Propranolol and Thyroidectomy in theTreatment of Thyrotoxicosis

THOMAS C. LEE, ROBERT J. COFFEY, BRADFORD M. CURRIER, XIU-PING MA, JOHN J. CANARY

For decades, the preparation of a hyperthyroid patient for sur-gery took several weeks or months utilizing thyroid blockingagents and iodine. In 1973, a preliminary report of 20 patientswith hyperthyroidism treated with propranolol and thyroidec-tomy was presented. It was found that a thyrotoxic patientcould be prepared for surgery, in an emergency, by intravenouspropranolol in less than an hour, or electively by oral pro-pranolol within 24 hours. Since then, 140 additional patientshave been similarly treated. It continues to be true at this in-stitution that propranolol, a beta-adrenergic blocking agent,effectively neutralizes the symptoms of autonomic hyperactiv-ity, including sweating, tremor, fever, dilation of blood vessels,and increased pulse rate without significantly affecting thyroidfunction. An average dose of 160 mg/day was used, with arange of 40 to 320 mg/day. In none of these patients was iodineused; in fact, its use with propranolol is considered unnecessary.A subtotal, near total, or total thyroidectomy was done in allpatients, resulting in a 55% incidence of hypothyroidism. Therewas no postoperative thyroid storm, nerve injury, or permanenthypoparathyroidism. It is believed that the administration ofpropranolol alone provides a rapid, safe, and effective prepa-ration of the thyrotoxic patient for thyroidal or extrathyroidalsurgical procedures during the perioperative period.

pROPRANOLOL, an adrenergic beta-receptor antago-nist, was introduced by Black3'4 in 1964. Its effec-

tive use in controlling hyperthyroid manifestations andcrisis was subsequently established. 6'927 Vinik be-lieved that this drug, combined with iodine, providedan efficient preparation for hyperthyroid patientsundergoing thyroidectomy.28 In 1970, Pimstone andJoffe'8 reported that the administration of propranololand iodine for 10 to 14 days was an ideal preoperativepreparation for their patients. In 1973, iodine was to-tally eliminated, and it was shown that propranololalone could be the sole drug to use in the preparationof hyperthyroid patients undergoing thyroidectomy.'3The preliminary study involved 20 patients. Since thenan additional 140 have been recorded, for a total of160. The continuing favorable response to this regimenis the subject of this report.

Presented at the Annual Meeting of the Southern Surgical Asso-ciation, December 7-9, 1981, Hot Springs, Virginia.

Reprint requests: Dr. Thomas C. Lee, Georgetown University Hos-pital, Washington, DC 20007.

Submitted for publication: December 29, 1981.

From the Georgetown University School of MedicineWashington, DC

Materials and Methods

One hundred sixty patients with classic clinical andlaboratory findings of hyperthyroidism were selected forsurgical treatment at Georgetown University Hospital.The mean age was 30 years, with a range of 14 to 66.One hundred twenty-six were female. Caucasians ac-counted for 113 of the patients, while 42 were blackand five oriental. The length of follow-up ranged fromone to 14 years. Vital signs were recorded frequently,as were estimates of psychomotor activity and bodywarmth. The presence or absence of eye signs was noted.Subjective evaluations were obtained regarding pa-tients' state of inner agitation and sense of well-being.

Venous blood samples for hormone analysis were ob-tained several times prior to operation, and two, four,and seven days and three and six weeks after operation.Serum thyroxine levels were measured initially by dis-placement analysis with a normal range for T4 (D) of6.0 to 11.5 g/dl and more recently by radioimmunoas-say. The T4 levels averaged 20.1 g/ 100 ml, with a rangeof 12.8 to greater than 25. Resin triiodothyronine up-take (RT3U) was measured (normal range 26-35%).The T3 uptake averaged 46.5%, with a range of 26.9to 56.8%. Iodine 131 thyroidal uptake was measuredat six and/or 24 hours after an oral dose of '3'I of 5to 50 u C: in the usual manner. The six-hour averagewas 54.8%, with a range of 35 to 86%. The 24-houraverage was 64.2%, with a range of 30 to 84%. Thyroidscans were done with '3'I or 99 M Technetium. Onehundred fifty-four of the scans showed diffuse hyper-thyroidism, and six demonstrated nodules. Protein-bound iodine determinations ranged from 8.4 to 25 g/100 ml, with an average of 13.7 g/ 100 ml. Plasma levelsof propranolol were measured in several patients beforeand after operation. These levels ranged from 35 to 200ng/ml, consistent with the development of beta-adren-ergic blockade. These specimens were iced immediately

0003-4932/82/0600/0766 $00.90 C J. B. Lippincott Company

766

PROPRANOLOL AND THYROIDECTOMY

and spun down in a refrigerated centrifuge. The plasmawas then separated and frozen at -20 C until deter-minations were carried out. The method utilized for themeasurement of propranolol was a modification of thatof Black et al. developed in this laboratory. Propranololwas extracted into heptanethanol (99:1 v/v) fromplasma alkalinized with 0.1 N sodium hydroxide. Theheptane extract was then re-extracted with 0.1 N hy-drochloric acid and propranolol in the acid phase quan-titated by fluorometry. The coefficient of variability inthis method is 4% at low levels and 8% at higher levelsof propranolol.The first 20 patients in this series were admitted four

days prior to surgery so that their response to propran-olol therapy could be closely evaluated; however, theremainder were started on this therapy as outpatients,observed, controlled, then admitted the afternoon priorto the day of surgery. Since propranolol is usually con-traindicated in the following conditions, no patients inthis group had a history of asthma, chronic obstructivepulmonary disease, second-degree heart block, sinusbradycardia, congestive heart failure, or hypoglycemia.Additionally, patients taking quinidine or psychotropicdrugs were excluded. No iodine or thionamides wereused to prepare these patients. Seventy-three patientshad been treated previously with thionamides; however,none had been used in the four months prior to theinstitution of propranolol. Initially, all patients weregiven 40 mg of propranolol every six hours. The dosewas increased or decreased, usually in increments of 20mg every six hours, contingent upon their response tothe medication, the greatest emphasis being placed onheart rate and sense of inner tranquility. Other impor-tant clinical features such as tremor, skin moisture,anxiety, nervousness, and generalized hyperkinesis werealso factors in judging the proper dosage. While theaverage amount of propranolol per day was 160 mg,the dose range in this latter group varied from 40 to320 mg per day. Six patients who did not respond clin-ically to increasing dosages of propranolol every sixhours did, however, respond to the same total daily dos-age given every four hours. Two patients who did notrespond favorably to propranolol were excluded fromthis series; both were subsequently placed on antithyroiddrugs and operated on without untoward response.The last propranolol medication before surgery was

given within one to two hours by mouth and resumedwithin four to six hours after operation, except in threepostoperative patients with vomiting who were given a1.0-mg bolus of the drug intravenously. Anesthesia wasinduced using a spectrum of drugs and gases; however,use of atropine was avoided as a preoperative medica-tion. All operations were done by two of the authors(TCL and RJC) and consisted of subtotal, near total,

767or total thyroidectomy, subtotal being most common.In all instances, both recurrent laryngeal nerves and atleast three parathyroid glands were identified, pro-tected, and retained. In four patients, after the thyroidgland had been excised, careful inspection of the spec-imen revealed a fourth parathyroid gland. This glandwas minced, placed in sternocleidomastoid pockets, andmarked with a metallic clip.

Results

Preoperative Period

Propranolol relieved essentially all the thyrotoxicsigns and symptoms of tachycardia, anxiety, sweating,and emotional stability within 48 hours, usually within12. In the initial 20 patients, significantly higher dos-ages of propranolol were used; however, with more ex-perience it was realized that the average propranololregimen could be 40 mg every six hours, with a totalrange of 40 to 320. g/day. The average pulse rate of theuntreated patient was 104 beats per minute, decreasingto 88 after the institution of propranolol. Body tem-perature and blood pressure were unaffected by treat-ment. Thyroxine levels remained essentially unchangedafter propranolol therapy was begun. There were noadverse or allergic responses to propranolol.

Intraoperative Period

A myriad of medications and gases was used by theanesthesiologists; however, atropine was avoided. Thethyroid gland was firm but not friable, and was consid-ered to be somewhat easier to handle than those pre-treated with iodine. A subtotal thyroidectomy was per-formed on the majority of earlier patients, exceptingthose with toxic nodules who were subjected to "nod-ulectomy" or lobectomy. More recently, patients havebeen subjected to near total or total thyroidectomy. Allpatients had their recurrent laryngeal nerves visualizedbilaterally; none was injured. Two patients had pre-sumed damage to the external branch of their superiorlaryngeal nerves. Dissection was kept close to the thy-roid gland so that the parathyroid blood supply wouldnot be compromised. The thyroid was examined care-fully at the moment of its removal. In four patients, asingle parathyroid was noted on the specimen; this wasdissected free, minced, placed in sternocleidomastoidpockets, and marked with a metallic clip. There wereno instances of permanent hypoparathyroidism. Bloodloss was estimated at 98 ml ± 10. The average time ofsurgery was 92 minutes ± 10. There were no significantchanges noted in the serum levels of T3 or T4 duringthe procedure.

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Ann. Surg. * June 1982

Early Postoperative Period

Propranolol was resumed within four to six hoursafter completion of surgery. The postoperative dosageschedule was the same as that given prior to operationand was maintained for 48 hours. On the third post-operative day, the dosage amount was halved, thenhalved again on the fourth day, then discontinued be-tween the fifth and seventh day, depending on the pa-tient's response. A slight increase in mean pulse rate,systolic blood pressure, and temperature was noted on

the first postoperative day; subsequently, progressiveimprovement was noted. T3 and T4 levels returned tonormal or low normal within 7.2 days in all patients.This result is close to the 6.2 days reported by Sterlingand Chodos.23 The reverse T3 concentration increasedduring the first 12 postoperative hours, then a very slowdecrease was noted. There were no patients with man-

ifestations of thyroid storm. There was no mortality.Ninety-six percent of the patients were discharged on

the fourth postoperative day.

Late Postoperative Period

There have been no recurrences of thyrotoxicity inany of the 160 patients. Three patients had temporaryunilateral recurrent laryngeal nerve damage, as mani-fested by cord dysfunction. All returned to normal cordand voice function in three, four, and six months.Whether this dysfunction was due to direct trauma,hematoma formation, or endotracheal intubation traumais unknown. The incidence of hypothyroidism was 55%(88 of 160).

Discussion

At the turn of the century, it was noted that in thenatural course of hyperthyroidism approximately 20%of patients died in acute crisis. Another 40% pursueda chronic course of exacerbations and remissions, re-

sulting in thyrocardiac disability. The remaining 40%included a few who improved spontaneously and otherswho lapsed into permanent hypothyroidism.2' It was

Kocher, the Nobel laureate, who first focused attention

on the surgical treatment of thyroid diseases. His fol-lowers included many of the great names in Americansurgery: Halstead, Crile, and Mayo, who soon realizedthat attempting to treat the hyperthyroid patient wasfrought with the dangers of thyroid storm and a mor-

tality rate approaching 20%. In attempting to diminishthe hazards of surgery, imaginative procedures were

devised, including those of injecting the gland with boil-ing water or carbolic acid, "stealing" the thyroid undernarcosis, adrenalectomy, ligation of the superior or in-ferior thyroid artery as a staged procedure, and count-less other innovative procedures. Despite these efforts,an alarming number of patients continued to die in crisisbefore, during, and after surgery.

History has recorded that the Chinese, Hippocrates,Galen, Napoleon, and others knew-and recognized thebeneficial effect of iodine-containing marine productson thyroid disease. Despite this, it was Plummer20 whoin 1923 realized that the use of Lugol's solution of io-dine in the preoperative period would revolutionize thesurgical treatment of thyroid disease. As a result, themortality rate was reduced to less than 1%. Plummer'sidea became a pillar of treatment.

Further improvement in treatment followed the in-troduction of antithyroid drugs by Astwood2; thesedrugs are still generally used today. Antithyroid drugsinhibit thyroid hormone synthesis and convert the hy-perthyroid patient to a euthyroid state. The time neededfor control usually involves several months, and thisregimen is then combined with adminstration of iodinebefore surgery is undertaken.The most recent class or group of compounds used

to prepare the hyperthyroid patient are the beta-block-ing agents. If a new regimen of therapy, such as pro-

pranolol, is to merit consideration it should be evaluatedindependently by others. Without attempting to makean exhaustive review of the literature, several au-

thors' 7'14"15'24'25 from several countries who also treatedhyperthyroid patients with propranolol alone as a peri-operative treatment were surveyed (see Table 1). These174 patients, combined with the 160 of the present se-

ries for a total of 334, establish the basis for this report.

TABLE 1. Patients (334) Treated with Propranolol and Thyroidectomy

Number ofAuthor Year Patients Propranolol Iodine Surgery Storm Results Country

Lee T, et al.'3 1973 20 Yes No Yes No Good U.S.A.Michie W."5 1976 47 Yes No Yes No Good EnglandToft A, et al.25 1976 40 Yes No Yes No Good ScotlandCaswell H, et al.7 1978 24 Yes No Yes No Good U.S.A.Anderberg B, et al.' 1979 38 Yes No Yes No Good SwedenTevaarwerk G, et al.24 1979 20 Yes No Yes No Good CanadaMalliere D, et al.'4 1980 5 Yes No Yes No Good FranceLee T, et al. 1982 140 Yes No Yes No Good U.S.A.

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PROPRANOLOL AND THYROIDECTOMY

Advantages of Propranolol

The prompt onset of action, blocking the symptomsof hyperthyroidism, allows much greater flexibility inthe timing of surgery. It is now feasible to prepare apatient for surgery, operate, and discharge the individ-ual from the hospital within one week, whereas formermethods required several weeks or months before sur-gery could even be contemplated.

If the patient is unable to take propranolol orally,that is, during surgery and/or after operation becauseof vomiting, the rapid action of a 1.0- or 2.0-mg bolusof the drug will rapidly ameliorate any threat of storm.If there is a good response, 10 to 15 mg can then beadded to 500 ml of dextrose and water or saline. Therate of infusion is judged by the pulse rate. This coursewas taken in one patient after operation. Propranololis also ideal in the management of a previously unsus-pected hyperthyroid patient undergoing emergencynonthyroidal surgery and the drug of choice in man-agement of thyroid crisis or storm.

Propranolol does not significantly affect objectivehormonal studies in the thyrotoxic state. The patient,under control, is clinically euthyroid, although remain-ing metabolically hyperthyroid. The mechanism bywhich the drug favorably modifies the clinical mani-festations of thyroid hormone excess and the responsepf such patients to the stress of surgery also remainunclear. So many of the signs and symptoms of thy-rotoxicosis resemble the manifestations of catechol-amine excess that the interrelationships of thyroid hor-mone and the sympathetic nervous system have longbeen the subject of controversy. The demonstration thatspinal anesthesia, sympathectomy, catecholamine-de-pleting agents, and propranolol ameliorate clinical man-ifestations of thyroid hormone excess supports a rela-tionship. This is reinforced by data indicating a positiveassociation between thyroid hormone levels and thenumber of myocardial cell catecholamine receptorsites.26 Propranolol's effects in decreasing peripheralconversion of thyroxine to the more biologically activetriiodothyronine may be clinically significant as well,but this possibility requires further clarification.

In a cost-conscious economy, this drug, combinedwith surgery, is the most cost-effective form of definitivetreatment for thyrotoxic patients.5

Disadvantages of Propranolol

It is not felt that there are actually disadvantages tothe drug per se. However, propranolol has a short half-life,22 and, therefore, it is imperative that it be takenevery six to eight hours; otherwise, the patient will es-cape the beneficial effects. If thyrotoxic patients cannotor will not adhere to the preoperative program of out-

769patient therapy, they should be hospitalized for morecontrolled supervision. Since the drug is a beta-adren-ergic blocking agent, it is not recommended in patientswith bronchial asthma, advanced grades of heart block,congestive heart failure, unstable insulin-dependent di-abetes, or in those patients taking quinidine or psycho-tropic drugs, which augment adrenergic activity.One young patient not included in this series who was

totally unresponsive to both oral and intravenous pro-pranolol was observed. There is no known explanationfor this phenomenon, but as a general rule, it has beenfound that younger patients do require higher dosageschedules.

Whither Iodine

Plummer's idea for iodine need, while one of the greatmedical discoveries at that time, no longer seems ap-plicable. Traditionally, surgeons have believed that io-dine helps prevent storm, makes the gland less vascular,and tends to "firm up" the thyroid. It was with cautioussteps that, in the mid- 1960s, the amount of preoperativeiodine was reduced at this institution, finally being elim-inated in 1967. Friend" noted that the usual recom-mended preoperative schedule of iodine amount oftenexceeded the actual requirement by more than 100times. He pointed out that one drop of Lugol's iodinecontains more than the daily iodine requirement for athyrotoxic patient, and one drop of a saturated solutionof potassium iodide (SKKI) exceeds the total iodinecontent of the entire body. The authors and others 1,15,25could find no difference before, during, or after thyroidsurgery in patients prepared with and without iodine.A further advantage of eliminating the use of iodine

is the avoidance of the jodbasedow effect, that is, theincrease in the severity Qf thyrotoxicosis in patients withendemic iodine-deficient goiters treated with iodine.8 ItiS believed that the 334 propranolol-treated patientsreported/reveiwed in this series prove that iodine is notnecessary to prevent storm and that blood-loss controland gland friability are as favorable if not better thanthose of patients treated with antithyroid drugs andiodine or propranolol and iodine.29

Anesthesia and Propranolol

Atropine was not used as a preoperative medicationso that tachycardia, which may result from parasym-pathetic blockade in thyrotoxic patients, would beavoided. The use of the anesthetic agents halothane andmethoxyflurane obviated the need for atropine, sincethey do not stimulate tracheobronchial secretions, con-strict bronchioles, or cause laryngospasm. Both of thesehalogenated agents also aid in the control of the cardiacrate, halothane by a combined vagotonic effect and

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LEE AND OTHERS

depression of sinoatrial and atrioventricular nodes, andmethoxyflurane by a vagotonic action. With this an-

esthetic technique, intramuscular atropine in doses of0.4 to 1.0 mg can be reserved for elective use duringoperation, to correct any significant bradycardia thatmay develop and that has not responded to a decreasein the concentration of the halogenated agents.

In the latter group of patients, a myriad of anestheticdrugs and gases were used without incident; however,it is believed that the halogenated compoinds are stillthe anesthetic agents of choice. Three patients were

given judicious amounts of atropine intraoperatively tocorrect bradycardia. Many were given atropine duringextubation, possibly explaining the slight increase inheart rate during the very early postoperative period.

Thyroidectomy Technique

No attempt will be made to go into detail of step-by-step thyroidectomy; rather, that will be left to classictexts and articles. In the following sections, deviationsfrom the traditional technique that were practiced inthe present series are discussed.

The Thyroid Remnant and Hypothyroidism

One of the time-honored rituals of a surgeon per-

forming subtotal thyroidectomy is to estimate theweight of the thyroid remnant. It is apparent that thelarger the remnant, the higher is the incidence of hy-perthyroidism, although there may be many exceptions.Michie's reported that 19% of patients who had a thy-roid remnant estimated at 10 g developed hypothyroid-ism. Since size is not necessarily related to weight andweight is not a predictable or reliable indicator of func-tion, it becomes apparent that this is a subjective ratherthan an objective exercise that this is questionable.Those surgeons who leave "10%" are also estimatingfunction on the basis of total weight, since thyroid sizevaries tremendously. Seemingly, the only objectivestatement that can be made in reference to the thyroidremnant is its measurements in centimeters. Early inthe present series, a remnant averaging 2 X 1 X 0.5 cmwas left; however, in the last 67 patients treated by one

of the authors (TCL), near total or total thyroidectomyhas been performed. Perzik'7 regarded postoperativehypothyroidism as the inevitable result of adequate sur-

gical treatment rather than as a complication. He uses

total thyroidectomy exclusively and has encountered no

recurrences. Cord paralysis and permanent hypocal-cemia in his series of 909 patients were exceptionallyrare. Farnell'0 recently reported 100 patients of whom75% developed hypothyroidism. It can be accepted that,idealistically, the thyroid remnant would establish eu-

thyroidism; however, since small remnants can resultin continuing hyperthyroidism and large remnants inhypothyroidism, the objective currently is to create hy-pothyroidism. Recurrent hyperthyroidism, if it occurs,must be treated either by reoperation, which is exceed-ingly hazardous to the recurrent laryngeal nerves andparathyroid gl4nds, or radioactive iodine, which per-force had to be initially rejected, for one or more rea-

sons.

The Parathyroid Glands

The blood supply to both superior and inferior para-

thyroid glands is usually the inferior thyroid artery;therefore, ligating it laterally is avoided. Dissection iscarried along the artery until it branches into the thy-roid. The branch to the inferior parathyroid usuallytakes off several millimeters from the thyroid and iseasily preserved. The superior parathyroid gland is oftenintimately associated with the thyroid. If that is thecase, the parathyroid is carefully lifted off the thyroid,with its blood supply intact, and reflected laterally. Ifthe gland becomes dark, developing a hematoma, or itsblood supply is embarrassed, the parathyroid is re-

moved, minced, and placed in a muscle pocket. If theoperating surgeon is not an experienced thyroid/para-thyroid surgeon, the above maneuvers are not recom-

mended, and he/she would be better off performing a

generous subtotal thyroidectomy rather than total lo-bectomy.

While most of the patients in the present series ex-

perienced a fall in serum calcium during the first twopostoperative days, all but three returned to normalrange by the third or fourth day. The three with per-

sistent hypocalcemia and hyperphosphatemia requiredcalcium supplement for several months before returningto normal serum calcium and phosphate levels. In none

was there permanent hypoparathyroidism.

The External Branch of the Superior Laryngeal Nerve

This nerve descends in close proximity to the superiorthyroid artery and is damaged much more often thanis recognized. The denervation to the cricothyroid mus-

cle results in a diminution in vocal cord tension. Despitecomplete and full movement of the vocal cords, as notedon direct laryngoscopy, there is a loss of volume andpitch, with easy tiring. Three of the patients have post-operative symptoms consistent with this complication.These patients consider this a minor annoyance, statingthat the only time they notice it is when they wish toshout, often at their spouses or children, and only a

normal volume is produced. They furthermore state thattheir families consider this deficit an asset.

770 Ann. Surg. * June 1982

Vol. 195 . No. 6 PROPRANOLOL AND THYROIDECTOMY 771

The Recurrent Laryngeal Nerve

The safest way to protect this nerve is to identify thenerve visually before any ligation is done other thanlateral thyroid veins. Nonrecurrent laryngeal nerveswere noted on the right side in three patients. In thisand the initial series, there were no nerve transections.

Blood Loss

It is not believed that blood loss is affected by themodality of preoperative preparations, whether it bewith antithyroid drugs, beta-adrenergic blockers, io-dine, or combinations thereof. Blood loss is a functionof the control of vascular components and the surgicaltechnique. The authors agree with Michie'5 that thy-roidectomy can be achieved with blood loss as minimalas 15 to 20 ml.

Thyroid Gland Friability

A major concern and objection to the preoperativetreatment of hyperthyroid patients without iodine wasthe fear of increased technical difficulties at operation.In this series, no complications were found, the glandwas easy to manipulate, and more firm yet pliable thanthose pretreated with antithyroid drugs and iodine. Thisobservation has been confirmed by others."5'25

Thyroid Storm or Crisis

None of the 334 hyperthyroid patients treated with-out iodine manifested symptoms of storm. Patients withpostoperative tachycardia and temperature elevationspoorly responsive or unresponsive to the administrationof increasing doses of propranolol should suggest someintercurrent process, such as infection or atelectasis.Two reports9"2 state that "propranolol does not preventthyroid storm." A total of three patients were presented.In the opinion of the authors, the data presented inthose reports do not fully support the conclusions drawn.Certainly, propranolol remains the drug of choice instorm.

Recurrent Hyperthyroidism

In this series of 160 patients and the 174 reviewed,no one has had a return of thyrotoxic symptoms orhormonally established recurrent disease. As stated, thisis considered not a reflection of propranolol usage oriodine nonusage, but rathera result of near total or totalthyroidectomy.

Conclusion

In conclusion, it appears that this study confirms pre-liminary observations that propranolol is quick, safe,

effective, and the agent of choice in the preparation ofhyperthyroid patients for surgery.

References1. Anderberg B, Kagedal B, Nilsson OR, et al. Propranolol and

thyroid resection for hyperthyroidism. Acta Chir Scand 1979;145:297.

2. Astwood EB. Treatment of hyperthyroidism with thiourea andthiouracil. JAMA 1943; 122:78.

3. Black JW, Crowther AF, Shanks RG, et al. New adrenergic beta-receptor antagonist. Lancet 1964; i: 1080.

4. Black JW, Duncan WAM, Shanks RG. Comparison of someproperties of pronethalol and propranolol. Br J Pharmacol1965; 25:577.

5. Canary JJ. Antithyroid drug therapy is not an efficient way totreat hyperthyroidism. In: Hamburger J1, Miller JM, eds.Commentary in Controversies in Clinical Thyroidology. NewYork: Springer-Verlag, 1981; 132-134.

6. Canary JJ, Mackin J, Fidler S. Bloqueo beta-adrenergico en latirotoxicosis. Reportes Medicos 1971; 2:35.

7. Caswell HT, Marks AD, Channick BJ. Propranolol for the pre-operative preparation of patients with hyperthyroidism. SurgGynecol Obstet 1976; 146:908.

8. Emerson C, Anderson A, Howard W, et al. Serum thyroxine andtriiodothyronine concentrations during iodine treatment of hy-perthyroidism. J Clin Endocrinol Metab 1975; 40:33.

9. Eriksson M, Rubenfeld S, Garber A, Kohler P. Propranolol doesnot prevent thyroid storm. N Engl J Med 1977; 296:263.

10. Farnell MB, Van Heerden JA, McConahey W, et al. Hypothy-roidism after thyroidectomy for Graves' disease. Am J Surg1981; 142:535.

11. Friend DG. Iodine therapy and the importance of quantitatingthe dose. N Engl J Med 1960; 263:1358.

12. Jamison M. Postop thyrotoxic crisis in a patient prepared forthyroidectomy with propranolol. Br J Clin Pract 1979; 33:82.

13. Lee TC, Coffey R, Mackin J, Canary J. The use of propranololin the surgical treatment of thyrotoxic patients. Ann Surg 1973;177:643-647.

14. Melliere D, Hazzard J, Germain V, et al. Value of high dosagepropranolol and preoperative hypothermia in thyroidectomywhen conventional preparatory treatment is unsuitable. NouvPresse Med 1980; 9:1497.

15. Michi W. Whither thyrotoxicosis. Br J Surg 1975; 62:673.16. Parsons V, Jewitt D. Beta adrenergic blockade in the management

of acute thyrotoxic crisis, tachycardia and arrythmia. PostgradMed J 1967; 43:756.

17. Perzik SL. The place of total thyroidectomy in the managementof 909 patients with thyroid disease. Am J Surg 1976; 132:480.

18. Pimstone B, Joffe B. The use and abuse of beta-adrenergic block-ade in the surgery of hyperthyroidism. S Afr Med J 1970;44: 1059.

19. Pimstone N, Marine N, Pimstone B. Beta-adrenergic blockadein thyrotoxic myopathy. Lancet 1968; ii:1219.

20. Plummer H. Abstract. JAMA 1923; 80:1955.21. Sattler H. Basedow's Disease (1908). Marchand GW, Marchand

JF, trans. New York: Grune and Stratton, 1952; 284.22. Shand D, Nuckolls JA, Oates JA. Plasma propranolol levels in

adults. Clin Pharmacol Ther 1970; 1 1:1 12.23. Sterling K, Chodos RB. Radiothyroxine turnover studies in myxe-

dema, thyrotoxicosis and hypermetabolism without endocrinedisease. J Clin Invest 1956; 35:806.

24. Tevaarwerk JM, Boyd D. Propranolol in thyrotoxicosis. Can JSurg 1979; 22:264.

25. Toft AD, Irvine WJ, McIntosh D, et al. Propranolol in the treat-ment of thyrotoxicosis by subtotal thyroidectomy. J Clin En-docrinol Metab 1976; 43:1312.

26. Tsai JS, Chen A. L-Triiodothyronine increases the level of,.-adrenergic receptor in cultured myocardial cells. Clin Res 1977(Abstract); 25:303.

772 LEE AND OTHERS Ann. Surg. * June 1982

27. Turner P, Granville-Grossman KL, Smart JV. Effect of adren-ergic receptor blockade on the tachycardia of thyrotoxicosisand anxiety states. Lancet 1965; ii:1316.

28. Vinik Al, Pimstone BL, Hoffenberg R. Sympathetic nervous sys-

tem blocking in hyperthyroidism. J Clin Endocrinol Metab1968; 28:725.

29. Zonszein J, Santangelo RP, Mackin JF, et al. Propranolol therapyin thyrotoxicosis. Am J Med 1979; 66:41 1.

DISCUSSION

DR. COLIN G. THOMAS, JR. (Chapel Hill, North Carolina): Letme re-emphasize what the results are: no remissions, no permanenthypoparathyroidism, no recurrent laryngeal nerve damage, three pa-tients with dysfunction of the external branch of the superior laryngealnerve, a 55% incidence of hypothyroidism, and no thyroid storm.

I do not think there are many centers in the world that can achievecomparable results, but I would assume that this is not merely theresults of propranolol alone. It represents a very careful selection ofpatients, and, obviously, superb surgical technique and management.The fact that patients can be prepared with propranolol alone does

not necessarily mean that this is the method of choice for all patientsor for all surgeons. We have been somewhat more conventional, andhave taken the point of view that thyroidectomy in thyrotoxicosis isan elective procedure and that most patients are going to be at theirlowest risk if they are euthyroid. Therefore, we have used the moreconventional preparation with antithyroid drugs and Lugol's solution.Our experience with propranolol is that it is frequently indicated

in the patient who is intolerant of thioamide drugs. The patient isprepared with propranolol and Lugol's solution, in an attempt to bringthe pulse rate to between 80 and 90. We have continued to use Lugol'ssolution in conjunction with propranolol because it does amelioratethe severity of the thyrotoxicosis, and permits a lower dosage of' pro-pranolol and earlier discontinuation of the drug in the immediatepostoperative period. The combination of propranolol and Lugol's so-lution is also appropriate for the noncompliant patient who can onlybe prepared while in the hospital. We have also used propranolol for"fine tuning" in patients prepared with thioamides and Lugol's so-lution.As Dr. Lee has emphasized, there are some precautions. Propranolol

should not be used in the patient with autoantibodies to beta adren-ergic receptors-for example, the patient with allergic asthma or cysticfibrosis-and there is an occasional normal individual who seems tohave such antibodies.

Furthermore, there are some patients who, for some unknown rea-son, do not respond; in Dr. Lee's manuscript, he noted two. We havehad one patient who was an example of this. An 8-year-old girl whowas intolerant of antithyroid drugs was started on Lugol's solutionand propranolol; her pulse remained above 120, despite an intravenousbolus of I or 2 mg. At this point, we could not use radioactive iodine,so we felt compelled to go ahead with thyroidectomy. She did perfectlyall right, but, still, this lack of response was of concern.As far as the overall approach, we would advise that most patients

be prepared with antithyroid drugs; if they prove to be intolerant, thengo ahead with propranolol and Lugol's solution. Propranolol shouldbe used first to demonstrate that the patient will respond, before add-ing Lugol's solution. Otherwise, you have not provided an opportunityto use radioactive iodine in the rare patient who cannot tolerate ordoes not respond to propranolol.As far as overall costs are concerned, I would agree that they may

be less when you consider patient time, but in-hospital costs are notnecessarily lower. With the patient being euthyroid at the time ofadmission to the hospital, most can be discharged on the third dayafter operation, some on the second, and usually all by the fourth.

I have three questions for Dr. Lee. Of patients being consideredcandidates for- thyroidectomy, how many were considered not to becandidates for preparation with propranolol?

Second, is the dosage of propranolol related to the severity of thedisease, and what are the desirable blood levels of propranolol in orderto achieve blockade?

Finally, in most surgeons' hands the incidence of hypoparathyroid-ism and recurrent nerve damage is related to the extent of the surgery;for example, it would be higher with total thyroidectomy than withsubtotal. With such good results with subtotal thyroidectomy, whyare you advocating total thyroidectomy in the management of thesepatients?

DR. JONATHAN A. VAN HEERDEN (Rochester, Minnesota): Withthe recent publicity regarding its efficacy after myocardial infarction,propranolol is rapidly achieving superdrug status. I think Dr. Lee hasjust given us another demonstration of why this status may well bejustified. I heartily recommend this manuscript to all those in theaudience who are interested in surgical endocrinology. Few centers,including our own, could duplicate the results just presented, as Dr.Thomas has emphasized.

In 160 patients, there was no operative mortality, not a single in-cidence of recurrent hyperthyroidism, and only three instances of tem-porary cord dysfunction. There are some cautionary notes, however.We all know and realize that complications following thyroid sur-

gery-in particular, thyroid storm and operative mortality-are, for-tunately, excessively rare. I would thus raise the question of whether160 patients is an adequate statistical sample from which to drawdefinitive conclusions. Should one have 1,000 patients, or 1,500, or2,000? I don't know.We also know that there is a synergistic action between iodine and

propranolol, in that greater reductions in T-4 can be obtained by theircombined usage, rather than by employing each separately. I wouldvalue Dr. Lee's opinion and thoughts about this, because he and hiscolleagues have used iodine and propranolol synergistically.

Dr. Lee and his colleagues report a 55% incidence of hypothyroid-ism. First, I would like to know the length of the follow-up period inthese patients, since we anticipate a steady increase in the percentage,with an accrual rate of roughly 3% per year; and second, was hypo-thyroidism diagnosed on clinical grounds only or by the measurementof TSH levels.

I might mention that we continue to prepare patients with Lugol'ssolution, as suggested by Henry Plummer in 1923, but we do addpropranolol in either those patients with significant tachycardia orthose patients who have cardiac awareness. We have seldom had toutilize a dose exceeding 80 mg/day.Three last comments or questions. First, I congratulate the authors

on employing, and once again emphasizing, nonligation of the inferiorthyroid artery. I think this is an important technical step. Since adopt-ing this policy in hyperthyroidism about five years ago, we believethat our incidence of postoperative hypocalcemia has decreased sig-nificantly.

Second, I would side with Dr. Thomas in disagreeing that totalthyroidectomy is ever indicated in thyrotoxicosis. We prefer to leavea 1 to 2 g rim of thyroid tissue posteriorly. With this policy, we haveachieved a recurrence rate of slightly less than 1%, and an acceptableincidence of cord and calcium problems.As Dr. Lee pointed out, the majority of patients surgically treated

will become hypothyroid if followed up long enough; this is similarto results with patients treated with iodine-131.

Finally, I'd like to ask Dr. Lee what the indications for surgicaltreatment of thyrotoxicosis are. One hundred forty surgical procedures