Cortisol metabolism in critical illness: implications for clinical care.

REVIEW URRENT C OPINION

Cortisol metabolism in critical illness: implications for clinical care Eva Boonen and Greet Van den Berghe

Purpose of review Critical illness is uniformly characterized by elevated plasma cortisol concentrations, traditionally attributed exclusively to increased cortisol production driven by an activated hypothalamic pituitary adrenal axis. However, as plasma adrenocorticotropic hormone (ACTH) concentrations are often not elevated or even low during critical illness, alternative mechanisms must contribute. Recent findings Recent investigations revealed that plasma clearance of cortisol is markedly reduced during critical illness, explained by suppressed expression and activity of the main cortisol metabolizing enzymes in liver and kidney. Furthermore, unlike previously inferred, cortisol production rate in critically ill patients was only moderately increased to less than double that of matched healthy subjects. In the face of low-plasma ACTH concentrations, these data suggest that other factors drive hypercortisolism during critical illness, which may suppress ACTH by feedback inhibition. These new insights add to the limitations of the current diagnostic tools to identify patients at risk of failing adrenal function during critical illness. They also urge to investigate the impact of lower hydrocortisone doses than those hitherto used. Summary Recent novel insights reshape the current understanding of the hormonal stress response to critical illness and further underline the need for more studies to unravel the pathophysiology of adrenal (dys)functioning during critical illness. Keywords cortisol, critical illness, hypothalamic-pituitary-adrenal axis

INTRODUCTION Critical illness is a life-threatening condition that triggers several, presumably protective, stress responses to increase the odds of survival. As part of this stress response, elevated plasma concentrations of the stress hormone cortisol hallmarks critical illness, thought to be evoked primarily by the stress-induced activation of the hypothalamicpituitary-adrenal (HPA) axis. Indeed, when the brain senses a stressful event, neuronal networks signal the hypothalamus to release corticotropin releasing hormone (CRH), which stimulates the anterior pituitary gland to release ACTH, in turn activating the adrenal cortex to synthesize and secrete more cortisol into the circulation, which brings about several vital endocrine and metabolic effects in organs and tissues. An intact HPA axis is indispensable to survive critical illness. This was evidenced by animal experiments showing that mortality of, for example, sepsis is much higher after adrenalectomy [1]. The more severe the critical

illness in human patients, and thus the higher the risk of death, the higher plasma cortisol concentrations appear to be, although also inappropriately low-plasma cortisol has been linked to increased mortality [2]. The latter has been explained by an insufficiently activated HPA axis that fails to cover the needs for cortisol to survive. As plasma cortisol in this condition is still higher than during health, it has been labeled ‘relative adrenal insufficiency’ [3], or more recently, ‘critical illness-related corticosteroid insufficiency’ (CIRCI) [4]. Both terms comprise the inability to raise adrenal steroid Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium Correspondence to Greet Van den Berghe, MD, PhD, Clinical Division and Laboratory of Intensive Care Medicine, KU Leuven, Herestraat 49, B3000 Leuven, Belgium. Tel: +32 16 34 40 21; fax: +32 16 34 40 15; e-mail: [email protected] Curr Opin Endocrinol Diabetes Obes 2014, 21:185–192 DOI:10.1097/MED.0000000000000066

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Adrenal cortex and medulla

KEY POINTS Cortisol production during critical illness is only moderately increased during critical illness. It is less than doubled and non-ACTH driven in patients suffering from the systemic inflammatory response syndrome, and unaltered in patients without systemic inflammatory response syndrome, in the face of several-fold higher plasma cortisol in all patients. Cortisol plasma clearance is substantially reduced during critical illness and contributes substantially to hypercortisolism during critical illness, irrespective of type and severity of illness and of the inflammation status. Suppressed plasma cortisol clearance and only slightly increased or unaltered cortisol production rates during critical illness complicate the diagnosis of adrenal failure during critical illness and may impose a dose adaptation when treatment with hydrocortisone is being considered.

observed that plasma ACTH concentrations in patients suffering from severe trauma or sepsis were only transiently elevated when compared to healthy control values and that after a few days ACTH dropped to values below the healthy lower limits of normality. Recently, we investigated plasma ACTH and cortisol concentrations during the first week of ICU stay in a heterogeneous critically ill patient population as compared with matched healthy controls. In this study, and in the face of elevated plasma cortisol, morning plasma ACTH concentrations were found to be uniformly suppressed from ICU admission onward, and stayed below the lower limit of normality throughout the first week of critical illness [12 ]. Whether the expected initial ACTH rise in response to stress was missed in this study, and had occurred prior to ICU admission, for example, in the operating room or emergency department, remains uncertain. Moreover, low-plasma ACTH concentrations in response to sustained sepsis-induced critical illness were also recently observed in a mouse model [13 ]. The study showed that after an initial rise in ACTH, circulating levels fell below baseline values within 48 h after onset of illness. This study attributed the low-plasma ACTH to low hypothalamic orexin activity in the prolonged phase of critical illness. Also, in our recent clinical study that reported uniformly low-plasma ACTH concentrations from ICU admission onward, we also quantified for the first time cortisol production rate with use of a stateof-the-art deuterated cortisol-tracer technique in critically ill patients as compared with matched healthy subjects [12 ]. Surprisingly, cortisol production rate was only moderately increased in patients and less than double the rates quantified in healthy controls [12 ]. In fact, cortisol production was only elevated in patients suffering from a systemic inflammatory response syndrome (SIRS) [14], possibly an effect of cytokines, whereas cortisol production in other critically ill patients was indistinguishable from healthy control subjects, despite total plasma cortisol as high as in SIRS patients (Fig. 1a) &

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production up to the level required to match the level of stress. Such relative failure could be due to a malfunctioning at any level of the HPA axis and/or to resistance of the peripheral tissues to cortisol during critical illness [4,5]. Although the concept of CIRCI is widely accepted, it remains highly debated whether or not it should be treated with exogenous glucocorticoids and if so, with which doses. Indeed, randomized controlled studies generated conflicting results [6,7]. As the exact underlying mechanisms of this relative failure of the HPA axis during critical illness remain unknown, also the diagnostic criteria are highly debated [8–10], this further complicates the correct identification of patients who might benefit from treatment and thus should be included in intervention trials.

HPA-AXIS ACTIVATION DRIVING HYPERCORTISOLISM DURING CRITICAL ILLNESS? From the classical concept of the HPA stress response, it is generally inferred that the elevated plasma cortisol concentrations during critical illness are primarily, if not exclusively, brought about by a several-fold increased adrenocortical production of cortisol, driven by elevated ACTH and CRH release. However, published data on plasma ACTH concentrations in critically ill patients are very scarce. This lack of data is likely explained by the essential requirements for correctly assaying plasma ACTH: blood samples should be placed on ice and spun cold prior to assay or freezing plasma for later assay. Already in 1995, however, Vermes et al. [11] 186


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REGULATED CORTISOL METABOLISM DURING CRITICAL ILLNESS The combination of low-plasma ACTH with high-plasma cortisol concentrations suggests that non-ACTH-dependent mechanisms play a role in maintaining hypercortisolemia during critical illness. Possible candidates are corticomedullary interactions, the neural input, the immune system, the vascular supply, growth factors and the intraglandular renin–angiotensin and CRH-ACTH Volume 21 Number 3 June 2014


Cortisol metabolism in critical illness Boonen and Van den Berghe

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FIGURE 1. Cortisol clearance and production during critical illness. (a) Cortisol production in critically ill patients with the systemic inflammatory response syndrome (dark gray bar) and no systemic inflammatory response syndrome (light gray bar) compared to controls (white bar). Based on these results, 24 h cortisol production was estimated and depicted with the arrows. Bar charts represent means and standard errors. (b) Cortisol plasma clearance in critically ill patients with the systemic inflammatory response syndrome (SIRS) (dark gray bar) and no systemic inflammatory response syndrome (light gray bar) compared to controls (white bar) as assessed with a small dose of deuterated-cortisol tracer. Bar charts represent means and standard errors. (c) The means and standard errors of the plasma cortisol concentration time course after injection of 100 mg hydrocortisone in patients (dark gray lines) and controls (black lines). (d) The calculated half-life determined in patients and controls; bar charts represent means and whiskers represent standard errors. For conversion of cortisol to SI units (nmol/l) multiply by 27.6. Reprinted with permission from [12 ]. &

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systems [15,16 ,17 ]. However, the finding that cortisol production rates during critical illness were only moderately increased, if at all, raised the possibility of another explanation. Indeed, hypercortisolemia in the presence of low-plasma ACTH could be evoked by reduced cortisol removal, which could suppress ACTH release via negative feedback inhibition. With use of stable isotopes, cortisol clearance was indeed found to be substantially suppressed in critically ill patients, irrespective of the inflammation status, type, severity and duration of critical illness (Fig. 1b) [12 ]. The principal route of cortisol breakdown in humans is via the A-ring reductases, 5a-reductase and 5b-reductase, in liver and adipose tissue (Fig. 2). Furthermore, cortisol can be inactivated to cortisone by 11b-hydroxysteroid dehydrogenase (11b-HSD) type 2 mainly in kidney and cortisol can be regenerated from cortisone via 11b-HSD 1 in liver and adipose tissue [18–20]. In critically ill patients, &

the expression and activity of the A-ring reductases in liver and the activity of 11b-HSD2 were found to be substantially reduced, while no relevant changes occurred in adipose tissue (Fig. 3a–d) [12 ]. The suppression of these enzymes rather than the plasma concentrations of ACTH explained the elevated plasma cortisol. It remains unclear, however, what is driving the downregulation of these cortisol metabolizing enzymes in liver and kidney during critical illness. Bile acids, both conjugated and unconjugated, are potent inhibitors of the cortisol metabolizing enzymes, via competitive inhibition at low-physiological concentrations and by suppression of gene and protein expression at elevated concentrations [21–23]. Circulating levels of predominantly conjugated bile acids recently were shown to be substantially increased during critical illness [24]. These elevated bile acid levels appeared brought about by ongoing bile acid synthesis, despite suppression of


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FIGURE 2. Schematic presentation of the major routes of cortisol metabolism. The principal route of cortisol clearance is via 5a-reductase in liver and adipose tissue and via 5b-reductase in liver. Furthermore, cortisol can be inactivated to cortisone mainly in kidney via 11b-hydroxysteroid dehydrogenase type-2 (11b-HSD2) and cortisol can be regenerated from cortisone via 11b-hydroxysteroid dehydrogenase type-1 (11b-HSD1) in liver and adipose tissue.

the nuclear receptors that function as sensors, which are subsequently conjugated within the hepatocyte and exported back toward the blood rather than to the bile. This phenomenon may be adaptive and beneficial as it could reduce energy expenditure by not exporting bile acids against a steep concentration gradient into the bile [24]. Furthermore, bile acids also have an immunomodulatory effect, as shown in septic mice, possibly mediated by their effect on hepatic glucocorticoid receptor expression

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[25 ]. As an inverse correlation was observed between the elevated plasma concentrations of bile acids in patients and the gene and protein expression levels of the A-ring reductases in liver (Fig. 3e–g), a role for bile acids in regulating cortisol metabolism during critical illness seems likely [12 ,24]. Intervention studies are obviously needed to further support causality. The concept of reduced cortisol metabolism as a vital part of the stress response to critical illness &

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FIGURE 3. Enzyme expression and activity in relation to circulating bile acids. (a) and (b) 5b-reductase mRNA and protein expression in patients and healthy controls. Bar charts represent means and standard errors. The mRNA data are expressed, normalized to GAPDH, as a fold difference from the mean of the controls. Protein data are expressed normalized for CK-18 protein expression, as a fold difference from the mean of the controls. (c) and (d) 5b-reductase enzyme activity estimated for patients and controls based on urinary metabolites quantified using GC-MS. Bar charts represent means and standard errors. (e)–(g) The relation of 5b-reductase protein expression and estimated enzyme activity with plasma total bile acid concentrations after logarithmic transformation. The shaded area represents 95% confidence interval. Reprinted with permission from [12 ]. &

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could be interpreted as an attempt of the human body to save energy when energy supply is low. Such adaptation of reduced cortisol breakdown in response to sustained stress and low energy availability is not only observed in critical illness but was also described in patients with anorexia nervosa, post-traumatic stress disorders and depression, suggesting that it could be a quite fundamental part of the prolonged stress response [26–28]. Also, elevating cortisol via the suppression of metabolizing enzymes predominantly in liver and kidney, which need cortisol effects for an optimal fight or flight response, could limit the exposure of immune cells and vulnerable target tissues such as skeletal muscle or brain to deleterious side-effects of excessive cortisol. Regulating effects of cortisol locally also seem to occur at the level of glucocorticoid receptor expression. Previous work indeed showed suppressed glucocorticoid receptor expression in white blood cells of critically ill children, which could be a way to allow the innate immune response to effectively protect the host against infections in the presence of elevated circulating cortisol levels [29 ,30]. Increasing evidence from animal studies shows that the regulation of the glucocorticoid receptor in other tissues is also important during critical illness [25 ,31 ]. The new insight that elevated plasma cortisol is maintained by reducing cortisol metabolism could theoretically explain the low-plasma ACTH concentrations via negative feedback inhibition at the level of the pituitary gland and/or hypothalamus. This should be further investigated by quantifying the relationship between ACTH and cortisol pulsatile secretion profiles and in animal studies by quantifying ACTH and CRH at tissue level. Studies should also focus on the consequences for the adrenal gland of low-plasma ACTH through the prolonged phase of critical illness. Indeed, ACTH exerts important trophic effects on the adrenal cortex, and depletion of ACTH, such as in pro-opiomelanocortin-deficient mice, could cause adrenal atrophy [32]. Such an effect could explain the 20-fold higher incidence of symptomatic adrenal insufficiency described in critically ill patients being treated in surgical intensive care for more than 14 days [33]. &

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DIAGNOSTIC IMPLICATIONS Suggested diagnostic criteria for CIRCI in critically ill patients were based on a landmark study by Annane et al. [34] who identified a plasma cortisol incremental response of less than 9 mg/dl after injection of 250 mg ACTH as most discriminative for increased risk of death. However, the American College of Intensive Care Medicine, in its recent

guidelines no longer recommends the use of the ACTH stimulation test for the diagnosis of CIRCI [35 ]. Furthermore, we recently showed that cortisol responses to ACTH stimulation in critically ill patients correlated positively with both cortisol production rate and cortisol plasma clearance [12 ]. Also, we found that patients who reveal a low response to ACTH, to the extent of absolute adrenal failure [36], were the ones with the most suppressed cortisol breakdown, whereas their cortisol production was still similar to that of healthy subjects [12 ]. These findings suggest that a low cortisol response to an ACTH injection may simply reflect the degree of negative feedback inhibition exerted by the cortisol that is not broken down. This condition resembles that of patients treated with exogenous glucocorticoids for an extended time, who also reveal a suppressed response to ACTH injection [37]. Whether or not such low response in the presence of elevated plasma cortisol during critical illness indicates that cortisol availability would be insufficient to cope with the stress of illness remains unclear. Alternatively, a random total cortisol of less than 10 mg/dl during critical illness has been suggested for the diagnosis of CIRCI [4]. However, total plasma cortisol concentration is the net result of adrenal production and secretion, distribution, binding and elimination of cortisol. Also, cortisol is secreted in a pulsatile manner [38 ]. It thus seems unlikely that one could judge the adequacy of the adrenal cortisol production in response to critical illness merely by a single measurement of total plasma cortisol. Furthermore, total plasma cortisol concentrations do not reflect glucocorticoid signaling. First, only free cortisol can pass the cell membrane to exert its function by binding to the glucocorticoid receptor. Critical illness acutely suppresses circulating levels of the binding proteins, cortisol binding globulin (CBG) and albumin, and also alters CBG binding affinity via increased cleavage from CBG at inflammatory loci or by increased temperature [10,39,40 ,41,42]. Hence, plasma free cortisol may be more appropriate than total cortisol to assess HPA-axis function. However, plasma-free cortisol assays are currently not readily available, and normal ranges for plasma-free cortisol during critical illness have not been defined. Additionally, increasing evidence from both animal and human experiments suggests that glucocorticoid receptor availability in different tissues, glucocorticoid receptor affinity and translocation are regulated during critical illness [29 ,30,43 ,44 ,45,46]. In septic patients, for example, the dominant negative bisoform of the glucocorticoid receptor was induced


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from admission, which downregulates glucocorticoid action [44 ]. Although these changes could be adaptive or maladaptive, they preclude conclusions about adequacy of cortisol availability and function during illness. Finally, assays that are commonly used to quantify plasma cortisol concentrations are often inaccurate and vary substantially [9] indicating that it is virtually impossible to define CIRCI based on one cut-off value in clinical practice without better standardizing the methodology. It may be necessary to use mass spectrometry for this purpose [47,48]. Recently, it was suggested that measuring interstitial cortisol levels could be interesting to assess the amount of active tissue cortisol levels in critically ill patients [49 ,50]. For this purpose, a microdialysis catheter is inserted into the subcutaneous adipose tissue. However, edema is frequently present and regional blood flow varies in critically ill patients [51]. Furthermore, the subcutaneous adipose tissue is not the main target tissue for cortisol nor is it the organ that regulates cortisol metabolism during critical illness [12 ]. Hence, the benefit of this invasive technique could be questioned. &

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IMPLICATIONS FOR TREATMENT When critically ill patients are assumed to suffer from CIRCI, such as patients with septic shock who are resistant to vasopressor therapy and fluid resuscitation, current guidelines propose treatment with hydrocortisone [35 ]. It is recommended to infuse 200 mg hydrocortisone per day preferably continuously to avoid fluctuations in blood glucose and sodium [35 ]. However, this dose regimen is based on the assumption that activation of the HPA axis brings about a several-fold increased cortisol production during critical illness. This assumption has now been proven incorrect [12 ]. Hence, the proposed dose of 200 mg hydrocortisone per day, although referred to as low dose, is in fact at least six times higher than the normal daily cortisol production in healthy humans (25–30 mg/day) [52]. Cortisol production in critical illness was recently shown to be only 1.8-fold higher than in healthy matched control subjects. Hence, it is not surprising that treating patients presumably suffering from relative adrenal failure with doses of 200 mg hydrocortisone per day results in severalfold higher plasma cortisol concentrations than endogenous levels in patients who have an adequate HPA-axis response [53]. In addition, the reduced cortisol breakdown should be taken into account when treatment is being considered. Plasma half-life of a bolus of 100 mg hydrocortisone was documented to be at least five-fold longer in critically &&

ill patients than in healthy control subjects (Fig. 1c,d) [12 ], and thus hydrocortisone doses of 200 mg/day will likely result in accumulation during critical illness. Excessive glucocorticoid levels could inferentially aggravate lean tissue wasting, increase the risk of myopathy and prolong ICU dependence, which could expose to potentially lethal complications [54,55]. Moreover, as glucocorticoid sensitivity could vary among individuals [56] and cell types [30,44 ,45] and glucocorticoid treatment may downregulate glucocorticoid receptor-a via induction of miR-124 limiting its anti-inflammatory effects, the dosing issue is further complicated [57 ]. Also, single nucleotide polymorphisms in the glucocorticoid receptor gene, with an enhanced or decreased response to glucocorticoids, have been identified [58 ,59 ]. It thus currently remains a challenge to identify specific clinical biomarkers of glucocorticoid receptor activation to guide optimal glucocorticoid therapy for individual patients and illnesses. The novel insights regarding altered cortisol metabolism and receptor expression during critical illness may help understand why the results from randomized controlled studies, assessing the effect of hydrocortisone treatment, were controversial. Indeed, the benefit of such treatment, originally observed in the pioneer trial, could not be confirmed [6,7]. Ongoing studies, such as the adjunctive corticosteroid treatment in critically ill patients with septic shock (ADRENAL) trial, still investigate the impact of 200 mg/day of hydrocortisone, which may be too high in the light of the suppressed cortisol metabolism [60]. &

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RECOMMENDATIONS It currently remains unclear how to best assess the adequacy of the HPA responses during critical illness, how to identify patients who may benefit from glucocorticoid treatment and which doses should be used to investigate the impact of such treatment. More research is needed to answer these key questions that are crucial for clinical practice. It does not seem appropriate to use a single cutoff value for total plasma cortisol concentration or the cortisol response to ACTH to diagnose CIRCI during critical illness. Repeated measurements may be useful, but this should be investigated further. Because cortisol production is only moderately increased and cortisol breakdown substantially reduced during critical illness, the effect of hydrocortisone, in doses that are lower than the ones hitherto used in clinical trials, should be investigated in the future. The stable isotope studies suggested that a dose of 60 mg of hydrocortisone, Volume 21 Number 3 June 2014



equivalent to about a doubling of the normal daily cortisol production, may be interesting to further investigate when patients at risk can be identified. A tapering down to the lowest effective dose as soon as possible should limit the adverse effects of excessive amounts of glucocorticoids during critical illness.

CONCLUSION The recent observation that cortisol metabolism is substantially reduced during critical illness represents a paradigm shift in the understanding of the HPA stress response. This novel insight further complicates the diagnosis and treatment of adrenal insufficiency during critical illness. High quality clinical studies are required to address the remaining questions. Acknowledgements The work summarized in this review has been supported by research grants from the Fund for Scientific Research Flanders Belgium (FWO G.0417.12), by the Methusalem Program funded by the Flemish Government (ME08/07), and by the European Research Council under the European Union’s Seventh Framework Program (FP7/2007-2013 ERC Advanced Grant Agreement no. 307523). Conflicts of interest There are no conflicts of interest.

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Reduced glucocorticoid receptor & protein expression in children with critical illness. Horm Res Paediatr 2013; 79:169–178. In this study, the authors investigate total, cytoplasmatic and nuclear protein expression of the glucocorticoid receptor in blood cells of critically ill children. Furthermore, they show a lack of correlation between glucocorticoid receptorexpression levels and circulating (total and free) cortisol levels, which further emphasizes the lack of appropriate diagnostic tools to assess adequate glucocorticoid functioning. 30. van den Akker EL, Koper JW, Joosten K, et al. Glucocorticoid receptor mRNA levels are selectively decreased in neutrophils of children with sepsis. Intensive Care Med 2009; 35:1247–1254.



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Adrenal cortex and medulla 31. Goodwin JE, Feng Y, Velazquez H, Sessa WC. Endothelial glucocorticoid receptor is required for protection against sepsis. Proc Natl Acad Sci U S A 2013; 110:306–311. The authors further support the reasoning that tissue-specific regulation of the glucocorticoid receptor is important in critical illness. In this study, they investigated the role of the endothelial glucocorticoid receptor in sepsis in mice and showed that endothelial glucocorticoid receptor is a critical regulator of nuclear factor (NF)-kB activation and nitric oxide synthesis in sepsis. 32. Coll AP, Challis BG, Yeo GS, et al. The effects of proopiomelanocortin deficiency on murine adrenal development and responsiveness to adrenocorticotropin. Endocrinology 2004; 145:4721–4727. 33. Barquist E, Kirton O. Adrenal insufficiency in the surgical intensive care unit patient. J Trauma 1997; 42:27–31. 34. Annane D, Sebille V, Troche G, et al. A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin. JAMA 2000; 283:1038–1045. 35. Dellinger RP, Levy MM, Rhodes A, et al. Moreno R: surviving sepsis campaign: && international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 2013; 41:580–637. These updated guidelines critically appraise the current literature and conclude that ACTH stimulation test is of no use in discriminating patients with adrenal failure from those with a normal HPA stress response. 36. Trainer PJ, Besser M. The Bart’s Endocrine Protocols. Edinburgh: Churchill Livingstone; 1995. 37. Sacre K, Dehoux M, Chauveheid MP, et al. Pituitary-adrenal function after prolonged glucocorticoid therapy for systemic inflammatory disorders: an observational study. J Clin Endocrinol Metab 2013; 98:3199–3205. 38. Gibbison B, Angelini GD. Lightman SL: dynamic output and control of the && hypothalamic-pituitary-adrenal axis in critical illness and major surgery. Br J Anaesth 2013; 111:347–360. This recent review gives a good overview of the problems in current understanding of the HPA-axis regulation in critical illness and further elaborates on the importance of hormone pulsatility, which is currently not studied in critical illness. 39. Cameron A, Henley D, Carrell R, et al. Temperature-responsive release of cortisol from its binding globulin: a protein thermocouple. J Clin Endocrinol Metab 2010; 95:4689–4695. 40. Chan WL, Carrell RW, Zhou A, Read RJ. How changes in affinity of & corticosteroid-binding globulin modulate free cortisol concentration. J Clin Endocrinol Metab 2013; 98:3315–3322. Increasing evidence shows that CBG is more than just a transporter protein. This is further corroborated by the recent findings that not only CBG levels but also affinity is affected by critical illness. 41. Holland PC, Hancock SW, Hodge D, et al. Degradation of albumin in meningococcal sepsis. Lancet 2001; 357:2102–2104. 42. Pugeat M, Bonneton A, Perrot D, et al. Decreased immunoreactivity and binding activity of corticosteroid-binding globulin in serum in septic shock. Clin Chem 1989; 35:1675–1679. 43. Bergquist M, Nurkkala M, Rylander C, et al. Expression of the glucocorticoid & receptor is decreased in experimental Staphylococcus aureus sepsis. J Infect 2013; 67:574–583. This study investigated glucocorticoid receptor expression and binding affinity in different tissues (blood, spleen and lymph nodes) of septic animals. Apart from progressively decreased expression, they also show decreased glucocorticoid receptor translocation in septic mice. This may explain why steroid treatment is only beneficial when administered early in sepsis and septic shock. 44. Guerrero J, Gatica HA, Rodriguez M, Estay R. Goecke IA: septic serum & induces glucocorticoid resistance and modifies the expression of glucocorticoid isoforms receptors: a prospective cohort study and in vitro experimental assay. Crit Care 2013; 17:R107. These authors show that in septic patients the dominant negative b-isoform of the glucocorticoid receptor is induced already from admission, which downregulates glucocorticoid action. This further suggests that patients with a normal circulating cortisol level in critical illness may not have adequate cortisol availability and function. &

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45. Peeters RP, Hagendorf A, Vanhorebeek I, et al. Tissue mRNA expression of the glucocorticoid receptor and its splice variants in fatal critical illness. Clin Endocrinol (Oxf) 2009; 71:145–153. 46. Siebig S, Meinel A, Rogler G, et al. Decreased cytosolic glucocorticoid receptor levels in critically ill patients. Anaesth Intensive Care 2010; 38:133–140. 47. Stenman UH. Standardization of hormone determinations. Best Pract Res Clin Endocrinol Metab 2013; 27:823–830. 48. Keevil BG. Novel liquid chromatography tandem mass spectrometry (LC-MS/ MS) methods for measuring steroids. Best Pract Res Clin Endocrinol Metab 2013; 27:663–674. 49. Vassiliadi DA, Ilias I, Tzanela M, et al. Interstitial cortisol obtained by micro& dialysis in mechanically ventilated septic patients: correlations with total and free serum cortisol. J Crit Care 2013; 28:158–165. This article introduces the use of interstitial cortisol measurements. Their critical appraisal of the limitations of this method is objective and informative. 50. Venkatesh B, Morgan TJ, Cohen J. Interstitium: the next diagnostic and therapeutic platform in critical illness. Crit Care Med 2010; 38:S630– S636. 51. Trzeciak S, Dellinger RP, Parrillo JE, et al. Early microcirculatory perfusion derangements in patients with severe sepsis and septic shock: relationship to hemodynamics, oxygen transport, and survival. Ann Emerg Med 2007; 49:88–98; 98. 52. Kraan GP, Dullaart RP, Pratt JJ, et al. The daily cortisol production reinvestigated in healthy men. The serum and urinary cortisol production rates are not significantly different. J Clin Endocrinol Metab 1998; 83:1247– 1252. 53. Vanhorebeek I, Peeters RP, Vander Perre S, et al. Cortisol response to critical illness: effect of intensive insulin therapy. J Clin Endocrinol Metab 2006; 91:3803–3813. 54. Hermans G, Wilmer A, Meersseman W, et al. Impact of intensive insulin therapy on neuromuscular complications and ventilator dependency in the medical intensive care unit. Am J Respir Crit Care Med 2007; 175:480– 489. 55. Hermans G, De Jonghe B, Bruyninckx F, Van den Berghe G. Clinical review: critical illness polyneuropathy and myopathy. Crit Care 2008; 12: 238. 56. Hauer D, Weis F, Papassotiropoulos A, et al. Relationship of a common polymorphism of the glucocorticoid receptor gene to traumatic memories and posttraumatic stress disorder in patients after intensive care therapy. Crit Care Med 2011; 39:643–650. 57. Ledderose C, Mohnle P, Limbeck E, et al. Corticosteroid resistance in sepsis & is influenced by microRNA-124–induced downregulation of glucocorticoid receptor-alpha. Crit Care Med 2012; 40:2745–2753. Acquired glucocorticoid resistance frequently complicates the therapy of sepsis. This study shows that previous glucocorticoid treatment downregulates glucocorticoid receptor-a via induced expression of miRNA-124, thereby limiting anti-inflammatory effects of glucocorticoids. This important finding suggests that ideally therapy should be adapted to patient specific characteristics. 58. Baker AC, Chew VW, Green TL, et al. Single nucleotide polymorphisms and & type of steroid impact the functional response of the human glucocorticoid receptor. J Surg Res 2013; 180:27–34. Baker et al. showed that different SNPs of the glucocorticoid receptor have effect on their function. Like miRNA, this further emphasizes the role of individual-guided therapy schedules. 59. Baker AC, Green TL, Chew VW, et al. Enhanced steroid response of a human & glucocorticoid receptor splice variant. Shock 2012; 38:11–17. Baker et al. showed that different SNPs of the glucocorticoid receptor have effect on their function. Like miRNAs, this further emphasizes the role of individual-guided therapy schedules. 60. Venkatesh B, Myburgh J, Finfer S, et al. The ADRENAL study protocol: adjunctive corticosteroid treatment in critically ill patients with septic shock. Crit Care Resusc 2013; 15:83–88.

Volume 21 Number 3 June 2014


Sex-dependent disparities in critical illness: methodological implications for critical care research.

Mistaking complications of critical illness for those of critical care.

Enhancing critical thinking in clinical practice: implications for critical and acute care nurses.

Reduced nocturnal ACTH-driven cortisol secretion during critical illness.

Palliative care in critical illness: challenges for research and practice.

Measurement of salivary cortisol level for the diagnosis of critical illness-related corticosteroid insufficiency in children.

Sleep neurobiology and critical care illness.

Physiological and management implications of obesity in critical illness.

Careful cone counting critical for clinical care.

Addressing 21st-century nursing ethics: implications for critical care nurses.

Ghrelin in Critical Illness.

Copeptin in critical illness.

Care of the patient with a critical illness.

Editorial: surviving critical illness: intensive care and beyond.

[Nutrition in critical illness].

Chronic critical illness: a growing legacy of successful advances in critical care*.

Effect of Palliative Care-Led Meetings for Families of Patients With Chronic Critical Illness: A Randomized Clinical Trial.

Dysphagia diagnosed by fiberoptic endoscopy is common and transient in critical illness polyneuropathy: are there any clinical implications?

Diaries for recovery from critical illness.

Lactic acidosis in critical illness.

Fever in critical neurologic illness.

Muscle weakness in critical illness.

Liver dysfunction in critical illness.

Clinical implications of variable antiarrhythmic drug metabolism.