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Endocrine Emergencies (Nondiabetic)
Endocrine Emergencies (Nondiabetic) GROSVENOR W. BISSELL, M.D., F.A.C.P. Chief, Medical Service, Veterans Administration Hospital, Buffalo, New York; Associate Professor of Medicine, University of Buffalo School of Medicine
PATRICK R. COSEGLIA, M.D. Staff Physician, Veterans Administration Hospital, Buffalo, New York; Research Fellow, Chautauqua County Tuberculosis and Public Health Association
is generally considered as being comprised of the thyroid, parathyroid, islands of Langerhans, adrenal medulla and adrenal cortex, the anterior and posterior lobes of the pituitary, and the gonads. Functionally, this system is purely regulatory. Its secretions modify many cellular reactions but, as Engel has pointed out, 3 they do not initiate or stop any of them. It is well known that the presence of the endocrine system is not essential for existence. For instance, even the adrenal cortex may not be necessary for the maintenance of life, when sufficient glucose and saline are provided. However, under situations requiring rapid metabolic adjustment, the lack of this regulatory system may lead to grave emergency. By the same token, sudden overactivity of some member of the endocrine system, such as the thyroid gland, may cause severe metabolic dislocation resulting in a true lifethreatening emergency. For the purposes of this discussion, emergencies resulting from the failure of the function of the islands of Langerhans-diabetes mellitusare omitted, as the title implies. Similarly, the emergencies considered hereafter are related only to the adult since the authors' experience has been limited in the field of pediatric endocrinology; however, the principles of therapy in this field are the same, differing only in the dosage of the indicated medications. THE ENDOCRINE SYSTEM
THYROID GLAND
Thyroid Storm "Thyroid storm," which has been accurately defined as "a lifeendangering augmentation of the symptoms of thyrotoxicosis,"12 is a
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BISSELL, PATRICK
R.
COSEGLIA
true medical emergency. Its exact pathogenesis is unknown. Numerous theories have recently been reviewed. 18 Although the evidence regarding its pathogenesis is conflicting, the most successful therapy is based on the assumption that this syndrome represents a sudden overproduction of thyroid hormone, probably associated with deficient adrenal cortical reHerve.9. 13 OCCUHRENCE. 1. Thyroid storm occurs most often in untreated, or partially treated, severely hyperthyroid patients, whose disease is usually of some duration, when subjected to infection, severe emotional trauma, or a surgical operation. Tooth extractions, pre-eclampsia, diabetic acidosis, digitalis intoxication, vigorous palpation of the thyroid,18 and abrupt withdrawal of a thiourylene drug 6 have been recorded also. 2. Any hyperthyroid patient submitted to subtotal thyroidectomy before complete control of thyroid hyperfunction with antithyroid drugH is achieved may experience thyroid storm. 3. The emergency may occur in untreated hyperthyroid caHes treated initially with radioactive iodine. In our own experience, mild "storm" has occurred in two hyperthyroid patients with cardiovascular disease treated with radioactive iodine even when the hypermetabolism waH well controlled with thiourylene drugs. Although rare and somewhat at variance with Waldstein's experience (vide infra),18 this latter observation has been made by others.! SYMPTOMS. All patients exhibit symptoms of hyperthyroidism of a Revere degree. This is associated with hyperpyrexia, often marked; mental disturbance of varying degree which may reach frank psychosiR; Revere tachycardia, and often congestive failure or cardiovascular eollapse. In very elderly patients these symptoms may be masked by a peculiar apathy.20 TREATMENT. The major objective of therapy is prevention. We have never seen thyroid storm occur following subtotal thyroidectomy provided the patient was made completely euthyroid by thiourylene drugs preceding surgical intervention. The complete control of hyperthyroidism by such means accounts for its current rarity following either surgery or radioactive iodine. The therapy of thyroid storm should be intense, rapid, and allinclusive. 1. Intravenous sodium iodide, 1 to 3 gm. daily, or Lugol's solution, 20 drops three times daily. 2. Propylthiouracil, 1000 to 1500 mg. daily in divided six-hour dosage, or methimazole (Tapazole) 100 mg. initially and then 30 mg. at eighthour intervals (both by intubation, if necessary). 3. Hydrocortisone, 300 mg. daily, preferably by intravenous drip, or intramuscularly, in divided doses (100 mg. every eight hours). 4. 2000 to 4000 cc. of 10 per cent glucose in physiological saline,
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intravenously per 24 hours, to which large doses of vitamin B supplement ha ve been added. 5. Reserpine, intramuscularly, 2.5 mg. every four to six hours. 6. Massive appropriate antimicrobial therapy, if infection is apparent. If infection is suspected but its exact proof undetermined, intravenous penicillin, at least 1,000,000 units per 1000 cc. of fluid, should be given. In cardiac failure, where fluids must be restricted, 1,000,000 units of penicillin intramuscularly every six hours is advised. 7. Oxygen by tent. 8. Aspirin, alcohol sponges, ice packs, etc., to control hyperpyrexia. The application of a hypothermia unit would seem to merit serious eonsideration. 8 9. Digitalization, if cardiac failure is apparent. 10. Quinidine may be indicated in the presence of cardiac arrhythmias. Improvement in the patient's condition, if it is going to eventuate, usually occurs in from one day to one week. As it becomes apparent, the therapy may be modified as circumstances indicate. Since all patients are still thyrotoxic following recovery, thiourylene and iodide therapy should be continued until euthyroidism obtains. Since many believe that steroid therapy is one of the more important newer therapeutic adjuvants in controlling storm, its administration should be tapered slowly. Final definitive therapy may be elected with the establishment of euthyroidism by both clinical and laboratory confirmation. Interestingly, Waldstein et aI., in their excellent study of the entire subject of thyroid storm based on a relatively large experience,18 have abandoned thyroidectomy in favor of radioiodotherapy since three of their patients had symptoms of partial recurrence suggesting thyroid storm following thyroidectomy even when well controlled preoperatively.
Hypothyroidism The medical emergencies encountered in secondary or "pituitary myxedema" will be dealt with separately (vide infra). Untreated primary myxedema may be compatible with long, even if not very productive, life. However, although they are rather rare, there are certain events which may precipitate true medical emergencies. HYPOTHYROIDISM AGGRAVA'l'ED BY THE ADMINISTRATION OF OPIUM DERIVATIVFJS TO MYXEDEMATOUS PA'fIEN'l'S. The opium derivatives may precipitate prolonged coma and vascular collapse in myxedematous patients. For treatment: 1. Nalorphine hydrochloride (Nalline) 10 to 40 mg. should be administered. 2. Triiodothyronine (Trionine, Cytomel) 100 mcg., (by intubation) should be given initially and continued in diminishing doses until metabolic control is achieved. (Some form of thyroid must then be continued throughout life to maintain euthyroidism).
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BISSELL,
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COSEGLIA
3. Because of the possibility of adrenal insufficiency in primary myxedema, hydrocortisone, 100 to 300 mg., by slow intravenous infusion over a 24 hour period initially, and then in diminishing dosage may be of value, as well as norepinephrine, should hypotension be evident. IATROGENIC HYPOTHYROIDISM. Many years ago Lahey and his group7 emphasized the danger of operating on hyperthyroid patients who had been made hypothyroid through excessive thiourylene therapy. Such patients have poor cerebral oxygenation, are susceptible to laryngeal edema, and are very sensitive to narcotics. Obviously, the therapy of this emergency is its prevention. Should it occur in an unrecognized rase, the therapy in the previous paragraph should be applied. HYPOTHERMIC MYXEDEMA COMA. The English literature mentions the rare occurrence of "hypothermic myxedema coma. "10 The therapy of this situation is the prompt administration of rapidly acting thyroid hormone, such as triiodothyronine (Trionine, Cytomel), 100 mcg. every 12 hours, by intubation. Cautious rewarming with blankets or a heat cradle is advised. Intravenous fluids should be avoided due to the possibility of associated myxedema heart failure, or acute tubular necrosis secondary to hypothermic renal damage. lo Administration of appropriate antimicrobial agents is advised. Hydrocortisone, 100 mg. every eight hours intramuscularly, would seem logical. 9, 13 Approximately 20 such cases have been described, most of which had a fatal termination. Obviously this syndrome should be considered in any case of obscure hypothermic coma. PARATHYROID GLANDS
Parathyroid Tetany
This is probably the best known endocrine emergency. This stems from the fact that its occurrence most often follows the removal of the parathyroids in about 1 per cent of thyroidectomies and thus it is more likely to be anticipated. OCCURRENCE. Parathyroid tetany occurs most often hours to days, and occasionally months, following thyroidectomy. Extremely rarely it may be an episode in idiopathic hypoparathyroidism, and even more infrequently in pseudohypoparathyroidism. SYMPTOMS. The neuromuscular irritability of acute hypoparathyroid tetany is well known. Nervous manifestations ranging from mild tingling, peripheral numbness, convulsions or laryngeal stridor may occur. Carpopedal spasm following the occlusion of blood flow by a blood pressure cuff for at least three minutes (Trousseau's sign) and twitching of the facial muscles upon tapping (Chvostek's sign) are almost always present. A serum calcium determination below 7 mg./lOO cc. of serum (the total protein being normal) is confirmatory.
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Worth mentioning is the warning that all patients with a history of "epilepsy" or episodes of vague neuromuscular irritability should be investigated from the viewpoint of hypoparathyroid function. TREATMENT OF ACUTE ATTACK. 1. The most important feature if; the administration of intravenous calcium salts, 10 to 30 cc. of a 10 per cent calcium gluconate, as often as necessary, or by slow intravenous infusion to control symptoms effectively. Calcium chloride may be used, but may cause vascular thrombosis. If the patient has been receiving digitalis, calcium salts should be administered with caution in view of the rare but recorded instances of cardiac standstill during such combined therapy.2o 2. Dihydrotachysterol (Hytakerol) 3 cc. daily. 3. Sedation such as chloral hydrate, 1 gm. daily, or one of the barbiturates in divided dosage is of aid. Because of expense, local reactions, and rapid antibody formation, parathormone finds little place in the modern treatment of hypoparathyroid tetany. As symptoms subside, the serum calcium and phosphorus return toward normal, and calcium begins to appear in the urine (as measured by the crude but useful Sulkowitch test). The patient now enters the stage of treatment for latent hypoparathyroidism. This consists of maintenance therapy with dihydrotachysterol or vitamin D, the ingestion of a high calcium-low phosphorus diet. Aluminum hydroxide gels are helpful in inhibiting the absorption of phosphorus from the gastrointestinal tract. Clear directions for prolonged therapy are readily available in most modern endocrine texts. 20 It seems worthy of mention that tetany due to alkalosis (especially brought about by hysterical overbreathing or prolonged vomiting) is by far more common than the hypoparathyroid variety. In such instances, calcium salts will not control symptoms but should not be withheld if the diagnosis is in doubt. The correction of the cause of the alkalosis is obviously indicated in such cases. Acute Parathyroid Hyperfunction
This extremely rare emergency (only 23 cases are reported)4 has been well summarized by Reifenstein as "hyperhyperparathyroidism."20 It should be suspected in patients with high calcium levels with a hyperfunctioning parathyroid tumor who suddenly exhibit diminished urinary volume, rapidly increasing hypercalcemia, and nitrogen retention. This is somewhat similar to the hypercalcemia seen occasionally in neoplastic disease. The authors have never seen such a case but therapy is advised as follows: The patient should be put on a low calcium and phosphorus intake and large amounts of intravenous physiological saline administered. The emergency removal of the tumor has been advised as
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R.
COSEGLIA
the most crucial part of therapy.4, 5, 21, * Chelating agents intravenously, such as 250 cc. of 2,5 per cent sodium citrate or suitable amounts of the sodium salt of ethylenediaminetriacetic acid may be tried. 14 , 20 Aluminum hydroxide gel to diminish phosphorus absorption would seem ind'cated. PANCREAS
Hypoglycemia Due to Islet Cell Tumors
Obviously this may represent a true medical emergency. As has been pointed out, functional islet tumors are often diagnosed only after periods of months to years19 and the patient may already have experienced severe, irreparable neurological defects due to hypoglycemia. It is beyond the scope of this article to delineate the varied symptoms which should alert the physician to the presence of t.his lesion. However, t.he following symptoms can be given as suggest.ive, warranting further investigat.ion, 1. Unaccount.able at.t.acks of coma or convulsions. All "epilept.ics" should have a blood sugar drawn during an at.t.ack. Charact.eristically such at.t.acks following periods of fast.ing are associated with blood sugar levels less t.han 40 mg./lOO cc. (Somogyi-Nelson method) with complet.e relief of symptoms following administ.rat.ion of glucose. 2. Patient.s who rapidly and unaccountably gain weight, with frequent. food ingest.ion and no obvious psychiatric cause, should be viewed with fillspicion. ;i. The precipit.at.ion of symptoms wit.h blood sugars of under 40 mg./lOO cc. after a 24 t.o 48 hour fast is t.he best. diagnostic test of t.his condition. 19 TUEATMEN'l'. Obviously, t.he prompt. administrat.ion of glucose by t.he most. appropriate rout.e is indicated, Thc patient. thcn should be given a high protein-low carbohydrate diet. preliminary to surgical explorat.ion if t.he lesion is seriously suspected upon further diagnostic testing. 19 An excellent. preoperative regimen is given in William's text.book "Diabet.es. "19 ADRENAL GLAND
Complications of Pheochromocytoma
We are not. aware of any emergencies which can be t.ruly classed as hyperepinephrinemia per se. However, t.wo situations may occur in relat.ion t.o pheochromocytomas t.hat. may precipit.at.e a medical emer-
* The accuracy of this opinion would seem to be confirmed by a cure of hyperparathyroid crisis with azotemia and hypercalcemia by parathyroidectomy of a tumor in a child, reported since this paper was written (Reinfrank, R. F. and EdwiLrds, T. L.: Parathyroid Crisis in a Child. J.A,M.A. 178: 468 (Nov. 4) 1961.
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gency. (1) In investigating a suspected medullary tumor the histamine test may precipitate a hypertensive crisis, should the lesion actually be present. (2) In the process of removing a pheochromocytoma, the surgical manipulation of the tumor may precipitate an alarming rise in blood pressure followed by just as dramatic hypotension. TREATMENT. During the hypertensive phases, intravenous phentolamine methanesulfonate (Regitine) should be administered immediately in sufficient dosage to reduce the hypertension. When testing a patient with histamine this material should be ready for immediate administration, preferably by way of a two-way stopcock. In similar fashion, phentolamine should be administered preoperatively and, as the surgecn is manipulating the tumor, it should be given in sufficient quantity intravenously to keep the blood pressure controlledP As a corollary, should severe hypotension result when the tumor is removed, intravenous levarterenol (Levophed) should be administered to maintain normotension until the pressure has become stable. Phenylephrine (Neosynephfine) subcutaneously may be useful in correcting milder hypotensive epiHodes. 17 Acute Adrenal Cortical Insufficiency (Adrenal Crisis)
By far the most dramatic and perhaps the most life-threateJling elldoerilw emergency (barring thyroid crisis) is acute adrenal cortical insufficiency. This clinical emergency may be precipitated by a number of circumstances: 1. In known, clinically controlled patients with primary or secondary adrenal immfficiency (the latter due to pituitary disease, i.e., pituitary adenomas, postpartum necrosis of pituitary (Sheehan's syndrome), etc., who are suddenly submitted to sudden withdrawal of steroid therapy or to superimposed stress (infections, accidental trauma or elective surgical trauma) without an increase in steroid maintenance. 2. In the unsuspected ease of primary or secondary adrenal insufficiem:y submitted to similar stress as above. Any patient admitted to the elinic with unaccountable shock associated with melanotic pigmentation (especially of recent surgical scars), history of past tuberculosis, past history of postpartum hemorrhage or postpartum infection should be suspect. 3. Patients on anticoagulant therapy (adrenal hemorrhage). 4. Patients presenting unaccountable severe shock following surgery.l5 5. Patients with meningococcemia (the Waterhouse-Friderichsen syndrome) are well known,!l but this may be occasionally associated with any overwhelming microbial infection. 6. Overwhelming infections which have not responded to indicated antimicrobial and intensive supportive therapy.I6 The data supporting true organic adrenal insufficiency in these eases and in those of No. 4
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GROSVENOR W. BISSELL, PATRICK R. COSEGLIA
is difficult to evaluate. However, when life is at stake, multiple therapeutic measures seem to be justified. 7. Iatrogenic adrenal insufficiency. Any patient with a history of previous chronic steroid administration within a period of six months, whether systemic or intra-articular, who is to undergo an elective surgical procedure of any degree of magnitude should be given protective steroid coverage preoperatively.I7 The superimposition of an infection should likewise warrant such consideration. 8. Rarely, spontaneous adrenal hemorrhage of unknown etiology.2 TREATMENT. Although the obtaining of confirmatory laboratory data (serum steroids, blood electrolytes, etc.) is highly desirable, therapy should never be deferred in a suspected case for the results of such determination, except in meningococcemia. Recent studies ll would seem to preclude the early use of glucocorticoids (hydrocortisone, cortisone) in meningococcal "Waterhouse-Friderichsen syndrome." It would appear that the early use of these substances enhances a Shartzman-like phenorr:enon which may account for the bilateral adrenal hemorrhage. In those cases in which laboratory tests clearly substantiate the presence of adrenal cortical insufficiency the use of these steroids is, of course, definitely indicated in the manner described below. Corticotropin should never be used, however, since it increases the size and function of the already taxed adrenal. The keystone of therapy of acute adrenal insufficiency is the prompt administration of adrenal cortical steroids, especially of the glucocorticoid type. It cannot be emphasized too strongly that such treatment demands the administration of the more potent salt-retaining steroids. The many substituted steroid analogues ,yhich have been developed in recent years are meant for the therapy of diseases where salt retention is to be avoided. Hydrocortisone and cortisone remain the most important hormones of the therapy of adrenal insufficiency. They should be available in every hospital pharmacy. Aqueous adrenal extract finds little place today in the therapy of this emergency with the wide availability of more potent compounds (except if these should be unavailable). 1. Hydrocortisone, * 100 to 400 mg. diluted in 1000 cc. of 5 per cent
* Hydrocortisonc is available in 50 per cent alcoholic solution, 100 mg. per 20 cc. (Cortef), to be diluted in 500 to 1000 cc. of 5 per cent glucose in physiological saline for intravenous use only. Hydrocortisone sodium succinate 133.7 mg. and 1.8 cc. sterile water per ampulc mixovial (Solu-Cortef) when mixed equals 100 my. of hydrocortisone and may be given intravenously as described, in an intravenous infusion, or intramuscularly. Hydrocortisone 21-phosphate (Injection Hydrocortone Phosphate) as the disodium salt is available in 2 cc. vials, each cubic centimeter containing 50 mg. of hydrocortisone, and may be given intravenously, intramuscularly or subcutaneously. Hydrocortisone is also available as the acetate in saline (Cortef acetate, Cortisole, Cortrel, Hycortole, Hydrocortone) for intramuscular use only (25 mg./cc.). Cortisone (Cortogen, Cortone) is available as the acetate in saline suspension for intramuscular use only (25 and 50 mg. per cc.). For practical use, dosages of hydrocortisone and cortisone are equivalent. (Footnote adapted from Thorn et al.l7).
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glucose and saline intravenously over a two to four hour period. In a de8perate emergency, one ampule of hydrocortisone hemisuccinate (SoluCortef) mixed as directed, or one 2 cc. vial of hydrocortisone 2l-phosphate (Injection Hydrocortone Phosphate), intravenously, should be given immediately. (The latter should be carried in every doctor's bag and given to any known Addisonian in coma.) 2. Hydrocortisone or cortisone, 25 to 50 mg. intramuscularly, every six hours. 3. Blood pressure should be checked hourly in the early stages and pressor amines administered if the blood pressure is extremely low. Levarterenol (Levophed) intravenously or phenylephrine (Neo-Synephrine) intramuscularly may be of use. In extreme shock, 5 to 25 mg. of serum albumin appropriately diluted, or 500 cc. of whole blood, may be indicated. This must be given with extreme caution. Morphine and sedatives are contraindicated. 4. In infectious cases, added massive antimicrobial therapy is indicated. 5. If, after about a four-hour period of intensive therapy, response is apparent, intravenous hydrocortisone, 100 to 200 mg. in 500 to 1000 cc. of 5 per cent glucose in saline, should be continued for about another 12 to 24 hour period. 6. In the usual case, if response is obtained during 24 hours, 50 mg. of cortisone or hydrocortisone acetate intramuscularly every six to eight hours is indicated. This may then be subsequently diminished daily by 50 per cent in therapeutic amounts every six to eight hours until maintenance is achieved. The patient should receive oral sustenance, especially of carbohydrate nature (ginger ale or fruit juice), as soon as feasible. Overtherapy with steroid and salt, indicated by the occurrence of edema or hypertension, should be avoided. If, by clinical response, initial and subsequent laboratory evidence, the patient proves to have permanent adrenal cortical insufficiency, his therapy must then be adjusted to the phase of chronic· adrenal insufficiency. Excellent therapeutic regimens are available.17. 20 PITUITARY GLAND.
I.
,.:
Anterior Pituitary
Emergencies involving the anterior pituitary are of two types: 1. Local-sudden enlargement, causing pressure on contiguous structures. Sometimes this is experienced during radiotherapy or is due to hemorrhage. The treatment is neurosurgical decompression. 2. General-due to secondary adrenal insufficiency especially following surgery. The therapy here is identical to that outlined for adrenal insufficiency. If secondary hypothyroidism is also evident, thyroid in small amounts may be added after the adrenal defect has been corrected.
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BISSELL, PATRICK
R.
COSEGLIA
Posterior Pituitary
Occasionally following hypophysectomy, head trauma, or rarely during the course of severe bacteremia, we have observed the sudden onset of the symptoms of diabetes insipidus. To avoid dehydration, vasopressin in aqueous solution or as the tannate in oily solution should be administered in sufficient amounts to control symptoms. Obviously, a careful check of fluid intake and output must be maintained. Specific gravity of the urine should be checked. The syndrome may be temporary, or permanent diabetes insipidus may result. GONADS
Insofar as we are aware, true endocrine emergencies, such as previously described for the other glands, do not occur. GENERAL ANTICIPATED EMERGENCIES
Obviously, endocrine emergencies due to situations demanding bilateral adrenalectomy or complete hypophysectomy should be anticipated and appropriate preoperative and postoperative precautions taken. The principles heretofore given may be applied in an anticipatory fashion. Excellent references for such operative regimens are given ill the bibliographyY. 20 Acknowledgment The authors wish to thank Mrs. Leona L. Muhl for aid in preparation of the man\!seript and checking; of the bibliography.
REFERENCES 1. Beierwaltes, W. H., Johnson, P. C. and Solari, A. J.: Clinieal Use of Radioiso-
topes. Philadelphia, W. P. Saunders Co., 1\.)57. 2. Berte, S. J.: Spontaneous Adrenal Hemorrhage in the Adult: Literature Review and Report of Two Cases. Ann. Int. Med. 38: 28-37 (Jan.) 1953. 3. Engel, F. L.: Endocrine Control of Metabolism. Bull. New York Acad. Med. 29: 175-201 (March) 1953. 4. Hewson, J. S.: Parathyroid Crisis; a Cause of Sudden Death. Arch. Int. Med. 102: 199-203 (Aug.) 1958. 5. Horowitz, W. and Berenbaum, A. A.: Primary Hyperparathyroidism Due to Parathyroid Adenoma: Ante-Mortem Diagnosis with Termination in Possible Acute Parathyroid Intoxication. Ann. Int. Med. 49: 181-189 (July) 1958. 6. Kelly, T. R. and Bliss, T. L.: Thyroid Crisis Subsequent to Withdrawal of Propylthiouracil. Ann. Int. Med. 40: 1223-1226 (.June) 1954. 7. Lahey, F. H.: Thyroid Disease Today. Postgrad. Med. 9: 400-407 (May) 1951. 8. Lamphier, T. A. and Wickman, W.: Postoperative Thyroid Storm (Use of Refrigeration Blanket in Storm). Postgrad. Med. 15: 493-502 (June) 1954. 9. Levin, M. E. and Daughaday. W. H.: Influence of the Thyroid on Adrenocortical Function. J. Clin. Endocrinol. 15: 1499-1511 (Dec.) 1955.
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10. MacDonald, D. W.: Hypothermic Myxedema Coma; 3 case reports. Brit. M. J. 2: 1144-1146 (Nov. 8) 1958. 11. Margaretten, W. and McAdams, A. J.: An Appraisal of Fulminant Meningococcocemia with Reference to the Shartzman Phenomenon. Am. J. Med. 25: 868-876 (Dec.) 1958. 12. McArthur, J. W., Rawson, R. W., Means, J. H. and Cope, 0.: Thyrotoxic Crisis; Analysis of 36 Cases Seen at Massachusetts General Hospital During Past 25 Years. J.A.M.A. 134: 868-874 (July 5) 1947. 13. Mikulaj, J. and Nemeth, S.: Contribution to the Study of Adrenocortical Secretory Function in Thyrotoxicosis. J. Clin. Endocrinol18: 539-542 (May) 1958. 14. Myers, W. P. L.: Hypercalcemia in Neoplastic Disease. Cancer 9: 1135-1140 (Nov.-Dec.) 1956. 15. Schneewind, J. H. and Cole, W. H.: Steroid Therapy in Surgical Patients. J.A.M.A. 170: 1411-1421 (July 18) 1959. 16. Spink, W. W.: Adrenocortical Steroids in the Management of Selected Patients with Infectious Diseases. Ann. Int. Med. 53: 1-32 (July) 1960. 17. Thorn, G. W., Nelson, D. H. and Renold, A. E.: Current Status of the Treatment of Adrenal Disorders. J.A.M.A. 168: 2130-2137 (Dec. 20) 1958. 18. Waldstein, S. S., Slodki, S. J., Kaganiec, 1. and Bronsky, D.: A Clinical Study of Thyroid Storm. Ann. Int. Med. 52: 626-42 (March) 1960. 19. Williams, R. H.: Hypoglycemosis. In Diabetes. New York, Paul B. Hoeber, 1960. 20. Williams, R. H.: Textbook of Endocrinology. 3rd Ed. Philadelphia, W. B. Saunders Co., 1962. 21. Young, J. H. and Emerson, K. Jr.: Parathyroid Carcinoma Associated with Acute Parathyroid Intoxication. Ann. Int. Med. 30: 823-837 (April) 1949.
PATRICK R. COSEGLIA, M.D. Staff Physician, Veterans Administration Hospital, Buffalo, New York; Research Fellow, Chautauqua County Tuberculosis and Public Health Association
is generally considered as being comprised of the thyroid, parathyroid, islands of Langerhans, adrenal medulla and adrenal cortex, the anterior and posterior lobes of the pituitary, and the gonads. Functionally, this system is purely regulatory. Its secretions modify many cellular reactions but, as Engel has pointed out, 3 they do not initiate or stop any of them. It is well known that the presence of the endocrine system is not essential for existence. For instance, even the adrenal cortex may not be necessary for the maintenance of life, when sufficient glucose and saline are provided. However, under situations requiring rapid metabolic adjustment, the lack of this regulatory system may lead to grave emergency. By the same token, sudden overactivity of some member of the endocrine system, such as the thyroid gland, may cause severe metabolic dislocation resulting in a true lifethreatening emergency. For the purposes of this discussion, emergencies resulting from the failure of the function of the islands of Langerhans-diabetes mellitusare omitted, as the title implies. Similarly, the emergencies considered hereafter are related only to the adult since the authors' experience has been limited in the field of pediatric endocrinology; however, the principles of therapy in this field are the same, differing only in the dosage of the indicated medications. THE ENDOCRINE SYSTEM
THYROID GLAND
Thyroid Storm "Thyroid storm," which has been accurately defined as "a lifeendangering augmentation of the symptoms of thyrotoxicosis,"12 is a
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BISSELL, PATRICK
R.
COSEGLIA
true medical emergency. Its exact pathogenesis is unknown. Numerous theories have recently been reviewed. 18 Although the evidence regarding its pathogenesis is conflicting, the most successful therapy is based on the assumption that this syndrome represents a sudden overproduction of thyroid hormone, probably associated with deficient adrenal cortical reHerve.9. 13 OCCUHRENCE. 1. Thyroid storm occurs most often in untreated, or partially treated, severely hyperthyroid patients, whose disease is usually of some duration, when subjected to infection, severe emotional trauma, or a surgical operation. Tooth extractions, pre-eclampsia, diabetic acidosis, digitalis intoxication, vigorous palpation of the thyroid,18 and abrupt withdrawal of a thiourylene drug 6 have been recorded also. 2. Any hyperthyroid patient submitted to subtotal thyroidectomy before complete control of thyroid hyperfunction with antithyroid drugH is achieved may experience thyroid storm. 3. The emergency may occur in untreated hyperthyroid caHes treated initially with radioactive iodine. In our own experience, mild "storm" has occurred in two hyperthyroid patients with cardiovascular disease treated with radioactive iodine even when the hypermetabolism waH well controlled with thiourylene drugs. Although rare and somewhat at variance with Waldstein's experience (vide infra),18 this latter observation has been made by others.! SYMPTOMS. All patients exhibit symptoms of hyperthyroidism of a Revere degree. This is associated with hyperpyrexia, often marked; mental disturbance of varying degree which may reach frank psychosiR; Revere tachycardia, and often congestive failure or cardiovascular eollapse. In very elderly patients these symptoms may be masked by a peculiar apathy.20 TREATMENT. The major objective of therapy is prevention. We have never seen thyroid storm occur following subtotal thyroidectomy provided the patient was made completely euthyroid by thiourylene drugs preceding surgical intervention. The complete control of hyperthyroidism by such means accounts for its current rarity following either surgery or radioactive iodine. The therapy of thyroid storm should be intense, rapid, and allinclusive. 1. Intravenous sodium iodide, 1 to 3 gm. daily, or Lugol's solution, 20 drops three times daily. 2. Propylthiouracil, 1000 to 1500 mg. daily in divided six-hour dosage, or methimazole (Tapazole) 100 mg. initially and then 30 mg. at eighthour intervals (both by intubation, if necessary). 3. Hydrocortisone, 300 mg. daily, preferably by intravenous drip, or intramuscularly, in divided doses (100 mg. every eight hours). 4. 2000 to 4000 cc. of 10 per cent glucose in physiological saline,
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intravenously per 24 hours, to which large doses of vitamin B supplement ha ve been added. 5. Reserpine, intramuscularly, 2.5 mg. every four to six hours. 6. Massive appropriate antimicrobial therapy, if infection is apparent. If infection is suspected but its exact proof undetermined, intravenous penicillin, at least 1,000,000 units per 1000 cc. of fluid, should be given. In cardiac failure, where fluids must be restricted, 1,000,000 units of penicillin intramuscularly every six hours is advised. 7. Oxygen by tent. 8. Aspirin, alcohol sponges, ice packs, etc., to control hyperpyrexia. The application of a hypothermia unit would seem to merit serious eonsideration. 8 9. Digitalization, if cardiac failure is apparent. 10. Quinidine may be indicated in the presence of cardiac arrhythmias. Improvement in the patient's condition, if it is going to eventuate, usually occurs in from one day to one week. As it becomes apparent, the therapy may be modified as circumstances indicate. Since all patients are still thyrotoxic following recovery, thiourylene and iodide therapy should be continued until euthyroidism obtains. Since many believe that steroid therapy is one of the more important newer therapeutic adjuvants in controlling storm, its administration should be tapered slowly. Final definitive therapy may be elected with the establishment of euthyroidism by both clinical and laboratory confirmation. Interestingly, Waldstein et aI., in their excellent study of the entire subject of thyroid storm based on a relatively large experience,18 have abandoned thyroidectomy in favor of radioiodotherapy since three of their patients had symptoms of partial recurrence suggesting thyroid storm following thyroidectomy even when well controlled preoperatively.
Hypothyroidism The medical emergencies encountered in secondary or "pituitary myxedema" will be dealt with separately (vide infra). Untreated primary myxedema may be compatible with long, even if not very productive, life. However, although they are rather rare, there are certain events which may precipitate true medical emergencies. HYPOTHYROIDISM AGGRAVA'l'ED BY THE ADMINISTRATION OF OPIUM DERIVATIVFJS TO MYXEDEMATOUS PA'fIEN'l'S. The opium derivatives may precipitate prolonged coma and vascular collapse in myxedematous patients. For treatment: 1. Nalorphine hydrochloride (Nalline) 10 to 40 mg. should be administered. 2. Triiodothyronine (Trionine, Cytomel) 100 mcg., (by intubation) should be given initially and continued in diminishing doses until metabolic control is achieved. (Some form of thyroid must then be continued throughout life to maintain euthyroidism).
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BISSELL,
P ATRICK R.
COSEGLIA
3. Because of the possibility of adrenal insufficiency in primary myxedema, hydrocortisone, 100 to 300 mg., by slow intravenous infusion over a 24 hour period initially, and then in diminishing dosage may be of value, as well as norepinephrine, should hypotension be evident. IATROGENIC HYPOTHYROIDISM. Many years ago Lahey and his group7 emphasized the danger of operating on hyperthyroid patients who had been made hypothyroid through excessive thiourylene therapy. Such patients have poor cerebral oxygenation, are susceptible to laryngeal edema, and are very sensitive to narcotics. Obviously, the therapy of this emergency is its prevention. Should it occur in an unrecognized rase, the therapy in the previous paragraph should be applied. HYPOTHERMIC MYXEDEMA COMA. The English literature mentions the rare occurrence of "hypothermic myxedema coma. "10 The therapy of this situation is the prompt administration of rapidly acting thyroid hormone, such as triiodothyronine (Trionine, Cytomel), 100 mcg. every 12 hours, by intubation. Cautious rewarming with blankets or a heat cradle is advised. Intravenous fluids should be avoided due to the possibility of associated myxedema heart failure, or acute tubular necrosis secondary to hypothermic renal damage. lo Administration of appropriate antimicrobial agents is advised. Hydrocortisone, 100 mg. every eight hours intramuscularly, would seem logical. 9, 13 Approximately 20 such cases have been described, most of which had a fatal termination. Obviously this syndrome should be considered in any case of obscure hypothermic coma. PARATHYROID GLANDS
Parathyroid Tetany
This is probably the best known endocrine emergency. This stems from the fact that its occurrence most often follows the removal of the parathyroids in about 1 per cent of thyroidectomies and thus it is more likely to be anticipated. OCCURRENCE. Parathyroid tetany occurs most often hours to days, and occasionally months, following thyroidectomy. Extremely rarely it may be an episode in idiopathic hypoparathyroidism, and even more infrequently in pseudohypoparathyroidism. SYMPTOMS. The neuromuscular irritability of acute hypoparathyroid tetany is well known. Nervous manifestations ranging from mild tingling, peripheral numbness, convulsions or laryngeal stridor may occur. Carpopedal spasm following the occlusion of blood flow by a blood pressure cuff for at least three minutes (Trousseau's sign) and twitching of the facial muscles upon tapping (Chvostek's sign) are almost always present. A serum calcium determination below 7 mg./lOO cc. of serum (the total protein being normal) is confirmatory.
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Worth mentioning is the warning that all patients with a history of "epilepsy" or episodes of vague neuromuscular irritability should be investigated from the viewpoint of hypoparathyroid function. TREATMENT OF ACUTE ATTACK. 1. The most important feature if; the administration of intravenous calcium salts, 10 to 30 cc. of a 10 per cent calcium gluconate, as often as necessary, or by slow intravenous infusion to control symptoms effectively. Calcium chloride may be used, but may cause vascular thrombosis. If the patient has been receiving digitalis, calcium salts should be administered with caution in view of the rare but recorded instances of cardiac standstill during such combined therapy.2o 2. Dihydrotachysterol (Hytakerol) 3 cc. daily. 3. Sedation such as chloral hydrate, 1 gm. daily, or one of the barbiturates in divided dosage is of aid. Because of expense, local reactions, and rapid antibody formation, parathormone finds little place in the modern treatment of hypoparathyroid tetany. As symptoms subside, the serum calcium and phosphorus return toward normal, and calcium begins to appear in the urine (as measured by the crude but useful Sulkowitch test). The patient now enters the stage of treatment for latent hypoparathyroidism. This consists of maintenance therapy with dihydrotachysterol or vitamin D, the ingestion of a high calcium-low phosphorus diet. Aluminum hydroxide gels are helpful in inhibiting the absorption of phosphorus from the gastrointestinal tract. Clear directions for prolonged therapy are readily available in most modern endocrine texts. 20 It seems worthy of mention that tetany due to alkalosis (especially brought about by hysterical overbreathing or prolonged vomiting) is by far more common than the hypoparathyroid variety. In such instances, calcium salts will not control symptoms but should not be withheld if the diagnosis is in doubt. The correction of the cause of the alkalosis is obviously indicated in such cases. Acute Parathyroid Hyperfunction
This extremely rare emergency (only 23 cases are reported)4 has been well summarized by Reifenstein as "hyperhyperparathyroidism."20 It should be suspected in patients with high calcium levels with a hyperfunctioning parathyroid tumor who suddenly exhibit diminished urinary volume, rapidly increasing hypercalcemia, and nitrogen retention. This is somewhat similar to the hypercalcemia seen occasionally in neoplastic disease. The authors have never seen such a case but therapy is advised as follows: The patient should be put on a low calcium and phosphorus intake and large amounts of intravenous physiological saline administered. The emergency removal of the tumor has been advised as
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W.
BISSELL, PATRICK
R.
COSEGLIA
the most crucial part of therapy.4, 5, 21, * Chelating agents intravenously, such as 250 cc. of 2,5 per cent sodium citrate or suitable amounts of the sodium salt of ethylenediaminetriacetic acid may be tried. 14 , 20 Aluminum hydroxide gel to diminish phosphorus absorption would seem ind'cated. PANCREAS
Hypoglycemia Due to Islet Cell Tumors
Obviously this may represent a true medical emergency. As has been pointed out, functional islet tumors are often diagnosed only after periods of months to years19 and the patient may already have experienced severe, irreparable neurological defects due to hypoglycemia. It is beyond the scope of this article to delineate the varied symptoms which should alert the physician to the presence of t.his lesion. However, t.he following symptoms can be given as suggest.ive, warranting further investigat.ion, 1. Unaccount.able at.t.acks of coma or convulsions. All "epilept.ics" should have a blood sugar drawn during an at.t.ack. Charact.eristically such at.t.acks following periods of fast.ing are associated with blood sugar levels less t.han 40 mg./lOO cc. (Somogyi-Nelson method) with complet.e relief of symptoms following administ.rat.ion of glucose. 2. Patient.s who rapidly and unaccountably gain weight, with frequent. food ingest.ion and no obvious psychiatric cause, should be viewed with fillspicion. ;i. The precipit.at.ion of symptoms wit.h blood sugars of under 40 mg./lOO cc. after a 24 t.o 48 hour fast is t.he best. diagnostic test of t.his condition. 19 TUEATMEN'l'. Obviously, t.he prompt. administrat.ion of glucose by t.he most. appropriate rout.e is indicated, Thc patient. thcn should be given a high protein-low carbohydrate diet. preliminary to surgical explorat.ion if t.he lesion is seriously suspected upon further diagnostic testing. 19 An excellent. preoperative regimen is given in William's text.book "Diabet.es. "19 ADRENAL GLAND
Complications of Pheochromocytoma
We are not. aware of any emergencies which can be t.ruly classed as hyperepinephrinemia per se. However, t.wo situations may occur in relat.ion t.o pheochromocytomas t.hat. may precipit.at.e a medical emer-
* The accuracy of this opinion would seem to be confirmed by a cure of hyperparathyroid crisis with azotemia and hypercalcemia by parathyroidectomy of a tumor in a child, reported since this paper was written (Reinfrank, R. F. and EdwiLrds, T. L.: Parathyroid Crisis in a Child. J.A,M.A. 178: 468 (Nov. 4) 1961.
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gency. (1) In investigating a suspected medullary tumor the histamine test may precipitate a hypertensive crisis, should the lesion actually be present. (2) In the process of removing a pheochromocytoma, the surgical manipulation of the tumor may precipitate an alarming rise in blood pressure followed by just as dramatic hypotension. TREATMENT. During the hypertensive phases, intravenous phentolamine methanesulfonate (Regitine) should be administered immediately in sufficient dosage to reduce the hypertension. When testing a patient with histamine this material should be ready for immediate administration, preferably by way of a two-way stopcock. In similar fashion, phentolamine should be administered preoperatively and, as the surgecn is manipulating the tumor, it should be given in sufficient quantity intravenously to keep the blood pressure controlledP As a corollary, should severe hypotension result when the tumor is removed, intravenous levarterenol (Levophed) should be administered to maintain normotension until the pressure has become stable. Phenylephrine (Neosynephfine) subcutaneously may be useful in correcting milder hypotensive epiHodes. 17 Acute Adrenal Cortical Insufficiency (Adrenal Crisis)
By far the most dramatic and perhaps the most life-threateJling elldoerilw emergency (barring thyroid crisis) is acute adrenal cortical insufficiency. This clinical emergency may be precipitated by a number of circumstances: 1. In known, clinically controlled patients with primary or secondary adrenal immfficiency (the latter due to pituitary disease, i.e., pituitary adenomas, postpartum necrosis of pituitary (Sheehan's syndrome), etc., who are suddenly submitted to sudden withdrawal of steroid therapy or to superimposed stress (infections, accidental trauma or elective surgical trauma) without an increase in steroid maintenance. 2. In the unsuspected ease of primary or secondary adrenal insufficiem:y submitted to similar stress as above. Any patient admitted to the elinic with unaccountable shock associated with melanotic pigmentation (especially of recent surgical scars), history of past tuberculosis, past history of postpartum hemorrhage or postpartum infection should be suspect. 3. Patients on anticoagulant therapy (adrenal hemorrhage). 4. Patients presenting unaccountable severe shock following surgery.l5 5. Patients with meningococcemia (the Waterhouse-Friderichsen syndrome) are well known,!l but this may be occasionally associated with any overwhelming microbial infection. 6. Overwhelming infections which have not responded to indicated antimicrobial and intensive supportive therapy.I6 The data supporting true organic adrenal insufficiency in these eases and in those of No. 4
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GROSVENOR W. BISSELL, PATRICK R. COSEGLIA
is difficult to evaluate. However, when life is at stake, multiple therapeutic measures seem to be justified. 7. Iatrogenic adrenal insufficiency. Any patient with a history of previous chronic steroid administration within a period of six months, whether systemic or intra-articular, who is to undergo an elective surgical procedure of any degree of magnitude should be given protective steroid coverage preoperatively.I7 The superimposition of an infection should likewise warrant such consideration. 8. Rarely, spontaneous adrenal hemorrhage of unknown etiology.2 TREATMENT. Although the obtaining of confirmatory laboratory data (serum steroids, blood electrolytes, etc.) is highly desirable, therapy should never be deferred in a suspected case for the results of such determination, except in meningococcemia. Recent studies ll would seem to preclude the early use of glucocorticoids (hydrocortisone, cortisone) in meningococcal "Waterhouse-Friderichsen syndrome." It would appear that the early use of these substances enhances a Shartzman-like phenorr:enon which may account for the bilateral adrenal hemorrhage. In those cases in which laboratory tests clearly substantiate the presence of adrenal cortical insufficiency the use of these steroids is, of course, definitely indicated in the manner described below. Corticotropin should never be used, however, since it increases the size and function of the already taxed adrenal. The keystone of therapy of acute adrenal insufficiency is the prompt administration of adrenal cortical steroids, especially of the glucocorticoid type. It cannot be emphasized too strongly that such treatment demands the administration of the more potent salt-retaining steroids. The many substituted steroid analogues ,yhich have been developed in recent years are meant for the therapy of diseases where salt retention is to be avoided. Hydrocortisone and cortisone remain the most important hormones of the therapy of adrenal insufficiency. They should be available in every hospital pharmacy. Aqueous adrenal extract finds little place today in the therapy of this emergency with the wide availability of more potent compounds (except if these should be unavailable). 1. Hydrocortisone, * 100 to 400 mg. diluted in 1000 cc. of 5 per cent
* Hydrocortisonc is available in 50 per cent alcoholic solution, 100 mg. per 20 cc. (Cortef), to be diluted in 500 to 1000 cc. of 5 per cent glucose in physiological saline for intravenous use only. Hydrocortisone sodium succinate 133.7 mg. and 1.8 cc. sterile water per ampulc mixovial (Solu-Cortef) when mixed equals 100 my. of hydrocortisone and may be given intravenously as described, in an intravenous infusion, or intramuscularly. Hydrocortisone 21-phosphate (Injection Hydrocortone Phosphate) as the disodium salt is available in 2 cc. vials, each cubic centimeter containing 50 mg. of hydrocortisone, and may be given intravenously, intramuscularly or subcutaneously. Hydrocortisone is also available as the acetate in saline (Cortef acetate, Cortisole, Cortrel, Hycortole, Hydrocortone) for intramuscular use only (25 mg./cc.). Cortisone (Cortogen, Cortone) is available as the acetate in saline suspension for intramuscular use only (25 and 50 mg. per cc.). For practical use, dosages of hydrocortisone and cortisone are equivalent. (Footnote adapted from Thorn et al.l7).
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glucose and saline intravenously over a two to four hour period. In a de8perate emergency, one ampule of hydrocortisone hemisuccinate (SoluCortef) mixed as directed, or one 2 cc. vial of hydrocortisone 2l-phosphate (Injection Hydrocortone Phosphate), intravenously, should be given immediately. (The latter should be carried in every doctor's bag and given to any known Addisonian in coma.) 2. Hydrocortisone or cortisone, 25 to 50 mg. intramuscularly, every six hours. 3. Blood pressure should be checked hourly in the early stages and pressor amines administered if the blood pressure is extremely low. Levarterenol (Levophed) intravenously or phenylephrine (Neo-Synephrine) intramuscularly may be of use. In extreme shock, 5 to 25 mg. of serum albumin appropriately diluted, or 500 cc. of whole blood, may be indicated. This must be given with extreme caution. Morphine and sedatives are contraindicated. 4. In infectious cases, added massive antimicrobial therapy is indicated. 5. If, after about a four-hour period of intensive therapy, response is apparent, intravenous hydrocortisone, 100 to 200 mg. in 500 to 1000 cc. of 5 per cent glucose in saline, should be continued for about another 12 to 24 hour period. 6. In the usual case, if response is obtained during 24 hours, 50 mg. of cortisone or hydrocortisone acetate intramuscularly every six to eight hours is indicated. This may then be subsequently diminished daily by 50 per cent in therapeutic amounts every six to eight hours until maintenance is achieved. The patient should receive oral sustenance, especially of carbohydrate nature (ginger ale or fruit juice), as soon as feasible. Overtherapy with steroid and salt, indicated by the occurrence of edema or hypertension, should be avoided. If, by clinical response, initial and subsequent laboratory evidence, the patient proves to have permanent adrenal cortical insufficiency, his therapy must then be adjusted to the phase of chronic· adrenal insufficiency. Excellent therapeutic regimens are available.17. 20 PITUITARY GLAND.
I.
,.:
Anterior Pituitary
Emergencies involving the anterior pituitary are of two types: 1. Local-sudden enlargement, causing pressure on contiguous structures. Sometimes this is experienced during radiotherapy or is due to hemorrhage. The treatment is neurosurgical decompression. 2. General-due to secondary adrenal insufficiency especially following surgery. The therapy here is identical to that outlined for adrenal insufficiency. If secondary hypothyroidism is also evident, thyroid in small amounts may be added after the adrenal defect has been corrected.
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GROSVENOR
'V.
BISSELL, PATRICK
R.
COSEGLIA
Posterior Pituitary
Occasionally following hypophysectomy, head trauma, or rarely during the course of severe bacteremia, we have observed the sudden onset of the symptoms of diabetes insipidus. To avoid dehydration, vasopressin in aqueous solution or as the tannate in oily solution should be administered in sufficient amounts to control symptoms. Obviously, a careful check of fluid intake and output must be maintained. Specific gravity of the urine should be checked. The syndrome may be temporary, or permanent diabetes insipidus may result. GONADS
Insofar as we are aware, true endocrine emergencies, such as previously described for the other glands, do not occur. GENERAL ANTICIPATED EMERGENCIES
Obviously, endocrine emergencies due to situations demanding bilateral adrenalectomy or complete hypophysectomy should be anticipated and appropriate preoperative and postoperative precautions taken. The principles heretofore given may be applied in an anticipatory fashion. Excellent references for such operative regimens are given ill the bibliographyY. 20 Acknowledgment The authors wish to thank Mrs. Leona L. Muhl for aid in preparation of the man\!seript and checking; of the bibliography.
REFERENCES 1. Beierwaltes, W. H., Johnson, P. C. and Solari, A. J.: Clinieal Use of Radioiso-
topes. Philadelphia, W. P. Saunders Co., 1\.)57. 2. Berte, S. J.: Spontaneous Adrenal Hemorrhage in the Adult: Literature Review and Report of Two Cases. Ann. Int. Med. 38: 28-37 (Jan.) 1953. 3. Engel, F. L.: Endocrine Control of Metabolism. Bull. New York Acad. Med. 29: 175-201 (March) 1953. 4. Hewson, J. S.: Parathyroid Crisis; a Cause of Sudden Death. Arch. Int. Med. 102: 199-203 (Aug.) 1958. 5. Horowitz, W. and Berenbaum, A. A.: Primary Hyperparathyroidism Due to Parathyroid Adenoma: Ante-Mortem Diagnosis with Termination in Possible Acute Parathyroid Intoxication. Ann. Int. Med. 49: 181-189 (July) 1958. 6. Kelly, T. R. and Bliss, T. L.: Thyroid Crisis Subsequent to Withdrawal of Propylthiouracil. Ann. Int. Med. 40: 1223-1226 (.June) 1954. 7. Lahey, F. H.: Thyroid Disease Today. Postgrad. Med. 9: 400-407 (May) 1951. 8. Lamphier, T. A. and Wickman, W.: Postoperative Thyroid Storm (Use of Refrigeration Blanket in Storm). Postgrad. Med. 15: 493-502 (June) 1954. 9. Levin, M. E. and Daughaday. W. H.: Influence of the Thyroid on Adrenocortical Function. J. Clin. Endocrinol. 15: 1499-1511 (Dec.) 1955.
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10. MacDonald, D. W.: Hypothermic Myxedema Coma; 3 case reports. Brit. M. J. 2: 1144-1146 (Nov. 8) 1958. 11. Margaretten, W. and McAdams, A. J.: An Appraisal of Fulminant Meningococcocemia with Reference to the Shartzman Phenomenon. Am. J. Med. 25: 868-876 (Dec.) 1958. 12. McArthur, J. W., Rawson, R. W., Means, J. H. and Cope, 0.: Thyrotoxic Crisis; Analysis of 36 Cases Seen at Massachusetts General Hospital During Past 25 Years. J.A.M.A. 134: 868-874 (July 5) 1947. 13. Mikulaj, J. and Nemeth, S.: Contribution to the Study of Adrenocortical Secretory Function in Thyrotoxicosis. J. Clin. Endocrinol18: 539-542 (May) 1958. 14. Myers, W. P. L.: Hypercalcemia in Neoplastic Disease. Cancer 9: 1135-1140 (Nov.-Dec.) 1956. 15. Schneewind, J. H. and Cole, W. H.: Steroid Therapy in Surgical Patients. J.A.M.A. 170: 1411-1421 (July 18) 1959. 16. Spink, W. W.: Adrenocortical Steroids in the Management of Selected Patients with Infectious Diseases. Ann. Int. Med. 53: 1-32 (July) 1960. 17. Thorn, G. W., Nelson, D. H. and Renold, A. E.: Current Status of the Treatment of Adrenal Disorders. J.A.M.A. 168: 2130-2137 (Dec. 20) 1958. 18. Waldstein, S. S., Slodki, S. J., Kaganiec, 1. and Bronsky, D.: A Clinical Study of Thyroid Storm. Ann. Int. Med. 52: 626-42 (March) 1960. 19. Williams, R. H.: Hypoglycemosis. In Diabetes. New York, Paul B. Hoeber, 1960. 20. Williams, R. H.: Textbook of Endocrinology. 3rd Ed. Philadelphia, W. B. Saunders Co., 1962. 21. Young, J. H. and Emerson, K. Jr.: Parathyroid Carcinoma Associated with Acute Parathyroid Intoxication. Ann. Int. Med. 30: 823-837 (April) 1949.