Adrenal insufficiency in septic shock

RBanim Urgences 2000 ; 9 : 633-8 0 2000 kiitions scientificlues et medicales Elsevier SAS. Tous droits r&xxv&

Adrenal insufficiencv r/

in septic shock B.A. Fo~x*, R.A. Little

Adrenal insufficiency may be primary or secondary. In primary adrenal insufficiency (Addison’s disease) there is destruction of the adrenal cortex. In years gone by this was most commonly the result of tuberculosis. Now in Western societies, where tuberculosis is much rarer, the com- monest cause is autoimmune destruction. Although the adrenal medulla is usually spared in primary adrenal insufficiency medullary function may be impaired as adrenaline production depends on the local concentration of co&sol being high.

In secondary adrenal insufficiency the failure of adrenal function is the consequence of pituitary or hypothalamic disease.

In a recent review acute adrenal insufficiency was defined as an “unex- plained catecholamine-resistant hypotension” [ 11. The author suggested that adrenal insufficiency should also be considered in a patient developing hyperpigmentation, vitiligo, pallor, a reduction in axillary or pubic hair, hyponatraemia, and hyperkalaemia.

MRC Trauma Group, North Western Injury Rescard Collaboration, Stapford Building, University of Manchester, Oxford Road, Manchester Ml 39 PT, Grande Bretagne.

* Correspondence and reprints. Adresses e-mail : [email protected] (B.A. Foex), rlittle@fsl .scg.man.ac.uk (R.A. Little).

Defining adrenal insufficiency bio- chemically is rather more difficult. A morning cdrtisol concentration of less than 3 pg.dL-1 (83 nmol.L-1) is considered diagnostic of adrenal insufficiency, while a morning cortisol concentration of more than 19 yg.dL-J (525 nmol.L-1) rules out the diagnosis [ 11. The relationship between pg.dL-1 and nmol.L-’ is given by: pg.dL-1 x 27.6 = nmol.L-l (Accordingly, 25 pg.dL-1 = 700 nmol.L-1 approximately).

Adrenal insufficiency could also be defined in terms of plasma corticotropin: a normal plasma corticotropin concentration would rule out primary adrenal insufficiency. In the primary condition the corticotropin concentration would be greater than 100 pg.dL-1 (22 nmol.L-1).

Adrenal insufficiency may also be defined in terms of the response to a known stimulus. The ‘Synac- then@‘-test, or corticotropin stimulation test (CST) is one way to achieve this [2-41. The test involves an I.M. or I.V. injection of 250 pg of synthetic corticotropin before 10:00 A.M. Plasma cortisol is then measured at 30 or 60 minutes. Adrenal function is normal if the plasma cortisol reaches at least 18 pg.dLm’ (500 nmol.Lm1). However, Oelkers concluded by saying that, “The plasma hormone values used to define normal and abnormal findings in this test... are not absolute, and clinical judgement must be used in interpreting them” [ 11.

Communications des experts

Haemorrhage: local and systemic? Adrenal haemorrhage has been

recognised as a pathological entity since the early part of the last century. Little in 1901 described a series of cases of purpura associated with bilateral suprarenal haemorrhages. Although cultures were taken no causative organism was isolated [5]. The nature of the condition associated with this suprarenal haemorrhage continued to elude physicians [6, 71.

Adrenal haemorrhage would be a possible cause for adrenal failure or insufficiency. Until the advent of CT scanning this was only a postmortem diagnosis. It seems clear that many patients dying in septic shock with adrenal insufficiency never had a postmortem, so the true incidence of this condition may never be known. Soni et al. mention that two of the five patients in their series with adrenal insufficiency had intact adrenal cor- tices [8].

Systemic haemorrhage is associated with HPA axis activation and increased steroid production. It was thought that there might be an increase in sensitivity to ACTH in haemorrhage. Two studies have shown that there is no change in ACTH sensitivity in haemorrhage [9, lo]. In fact, these studies showed that with pro- found haemorrhagic shock there was a reduction in steroid production.

A later study showed that if adrenal venous blood flow was less than 1 mL.min-1 there was a reduction in glucocorticoid secretion, which was not always restored when flow was restored [l l]. Silicone perfusion of the adrenals of dogs in control and haemorrhagic shock conditions (sys- tolic blood pressure 55 mmHg for 30 minutes) was used to study changes in the microvasculature [ 121. Haemorrhagic shock resulted in

B.A. Fotix, R.A. Little

patchy flow to the adrenal cortex, caused by active vasoconstriction, while flow to the medulla seemed to be maintained. The implication was that in hypovolaemic hypotension there was shunting of blood from the adrenal cortex to the medulla, which may cause a reduction in steroid production as a result of adrenal cortex hypoperfusion.

A ‘septic mediator’? Endotoxaemia has been shown to

result in an increase in plasma cortisol in dogs [ 131. This was the result of an increase in adrenal secretory acti- vity, which was similar to that seen with intravenous corticotropin. How- ever, the adrenal response to endotoxin was abolished in hypophysec- tomised dogs, suggesting that the adrenal response was dependent on the production of ACTH. Paradoxi- cally, a lethal dose of endotoxin reduced the adrenal response.

Much interest has focused on the effect of corticosteroids in endotoxaemia. From studies in the rabbit it appeared that corticosteroids reduced the rate of absorption of endotoxin from the gut [14]. It was also suggested that the steroids reduced the vasoconstrictor effect of endotoxaemia on reticula-endothelial system (RES) function. It was thought that by this effect there was increased clear- ance of endotoxin by the RES.

Adrenocortical function has been studied using isolated cell cultures. Keri et al. used rat adrenocortical cell cultures and exposed them to control rabbit plasma or plasma from rabbits with induced septic shock [I 51. When adrenocortical cells were cultured with either plasma there was steroid production. However, the septic shock plasma reduced the ability of cultured adrenocortical cells to pro- duce corticosteroids in response to ACTH. It seemed that there was some

inhibitory factor in the septic shock plasma.

Further studies using the adrenocortical cell cultures were performed to try to elucidate the mechanisms of this inhibition [16]. The authors suggested that inhibition of steroidogenesis might take place at three sites: 1) by inhibiting the binding of corticotropin at the cell receptor; 2) by inhibition of CAMP production; and 3) by inhibition of the conversion of cholesterol to pregnenolone. One of their observations was that there was great variability in the amount of adrenocortical depression produced by different plasma samples. This echoes the variability in plasma cortisol seen in different critically ill patients.

What might be origin of this inhibitory effect? Endotoxaemia results in the production of many inflamma- tory mediators. One of these is tumour necrosis factor a (TNF-a) [ I7- 191.

Could TNFa play a part? TNFa has been proposed as a regu-

latory factor in adrenocortical function: Jaattela et al. showed that TNFa inhibited the stimulatory effect of ACTH on foetal adrenal cells [20]. In 1991 this group showed that there was a dose-dependent inhibition of ACTH-induced steroidogenesis in cultured foetal adrenal cells [21]. However, there are marked differ- ences in foetal and adult adrenal function. In the foetus the androgenl corticosteroid ratio is much higher and foetal adrenals often contain TNF-a, which is not present in adult tissue [20].

By contrast there is also evidence that TNFa may stimulate cortisol production in dogs ]22] and in rats [23, 241. Sharp et al. showed that TNF-a, injected peripherally, may induce pituitary cells to release ACTH and so stimulate steroid production from the

adrenals [24]. Direct injection of TNFa into the brain did not. The mechanism of action of TNF-a re- mained unclear.

Darling et al., as part of their 1989 study, looked at cortisol production by adult human adrenocortical cell cultures [23]. They found that incubating adult adrenal cells with TNF-a resulted in a dose-dependent increase in cortisol secretion. This was interpreted as a direct action of TNF on adrenocortical cells. However, their earlier work with rats, which showed an increase in ACTH production, suggested that TNF also had a central action.

From these studies it is far from evident how adrenal insufficiency in the septic patient might come about. Quite the reverse would seem to apply: one of the mediators of the ‘septic state’ (TNF-a), actually seems to stimulate a cortisol response. And, as Beutler showed, steroids actually block TNF-a production, if given pro- phylactically before endotoxaemia ~251.

Diagnosis of adrenal insufficiency in the critically ill

Diagnosis may be made at two levels:

-basal or baseline cortisol concentration;

- the response to a stimulation test. There are many reports of stressed

patients having high baseline cortisol concentrations [26-281. Surprisingly, Marines injured in Vietnam, and suf- fering from traumatic shock, had a mean cortisol concentration of only 25.7 pg.dL-1 on admission [29]. The range of cortisol concentrations over the three-day observation period was only 20-3 1 l-tg.dL-1.

Any patient with a low or normal cortisol may be considered to have an adrenal insufficiency: Duggan et al. considered that random cortisols of 0.01 pmol.L-1 to 0.245 prnol.Lmr were

Adrenal insufficiency in septic shock 635

inadequate for severely ill patients [301.

McKee and Finlay considered that ‘A negative response to ‘SynactherP’ is virtually pathognomonic of adrenocortical insufficiency” [3 11. They defined a negative response as less than a 200 nmol.L-l increase in cortisol after ACTH.

In contrast, Melby and Spink found high basal cortisol concentrations in all their shocked patients and found that even in moribund patients there was a response to corticotropin stimulation (that is to say, cortisol at least doubled and so fulfilled the 200 nmol.L-1 increase criterion) [26].

Interestingly, Briegel et al. found no significant difference in basal cortisol concentrations in 20 patients in septic shock and after their recovery [32].

In contrast, Bouachour et al. found that 22 patients in septic shock all had basal cortisol concentrations greater than 275 nmol.L-i [33]. Short corticotropin stimulation tests (CST) were performed on days 1 and 2 after diagnosis of septic shock. Only six patients did not have an ‘adequate’ response to either of the CSTs. ‘Ade- quate’ was defined as a > 200 nmol.Lm1 increase in cortisol. Nine of the patients showed an ‘inadequate’ response to one of the two tests. The authors found that peak cortisol concentrations were more useful. How- ever, the lack of a significant difference in the responses of survivors and the non-survivors to the CST led the authors to conclude that adrenocortical impairment was not a major problem in patients with septic shock.

In a larger series this same group found a mean basal cortisol concentration of 36.8 PgdLl in 40 septic patients [34]. Ninety-two percent of them had a basal cortisol greater than 15 pg.dL-1 and only 6.25% had a post- ACTH cortisol of less than 18 pg.dL-1.

The authors concluded that adrenal insufficiency was rare in septic shock.

A cautionary note is sounded by Knighton et al. [35] from their expe- rience with eight patients with prolonged vasopressor-dependent septic shock. All eight improved cardio- vascularly with physiological doses of hydrocortisone, but only four had biochemical evidence of adrenal failure (low serum cortisol) or relative adrenal insufficiency, that is to say, an elevated baseline cortisol concentration but an inadequate cortical response to corticotropin (< 200 nmol.L-i increase in cortisol). They suggested that corticotropin testing was not the best way of deciding whether to give a patient physiological doses of steroids. Instead, they suggested any patient with prolonged vasopressor- dependent shock should be considered for steroid replacement therapy.

Two small series of surgical patients have used the failure to double plasma cortisol after a CST as a definition of adrenal insufficiency [36, 371. Bald- win and Allo, in their series of four patients, used the positive haemodynamic response to physiological doses of steroids as additional proof of ‘hypoadrenalism’ [37].

A rise in serum cortisol concentration was rejected as the criterion for defining adrenocortical function by Jurney et al. [38]. They defined normal adrenal function as a serum cortisol concentration in excess of 18 pg.dL-1, 30 or 60 minutes after a 250 pg injection of synthetic ACTH. The rationale for this definition was that patients with elevated basal serum cortisol would not show much response to synthetic ACTH anyway. This definition was used by Soni et al. [8]. Soni et al. considered that any patient in septic shock not respond- ing to conventional treatment should be considered as having adrenal insufficiency [8]. This could then be

ruled out if the plasma cortisol after 250 mg.dLmr ACTH exceeded 18 mg.dL-1. In their 2 1 patients only five (23.8%) met this definition for adrenal insufficiency.

Others have taken simpler definitions. Schein et al. considered that a random serum cortisol greater than 20 pg.dL-i represented an appropriate and adequate cortisol response in critically ill patients [39].

Vermes et al. considered that a plasma cortisol of more than 25 pg.dL-1 (700 nmol.L-I) ruled out adrenal insufficiency in critically ill patients [40].

Moran et al. took a plasma cortisol concentration of less than 500 nmol.L-1 as being “low” [41], based on the results of Sibbald et al. [42], which showed that the mean cortisol for non-agonal septic patients was 520 nmol.L-1.

Finally, Hatherill et al. defined adrenal insufficiency as a post-‘Syn- acthen@’ cortisol increment of less than 200 nmol.L-1 1431. In their paediatric population the incidence of adrenal insufficiency was 52% by this definition. They also provided a table listing various definitions of adrenal failure and insufficiency and the percentage of their patients meeting these criteria. Depending on the criteria the incidence of adrenal insufficiency varied from 12-85% in their small sample (table I).

Defining those patients who might benefit from the use of corticosteroids

One of the difficulties in trying to understand the problem of adrenal insufficiency in septic shock is that much of the work done on the thera- peutic role of steroids in septic shock was based on their effects on comple- ments (and other actions), rather than, for example, on the premise of correcting adrenal insufficiency [44]. Other studies referred to laboratory

B.A. Fogx, R.A. Little

Table I. Incidence of adrenal insufficiency.

Definition of adrenal insufficiency (cortko/, nmoYL)

Baseline < 100 Increment< 200 Increment< 250 Peak< 500 Peak< 500 plwincrement~200 Peak c (baseline x2)

Percent of patients in study

3 52 55 12 12 85

(Adapted from [43]).

animal studies showing the benefits of steroids but made no mention of the possibility of correcting an adrenal insufficiency, for example [45-471. The result was that patients were recruited on the basis of septic shock criteria rather than adrenal function. It has now become clear that many patients, even critically ill, do not show evidence of adrenal insufficiency. In this light it is perhaps less surprising that the large-scale trials failed to show any benefit from the use of corticosteroids.

Defining these patients is difficult,

Bollaert et al. defined those to be

particularly if we accept that the CST

entered into their trial of hydrocorti-

may not pick out those patients most likely to benefit. A ‘vasopressor- dependent shock state’-type defini-

sone as patients in septic shock who

tion might help.

needed an infusion of catecholamines

Briegel et al. point out that ‘stress’ doses of hydrocortisone are very much smaller than the doses used in

for more than 48 hours [49].

the high-dose trials of 1987, and that these trials were not aimed at the longer term problem of adrenocortical insufficiency [48].

There is some evidence that steroids may be of benefit even in well-esta- blished septic shock. Schneider and Voerman saw haemodynamic im- provements in seven patients treated

with physiological doses of hydrocortisone six days after the start of septic shock [50]. These patients had normal cortisol concentrations. The authors considered that the patients exhibited relative adrenocortical insufficiency. As there was no change in heart rate or cardiac output it appeared that the steroids may have enhanced the peripheral response to pressor agents.

In contrast, two studies which were able to achieve mean times of less than three hours from diagnosis of sepsis to infusion of methylprednisolone both found no benefit [46-471.

There is some debate about the early use of steroids. Sprung et al. found a significant degree of shock reversal in patients given methyprednisolone, or dexamethasone, within four hours of onset of shock. Shock reversal was not significantly different between these treatment groups and controls, when the steroids were given after four hours. In this study the steroids were given as a single dose (mean time from onset of’shock 17.5 hours). There was a reduction in mortality in the treatment groups but only over the first 150 hours. Overall hospital mortality was not affected by the use of steroids.

Meta-analysis has reached similar conclusions when looking at sepsis in general. Cronin et al. found that there was an increase in mortality, an increase in mortality from secondary

infections and a higher rate of gas- trointestinal bleeding associated with corticosteroid treatment [5 11. Lefer- ing and Neugebauer were able to in- clude one more study in their meta- analysis [52]. They came to a similar general conclusion. However, they did find that in the sub-group of patients with a Gram-negative infection there was some benefit.

How common is adrenal insufficiency?

Twenty percent of the patients studied by Sibbald et al. were found to have an inadequate response to artifi- cial ACTH [42]. Half of their ‘agonal’ group of patients did not respond to ACTH, although they had significantly elevated basal concentrations of cortisol.

Adrenal insufficiency was not common in 70 ICU patients [38]. The authors of this study concluded that routine screening for adrenal insufficiency was not warranted in all ICU patients. Schein et al. came to a similar conclusion after finding that the median serum cortisol concentration from 37 patients in septic shock was< 50.7 pg.dL-1 (range 15.6-400), and that 90% of them had a cortisol concentration greater than 27 PgdL-J [39]. In contrast to Jurney et al. they found no correlation between serum cortisol and the severity of the shock [38].

Vadas et al.‘s study of eight patients with septic shock found high peak serum cortisol concentration in all patients [53]. In the survivors peak serum cortisol concentration ranged from 662-2,480 nmol.L-1, in non-survivors peak serum cortisols concentrations ranged from 450- 2,320 nmol.L-1. Serum ACTH concentrations were described as “con- sistently less than 5 pmol.L-I” [53]. In these patients there was no evidence of either primary or secondary adrenal insufficiency. The fact that

Adrenal insufficiency in septic shock

ACTH concentrations were so low means that there may have been some mechanism outside the HPA axis stimulating steroidogenesis. The authors suggested, based on other studies, that ACTH-like peptides se- creted from leukocytes may have been responsible for stimulating the production of steroids.

One study has shown that patients benefited from hydrocortisone irres- pective of whether they responded or not to CST [49]. The authors suggested that hydrocortisone may be ef- fective in its own right or that the definition of adrenocortical insufficiency in septic shock is inappropriate. They did concede that the patients in their study did not represent the full spectrum of septic shock, as they excluded patients in early septic shock and those in very severe septic shock.

Using the definition of adrenal insufficiency as a cortisol concentration of less than 18 mg.dL-t after a short Synacthenm test can result in rather different incidences for the condition. Soni et al. found that 23.8% of patients with septic shock also had adrenal insufficiency [S], while Boua- chour et al. found the incidence at only 6.25% [34].

In Hatherill et al’s paediatric population the incidence of adrenal insufficiency was higher still: 52% [43]. They noted that the incidence de- pended very much on the definition of the condition: a problem acknowl- edged by Bouachour et al. [34].

A study of adults with septic shock, using the same definition for adrenal insufficiency, found that two-thirds of those who had an ACTH test had an increment in plasma cortisol of less than 200 nmol.L-1 [41].

Discussing adrenal insufficiency in septic shock is fraught with

difficulties. These begin with the un- certainty of the aetiology of the condition. Certainly adrenal haemorrhage results in adrenal insufficiency, but this seems to be a rare event. Changes in adrenal blood flow in haemorrhagic hypotension can cause adrenal insufficiency, but this has yet to be studied in septic shock. There may be a septic mediator, but in the case of TNFa the evidence is far from clear.

Then there is the problem of defining adrenal insufficiency. This may be done in relation to cortisol concentration or in relation to the response to a stimulation test. For the latter, particularly, different authors have used different criteria. The result of this un- certainty is that there is considerable variation in the reported rates of adrenal insufficiency in septic shock. In only two studies was the incidence reported greater than 50% [41,43].

The role of steroids in the therapy of septic shock remains controversial. While the large studies of the 1980s showed no overall benefit from steroids, more recent studies, such as that by Bollaert et al. [49], hint that in well-selected patients steroids may yet have a role.

Much work remains to be done.

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Adrenal insufficiency in septic shock