ENDOCRINE CRISES (0889-8529/93 $0.00 ~ .20 LIFE-THREATENING THYROTOXICOSIS Thyroid Storm Henry B. Burch, MD, and Leonard Wartofsky, MD, MACP ‘The clinical spectrum of thyrotoxicosis ranges in severity from asympto- ‘matic biochemical abnormalities to a cataclysmic metabolic crisis with mullisys- tem dysfunction and high associated mortality rate. A number of factors contribute to determine the point in this continuum at which an individual thyrotonic patient appears, These include patient age, the presence of concur- rent illress such as infection or cardiovascular disease, and the rapidi:y of onset of thyroid hormone excess. Thyroid crisis or storm is precipitated when the aggregate effect of these parameters surpasses the individual patient's ability t maintain adequate metabolic, thermoregulatory, and cardiovascular compensatory mechanisms. Despite the absence of uniform criteria for defining the poirt at which severe thyrotoxicosis becomes thyroid storm, certain clinical features, such as advanced fever, mental status aberration, and evidence of ‘multisystem involvement, are important harbingers of thyroid storm yet are ‘uncommon in uncomplicated thyrotoxicosis. The high morbidity and morality still associated with this disorder underscores the critical requirement for early recognition of these disease concomitants if an accurate diagnosis and life- saving therapeutic intervention are to be accomplished, CLINICAL PRESENTATION General Features The clinical features seen in uncomplicated thyrotoxicosis are generally present and often accentuated in thyroid storm. Thus, the majority of patients “will have goiter and, in the presence of Graves’ disease, concurrent ophthal- From the Endoctine-Metabolic Service, Kyle Metabolic Unit, Department of Medicine, ‘Walter Reed Army Medical Center, Washington, DC; and the Uniformed Services University ofthe Health Sciences, Bethesda, Maryland ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA ‘VOLUME22 + NUMBER2-]UNE 19 263264 BURCH & WARTOFSKY mopathy, lending early reviewers to desrbe thyroid storm as “the esis of rophthsimic goer The heat intolerance and dlaphoress common in simple thyrotoxicosis tay be manifest in thyroid storm a8 severe hyperpyrexia wih temperatures occasionally in excess of 10S." The eandiovascuar findings of mld tormoderate sinus tachycardia found in uncompeated thyrotoxicosis may be supplanted in thyroid storm by an accelerated tachycardia, often over 140 beatsfnin, and a high propensity for atrial dyerhythmiae™* 25 well as varying Aegres of venrclsdysuncion and congestive heat aur” The sly tnd resissness common to simple thyrotocossfrequenly are superseded in thyroid storm by severe apation, delta, o Frank psychosis, progressing in Some instances to stupor and coma.” " * ® Gastrointestinal and hepatic involvement, commonly limited to an enhanced intestinal transport and id transaminase elevation in imple thyrotoxicosis, may dominate the presentation in thyroid storm, with nase, vomiting, fark diaahea, and marked hepato Cillular dysfunction manifested by ounce" “Although not universally present or recognized, a key clinical feature in thyroid storm is the presence of a preiplating event of intercurrent iness. ‘Thyroid surgery, once the most common precipitant of thyroid storm, has become a relatively rare cause of this disorder.° Ths is largely attbutable to the current practice of rendering the thyrotoxc patent euthyroid before surgery ts well as (0 a decrease In the number of patients being subjected to surgery swing to the general popularity and elicay of sadioindine ablation therapy for thyrotoxicosis Nonthyroidal surgery in patients with unrecognized Inyro- toticosis may continue to act as surgical preiptant of thyroid storm.” A list of events Known to be astocated withthe precipitation of thyroid stom is Shown in Table 1. These ean be grouped into thove conditions associated with a rapid increase in circulating thyroid hormone levelsand those associated with an underlying acute or subacute nonthyroidal ness as will be discussed later Recognition of Impending Storm: Diagnostic Criteria ‘The most important determinant of effective clinical management in life- threatening thyrotoxicosis is early zecognition and institution of appropriate therapy. A common theme in early clinical series of severe thyrotoxicosis was ‘rapid downward spiral, culminating in death within hours to days of crisis Thyroid surgery withdrawal of anuthyeoid drug therapy FRadiolodine therapy Vigorous thyroid palpation Todinated contrast dyes Conditions Astociated with an Acute or Subacute Nonthyroldalliness Nonthyroidal surgery Infection ‘Cerebrovascular accident Pulmonary thromboembolism Paruron Diabetic ketoacidosis moter sessLIFE-THREATENING THYROTOXICOSIS 265 onset * Even with modem therapeutic and technologic advances, any delay in establishing this agnosie may up the balance from csi revere! tovard & fatal ontcam®s Yet, the clnicen’s dingronte eflrts ee thwted om vcr fronts Fret, inboratory parameters have historically been of ie value in disingushing uncomplicted thyrotoxicosis from thyroid storm owing to ex tensive overlap in serum levels of thyroxine (T.) and tiodothyronine (levels between these two groups The recent recognition ofa relative increase in free hermone levels'inthyrod cise patients compared to those with uncom Plicated thyrotoxicosis" may have more import in deciphering the pathogenesis 1 thyroid storm than in providing a iagnos,becaise even a roclyeteated free T level cannot be considered diagnostic of an impending criss in the ateence of other characterise clinical features, Next, published diagnostic criteria for thyroid storm are far from uniform, Lahey, "in 1926, described early Signs of exis 08 those of increasing toxcty” witha pulse rate reaching "200 or move," and temperature “normal or elevated 10.108 or 10S." Hayley! tmphasized the symptom compler of “slepless nights, Giahes, anorexia, Vomiting, marked sweating, and great emotional insabiiy” as having dag. rosie importance in predicting impending thyroid storm. McArthur etna 1047 review of 36 cases of thyrokd crisis at Massachusetts General Hospital, Geined tis entity simply a8"s lifeendangering gmenttion ofthe symptoms of thyrotoicosis in which the patient's esponse is ou of proporion to the exciting stimulus” Rives et al in 1951, defined thyroid storm somewhal mare concretely as the combination of "ever above 1038, a pulse rte In exess of {M0 per minute, extreme reslessness, and augmenttion ofthe usual picture ct hyperthyroidism.” Finally, Walsten et an 1960 publication retired 9 tempermture of 100° or greeter and “masked tachycardia" in association with “fegenuaed signs and Symptoms of thyrotoxicosis,” to which Mazzafer et ain 96 added a fourth, optional cterion conceming evidence of dysfunction in one or more of the cental nervovs, cardhovacsar, or gastrointestinal systems. Although hyperthermia, marked tachycardia nd central nervous system dysfunction are agnostic criteria common to each of these se7iews, fuumerous examples can be found in the Ierature in which one or more of these fetures was either a minor controutoror absent In any piven patient the net effect of multiple contbuting aberrancies and unique predispentions wil culminate in thyroid stormy therefore, the authors have’ constructed diagnostic point scale forthe purpose of enabling a semiguantiative distinction betieen uncomplicated thyrotoxicosis, impending thyroid storm, and estab lished ‘hyrotote storm Cable 2). When applied to 61 cases in the itertae in tihich sulfcentindvidal patient data wae avalabe, the point scale identified 5 cases a8 thyrovd storm and redatiied two cases a8 impending, sor Although obviously no substitute for sound clinical judgement, the se of euch 2 point sale may facitate prompt recognition of impending thyrotd storm and hence, an early’comimitment tovan aggressive therapeutic proach. Further, Compasson of festures such as survival in varios sees of thyroid ston with divergent diagnostic criteria is greatly facilitated with a scle such as that proved. ‘Atypical Presentations of Thyroid Storm Thyrotoxic storm has occasionally been described in patients with masked or “apathetic” hyperthyroidism. Lahey* was the fist to recognize this variant of hyperthyroidism, which he noted to occur in an older patient population,266 BURCH & WARTORSKY Table 2. DIAGNOSTIC CRITERIA FOR THYROID STORM ‘Thormoregulatory Dysfunction Cardiovascular Dysfunction Temp Tachycardia 99-999 5 90-109 5 400-1009 10 Hot8 0 tor-1018 6 120-129 16 302-1029 20 130-198 20 403-1039 25 140 Ey 21040 20 Central Nervous System Etfects Absent © Congestive Heat Failure Mi 10 Absent ° Agitation Mig 5 Moderate dal edema, Delia 20 Moderate 10 Poychosis Bibaslar ales Extreme lethargy Severe 16 Severe 30 Pulmonary edema ‘Solzure ata! Fiaion Coma ‘Rosent o Preeant 10 Gastrointestinal-Hepatic Dysfunction Absent © Precipitant History Moderate 10 Negative o Diarihea Pose 10 Nausoa/vomiting ‘Abdominal palo Severe 20 Unexplained jauncice “in patois with severe yates, pois are assigned fo be Highest wailed descrpion ‘opteabve in oaen category and sores flies. When itis nt posal to eutralch tho at ot an ‘rca nest rom toe ote severe tyrolocoas ger e portsafe awarded uch a6 aver {he sagnoss of torn and heres, empire Nerapy. A sco of 4 ot gears Nighy suggest af {roid sor: a saore of 25-44 euggotve of pening Storm, anda soore Blow 25 eka ‘epresert yl som frequently in individuals without prominent goiter er exophthalmos, with a genenly lower pulse rate and tendency to lapse “comfortably, ously" into ‘semistupor and death with “ practically none of those gruesome activation signs which accompany death withthe ypc activation thyridsm.” Others have since expanded on this entty.**” Although most commonly seen in the elderly, apathetic thyrotoxicosis with thyroid storm has since been described in all age groups,” including pediatric patients.” Other reports have described thyroid. ‘crisis presenting initially as coma, « status epilepticus,® and nonembolic ‘cerebral infarction.” Even less common presentations nave included abdominal pain and fever in a young woman” and acute renal failure resulting from an Apparently associated shabdomyolysis” PATHOPHYSIOLOGY ‘The exact pathogenetic mechanisms underlying thyroid storm remain poorly understood. The relative rarity of this disorder, the need for immediate ‘therapeutic intervention once recognized, and the diversity of precipitants and presenting characteristics in individual cases have all contributed to thisLURE-THREATENING THYROTONCOsIS 267 knowledge deficit. Modern hypotheses regarding the pathogenesis of thy Storm should incomporateadvanees in our ndestaning ofthe mechanism of thyroid honmone Action at the cllsar level Tia acon in dependent on hormone entry into target cell nucle, where, fllowing binding to specific thyrold hormone receptors, a direct interaction with nidelc aid segments known as thyroid response elements occurs. This interacon permits thyroid hormone mediation of ssue specific gene exprestion, witha resultant alteation in callar and tseue metabolism ‘Ar enhanced avalablity offre thyroid hormone for ellular entry would therefore intultvely seem to occupy a central role inthe exaggerated ate of thyrotcsicosis and subsequent decompensation characteristic of thyroid storm. Yetras noted earlier, no clear distincion between uncomplicated thyrotoicos snd thyroid storm ean be made sed on absolut level of ereulatng thyroid Rormones. Recent studies have shown, however, significant elevations free thyroie hormone levels in thyroid storm patents compared to those with uncomplicated thyrotoxicosis. A report by Brooks and Waldsei" reveled a signifant elevation in free T, concentrations in a series of five thyroid storm patient compared to a larger grou of patients with simple thyrotoncosi, Gespite the presence of similar levels of total T,. In a recent case report modes: elevations in total thyroxine and normal levels of taal T, were som panied by marked elevations in free T, and free T, ina patient who developed fhyroie storm after discontinuation of thionamide therapy. Interesting, the authors ofthis latter study demonstrated a tranient thyroxine binding ghbulin deficiency a the inception of thyroid storm, which reversed with rss recovery iivanother case report,” total and fre T, levels were within the normal ange, Yet total and fee Teves were sgnlicanly elevated in.a patient who developed thyroic storm after » subtotal thyroidectomy. Indeed, an elevation in the percent fey dalyzable'T, and T, has been well desrbed In patent with onthyroida nesses" * explaining perhaps, in prt, the diverse assoriment of molica conditions capable of predpiating thyroid storm (eee Table 1) Enhanced cellular availabity of free thyroid hormone may also have pahoge pate imporance nthe group of precptnts ascited wih in total and free thyroid hormones. Hence, a transient saturation of plasms binding capscty sulicien to increase concentrations of unbound hermone ‘would by this model result in increased celular enzy of re thyroid hormone ‘Additonal support for the. possble importance of this mechanism inthe pathogenesis of thy7old storm comes from observations of prompt dinkal Fesponae inpatient with refractory thyroid storm following rapid normalization of farctlating hormone levels through plasmapheresis or charcoal plasnaper. fusion?" Lastly in further support of this mechanism, the development of thyroid criss following the acute ingestion of thyroid hormone has been ll documented in two previous case reports," although this isnot an inetable Steven typ outcome ofaceldentl thyroid Ronmone overdose ™ “Adrenergic estem activation likely plays an important contributory le in the pathogenesis of both uncomplicated hyrotoncosis and thyroid storm, Many of the clinial features of severe thyrotoxicosis, including agiation, tachycardia, dysthythmia, and. hyperthermia, may be owing to either direct Catecholamine action or an interaction between the adrenetglc system and ‘rcesthe culating thyroid Rormone Probably the best evidence for 8 Significant ole ofthe adrenergic system in this disorders the dramatic dca improvement afforded thyroid csi patents following the addition of spe tttenergic blockade tothe therapeutie regimen. Ths is mast css seen in arly sports on the use of B blockade in thyroid cis, in which patent with268 BURCH & WARTOFSKY continued deterioration during conventional combination therapy with antithy- roid drugs, stable fodine, and corticosteroids experienced a remarkable clinic turnaround following the addition, often in desperatin, ofthis “newer” mode of therapy." *"" Certain experimental findings mitigate against the existence of primary adrenergic system defect atthe root of thyroid storm, however, ‘These include the observation that circulating levels of catecholamines are normal or low in thyroid storm-* the finding that propranolol, even at high foses, dacs not always. prevent or ameliorste thyroid storm,*°*" and the finding that propranolol therapy has no. effec on either thyroid hormone synthesis or felense.” The hyperadrenergic state seen both in thyrotoxicosis and thyroid storm may be owing, in port, 10 influences such as a thyroid hormone mediated increase in taeget cell fradrenenge receptor density and postreceptor mechanisms,” although this remains somewhat controversial.” ‘A nlmber of additional mechanisms may be operstive in the pathogens of thyroid storm in patents with an undetiying acite or subacute nonthyroidal iiiness. A paral decoupling of oxidative phosphorylation as result of such disorders, leading to an enhanced rat of lipolyss, whch, following subsequent fatty acid oxidation, could contribute to the heightened oxygen constimption, calorigenesis, and hyperthermia characteristic of thyroid storm has been pos. tulated to occur. Preferential production of thermal energy over adenosine triphosphate trough this mechanism could also contribute fo the hyperthermia seen in this disorder **™ A decreased hepatic and renal clearance of thyroid hormone during systemic illness" as well as enkanced generation of the metabolically active T, congener, triodoacetic acid (TRIAC), may each also be of pathophysiologic significance in thyroid storm. Lastly, an augmented tissue response to a given level of circulating thyroid hormone during nonthyroidal iliness has also been proposed ss a. potentator of thyroid storm. Modem mechanisms for such activity could ental enhanced cellular or nuclear entry of hormone, an alteration in binding to niclosr hormone receptors, or altered binding of the hormone-receptor complex to thyro response clement in target genes, although experimental evidence in support ofthis hypothesis is Inching ‘Although the mechanisms underlying the pathogenesis of thyroid storm remain incompletely understood or speculative, important inferences can be Gerived from ‘he available data. A dramatic increase in free hormone levels is likely s common denominator in the precipitation of thyroid storm, Adtional factors, including poor nutrition and the compliatitg influences of medical, surgical, and emotional stresses on thyroid hormone binding, metabolic clear ance, and general physiologic reserve are other important contributors. I is the net etlect of multple such influences, superimposed ona. susceptible patient substrate, that Fesulls in the catastrophic metabolic crisis of thyroid Storm. ‘TREATMENT General Treatment Strategy ‘The treatment of impending of established thyroid storm is diected at every therapeutically acomsible point inthe thyroid hormone synthetic, secre- tory and peripheral action pathways. Concurzenly, aggresive intervention Is Alected af reversal of ongolng or iniplent decompensation of normal homeo- State mechanisms, An assiduous search fs undertaken forthe precipitant of the crisis Test each of the measures mentioned be performed in vain. TheLUFE-THREATENING THYROTOXICOSIS 269 esive level of care, including continuous monitoring and minute-to-minute {tiation of therapy mandate an intensive care setting forthe early management Gfeoeblslied tyro slo. The therapeutic endeavors in thyroid storm say bbe grouped as follows therapy directed against the thyroid gland, antagonism of te peripheral actions of thyrold hormone, reversal or prevention of systemic decompensation, therapy directed at the precipitating event oF intercsrrent ilnes, and filly, defintive therapy. Therapy Directed Against the Thyroid Gland Management ofthe thyroid storm is outined in Table 3. A nearly complete blockade of new hormone synthesis i established eal In the teatment course throug the use of the anithyroid compotnds popythirad (PTD) or tethinazole (MMA). These agents are not availabe fs parenteral formultions nd ae therefore generally given orally o per nasogaine tube in the stuporou, somata, or ire uncooperative patent, etl emnntaton of cho se sgents hat also been osed succssfally >= 3 Toalng dove of G00 to 100) mg DTU shouldbe given at docs of 100 fo 10D mg day ns 20 to 250 mg every 4 hours. MMi is given ata toll dally dose of 128 mg in divided doses of 20 ing every 4 hours nial blockade of dine orgeifation Table & MANAGEMENT OF THYROID STORM ‘Treatment Directed against the Thyroid Gland Innibiton of new hormone synthesis ‘Thionamide drugs (PTU, MAM) Innition of thyroid hormone release Todine ‘Orel: Potassium iodide (SSK), Lugo’ solution, ipodate Luthitn earbonate ‘Treatmant Directed against Peripheral Effects of Thyroid Hormone Inhibition of Tete, conversion TU Conicosteroids ropranool Inacio, topanoic acl, amiodarone Bradrenerbio blockade Propranolol, cardoselectve p-bocking agents Removal of excess circulating thyroid hormone Plasmaphorosis ‘Charcoal plasmapertusion ‘Treatment Directed against Systemic Decompensation ‘Treatment of hyperthermia “Acetaminophen Cootng Correcion of dehydration and nutitonal defi Flis and olecrolyies ice arine ‘Suoporive therapy Gorteosterods Vasonrescore ‘Treatment of congestive hear falure (digoxin, diuretics) ‘Treatment Directed at a Precipitating Event In Thyrold Storm Etiolegy-dependent therapy270 BURCH & WARTORSKY is established within an hour of administration of either ofthese agents. PTU has the advantage of inhibiting peripheral conversion of, to, a property ot shared by MIMI. As sich, thyroid stor continues to be ofe of several Conditions in which PTU is used preferentially over the more potent antithyroid, ML" Although history of antithyrod drug, zeted agranulocytosis or ‘moderate hepatocellular dystuntion should prompt the use of alternate modes fof therapy, a history of minor adverse reactions sich as trtcaria or rash i not Sullcient cause to abandon this Important am of the therapeutic regimen in {hyzoid storm. It is important to be aware that antithyroid therapy, although Highly effective at inhibiting new hormone synthesis, has it’ effect on alandular release of preformed thyroid hormane, a role which is therefore eneraly delegated to inorganic fodine therapy Thofganic iodine drelly inhibits colloid proteolysis and release of T, and 1, from the thyroid gland a well as having tansint inhibitory effects on new hormone synthesis. Recommended oral doses range from 0° to 2 gid, piven as ether Lagos solution drops every 6 hours or saturated solution of potassium josie (SSKD, 5 drops every 6 hours. Parenteral administration by ow intravenous infusion as sodium iodide, 0.5 to I g every 12 hours, has ibcen employed, but sterile Nal or ntravenous use recently has been withdrawn from US makes. Although it may become avallatie agin, the oral route should be almost equally eficacious, Its essential tht iodine therapy not be administered until an elfectve Blockade of new hormone synthesis has been tstablshed with antithyroid therapy (approximately Thou), beeause Iodine Alone will lead to a further fortifenon of thyreid hormone stores, thereby increasing the risk of an exacerbation of the thyrotoxe state. Further, such “Tunprotected’ use of iodine wil complicate any planned subsequent manage- ment by delaying the effectiveness of antithyroid therapy, increasing surgical Gk owing to an enrichment of glandular hormone stores, or postponing Fadioiodine ablation pending clearsnce of the substantial sable iodine lad Patients with a history of fodine induced anaphylais may be allematively tueated with lthium carbonate, which also impairs thyroidal hormone release. Lithium i used tinal doses of 300 mg every 6 hours, adjusted thereafter to maintain serum Ithium levels of les than 1 mBgt. Beyond the limited txperience vith this agent in thyroid storm, significant renal and neurologic toxicity impair its clinical ull. Further, thyroid sorm has been reported fellowing subtotal thyroidectomy in a paent prepared with Ithiuay and B- adrenergic blockade alone aller developing agganuocylosi: on anthyroid therapy.” The. patient had also received bref course of iodine therapy however, which although stopped 2 weeks before surgery, extended 1 week past the dlacontinuaton of angthyrold therapy, therey perhaps predisposing to thyroid storm through enrichment of intathyrokdal hormone stores via the mechanisms described. ‘Another agent finding increasing utlty in the management of thyrotoxt- couis is the radiograph contast dye ipodate (Oragraliny This drug, by virtue fa lange content of sable iodine (08 m0 mg capsule) has benelical effects fn thyroid hormone release similar to Inorganic iodine. In addition, its a stint espera] conveson of nt and ay alanis mone binding {o nuclear receptor. Ipodste is given ata dally dose of] 3ig and, as with iodine, should not be Used without simultaneous Blockade of injold hormone synihess with PTU or MME. Although the utity of ipodate in thyroid storm has not been extensively examined, dramatic redactions in circulating, T, and T, levels (by a8 mich as 30% to 54% within 48 hous of initating therapy) have been reported in uncomplicated thyrotoxicosis”LURE-THREATENING THYROTOXICOSIS 271 Treatment Directed against Peripheral Eifects of Thyroid Hormone This category includes treatment given to antagonize the hyperadrene ‘manifestations of severe hyperthyroidism, pharmacologic measures to inhibit the peripheral conversion of T, to the more physiologically active T, and procedures designed to physically remove thyroid hormone from the circula- tion. The therapeutic use of antiadrenergic agents in thyrotoxic patients was first insroduced in the form of reserpine, an alkaloid with the ability to ceplete catecholamine stores in sympathetic nerve terminals and the central nervous system. Guanethidine, a catecholamine release inhibitor, was subsequently added with similar beneficial effect in the management of thyrotoxicosis.”:* ‘Owing to untoward side effects associated with each of these agents, however, including hypotension, sedation, depression, and diarrhea, their use has been. largely superceded by the newer f-adrenergic receptor blockers, of which propranolol is the most frequently used in the United States. The dramatic ‘Clinical response to B-blockers makes them one of the most valuable forms of therapy available for both uncomplicated thyrotoxicosis and thyroid storm. In additicn to antiadrenergic effects, these agents have the added benefit of a ‘modest inhibition of the peripheral conversion of T, to T,, The oral dose of propranolol in thyroid crisis is 60 to 80 mg every 4 hours, an amount rotably higher than that customarily used in uncomplicated thyrotoxicosis. Plasma propranolol levels in excess of 50 ng/mL may be necessary to maintain adequate blockade in thyrotoxicosis,**” and it should be noted that the dose required to ‘maintain this level may vary considerably in different thyrotoxic individuals.” For a more rapid effect, intravenous propranolol may be given at an initial dose of 0.5 to 1 mg with continuous monitoring of the patient's cardiac rhythm. Subsequent intravenous doses as high as 2 to 3 mg may be given over 15, minutt, to be repeated every several hours while awaiting the effects ofthe oral formulation.* Certain precautions should be observed when considering the use of B blocke:s, Patients experiencing moderate to severe congestive heart failure should generally not be treated with this class of drugs other than possibly in associction with invasive hemodynamic monitoring in a careful attempt to nullify any hyperadrenergic component to the cardiac dysfunction. Propranolol, is also contraindicated in patients with a history of asthma or bronchospasm, who should receive reserpine or guanethidine instead. Hypoglycemic una- ‘wareness may be an important reason to avoid noncardioselective B-blockade in patients predisposed to this metabolic derangement. A patient experiencing severe bradycardia in reponse fo propranolol may be tented with atopic, Likewise, isoproterenol is recommended for patients experiencing broncho- spasm of left ventricular compromise as an unexpected result of propranolol then Recently, the drug esmolol, an ultre-short acting f-blocking agent, has been used sicessully in perioperative management of severe thyrotoxicosis as well as thyroid storm. A loading dose of 250 to 500 pglkg followed by €ontinzous infusion rates of 50 to 100 pg/kg per minut, allows a rapid tration Sf dsug level to the desived effect ™'S ter patents with containdicatons to adrenergic receptor blockade, alternative terapy with reserpine, 25 to 5 mg intramuscularly every 4 hours, of guanethidine, 30 to 40 mg orally every € hours, may be used effectively; however, neither agent should be used in the presence of cardiovascular collapse or shock, Reserpine has also found recent alin ae of gro tn that wes ere lrge doses of pope lol272 BURCH & WARTOFSKY Inhibition of peripheral conversion of T, to T,,a theoretically important aspect of care in thyroid storm, is accomplished as an ancillary effect of several therapeutic agents used for another primary purpose in treating this disorder. These include PTU (but not MMI), propranolol, ipodate, and glucocorticoids Lastly, physical removal of circulating hormone in thyroid storm hes been accomplished using both plasmapheresis and charcoa! plasmaperfusion tech- riques with striking clinical improvement.” "7" These measures are gener ally reserved for cases in which continued clinical deterioration occurs despite conventional therapy for thyroid crisis, Measures Directed against Systemic Decompensation ‘This section describes methods to combat systemic decompensation occur- ring during or as a result of thyroid storm. This includes reversal of hyperther- mia, dehydration, congestive heart failure, and dysthythmia, as well as pre- vention of concomitant adrenal crisis. Hyperthermia should be aggressively treated with measures aimed at both thermoregulatory setpoint modification and peripheral cooling. Hence, acetaminophen is given as antipyretic therapy, and cooling techniques such as alcohol washes, ice packs, and cooling blankets are used to enhance the patient's ability to dissipate thermal energy. Salicylates are specifically avoided owing to their ability to displace thyroid hormone from serum binding sites, which could theoretically aggravate the state of thyrotox- icosis. Gastrointestinal and insensible fluid Iosses are potentially immense during thyroid crisis and should be aggressively replaced to prevent cardiovas- cular collapse and shock. Fluid requirements of 3 to 5 Lid are not uncommon in thyroid storm. Elderly patients and individuals with evidence of congestive heart failure should be carefully monitored, invasively if necessary, during fluid replacement to prevent volume overload. Depletion of hepatic glycogen stores occurs readily during thyroid storm and has been cited as a characteristic histologic finding at autopsy in patients dying from this disorder.» As such, ravenous fluids containing 5% to 10% dextrose in addition to required electrolytes should be used in patients with thyroid storm. Vitamin supple- ‘ments, particularly thiamine, should be given intravenously to replace any possible coexisting deficiency. Cardiovascular complications including atrial €ysrhythmia and congestive heart failure are treated with conventional means including antiarrhythmic agents, digoxin, and diuretics. Congestive heart failure occurs largely as a result of impaired myocardial contractility and is aggravated by atrial dysrhyth- ‘mia, particularly fibrillation. Somewhat larger loading and maintenance doses of digoxin may be required in severe thyrotoxicosis owing, presumably, to an Increased distribution space and/or rapid metabolism of this drug. Serum digoxin levels should be closely monitored however, particularly as thyrotoxi- cosis improves, to prevent digitalis toxicity. Strong consideration should be given to Swan-Ganz monitoring of central hemodynamics in patients with ‘moderate to severe congestive heart failure. ‘The empiric use of glucocorticoids or corticotropin in the treatment of thyroid storm was begun in the 1950s* in an attempt to treat the accelerated release and turnover as well as diminished physiologic effectiveness of corti- costeroids in thyroid storm.” Indeed, inappropriately normal (rather than elevated) levels of serum cortisol have been noted in thyroid storm compared to other periods of significant stress. Apart from these potential benefits, slucocorticoids such as dexamethasone and hydrocortisone have inhibitory effects on the peripheral conversion of T, to'T Fusther, the use of these agentsLUFE-THREATENING THYROTOXICOSIS 273, appears to have led to improved survival in thyroid storm.®* For each o* these reasons, continued use of corticosteroids in thyroid storm appears justified. Hydrocortisone is given intravenously at an initial dese of 300 mg, followed by 100 mg every 8 hours during the intial stages of thyroid storm. The dose may be subsequently reduced and discontinued as allowed by the clinical response of the individual patient. Measures Directed Against Preciptting Events in Thyroid Although the event precipitating thyroid storm may be quite obvious, such ‘as surgery, labor," withdrawal of thionamides,* or recent use of radioiodine therapj,* this is frequently not the case. This is particularly true in the instance of an underlying infection. The fever and leukocytosis found in thyroid storm. ‘even in the absence of infection" may be difficulé to distinguish from an occult infectious process. A careful culturing of blood, sputum, and urine is therefore indicated in the febrile thyrotoxic individual. The routine empiric use of broad spectrum antibiotics is, however, not recommended in the absence of other evidence suggestive of infection. In cases of thyroid storm precipitated by Inypogiycemia, diabetic ketoacidosis, stroke, or pulmonary embolism, stendard therapeutic approaches apply and should be instituted sinvultaneously with the treatment of the thyroid crisis. In the stuporous or comatose patient who is tunable to provide a history suggestive of particular precipitating event, a high index of suspicion for these varied etiologies must be maintained. It should be remembered that in some individuals no precipitant will be identified, leven in retrospect. In fact, in previous clinical series, as many as 25% to 43% of cases of thyroid storm occurred without an identified precipitating event." Definitve Therapy In planning definitive therapy for the patient successfully treated during the acute stages of thyroid storm, a key objective should be the prevention of a recurrent crisis, A the severely thyrotoxic patient improves clinically, a ‘gradual withdrawal of treatment modalities is possible. Corticosteroids should be rapidly tapered and discontinued. Owing to the large load of iodine used in the management of the acute stages of thyroid storm, the use of radiciodine as ablative therapy is not feasible, except at some later date. If this approach is planned, the patient should be continuously maintained on antithyroid therapy, ‘without iodine, until such time as the glandular stores of thyroid hormene are sufficiently depleted to allow the use of radioiodine. This may require several mont of medial therapy, the adequacy of which should be assessed erally with thyroid function testing, B-blockade, unless contraindicated, shoald be continued as well during this period. A surgical ablation with subtotal thyroid- fectomy is a therapeutic option with the advantage of expediency. Care must be taken, however, to ensure that the patient has had adequate control of thyrotoxicosis, in order to reduce the risk of another episode of thyroid crisis following, anesthesia induction or the surgery itself, Although some centers Ihave reported successfull medical preparation for thyroidectomy with propran- lol alone in thyrotoxic patients,” this may be excessively cavalier,” particularly in the setting of a patient with a prior history of thyroid sto-m, PREVENTION OF THYROID STORM ‘The marked decrease in the frequency of “surgical” thyroid storm between 1920 and 1970 was largely the result of the successive introduction of iodine,274 BURCH & WARTOFSKY antthyzoid therapy, conticosteroids and finally, @adienergic blockade in the ‘medical preparation of patients for surgery. In addition a series of introspective tnalyecs™™ © alowed an accurate entiation of pattems of racic and individual patent characteristics predisposing to postoperative thyrold crisis that eventually virtually eradicated this surgical” diaster. In that the Vast majority of cass of thyroid ers today may be conskered “medica” storm, 4 similar awareness inthe medical management of thyrotoxicosis should yiekd a farther reduction in the fsequency of this potentaly faa complication Hence, the physician and patient alike should be aware thatthe development ofan intercurrent Hness during the medical management of thyrotoxicosis warrants particular scrutiny for signs of metabolic decompensation. Likewise, minor eletive procedures such ae tooth extracion should be deferred unt adequate contd of thyrotoxicosis i attained. The popular use of radioiodine Ablation for thyrotoxicosis simultaneously exposes patients #0 two known precipitant of thyroid storm—thionamide withdrawaland the ablation therapy Reif” Although this appears to occur most frequent in older patients wth other medical conditions," we are aware of a recent case of thyroid stom complicated. by ‘myocardial infarction in a dityearold, olhervise. healthy ‘woman, following treatment with radioiodine—an event that occured despite 2 month course of preparatory antithyroid therapy. Thyrold storm has Also been described following. diagnostic and therapextc use. of radioiodine in patients with metastatic dfferentioted thyrokd carcinoma.” Such occurrences, Elbet raze, mandate close observation following "ablation therapy, partic Tnnly in patients with other chronic Mnesses. The use of adrenergic Dockade in the period preceding and immediately foliowing racoiodine should provide aciticnal protection against this potentially devastating outcome. sUMMARY Although important strides in recognition and therapy have significantly reduced the mortality in this disorder from the nearly 100% fatality rate noted by Lahey, survival i by no means guaraniged More recent series have yielded fatality rates between 20% and 50%.** Although some authors have attributed this improvement, in part, to a relaxation of the diagnostic criteria for thyroid storm, it more likely represents improvements in early recognition and the beneficial effects of the serial addition of antithyroid, corticosteroid, ‘and antiadrenergic therapies to the treatment of this disorder. = ‘Thyroid storm is a dreaded, fortunately rare complication of very common disorder. Most cases of thyroid storm occur following a precipitating event or intercurrent illness. Effective management is predicated on a prompt recognition ‘of impending thyroid storm which is, in turn, dependent on a thorough Knowledge of both the typical and atypical presentations of this disorder. An ‘unwavering commitment to an aggressive, multifaceted therapeutic interven- tion as outlined herein is critical to the obtainment of a satisfactory outcome. References 1. Anaisse E, Tohm¢ JF: Reserpine in propranolol-resistant thyroid storm. Arch Inter ‘Med 185:2248-2249, 1985 2. Ashkar FS, Katims RB, Smoak WM Ill, et ak Thyroid storm treatment with blood ‘exchange plasmapheresis. JAMA 214:1275-1279, 1970,10. a 2. 1. 1M. 15 16. v. BRRRERRE 88 LUPETHREATENING THYROTOXICOSIS. 275 Astkar FS, Miller R, Gibson AJ: Thyroid function and serum thyroxine in éhytoid ‘tom. South Med J 68:372-374, 1972 |. Bayley RE: Thyroid erei. Surg Gynec Obstet 8-41-47, 1954 5: Bennett WR, Huston DP: Rhabdomyolysis in thyroid storm. 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GL. etal: Fallure of propranolel to alter thyroid Inaine roloave, thyroxine turnover, Gr the TSH and PRL responses to thyrtpin Telessing hormone in patients with thyrotoxicosis] Clin Erdocsnol Metab 41 285- 550 19% {8 WE S:Y, Chopra I], Solomon DH, et alk The elect of repested edminisation of ipa (Org in ypertydam. ln Enda Mab 71386 136 107 89, Zoneasin J, Santangelo RE, Mackin JE, et ak Propranolol therapy in 84 patents Undergoing surgery: Am J Med 6641-416, 179 Aaress reprint roquess to Leonard Wartofky, MD Endocrinology-Metablism Service Kyle Metablic Unit, Walter Reed Army Medical enter Washington, Do 20307