Log in | Register

Initial observations regarding free cortisol quantification logistics among critically ill children

Jerry J. Zimmerman| Ruth M. Barker| Rhona Jack
Pediatric Original
Volume 36, Issue 11 / November , 2010

Pages 1914 - 1922

Abstract

Purpose

Corticosteroid insufficiency may occur among critically ill patients, but the diagnosis remains controversial. Historically assessment of free cortisol (FC) by means of equilibrium dialysis (ED) has required large blood volumes and prolonged fractionation time preceding analysis. We hypothesized that temperature-controlled centrifugal ultrafiltration with chemiluminescence immunoassay (CU/CI) would provide real-time FC data that highly correlated with ED/radioimmunoassay (ED/RI) or liquid chromatography/mass spectrometry (LC/MS) techniques.

Methods

We quantified and correlated baseline and corticotropin-stimulated TC and FC by means of CU/CI, ED/RI, and LC/MS among healthy adults and 37 critically ill children.

Results

Among critically ill children, FC was three- to fivefold higher than the healthy adults at baseline and increased another five- to eightfold following corticotropin administration. While TC increased approximately twofold following corticotropin administration, FC increased on average more than eightfold. Serum FC per CU/CI highly correlated with FC per ED/RI or LC/MS, but results were available in a fraction of the time. Children failing to increase TC by >9.0 μg/dL (248 nM) following corticotropin demonstrated an appropriate FC increase. Nearly 50% of critically ill children exhibited FC <2.0 μg/dL (55 nM). Neither FC nor TC concentrations correlated significantly with measures of illness severity.

Conclusions

Quantification of FC utilizing CU/CI was fast (1–2 h) and results correlated highly with ED/RI or LC/MS methodologies. These data require validation with larger cohorts of healthy and critically ill children but indicate that real-time FC quantification is available to guide cortisol replacement therapy.

Keywords

References

  1. Webster JI, Tonelli L, Sternberg EM (2002) Neuroendocrine regulation of immunity. Annu Rev Immunol 20:125–163
    • View reference on publisher's website
    • View reference on PubMed
  2. Chrousos GP (1995) The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation. N Engl J Med 332:1351–1362
    • View reference on publisher's website
    • View reference on PubMed
  3. Bone RC (1996) Sir Isaac Newton, sepsis, SIRS, and CARS. Crit Care Med 24:1125–1128
    • View reference on publisher's website
    • View reference on PubMed
  4. Marik PE, Pastores SM, Annane D, Meduri GU, Sprung CL, Arlt W, Keh D, Briegel J, Beishuizen A, Dimopoulou I, Tsagarakis S, Singer M, Chrousos GP, Zaloga G, Bokhari F, Vogeser M (2008) 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. Crit Care Med 36:1937–1949
    • View reference on publisher's website
    • View reference on PubMed
  5. Annane D (2003) Time for a consensus definition of corticosteroid insufficiency in critically ill patients. Crit Care Med 31:1868–1869
    • View reference on publisher's website
    • View reference on PubMed
  6. Hamrahian AH, Oseni TS, Arafah BM (2004) Measurements of serum free cortisol in critically ill patients. N Engl J Med 350:1629–1638
    • View reference on publisher's website
    • View reference on PubMed
  7. Loriax L (2004) Glucocorticoid therapy in the intensive care unit. N Engl J Med 350:1601–1602
    • View reference on publisher's website
  8. Beishuizen A, Thijs LG, Vermes I (2001) Patterns of corticosteroid-binding globulin and the free cortisol index during septic shock and multitrauma. Intensive Care Med 27:1584–1591
  9. 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
    • View reference on publisher's website
    • View reference on PubMed
  10. Sprung CL, Annane D, Keh D, Moreno R, Singer M, Freivogel K, Weiss YG, Benbenishty J, Kalenka A, Forst H, Laterre PF, Reinhart K, Cuthbertson BH, Payen D, Briegel J (2008) Hydrocortisone therapy for patients with septic shock. N Engl J Med 358:111–124
    • View reference on publisher's website
    • View reference on PubMed
  11. Lentjes EG, Romijn F, Maassen RJ, de Graaf L, Gautier P, Moolenaar AJ (1993) Free cortisol in serum assayed by temperature-controlled ultrafiltration before fluorescence polarization immunoassay. Clin Chem 39:2518–2521
    • View reference on PubMed
  12. Hatherill M, Tibby SM, Hilliard T, Turner C, Murdoch IA (1999) Adrenal insufficiency in septic shock. Arch Dis Child 80:51–55
    • View reference on publisher's website
    • View reference on PubMed
  13. Goldstein B, Giroir B, Randolph A (2005) International Pediatric Sepsis Consensus Conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med 6:2–8
    • View reference on publisher's website
    • View reference on PubMed
  14. Pollack MM, Patel KM, Ruttimann UE (1996) PRISM III: an updated pediatric risk of mortality score. Crit Care Med 24:743–752
    • View reference on publisher's website
    • View reference on PubMed
  15. Leteurtre S, Martinot A, Duhamel A, Gauvin F, Grandbastien B, Nam TV, Proulx F, Lacroix J, Leclerc F (1999) Development of a pediatric multiple organ dysfunction score: use of two strategies. Med Decis Making 19:399–410
    • View reference on publisher's website
    • View reference on PubMed
  16. Leteurtre S, Martinot A, Duhamel A, Proulx F, Grandbastien B, Cotting J, Gottesman R, Joffe A, Pfenninger J, Hubert P, Lacroix J, Leclerc F (2003) Validation of the Paediatric Logistic Organ Dysfunction (PELOD) score: prospective, observational, multicentre study. Lancet 362:192–197
    • View reference on publisher's website
    • View reference on PubMed
  17. Wernovsky G, Wypij D, Jonas RA, Mayer JE Jr, Hanley FL, Hickey PR, Walsh AZ, Chang AC, Castaneda AR, Newburger JW et al (1995) Postoperative course and hemodynamic profile after the arterial switch operation in neonates and infants. A comparison of low-flow cardiopulmonary bypass and circulatory arrest. Circulation 92:2226–2235
    • View reference on PubMed
  18. Skippen PW, Krahn GE (2005) Acute renal failure in children undergoing cardiopulmonary bypass. Crit Care Resusc 7:286–291
    • View reference on PubMed
  19. Bland JM, Altman DG (1999) Measuring agreement in method comparison studies. Stat Methods Med Res 8:135–160
    • View reference on publisher's website
    • View reference on PubMed
  20. Annane D, Maxime V, Ibrahim F, Alvarez JC, Abe E, Boudou P (2006) Diagnosis of adrenal insufficiency in severe sepsis and septic shock. Am J Respir Crit Care Med 174:1319–1326
    • View reference on publisher's website
    • View reference on PubMed
  21. Dellinger RP (2008) Steroid therapy of septic shock: the decision is in the eye of the beholder. Crit Care Med 36:1987–1989
    • View reference on publisher's website
    • View reference on PubMed
  22. Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, Calandra T, Dhainaut JF, Gerlach H, Harvey M, Marini JJ, Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson BT, Townsend S, Vender JS, Zimmerman JL, Vincent JL (2008) Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 36:296–327
    • View reference on publisher's website
    • View reference on PubMed
  23. Waterhouse R (1911) A case of suprarenal apoplexy. Lancet 1:577–578
    • View reference on publisher's website
  24. Geiseler D, Ritter M (1983) On the validity of free hormone measurements. Anal Biochem 132:174–182
    • View reference on publisher's website
    • View reference on PubMed
  25. Waters NJ, Jones R, Williams G, Sohal B (2008) Validation of a rapid equilibrium dialysis approach for the measurement of plasma protein binding. J Pharm Sci 97:4586–4595
    • View reference on publisher's website
    • View reference on PubMed
  26. Janzen N, Sander S, Terhardt M, Peter M, Sander J (2008) Fast and direct quantification of adrenal steroids by tandem mass spectrometry in serum and dried blood spots. J Chromatogr B Analyt Technol Biomed Life Sci 861:117–122
    • View reference on publisher's website
    • View reference on PubMed
  27. Christ-Crain M, Jutla S, Widmer I, Couppis O, Konig C, Pargger H, Puder J, Edwards R, Muller B, Grossman AB (2007) Measurement of serum free cortisol shows discordant responsivity to stress and dynamic evaluation. J Clin Endocrinol Metab 92:1729–1735
    • View reference on publisher's website
    • View reference on PubMed
  28. Vogeser M, Mohnle P, Briegel J (2007) Free serum cortisol: quantification applying equilibrium dialysis or ultrafiltration and an automated immunoassay system. Clin Chem Lab Med 45:521–525
    • View reference on publisher's website
    • View reference on PubMed
  29. Patel RS, Shaw SR, Macintyre H, McGarry GW, Wallace AM (2004) Production of gender-specific morning salivary cortisol reference intervals using internationally accepted procedures. Clin Chem Lab Med 42:1424–1429
    • View reference on publisher's website
    • View reference on PubMed
  30. Dennesen P, van der Ven A, Vlasveld M, Lokker L, Ramsay G, Kessels A, van den Keijbus P, van Nieuw Amerongen A, Veerman E (2003) Inadequate salivary flow and poor oral mucosal status in intubated intensive care unit patients. Crit Care Med 31:781–786
    • View reference on publisher's website
    • View reference on PubMed
  31. Poomthavorn P, Lertbunrian R, Preutthipan A, Sriphrapradang A, Khlairit P, Mahachoklertwattana P (2009) Serum free cortisol index, free cortisol, and total cortisol in critically ill children. Intensive Care Med 35:1281–1285
  32. Rosner W (1991) Plasma steroid-binding proteins. Endocrinol Metab Clin North Am 20:697–720
    • View reference on PubMed
  33. Riche FC, Boutron CM, Valleur P, Berton C, Laisne MJ, Launay JM, Chappuis P, Peynet J, Vicaut E, Payen D, Cholley BP (2007) Adrenal response in patients with septic shock of abdominal origin: relationship to survival. Intensive Care Med 33:1761–1766
  34. Rady MY, Johnson DJ, Patel B, Larson J, Helmers R (2005) Cortisol levels and corticosteroid administration fail to predict mortality in critical illness: the confounding effects of organ dysfunction and sex. Arch Surg 140:661–668; discussion 669
  35. Schroeder S, Wichers M, Klingmuller D, Hofer M, Lehmann LE, von Spiegel T, Hering R, Putensen C, Hoeft A, Stuber F (2001) The hypothalamic-pituitary-adrenal axis of patients with severe sepsis: altered response to corticotropin-releasing hormone. Crit Care Med 29:310–316
    • View reference on publisher's website
    • View reference on PubMed
  36. Soni A, Pepper GM, Wyrwinski PM, Ramirez NE, Simon R, Pina T, Gruenspan H, Vaca CE (1995) Adrenal insufficiency occurring during septic shock: incidence, outcome, and relationship to peripheral cytokine levels. Am J Med 98:266–271
    • View reference on publisher's website
    • View reference on PubMed
  37. Cooper MS, Stewart PM (2003) Corticosteroid insufficiency in acutely ill patients. N Engl J Med 348:727–734
    • View reference on publisher's website
    • View reference on PubMed
  38. Marik PE, Zaloga GP (2003) Adrenal insufficiency during septic shock. Crit Care Med 31:141–145
    • View reference on publisher's website
    • View reference on PubMed
  39. Annane D, Sebille V, Troche G, Raphael JC, Gajdos P, Bellissant E (2000) A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin. JAMA 283:1038–1045
    • View reference on publisher's website
    • View reference on PubMed
  40. Pizarro CF, Troster EJ, Damiani D, Carcillo JA (2005) Absolute and relative adrenal insufficiency in children with septic shock. Crit Care Med 33:855–859
    • View reference on publisher's website
    • View reference on PubMed
  41. Casartelli CH, Garcia PC, Branco RG, Piva JP, Einloft PR, Tasker RC (2007) Adrenal response in children with septic shock. Intensive Care Med 33:1609–1613
  42. van Woensel JB, Biezeveld MH, Alders AM, Eerenberg AJ, Endert E, Hack EC, von Rosenstiel IA, Kuijpers TW (2001) Adrenocorticotropic hormone and cortisol levels in relation to inflammatory response and disease severity in children with meningococcal disease. J Infect Dis 184:1532–1537
    • View reference on publisher's website
    • View reference on PubMed
  43. De Kleijn ED, Joosten KF, Van Rijn B, Westerterp M, De Groot R, Hokken-Koelega AC, Hazelzet JA (2002) Low serum cortisol in combination with high adrenocorticotrophic hormone concentrations are associated with poor outcome in children with severe meningococcal disease. Pediatr Infect Dis J 21:330–336
    • View reference on publisher's website
    • View reference on PubMed
  44. Joosten KF, de Kleijn ED, Westerterp M, de Hoog M, Eijck FC, Hop WCJ, Voort EV, Hazelzet JA, Hokken-Koelega AC (2000) Endocrine and metabolic responses in children with meningoccocal sepsis: striking differences between survivors and nonsurvivors. J Clin Endocrinol Metab 85:3746–3753
    • View reference on publisher's website
    • View reference on PubMed
  45. Riordan FA, Thomson AP, Ratcliffe JM, Sills JA, Diver MJ, Hart CA (1999) Admission cortisol and adrenocorticotrophic hormone levels in children with meningococcal disease: evidence of adrenal insufficiency? Crit Care Med 27:2257–2261
    • View reference on publisher's website
    • View reference on PubMed
  46. Onenli-Mungan N, Yildizdas D, Yapicioglu H, Topaloglu AK, Yuksel B, Ozer G (2004) Growth hormone and insulin-like growth factor 1 levels and their relation to survival in children with bacterial sepsis and septic shock. J Paediatr Child Health 40:221–226
    • View reference on publisher's website
    • View reference on PubMed

Sign In

Connect with ICM

Top 5 Articles Editors Picks Supplement