Free Cortisol and Critically Ill Patients
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《新英格兰医药杂志》
To the Editor: Hamrahian et al. (April 15 issue)1 describe a technique for measuring free cortisol concentrations that is technically difficult, likely to be expensive, and not widely available. They do not correlate the measured serum free cortisol value with the free cortisol index to determine the comparability of the two measurements. They conclude that measuring serum free cortisol concentrations in critically ill patients with hypoproteinemia may help prevent unnecessary glucocorticoid therapy but do not provide any data regarding the use of glucocorticoid therapy in critically ill patients. The appropriate cortisol response to severe sepsis and septic shock is highly variable, and the use of data derived from patients without sepsis is neither appropriate nor meaningful, in our view. Thus, no conclusions about whether glucocorticoid therapy is advantageous can be derived from the data presented. Studies that have focused on hemodynamic stability as well as survival as clinical end points2,3 have shown that glucocorticoid therapy is beneficial in the treatment of critically ill patients with septic shock.
Tehmina Khan, M.D.
Yizhak Kupfer, M.D.
Sidney Tessler, M.D.
Maimonides Medical Center
Brooklyn, NY 11219
stessler@maimonidesmed.org
References
Hamrahian AH, Oseni TS, Arafah BM. Measurements of serum free cortisol in critically ill patients. N Engl J Med 2004;350:1629-1638.
Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002;288:862-871.
Chawla K, Kupfer Y, Goldman I, Tessler S. Hydrocortisone reverses refractory septic shock. Crit Care Med 1999;27:Suppl:A33-A33. abstract.
To the Editor: Hamrahian et al. used a supraphysiologic dose of cosyntropin (250 μg) to test the adrenal response. Lower doses may more accurately reflect adrenal responsiveness, especially in critically ill patients.1,2
In addition, the study included 18 patients with sepsis but apparently none with severe septic shock and multiple-organ dysfunction. This omission is important because the greatest benefits of corticosteroid administration are seen in the latter category of patients.3 Most patients with late-stage septic shock have hypoproteinemia, and it remains to be determined how the current findings will apply in this situation. We submit that, at this moment, in the absence of well-validated and accurate tests for adrenal responsiveness, the clinical response to the administration of corticosteroids (e.g., hemodynamic stabilization and decreased dependence on vasopressor drugs) should be used to determine whether treatment is continued in patients with sepsis.
Kees H. Polderman, M.D.
Vrije Universiteit Medical Center
1007 MB Amsterdam, the Netherlands
k.polderman@tip.nl
Arthur van Zanten, M.D.
Gelderse Vallei Hospital
6710 HN Ede, the Netherlands
Armand R.J. Girbes, M.D.
Vrije Universiteit Medical Center
1007 MB Amsterdam, the Netherlands
References
Grinspoon SK, Biller BM. Laboratory assessment of adrenal insufficiency. J Clin Endocrinol Metab 1994;79:923-931.
Beishuizen A, Thijs LG. Relative adrenal failure in intensive care: an identifiable problem requiring treatment? Best Pract Res Clin Endocrinol Metab 2001;15:513-531.
Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002;288:862-871.
To the Editor: In her Perspective article, Loriaux1 proposes an experiment to validate a new paradigm based on free cortisol for the diagnosis and treatment of relative adrenal insufficiency in persons who are critically ill. We agree that the determination of "appropriate" free cortisol concentrations in this population would be helpful. However, we have reported that the association between impaired adrenal reserve (as assessed by high-dose cosyntropin stimulation testing) and the severity of illness (as determined by the Acute Physiology and Chronic Health Evaluation II score) in patients with septic shock is not particularly robust.2 Similar observations have been made by others.3,4 Although free cortisol concentrations may be directly correlated with the severity of illness, such a correlation remains speculative. In addition, the marked heterogeneity of critically ill patients may hinder the timely establishment of normative concentrations that can be considered definitive. Until additional research clarifies the role of free cortisol in guiding management, "existential" clinical judgment will remain paramount.
(The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense.)
William L. Jackson, Jr., M.D.
Andrew F. Shorr, M.D., M.P.H.
Walter Reed Army Medical Center
Washington, DC 20307
william.jackson1@na.amedd.army.mil
References
Loriaux L. Glucocorticoid therapy in the intensive care unit. N Engl J Med 2004;350:1601-1602.
Jackson WL Jr, Shorr AF. Impaired adrenal reserve correlates weakly with severity of illness scoring in patients with septic shock. Am J Respir Crit Care Med 2004;169:A636-A636. abstract.
Rothwell RM, Udwadia ZF, Lawler PG. Cortisol response to corticotropin and survival in septic shock. Lancet 1991;337:582-583.
Soni A, Pepper GM, Wyrwinski PM, et al. Adrenal insufficiency occurring during septic shock: incidence, outcome, and relationship to peripheral cytokine levels. Am J Med 1995;98:266-271.
To the Editor: Hamrahian et al. report on the limitations of the measurement of serum total cortisol in critically ill patients. We have previously used equilibrium-dialysis isotope-dilution liquid chromatography–tandem mass spectrometry to investigate free serum cortisol concentrations in critically ill patients after cardiac surgery.1 The data, which are in good agreement with those of Hamrahian et al., indicate that the serum total cortisol concentration approximately doubles and that the serum free cortisol concentration increases by a factor of approximately seven under conditions of maximal adrenal stimulation and hypoproteinemia, when compared with the values in normal volunteers. From these data, the development of routine assays for the direct measurement of serum free cortisol — corresponding to the measurement of free thyroid hormones — is clearly warranted. Currently, the technique of ultrafiltration with the use of a thermostat-equipped benchtop centrifuge and commercially available filtration devices is an alternative approach that permits routine quantification of free cortisol in the laboratory.2
Michael Vogeser, M.D.
Josef Briegel, M.D.
Hospital of the University of Munich, Germany
D-81377 Munich, Germany
michael.vogeser@med.uni-muenchen.de
References
Vogeser M, Groetzner J, Küpper C, Briegel J. Free serum cortisol during the postoperative acute phase response determined by equilibrium dialysis liquid chromatography-tandem mass spectrometry. Clin Chem Lab Med 2003;41:146-151.
Lentjes EG, Romijn F, Maassen RJ, de Graaf L, Gautier P, Moolenaar AJ. Free cortisol in serum assayed by temperature-controlled ultrafiltration before fluorescence polarization immunoassay. Clin Chem 1993;39:2518-2521.
Dr. Arafah replies: In response to the issues raised by Dr. Khan and colleagues: The assay used to determine serum free cortisol concentrations is technically demanding yet available at many reference laboratories. Previous experience with free thyroxine measurements suggests that increasing interest in the measurement of free cortisol would probably lead to the development of faster and less costly assays. As my colleagues and I state in our article, the free cortisol index represents a calculated value that accounts for a low concentration of corticosteroid-binding globulin but not a low concentration of albumin. The limitations of the free cortisol index are evident from our observation that the values in patients with hypoalbuminemia were lower than those in patients with near-normal serum albumin concentrations (P<0.01). Other investigators have recently expressed similar concerns.1 Not surprisingly, however, the measured serum free cortisol concentration correlated with the calculated free cortisol index (r=0.55 and r=0.68 in patients with serum albumin concentrations of 2.5 g per deciliter or lower and those with concentrations above 2.5 g per deciliter, respectively). We examined neither the need for, nor the advantages of, glucocorticoids in critical illness; therefore, we made no additional recommendations. Instead, our study addressed serious limitations of tests used routinely to assess adrenal function in critically ill patients.
Dr. Polderman and colleagues raise a frequently cited limitation of the standard-dose cosyntropin test. Although the low-dose (1-μg) cosyntropin test provides improved sensitivity and specificity, recent data show that it is still imperfect.2 Although use of the low dose has advantages over use of the standard dose test in ambulatory patients, this point has not been adequately investigated in critically ill patients in whom adrenal function is already highly stimulated, as indicated by baseline serum free cortisol concentrations that are at least double the cosyntropin-stimulated concentrations in healthy volunteers. Considering the extensive published experience with the standard cosyntropin test, particularly during critical illness, and acknowledging its known limitations, we elected to use this test in our study.
We agree with Dr. Polderman and colleagues and Drs. Jackson and Shorr that clinical judgment should always be exercised in making decisions about the use of glucocorticoid therapy during critical illness. We also agree with Drs. Jackson and Shorr that the severity of illness might not be the sole determinant of the adrenal response to critical illness. A large prospective study would be necessary to address that question.
Finally, we appreciate the comments of Drs. Vogeser and Briegel and regret that we did not refer to their study, which appeared after our article was submitted for publication. Newer assay methods such as the one they suggest should provide reliable data in a timely manner.
Baha M. Arafah, M.D.
Case Western Reserve University
Cleveland, OH 44106
bxa@po.cwru.edu
References
Vogeser M, Groetzner J, Küpper C, Briegel J. Free serum cortisol during the postoperative acute phase response determined by equilibrium dialysis liquid chromatography-tandem mass spectrometry. Clin Chem Lab Med 2003;41:146-151.
Nasrallah MP, Arafah BM. The value of dehydroepiandrosterone sulfate measurements in the assessment of adrenal function. J Clin Endocrinol Metab 2003;88:5293-5298.
Dr. Loriaux replies: I agree completely with the comments of Drs. Jackson and Shorr on diagnosing adrenal insufficiency in critically ill patients. Additional study is needed to clarify the clinical usefulness of the plasma "free cortisol" concentration in these patients. That was my thesis.
Lynn Loriaux, M.D.
Oregon Health and Science University
Portland, OR 97239
Tehmina Khan, M.D.
Yizhak Kupfer, M.D.
Sidney Tessler, M.D.
Maimonides Medical Center
Brooklyn, NY 11219
stessler@maimonidesmed.org
References
Hamrahian AH, Oseni TS, Arafah BM. Measurements of serum free cortisol in critically ill patients. N Engl J Med 2004;350:1629-1638.
Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002;288:862-871.
Chawla K, Kupfer Y, Goldman I, Tessler S. Hydrocortisone reverses refractory septic shock. Crit Care Med 1999;27:Suppl:A33-A33. abstract.
To the Editor: Hamrahian et al. used a supraphysiologic dose of cosyntropin (250 μg) to test the adrenal response. Lower doses may more accurately reflect adrenal responsiveness, especially in critically ill patients.1,2
In addition, the study included 18 patients with sepsis but apparently none with severe septic shock and multiple-organ dysfunction. This omission is important because the greatest benefits of corticosteroid administration are seen in the latter category of patients.3 Most patients with late-stage septic shock have hypoproteinemia, and it remains to be determined how the current findings will apply in this situation. We submit that, at this moment, in the absence of well-validated and accurate tests for adrenal responsiveness, the clinical response to the administration of corticosteroids (e.g., hemodynamic stabilization and decreased dependence on vasopressor drugs) should be used to determine whether treatment is continued in patients with sepsis.
Kees H. Polderman, M.D.
Vrije Universiteit Medical Center
1007 MB Amsterdam, the Netherlands
k.polderman@tip.nl
Arthur van Zanten, M.D.
Gelderse Vallei Hospital
6710 HN Ede, the Netherlands
Armand R.J. Girbes, M.D.
Vrije Universiteit Medical Center
1007 MB Amsterdam, the Netherlands
References
Grinspoon SK, Biller BM. Laboratory assessment of adrenal insufficiency. J Clin Endocrinol Metab 1994;79:923-931.
Beishuizen A, Thijs LG. Relative adrenal failure in intensive care: an identifiable problem requiring treatment? Best Pract Res Clin Endocrinol Metab 2001;15:513-531.
Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002;288:862-871.
To the Editor: In her Perspective article, Loriaux1 proposes an experiment to validate a new paradigm based on free cortisol for the diagnosis and treatment of relative adrenal insufficiency in persons who are critically ill. We agree that the determination of "appropriate" free cortisol concentrations in this population would be helpful. However, we have reported that the association between impaired adrenal reserve (as assessed by high-dose cosyntropin stimulation testing) and the severity of illness (as determined by the Acute Physiology and Chronic Health Evaluation II score) in patients with septic shock is not particularly robust.2 Similar observations have been made by others.3,4 Although free cortisol concentrations may be directly correlated with the severity of illness, such a correlation remains speculative. In addition, the marked heterogeneity of critically ill patients may hinder the timely establishment of normative concentrations that can be considered definitive. Until additional research clarifies the role of free cortisol in guiding management, "existential" clinical judgment will remain paramount.
(The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense.)
William L. Jackson, Jr., M.D.
Andrew F. Shorr, M.D., M.P.H.
Walter Reed Army Medical Center
Washington, DC 20307
william.jackson1@na.amedd.army.mil
References
Loriaux L. Glucocorticoid therapy in the intensive care unit. N Engl J Med 2004;350:1601-1602.
Jackson WL Jr, Shorr AF. Impaired adrenal reserve correlates weakly with severity of illness scoring in patients with septic shock. Am J Respir Crit Care Med 2004;169:A636-A636. abstract.
Rothwell RM, Udwadia ZF, Lawler PG. Cortisol response to corticotropin and survival in septic shock. Lancet 1991;337:582-583.
Soni A, Pepper GM, Wyrwinski PM, et al. Adrenal insufficiency occurring during septic shock: incidence, outcome, and relationship to peripheral cytokine levels. Am J Med 1995;98:266-271.
To the Editor: Hamrahian et al. report on the limitations of the measurement of serum total cortisol in critically ill patients. We have previously used equilibrium-dialysis isotope-dilution liquid chromatography–tandem mass spectrometry to investigate free serum cortisol concentrations in critically ill patients after cardiac surgery.1 The data, which are in good agreement with those of Hamrahian et al., indicate that the serum total cortisol concentration approximately doubles and that the serum free cortisol concentration increases by a factor of approximately seven under conditions of maximal adrenal stimulation and hypoproteinemia, when compared with the values in normal volunteers. From these data, the development of routine assays for the direct measurement of serum free cortisol — corresponding to the measurement of free thyroid hormones — is clearly warranted. Currently, the technique of ultrafiltration with the use of a thermostat-equipped benchtop centrifuge and commercially available filtration devices is an alternative approach that permits routine quantification of free cortisol in the laboratory.2
Michael Vogeser, M.D.
Josef Briegel, M.D.
Hospital of the University of Munich, Germany
D-81377 Munich, Germany
michael.vogeser@med.uni-muenchen.de
References
Vogeser M, Groetzner J, Küpper C, Briegel J. Free serum cortisol during the postoperative acute phase response determined by equilibrium dialysis liquid chromatography-tandem mass spectrometry. Clin Chem Lab Med 2003;41:146-151.
Lentjes EG, Romijn F, Maassen RJ, de Graaf L, Gautier P, Moolenaar AJ. Free cortisol in serum assayed by temperature-controlled ultrafiltration before fluorescence polarization immunoassay. Clin Chem 1993;39:2518-2521.
Dr. Arafah replies: In response to the issues raised by Dr. Khan and colleagues: The assay used to determine serum free cortisol concentrations is technically demanding yet available at many reference laboratories. Previous experience with free thyroxine measurements suggests that increasing interest in the measurement of free cortisol would probably lead to the development of faster and less costly assays. As my colleagues and I state in our article, the free cortisol index represents a calculated value that accounts for a low concentration of corticosteroid-binding globulin but not a low concentration of albumin. The limitations of the free cortisol index are evident from our observation that the values in patients with hypoalbuminemia were lower than those in patients with near-normal serum albumin concentrations (P<0.01). Other investigators have recently expressed similar concerns.1 Not surprisingly, however, the measured serum free cortisol concentration correlated with the calculated free cortisol index (r=0.55 and r=0.68 in patients with serum albumin concentrations of 2.5 g per deciliter or lower and those with concentrations above 2.5 g per deciliter, respectively). We examined neither the need for, nor the advantages of, glucocorticoids in critical illness; therefore, we made no additional recommendations. Instead, our study addressed serious limitations of tests used routinely to assess adrenal function in critically ill patients.
Dr. Polderman and colleagues raise a frequently cited limitation of the standard-dose cosyntropin test. Although the low-dose (1-μg) cosyntropin test provides improved sensitivity and specificity, recent data show that it is still imperfect.2 Although use of the low dose has advantages over use of the standard dose test in ambulatory patients, this point has not been adequately investigated in critically ill patients in whom adrenal function is already highly stimulated, as indicated by baseline serum free cortisol concentrations that are at least double the cosyntropin-stimulated concentrations in healthy volunteers. Considering the extensive published experience with the standard cosyntropin test, particularly during critical illness, and acknowledging its known limitations, we elected to use this test in our study.
We agree with Dr. Polderman and colleagues and Drs. Jackson and Shorr that clinical judgment should always be exercised in making decisions about the use of glucocorticoid therapy during critical illness. We also agree with Drs. Jackson and Shorr that the severity of illness might not be the sole determinant of the adrenal response to critical illness. A large prospective study would be necessary to address that question.
Finally, we appreciate the comments of Drs. Vogeser and Briegel and regret that we did not refer to their study, which appeared after our article was submitted for publication. Newer assay methods such as the one they suggest should provide reliable data in a timely manner.
Baha M. Arafah, M.D.
Case Western Reserve University
Cleveland, OH 44106
bxa@po.cwru.edu
References
Vogeser M, Groetzner J, Küpper C, Briegel J. Free serum cortisol during the postoperative acute phase response determined by equilibrium dialysis liquid chromatography-tandem mass spectrometry. Clin Chem Lab Med 2003;41:146-151.
Nasrallah MP, Arafah BM. The value of dehydroepiandrosterone sulfate measurements in the assessment of adrenal function. J Clin Endocrinol Metab 2003;88:5293-5298.
Dr. Loriaux replies: I agree completely with the comments of Drs. Jackson and Shorr on diagnosing adrenal insufficiency in critically ill patients. Additional study is needed to clarify the clinical usefulness of the plasma "free cortisol" concentration in these patients. That was my thesis.
Lynn Loriaux, M.D.
Oregon Health and Science University
Portland, OR 97239