aim to attenuate this risk. Some have considered beta-blockers relatively contraindicated in patients with CHF or reactive airway disease,41 but given the fundamental role of beta-blockade in the management of thyroid storm, use should not be omitted unless absolutely necessary.
Antithyroid Drugs
Antithyroid drugs (ATD), methimazole and propothyouracil (PTU), inhibit the enzymatic steps necessary for thyroid hormone production. PTU is favored in the treatment of thyroid storm because it decreases peripheral conversion of T4 to T3, and has been shown to reduce serum thyroid hormone levels more rapidly than methimazole.42,43 Though the absolute risks are very small, vasculitis and hepatic failure are more frequent side effects of PTU compared with methimazole.44 Other adverse reactions of ATD therapy include agranulocytosis, transaminase elevation, cholestasis, or urticarial rash. A previous significant adverse reaction such as agranulocytosis is a contraindication to ATD use. If other adverse reactions occur with PTU use, treatment with methimazole can be attempted. Recommended PTU treatment is a loading dose of 500 to 1000 mg, then 250 mg every 4 hours. Alternatively, methimazole is administered at 60 to 80 mg daily.15 ATD should be given at least 1 hour before iodine preparations in the treatment of thyrotoxicosis to prevent iodine from being used to produce additional thyroid hormone.
Only oral formulations of ATD are available in the United States, but patients with vomiting, altered mental status, or critical illness may have barriers to enteric administration or absorption of medications. Rectal and intravenous formulations of ATD have been employed to address this.45 Per rectum administration of PTU and methimazole has been reported, but requires specially made suppository or enema formulations. One study made an IV preparation of PTU dissolving tablets in isotonic saline with an alkaline pH of 9.25 to create a dose of 50 mg/mL. Perhaps because it is more readily soluble, IV methimazole has been more frequently reported, with reconstitution in 0.9% saline solution and given as a slow IV push.46,47
Iodine
Inorganic iodine produces rapid decreases in thyroidal hormone release and circulating thyroid hormone levels near normal within 4 to 5 days.48 This may be given as saturated solution of potassium iodide (SSKI) 250 mg every 6 hours. Iodine treatment should not be started until 1 hour after administration of ATD in order to prevent iodine incorporation and increased production of thyroid hormone.13 The benefit of iodine treatment is likely limited to 72 hours of treatment.
Lithium
Lithium causes inhibition of thyroid hormone release from the thyroid and has been utilized in the treatment of thyroid storm.49 Data regarding the efficacy of lithium are limited, but expert guidance for dosing recommends 300 mg lithium carbonate given every 6 hours with titration to serum lithium levels of 0.8 to 1.2 mEq/L.15,26 Although not a component of standard therapy, lithium is occasionally used in cases where ATD are contraindicated.
Steroids
The use of glucocorticoids in the treatment of thyroid storm acts to reduce conversion of T4 to T3, as well as addressing the possibility of concurrent adrenal insufficiency that may exist, particularly in autoimmune etiologies of thyrotoxicosis. An initial dose of hydrocortisone 300 mg followed by 100 mg every 8 hours is considered adequate therapy.15 Glucocorticoids may worsen hyperglycemia. Animal and human studies have raised concern that glucocorticoid use post–myocardial infarction is associated with ventricular thinning and free wall rupture,50 but a metaanalysis of the limited data available did not find an increased risk.51 Glucocorticoid therapy should still be considered carefully in this population. Another population where the use of steroids should be considered on an individual basis is patients with thyroid storm due to checkpoint inhibitor immunotherapy (e.g., PD-1, CTLA-4 inhibitors). These drugs mediate a destructive thyroiditis, the severity and duration of which were not significantly decreased by glucocorticoid use in one retrospective analysis,18 and it remains unclear whether steroids may decrease the effectiveness of cancer immunotherapy.
Adjunct Treatments
In cases where patients remain critically ill despite therapy for thyroid storm, or when aspects of therapy are contraindicated, adjunctive therapies have been employed, including plasmapheresis, L-carnitine, and thyroidectomy. Perhaps the most common situation when these adjuncts are considered is in the face of life-threatening thyrotoxicosis in a patient with contraindications to ATD (e.g., agranulocytosis, hepatocellular injury). The evidence for these measures remains largely anecdotal or retrospective, but may be considered when standard therapy is insufficient. Plasmapheresis, or therapeutic plasma exchange, is an adjunctive therapy used in patients with severe thyrotoxicosis or thyroid storm who remain critically ill despite standard therapy.52–55 Treatment has been reported to reduce free thyroid hormone levels and result in clinical improvement. Plasmapheresis has been employed in the preoperative period to improve manifestations of thyrotoxicosis and enable patients to undergo surgery more safely.56
The proposed mechanism of plasmapheresis therapy in thyroid storm is removal of circulating thyroid hormone, which has a long serum half-life and is largely protein bound. In this procedure, patient plasma is extracted from other blood components and replaced with a colloid solution, such as fresh frozen plasma and albumin. Thyroid-binding globulin with bound thyroid hormone is removed, and colloid replacement provides new binding sites for circulating free thyroid hormone. Estimated adverse event rates of 5% include transfusion reaction, citrate-related nausea, vasovagal or hypotensive reactions, respiratory distress, and tetany or seizure.
The use of plasmapheresis can be considered in patients refractory to conventional therapy, particularly when ATD are contraindicated, as a stabilizing measure or bridge to safer definitive surgery, or for destructive etiologies of thyroid storm (e.g., thyroiditis, AIT) that are less responsive to ATD. The usual plasmapheresis protocols reported in patients with thyroid storm used a 2.5- to 3-L volume of combined fresh-frozen plasma and 5% albumin.53,55,57–59
Additionally, use of albumin-based dialysis when initial plasmapheresis was unsuccessful has been reported.60,61 Thyroid hormone is ineffectively cleared by usual hemodialysis, but rapid hormone clearance may be achieved with continuous renal replacement therapy or other equivalent forms of continuous hemodialysis with albumin supplementation to dialysate in hemodynamically unstable patients. Techniques extrapolated from those used in liver failure and hepatorenal syndrome have been reported for thyroid storm, including 4% human serum albumin with blood flow at 150 mL/minute, dialysate flow at 1.5 L/hour, and durations lasting 12 hours.61 Furthermore, because of the continuous nature of these therapies, which are not dose limited by the exchange transfusion risks of plasmapheresis, more cumulative thyroxine may be removed.60,61
L-carnitine has been suggested as a therapy for hyperthyroidism and thyroid storm, usually in cases refractory to conventional therapy or where ATD are contraindicated. The proposed mechanism of action is inhibition of thyroid hormone (T3) uptake into cell nuclei by amine L-carnitine. Several case reports of L-carnitine in thyroid storm claim clinical improvement in mental status, but results are confounded by concurrent administration of other treatments.62–64 The current data are insufficient to suggest use of L-carnitine in thyroid storm patients.
Thyroidectomy provides definitive therapy for thyrotoxicosis caused by thyroidal production or release of hormone. Thyroid surgery may be considered particularly in cases with hyperthyroidism due to more persistent and recalcitrant causes, such as refractory AIT or Graves’ disease. In thyroid storm, the benefit of thyroidectomy is often weighed against the risk of anesthesia and surgery. Retrospective reports of total or subtotal thyroidectomy in thyrotoxic patients demonstrate decreased serum thyroid hormone levels and clinical improvement over 2 to 10 days postoperatively. Kaderli et al.65 described a cohort of 11 patients with AIT who failed medical therapy and were treated with total thyroidectomy under general anesthesia. In this series there were no major intraoperative complications, no incident thyroid storm, and all patients survived. Similar results were seen in earlier series of AIT, including in patients with significant heart failure.66–68 In patients with thyrotoxicosis due to Graves’ disease, a recent retrospective case series compared surgical outcomes in 247 patients undergoing elective thyroidectomy after complete medical control of Graves’ disease versus 19 patients undergoing urgent thyroidectomy after rapid optimization for 1 to 2 weeks, at a single center.69 This study found no differences between populations with regard to the incidence of thyroid storm, vocal cord palsy, postoperative bleeding, or hypoparathyroidism. Although prospective, randomized data is lacking, these studies suggest that, in patients intolerant of standard medical management, with an experienced multidisciplinary team, surgery may be considered as an alternative definitive therapy.
TREATMENT OF COMPENSATED THYROTOXICOSIS
Patients without thyroid storm who are nonetheless thyrotoxic may benefit from diseasespecific treatment while hospitalized. Adequate fluid resuscitation should be provided to
adequately correct hypovolemia. The application of beta-blockers for the amelioration of adrenergic symptoms is generally appropriate regardless of the etiology of thyrotoxicosis, with initial doses of propranolol of 10 to 40 mg every 8 hours, or an equivalent, depending on the degree of symptoms, blood pressure and heart rate tolerability, the presence of CHF, and any contraindications. The use of beta-blockers, diuretics for management of volume excess, or sedative-hypnotics for treating insomnia or anxiety must be monitored closely, as blood pressure reductions and hypoperfusion can precipitate thyroid storm.
Socioeconomic Factors
Compared with compensated thyrotoxicosis, thyroid storm portends a higher hospital mortality, greater incidence of ICU admission and intubation, and overall longer hospital and ICU length of stay.8,9 Additionally, within patients diagnosed with thyroid storm, patients who were male, older than 65 years, Black, and who had multiple other comorbid conditions had longer hospitalizations and greater healthcare costs.9 Sherman et al.70 previously reported that poor socioeconomic conditions were a risk factor for complicated thyrotoxicosis and thyroid storm. These findings were recently corroborated by a retrospective study of thyrotoxic patients from 2011–2017 by Rivas et al.,19 with an increased risk of thyroid storm associated with lack of health insurance, lower education, and residing in areas with lower median income. These factors likely underlie, in part, the higher frequency of thyroid storm reported among patients with thyrotoxicosis in studies based at medical centers serving large underserved populations8,19 compared with nationwide, database studies.9 Given the higher morbidity, mortality, and healthcare costs associated with thyroid storm, improving access to medical care and addressing societal factors leading to medication noncompliance or late diagnosis of thyrotoxicosis may be steps to improve outcomes for thyroid storm.
Follow-up After Discharge
Discharge plan should include a timely follow-up visit with an endocrinologist for continued treatment. Interruption of prescribed doses of beta-blockers, antithyroid drugs, or steroids can result in recurrence of clinical symptoms. Strong consideration should be given to definitive treatment of persistent causes of thyrotoxicosis, such as Graves’ disease, given the possibility of further morbidity or thyroid storm if there is recurrent thyrotoxicosis.
Conclusions
Thyroid storm is a rare but life-threatening endocrine emergency that must be considered in the presentation of a patient with thyrotoxicosis. When diagnosed, prompt treatment should be initiated to correct hemodynamic instability and attenuate the presence and effects of excess thyroid hormones. Application of current critical care medicine and multimodality treatment of thyrotoxicosis has been successful in substantially lowering the mortality of thyroid storm.
References
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2. Pimentel L, Hansen KN. Thyroid disease in the emergency department. A clinical and laboratory review. Clin Lab Em Med. 2005;28(2):201–209.
3. Tietgens ST, Leinung MC. Thyroid storm. Med Clin North Am. 1995;79(1):169–184.
4. Nicoloff JT. Thyroid storm and myxedema coma. Med Clin North Am. 1985;69(5):1005–1017.
5. Maddock WG, Pedersen S, Coller FA. Studies of the blood chemistry in thyroid crisis. JAMA. 1937; 109(26):2130–2135.
