critical illness thereby counteracting the protein catabo- lism that occurs during critical illness. 43–45 INTENSIVE INSU LIN THERAPY IN THE CRITICALLY ILL Van Den Berghe et al, in a prospective, randomized, controlled st udy involving 1548 patients, demonstrated that intensive insulin therapy reduced mortality and morbidity among patients admitted to a surgical critical care unit (the Leuven Intensive Insulin Therapy Trial). 1,46 These authors compared an intensive insulin therapy regimen aime d to maintain blood glucose be- tween 80 and 110 mg/dL with conventional treatment in which insulin infusion was only initiated when glucose level was greater than 215 mg/dL and maintenance of glucose between 180 and 200 mg/dL. At 12 months the mortality was 4.6% with the intensive insulin regimen compared with 8.0% in the control group. The benefit was most apparent in patients with greater than 5 days of stay in the intensive care unit. Tight and early glycemic control was associated with the more rapid improvement of insulin resistance. 46 Intensive insulin therapy was associated with reduced bloodstream infections by 46%, acute renal failure by 41%, and critical illness polyneuropathy by 44%. Using multivariate analysis the authors suggested that improved metabolic control, as reflected by normoglycemia, rather than the infused insulin dose per se, was responsible for the beneficial effects of intensive insulin therapy. However, achieving normoglycemia and the administration of insulin are linked, and from the available evidence it appears likely that both factors played a key role in the improved outcome. The o utcome data from the Leuven Intensive Insulin Therapy Trial indicates that there is a direct relationship between the degree of glycemic control and hospital mortality. 46 In the long-stay patients (> 5 days in the ICU) the cumulative hospital mortality was 15% in patients with a mean blood glucose less than 110 mg/ dL, 25% in those with a blood glucose between 110 and 150 mg/dL, and 40% in those with a mean blood glucose of greater than 150 mg/dL. In diabetic patients with acute myocardial infarction, therapy to maintain blood glucose at a level below 215 mg/dL improves out- come. 24,26,27 These data suggest that even ‘‘modest’’ glycemic control will have an impact on patient outcome. This is importan t because in the ‘‘real world’’ it may be difficult (if not somewhat risky) to attempt to maintain blood glucose in the range of 80 to 110 mg/dL. This often requires the use of a continuous insulin infusion protocol and frequent blood glucose monitoring. How- ever, this goal may only be achievable in ICUs with a high nursin g to patient ratio and close physician super- vision. On the other hand, the Leuven study showed that to improve morbidity by reducing the incidence of bacteremia, acute renal fai lure, critical illness poly- neuropathy, and transfusion requirements, a blood glucose level of less than 110 mg/dL was required. Indeed, a blood glucose level of 110–150 mg/dL was not effective on these morbidity measures as compared with > 150 mg/dL. 46 Krinsley and Grissler, 47 evaluated an intensive glucose management protocol in 800 heterogeneous critically ill adult patients. The protocol involved in- tensive monitoring and treatment to maintain plasma glucose values lower than 140 mg/dL. Continuous intravenous insulin was used if glucose values exceeded 200 mg/dL. The mean glucose value decreased from 152.3 to 130.7 mg/dL (p < .001), marked by a 56.3% reduction in the percentage of glucose values of 200 mg/dL or higher, without a significant change in incidence of hypoglycemia. The development of new renal insufficiency decreased by 75% (p ¼ 0.03), and the number of patients undergoing transfusion of packed red blood cells decreased by 18.7% (p ¼ .04). H ospit al mortality decreased by 29.3% (p ¼ .002), and length of stay in the ICU decreased by 10.8% (p ¼ .01). In addition, intensive insulin therapy was shown to cause a significant reduction in the incidence of total nosoco- mial infections, including intravascular device, blood- stream, intravascular device–related bloodstream, and surgical site infections. Grey and Perdrizet 48 randomized 61 surgical ICU patients requiring treatment of hyperglycemia (glucose values > or ¼ 140 mg/dL) to receive either standard insulin therapy (target glucose range, 180 to 220 mg/dL) or strict insulin therapy (target glucose range, 80 to 120 mg/dL) throughout their ICU stay. A significant reduction (p < .001) in mean daily glucose level was achieved in the strict glycemic control group (125 Æ 36 mg/dL) in comparison with the standard glycemic control group (179 Æ 61 mg/dL). A significant reduction (p < .05) in the incidence of total nosocomial infections, including intravascular device, bloodstream, and surgical wound infection s, was observed in the strict glucose control group in comparison with the standard glucose control group . It is noteworthy that in the Leuven Intensive Insulin Therapy Trial, all patients received between 200 and 300 g of intravenous glucose on the day of admission followed by parenteral or enteral (or both) nutrition started on the second ICU day. However, although early enteral feeding has been reported to improve organ function and decrease the length of hospital st ay, 49 parenteral nutrition is associated with adverse outcomes during critical illness. 50 Furthermore, hypocaloric enteral nutrition administered with slowly absorbed carbohydrate induces less hyperglycemia than parenteral nutrition among critically ill. 51–53 Based on the foregoing results we recommend the initiation of early enteral nutrition in all ICU patients on E N DOC R INED I SOR DER S /RAGHAVAN, MARIK 277 the day of ICU admission. 49,50,54 Enteral nutrition should be commenced at a rate of 33 to 66% of calculated intake (15 to 20 kcal/kg/d) and advanced to full calorific goal of 20 to 25 kcal/kg/d over 3 to 5 days. 55 Insulin infusion should be commenced in patients with blood glucose above 150 mg/dL (a threshold of 110 mg/dL may be appropriate in select ICUs). Subcutaneous in- sulin ‘‘sliding scales’’ may control stress hyperglycemia. However, an insulin infusion is recommended if the blood glucose remains above 150 mg/dL after 24 hours on a sliding scale. ADRENAL INSUFF ICIENCY IN THE CRITICALLY ILL In critically ill patients there has been a great deal of interest regarding the assessment of adrenal function and the indications for adrenal replacement therapy. 9,11,56–58 A-1, although once considered a rare diagnosis in the ICU, is currently being reported with increased fre- quency in critically ill patients. Although the exact incidence of A-1 varies with the diagnostic test and concentration of cortisol used to diagnose the disorder, in one series $61% of critically ill septic shock patients had A-1 when a baseline cortisol concentration of < 25 mg/dL was used as the diagnostic threshold. 56 Adrenal failure can be caused by structural damage to the adrenal gland, pituitary gland, or hypothalamus; however, many critically ill patients develop reversible failure of the HPA axis. 9 HYPOTHALAMO-PITUITARY AXIS AND CORTISOL DURING STRESS Severe illness and stress activate the HPA axis and stimulate the release of corticotropin [also known as adrenal corticotropic hormone (ACTH)] from the pi- tuitary, which in turn increases the release of cortisol from the adrenal cortex. This activation is an essential component of the genera l adaptation to illness and stress, and contributes to the maintenance of cellular and organ homeostasis. CAUSES OF ADRENAL INSUFFICIENCY IN THE INTENSIVE CARE UNIT Acute A-1 occurs in patients who are unable to increase their production of cortisol during acute stress. This includes patients with hypothalamic and pituitary dis- orders (secondary A-1) and patients with destructive diseases of the adrenal glands (primary A-1) (Table 1). Secondary A-1 is common in patients who have been treated with exogenous corticosteroids. Increasingly A-1 is being reported in patients with sepsis, human immu- nodeficiency virus infection, acute and subacute liver failure, brain-dead organ donors, and cardiac surgery patients. 56,59–62 However, the most common cause of acute A-1 is sepsis and systemic inflammatory response syndrome (SIRS) 56,63,64 (Table 1). PATHOPHYSIOLOGY OF A-1 DURING CRITICAL ILLNESS Sepsis and Systemic Inflammatory Response Syndrome–Induced Acute Reversible Adrenal Insufficiency There is increasing evidence of HPA insufficiency in critically ill septic patients, 56,65 which appears to result from circulating suppressive factors released during sys- temic inflammation. 66 It is important to recognize these patients because this disorder has a high mortality rate if Table 1 Etiology of Adrenal Insufficiency during Critical Illness Syndromes Mechanism of A-1 COMMON Reversible dysfunction of the HPA axis Sepsis/SIRS Primary a and secondary b Drugs Corticosteroids Secondary Etomidate Primary Ketoconazole Primary Rifampin Increased cortisol metabolism Phenytoin Increased cortisol metabolism ACTH and cortisol resistance Primary and secondary Adrenal Exhaustion Secondary Hypothermia Primary Liver disease (hepatoadrenal syndrome) HDL (apolipoprotein-1) deficiency Primary Fulminant hepatic failure Primary and secondary Chronic liver failure (cirrhosis) Primary Liver transplantation Primary Anticoagulation Primary and secondary Heparin-induced thrombocytopenia Primary and secondary Brain dead organ donors Primary and secondary RARE Metastatic cancer Primary and secondary Pituitary diseases Secondary HIV infection Primary and secondary Granulomatous diseases Primary and secondary ACTH, adrenal corticotropic hormone; A-1, adrenal Insufficiency; HDL, high density lipoprotein; HIV, human immunodeficiency virus; HPA, hypothalamic-pituitary-adrenal; SIRS, systemic inflammatory response syndrome. a Primary A-1 is defined as the failure of the adrenal gland to produce cortisol. 9 b Secondary A-1 is defined as adrenal failure secondary to hypo- thalmo-pituitary-axis dysfunc tion. 9,61 278 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 27, NUMBER 3 2006 untreated. 67 In our series of 59 patients with septic shock, 15 patients (25%) had primary A-1, 10 patients (17%) had HPA-axis failure, and 11 patients (19%) had ACTH resistance. 56 Surviving septic patients had return of adrenal function and did not require long-term treat- ment with corticosteroids. Adrenocorticotropin and Cortisol Resistance Patients with systemic infections [e.g., sepsis, human immunodeficiency virus (HIV)] may acquire A-1 asso- ciated with resistance to ACTH. In two recent studies in critically ill patients, we found that 30% of patients with septic shock and 25% of critically ill, HIV-infected patients acquired A-1 associated with AC TH resist- ance. 59,68 In these patients pharmacological doses of exogenous corticotropin did not increase their serum cortisol levels, but high doses of corticotropin were able to increase the levels into the normal range suggesting corticotropin resistance. Ali and colleagues reported a 40% decline in the number of glucocorticoid receptors (GRs) in the liver of septic rats. 69 The decline in hor mone-binding activity was associated with a fall in GR messenger ribonucleic acid (mRNA). Decreased affinity of the GR from mononuclear leukocytes of patients with sepsis has also been reported. 70 In addition, Norbiato et al re- ported resistance to glucocorticoids in patients with acquired immunodeficiency syndrome (AIDS). 68 Cor- tisol-resistant patients had clinical evidence of A-1 associated with decreased affinity of GRs for glucocor- ticoids and decreased GR function. We as well as others have found that cortisol clearance from the circulation is impaired in many critically ill patients. 71 This de- creased clearance reflects decreased tissue uptake and metabolism of cortisol. Liver Failure–Associated Adrenal Insufficiency (the ‘‘Hepatoadrenal’’ Syndrome) We have found a high incidence of adrenal failure in critically ill patients with liver disease, an entity for which we have coined the term hepatoadrenal syndrome. 72 In our study of 245 patients with hepatoadrenal syn- drome, high density lipoprotein (HDL) level at the time of adrenal testing was the only variable predictive of adrenal insufficiency (p < .0001). In vasopressor-de- pendent patients with A-1, treatment with hydrocorti- sone was associated with a significant reduction (p < .02) in the dose of norepinephrine at 24 hours, whereas the dose of norepinephrine was significantly higher (p < .04) in those patients with adrenal failure not treated with hydrocortisone. In vasopressor-dep endent patients with- out A-1, treatment with hydrocortisone did not affect vasopressor dose at 24 hours. One hundred and forty- one of a total 340 patients (41%) died during their hospitalization. The baseline serum cortisol was 18.8 Æ 16.2 mg/dL in the nonsurvivors compared with 13.0 Æ 11.8 mg/dL in the survivors (p < .001). Of those patients with adrenal failure who were treated with glucocorticoids, the mortality rate was 26% compared with 46% (p < .002) in those who were not treated. In those patients receiving vasopressor agents at the time of adrenal testing, the basel ine cortisol was 10.0 Æ 4.8 mg/ dL in those with A-1 compared with 35.6 Æ 21.2 mg/dL in those with normal adrenal function. Vasopressor- dependent patients who did not have adrenal failure had a mortality rate of 75%. 72 High Density Lipoprotein Deficiency and Adrenal Insufficiency A-1 is increasingly being reported in patients with acute and subacute liver failure. 60,72–75 The finding of an association between low serum apolipoprotein A-1 (Apo-1) in patients with hepatic failure and A-1 sup- ports the notion that liver disease may lead to impaired cortisol synthesis. 74–76 Apo-1 is the major protein com- ponent of HDL cholesterol synthesized principally by the liver. Experimental studies suggest that HDL is the preferred lipoprotein source of steroidogenic substrate in the adrenal gland. 76 At rest and during stress, $ 80% of circulating cortisol is derived from plasma cholesterol, the remaining 20% being synthesized in situ from acetate and other precursors. 77 Recently, mouse scavenger receptor, class B, type 1 (SR-B1) and its human homologue (CLA-1) were identified as the high affinity HDL receptor mediating selective cholesterol uptake. 78 The receptor for HDL (CLA-1) is expressed at high levels in the parenchymal cells of the liver and the steroidogenic cells of the adrenal glands, ovaries, and testes. CLA-1 mRNA is highly expressed in human adrenal glands, and the accumula- tion of CLA-1 messenger RNA is upregulated by adrenocorticotropin in primary cultures of normal hu- man adrenocortical cells. 77 Low Apo-1/HD L levels in the critically ill may be pathogenetically linked to the high incidence of adrenal failure in this group of patients. Van der Voort and colleagues 79 demonstrated that in critically ill patients, low HDL levels were associated with an attenuated response to Synacthen. Indeed, an inverse relationship noted between proin- flammatory mediators and HDL/Apo-1 levels is asso- ciated with poor outcome in the critically ill. 80 This may be mediated by low serum cortisol level and A-1, suggesting that further studies are required to define the pathogenetic role and mechanisms of altered HDL/ Apo-1 metabolism in acute illness. 74 In our series of patients with end-stage liver failure, we noted an incidence of adrenal fa ilure in $15% of patients with fulminant liver failure, 40 to 50% in patients with end-stage liver failure, and $ 90% E N DOC R INED I SOR DER S /RAGHAVAN, MARIK 279 of patients undergoing liver transplantation. 72 Because HDL is synthesized primarily by the liver and plays a fundamental role in transporting cholesterol to the adrenal gland, patients with the hepatoadrenal syndrome have low HDL levels. In our study, the mean HDL leve l was 8 mg/dL in patients with hepatoadrenal syndrome, whereas it was 34 mg/dL (p ¼ .01) in patients with normal adrenal function. Furthermore, a low HDL level at admission to the ICU was predictive of the develop- ment of adrenal failure (adrenal exhaustion syndrome) in patients who had preserved adrenal function at admis- sion. Based on these findings, we suggest the routine measurement of a random cortisol and HDL level in all patients with end-stage liver disease and in all critically ill patients at risk of adrenal failure. Endotoxemia and Adrenal Insufficiency Apart from low HDL levels and the reduced delivery of substrate for cortisol synthesis, other mechanisms may contribute to the pathophysiology of the hepatoadrenal syndrome. Patients with acute and chronic liver disease have increased levels of circulating endotoxin [lipopoly- saccharide (LPS)] and proinflammatory mediators such as TNF. 81 It is postulated that intestinal bacterial over- growth with increased bacterial translocation, together with reduced Kupffer cell activity and portosystemic shunting results in systemic endotoxemia with increased transcription of proinflammatory mediators. 82,83 In ad- dition, serum endotoxin levels increase further during the anhepatic phase of liver transplantation and remain high for several days following transplantation. 82 LPS as well as TNF may inhibit cortisol synthesis. Endotoxin has been shown to bind with high affinity to the HDL receptor (CLA-1) with subsequent internalization of the receptor. 84,85 LPS may therefore limit the delivery of HDL cholesterol to the adrenal gland. Furthermore, TNF as well as interleukin-1b and interleukin-6 has been demonstrated to decrease hepatocyte synthesis and secretion of Apo-1 86 (Fig. 1). DIAGNOSIS OF HYPOTHALAMIC- PITUITARY-ADRENAL AXIS FAILURE Because there are no clinically useful tests to assess the cellular actions of cortisol (i.e., end-organ effects), the diagnosis of A-1 is based on the measurement of serum cortisol leve ls; this has resulted in much confusion and misunderstanding. 58,87–90 Circulating cortisol is bound to corticosteroid-binding globulin with < 10% in the free bioavailable form. During acute illness, there is an acute decline in the concentration of corticosteroid- binding globulin as well as decreased binding affinity for cortisol, resulting in an increase in the free bio- logically active fraction of the hormone. 65,90 In addition, the numbe r of intracellular GRs has been reported to be both upregulated or downregulated (tissue resistance) during stress. 91,92 These data suggest that the total circulating cortisol level may be a poor indicator of glucocorticoid activity at the nuclear level. Notwith- standing these caveats and the fact that we currently do not have a test that measures glucocorticoid activity, assessment of the HPA axis is usually made on the basis of a random (stress) cortisol level or the corticotropin stimulation test. In a highly stressed patient such as with severe sepsis and other shock states a random cortisol level assesses the integrity of the entire HPA axis. 88 Dysfunction at the hypothalamic, pituitary, or adrenal level will result in low circulating cortisol levels (< 20 mg/dL). A stress cortisol level of < 20 mg/dL in a patient with refractory hypotension should be treated with low-dose (stress dose) hydrocortisone. 9 Because this cutoff is rather arbitrary, a patient with a cortisol level greater than 20 mg/dL but less than 35 mg/dL, who has refractory hypotension may warrant a trial of low- dose hydrocortisone. It should be emphasized that a cortisol level of > 20 mg/dl does not exclude A-1 due to tissue resistance. A random cortisol level of < 15 mg/dL in a moderately stressed (vasopressor-independent) ICU pa- tient is suggestive of HPA dysfunction. 57 In moderately stressed patients, ‘‘adrenal reserve’’ can be assessed by the low dose (LD; 1 mg) corticotropin (Synacthen) stimula- tion test. A serum cortisol level of < 20 mg/dL 30 minutes after an LD corticotropin stimulation test is suggestive of primary A-1. It is important to empha- size that the random and stimulated cortisol levels must be interpreted in conjunction with the severity of illness and the patient’s clinical features. 89 A moderately stressed ICU patient with a random cortisol level of < 15 mg/dL or a stimulated level of < 20 mg/dL who has no clinical signs of A-1 (unexplained fever, confusion, hemodynamic instability, or eosinophilia) does not warrant treatment with stress doses of hydrocortisone. Annane et al 11 showed that a high baseline cortisol as well as inability to increase cortisol by 9 mg/dL (delta cortisol) after a high dose corticotropin (250 mg tetracosactrin) stimulation test was associated with a worse likelihood of survival. Following this study the delta cortisol has become the standard diagnostic test of choice to diagnose A-1 in the ICU (see later discussion). The ‘‘delta 9’’ has become the magical number that distinguishes normal adrenal function from ‘‘relative’’ adrenal failure. However, the delta cortisol is a measure of adrenal reserve and adrenal responsiveness to cortico- tropin; it does not assess the integrity of the HPA axis and is not a measure of adrenal function. In a study by Dimopoulou and coauthors who evaluated the HPA axis dysfunction in critically ill patients with traumatic brain injury, > 50% of healthy volunteers had a delta cortisol of < 9 mg/dL. 93 Similarly, in a study of patients with respiratory failure and no evidence of HPA disease, 280 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 27, NUMBER 3 2006 50% had a delta cortisol of < 9 mg/dL after endotracheal intubation with midazolam anesthesia. 94 We believe that the standard corticotropin stimulation test lacks sensitiv- ity for the diagnosis of A-1. 89 As already discussed, a threshold cortisol level of < 20 g/dL is inappropriately low in critically ill patients. ‘‘Normal’’ critically ill patients should elevate their cortisol level ! 25 mg/dL. Further- more, 250 mg of corticotropin is supraphysiological (! 100-fold higher than normal maximal-stress ACTH levels). 87,95 The very high levels of corticotropin obtained with 250 mg can override adrenal resistance to ACTH and result in a normal cortisol response. Therefore the decision to treat patients with glucocorticoids should be based on serum cortisol levels in conjunction with the patient’s clinical features and severity of illness. In pa- tients with subtle clinical signs or a borderline random cortisol level, a therapeutic trial of treatment with stress- level doses of glucocorticoids may be warranted. The potential benefit of treatment with hydrocortisone in certain patient groups, including those with severe sepsis (not septic shock), hemodynamic instability in nonseptic patients, severe community acquired pneumonia; patients treated with etomidate; and patients being weaned from mechanical ventilation, deserve further investigation. THERAPY OF ADRENAL INSUFFICIENCY During septic shock, treatment with stress-level doses of hydrocortisone has been demonstrated to improve he- modynamic status, downregulate the proinflammatory response, and improve survival 10,11,96–98 Annane and colleagues in a landmark placebo-controlled, random- ized, doub le-blind, multicenter study, enrolled 300 adult patients with septic shock after undergoing a short high- dose (250 mg) corticotropin test. 11 Patients were ran- domly assigned to receive either hydrocortisone (50 mg IV q6h) and fludrocortisone (50 mg tablet once daily) (n ¼ 151) or matching placebos (n ¼ 149) for 7 days. The mortality was 53% in the corticosteroid group and 63% in the placebo group. Vasopressor therapy was with- drawn in 40% of patients who received placebo and in 57% in the corticosteroid group (hazard ratio, 1.91; 95% confidence interval, 1.29 to 2.84; p ¼ .001). Marik and Zaloga compared whether a baseline (random) cortisol concentration < 25 mg/dL was a better discriminator of adrenal insufficiency than the standard (250 mg) and the low-dose (1 mg) corticotropin stim- ulation tests in 59 patients with septic shock. 56 Follow- ing baseline cortisol level, patients were given 1 mgof corticotropin (low dose), followed 60 minutes later by an injection of 249 mg of corticotropin (high-dose test). Cortisol concentrations were obtained 30 and 60 mi- nutes after low- and high-dose corticotropin. All pa- tients were administered hydrocortisone (100 mg q8h) for the first 24 hours while awaiting results of cortisol assessment. Patients were considered steroid responsive if the pressor agent could be discontinued within 24 hours of the first dose of hydrocortisone. Sixty-one percent of patients met the criteria of A-1 when a baseline cortisol concentration of < 25 mg/dL was used. Ninety-five percent of steroid-responsive pa- tients had a baseline cortisol concentration < 25 mg/dL. Receiver operating characteristic curve analysis revealed that a stress cortisol concentration of 23.7 mg/dL was the most accurate diagnostic threshold for determination of the hemodynamic response to glucocorticoid therapy. The sensitivity of a baseline cortisol < 25 mg/dL in predicting steroid responsiveness was 96%, compared with 54% for the low-dose test and 22% for the high dose test. The specificities of the tests were 57, 97, and 100%, respectively. The area under the receiver operating characteristic curve of the stress (baseline) cortisol con- centration was 0.84; a stress cortisol concentration of 23.7 mg/dL had the best discriminating power, with a sensitivity of 0.86, a specificity of 0.66, a likelihood ratio of 2.6, a positive predictive value of 0.62, and a negative predictive value of 0.88. However, as discussed previously, it is unclear at this time whether a threshold of 20 mg/dL or 25 mg/dL should be used to determine treatment with hydro- cortisone. Due to poor sensitivity of low-dose and high-dose corticotropin stimulation testing we recom- mend that these tests be avoided in severely stressed, vasopressor-dependant septic shock patients to diagnose A-1. 56,89,99 From a practical point of view it is reasonable to initiate treatment with low-dose steroids in any patient presenting with septic shock and refractory hypotension pending the results of random cortisol (Fig. 2). 97 Glu- cocorticoids should be continued in those patients with a stress cortisol level of < 20 mg/dL and in those patients with a level > 20 mg/dL who have demonstrated a clear- cut hemodynamic response (lesser vasopressor require- ment) to glucocorticoid replacement. 56,64,89 We believe this to be a useful (although not the only) approach to the management of adrenal failure in the critically ill patient until more specific diagnostic tests become avail- able th at can quantitate glucocorticoid activity at the cellular or nuclear level. The ‘‘best’’ dosing schedule has yet to be determined; however, currently hydrocortisone at a dose of 50 mg q6h or 100 mg q8h is recommended. Alternatively hydrocortisone can be given as a 100 mg bolus, followed by an infusion at 10 mg/h. This latter regimen may result in better glycemic control. Hydro- cortisone should be continued for 5 to 7 days at the above dose before tapering, assuming that th ere is no recur- rence of signs of sepsis or shock. The hydrocortisone dose should then be reduced every 2 to 3 days by 50%, unless there is clinical deterioration, which would re- quire an increase in hydrocortisone dose. Currently, there are no data available to suggest how long hydro- cortisone should be continued and when and if ACTH E N DOC R INED I SOR DER S /RAGHAVAN, MARIK 281 testing should be performed (to confirm recovery of adrenal function). Furthermore, although there are few data, routine treatment with fludrocortisone is not rec- ommended at this time. CONCLUSION Stress hyperglycemia and A-1 are common in critically ill patients. Multiple pathogenetic mechanisms are re- sponsible for each of these distinct metabolic syndromes; however, increased release of proinflammatory mediators and counterregulatory hormones may play a pivotal role. Hyperglycemia per se is proin flammatory, whereas in- sulin has antiinflammatory properties. Similarly, A-1 is associated with a proinflammatory state, whereas steroid supplementation attenuates cortisol deficiency and in- flammation. If untreated, both are associated with a higher mortality. Currently available evidence is robust enough to suggest that a tight glycemic control with insulin and therapy of A-1 with steroid supplementation will improve survival in critically ill patients. AUTHORS’ NOTE The authors have no financial interest in any of the products mentioned in this article. REFERENCES 1. Van den Berghe G, Wouters P, Van Weekers F, et al. 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Comparison of low and high dose corticotropin stimulation tests in patients with pituitary disease. J Clin Endocrinol Metab 1998;83:1558–1562 E N DOC R INED I SOR DER S /RAGHAVAN, MARIK 285 Hematologic Disorders in Critically Ill Patients Kelly W. Mercer, M.D., 1 B. Gail Macik, M.D., 1 and Michael E. Williams, M.D. 1 ABSTRACT Hematologic disorders are frequently encountered in the intensive care unit. Thrombocytopenia, often defined as a platelet count below 100,000/mL, is common in critically ill patients and may be associated with adverse outcomes. A systematic evaluation of clinical and laboratory findings is necessary to ascertain the cause of the thrombocyto- penia and to determine the correct therapy. Reco gnition of heparin-induced thrombocy- topenia (HIT) is particularly important, given the risk of thrombosis associated with this condition. Prompt cessation of all heparin products is required, and anticoagulation with a direct thrombin inhibitor is recommended if HIT is strongly suspected. Coagulopathies are also common in the critically ill, and are often due to vitamin K deficiency or disseminated intravascular coagulation (DIC). A careful history and interpretation of clotting studi es are useful in defining the coagulation defect. Advances in understanding the pathogenesis of DIC have generated new treatment approaches, such as the use of recombinant activated protein C. Recombinant factor VIIa (rFVIIa) is a novel drug approved for use in patients with congenital hemophilias and inhibito rs. Although its use as a hemostatic agent is currently being evaluated in several off-label scenarios, including trauma, intracerebral hemorrhage, and liver disease, there are limited data to guide therapy in these conditions. KEYWORDS: Thrombocytopenia, coagulopathy, heparin-induced thrombocytopenia, disseminated intravascular coagulation, recombinant factor VIIa Hematologic disorders are common among crit- ically ill patients and frequently contribute to adverse outcomes. This review describes the most frequent non- neoplastic hematologic problems encountered in the intensive care unit and summarizes current approaches to diagnosis and management. THROMBOCYTOPENIA IN THE INTENSIVE CARE UNIT Thrombocytopenia is one of the most common labo- ratory abnormalities in the intensive care unit (ICU). It may occur via several mechanisms and in a variety of clinical scenarios. Thrombocytopenia may result in a bleeding diathesis necessitating transfusions; it may also predict for increased morbidity and mortality. Successful management of thrombocytopenia requires prompt and accurate recognition of its underlying cause. Drug-induced thrombocytopenia can be partic- ularly challenging because many critically ill patients receive multiple medications. Heparin-induced throm- bocytopenia is of special concern, given the associated risk of thrombosis and the unique treatment of this disorder. Thrombocytopenia is frequently defined as a platelet count below 100,000/mL. The incidence of 1 Division of Hematology/Oncology, University of Virginia School of Medicine, Charlottesville, Virginia. Address for correspondence and reprint requests: Michael E. Williams, M.D., Hematology/Oncology Division, Box 800716, Uni- versity of Virginia School of Medicine, Jefferson Park Ave., Charlot- tesville, VA 22908. E-mail: mew4p@virginia.edu. Non-pulmonary Critical Care: Managing Multisystem Critical Illness; Guest Editor, Curtis N. Sessler, M.D. Semin Respir Crit Care Med 2006;27:286–296. Copyright # 2006 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662. DOI 10.1055/s-2006-945529. ISSN 1069-3424. 286 [...]... diagnosis of HIT.29,32 2 87 288 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 27, NUMBER 3 Table 1 2006 Comparison of Argatroban and Lepirudin for Heparin-Induced Thrombocytopenia Argatroban Approved indication Lepirudin Prophylaxis or treatment of HIT; Treatment of HIT and associated PCI in patients with HIT thrombosis Structure Small molecule Recombinant hirudin Clearance Half-life Hepatic 40–50... hours after adjustments None 4 hours after adjustments None Special Issues - Dose reduction required in hepatic insufficiency: - Prolonged half-life in renal failure may with HIT, 2 mg/kg/min HIT without thrombosis 0.5 mg/kg/min require marked dose reduction - Significantly prolongs PT/INR - Antihirudin antibody formation in 50%; - Dose for PCI in patients may increase risk of bleeding; may with HIT: bolus... thrombocytopenia Bone marrow aspiration and biopsy may be necessary, particularly if a primary bone marrow disorder is suspected HEPARIN-INDUCED THROMBOCYTOPENIA Recognition of heparin-induced thrombocytopenia (HIT) and HIT with thrombosis (HITT) is of particular importance given its paradoxical association with thrombosis HIT/HITT is an immune-mediated disorder that is triggered by exposure to any form of... fibrin-fibrinogen degradation products (FDPs) and D-dimers, both of which indicate fibrinolysis and are elevated in consumptive coagulopathies such as DIC Examination of the peripheral blood smear can help rule out a microangiopathic process Coagulopathy associated with clinically important bleeding is noted in a significant minority of critical care patients Chakraverty et al studied 235 intensive care. .. to any form of heparin13,14; it is also known as type II HIT, to distinguish it from the non-immune-mediated, mild thrombocytopenia associated with heparin termed type I HIT Type II HIT is caused by the generation of heparin-induced, plateletactivating immunoglobulin G (IgG) antibodies that recognize heparin-platelet factor 4 complexes.15–18 The resulting platelet activation and thrombin generation... causes prolongation of the PT and a rise in the INR In cases of protracted and severe deficiency, the aPTT may also lengthen Vitamin K deficiency is a common cause of acquired coagulopathy in critical care patients .7, 36, 37 Factors contributing to the development of vitamin K deficiency include inadequate oral intake, recent major surgery, gastrointestinal disorders, and the use of broad spectrum antibiotics.38–40... nonimmune mechanisms, represents the most common reason for thrombocytopenia in ICU patients.10 Sepsis syndrome, DIC, immune thrombocytopenic purpura (ITP), drug-induced thrombocytopenia, and thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) are all associated with increased platelet destruction Assessment of the patient with thrombocytopenia should involve a thorough history and physical... platelet activation and antigen-based assays are available The serotonin release assay and the heparininduced platelet aggregation assay are functional tests of platelet activation Although these assays are more specific for clinical HIT than antigen-based tests, they are technically demanding to perform and are not widely available.16,33 The most commonly used test is an enzyme-linked immunoassay (ELISA)... platelet count has recovered to at least 100 Â 109/L, and only when given during overlapping therapy with an alternate anticoagulant.29 COAGULOPATHY IN THE INTENSIVE CARE UNIT Coagulation defects are common in critically ill patients.3 7 An adequate assessment of the bleeding patient requires not only a thorough history and physical examination but also a good understanding of coagulation laboratory... its underlying cause Coagulopathy due to DIC is of particular interest, given recent advances regarding its pathogenesis, diagnosis, and management Recombinant factor VIIa (rFVIIa) is a novel hemostatic agent being tested in several off-label clinical settings including trauma, intracerebral hemorrhage, and liver disease HEMATOLOGIC DISORDERS IN CRITICALLY ILL PATIENTS/MERCER ET AL Coagulopathic bleeding . produce cortisol. 9 b Secondary A-1 is defined as adrenal failure secondary to hypo- thalmo-pituitary-axis dysfunc tion. 9,61 278 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 27, NUMBER 3 2006 untreated. 67 In. levels and poor outcome in the critically ill? Crit Care Med 2004;32:1 977 –1 978 284 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 27, NUMBER 3 2006 75 . Yaguchi H, Tsutsumi K, Shimono. Box 80 071 6, Uni- versity of Virginia School of Medicine, Jefferson Park Ave., Charlot- tesville, VA 22908. E-mail: mew4p@virginia.edu. Non-pulmonary Critical Care: Managing Multisystem Critical