Crit Care Clin 22 (2006) 161 – 179 Endocrine Markers of Severity and Prognosis in Critical Illness Eric S. Nylén, MDa,b,T, Nitin Seam, MDc, Rahul Khosla, MDa,b a b Veteran Affairs Medical Center, 50 Irving Street, NW, Washington, DC, 20422, USA George Washington University School of Medicine, 2150 Pennsylvania Avenue, NW, Washington, DC, 20037, USA c National Institutes of Health, 9000 Rockville Pike, Bethesda, MD, USA The mortality of critically ill patients in the ICU remains unacceptably high despite advancements in supportive care over the last few decades. However, a recently developed endocrine-based intervention, intensive insulin therapy to control stress hyperglycemia, has successfully reduced mortality in the critically ill and has restored hope that outcomes can be substantially improved. Another crucial challenge, in which endocrine marker strategy may have an important impact, is the identification of high-risk patients. In this regard, the list of potential biomarkers is burgeoning as is the expanding concept of endocrine constituents. In this review, an attempt has been made to cast a wide net for potential endocrine markers that confer useful information regarding severity and outcome in critical illness. Hormonal markers Cortisol Activation of the hypothalamic-pituitary-adrenal (HPA) axis with enhanced cortisol concentrations is perhaps the best documented endocrine response to severe systemic stress. In critical illness, cortisol exerts a regulatory role which is T Corresponding author. Veteran Affairs Medical Center, 50 Irving Street, NW, Washington, DC, 20422. E-mail address: [email protected] (E.S. Nylén). 0749-0704/06/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ccc.2005.08.002 criticalcare.theclinics.com 162 nylÉn et al essential to prevent immunotoxicity, and to provide metabolic substrate, promote catecholaminergic cardiovascular action, optimize vascular tone and integrity, and ultimately enhance survival [1,2]. Typically, serum cortisol levels can increase 5 to 10 fold in close proximity to the insult, but assessment based on single cortisol values or following exogenous cortisol stimulation can be misleading, especially because the optimal range of cortisol response is still a matter of debate. Many patients with frequent hypoproteinemia have demonstrated a robust cortisol response when assessed by serum-free cortisol assays, which more accurately reflect bioactive cortisol . In general, there is a graded cortisol response to the degree of stress, such as the type of surgery. Cortisol levels also correlate with the severity of injury , the Glasgow Coma Scale , and the acute physiology and chronic health evaluation (APACHE) scoring system . There is often a wide, bimodal spectrum of cortisol concentrations in the ICU and the patients at either extreme fare the worst. An inverse correlation of cortisol response to the outcome of sepsis has been frequently established [6–8] (Fig. 1). In a mixed ICU population, admission cortisol varied from a mean of 27 mg/dL in survivors, to a mean of 47 mg/dL in non-survivors, differences that predicted outcome . Serial cortisol measurements with increasing values also signify worse survival . Discriminatory prognostic values incorporating cortsiol response to corticotrophin (ACTH) stimulation in septic shock has been reported. This approach, however, relies on ad100 Cortisol group 1 Cortisol group 2 Cortisol group 3 Cortisol group 4 Survival (%) 80 60 40 20 0 0 20 40 60 80 100 Days after admission Fig. 1. Ninety-day survival (Kaplan-Meier curve) in 100 medical ICU patients who have severe sepsisseptic shock stratified according to the total serum cortisol concentration (within 48 hours of admission). Group 1, cortisol 345 nmol/L (12.3 mg/dL); group 2, cortisol 345–552 nmol/L (12.3– 19.7 mg/dL); group 3, cortisol 552–1242 nmol/L (19.7–44.4 mg/dL); group 4, cortisol 1242 nmol/L (44.4 mg/dL). Group 4 versus groups 1–3 P b 0.02 (Mantel-Cox log rank test). (From Sam S, Corbridge TC, Mokhlesi B, et al. Cortisol levels and mortality in severe sepsis. Clin Endocrinol (Oxf) 2004;60:29–35; with permission.) endocrine markers 163 renal synthetic reserves rather than on the overall integrated adrenal axis, which includes extra-adrenal cortisol stimulation, and the response to ACTH can be low in otherwise healthy subjects [2,10]. Dehydroepiandosterone sulfate The adrenocortical sex steroid hormone dihydroepiandosterone (DHEA) sulfate was reported to correlate inversely with the APACHE score and to be particularly low in septic shock and non-survivors compared with multiple trauma and control subjects . Interestingly, the levels of the principal adrenal androgen, DHEA, may actually increase in sepsis . Thyroid hormones Serum thyroid hormone levels undergo predictable changes in systemic nonthyroidal illness (NTI). The initial change in the hypothalamic-pituitary-thyroid (HPT) axis during a mild illness is a decrease in triiodothyronine (T3) production caused by inhibition of the conversion of thyroxine (T4) to T3, with a reciprocal increase in reverse T3 (rT3), the so-called low T3 syndrome. This decrease can occur very rapidly  and both the decrease in serum T3 and rise in rT3 have been reported to correlate with severity of illness [14,15]. With advanced severity of illness, T4 also decreases; low T4 syndrome is often seen in adult and pediatric subjects with chronic or severe illnesses . Decreased T4 and T3 concentrations correlate with increased mortality: a total T4 level b 3 mg/dL was associated with an 84% mortality and a T4 level N 5 mg/dL had 15% mortality . In critical illness, the concentration of serum thyroid-stimulating hormone (TSH) is often low–normal. A prospectively obtained admission TSH was lower in nonsurvivors than survivors . Additional insights into the HPT axis relationship to outcome was reported in a cohort of 451 critically ill patients who stayed in an ICU for more than 5 days, randomized to conventional versus intensive insulin management . In addition to confirming the prognostic role of T3 and T4, both elevated rT3 and the decreased T3 /rT3 ratio were prognostic for nonsurvivors on the day of admission. These parameters showed increased significance by the last day (predictive area under curve receiver operating characteristics [AUROC] value 0.76 and 0.84, respectively). Interestingly, TSH showed a significant divergence by day 5: non-survivors remained low whereas survivors showed a more than 2-fold increase, preceding the rise in T3 and T4, which suggests that serial monitoring may have a role. Although TSH is often low–normal in NTI, there is a blunted response to thyrotropin releasing hormone (TRH), which portends a worse outcome, as does low TSH levels [19,20]. Natriuretic peptides Atrial natriuretic peptide (ANP) is synthesized in atrial myocyctes and is released in response to atrial distension causing vasodilatory and natriuretic 164 nylÉn et al bioactions . An ANP receptor-mediated modulation of macrophage function  and priming of neutrophils has been observed , which suggests a link to the inflammation. ANP was increased approximately fivefold in a small study of septic shock patients, which correlated with the peak of interleukin-6 (IL-6). N-terminal proANP levels correlated with severity of sepsis and cardiac depression  and death (AUROC of 0.88), were significantly greater than levels for procalcitonin (proCT) and C-reactive protein (CRP), but were similar to APACHE scores . Brain natriuretic peptide (BNP) is released primarily from ventricular cardiomyocytes in response to myocardial tension and stretch, and has overlapping bioactions with ANP . In a prospective observational study of severe sepsis and septic shock, BNP correlated with evidence of reduced myocardial systolic performance and elevated BNP at days 2 and 3 of the ICU stay, and was associated with an increased mortality . N-terminal proBNP performed in a similar manner and was prognostic within 1–2 days of shock; a level of N13,600 pg/mL predicted mortality (AUROC 0.8) . Despite BNP being elevated with renal dysfunction, cardiac indices have been shown to be independent determinants of plasma BNP levels in patients who have chronic renal failure. Although not all studies confirm their prognostic properties , ongoing work suggests a role of these peptides in various aspects of the immune system activity relevant to critical illness. Metabolic markers Glucose Stress hyperglycemia (SH), hyperglycemia in previously euglycemic patients that corrects once the acute process resolves, is a well-recognized process in critically ill patients. SH is the result of a complex interaction between stress metabolism, cytokine influences, oxidative stress, and stress signaling pathways. The net result is defective insulin signaling, insulin resistance, enhanced glycogenolysis, increased hepatic gluconeogenesis, and decreased use of glucose . The influence of diabetes (DM) as an independent risk factor for coronary artery disease (CAD) has been known for some time, but the correlation between hyperglycemia and outcomes in patients with myocardial infarction (MI) has only recently been recognized. In the Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) trial, maintaining blood glucose b 215 mg/dL in post-MI DM was associated with 25% decreased mortality at 3.4 years follow-up in the insulin-treated group . The same study then retrospectively examined 197 post-MI non-DM patients and found admission hyperglycemia as an independent predictor of nonfatal reinfarction, hospitalization for congestive heart failure, and major cardiovascular events in the 1.5– 2.5 years of follow-up . Another study of 336 patients post acute MI, found that admission hyperglycemia independently predicted increased 1-year mortality endocrine markers 165 in both DM and non-DM . The detrimental in-hospital prognosis for both DM and non-DM with MI, and of stress hyperglycemia, was further substantiated in a meta-analysis study . Several retrospective studies of acute stroke found an association between admission hyperglycemia and worse clinical outcome [35,36]. Admission hyperglycemia may also predispose to hemorrhagic conversion of an acute cerebral infarct . Persistent post-stroke hyperglycemia (mean glucose level N7 mmol/L; N126 mg/dL) was also associated with worse outcome, increased final infarct volume change, a worse NIH stroke scale, and modified Rankin Scale scores at 72 hours . The increased mortality or functional recovery following ischemic stroke in non-DM, in association with stress hyperglycemia, was substantiated in a large review of the literature . Several studies have shown improved outcomes in critically ill (mostly) surgical patients with control of blood glucose. Most notably, a prospective randomized trial of 1548 adults (13% of patients had history of DM) who received mechanical ventilation in a surgical ICU, studied intensive insulin therapy (achieved mean glucose was 100 mg/dL in the intensively treated group versus 158 mg/dL in the control group) versus conventional therapy and found a significant decrease in ICU mortality (the primary endpoint) as well as in-hospital mortality with intensive insulin therapy . Control of blood glucose, not insulin administration itself, was the cause of improved outcome . This conclusion was supported by a prospective observational trial of 531 patients admitted to a single ICU (88% of the patients had undergone surgery) in which increased insulin administration was positively associated with death, regardless of glucose level . In another study, 800 consecutive patients were admitted to a single medical-surgical ICU before the use of the insulin protocol and were compared with 800 consecutive patients after the protocol was put in place. There was a 29.3% decrease in hospital mortality and 10.8% decrease in length of ICU stay after the protocol was started . Moreover, in a recent prospective study of 942 consecutive trauma patients admitted to a single SICU over 2 years, patients with persistent hyperglycemia had increased mortality, time on the ventilator, and length of hospital stay (by univariate analysis) . In the medical ICU the APACHE II can correlate with admission glucose (Fig. 2); mortality was significantly lower in patients with a mean glucose of 4–6 mmol/L (72–108 mg/dL) compared with the group with a mean glucose level of 6–10 mmol/L (108–180 mg/dL) . However, in a prospective study of 135 consecutive non-DM patients who were admitted to a non-cardiac multidisciplinary ICU over 6 months, maximum blood glucose levels while in the ICU correlated with ICU mortality only in the surgical, and not medical, patients . Lipids Hypocholesterolemia ensues early in the course of a variety of critical illnesses, and correlates with severity, nosocomial infections, and mortality. A 166 nylÉn et al Fig. 2. Regression analysis of the APACHE II scores and admission serum glucose in 73 consecutive medical ICU patients who have a variety of critical illnesses (diabetics excluded) (R = 0.39; r 2 = 0.15; Pb0.001). U-type of association has been described between mortality and cholesterol in large groups of hospitalized patients . Admission cholesterol and lipoproteins are typically decreased (eg, a cut- off of median total cholesterol of b120 mg/dL predicted clinical outcome) and correlate inversely with cytokines such as IL-6 and interleukin-10 (IL-10) . In another surgical ICU study of patients with systemic inflammatory response syndrome (SIRS), cholesterol levels were low on day 2, which persisted and were independently associated with mortality along with the APACHE III score . Lipolysis, based on plasma-free fatty acid and glycerol concentrations, is markedly elevated in septic patients and these parameters, along with low triglycerides, correlated with clinical severity; high-density lipoprotein (HDL) shows an inverse correlation . The free glycerol concentration was additive to the APACHE score in predicting mortality. The role of HDL is of particular interest because of its ability to bind and inactivate lipopolysaccharide (LPS) as well as other anti-inflammatory properties. The prognostic significance of serum lipids such as HDL may be significant because of the salutary contribution of the lipid response (ie, increased low-density lipoprotein and HDL) to intensive insulin management and enhanced outcome . In obesity, there is adipose infiltration of active macrophages and upregulation of a host of inflammatory genes, which contribute to a state of chronic heightened inflammation and down-regulated bioenergetics. The few studies that evaluate the impact of obesity on the severity or prognosis of critical illness are contradictory. However, one prospective study suggested that that a body mass index N27 kg/m2 correlated with severity, ICU mortality, and length of ICU stay . Another pediatric study noted increased weight with mortality from sepsis . endocrine markers 167 Immune markers Cytokines The inflammatory response syndrome is to a large extent initiated by transient expression of cytokines such as tumor necrosis factor a (TNF-a) and IL-1ba. These proinflammatory cytokines trigger IL-6 production furthering the inflammatory activation process, which includes the acute phase response. IL-6 concentrations are rather stable and easy to detect, and show reasonable correlation— in contrast to TNF-a and IL-1b—to the severity of illness [54,55], the degree of overall cytokinemia , stress hyperglycemia , the presence of adult respiratory distress syndrome (ARDS) , and outcome [59–61]. IL-6 has also served as a prototype stratification marker [62–64]. Thus, IL-6 may enhance prognostication compared with current clinical criteria. In predicting hospital mortality from sepsis, day 2 IL-6 (and ProCT) reached N 0.75 AUROC . Interleukin-8 is a proinflammatory chemokine that stimulates migration of neutrophils and macrophages to inflammatory sites. IL-8 increases in the early stages of sepsis and has been correlated to IL-6 levels . IL-8 is also associated with viral conditions such as dengue fever and its outcome . IL-8 has been reported to be significant in sepsis and multiple organ failure (MOF)  and is elevated in patients that die from lung injury . Interleukin-10 is a potent anti-inflammatory cytokine and may be a useful prognostic marker for organ failure in pancreatitis , sepsis mortality , and myocarditis mortality [72,73]. Interleukin-18, previously known as the inducer of interferon-gamma, has potent immunomodulatory actions that involve T cells. IL-18 levels increase in those who develop SIRS, in subjects with peritonitis, and organ failure patients , and can be predictive of outcome . In sepsis, IL-18 correlates with severity and, together with IL-6, is considerably higher in patients with grampositive compared with gram-negative infections . C-reactive protein C-reactive protein (CRP) is an acute phase protein that is predominantly produced and secreted by hepatocytes in response to cytokines such as IL-6. Plasma levels of CRP are below 10 mg/L in 99% of healthy individuals and usually rise 4 to 6 hours after an infectious stimulus to reach a peak after 36 to 50 hours. A CRP level N10 mg/dL on ICU admission was associated with high mortality . In children with hematopoietic stem cell transplants, a CRP level N10 mg/dL was predictive of poor outcome . Patients who had acute myocardial infarction and CRP levels N2.23 mg/dL on admission, had a significantly higher mortality and heart failure rate . A strong correlation between the CRP to pre-albumin ratio and severity of organ dysfunction at 48 hours and 120 hours has been noted in critically ill patients . In patients who have chronic respiratory failure, elevated CRP levels are strongly predictive of rate of 168 nylÉn et al hospitalizations and survival . Moreover, persistently high CRP concentrations in the ICU are associated with a poor outcome . However, although CRP is a very sensitive marker and is elevated in both inflammation and infection, it is non-specific, and not able to differentiate from underlying inflammatory diseases such as auto-immune diseases, trauma, major surgeries, burns, and malignant diseases. Calcitonin precursors and procalcitonin High molecular fractions cross-reacting with polyclonal calcitonin antisera was first recognized to be associated with infections in the staphylococcal toxic shock syndrome . Subsequent studies have revealed that a variety of critical illnesses can increase the circulating concentration of several precursor peptides to calcitonin (ie, calcitonin precursors; CTpr) including procalcitonin (ProCT) . In critical illness, the source of CTpr appears to be a diversity of nonthyroidal cells without the ability to complete cellular hormonal packaging. Although CTpr levels can be detected in normal healthy sera , it is markedly (and persistently) increased by 24–36 hours following exposure to bacteria, LPS, or proinflammatory cytokines. Similar responses also occur in severe systemic conditions such as burns and heat stroke, and a more muted response has been noted to viral infections, whereas the response to fungi is variable . ProCT release appears to be unimpeded and remains useful in neutropenic states . Several studies show a strong correlation of CTpr with severity scores such as APACHE , SOFA (sequential organ failure assessment) , SAPS (Simplified Acute Physiology Score) , and PRISM (Pediatric Risk of Mortality) . Across the spectrum of severity, from SIRS to septic shock, CTpr levels are much less variable than IL-6 or CRP . CTpr also correlates with mortality; a cutoff value of 6 ng/mL on day 1 separated patients who died from those who survived with 87.5% sensitivity and 45% specificity ; a day 2 ProCT reached a predictive value of hospital mortality (AUROC N 0.75) ; a maximal ProCT value b 2.1 ng/mL was seen in 100% of survivors . Sequencial decrease in ProCT can also suggest improved survival . Peak PCT (and the albumin level) outperformed the Euroscore (European System for Cardiac Operative Risk Evaluation) for predicting post-operative mortality following bypass surgery . Monocyte migration inhibitory factor Monocyte migration inhibitory factor (MIF) is a pleiotropic mediator with hormonal, cytokine, and enzymatic activities implicated in the regulation of immune and inflammatory responses. In addition to monocytes and macrophages, MIF is produced in a variety of cells including a variety of endocrine cells. Glucocorticoids induce the secretion of MIF and MIF, in turn, can antagonize glucocorticoid release. It has also been shown that treatment of septic patients with glucocorticoids can result in decreased MIF release . The proinflamma- endocrine markers 169 tory mediator role of MIF in sepsis has been established in experimental studies . In human studies, the MIF concentration is elevated in sepsis, and is highest in those with septic shock . In another study, sepsis patients had significantly higher MIF levels compared with trauma or control patients on the day of admission; levels which were persistently elevated . MIF levels were also significantly higher in non-survivors compared with survivors of septic shock. Similarly, MIF was higher in subjects who had ARDS compared with non-ARDS subjects and predicted mortality outcome better than ARDS. In a comparative study of 25 patients with sepsis, both MIF and IL-6 were significantly higher in patients who died. In this study, an MIF level of N1100 pg/mL had a sensitivity of 100% and specificity of 64% for a fatal outcome . Higher circulating MIF levels 6 hours post-cardiopulmonary bypass surgery were associated with worse outcome . High mobility group-1 High mobility group-1 (HMG-1) is a highly conserved DNA-binding protein with proinflammatory cytokine-like properties, which elicits a sepsis-like syndrome when administered . Moreover, antibodies to HMG-1 confer delayed protection against experimental sepsis . HMG-1 is considered a ‘‘late’’ mediator and is released 8–32 hours following endotoxin exposure. Moreover, in human sepsis, HMG-1 remained elevated, whereas cytokines such as IL-6, IL-8, and IL-10, had returned to near normal values . However, although IL-6, IL-8, and IL-10 correlated with the SOFA score, there was no such correlation with the levels of HMG-1. Platelet activating factor and platelet activating factor-acetyhydrolase Platelet activating factor (PAF) and other cell membrane-derived phospholipids have been reported to be proinflammatory mediators and are elevated in sepsis and involved in organ failure [105,106]. In hypoxic-ischemic encephalopathy, PAF levels were twice that of healthy controls and correlated with the clinical severity . PAF binding to platelets correlated to the extent, infarct volume, and neurological impairment in stroke victims . PAF is inactivated by PAF–acetylhydrolase (PAF-AH). In acute MI, trauma, and sepsis, the PAF-AH is decreased and related to organ failure [106,109]. Soluble triggering receptor expressed on myeloid cells-1 The triggering receptor expressed on myeloid cells (TREM-1) is a member of the immunoglobulin super family, the expression of which is up-regulated on phagocytic cells in the presence of bacteria or fungi . In noninfectious inflammatory disorders TREM-1 is weakly expressed . A soluble form of TREM-1 (sTREM-1) is released from activated phagocytes and determination of the level of s-TREM-1 in biological fluids as plasma  and bronchoalveolar 170 nylÉn et al lavage  has been shown to be helpful to identify an infectious process. Moreover, it had a favorable prognostic performance relative to ProCT and CRP . Decreasing level of sTREM-1 over time is associated with a favorable clinical outcome . Endohelial markers Nitric oxide and asymmetric dimethylarginine Nitric oxide (NO) is a free radical formed by a group of NO synthases, which rapidly convert l-arginine into NO and l-citrullin. Being in a gaseous state, NO is often indirectly measured by metabolites such as nitrite and nitrate. As a potent vasodilator, NO is implicated in the vasodilatory state of septicemia, the hypotension of which may cause organ failure. It also decreases endothelin-1 levels, a potent vasoconstrictor. Actual NO production appears to be increased in sepsis  and indirect NO measures suggest that it is elevated in SIRS, burns, sepsis, and heatstroke. In heatstroke, excessive NO production is proportional to the severity of illness . The serum NO level has been used as a predictor of postoperative morbidity . Asymmetric dimethylarginine (ADMA), an L-arginine analog and an endogenous inhibitor of NO synthase, with its own vasoconstrictive properties, has been shown to be associated with organ failure such as hepatic failure and also being a strong and independent predictor of mortality . In another study, the mortality correlation to ADMA was confirmed. In addition, ADMA correlated to APACHE and several other important illness parameters . Endothelin-1 This 21 amino acid peptide is a potent vasoconstrictor which stimulates the production of endothelial NO. The serum level of endothelin is elevated in a variety of states, especially in sepsis and septic shock, and correlates with severity and mortality [120,121]. For example, endothelin-1 levels were highest in culture-positive neonatal sepsis, and correlated with SNAP (severity instrument Score for Neonatal Acute Physiology) . Complement markers The complement cascade is a part of the innate immunity and its activation has been documented in sepsis, trauma, burns, and cardiopulmonary bypass . In trauma, the complement 3a (C3a/C3) levels increase with illness severity and the level is significantly higher in non-survivors than survivors . In sepsis, complement is activated by bacterial cell components as evidenced by the increase in plasma concentration of C3a and C5a upon injection of LPS . The role of complement in combating septicemia is paradoxical, because lysis or opsonization of invading microorganism is an important part of host defense, but excessive complement activation can lead to harmful tissue destruction caused by severe inflammation. Selective inhibition of specific pathways endocrine markers 171 may be more advantageous. Inhibition of C3a receptor has increased survival during sepsis . Anti-C5a antibodies alleviate symptoms of ARDS in septic primates . Cardiopulmonary bypass induces a systemic inflammatory response that contributes to clinical morbidity: two complement inhibitors, TP10 (a C3/C5 convertase inhibitor) and pexelizumab, both anti-C5 monoclonal antibodies, are in clinical trials. TP10 has been shown to limit tissue injury and improve myocardial dysfunction during and following experimental cardiopulmonary bypass . Pexelizumab was shown to reduce post cardiopulmonary bypass graft incidence of non-Q wave myocardial infarction and mortality . Coagulation markers The activation of the coagulation cascade has been shown to be associated with the development of MOF and poor prognosis in septic patients [130–132]. Protein C (PC) is a key molecule in the coagulation cascade and reduced concentration is observed in septic patients and is associated with poor outcomes [133,134]. PC is activated by binding to the endothelial PC receptor and the thrombumodulin-thrombin complex. The activated protein C has antithrombotic, profibrinolytic, antiapoptotic, and anti-inflammatory properties . Low levels of PC is associated with worse outcome in sepsis [136,137], and plasma levels are also reduced in patients with acute lung injury and ARDS . D-dimer (DD) formation results from the destruction of cross-linked fibrin and is a measure of clot formation and lysis. Elevated levels of DD are associated with increased mortality, severity of sepsis, ARDS, and MOF [139,140]. Higher levels of DD in patients with community acquired pneumonia were shown to be associated with APACHE scores and higher in-hospital mortality . DD levels N2000 ng/mL in patients who have a pneumonia severity index of category IV, correlated with increased risk of in-hospital death. Coagulopathic dynamics continues to be a very important area of exploration, many markers of which augment early prognostication . Summary The progression and outcome of critical illness is a highly complex and heterogeneous confluence of variably definable factors, which seem to defy simplification into a few circulating endocrine markers. Attributes that would make the current plethora of markers clinically useful include: (1) an early and timely phase of detectability, (2) a strong discriminatory assay signal associated with the illness, (3) a reciprocal change in the concentration with the recovery and successful treatment of the illness, (4) a performance that is synergistic with other clinical severity and outcome instruments, and (5) a definable performance in a variety of critical illnesses. Few of the above reviewed substances (or those illustrated in Table 1) clearly meet all or most of these criteria. However, as insights into the pathophysiology of many of these conditions is advanced, there 172 nylÉn et al Table 1 Examples of additional endocrine markers of severity and outcome in critical illness Marker Action ICU correlations Reference Soluble adhesion molecules Adrenomedullin sFas Glycosides (ouabain) sHSP70 IGFBP-1 Isoprostane Leptin Microalbuminuria Thrombopoietin Troponin vW Leukocyte attachment Vasodilatory Apoptosis signal Inhibits Na/K ATPase Molecular chaperones Regulate free IGFs Oxidative stress marker Immunomodulator Capillary leak Platelet growth factor Contractile-regulating proteins Platelet adhesion mediator MOF/mortality APACHE/MOF MOF/mortality APACHE II/cortisol MOF APACHE/mortality MOF/mortality Mortality SAPS/APACHE/mortality Severity of sepsis Mortality Mortality [143,144]            Abbreviations: APACHE, acute physiology and chronic health evaluation; IGF, insulin growth factor; IGFBP-1, insulin growth factor binding protein-1; MOF, muliple organ failure; SAP, simplified acute physiology score; sHSP70, soluble heat shock protein 70; vW, von Willebrand factor. is certainly reason to expect that there will be excellent candidate markers with the requisite prognostic characteristics that will have an important impact on critical illness outcome. 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