DRUG THERAPY

Review Article

Drug Therapy decreased cardiac contractility. However, a variety of hemodynamic abnormalities have been described dur- ing acute . They include hypo- A LASTAIR J.J. WOOD, M.D., Editor volemic shock (decreased preload, depressed myo- cardial contractility, and increased systemic vascular resistance)19,20 and hyperdynamic shock (high cardi- T HERAPY IN S EVERE ac output and decreased systemic vascular resistance similar to those in septic shock).20-24 These different ILLNESS hemodynamic findings may reflect the fact that some patients had already received some volume replace- STEVEN W.J. LAMBERTS, HAJO A. BRUINING, ment before cardiovascular function was studied or AND FRANK H. DE JONG that their secretion varied depend- ing on whether they had primary or secondary ad- EVERE illnesses, trauma, anesthesia, and sur- renal insufficiency. One important conclusion is that gery are accompanied by activation of the hypo- in patients with adrenal insufficiency Sthalamic–pituitary–adrenal axis, as demonstrat- may mimic either hypovolemic or septic shock, a con- ed by increased serum corticotropin and clusion that emphasizes the need to include adrenal concentrations.1-7 This activation is an essential com- insufficiency in the differential diagnosis of both.20 ponent of the general adaptation to stress and con- tributes to the maintenance of homeostasis.8 The THE NORMAL RESPONSE OF THE of replacement doses or high doses of cor- HYPOTHALAMIC–PITUITARY–ADRENAL ticosteroids in patients with severe illness, especial- AXIS TO CRITICAL ILLNESS AND THE ly those with multiorgan-system diseases, is uncer- CONCEPT OF RELATIVE ADRENAL tain.9-12 The uncertainty is even greater in patients INSUFFICIENCY who are already taking . Standard ther- Pain, , and hypovolemia all result in a sustained apy for the latter patients consists of the administra- increase in corticotropin and cortisol secretion.8,25,26 tion of high doses of corticosteroids during any severe During surgical procedures such as laparotomy, se- illness and perioperatively. We review here the value rum corticotropin and cortisol concentrations rise of corticosteroid administration during severe illness rapidly but usually return to base-line values within in patients with normal hypothalamic–pituitary–adre- 24 to 48 hours27,28 (Fig. 1A). The magnitude of the nal function and in patients receiving corticosteroid postoperative increase in serum cortisol concentra- treatment or replacement therapy before the illness. tions is positively correlated with the extent of sur- gery.29,31 As compared with the concentrations be- EFFECT OF CORTICOSTEROIDS fore surgery, mean serum cortisol concentrations ON CIRCULATORY ASPECTS measured for 24 hours beginning two days after sur- OF THE STRESS RESPONSE gery were increased by 84 percent after laparotomy, Cortisol has a vital supportive role in the main- but by only 36 percent after less extensive proce- tenance of vascular tone, endothelial integrity, vas- dures such as operations on the joints, breast, or cular permeability, and the distribution of total neck (P0.005).32 After operation, there is initial- body water within the vascular compartment.13-15 It ly no circadian variation in serum cortisol concen- also potentiates the vasoconstrictor actions of cate- trations (Fig. 1A). During severe illness, serum cor- cholamines.13,14 predisposes animals tisol concentrations tend to be even higher (Fig. to hypovolemic and laparotomy-induced circulatory 1B).30,32-34 The values are highest in patients with the shock,16,17 which can be prevented by replacement highest illness-severity scores3,5,7,30,32-35 and in those doses of corticosteroids.18 with the highest mortality,5 and the values are very In humans, chronic adrenal deficiency is charac- high (30 to 260 mg per deciliter [828 to 7173 nmol terized by decreased systemic vascular resistance and per liter]) shortly before death.36 Adrenal function in severely ill patients is often eval- uated by a corticotropin-stimulation test, in which From the Departments of Medicine (S.W.J.L., F.H.J.) and Surgery serum cortisol is measured at base line and 30 to (H.A.B.), Erasmus University, Rotterdam, the Netherlands. Address reprint 60 minutes after the intravenous administration of requests to Dr. Lamberts at the Department of Medicine, University Hospi- tal Dijkzigt, 40 Dr. Molewaterplein, 3015 GD Rotterdam, the Netherlands. 250 mg of cosyntropin. The interpretation of the re- ©1997, Massachusetts Medical Society. sponses is difficult in seriously ill patients, however. Se-

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60

50

40 g/dl) m

30

20 Serum Cortisol (

10 Operation

0 M M M M M M M 8 a.m.4 p.m. 8 a.m. 8 a.m.4 p.m. 8 a.m.4 p.m. 8 a.m.4 p.m. 8 a.m.4 p.m. 8 a.m.8 a.m.4 p.m. 8 a.m.8 a.m.4 p.m. 8 a.m.

A Before Day 0 Day 1 Day 2 Day 3 Day 5 Day 7 Surgery

Patients with severe sepsis Figure 1. Serum Cortisol Concentrations during Surgery and 60 Patients with multiple trauma Acute Illness. Normal subjects Panel A shows the serum cortisol concentrations in a 70-year- 50 old patient who underwent total gastrectomy. The circadian g/dl)

m rhythm of serum cortisol on the day before surgery was nor- 40 mal. Serum cortisol concentrations increased markedly during and after surgery (day 0), remaining high for more than 72 30 hours with no apparent circadian rhythm until day 7. M de- notes midnight. Adapted from Naito et al.29 with the permis- 20 sion of the publisher. Panel B shows the mean (SD) serum cortisol concentrations 10 on admission (day 0), at eight-hour intervals on days 1 and 2, Serum Cortisol ( and once daily on days 3 to 8 in 18 consecutive patients with 0 severe sepsis and 12 patients who underwent surgery for mul- 012345678 tiple trauma. The serum cortisol concentrations remained ele- vated for more than a week. Adapted from Vermes et al.30 with B Days the permission of the publisher. To convert values for cortisol to nanomoles per liter, multiply by 27.6. rum cortisol concentrations that are regarded as nor- value with regard to mortality.5 Among 32 patients mal in normal subjects may be inappropriately low in with septic shock, all but 1 of whom had basal serum patients who are severely ill, suggesting the existence cortisol concentrations above 11 mg per deciliter (303 of relative adrenal insufficiency. For example, a cortisol nmol per liter), all 13 who had a poor response to cor- concentration of less than 10 mg per deciliter (276 ticotropin (increase in serum cortisol, less than 9 mg nmol per liter) in a random serum sample has been per deciliter [248 nmol per liter]) died. In contrast, proposed as abnormal during acute illness37 and, con- only 6 of the 19 patients who had an increase in serum versely, serum cortisol concentrations above 18 mg per cortisol of more than 9 mg per deciliter died.41 In an- deciliter (497 nmol per liter) after corticotropin stim- other study, 5 of 26 patients with sepsis had subnor- ulation as indicating adequate adrenal reserve. mal responses; only 1 of the 5 patients survived, and Several patterns of response in critically ill patients this patient was treated with corticosteroids.25 On the can be recognized. In most patients, serum cortisol other hand, the failure of the rapid corticotropin test concentrations increase to levels above 18 mg per dec- to reveal corticotropin deficiency demonstrable by in- iliter after the administration of corticotropin,38-40 but sulin tolerance42,43 or testing44,45 means in those with high base-line serum cortisol concentra- that it cannot be fully relied on, especially in patients tions, the increment after corticotropin administration with hypothalamic or pituitary disease.46 may be small, a finding that might have a predictive The relative lack of a serum cortisol response to

1286 October 30, 1997

DRUG THERAPY corticotropin in some critically ill patients may be due to the fact that the normal hypothalamic–pituitary– TABLE 1. FACTORS CONTRIBUTING TO THE adrenal axis is already maximally stimulated, but it DEVELOPMENT OF RELATIVE HYPOADRENALISM IN CRITICALLY ILL PATIENTS. may also be due to interference with the corticoster- oid-synthesizing capacity of the adrenal cortex (for Partial destruction of the adrenal cortex example, by adrenal hemorrhage, adrenal metastases, Preexisting or previously undiagnosed asymptomatic diseases or drugs; see below and Table 1). Support for a con- of the adrenal glands tributory role of limited adrenocortical reserve in the Autoimmune adrenalitis Tuberculosis deterioration of critically ill patients comes from a Metastases study showing that, of 133 consecutive patients in an Acute partial destruction of the adrenal glands Hemorrhage intensive care unit whose morning serum cortisol Massive retroperitoneal bleeding concentrations progressively fell to less than 11.8 mg Thrombocytopenia per deciliter (326 nmol per liter), 27 percent died.48 Anticoagulant therapy Bacterial (meningococcemia), viral, or fungal In recent years there have been reports of a num- Previously unknown hypothalamic–pituitary disease resulting ber of critically ill patients with relative adrenal in- in undiagnosed secondary hypothalamic–pituitary– sufficiency.49,50 Virtually all these patients had com- adrenal insufficiency Cytokine-mediated inhibition of corticotropin release during plicated multiorgan disease, high cardiac output, low septic shock?47 peripheral vascular resistance, shock, and normal se- Drug-related factors rum cortisol concentrations, findings that rule out Previously unknown corticosteroid therapy primary adrenal insufficiency. In these patients, ad- Medroxyprogesterone, Increased of cortisol: , phenobarbi- ministration of (100 to 300 mg per tal, rifampin 24 hours) diminished or eliminated the requirement Changes in cortisol synthesis: , etomidate, for vasopressor drugs, supporting the concept of oc- aminoglutethimide, metyrapone, , 10,11 Interference with corticotropin action: suramin cult relative adrenal insufficiency. Peripheral -receptor blockade: Evidence of the important role of intact hypotha- lamic–pituitary–adrenal function in the survival of critically ill patients with multiple trauma and the role of occult relative adrenal insufficiency comes from the intensive care unit of the University Hospital of Glas- gow, Scotland.51 Between 1969 and 1980, the mor- The incidence of acute (total) adrenal insufficien- tality rate among patients with multiple injuries var- cy after routine surgery is low, ranging from 0.01 to ied between 22 and 29 percent. In 1981 and 1982, 0.7 percent in more than 70,000 patients.54-56 Total mortality rose to 44 percent, despite the absence of adrenal insufficiency is also rare in severely ill pa- change in the injury-severity score of the patients at tients, occurring in 2 to 3 percent of patients.3,5,57 the time of admission. This increase in mortality co- However, the notion of total adrenal insufficiency incided with the introduction of a short-acting hyp- has been gradually replaced by the concept of occult notic drug, etomidate, given to optimize respiratory or relative adrenal insufficiency, caused by preexist- assistance. This drug was subsequently found to be a ing disease, concomitant factors, or complications selective inhibitor of adrenal 11b-hydroxylase, the en- that only partially reduce the adrenocortical capacity zyme that converts deoxycortisol to cortisol.52 to produce cortisol (Table 1). This relative adrenal As shown in Figure 2, administration of etomidate insufficiency might contribute to a fatal outcome, during an elective short surgical procedure was ac- especially in patients with multiorgan failure.25,58 companied by a subnormal increase in serum cortisol Symptoms and signs that might raise suspicion of concentrations, despite an increase in corticotropin the existence of relative adrenal insufficiency are and deoxycortisol secretion. The clinical outcome of shown in Table 2. Inappropriately low serum corti- the minor surgical procedure was not altered in these sol concentrations or impaired serum cortisol re- patients. However, in patients with multiple injuries sponses to corticotropin also suggest the presence of (including those with hypovolemia, infections, and relative adrenal insufficiency. It is important to rec- organ failure), etomidate-induced partial adrenocorti- ognize this condition, because therapy with cortico- cal insufficiency seemed to be the additional factor can improve the clinical condition of these that changed the course of the illness, nearly doubling patients, making their outcome dependent only on mortality.51,53 These findings indicate that even slight the underlying disease. impairment of the adrenal response during severe ill- In conclusion, the practical use of the corticotro- ness can be lethal, and they support the concept that pin test in severely ill patients is at present limited to the apparently poor serum cortisol responses to cor- the diagnosis of total adrenal insufficiency, and in ticotropin and the decline in morning serum cortisol exceptional cases the diagnosis of secondary adrenal concentrations in these patients may be causes, rather insufficiency is missed. No strict biochemical criteria than consequences, of the severe illness. for relative adrenal insufficiency are currently avail-

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200 Control200 Etomidate

160 160

120 120

80 80

40 40

0 0 g/dl) Serum Corticotropin (ng/l) m 6 6

4 4

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Serum Deoxycortisol ( 0 0

40 40 g/dl) m 30 30

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10 10 Serum Cortisol (

0 0 Before Hour Hour Hour Next Before Hour Hour Hour Next Anesthesia 0 1 3 Day Anesthesia 0 1 3 Day

Figure 2. Effect of Anesthesia with Thiopental, Pancuronium, and Fentanyl (Control, Five Patients) and with Etomidate (Seven Pa- tients) in Patients Undergoing Peroral Endoscopy and Microlaryngeal (Laser) Surgery of the Larynx. The course of surgery and anesthesia (hour 0) and the outcome (up to 24 hours) were similar in both groups of patients, with no subjective reports of symptoms and no differences in blood pressure. Note the inhibition of 11b-hydroxylation of the adrenal cortex by etomidate, as evidenced by increased serum corticotropin and 11-deoxycortisol concentrations and lowered serum cortisol con- centrations. Adapted from de Jong et al.52 with the permission of the publisher. To convert values for cortisol to nanomoles per liter, multiply by 27.6; to convert values for deoxycortisol to nanomoles per liter, multiply by 28.9; to convert values for corticotropin to picomoles per liter, multiply by 0.22.

able. This diagnosis should be suspected, however, pituitary–adrenal axis is controversial. Most clinical when administration of hydrocortisone to severely ill studies have been carried out in patients with sepsis, patients is followed by a period of diminished or no often complicated by shock and multiorgan failure.59 need for vasopressor drugs. In two meta-analyses of the effect of corticosteroids in patients with sepsis or septic shock,60,61 only 9 of CORTICOSTEROID THERAPY 49 and 10 of 124 studies were considered of suffi- FOR CRITICAL ILLNESS cient methodologic quality to be included. Overall, The value of high-dose corticosteroid therapy in there was no beneficial effect of corticosteroids on critically ill patients with an intact hypothalamic– survival in patients with sepsis or septic shock.60,61

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However, some circumstances and conditions in which corticosteroid administration might have been TABLE 2. SYMPTOMS AND SIGNS THAT RAISE THE beneficial should be mentioned. SUSPICION OF HYPOADRENALISM IN CRITICALLY ILL PATIENTS. First, in some studies, administration of corticoster- oids was beneficial only during the first few hours Unexplained circulatory instability after the onset of shock.59 The meta-analyses did not Discrepancy between the anticipated severity of the disease address this aspect of the therapy because of lack of and the present state of the patient, including , , orthostatic hypotension, dehydration, abdom- information in the published trials about the time inal or flank pain (indicating acute adrenal hemorrhage), of administration of corticosteroids. Nonetheless, de- , and weight loss lays in administering corticosteroids could explain in High fever without apparent cause (negative cultures), not responding to antibiotic therapy part the lack of benefit of corticosteroid therapy with Unexplained mental changes: apathy or without a respect to outcome in patients with septic shock. specific psychiatric disturbance Vitiligo, altered pigmentation, loss of axillary or pubic hair, Second, in the two clinical trials with the best , hypogonadism methodologic-quality scores,59,62 patients with gram- , , hyperkalemia, neutropenia, negative sepsis responded better to corticosteroid eosinophilia treatment than did patients with other infections. However, the slight advantage for the patients with gram-negative sepsis was outweighed by a higher mor- tality among the corticosteroid-treated patients with example, from adenomas), or the adrenals (for ex- sepsis that was caused by gram-positive organisms. ample, from Addison’s disease). It is therefore possible that very early initiation of treatment or even prophylactic therapy with cortico- Patients with Chronic Autoimmune or Inflammatory steroids in patients at risk for gram-negative infec- Diseases Treated with Corticosteroids tions might be effective in reducing the generalized The duration of corticosteroid therapy, the high- inflammatory response to those infections. Corti- est dose, and the total cumulative dose have long costeroids were also beneficial in randomized trials been considered important predictors of the sup- in patients with bacterial meningitis,63 typhoid fe- pression of hypothalamic–pituitary–adrenal func- ver,64 acute spinal cord injury,65 Pneumocystis carinii tion.70-74 However, high-dose corticosteroid therapy pneumonia,66 and the adult respiratory distress syn- and prolonged treatment do not invariably correlate drome.67 with the degree and duration of hypothalamic–pitu- Another shortcoming of the meta-analyses of stud- itary–adrenal suppression,72,73,75,76 and the time to ies of corticosteroids in patients with sepsis or septic recovery after discontinuation of corticosteroid ther- shock is the lack of information about patients with apy is highly variable. It can be as short as two to underlying adrenocortical disease or relative adreno- five days 76 or as long as nine months to one year.70,71 cortical insufficiency. Such patients benefit from cor- Therefore, it is hard to predict, on the basis of the ticosteroid treatment, but they are lost in the overall history of corticosteroid therapy, which patient will analysis. Genetically based variations among normal have hypothalamic–pituitary–adrenal deficiency when subjects in the threshold level of corticosteroid re- therapy is discontinued, even if the patient was tak- sponses to stress could also affect the subjects’ surviv- ing a single daily dose or alternate-day doses.77,78 al when given corticosteroid therapy.68,69 An important question is how well a test of hypo- thalamic–pituitary–adrenal function predicts the re- CORTICOSTEROID THERAPY IN PATIENTS sponses of the cardiovascular system and of other sys- WITH KNOWN ADRENAL DYSFUNCTION tems to acute stress in a patient who has been treated Hypothalamic–pituitary–adrenal activation during with corticosteroids. In an early study of several tests surgery and severe illness is even more complicated in (insulin-induced hypoglycemia, metyrapone, lysine patients receiving corticosteroid therapy than in pa- vasopressin, and corticotropin) and the subsequent tients presumed to have previously normal adrenal response to surgery in a group of corticosteroid- function. Patients receiving corticosteroid therapy treated patients,73,79 more patients had subnormal se- can be divided into two categories. One category rum cortisol responses to insulin and metyrapone consists of patients with chronic autoimmune or than to the other tests, but the best indicator of the inflammatory diseases (such as asthma, ulcerative maximal serum cortisol concentration during surgery colitis, rheumatoid arthritis, or skin disease) who are was the peak serum cortisol concentration after the being treated or have recently been treated with administration of corticotropin.73,79,80 high doses of corticosteroids. The second category The most important measure of the value of any consists of patients receiving cortisol-replacement test of hypothalamic–pituitary–adrenal function, how- therapy because of hypothalamic–pituitary–adrenal ever, is its ability to predict the clinical response of a hypofunction, whether of the hypothalamus (for ex- patient to the stress of surgery or acute illness. When ample, from previous irradiation), the pituitary (for blood pressure during and after surgery is taken as

Volume 337 Number 18 1289 The New England Journal of Medicine

40 Patients with a Recent studies indicate that the daily rate of cor- nodule tisol production in normal subjects is lower than Patients with primary hyperparathyroidism previously thought (5.7 mg [15.7 mmol] per square meter of body-surface area per day), as opposed to 12 to 15 mg (33 to 41 mmol) per square meter per day.85 This lower rate of cortisol production corre- 30 sponds to about 10 to 12 mg of oral hydrocortisone equivalent per square meter per day, because of in- complete resulting from first-pass he- g/dl)

m patic metabolism of oral hydrocortisone. In adults the adrenal glands produce about 50 mg (138 20 mmol) of cortisol per 24 hours during minor surgi- cal procedures and 75 to 150 mg (207 to 414 mmol) per 24 hours during major surgery 40; cortisol secretion in the first 24 hours after surgery seldom 9,40

Serum Cortisol ( exceeds 200 to 300 mg (552 to 828 mmol), sug- gesting that in critically ill patients those are the 10 maximal doses of hydrocortisone that should be ad- ministered, preferably as a continuous intravenous infusion. The reasons for withholding higher doses include the catabolic effects of high doses on muscle and wound healing, the anti-insulin effects on glu- cose metabolism, and the antiinflammatory effects 0 9 8 9 10 11 that may allow infections to worsen. In several recent studies of corticosteroid-treated Hours patients undergoing surgery while receiving their Figure 3. Effect of Anesthesia and Neck Exploration on Mean previous doses, no patient had any intraoperative or (SE) Serum Cortisol Concentrations in Seven Control Patients postoperative hypotension or other problems of any with a Thyroid Nodule and Six Patients with Primary Hyper- kind.86-88 Studies in adrenalectomized monkeys also parathyroidism Treated for 10 Days with 30 mg of support the concept that a replacement dose of hy- Daily up to 3 Days before Operation. drocortisone is enough to maintain normal cardiac During identical routine anesthesia and a similar surgical pro- cedure, as well as during the subsequent 24 hours, there were contractility and vascular tone during the stress of a no differences in subjective reports of symptoms or blood short, uncomplicated surgical procedure.18 However, pressure between the two groups. Adapted from Janssens89 the doses of hydrocortisone given to these monkeys with the permission of the publisher. To convert values for cor- during surgery might have been rather high (32 mg tisol to nanomoles per liter, multiply by 27.6. [88 mmol] per square meter per day). Larger doses of corticosteroids can blunt the en- dogenous hypothalamic–pituitary–adrenal response the end point, neither basal nor corticotropin-stim- to surgery but are not associated with any clinical or ulated serum cortisol concentrations predict changes metabolic abnormalities. For example, the serum in blood pressure in corticosteroid-treated patients cortisol concentrations during exploratory neck sur- undergoing surgical stress without corticosteroid gery were lower in patients given 30 mg of predni- supplementation.40,73,79 sone for 10 days preoperatively than in untreated pa- A number of case histories and more extensive tients (Fig. 3), but none had any intraoperative or studies of corticosteroid-treated patients 5,9-11,25,40,81-83 postoperative problems.89 describe the catastrophic effects of hypocortisolism These results have led to the suggestion that for during surgery and the dramatic beneficial effects of elective surgery and most acute illnesses, continua- corticosteroid therapy. In retrospect, however, many tion of the current dose of corticosteroids suffices to confounding factors were present that make the in- maintain cardiovascular function.86-88 However, if the terpretation of these reports difficult. These factors operation or acute illness is complicated or prolonged, include interfering diseases, complications of surgery especially in the presence of the factors listed in Ta- or anesthesia, the use of drugs acting directly or in- ble 1, higher doses of corticosteroids should be ad- directly on adrenal function (Table 1), and the devel- ministered, by doubling or tripling the current oral opment of the corticosteroid-withdrawal syndrome dose or by giving hydrocortisone intravenously at a in patients who suddenly stop long-term therapy with dose of 100 to 150 mg daily. high-dose corticosteroids,84 with symptoms and signs The approach of increasing the dose of cortico- similar to those of acute adrenal insufficiency (anorex- steroids only in patients with complications or pro- ia, nausea, vomiting, weight loss, and depression). longed illness, however, has practical risks. Although

1290 October 30, 1997 DRUG THERAPY

most patients treated with 5 to 15 mg of prednisone REFERENCES daily, for example, may respond normally, even to se- 1. Chrousos GP. The hypothalamic–pituitary–adrenal axis and immune- vere stress,9,86,87 some may not, and if supplemental mediated inflammation. N Engl J Med 1995;332:1351-62. corticosteroid is not given, physicians must remain 2. Parker LN, Levin ER, Lifrak ET. Evidence for adrenocortical adaptation to severe illness. J Clin Endocrinol Metab 1985;60:947-52. alert to the possibility of unexpected complications 3. Drucker D, Shandling M. Variable adrenocortical function in acute for which additional corticosteroid might be benefi- medical illness. Crit Care Med 1985;13:477-9. cial. Overtreatment for a day or two is unlikely to 4. Drucker D, McLaughlin J. Adrenocortical dysfunction in acute medical illness. Crit Care Med 1986;14:789-91. cause any harm. 5. Jurney TH, Cockrell JL Jr, Lindberg JS, Lamiell JM, Wade CE. Spec- A consensus paper 9 makes reasonable and clear trum of serum cortisol response to ACTH in ICU patients: correlation with degree of illness and mortality. Chest 1987;92:292-5. recommendations for the dose and duration of cor- 6. Chopra MP, Thadani U, Aber CP, Portal RW, Parkes J. Plasma cortisol, ticosteroid supplementation according to both the urinary 17-hydroxycorticoids, and urinary vanilyl mandelic acid after acute previous dose and the severity of the surgical stress myocardial infarction. Br Heart J 1972;34:992-7. 7. Reincke M, Allolio B, Würth G, Winkelmann W. The hypothalamic- and illness. For minor stress, a total dose of 25 mg pituitary-adrenal axis in critical illness: response to and cor- is recommended; for moderate stress, 50 to 75 mg; ticotropin-releasing hormone. J Clin Endocrinol Metab 1993;77:151-6. and for major stress, 100 to 150 mg of hydrocorti- 8. Munck A, Guyre PM, Holbrook NJ. Physiological functions of gluco- corticoids in stress and their relation to pharmacological actions. Endocr sone or its equivalent should be given for one to Rev 1984;5:25-44. three days.9 A special group of patients consists of 9. Salem M, Tainsh RE Jr, Bromberg J, Loriaux DL, Chernow B. Periop- erative glucocorticoid coverage: a reassessment 42 years after emergence of those who receive corticosteroids topically (by inha- a problem. Ann Surg 1994;219:416-25. lation, intranasally, transdermally, or by enema). Hy- 10. Baldwin WA, Allo M. Occult hypoadrenalism in critically ill patients. pothalamic–pituitary–adrenal suppression is very rare Arch Surg 1993;128:673-6. 5,40 11. Kidess AI, Caplan RH, Reynertson RH, Wickus GG, Goodnough DE. in these patients, and it seems safe to withhold ad- Transient corticotropin deficiency in critical illness. Mayo Clin Proc 1993; ditional corticosteroid during minor or moderate sur- 68:435-41. gical procedures or illnesses in these patients, as long 12. Schein RMH, Sprung CL, Marcial E, Napolitano L, Chernow B. Plasma cortisol levels in patients with septic shock. Crit Care Med 1990;18:259-63. as their clinical course is uncomplicated. 13. Besse JC, Bass AD. Potentiation by hydrocortisone of responses to cat- echolamines in vascular smooth muscle. J Pharmacol Exp Ther 1966;154: Patients with Previously Diagnosed Hypothalamic– 224-38. Pituitary–Adrenal Insufficiency 14. Kalsner S. Mechanism of hydrocortisone potentiation of responses to epinephrine and norepinephrine in rabbit aorta. Circ Res 1969;24:383-95. Few, if any, patients receiving hydrocortisone- 15. Iversen LL, Salt PJ. Inhibition of catecholamine uptake-2 by steroids in the isolated rat heart. Br J Pharmacol 1970;40:528-30. replacement therapy for corticotropin or cortisol de- 16. Swingle WW, Pfiffner JJ, Vars HM, Bott PA, Parkins WM. The func- ficiency have an increase in serum cortisol concen- tion of the adrenal cortical hormone and the cause of death from adrenal trations during surgery, trauma, infections, or other insufficiency. Science 1933;77:58-64. 17. Swingle WW, DaVanzo JP, Crossfield HC, et al. and severe illnesses. All these patients should be given maintenance of blood pressure and plasma volume of adrenalectomized supplemental corticosteroid therapy in the form of dogs subjected to stress. Proc Soc Exp Biol Med 1959;100:617-22. 18. Udelsman R, Ramp J, Gallucci WT, et al. Adaptation during surgical 100 to 150 mg of hydrocortisone by continuous in- stress: a reevaluation of the role of glucocorticoids. J Clin Invest 1986;77: travenous infusion during any severe illness or sur- 1377-81. gery. Patients who travel frequently should wear a 19. Case Records of the Massachusetts General Hospital (Case 15-1985). N Engl J Med 1985;312:976-83. bracelet with multilingual information concerning 20. Bouachour G, Tirot P, Varache N, Gouello JP, Harry P, Alquier P. He- their corticosteroid dependence. modynamic changes in acute adrenal insufficiency. Intensive Care Med 1994;20:138-41. 21. Dorin RI, Kearns PJ. High output circulatory failure in acute adrenal CONCLUSIONS insufficiency. Crit Care Med 1988;16:296-7. 22. Ernest D, Fisher MM. Heparin-induced thrombocytopenia complicat- During critical illness, the hypothalamic–pituitary– ed by bilateral adrenal haemorrhage. Intensive Care Med 1991;17:238-40. adrenal axis is activated, as demonstrated by increased 23. Melby MJ, Bergman K, Ramos T, Reinhold R, Mackey W. Acute adre- serum corticotropin and cortisol concentrations. In nal insufficiency mimicking septic shock: a case report. Pharmacotherapy 1988;8:69-71. most patients with adrenal insufficiency, determi- 24. Claussen MS, Landercasper J, Cogbill TH. Acute adrenal insufficiency nation of the response of the serum cortisol con- presenting as shock after trauma and surgery: three cases and review of the literature. J Trauma 1992;32:94-100. centration to corticotropin is helpful in making the 25. Sibbald WJ, Short A, Cohen MP, Wilson RF. Variations in adrenocortical diagnosis. However, occult relative adrenal insuffi- responsiveness during severe bacterial infections: unrecognized adrenocortical ciency, defined as a state in which corticosteroid ad- insufficiency in severe bacterial infections. Ann Surg 1977;186:29-33. 26. Hiebert JM, Egdhal RH. Cortisol responses to normotensive and hy- ministration diminishes or eliminates the require- potensive oligemia in unanesthetized primates. Surg Forum 1972;23:69-77. ment for vasopressor drugs, rather than as a state 27. Hume DM, Bell CC, Bartter F. Direct measurement of adrenal secre- in which hypothalamic–pituitary–adrenal function is tion during operative trauma and convalescence. Surgery 1962;52:174-87. 28. Cooper CE, Nelson DH. ACTH levels in plasma in preoperative and clearly abnormal, may occur in some critically ill pa- surgically stressed patients. J Clin Invest 1962;41:1599-605. tients. Patients receiving treatment with cortico- 29. Naito Y, Fukata J, Tamai S, et al. Biphasic changes in hypothalamo- pituitary-adrenal function during the early recovery period after major ab- steroids for chronic autoimmune or inflammatory dominal surgery. J Clin Endocrinol Metab 1991;73:111-7. diseases need less additional corticosteroid during 30. Vermes I, Beishuizen A, Hampsink RM, Haanen C. Dissociation of severe illness and perioperatively than those receiv- plasma adrenocorticotropin and cortisol levels in critically ill patients: pos- sible role of endothelin and atrial natriuretic hormone. J Clin Endocrinol ing replacement therapy for hypothalamic–pituitary– Metab 1995;80:1238-42. adrenal insufficiency. 31. McIntosh TK, Lothrop DA, Lee A, Jackson BT, Nabseth D, Egdahl

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RH. Circadian rhythm of cortisol is altered in postsurgical patients. J Clin 62. The Veterans Administration Systemic Sepsis Cooperative Study Endocrinol Metab 1981;53:117-22. Group. Effect of high-dose glucocorticoid therapy on mortality in patients 32. Wade CE, Lindberg JS, Cockrell JL, et al. Upon-admission adrenal with clinical signs of systemic sepsis. N Engl J Med 1987;317:659-65. steroidogenesis is adapted to the degree of illness in intensive care unit pa- 63. Lebel MH, Freij BJ, Syrogiannopoulos GA, et al. Dexamethasone tients. J Clin Endocrinol Metab 1988;67:223-7. therapy for bacterial meningitis: results of two double-blind, placebo-con- 33. Barton RN, Stoner HB, Watson SM. Relationships among plasma cor- trolled trials. N Engl J Med 1988;319:964-71. tisol, adrenocorticotrophin, and severity of injury in recently injured pa- 64. Hoffman SL, Punjabi NH, Kumala S, et al. Reduction in mortality in tients. 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(Doctoral thesis. Rotterdam, the Netherlands: Erasmus Univer- 23:1430-9. sity, 1984.)

1292 October 30, 1997