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Molenaar et al. [1] observed that free cortisol (FC) measurements correlated closely with those of total cortisol (TC) in critically ill patients and thus concluded that measurements of FC were of marginal benefit. We do not believe this conclusion to be justified.
Plasma TC and FC are dependent variables and this relationship forms the basis of the well-known Coolens equation [2]. Correlation between FC and TC, either between baseline or post ACTH stimulation, is expected. It would have been very unusual if the authors demonstrated a regression line between the TC and FC increment that was not statistically significantly from zero (P > 0.05) and as such the observed P < 0.001 is entirely in keeping with what has been previously reported.
The correlation coefficient of 0.77–0.79 (R 2 = 0.59) does not imply the tests can be used interchangeably. Concordance around the suggested decision limits of 77 and 250 nmol/L was not demonstrated, and formal tests of concordance such as Cohen’s kappa and the McNemar test would be more appropriate to demonstrate any relationship. From Fig. 1a and c it is evident that there were samples with an appropriate FC increment and a TC increment below 250 nmol/L, which argues against the authors’ conclusion that the increments are interchangeable. Observations from our group have documented significant discordance in diagnosis of adrenal insufficiency using TC and FC criteria in patients with liver disease, and in septic shock [3, 4].
The authors’ own observations that relative increases of FC were significantly higher than those of TC, as well as the documented stronger association of FC with sickness severity [5], suggest that FC may be a more valid index of adrenal function. Robust examination of the association of FC with outcome will be required to investigate this issue. It is our opinion that the authors’ recommendation that the TC increment was sufficient to assess adrenal reserve, especially in sepsis, is premature and not supported by their data.
References
Molenaar N, Johan Groeneveld AB, Dijstelbloem HM, de Jong MF, Girbes AR, Heijboer AC, Beishuizen A (2011) Assessing adrenal insufficiency of corticosteroid secretion using free versus total cortisol levels in critical illness. Intensive Care Med 37:1986–1993. doi:10.1007/s00134-011-2342-x
Coolens JL, Van Baelen H, Heyns W (1987) Clinical use of unbound plasma cortisol as calculated from total cortisol and corticosteroid-binding globulin. J Steroid Biochem 26:197–202
Cohen J, Lassig-Smith M, Deans R, Pretorius CJ, Ungerer JP, Tan T, Jones M, Venkatesh B (2012) Serial changes in plasma total cortisol, plasma free cortisol and tissue cortisol activity in patients with septic shock: an observational study. Shock 37(1):28–33
Tan T, Chang L, Woodward A, McWhinney B, Galligan J, Macdonald GA, Cohen J, Venkatesh B (2010) Characterising adrenal function using directly measured plasma free cortisol in stable severe liver disease. J Hepatol 53:841–848
Ho JT, Al-Musalhi H, Chapman MJ, Quach T, Thomas PD, Bagley CJ, Lewis JG, Torpy DJ (2006) Septic shock and sepsis: a comparison of total and free plasma cortisol levels. J Clin Endocrinol Metab 91:105–114
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An author’s reply to this comment is available at: doi:10.1007/s00134-012-2507-2.
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Cohen, J., Pretorius, C. & Venkatesh, B. Dismissal of the utility of free cortisol measurement is premature. Intensive Care Med 38, 718 (2012). https://doi.org/10.1007/s00134-012-2505-4
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DOI: https://doi.org/10.1007/s00134-012-2505-4