Occult Adrenal Insufficiency in Surgical Patients CHARLES A. HUBAY, M.D., ELDEN C. WECKESSER, M.D., RICHARD P. LEVY, M.D. Eight patients admitted to a University hospital with acute surgical problems and related adrenal insufficiency were reviewed and three are presented in detail. Surgical stress and continued sepsis played major roles in the lack of responsiveness to usual modes of therapy until the adrenal insufficiency was corrected. The patients fell into three major clinical categories of adrenal insufficiency. Chronic illness and sepsis are shown to affect steriod production and metabolism, as well as adrenal responsiveness to ACTH. Pharmacologic amounts of steroids are often needed in patients with shock, gram negative sepsis and prolonged illnesses, even if normal or elevated serum cortisols are present. Therapeutic trials ofcortisol administration are shown to be confusing when not accompanied by easily performed diagnostic tests of adrenal function. It is emphasized that a pretreatment serum cortisol should be obtained whenever possible. The evaluation of adrenal function is of lifelong importance to the patient.
From the Departments of Surgery and Medicine, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Cleveland, Ohio
emergency unit or to the hospital in extremis, or hypotensive from unknown causes, in whom adrenal failure may possibly play a role. It is in this latter group of patients in whom pharmacologic doses of glucocorticoid therapy may be indicated as one form of nonspecific therapy. This might include patients with severe gram-negative infections, the Waterhouse-Friderichsen syndrome, postmyocardial infarction patients on anticoagulants, patients with metastatic carcinoma to the adrenals, and pseudotumor cerebri. The adrenal secretory responses to continued infection, T HE SURGEON is often faced with acute situations chronic illness and stress are poorly understood. Depreswherein his patient exhibits nonresponsiveness to the sion of adrenal secretion and diminished responsiveness to usual therapeutic maneuvers. Under these circumstances, ACTH often develop during severe orprolonged infection. This report is concerned with eight patients (Table 1) attention is usually focused on hypovolemic states, the myocardium, respiratory tract, sepsis, and pulmonary or admitted to the surgical service at University Hospitals of fat embolism. Unrecognized adrenal insufficiency should Cleveland presenting acute problems and related adrenal insufficiency during their hospital course. Surgical stress be included in the differential diagnosis. Acute adrenal insufficiency is seen in three major clinical and continued sepsis played strategic roles in the lack of responsiveness to therapy in some of these patients until situations: I. In the firstgroup are patients with unrecognized Addi- the adrenal insufficiency was corrected. son's disease in whom a crisis has been precipitated by Three examples of patients with adrenal insufficiency trauma, a surgical procedure, intercurrent infection or in- are summarized to emphasize the problems encountered in advertent discontinuation of corticosteroid therapy. their surgical care and convalescence. II. Inthe secondgrouparethosepatients withiatrogenic adrenal insufficiency in whom long-term adrenocortical Case Reports steroid therapy has been discontinued for one reason or G.S. #235-103. A 53-year-old female was admitted to the Medical another, and in whom acute stress may precipitate adrenal Service of University Hospitals January 21, 1968 with weakness and insufficiency. The number of patients in this category is vomiting of one month's duration. Chills and fever had been present for rising rapidly as disease complexes responding to steroid three weeks. She continued to have anorexia, vomited frequently, and had lost 16 pounds. There was no change in bowel habits, jaundice or therapy increase. of peptic ulcer. III. In the third group are patients admitted to an symptoms Past history was noncontributory except for congenital toxoplasmosis Submitted for publication July 8, 1974.. Reprint requests: Charles A. Hubay, M.D., 2065 Adelbert Road, Cleveland, Ohio 44106.
of the eyes. Physical examination: T. 36.5C; P. 80/min; R 20/min; B.P. 110/70 mm Hg. Examination revealed a slender woman in no acute distress. Abdomen
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HUBAY, WECKESSER AND LEVY
TABLE 1. Summary of Patients with Nonresponsive Clinical Problems Associated with Hypoadrenalism
Age
Sex
Presenting Clinical Problems
Surgical Diagnosis
Categ6ry Of Hypoadrenalism
G. S.
53
F
Hypotension, Fever, Vomiting
Cholelithiasis
I
M.B.
71
F
Sepsis, Toxic Delirium, Fever
Perforated Sigmoid
I
Patient
Diverticulitis B.A.
57
F
Hypotension, Fever
D.F.
79
M
Vomiting, Distension, Diarrhea, Lethargy, Sepsis
Agnogenic Myeloid Metaplasia Splenectomy
II
Rheumatoid Arthritis
II
Sigmoid Vesical Fistula Colostomy
M.E.B.
58
F
Hypotension, Fever, Lethargy, Apnea
Rheumatoid Arthritis Necrosis of Hip
II
R. Y.
45
F
Hypotension, Sepsis, Fever
Laparotomy Gram Negative Sepsis
III
W.B.
57
M
Weakness, Vomiting, Weight Loss
Metastatic Carcinoma of Prostate
III
C.P.
17
M
Chronic Illness, Sepsis, Fever
Portal Vein Hypertension Meso-caval Shunt
III
showed minimal tenderness in the epigastrium and to the right of the umbilicus. Bowel sounds were normal. No masses palpated. Laboratory findings were normal. Urinalysis negative. X-ray examination of the chest showed no significant pulmonary
pathology. Electrocardiography on admission showed ST-T-U changes across the anterior precordium, consistent with electrolyte imbalance. The gallbladder demonstrated numerous small nonopaque calculi. Gastrointestinal x-rays showed a small hiatus hernia.
28-
Respiration/min
24-
20] 1101
Systolic
100
Blood Pressure 90
-
80 -
70 -
Temperature CP
0
FIG. 1. Outline of physiologic derangements following cholecystectomy in patient G.S., subsequently shown to have Addison's Disease.
4038- -
36 l20-
Pulse
Rate/min--I
12
2 pm 4
6
8
10
H ours
12
2om 4
6
8
10
12am
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patient was further evaluated with determinations of plasma cortisols and urinary 17-hydroxy corticosteroids (Table 2). The patient was discharged on her 13th postoperative day, receiving cortisone acetate 37.5 mg daily in divided doses, plus 0.1 mg offludrocortisone acetate daily. She has remained well.
TABLE 2. Plasma and Urine Steroid Data in patient G.S. with Addison's Disease, Demonstrating Lack of Response to Intravenous ACTH
Date
2/4-2/8/68-Dexamethasone 2/6/68 2/6/68-ACTH 50 u IV (8 hrs) 2/7/68-ACTH 50 u IV (8 hrs) 2/8/68-ACTH 50 u IV (8 hrs)
Urine Plasma Cortisol A.M. P.M. 17-OHCS 17-KS
0.5 mg q 6 hr. 2.0
1.2 7.2
2.4 (0.9) 11 A.M. 7.1
1.4 3.0 0.7 4.1
Comment In patient G.S. the diagnosis of Addison's disease could have been suggested on the basis of symptoms and abnormal pigmentation if the condition had been considered. She was admitted prior to our present practice of obtaining routine serum electrolytes on admission. Elec-
The nature of this patient's weakness and vomiting were not recognized. Cholecystectomy was recommended and accepted. On 1-29-68 cholecystectomy was performed (ECW) without incident. During the early postoperative hours, emesis occurred. The patient became febrile to 40.2C (Fig. 1). Blood pressure was 98/70 mm Hg and pulse 96/min. Confluent pneumonitis in the right upper lobe was seen. Vigorous pulmonary toilet was begun with little change in temperature. She remained febrile and the blood pressure gradually dropped to 86/54 mm Hg. Hematocrit was 42%. The patient was transferred to the Intensive Care division. Penicillin and chloramphenicol had been started. The pulse continued rapid, the temperature near 40C and the blood pressure continued to fall to 50 mm Hg systolic. At 4:40 a.m. 250 mg of cortisol hemisuccinate was given intravenously along with one unit of dextran. Serum electrolytes showed serum sodium of 1 19/mEq/L, potassium4.3 mEq/L. The patient improved and she receivedanother250mgofcortisol at7:00a.m. Twohourslaterher temperature was 37C, pulse 104/min. and the blood pressure 120/80 mm Hg. Lethargy and occasional disorientation continued. She was continued on cortisol hemisuccinate, 50 mg every 6 hours. She was seen by an endocrinologist who made the additional observation that the patient had noted tanning of the skin the previous summer which had failed to lighten as usual. She had noticed deep pigmentation overthe elbows and knuckles which became more prominent. Additional physical examination revealed increased pigmentation of the skin, especially of the elbows, dorsum of the hands and also in the gums. A presumptive diagnosis of Addison's disease was made and the
42 40
Temp Co FIG. 2. Outline of clinical with sepsis, fever and electrolyte changes in patient M.B. Delirium, vasomotor instability and collapse were major signs of adrenal insufficiency (see text) responding to meq/L cortisol therapy. course
trocardiography, however, revealed suggestive changes of electrolyte imbalance. Another example of unrecognized Addisonian crisis is patient M.B. (Fig. 2) with sepsis following drainage of a pelvic abscess and colostomy for ruptured diverticulitis. This patient had borderline adrenal function probably secondary to tuberculosis prior to her acute illness and incapable of normal response to sepsis and the surgery. Here, the adrenal hypofunction was manifested by a toxic psychosis, confusion and lethargy. Adrenal reserve, although marginal, allowed her to be discharged without exogenous steroids, but 15 days later she was admitted with frank adrenal insufficiency. Studies of her adrenal function are presented in Table III. The following patient is presented to demonstrate iatrogenic adrenal insufficiency. B.A. #684-637. Admitted on 12-2-56. This was the first University Hospital admission of a 57-year-old female with a seven-year history of polycythemia vera. Over the past three years she had received two courses of radioactive phosphorus, as well as multiple venesections. One and one-half years prior to admission her hematocrit began to drop spontaneously and her spleen began to enlarge. Immature granulocytes and
39-
Hypotension /. V Cortisol
Vomiting
DRAINAGE OF P.RFORAr6ED TED SIGMOID SIGMWOID .PERFORA
AND
327
De/erium
Herpes Zoster
COLOSTOMY
_ Cotsn
COrtis
M
I/M.
Z~~~1 H\Z / ~~~~~~~~~~~~~~~~~~~~~
38 -
37 -
36150
140
130-
5 -
120 I-
I I I
April 8
10
I
I
12
I
I
14
I
I
16
I
I
18
I
I
20
I
I
22
Days
I
I
24
I
I
26
II I
28 30 Moy2
4
K
3meq/L I
HUBAY, WECKESSER AND LEVY
328
nucleated red blood cells appeared in the peripheral blood. Recently her hematocrit began to fall more rapidly despite therapy with 150 mg cortisone daily. At the time of this admission the hematocrit was 18.5%. Reticulocyte count 6.5%. White count 5,800/mm3 with l1o blasts. A diagnosis of agnogenic myeloid metaplasia with acquired hemolytic anemia was made. On physical examination blood pressure was 140/80 mm Hg, pulse 105/min. and respirations 20/min. The patient was a slender, chronically ill, white female with pallor and weakness. Physical examination revealed hepatosplenomegaly. Bone marrow examination was consistent with agnogenic myeloid metaplasia. Osmotic fragility of the red blood cells was noted to be increased. On 1- 13-56 a splenectomy was done under continuous spinal anesthesia. Throughout the operative procedure the patient's blood pressure ranged from 160/90 to 150/80 mm Hg. Three hours after completion of the surgery the patient's temperature was 39.9C, pulse 124/min. and blood pressure 96/80 mm Hg. Four hours later temperature was 39.4C, blood pressure 68/40 mm Hg. She was nauseated and a nasogastric tube drained moderate amounts of gastric contents. She was transfused with whole blood and given intravenous fluids. Blood pressure continued at hypotensive levels. Urinary output was scant. At 2:25 a.m. the following morning 100 mg of cortisol hemisuccinate was given intravenously with prompt rise ofblood pressure and a slowing of the pulse rate. By 7:00 a.m. the patient's temperature had returned to normal and pulse and blood pressure stabilized. The remainder of herpostoperative course was uneventful and she was continued on cortisone acetate.
Ann. Surg.
March 1975
TABLE 3. Plasma and Urine SteroidData in Patient M.B. Before andAfter Metyrapone and Intravenous ACTH Administration, Showing Limited Response to Endogenous and Exogenous ACTH*
Date
Plasma Cortisolt Urine A.M. P.M. 17-OHCSt 17-KS§
5/30/71 Admitted 5/31/71 1.8 mcg 6/1/71 2.1 mcg 6/13-14/71 5.5 0.8 6/14-15/71 Metyrapone 750mgq4hx6 2.1 1.4 6/15-16/71 5.4 mcg 1.9 1.0 6/16-17/71 ACTH 25 u IV/8 hrs 1.0 0.1 0.5 mcg 0.5 mcg 6/17-18/71 ACTH 25 u IV/8 hrs 0.4 1.9 6/18-19/71 ACTH 25 u IV/8 hrs 3.6 mcg 4.3 mcg *Metyrapone selectively inhibits 1 1-betahydroxylation during steroid synthesis and is useful in the diagnosis of suspected hypopituitarism. tn=5-20 mcg/100 ml. tn=4-12 mg/24 hr. §n=4-17 mg/24 hr.
the entire surgical team to ensure proper postoperative steroid support and look for this omission in the failing
patient. Another patient, D.F. (Table 1) represents the hazard of allowing patient self-treatment, as there was confusion This patient previously reported8 represents an adrenal regarding his steroid therapy for arthritis. It was finally crisis brought on by the simple error of omission in writing postoperative orders in a patient known to be on corticos- ascertained that prednisone had been stopped three teroids for the hematological disorder. Administration of a months prior to admission, but had been used for a long single intravenous bolus of 100 mg reversed completely the period prior to cessation. He may represent an ACTH hypotensive-febrile crisis. It should be the responsibility of deficiency as pointed out by Danowski.5 Sepsis and surgery precipitated adrenal crisis. Inadequate preoperative preparation with steroids and no steroids postoperatively were errors in therapy. Nausea, vomiting, abdominal distention, weakness and lethargy, hallmarks of adrenal insufficiency reversed rapidly with resumption of steroid therapy. Patient M.E.B. (Table I) represented a severe arthritic, who, taking more steroids than her physician prescribed, suffered hypotension, fever, lethargy and apnea, thought to be secondary to gram-negative sepsis, when low oral doses were given. Recovery was prompt after intravenous use of corticosteroids and continued with adequate doses of oral steroids. The mechanism here is undocumented, but may be a combination of ACTH depression by exogenous steroids (Fig. 3) and inadequate steroid administration after admission to the hospital. The following patient, R.Y., illustrates a category III type, in whom adrenal failure may have contributed to lack of clinical responsiveness by one of several possible mechanisms. Comment
FIG. 3. Normal regulation of adrenocortical secretion. (CRFcorticotropin releasing factor) Note that pituitary insufficiency will have little effect on aldosterone secretion and that ACTH therapy, while causing adrenal hypertrophy, causes pituitary unresponsiveness to changing cortisol concentrations.
R.Y. #966-109. Admitted on 6-21-73. This was the second hospital admission ofthis 45-year-old female who was seen in the Emergency Ward on the evening of admission after being transferred from a nursing home. The history obtained was that the patient had been alert and well until shortly before the evening meal, when she developed acute, severe,
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329
represents hypothalmic-hypophyseal insufficiency produced by prolonged ACTH administration rather than true adrenal failure. Although 400 mg/24 hrs. of cortisol should have been adequate for physiological replacement, the need for additional amounts, given along with other therapeutic measures, is difficult to evaluate. With severe sepsis, increased amounts of steroids are sometimes needed, and for a longer period, before stabilization is observed.
abdominal pain and sudden collapse. On arrival in the Emergency Ward she was obtunded, but was able to answer simple questions. Her past history revealed that she had been thought to have multiple sclerosis since July, 1971 and had previously been admitted for evaluation in March, 1972. Numerous studies were done, following which she was discharged to an extended care facility with the diagnosis of multiple sclerosis. She was next transferred to a nursing home on hydrochlorothiazide 50 mg daily, KCl elixir 20%, ACTH gel 10 units twice daily. Discussion Temperature on admission was 39.8C. P. 132/min. B.P. 160/40 mm Hg. Hematocrit 40%o. White count 18,700/mm3 with a shift to the left. Physical Hypofunction of the adrenal cortex is brought about by a examination revealed heart and lungs to be clear. The abdomen was distended, rigid and silent. Pelvic and rectal examinations were unre- number of mechanisms involving destruction of adrenal markable. Stool was negative for occult blood. A Foley catheter was tissue. These include granulomatous infections, autoimplaced and yielded only 10 ml of urine. Urinalysis revealed many white mune atrophy, adrenotoxic drugs, such as O,P'DDD, incells and red cells. Serum electrolytes revealed a sodium of 150 mEq/L, deficiency, metastatic potassium 1.7 mEq/L, chlorides 85 mEq/L, CO2 42 mmoles/L, glucose 265 born errors of metabolism, ACTH such as seen in hemorrhage adrenal amyloidosis, tumors, mg/100 ml, BUN 23 mg/l00 ml, and abdominal and chest films revealed the Waterhouse-Friderichsen syndrome, anti-coagulant only a distended stomach without evidence of free air. It was the impression of the examining physicians that she had a perfo- therapy,4 and iatrogenic suppression. Danowski5 and rated viscus. At laparotomy no abnormality wasfound. During the surgery Liddle'2 point out that a brief (up to several weeks) adgreat difficulty was encountered in maintaining the blood pressure, requirdoses of cortisol or syning vasopressors and she was given 250 mg of cortisol hemisuccinate. It ministration of pharmacological in a results prompt suppression of thetic glucocorticoids was thought that her lack of response was secondary to gram negative will rapidly after the recover which secretion ACTH of colonies over revealed 100,000 sepsis of the urinary tract. Urine culture Coli aerogenes. She was started on penicillin and chloramphenicol post- exogenous steroids are withdrawn. If, however, long term operatively, as well as cortisol hemisuccinate 100 mg every 6 hrs. Temper- therapy of a year or more has been used, then a true defiature remained elevated and she remained hypotensive, requiring large of ACTH occurs, which may persist for many weeks infusions of fluids with vasopressors. With an episode of pulmonary ciency the after hypercorticoid state itself has been corrected. The edema, she was digitalized. The diagnosis of relative adrenal insufficiency adrenal responsiveness lags behind the reShe cortisol. subsequent of was postulated and she was given increasing amounts improved and temperature returned to normal. She was restarted on sumption ofnormal ACTH production by several weeks. In ACTH gel 15 units t.i.d. and was discharged improved on her 17th post- general, the longer and the more intense the exogenous operative day. the more likely the patient is to be This patient, receiving ACTH for multiple sclerosis, was admitted with corticosteroid therapy, their cessation. after steroids on dependent fulminating gram negative sepsis of urinary tract origin, and probably had 29 have summarized the Thorn and Knowlton10 chronic hypercorticism on admission, but this was not documented. She
IaD PEL VC ABSCESS /. V
MESOCAVAL SHUNT
C.P.
Hydrocort/sone I/. V Hydrocortisone
I
qBh
Temp C° FIG. 4. Outline of clinical course of patient C.P. with prolonged illness, surgery and gram negative sepsis, responding to steroid ad-
ministration, successfully discontinued later.
Sept21
23
25 27
29 Octl
3
Days
5
7
9
11
13
15
330
HUBAY, WECKESSER AND LEVY
symptoms and the usual abnormal findings in Addison's crises. In addition to the classical symptoms of cortisol hyposecretion, exhibited by several of the patients in the preceding case summaries, a variety of central nervous system symptoms can be observed, such as mania, paranoid psychosis, acute brain syndrome and so-called toxic psychoses. This is particularly well illustrated by case M.B. whose delirium and mental aberrations coincided with clinical deterioration manifested by increased fever, hyponatremia and circulatory collapse. Her mental aberrations and toxic delirium took several days to clear after steroid replacement. The role ofsepsis, particularly ofthe gram-negative type, on steroid metabolism has been reviewed by Beisel and Rapoport.2 They point out that interpretation of changes in serum cortisol* during infection must include a consideration of diurnal periodicity, plasma protein binding factors, and changing rates of both steroid secretion and degradation. During uncomplicated acute infectious illness, the earliest measurable change in plasma hydroxycorticosteroid (17-OHCS) is the loss of diurnal variation. Under situations of acute infection, cortisol secretion rates are shown to be increased 11/2 to 6 times normal. In chronic illnesses, adrenocortical secretion is generally depressed, although most data are based on the studies of patients with tuberculosis. The exact mechanism is not known. It is not related to destruction of the adrenal cortex except in unusual circumstances by metastatic tumor or amyloidosis. Plasma cortisol levels are noted to be elevated in acute surgical stress, severe infections and infection-induced shock. 16'17 Done7 has pointed out that plasma cortisol levels increased progressively during the agonal periods in acute fatal illnesses. In moribund patients, it has been noted that degradation of plasma cortisol was shown to be delayed at a time when plasma 17-OH corticosteroids could be raised still further by ACTH administration.25 Changes in peripheral cortisol metabolism during infection, therefore, may involve mechanisms distinct from those involving depressed activity of hepatic enzymes.25 Hemmorrhagic necrosis of the adrenals during acute meningitis has long been observed and is accompanied by low plasma cortisol values."1 Bacterial toxins, anaphylaxis, generalized toxemia, endotoxin, in combination with epinephrine, and the Shwartzman reaction have all been implicated in the pathogenesis of hemorrhagic adrenocortical necrosis. It may also be a local manifestation of disseminated intravascular coagulation in the presence of shock. Melby16 demonstrated that large doses of bacterial endotoxin produced a maximal increase in glucocorticoid secretion. Normally ACTH secretion by hypophyseal mechanisms in surgical stress *In this paper we use "plasma cortisol" and "serum cortisol" interchangeably because comparable results are obtained from both sources as long as red cells are removed promptly.
Ann. Surg. * March 1975
appears to take precedence over the normal feedback regulatory control. Pituitary stimulation may, however, be less than maximal during chronic infections or overwhelming sepsis, for in both, an additional adrenal response .may be elicited by exogenous ACTH. The mechanisms through which an infectious process, a bacterial pyrogen or exogenously produced fever serves to stimulate hypophyseal centers remains unknown. It may require mediators released from cells such as leuko-
cytes.'7
Patients with a variety of acute generalized infections show a relatively limited transient increase in the adrenal output. Less is known concerning the serial progression of adrenal changes as an infectious illness persists or worsens. A depression of adrenal secretion or lack of responsiveness to ACTH may develop during severe or prolonged infection. High plasma cortisol levels found during septicemia, secondary to gram negative organisms, results principally from afailure in hepatic clearance and metabolism, rather than from any extraordinary increase in adrenal secretion.2 Braunstein and Yamaguchi3 demonstrated cortisol lipid depletion commonly found in patients severely stressed. Oaks,21 Lillehei,13"4 Deitzman,6 Spath ,27 Weil,20,30 Alho,1 Rokkanen,24 and others9'11 19'22'23 have postulated the mechanisms of action of the corticosteroids in shock and sepsis. Lillehei presents evidence that the corticosteroids cause vasodilation in gram negative shock in several ways: 1) by slowing nerve impulse transmission in postganglionic sympathetic nerves; 2) by preserving the integrity of small vessels avoiding leakage into the microcirculation; and 3) by decreasing platelet adhesiveness and preserving their integrity, an important factor in preventing or correcting stagnant anoxia in the microcirculation. He also points out that almost always in shock the adrenal cortex responds with increased cortisol output for physiologic needs, just as the adrenal medulla increases its epinephrine output. For therapeutic maneuvers, however, large doses of steroid are needed. These authors also point out that methylprednisolone potentiates the effect of isoproterenol and the treatment of shock requires dosages in the order of 30 mg/kg repeated in 2-4 hours. Spath27 in an experimental study in dogs revealed that glucocorticoids did not prevent splanchnic vasoconstriction, but appeared to stabilize lysosomal membranes preventing lysosomal release of acid hydrolases and other proteolytic enzymes. They, in contrast to Lillehei and others, could not demonstrate vasodilatation or a positive inotropic effect. Rokkanen24 studied 29 patients in shock with severe trauma, of whom one-half received in a random fashion, pharmacologic doses of methylprednisolone. Although the steroid treated group demonstrated hormonal effects, such as elevated glucose levels, diminished sodium and sodiumpotassium ratio in the urine, and possible increased catabolism, the only significant therapeutic difference
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Therapy Fortunately, adrenal dysfunction is rare and its therapy specific, but in life-threatening situations the surgeon must be able to utilize therapeutic maneuvers to allow his patient to withstand the stress of infection and surgery by effective preoperative preparation, steroid maintenance during surgery and on into the postoperative period. In endotoxic shock, the data of Weil20'30 indicate that early therapy is important. In the human situation there is usually continued liberation of endotoxin. Here, corticosteroid therapy should be undertaken even though the time of initiation is later in the course of the disease. Pharmacologic doses of corticosteroids are required. In non-emergency situations for patients with partial or complete adrenal insufficiency, repair of hypovolemia, hyponatremia and hyperkalemia should be begun promptly. Large doses of cortisol given initially (200-300 mg daily, beginning with 100 mg intravenously) will have sufficient mineralocorticoid effect, but as physiologic doses of the are reached, a mineralocorticoid should be glucocorticoid Evaluation of Adrenal Insufficiency in Surgical Patients is the drug of choice to correct the Fludrocortisone added. secretion. When aldosterone aldosterone normal of Because it is a rare disorder, it is not surprising that lack in pituitary insufficiency, only as adequate, adrenocortical insufficiency is not considered more often secretion is needed. in a differential diagnosis. Patients should be questioned cortisone will be and examined for evidence of tuberculosis, autoimmune diseases, deficiencies ofthe pituitary-target organ axis, and References a history of chronic therapy with steroids in the past two 1. Alho, A., Motsay, G.J. and Lillehei, R.C.: Effects of Therapy on years. Lysosomal Changes in Shock. In Shock in Low- and High-Flow Whenever adrenocortical insufficiency is suspected, a States. B.K. Forscher, et al., editors. Amsterdam, Excerpta Medica, 263, 1973. serum sample for cortisol determination should be obW.R. and Rapoport, M.I.: Inter-relations Between Adtained before therapy. A low value in an already stressed 2. Beisel, renocortical Functions and Infectious Illness. N. Engl. J. Med., but untreated patient virtually establishes the diagnosis. 280:541, 1969. Jr.: The Human Adrenal in Under less urgent circumstances a fasting early morning 3. Braunstein, H. and Yamaguchi, B.T.,Am. J. Pathol., 44:113, 1964. Illness. Chronic and Death Rapid serum cortisol determination, followed by an intravenous 4. Danese, C.A. and Viola, R.M.: Adrenal Hemorrhage During Aninjection of 0.25 mg of Cosyntropin, with a second serum ticoagulant Therapy. Ann. Surg., 179:70, 1974. G., et al.: Probabilities of cortisol drawn exactly 30 minutes later, will help establish 5. Danowski, T.S., Bonessi, J.V., Sabeh, after Steroid Therapy. Ann. Responsiveness Pituitary-adrenal the diagnosis.28 In normal persons, the test produces at Intern. Med., 61:11, 1964. least a doubling of the serum cortisol, while there is little or 6. Dietzman, R.H., Block, J.H. and Lillehei, R.C.: Treatment of Shock. G.P., 36: 134, 1967. no response in a patient with primary adrenal failure. 7. A.K., Ely, R.S. and Kelley, V.C.: Studies of 17Done, If adrenal failure secondary to hypopituitarism is sushydroxycorticosteroids: XIV. Plasma 17-hydroxycorticosteroid pected, more elaborate testing will be needed. This may be Concentrations at Death in Human Subjects. Am. J. Dis. Child., 96:655, 1958. delayed until after necessary medical and surgical treatR.E. and Holden, W.D.: Metabolic Deficits and Surgical ment has been given. A chronically unstimulated normal 8. Hermann, Complications. Postgrad. Med., 32:195, 1962. adrenal may require 3 days of corticotrophin stimulation. 9. Jeffries, C.D. and Wilkins, J.: Effect of Exogenous Steroids and Inhibitors of Steroidogenesis on Endotoxin Shock. Proc. Soc. After this a metyrapone test will establish whether or not Exp. Biol. Med., 142:656, 1973. the pituitary can increase its secretion of ACTH (Fig. 1). 10. Knowlton, A.I.: Addison's Disease: A Review of its Clinical Course It should be emphasized that a pretreatment serum corand Management. In The Human Adrenal Cortex. N.P. Christy, editor. New York, Harper and Row, Chap. 12, 1971. tisol should be obtained whenever possible. If the serum is A.M. and Verrier, R. L.: Role of Corticosteroids in the Treat11. Lefer, separated from the whole blood promptly, the test will be ment of Circulatory Collapse States. Clin. Pharm. Ther, 11:630, valid even if the sample has to be kept in a refrigerator for a 1970. 12. Liddle, G.W.: Pathogenesis of Glucocorticoid Disorders. Am. J. week-end or mailed to a distant laboratory. Med., 53:638, 1972. Because it is of lifelong importance to the patient, a 13. Lillehei, R.C., Dietzman, R.H., Motsay, G.J., et al.: The Pharmacologic Approach to the Treatment of Shock I, II. Geriatrics, precise diagnosis of adrenal function should be made 27:73, 1972 and Geriatrics, 27:81, 1972. whenever possible.
between the groups was a diminished incidence of fat embolism in the steroid treated group. In another study, Alho, Motsay and Lillehei1 stressed that the modifying effects of the treatment of shock with glucocorticoids on the lysosomal enzyme changes may be due to improved capillary profusion or membrane stabilization. Schumer26 measured the release of histamine from mast cells exposed to endotoxin and proposed that steroids exert their effect by interfering with the endotoxin-induced immune reaction by decreasing either complement or complement fixation, thus preventing the production of anaphylatoxin or other shock toxins. Lefer" has recently demonstrated a myocardial depressant factor (MDF) in the blood of shock animals, thought to be a biologically active peptide released by hypoxia and ischemia from the pancreas. Glucocorticoids are thought to have a potentially beneficial effect by preventing lysosomal disruption and the formation of MDF.
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HUBAY, WECKJE,SSER AND LEVY
14. Lillehei, R.C., Longerbeam, J.K., Block, J.H. and Manax, W.G.: The Nature of Irreversible Shock: Experimental and Clinical Observations. Ann. Surg., 160:682, 1964. 15. Marks, L.J., Heizer, J.W. and Braunstein, L.: Physiologic Considerations in the Management of Patients with Corticosteroidinduced Adrenal Suppression Who Undergo Operation. Surgery, 49:657, 1961. 16. Melby, J.C., Egdahl, R.H. and Spink, W.W.: Secretion and Metabolism of Cortisol After Injection of Endotoxin. J. Lab. Clin. Med., 56:50, 1960. 17. Melby, J.C. and Spink, W.W.: Comparative Studies on Adrenal Cortical Function and Cortisol Metabolism in Healthy Adults and in Patients with Shock Due to Infection. J. Clin. Invest., 37:1791, 1958. 18. Migeon, C.J., Kenny, F.M., Hung, W. and Voorhess, M.L.: Study of Adrenal Function in Children with Meningitis. Pediatrics, 40:163, 1967. 19. Mills, L.C.: Corticosteroids in Endotoxic Shock. Proc. Soc. Exp. Biol. Med., 138:507, 1971. 20. Mills, L.C. and Moyer, J.H., eds.: Shock and Hypotension: Pathogenesis and Treatment. The Twelfth Hahnemann Symposium. New York, Grune and Stratton, 1965. 21. Oaks, W.W. and Cohen, H.E.: Endotoxin Shock in the Geriatric Patient. Geriatrics, 22:120, 1967.
Ann. Surg. * March 1975
22. Petersdorf, R.G. and Beaty, H.N.: The Role of Antibiotics, Vasoactive Drugs and Steroids in Gram-negative Bacteremia. Ann. N.Y. Acad. Sci., 145:319, 1967. 23. Rao, P.S. and Cavanagh, D.: Endotoxin Shock in the Subhuman Primate: II. Some Effects of Methylprednisolone Administration. Arch. Surg., 102:486, 1971. 24. Rokkanen, P., Alho, A., Avikainen, V., et al.: The Efficacy of Corticosteroids in Severe Trauma. Surg. Gynecol. Obstet., 138:69, 1974. 25. Sandberg, A.A., Eik-Nes, K., Migeon, C.J. and Samuels, L.T.: Metabolism of Adrenal Steroids in Dying Patients. J. Clin. Endocrinol. Metab., 16:1001, 1956. 26. Schumer, W., Erve, P.R. and Obernolte, R.P.: Mechanisms of Steroid Protection in Septic Shock. Surgery, 72:119, 1972. 27. Spath, J.A., Jr., Gorczynski, B.A. and Lefer, A.M.: Possible Mechanisms of the Beneficial Action of Glucocorticoids in Circulatory Shock. Surg. Gynecol. Obstet., 137:597, 1973. 28. Speckart, P.F., Nicoloff, J.T. and Bethune, J.E.: Screening for Adrenocortical Insufficiency with Cosyntropin (Synthetic ACTH). Arch. Int. Med., 128:761, 1971. 29. Thorn, G.W. and Lauler, D.P.: Clinical Therapeutics of Adrenal Disorders. Am. J. Med., 53:673, 1972. 30. Weil, M.H., Shubin, H. and Biddle, M.: Shock Caused by Gram Negative Microorganisms. Ann. Int. Med., 60:384, 1964.
From the Departments of Surgery and Medicine, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Cleveland, Ohio
emergency unit or to the hospital in extremis, or hypotensive from unknown causes, in whom adrenal failure may possibly play a role. It is in this latter group of patients in whom pharmacologic doses of glucocorticoid therapy may be indicated as one form of nonspecific therapy. This might include patients with severe gram-negative infections, the Waterhouse-Friderichsen syndrome, postmyocardial infarction patients on anticoagulants, patients with metastatic carcinoma to the adrenals, and pseudotumor cerebri. The adrenal secretory responses to continued infection, T HE SURGEON is often faced with acute situations chronic illness and stress are poorly understood. Depreswherein his patient exhibits nonresponsiveness to the sion of adrenal secretion and diminished responsiveness to usual therapeutic maneuvers. Under these circumstances, ACTH often develop during severe orprolonged infection. This report is concerned with eight patients (Table 1) attention is usually focused on hypovolemic states, the myocardium, respiratory tract, sepsis, and pulmonary or admitted to the surgical service at University Hospitals of fat embolism. Unrecognized adrenal insufficiency should Cleveland presenting acute problems and related adrenal insufficiency during their hospital course. Surgical stress be included in the differential diagnosis. Acute adrenal insufficiency is seen in three major clinical and continued sepsis played strategic roles in the lack of responsiveness to therapy in some of these patients until situations: I. In the firstgroup are patients with unrecognized Addi- the adrenal insufficiency was corrected. son's disease in whom a crisis has been precipitated by Three examples of patients with adrenal insufficiency trauma, a surgical procedure, intercurrent infection or in- are summarized to emphasize the problems encountered in advertent discontinuation of corticosteroid therapy. their surgical care and convalescence. II. Inthe secondgrouparethosepatients withiatrogenic adrenal insufficiency in whom long-term adrenocortical Case Reports steroid therapy has been discontinued for one reason or G.S. #235-103. A 53-year-old female was admitted to the Medical another, and in whom acute stress may precipitate adrenal Service of University Hospitals January 21, 1968 with weakness and insufficiency. The number of patients in this category is vomiting of one month's duration. Chills and fever had been present for rising rapidly as disease complexes responding to steroid three weeks. She continued to have anorexia, vomited frequently, and had lost 16 pounds. There was no change in bowel habits, jaundice or therapy increase. of peptic ulcer. III. In the third group are patients admitted to an symptoms Past history was noncontributory except for congenital toxoplasmosis Submitted for publication July 8, 1974.. Reprint requests: Charles A. Hubay, M.D., 2065 Adelbert Road, Cleveland, Ohio 44106.
of the eyes. Physical examination: T. 36.5C; P. 80/min; R 20/min; B.P. 110/70 mm Hg. Examination revealed a slender woman in no acute distress. Abdomen
325
326
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HUBAY, WECKESSER AND LEVY
TABLE 1. Summary of Patients with Nonresponsive Clinical Problems Associated with Hypoadrenalism
Age
Sex
Presenting Clinical Problems
Surgical Diagnosis
Categ6ry Of Hypoadrenalism
G. S.
53
F
Hypotension, Fever, Vomiting
Cholelithiasis
I
M.B.
71
F
Sepsis, Toxic Delirium, Fever
Perforated Sigmoid
I
Patient
Diverticulitis B.A.
57
F
Hypotension, Fever
D.F.
79
M
Vomiting, Distension, Diarrhea, Lethargy, Sepsis
Agnogenic Myeloid Metaplasia Splenectomy
II
Rheumatoid Arthritis
II
Sigmoid Vesical Fistula Colostomy
M.E.B.
58
F
Hypotension, Fever, Lethargy, Apnea
Rheumatoid Arthritis Necrosis of Hip
II
R. Y.
45
F
Hypotension, Sepsis, Fever
Laparotomy Gram Negative Sepsis
III
W.B.
57
M
Weakness, Vomiting, Weight Loss
Metastatic Carcinoma of Prostate
III
C.P.
17
M
Chronic Illness, Sepsis, Fever
Portal Vein Hypertension Meso-caval Shunt
III
showed minimal tenderness in the epigastrium and to the right of the umbilicus. Bowel sounds were normal. No masses palpated. Laboratory findings were normal. Urinalysis negative. X-ray examination of the chest showed no significant pulmonary
pathology. Electrocardiography on admission showed ST-T-U changes across the anterior precordium, consistent with electrolyte imbalance. The gallbladder demonstrated numerous small nonopaque calculi. Gastrointestinal x-rays showed a small hiatus hernia.
28-
Respiration/min
24-
20] 1101
Systolic
100
Blood Pressure 90
-
80 -
70 -
Temperature CP
0
FIG. 1. Outline of physiologic derangements following cholecystectomy in patient G.S., subsequently shown to have Addison's Disease.
4038- -
36 l20-
Pulse
Rate/min--I
12
2 pm 4
6
8
10
H ours
12
2om 4
6
8
10
12am
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patient was further evaluated with determinations of plasma cortisols and urinary 17-hydroxy corticosteroids (Table 2). The patient was discharged on her 13th postoperative day, receiving cortisone acetate 37.5 mg daily in divided doses, plus 0.1 mg offludrocortisone acetate daily. She has remained well.
TABLE 2. Plasma and Urine Steroid Data in patient G.S. with Addison's Disease, Demonstrating Lack of Response to Intravenous ACTH
Date
2/4-2/8/68-Dexamethasone 2/6/68 2/6/68-ACTH 50 u IV (8 hrs) 2/7/68-ACTH 50 u IV (8 hrs) 2/8/68-ACTH 50 u IV (8 hrs)
Urine Plasma Cortisol A.M. P.M. 17-OHCS 17-KS
0.5 mg q 6 hr. 2.0
1.2 7.2
2.4 (0.9) 11 A.M. 7.1
1.4 3.0 0.7 4.1
Comment In patient G.S. the diagnosis of Addison's disease could have been suggested on the basis of symptoms and abnormal pigmentation if the condition had been considered. She was admitted prior to our present practice of obtaining routine serum electrolytes on admission. Elec-
The nature of this patient's weakness and vomiting were not recognized. Cholecystectomy was recommended and accepted. On 1-29-68 cholecystectomy was performed (ECW) without incident. During the early postoperative hours, emesis occurred. The patient became febrile to 40.2C (Fig. 1). Blood pressure was 98/70 mm Hg and pulse 96/min. Confluent pneumonitis in the right upper lobe was seen. Vigorous pulmonary toilet was begun with little change in temperature. She remained febrile and the blood pressure gradually dropped to 86/54 mm Hg. Hematocrit was 42%. The patient was transferred to the Intensive Care division. Penicillin and chloramphenicol had been started. The pulse continued rapid, the temperature near 40C and the blood pressure continued to fall to 50 mm Hg systolic. At 4:40 a.m. 250 mg of cortisol hemisuccinate was given intravenously along with one unit of dextran. Serum electrolytes showed serum sodium of 1 19/mEq/L, potassium4.3 mEq/L. The patient improved and she receivedanother250mgofcortisol at7:00a.m. Twohourslaterher temperature was 37C, pulse 104/min. and the blood pressure 120/80 mm Hg. Lethargy and occasional disorientation continued. She was continued on cortisol hemisuccinate, 50 mg every 6 hours. She was seen by an endocrinologist who made the additional observation that the patient had noted tanning of the skin the previous summer which had failed to lighten as usual. She had noticed deep pigmentation overthe elbows and knuckles which became more prominent. Additional physical examination revealed increased pigmentation of the skin, especially of the elbows, dorsum of the hands and also in the gums. A presumptive diagnosis of Addison's disease was made and the
42 40
Temp Co FIG. 2. Outline of clinical with sepsis, fever and electrolyte changes in patient M.B. Delirium, vasomotor instability and collapse were major signs of adrenal insufficiency (see text) responding to meq/L cortisol therapy. course
trocardiography, however, revealed suggestive changes of electrolyte imbalance. Another example of unrecognized Addisonian crisis is patient M.B. (Fig. 2) with sepsis following drainage of a pelvic abscess and colostomy for ruptured diverticulitis. This patient had borderline adrenal function probably secondary to tuberculosis prior to her acute illness and incapable of normal response to sepsis and the surgery. Here, the adrenal hypofunction was manifested by a toxic psychosis, confusion and lethargy. Adrenal reserve, although marginal, allowed her to be discharged without exogenous steroids, but 15 days later she was admitted with frank adrenal insufficiency. Studies of her adrenal function are presented in Table III. The following patient is presented to demonstrate iatrogenic adrenal insufficiency. B.A. #684-637. Admitted on 12-2-56. This was the first University Hospital admission of a 57-year-old female with a seven-year history of polycythemia vera. Over the past three years she had received two courses of radioactive phosphorus, as well as multiple venesections. One and one-half years prior to admission her hematocrit began to drop spontaneously and her spleen began to enlarge. Immature granulocytes and
39-
Hypotension /. V Cortisol
Vomiting
DRAINAGE OF P.RFORAr6ED TED SIGMOID SIGMWOID .PERFORA
AND
327
De/erium
Herpes Zoster
COLOSTOMY
_ Cotsn
COrtis
M
I/M.
Z~~~1 H\Z / ~~~~~~~~~~~~~~~~~~~~~
38 -
37 -
36150
140
130-
5 -
120 I-
I I I
April 8
10
I
I
12
I
I
14
I
I
16
I
I
18
I
I
20
I
I
22
Days
I
I
24
I
I
26
II I
28 30 Moy2
4
K
3meq/L I
HUBAY, WECKESSER AND LEVY
328
nucleated red blood cells appeared in the peripheral blood. Recently her hematocrit began to fall more rapidly despite therapy with 150 mg cortisone daily. At the time of this admission the hematocrit was 18.5%. Reticulocyte count 6.5%. White count 5,800/mm3 with l1o blasts. A diagnosis of agnogenic myeloid metaplasia with acquired hemolytic anemia was made. On physical examination blood pressure was 140/80 mm Hg, pulse 105/min. and respirations 20/min. The patient was a slender, chronically ill, white female with pallor and weakness. Physical examination revealed hepatosplenomegaly. Bone marrow examination was consistent with agnogenic myeloid metaplasia. Osmotic fragility of the red blood cells was noted to be increased. On 1- 13-56 a splenectomy was done under continuous spinal anesthesia. Throughout the operative procedure the patient's blood pressure ranged from 160/90 to 150/80 mm Hg. Three hours after completion of the surgery the patient's temperature was 39.9C, pulse 124/min. and blood pressure 96/80 mm Hg. Four hours later temperature was 39.4C, blood pressure 68/40 mm Hg. She was nauseated and a nasogastric tube drained moderate amounts of gastric contents. She was transfused with whole blood and given intravenous fluids. Blood pressure continued at hypotensive levels. Urinary output was scant. At 2:25 a.m. the following morning 100 mg of cortisol hemisuccinate was given intravenously with prompt rise ofblood pressure and a slowing of the pulse rate. By 7:00 a.m. the patient's temperature had returned to normal and pulse and blood pressure stabilized. The remainder of herpostoperative course was uneventful and she was continued on cortisone acetate.
Ann. Surg.
March 1975
TABLE 3. Plasma and Urine SteroidData in Patient M.B. Before andAfter Metyrapone and Intravenous ACTH Administration, Showing Limited Response to Endogenous and Exogenous ACTH*
Date
Plasma Cortisolt Urine A.M. P.M. 17-OHCSt 17-KS§
5/30/71 Admitted 5/31/71 1.8 mcg 6/1/71 2.1 mcg 6/13-14/71 5.5 0.8 6/14-15/71 Metyrapone 750mgq4hx6 2.1 1.4 6/15-16/71 5.4 mcg 1.9 1.0 6/16-17/71 ACTH 25 u IV/8 hrs 1.0 0.1 0.5 mcg 0.5 mcg 6/17-18/71 ACTH 25 u IV/8 hrs 0.4 1.9 6/18-19/71 ACTH 25 u IV/8 hrs 3.6 mcg 4.3 mcg *Metyrapone selectively inhibits 1 1-betahydroxylation during steroid synthesis and is useful in the diagnosis of suspected hypopituitarism. tn=5-20 mcg/100 ml. tn=4-12 mg/24 hr. §n=4-17 mg/24 hr.
the entire surgical team to ensure proper postoperative steroid support and look for this omission in the failing
patient. Another patient, D.F. (Table 1) represents the hazard of allowing patient self-treatment, as there was confusion This patient previously reported8 represents an adrenal regarding his steroid therapy for arthritis. It was finally crisis brought on by the simple error of omission in writing postoperative orders in a patient known to be on corticos- ascertained that prednisone had been stopped three teroids for the hematological disorder. Administration of a months prior to admission, but had been used for a long single intravenous bolus of 100 mg reversed completely the period prior to cessation. He may represent an ACTH hypotensive-febrile crisis. It should be the responsibility of deficiency as pointed out by Danowski.5 Sepsis and surgery precipitated adrenal crisis. Inadequate preoperative preparation with steroids and no steroids postoperatively were errors in therapy. Nausea, vomiting, abdominal distention, weakness and lethargy, hallmarks of adrenal insufficiency reversed rapidly with resumption of steroid therapy. Patient M.E.B. (Table I) represented a severe arthritic, who, taking more steroids than her physician prescribed, suffered hypotension, fever, lethargy and apnea, thought to be secondary to gram-negative sepsis, when low oral doses were given. Recovery was prompt after intravenous use of corticosteroids and continued with adequate doses of oral steroids. The mechanism here is undocumented, but may be a combination of ACTH depression by exogenous steroids (Fig. 3) and inadequate steroid administration after admission to the hospital. The following patient, R.Y., illustrates a category III type, in whom adrenal failure may have contributed to lack of clinical responsiveness by one of several possible mechanisms. Comment
FIG. 3. Normal regulation of adrenocortical secretion. (CRFcorticotropin releasing factor) Note that pituitary insufficiency will have little effect on aldosterone secretion and that ACTH therapy, while causing adrenal hypertrophy, causes pituitary unresponsiveness to changing cortisol concentrations.
R.Y. #966-109. Admitted on 6-21-73. This was the second hospital admission ofthis 45-year-old female who was seen in the Emergency Ward on the evening of admission after being transferred from a nursing home. The history obtained was that the patient had been alert and well until shortly before the evening meal, when she developed acute, severe,
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329
represents hypothalmic-hypophyseal insufficiency produced by prolonged ACTH administration rather than true adrenal failure. Although 400 mg/24 hrs. of cortisol should have been adequate for physiological replacement, the need for additional amounts, given along with other therapeutic measures, is difficult to evaluate. With severe sepsis, increased amounts of steroids are sometimes needed, and for a longer period, before stabilization is observed.
abdominal pain and sudden collapse. On arrival in the Emergency Ward she was obtunded, but was able to answer simple questions. Her past history revealed that she had been thought to have multiple sclerosis since July, 1971 and had previously been admitted for evaluation in March, 1972. Numerous studies were done, following which she was discharged to an extended care facility with the diagnosis of multiple sclerosis. She was next transferred to a nursing home on hydrochlorothiazide 50 mg daily, KCl elixir 20%, ACTH gel 10 units twice daily. Discussion Temperature on admission was 39.8C. P. 132/min. B.P. 160/40 mm Hg. Hematocrit 40%o. White count 18,700/mm3 with a shift to the left. Physical Hypofunction of the adrenal cortex is brought about by a examination revealed heart and lungs to be clear. The abdomen was distended, rigid and silent. Pelvic and rectal examinations were unre- number of mechanisms involving destruction of adrenal markable. Stool was negative for occult blood. A Foley catheter was tissue. These include granulomatous infections, autoimplaced and yielded only 10 ml of urine. Urinalysis revealed many white mune atrophy, adrenotoxic drugs, such as O,P'DDD, incells and red cells. Serum electrolytes revealed a sodium of 150 mEq/L, deficiency, metastatic potassium 1.7 mEq/L, chlorides 85 mEq/L, CO2 42 mmoles/L, glucose 265 born errors of metabolism, ACTH such as seen in hemorrhage adrenal amyloidosis, tumors, mg/100 ml, BUN 23 mg/l00 ml, and abdominal and chest films revealed the Waterhouse-Friderichsen syndrome, anti-coagulant only a distended stomach without evidence of free air. It was the impression of the examining physicians that she had a perfo- therapy,4 and iatrogenic suppression. Danowski5 and rated viscus. At laparotomy no abnormality wasfound. During the surgery Liddle'2 point out that a brief (up to several weeks) adgreat difficulty was encountered in maintaining the blood pressure, requirdoses of cortisol or syning vasopressors and she was given 250 mg of cortisol hemisuccinate. It ministration of pharmacological in a results prompt suppression of thetic glucocorticoids was thought that her lack of response was secondary to gram negative will rapidly after the recover which secretion ACTH of colonies over revealed 100,000 sepsis of the urinary tract. Urine culture Coli aerogenes. She was started on penicillin and chloramphenicol post- exogenous steroids are withdrawn. If, however, long term operatively, as well as cortisol hemisuccinate 100 mg every 6 hrs. Temper- therapy of a year or more has been used, then a true defiature remained elevated and she remained hypotensive, requiring large of ACTH occurs, which may persist for many weeks infusions of fluids with vasopressors. With an episode of pulmonary ciency the after hypercorticoid state itself has been corrected. The edema, she was digitalized. The diagnosis of relative adrenal insufficiency adrenal responsiveness lags behind the reShe cortisol. subsequent of was postulated and she was given increasing amounts improved and temperature returned to normal. She was restarted on sumption ofnormal ACTH production by several weeks. In ACTH gel 15 units t.i.d. and was discharged improved on her 17th post- general, the longer and the more intense the exogenous operative day. the more likely the patient is to be This patient, receiving ACTH for multiple sclerosis, was admitted with corticosteroid therapy, their cessation. after steroids on dependent fulminating gram negative sepsis of urinary tract origin, and probably had 29 have summarized the Thorn and Knowlton10 chronic hypercorticism on admission, but this was not documented. She
IaD PEL VC ABSCESS /. V
MESOCAVAL SHUNT
C.P.
Hydrocort/sone I/. V Hydrocortisone
I
qBh
Temp C° FIG. 4. Outline of clinical course of patient C.P. with prolonged illness, surgery and gram negative sepsis, responding to steroid ad-
ministration, successfully discontinued later.
Sept21
23
25 27
29 Octl
3
Days
5
7
9
11
13
15
330
HUBAY, WECKESSER AND LEVY
symptoms and the usual abnormal findings in Addison's crises. In addition to the classical symptoms of cortisol hyposecretion, exhibited by several of the patients in the preceding case summaries, a variety of central nervous system symptoms can be observed, such as mania, paranoid psychosis, acute brain syndrome and so-called toxic psychoses. This is particularly well illustrated by case M.B. whose delirium and mental aberrations coincided with clinical deterioration manifested by increased fever, hyponatremia and circulatory collapse. Her mental aberrations and toxic delirium took several days to clear after steroid replacement. The role ofsepsis, particularly ofthe gram-negative type, on steroid metabolism has been reviewed by Beisel and Rapoport.2 They point out that interpretation of changes in serum cortisol* during infection must include a consideration of diurnal periodicity, plasma protein binding factors, and changing rates of both steroid secretion and degradation. During uncomplicated acute infectious illness, the earliest measurable change in plasma hydroxycorticosteroid (17-OHCS) is the loss of diurnal variation. Under situations of acute infection, cortisol secretion rates are shown to be increased 11/2 to 6 times normal. In chronic illnesses, adrenocortical secretion is generally depressed, although most data are based on the studies of patients with tuberculosis. The exact mechanism is not known. It is not related to destruction of the adrenal cortex except in unusual circumstances by metastatic tumor or amyloidosis. Plasma cortisol levels are noted to be elevated in acute surgical stress, severe infections and infection-induced shock. 16'17 Done7 has pointed out that plasma cortisol levels increased progressively during the agonal periods in acute fatal illnesses. In moribund patients, it has been noted that degradation of plasma cortisol was shown to be delayed at a time when plasma 17-OH corticosteroids could be raised still further by ACTH administration.25 Changes in peripheral cortisol metabolism during infection, therefore, may involve mechanisms distinct from those involving depressed activity of hepatic enzymes.25 Hemmorrhagic necrosis of the adrenals during acute meningitis has long been observed and is accompanied by low plasma cortisol values."1 Bacterial toxins, anaphylaxis, generalized toxemia, endotoxin, in combination with epinephrine, and the Shwartzman reaction have all been implicated in the pathogenesis of hemorrhagic adrenocortical necrosis. It may also be a local manifestation of disseminated intravascular coagulation in the presence of shock. Melby16 demonstrated that large doses of bacterial endotoxin produced a maximal increase in glucocorticoid secretion. Normally ACTH secretion by hypophyseal mechanisms in surgical stress *In this paper we use "plasma cortisol" and "serum cortisol" interchangeably because comparable results are obtained from both sources as long as red cells are removed promptly.
Ann. Surg. * March 1975
appears to take precedence over the normal feedback regulatory control. Pituitary stimulation may, however, be less than maximal during chronic infections or overwhelming sepsis, for in both, an additional adrenal response .may be elicited by exogenous ACTH. The mechanisms through which an infectious process, a bacterial pyrogen or exogenously produced fever serves to stimulate hypophyseal centers remains unknown. It may require mediators released from cells such as leuko-
cytes.'7
Patients with a variety of acute generalized infections show a relatively limited transient increase in the adrenal output. Less is known concerning the serial progression of adrenal changes as an infectious illness persists or worsens. A depression of adrenal secretion or lack of responsiveness to ACTH may develop during severe or prolonged infection. High plasma cortisol levels found during septicemia, secondary to gram negative organisms, results principally from afailure in hepatic clearance and metabolism, rather than from any extraordinary increase in adrenal secretion.2 Braunstein and Yamaguchi3 demonstrated cortisol lipid depletion commonly found in patients severely stressed. Oaks,21 Lillehei,13"4 Deitzman,6 Spath ,27 Weil,20,30 Alho,1 Rokkanen,24 and others9'11 19'22'23 have postulated the mechanisms of action of the corticosteroids in shock and sepsis. Lillehei presents evidence that the corticosteroids cause vasodilation in gram negative shock in several ways: 1) by slowing nerve impulse transmission in postganglionic sympathetic nerves; 2) by preserving the integrity of small vessels avoiding leakage into the microcirculation; and 3) by decreasing platelet adhesiveness and preserving their integrity, an important factor in preventing or correcting stagnant anoxia in the microcirculation. He also points out that almost always in shock the adrenal cortex responds with increased cortisol output for physiologic needs, just as the adrenal medulla increases its epinephrine output. For therapeutic maneuvers, however, large doses of steroid are needed. These authors also point out that methylprednisolone potentiates the effect of isoproterenol and the treatment of shock requires dosages in the order of 30 mg/kg repeated in 2-4 hours. Spath27 in an experimental study in dogs revealed that glucocorticoids did not prevent splanchnic vasoconstriction, but appeared to stabilize lysosomal membranes preventing lysosomal release of acid hydrolases and other proteolytic enzymes. They, in contrast to Lillehei and others, could not demonstrate vasodilatation or a positive inotropic effect. Rokkanen24 studied 29 patients in shock with severe trauma, of whom one-half received in a random fashion, pharmacologic doses of methylprednisolone. Although the steroid treated group demonstrated hormonal effects, such as elevated glucose levels, diminished sodium and sodiumpotassium ratio in the urine, and possible increased catabolism, the only significant therapeutic difference
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331
Therapy Fortunately, adrenal dysfunction is rare and its therapy specific, but in life-threatening situations the surgeon must be able to utilize therapeutic maneuvers to allow his patient to withstand the stress of infection and surgery by effective preoperative preparation, steroid maintenance during surgery and on into the postoperative period. In endotoxic shock, the data of Weil20'30 indicate that early therapy is important. In the human situation there is usually continued liberation of endotoxin. Here, corticosteroid therapy should be undertaken even though the time of initiation is later in the course of the disease. Pharmacologic doses of corticosteroids are required. In non-emergency situations for patients with partial or complete adrenal insufficiency, repair of hypovolemia, hyponatremia and hyperkalemia should be begun promptly. Large doses of cortisol given initially (200-300 mg daily, beginning with 100 mg intravenously) will have sufficient mineralocorticoid effect, but as physiologic doses of the are reached, a mineralocorticoid should be glucocorticoid Evaluation of Adrenal Insufficiency in Surgical Patients is the drug of choice to correct the Fludrocortisone added. secretion. When aldosterone aldosterone normal of Because it is a rare disorder, it is not surprising that lack in pituitary insufficiency, only as adequate, adrenocortical insufficiency is not considered more often secretion is needed. in a differential diagnosis. Patients should be questioned cortisone will be and examined for evidence of tuberculosis, autoimmune diseases, deficiencies ofthe pituitary-target organ axis, and References a history of chronic therapy with steroids in the past two 1. Alho, A., Motsay, G.J. and Lillehei, R.C.: Effects of Therapy on years. Lysosomal Changes in Shock. In Shock in Low- and High-Flow Whenever adrenocortical insufficiency is suspected, a States. B.K. Forscher, et al., editors. Amsterdam, Excerpta Medica, 263, 1973. serum sample for cortisol determination should be obW.R. and Rapoport, M.I.: Inter-relations Between Adtained before therapy. A low value in an already stressed 2. Beisel, renocortical Functions and Infectious Illness. N. Engl. J. Med., but untreated patient virtually establishes the diagnosis. 280:541, 1969. Jr.: The Human Adrenal in Under less urgent circumstances a fasting early morning 3. Braunstein, H. and Yamaguchi, B.T.,Am. J. Pathol., 44:113, 1964. Illness. Chronic and Death Rapid serum cortisol determination, followed by an intravenous 4. Danese, C.A. and Viola, R.M.: Adrenal Hemorrhage During Aninjection of 0.25 mg of Cosyntropin, with a second serum ticoagulant Therapy. Ann. Surg., 179:70, 1974. G., et al.: Probabilities of cortisol drawn exactly 30 minutes later, will help establish 5. Danowski, T.S., Bonessi, J.V., Sabeh, after Steroid Therapy. Ann. Responsiveness Pituitary-adrenal the diagnosis.28 In normal persons, the test produces at Intern. Med., 61:11, 1964. least a doubling of the serum cortisol, while there is little or 6. Dietzman, R.H., Block, J.H. and Lillehei, R.C.: Treatment of Shock. G.P., 36: 134, 1967. no response in a patient with primary adrenal failure. 7. A.K., Ely, R.S. and Kelley, V.C.: Studies of 17Done, If adrenal failure secondary to hypopituitarism is sushydroxycorticosteroids: XIV. Plasma 17-hydroxycorticosteroid pected, more elaborate testing will be needed. This may be Concentrations at Death in Human Subjects. Am. J. Dis. Child., 96:655, 1958. delayed until after necessary medical and surgical treatR.E. and Holden, W.D.: Metabolic Deficits and Surgical ment has been given. A chronically unstimulated normal 8. Hermann, Complications. Postgrad. Med., 32:195, 1962. adrenal may require 3 days of corticotrophin stimulation. 9. Jeffries, C.D. and Wilkins, J.: Effect of Exogenous Steroids and Inhibitors of Steroidogenesis on Endotoxin Shock. Proc. Soc. After this a metyrapone test will establish whether or not Exp. Biol. Med., 142:656, 1973. the pituitary can increase its secretion of ACTH (Fig. 1). 10. Knowlton, A.I.: Addison's Disease: A Review of its Clinical Course It should be emphasized that a pretreatment serum corand Management. In The Human Adrenal Cortex. N.P. Christy, editor. New York, Harper and Row, Chap. 12, 1971. tisol should be obtained whenever possible. If the serum is A.M. and Verrier, R. L.: Role of Corticosteroids in the Treat11. Lefer, separated from the whole blood promptly, the test will be ment of Circulatory Collapse States. Clin. Pharm. Ther, 11:630, valid even if the sample has to be kept in a refrigerator for a 1970. 12. Liddle, G.W.: Pathogenesis of Glucocorticoid Disorders. Am. J. week-end or mailed to a distant laboratory. Med., 53:638, 1972. Because it is of lifelong importance to the patient, a 13. Lillehei, R.C., Dietzman, R.H., Motsay, G.J., et al.: The Pharmacologic Approach to the Treatment of Shock I, II. Geriatrics, precise diagnosis of adrenal function should be made 27:73, 1972 and Geriatrics, 27:81, 1972. whenever possible.
between the groups was a diminished incidence of fat embolism in the steroid treated group. In another study, Alho, Motsay and Lillehei1 stressed that the modifying effects of the treatment of shock with glucocorticoids on the lysosomal enzyme changes may be due to improved capillary profusion or membrane stabilization. Schumer26 measured the release of histamine from mast cells exposed to endotoxin and proposed that steroids exert their effect by interfering with the endotoxin-induced immune reaction by decreasing either complement or complement fixation, thus preventing the production of anaphylatoxin or other shock toxins. Lefer" has recently demonstrated a myocardial depressant factor (MDF) in the blood of shock animals, thought to be a biologically active peptide released by hypoxia and ischemia from the pancreas. Glucocorticoids are thought to have a potentially beneficial effect by preventing lysosomal disruption and the formation of MDF.
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14. Lillehei, R.C., Longerbeam, J.K., Block, J.H. and Manax, W.G.: The Nature of Irreversible Shock: Experimental and Clinical Observations. Ann. Surg., 160:682, 1964. 15. Marks, L.J., Heizer, J.W. and Braunstein, L.: Physiologic Considerations in the Management of Patients with Corticosteroidinduced Adrenal Suppression Who Undergo Operation. Surgery, 49:657, 1961. 16. Melby, J.C., Egdahl, R.H. and Spink, W.W.: Secretion and Metabolism of Cortisol After Injection of Endotoxin. J. Lab. Clin. Med., 56:50, 1960. 17. Melby, J.C. and Spink, W.W.: Comparative Studies on Adrenal Cortical Function and Cortisol Metabolism in Healthy Adults and in Patients with Shock Due to Infection. J. Clin. Invest., 37:1791, 1958. 18. Migeon, C.J., Kenny, F.M., Hung, W. and Voorhess, M.L.: Study of Adrenal Function in Children with Meningitis. Pediatrics, 40:163, 1967. 19. Mills, L.C.: Corticosteroids in Endotoxic Shock. Proc. Soc. Exp. Biol. Med., 138:507, 1971. 20. Mills, L.C. and Moyer, J.H., eds.: Shock and Hypotension: Pathogenesis and Treatment. The Twelfth Hahnemann Symposium. New York, Grune and Stratton, 1965. 21. Oaks, W.W. and Cohen, H.E.: Endotoxin Shock in the Geriatric Patient. Geriatrics, 22:120, 1967.
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22. Petersdorf, R.G. and Beaty, H.N.: The Role of Antibiotics, Vasoactive Drugs and Steroids in Gram-negative Bacteremia. Ann. N.Y. Acad. Sci., 145:319, 1967. 23. Rao, P.S. and Cavanagh, D.: Endotoxin Shock in the Subhuman Primate: II. Some Effects of Methylprednisolone Administration. Arch. Surg., 102:486, 1971. 24. Rokkanen, P., Alho, A., Avikainen, V., et al.: The Efficacy of Corticosteroids in Severe Trauma. Surg. Gynecol. Obstet., 138:69, 1974. 25. Sandberg, A.A., Eik-Nes, K., Migeon, C.J. and Samuels, L.T.: Metabolism of Adrenal Steroids in Dying Patients. J. Clin. Endocrinol. Metab., 16:1001, 1956. 26. Schumer, W., Erve, P.R. and Obernolte, R.P.: Mechanisms of Steroid Protection in Septic Shock. Surgery, 72:119, 1972. 27. Spath, J.A., Jr., Gorczynski, B.A. and Lefer, A.M.: Possible Mechanisms of the Beneficial Action of Glucocorticoids in Circulatory Shock. Surg. Gynecol. Obstet., 137:597, 1973. 28. Speckart, P.F., Nicoloff, J.T. and Bethune, J.E.: Screening for Adrenocortical Insufficiency with Cosyntropin (Synthetic ACTH). Arch. Int. Med., 128:761, 1971. 29. Thorn, G.W. and Lauler, D.P.: Clinical Therapeutics of Adrenal Disorders. Am. J. Med., 53:673, 1972. 30. Weil, M.H., Shubin, H. and Biddle, M.: Shock Caused by Gram Negative Microorganisms. Ann. Int. Med., 60:384, 1964.
