Septic Shock and Sepsis: A Comparison of Total and Free Plasma Cortisol Levels

Ho, J. T.; Al-Musalhi, H.; Chapman, M. John; Quach, Tam; Thomas, Peter D. G.; Bagley, Christopher J.; Lewis, John G.; Torpy, David J.

doi:10.1210/jc.2005-0265

Cited by 290 publications

(269 citation statements)

References 30 publications

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“…The latter may thus help to explain the lower total (rather than free) cortisol levels in non-septic, hypoalbuminemic patients with a relatively low CBG vs. those with higher protein levels, in line with the results in predominantly non-septic patients studied by Hamrahian et al [4]. In contrast, hypoalbuminemia in septic patients was not associated with a low and potentially saturated CBG, and thus low total and high free cortisol, in line with others [5,15]. CBG and albumin apparently often change in dissimilar directions in sepsis as compared to non-sepsis, as suggested before [18].…”

Section: Discussionsupporting

confidence: 84%

“…Finally, increases in free cortisol upon ACTH depend less on low binding proteins than raw levels, so that increases in total cortisol suffice in assessing adrenal insufficiency, particularly in sepsis. CBG is the major cortisol binding-protein in blood, so that, as our data confirm, the free cortisol fraction is only about 25% of total cortisol even in the critically ill, and direct measurements are needed when trying to assess free from total cortisol levels [1,4,5,9,11,[14][15][16][17][18]. Cortisol binding to CBG is saturable (690 nmol/l) and characterized by a molar binding ratio at high affinity [18].…”

Section: Discussionmentioning

confidence: 50%

“…This issue was refuted by others, however [5,15,21]. Differences in case mix may partly underlie the discrepancies between studies, because of healthy volunteers or non-septic patients predominating in some studies [4,11,14,17] and of septic patients in others [5,15,21]. Moreover, CIRCI may be more frequent in sepsis than in non-sepsis patients, and sometimes only calculated free cortisol was evaluated, thereby assuming normal albumin levels, while both CBG and albumin may be lowered [1-3, 5, 6, 8, 18, 22, 23].…”

Section: Introductionmentioning

confidence: 97%

“…Indeed, low binding proteins may overestimate relative adrenal insufficiency assessed from (increases in) total cortisol. This issue was refuted by others, however [5,15,21]. Differences in case mix may partly underlie the discrepancies between studies, because of healthy volunteers or non-septic patients predominating in some studies [4,11,14,17] and of septic patients in others [5,15,21].…”

Section: Introductionmentioning

confidence: 99%

“…Foregoing studies can be criticized because of changes in binding proteins such as cortisol-binding globulin (CBG) and albumin, confounding estimation of biologically active free cortisol from total cortisol measurements and thereby assessment of adrenal function [1,4,5,[7][8][9][10][11][12][13][14][15][16][17][18][19][20]. Indeed, low binding proteins may overestimate relative adrenal insufficiency assessed from (increases in) total cortisol.…”

Section: Introductionmentioning

confidence: 99%

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Assessing adrenal insufficiency of corticosteroid secretion using free versus total cortisol levels in critical illness

et al. 2011

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Purpose: To study the value of free versus total cortisol levels in assessing relative adrenal insufficiency during critical illnessrelated corticosteroid insufficiency. Methods: A prospective study in a mixed intensive care unit from 2004 to 2007. We consecutively included 49 septic and 63 non-septic patients with treatment-insensitive hypotension in whom an adrenocorticotropic hormone (ACTH) test (250 lg) was performed. Serum total and free cortisol (equilibrium dialysis), corticosteroid-binding globulin (CBG) and albumin were assessed. Results: Although a low CBG resulted in a high free cortisol level relative to total cortisol, free and total cortisol and their increases were well correlated (r = 0.77-0.79, P \ 0.001). In sepsis, hypoalbuminemia did not affect total and free cortisol, and increases in total cortisol upon ACTH predicted increases in free cortisol regardless of low binding proteins. In non-sepsis, total cortisol was lower with than without hypoalbuminemia; free cortisol did not differ, since hypoalbuminemia concurred with a low CBG. Increases in total cortisol depended less on binding proteins than on raw levels. The areas under the receiver operating characteristic curve for predicting increases in free from total cortisol were 0.93-0.97 in sepsis and 0.79-0.85 in non-sepsis (P = 0.044 or lower for sepsis vs. non-sepsis). Conclusions: Although the biologically active free cortisol fraction depends on binding proteins, total cortisol correlates to free cortisol in treatment-insensitive hypotension during critical illness. In sepsis, albumin is not an important binding molecule. Subnormal increments in total cortisol upon ACTH suffice in assessing relative adrenal insufficiency, particularly in sepsis.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 50%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Assessing adrenal insufficiency of corticosteroid secretion using free versus total cortisol levels in critical illness

et al. 2011

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Determination of unbound prednisolone, prednisone and cortisol in human serum and saliva by on‐line solid‐phase extraction liquid chromatography tandem mass spectrometry and potential implications for drug monitoring of prednisolone and prednisone in saliva

Ruiter

Teeninga

Nauta

et al. 2011

Biomedical Chromatography

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Prednisolone (PLN) and prednisone (PN) are widely used glucocorticoids. Drug monitoring of PLN and PN is not routinely done owing to the need for multiple blood sampling and challenging measurement of unbound PLN and PN in blood. Here we present a robust method for quantification of cortisol, PLN and PN in serum, ultrafiltrate and saliva by on-line solid-phase extraction LC-MS/MS. The method is linear for the three analytes over the range of 6-1400 nmol/L for serum and 2-450 nmol/L for ultrafiltrate and saliva. Within-run precision of all three analytes was <10% and total precision was <15%. This method was applied to create time-concentration profiles of cortisol, PLN and PN after an oral dose of prednisolone in a healthy volunteer. Salivary levels of PLN correlated well with ultrafiltrate levels (p < 0.01), while this correlation was only marginal for PN (p = 0.052). The PN/PLN ratio was significantly higher in saliva than in ultrafiltrate and serum (p < 0.01). Addition sums of both metabolites in saliva showed excellent correlation with those of ultrafiltrate (p < 0.01). These findings have not been presented before and may have important implications for future studies concerning drug monitoring of PLN and PN in saliva.

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Adrenocortical Stress Response during the Course of Critical Illness

Peeters

Langouche

Berghe

2017

Comprehensive Physiology

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Critically ill patients have elevated plasma cortisol concentrations, in proportion to illness severity. This was traditionally attributed exclusively to a central activation of the hypothalamus-pituitary axis. However, low rather than high plasma ACTH concentrations have been reported in critically ill patients, with loss of diurnal ACTH and cortisol rhythm. Low ACTH together with high cortisol is referred to as "ACTH-cortisol dissociation." Although cortisol production is somewhat increased with inflammation, a reduced cortisol breakdown explains to a larger extent the hypercortisolism during critical illness. Inflammation-driven decrease in cortisol binding proteins further increase the active free cortisol fraction. Several drugs administered to ICU patients suppress plasma cortisol in a dose-dependent manner. Sustained low circulating ACTH might contribute to adrenal atrophy and dysfunction in the prolonged phase of critical illness. In the acute phase of sepsis or septic shock, a condition referred to as "relative adrenal insufficiency" has been suggested to ensue from glucocorticoid resistance and insufficiently elevated circulating cortisol to overcome such resistance, with pathological changes possibly occurring at every level of the HPA axis. However, it remains highly controversial whether tissue-specific glucocorticoid resistance is adaptive or maladaptive, how to diagnose "relative" adrenal insufficiency, and how it should be treated. Large RCTs, investigating the effect of 200 mg/d hydrocortisone treatment for sepsis or septic shock have shown conflicting, mainly negative, results. Not taking into account the reduced cortisol breakdown, which increases the risk of overdosing hydrocortisone, might have played a role. Further research on diagnostic, therapeutic and dosing aspects is urgently warranted. Compr Physiol 8:283-298, 2018.

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Septic Shock and Sepsis: A Comparison of Total and Free Plasma Cortisol Levels

Cited by 290 publications

References 30 publications

Assessing adrenal insufficiency of corticosteroid secretion using free versus total cortisol levels in critical illness

Assessing adrenal insufficiency of corticosteroid secretion using free versus total cortisol levels in critical illness

Determination of unbound prednisolone, prednisone and cortisol in human serum and saliva by on‐line solid‐phase extraction liquid chromatography tandem mass spectrometry and potential implications for drug monitoring of prednisolone and prednisone in saliva

Adrenocortical Stress Response during the Course of Critical Illness

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