View source for Critical illness–related corticosteroid insufficiency

{{SI}}


==Overview==
'''Critical illness-related corticosteroid insufficiency (CIRCI)''' is a form of [[adrenal insufficiency]] in [[critical illness|critically ill]] patients who have blood [[corticosteroid]] levels which are inadequate for the severe [[stress response]] they experience. Combined with decreased [[glucocorticoid receptor]] sensitivity and tissue response to corticosteroids, this adrenal insufficiency constitutes a negative [[prognostic]] factor for [[intensive care]] patients.<ref name="pmid18496365">{{cite journal |author=Marik PE, Pastores SM, Annane D, ''et al'' |title=Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine |journal=Crit. Care Med. |volume=36 |issue=6 |pages=1937–49 |year=2008 |month=June |pmid=18496365 |doi=10.1097/CCM.0b013e31817603ba |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?doi=10.1097/CCM.0b013e31817603ba}}</ref>

The [[hypothalamic-pituitary-adrenal axis]] (HPA axis), in which the [[hypothalamus]] and [[pituitary gland]] control [[adrenal gland|adrenal]] secretions,  undergoes profound changes during critical illness. Both very high and very low levels of [[cortisol]] have been linked to a poor outcome in intensive care patients.<ref name="pmid8001391">{{cite journal |author=Rothwell PM, Lawler PG |title=Prediction of outcome in intensive care patients using endocrine parameters |journal=Crit. Care Med. |volume=23 |issue=1 |pages=78–83 |year=1995 |month=January |pmid=8001391 |doi= |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0090-3493&volume=23&issue=1&spage=78}}</ref> It has been suggested that high levels could represent severe stress, whereas low levels are due to blunted cortisol production and response.<ref name="pmid10697064">{{cite journal |author=Annane D, Sébille V, Troché G, Raphaël JC, Gajdos P, Bellissant E |title=A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin |journal=JAMA |volume=283 |issue=8 |pages=1038–45 |year=2000 |month=February |pmid=10697064 |doi= |url=http://jama.ama-assn.org/cgi/pmidlookup?view=long&pmid=10697064}}</ref>

CIRCI can be suspected in patients with [[low blood pressure]] (low blood pressure) despite [[resuscitation]] with [[intravenous fluids]] and [[vasopressor]] drugs.<ref name="pmid18158437">{{cite journal |author=Dellinger RP, Levy MM, Carlet JM, ''et al'' |title=Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008 |journal=Crit. Care Med. |volume=36 |issue=1 |pages=296–327 |year=2008 |month=January |pmid=18158437 |doi=10.1097/01.CCM.0000298158.12101.41 |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?doi=10.1097/01.CCM.0000298158.12101.41}}</ref> The [[Surviving Sepsis Campaign]] guidelines advocate intravenous [[hydrocortisone]] only in adults with [[septic shock]] and refractory hypotension.<ref name="pmid18158437"/> The exact definition of this condition, the best ways to test for corticoid insufficiency in critically ill patients, and the therapeutic use of (usually low doses) of corticosteroids remains a subject of debate.<ref name="pmid18695699">{{cite journal |author=Mesotten D, Vanhorebeek I, Van den Berghe G |title=The altered adrenal axis and treatment with glucocorticoids during critical illness |journal=Nat Clin Pract Endocrinol Metab |volume=4 |issue=9 |pages=496–505 |year=2008 |month=September |pmid=18695699 |doi=10.1038/ncpendmet0921 |url=http://dx.doi.org/10.1038/ncpendmet0921}}</ref>

==Symptoms==
The best known feature that suggests a possible underlying adrenal insufficiency is low blood pressure despite resuscitation with intravenous fluids, requiring vasopressor drugs.<ref name="pmid18158437"/> These patients typically display [[tachycardia]] and other signs of hyperdynamic shock.<ref name="pmid18695699"/> Other symptoms include [[fever]], [[purpura fulminans]], and [[gastrointestinal]] or [[neurological]] disturbances.<ref name="pmid18695699"/> All these features are relatively non-specific in intensive care patients.<ref name="pmid18695699"/>

In some patients a specific reason for adrenal insufficiency can be suspected, such as prior intake of corticosteroids that suppressed the HPA axis, or use of [[enzyme induction|enzyme inducing]] drugs such as [[phenytoin]].<ref name="pmid18695699"/> Treatment with [[imidazole]] drugs such as [[etomidate]], [[ketoconazole]] and [[miconazole]] can also suppress the HPA axis, as well as drugs used specifically for this purpose, such as [[metyrapone]].<ref name="pmid3027305">{{cite journal |author=Lamberts SW, Bons EG, Bruining HA, de Jong FH |title=Differential effects of the imidazole derivatives etomidate, ketoconazole and miconazole and of metyrapone on the secretion of cortisol and its precursors by human adrenocortical cells |journal=J. Pharmacol. Exp. Ther. |volume=240 |issue=1 |pages=259–64 |year=1987 |month=January |pmid=3027305 |doi= |url=http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=3027305}}</ref>

Several [[blood test]] abnormalities can suggest corticosteroid insufficiency, such as [[hypoglycaemia]], [[hyponatremia]], [[hyperkalemia]], [[hypercalcemia]], [[neutropenia]], [[eosinophilia]], [[hyperprolactinemia]] and [[hypothyroidism]].<ref name="pmid18695699"/>

==Diagnosis==
The exact diagnostic tests and cut-off values to diagnose critical illness-related corticosteroid insufficiency are not agreed upon.<ref name="pmid18496365"/> This also applies to the distinction between absolute and relative adrenal insufficiency, a reason why the term critical illness–related corticosteroid insufficiency is preferred to relative adrenal insufficiency.<ref name="pmid18695699"/> The variation in cortisol levels according to disease type and severity, as well as variation within the same patient, hampers the establishment of a clear threshold below which CIRCI occurs.<ref name="pmid18695699"/> Moreover, in patients who's adrenals are already maximally stimulated, a stimulation test would not be informative.<ref name="pmid18695699"/> Furthermore, a short test might not adequately assess response to the chronic stress of critical illness.<ref name="pmid18695699"/>

Both random total cortisol levels, total cortisol levels or increment after ACTH stimulation tests, free cortisol levels, or a combination of these have been proposed as diagnostic tests. Other stimulation tests for adrenal insufficiency which are used in non-critical patients, such as the test using [[metyrapone]] or a test which employs [[insulin]] to induce [[hypoglycemia]], are not preferred for CIRCI.<ref name="pmid18695699"/> Both a metyrapone-induced decrease in cortisol and hypoglycemia are potentially harmful to intensive care patients. The exact dose of ACTH remains a matter of debate.<ref name="pmid15886236">{{cite journal |author=Widmer IE, Puder JJ, König C, ''et al'' |title=Cortisol response in relation to the severity of stress and illness |journal=J. Clin. Endocrinol. Metab. |volume=90 |issue=8 |pages=4579–86 |year=2005 |month=August |pmid=15886236 |doi=10.1210/jc.2005-0354 |url=http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=15886236}}</ref> In the CORTICUS study, ACTH stimulation testing predicted mortality whereas baseline cortisol levels did not.<ref name="pmid17334243">{{cite journal |author=Lipiner-Friedman D, Sprung CL, Laterre PF, ''et al'' |title=Adrenal function in sepsis: the retrospective Corticus cohort study |journal=Crit. Care Med. |volume=35 |issue=4 |pages=1012–8 |year=2007 |month=April |pmid=17334243 |doi=10.1097/01.CCM.0000259465.92018.6E |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?doi=10.1097/01.CCM.0000259465.92018.6E}}</ref> However, possible benefits of corticosteroid therapy do not seem to be completely predicted by ACTH stimulation testing.<ref name="pmid18184957">{{cite journal |author=Sprung CL, Annane D, Keh D, ''et al'' |title=Hydrocortisone therapy for patients with septic shock |journal=N. Engl. J. Med. |volume=358 |issue=2 |pages=111–24 |year=2008 |month=January |pmid=18184957 |doi=10.1056/NEJMoa071366 |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=18184957&promo=ONFLNS19}}</ref><ref name="pmid12186604">{{cite journal |author=Annane D, Sébille V, Charpentier C, ''et al'' |title=Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock |journal=JAMA |volume=288 |issue=7 |pages=862–71 |year=2002 |month=August |pmid=12186604 |doi= |url=http://jama.ama-assn.org/cgi/pmidlookup?view=long&pmid=12186604}}</ref> For these reasons, guidelines currently do not recommend that ACTH stimulation testing should guide the decision whether or not to administer corticosteroids.<ref name="pmid18496365"/><ref name="pmid18158437"/> Cortisol [[immunoassays]] on the other hand have been shown to be prone to both over- and underestimation.<ref name="pmid18158437"/>

==Treatment==
In adults with septic shock and refractory hypotension despite resuscitation with intravenous fluids and vasopressors, [[hydrocortisone]] is the preferred corticosteroid. It can be divided in several doses or administered as a continuous infusion.<ref name="pmid18496365"/> Fludrocortisone is optional in CIRCI, and dexamethasone is not recommended.<ref name="pmid18158437"/> Little evidence is available to judge when and how corticosteroid therapy should be stopped; guidelines recommend tapering corticosteroids when vasopressors are no longer needed.<ref name="pmid18496365"/><ref name="pmid18158437"/>

Corticosteroid treatment has also been suggested as an early treatment option in patient with [[acute respiratory distress syndrome]]. Steroids have not been shown beneficial for sepsis alone.<ref name="pmid7600840">{{cite journal |author=Lefering R, Neugebauer EA |title=Steroid controversy in sepsis and septic shock: a meta-analysis |journal=Crit. Care Med. |volume=23 |issue=7 |pages=1294–303 |year=1995 |month=July |pmid=7600840 |doi= |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0090-3493&volume=23&issue=7&spage=1294}}</ref> Historically, higher doses of steroids were given, but these have been suggested to be harmful compared to the lower doses which are advocated today.<ref name="pmid15238370">{{cite journal |author=Minneci PC, Deans KJ, Banks SM, Eichacker PQ, Natanson C |title=Meta-analysis: the effect of steroids on survival and shock during sepsis depends on the dose |journal=Ann. Intern. Med. |volume=141 |issue=1 |pages=47–56 |year=2004 |month=July |pmid=15238370 |doi= |url=}}</ref>

In the CORTICUS study, hydrocortisone hastened the reversal of septic shock, but did not influence mortality, with an increased occurence of septic shock relapse and [[hypernatremia]].<ref name="pmid18184957"/> The latter findings tempered enthusiasm for the broad use of hydrocortisone in septic shock.<ref name="pmid18158437"/> Prior to this study, several other smaller studies showed beneficial effects of long courses of low doses of corticoid.<ref name="pmid15289273">{{cite journal |author=Annane D, Bellissant E, Bollaert PE, Briegel J, Keh D, Kupfer Y |title=Corticosteroids for severe sepsis and septic shock: a systematic review and meta-analysis |journal=BMJ |volume=329 |issue=7464 |pages=480 |year=2004 |month=August |pmid=15289273 |pmc=515196 |doi=10.1136/bmj.38181.482222.55 |url=http://bmj.com/cgi/pmidlookup?view=long&pmid=15289273}}</ref><ref name="pmid12186604"/><ref name="pmid10321661">{{cite journal |author=Briegel J, Forst H, Haller M, ''et al'' |title=Stress doses of hydrocortisone reverse hyperdynamic septic shock: a prospective, randomized, double-blind, single-center study |journal=Crit. Care Med. |volume=27 |issue=4 |pages=723–32 |year=1999 |month=April |pmid=10321661 |doi= |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0090-3493&volume=27&issue=4&spage=723}}</ref><ref name="pmid9559600">{{cite journal |author=Bollaert PE, Charpentier C, Levy B, Debouverie M, Audibert G, Larcan A |title=Reversal of late septic shock with supraphysiologic doses of hydrocortisone |journal=Crit. Care Med. |volume=26 |issue=4 |pages=645–50 |year=1998 |month=April |pmid=9559600 |doi= |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0090-3493&volume=26&issue=4&spage=645}}</ref><ref name="pmid16276166">{{cite journal |author=Oppert M, Schindler R, Husung C, ''et al'' |title=Low-dose hydrocortisone improves shock reversal and reduces cytokine levels in early hyperdynamic septic shock |journal=Crit. Care Med. |volume=33 |issue=11 |pages=2457–64 |year=2005 |month=November |pmid=16276166 |doi= |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0090-3493&volume=33&issue=11&spage=2457}}</ref><ref name="pmid12133187">{{cite journal |author=Yildiz O, Doganay M, Aygen B, Güven M, Keleştimur F, Tutuû A |title=Physiological-dose steroid therapy in sepsis [ISRCTN36253388] |journal=Crit Care |volume=6 |issue=3 |pages=251–9 |year=2002 |month=June |pmid=12133187 |pmc=125315 |doi= |url=http://ccforum.com/content/6/3/251}}</ref><ref name="pmid12426230">{{cite journal |author=Keh D, Boehnke T, Weber-Cartens S, ''et al'' |title=Immunologic and hemodynamic effects of "low-dose" hydrocortisone in septic shock: a double-blind, randomized, placebo-controlled, crossover study |journal=Am. J. Respir. Crit. Care Med. |volume=167 |issue=4 |pages=512–20 |year=2003 |month=February |pmid=12426230 |doi=10.1164/rccm.200205-446OC |url=http://ajrccm.atsjournals.org/cgi/pmidlookup?view=long&pmid=12426230}}</ref> Several factors (such as lack of [[statistical power]] due to slow recruitment) could have led a [[false-negative]] finding on mortality in the CORTICUS study; thus, more research is needed.<ref name="pmid18695699"/>

==Physiology==
In acute states of severe stress, cortisol secretion by the adrenal gland increases up to six-fold, parallel to the severity of the condition.<ref name="pmid15084695"/> This is partly due to an increased secretion of [[corticotropin-releasing hormone]] (CRH) and [[adrenocorticotropic hormone]] (ACTH). Several [[cytokines]] have been also shown to interfere with the HPA axis at multiple levels.<ref name="pmid12426284">{{cite journal |author=Marik PE, Zaloga GP |title=Adrenal insufficiency in the critically ill: a new look at an old problem |journal=Chest |volume=122 |issue=5 |pages=1784–96 |year=2002 |month=November |pmid=12426284 |doi= |url=http://www.chestjournal.org/cgi/pmidlookup?view=long&pmid=12426284}}</ref>
There is also an increase in the number and affinity of glucocorticoid receptors.<ref name="pmid18695699"/> Levels of [[corticosteroid-binding globulin]] (CBG) and [[albumin]], which normally bind cortisol, are decreased, resulting in increased levels of free cortisol.<ref name="pmid15084695">{{cite journal |author=Hamrahian AH, Oseni TS, Arafah BM |title=Measurements of serum free cortisol in critically ill patients |journal=N. Engl. J. Med. |volume=350 |issue=16 |pages=1629–38 |year=2004 |month=April |pmid=15084695 |doi=10.1056/NEJMoa020266 |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=15084695&promo=ONFLNS19}}</ref> Furthermore, [[anaesthesia]] drugs like etomidate could interfere with the HPA axis.<ref name="pmid2982387">{{cite journal |author=Duthie DJ, Fraser R, Nimmo WS |title=Effect of induction of anaesthesia with etomidate on corticosteroid synthesis in man |journal=Br J Anaesth |volume=57 |issue=2 |pages=156–9 |year=1985 |month=February |pmid=2982387 |doi= |url=http://bja.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=2982387}}</ref>
The secretion also loses its normal [[diurnal]] pattern of morning peak levels and evening and night time troughs.<ref name="pmid12594318">{{cite journal |author=Cooper MS, Stewart PM |title=Corticosteroid insufficiency in acutely ill patients |journal=N. Engl. J. Med. |volume=348 |issue=8 |pages=727–34 |year=2003 |month=February |pmid=12594318 |doi=10.1056/NEJMra020529 |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=12594318&promo=ONFLNS19}}</ref> Nevertheless, secretion remains pulsatile and there is a marked variation in blood samples from the same individual.<ref name="pmid15960402">{{cite journal |author=Venkatesh B, Mortimer RH, Couchman B, Hall J |title=Evaluation of random plasma cortisol and the low dose corticotropin test as indicators of adrenal secretory capacity in critically ill patients: a prospective study |journal=Anaesth Intensive Care |volume=33 |issue=2 |pages=201–9 |year=2005 |month=April |pmid=15960402 |doi= |url=}}</ref>

High blood levels of cortisol during critical illness could theoretically be protective because of several reasons. They modulate [[metabolism]] (for example, by inducing high blood sugar levels, thereby providing energy to the body). They also suppress excessive [[immune system]] activation and exert supporting effects on the [[hemodynamics|circulatory system]].<ref name="pmid12426284"/><ref name="pmid9626104">{{cite journal |author=Van den Berghe G, de Zegher F, Bouillon R |title=Clinical review 95: Acute and prolonged critical illness as different neuroendocrine paradigms |journal=J. Clin. Endocrinol. Metab. |volume=83 |issue=6 |pages=1827–34 |year=1998 |month=June |pmid=9626104 |doi= |url=http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=9626104}}</ref> Increased susceptibility to infections, [[hyperglycemia]] (in patients already prone to [[stress hyperglycemia]]), [[gastrointestinal bleeding]], [[electrolyte]] disturbances and steroid-induced [[myopathy]] (in patients already prone to [[critical illness polyneuropathy]]) are possible harmful effects.<ref name="pmid18695699"/>

Blood levels of [[dehydroepiandrosterone]] increase, and levels of [[dehydroepiandrosterone sulfate]] decrease in response to critical illness.<ref name="pmid16608898">{{cite journal |author=Arlt W, Hammer F, Sanning P, ''et al'' |title=Dissociation of serum dehydroepiandrosterone and dehydroepiandrosterone sulfate in septic shock |journal=J. Clin. Endocrinol. Metab. |volume=91 |issue=7 |pages=2548–54 |year=2006 |month=July |pmid=16608898 |doi=10.1210/jc.2005-2258 |url=http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=16608898}}</ref><ref name="pmid12771606">{{cite journal |author=Marx C, Petros S, Bornstein SR, ''et al'' |title=Adrenocortical hormones in survivors and nonsurvivors of severe sepsis: diverse time course of dehydroepiandrosterone, dehydroepiandrosterone-sulfate, and cortisol |journal=Crit. Care Med. |volume=31 |issue=5 |pages=1382–8 |year=2003 |month=May |pmid=12771606 |doi=10.1097/01.CCM.0000063282.83188.3D |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0090-3493&volume=31&issue=5&spage=1382}}</ref><ref name="pmid11800520">{{cite journal |author=Vermes I, Beishuizen A |title=The hypothalamic-pituitary-adrenal response to critical illness |journal=Best Pract. Res. Clin. Endocrinol. Metab. |volume=15 |issue=4 |pages=495–511 |year=2001 |month=December |pmid=11800520 |doi=10.1053/beem.2001.0166 |url=}}</ref>

In the chronic phase of severe illness, cortisol levels decrease slowly and return to normal when the patient recovers. ACTH levels are however low, and CBG levels increase.<ref name="pmid18695699"/>

==Footnotes==
{{reflist|2}}

{{Intensive care medicine}}

[[Category:Intensive care medicine]]
[[Category:Endocrinology]]
{{WH}}
{{WS}}