Non-pulmonary Critical Care - part 7 pdf

critical illness thereby counteracting the protein catabolism 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 between 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 outcome. 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 polyneuropathy, 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 intensive 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 nosocomial infections, including intravascular device, bloodstream, 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 insulin ‘‘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 pituitary, 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 disorders (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 immunodeficiency 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 systemic 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 treatment with corticosteroids. Adrenocorticotropin and Cortisol Resistance Patients with systemic infections [e.g., sepsis, human immunodeficiency virus (HIV)] may acquire A-1 associated 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 resistance. 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 reported 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 glucocorticoids 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 decreased 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 syndrome, high density lipoprotein (HDL) level at the time of adrenal testing was the only variable predictive of adrenal insufficiency (p < .0001). In vasopressor-dependent patients with A-1, treatment with hydrocortisone 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 without 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 component 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 accumulation of CLA-1 messenger RNA is upregulated by adrenocorticotropin in primary cultures of normal human 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 proinflammatory mediators and HDL/Apo-1 levels is associated 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 development of adrenal failure (adrenal exhaustion syndrome) in patients who had preserved adrenal function at admission. 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 [lipopolysaccharide (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 addition, 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 patient is suggestive of HPA dysfunction. 57 In moderately stressed patients, ‘‘adrenal reserve’’ can be assessed by the low dose (LD; 1 mg) corticotropin (Synacthen) stimulation 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 corticotropin; 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 sensitivity 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 patients 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 hemodynamic status, downregulate the proinflammatory response, and improve survival 10,11,96–98 Annane and colleagues in a landmark placebo-controlled, randomized, 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 stimulation 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 minutes after low- and high-dose corticotropin. All patients 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 patients 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 concentration 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 hydrocortisone. Due to poor sensitivity of low-dose and high-dose corticotropin stimulation testing we recommend 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 available 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 require an increase in hydrocortisone dose. Currently, there are no data available to suggest how long hydrocortisone 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 recommended at this time. CONCLUSION Stress hyperglycemia and A-1 are common in critically ill patients. Multiple pathogenetic mechanisms are responsible 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 insulin has antiinflammatory properties. Similarly, A-1 is associated with a proinflammatory state, whereas steroid supplementation attenuates cortisol deficiency and inflammation. 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. Intensive insulin therapy in the critically ill patients. N Engl J Med 2001;345:1359–1367 Figure 2 Recommended strategy for evaluation and treatment of adrenal insufficiency among the critically ill. 282 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 27, NUMBER 3 2006 2. Van den Berghe G, Schoonheydt K, Becx P, Bruyninckx F, Wouters PJ. Insulin therapy protects the central and peripheral nervous system of intensive care patients. Neurology 2005;64: 1348–1353 3. Krinsley JS. Effect of an intensive glucose management protocol on the mortality of critically ill adult patients. Mayo Clin Proc 2004;79:992–1000 4. Bochicchio GV, Sung J, Joshi M, et al. Persistent hyperglycemia is predictive of outcome in critically ill trauma patients. J Trauma 2005;58:921–924 5. Laird AM, Miller PR, Kilgo PD, Meredith JW, Chang MC. Relationship of early hyperglycemia to mortality in trauma patients. J Trauma 2004;56:1058–1062 6. Finney SJ, Zekveld C, Elia A, Evans TW. Glucose control and mortality in critically ill patients. JAMA 2003;290:2041–2047 7. Pittas AG, Siegel RD, Lau J. Insulin therapy for critically ill hospitalized patients: a meta-analysis of randomized controlled trials. Arch Intern Med 2004;164:2005–2011 8. Krinsley JS. Association between hyperglycemia and increased hospital mortality in a heterogeneous population of critically ill patients. Mayo Clin Proc 2003;78:1471–1478 9. Marik PE, Zaloga GP. Adrenal insufficiency in the critically ill: a new look at an old problem. Chest 2002;122:1784–1796 10. Annane D, Bellissant E, Bollaert PE, Briegel J, Keh D, Kupfer Y. Corticosteroids for severe sepsis and septic shock: a systematic review and meta-analysis. BMJ 2004;329:489 11. Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002;288:862– 871 12. Marik PE, Raghavan M. Stress-hyperglycemia, insulin and immunomodulation in sepsis. Intensive Care Med 2004;30: 748–756 13. Hart BB, Stanford GG, Ziegler MG, Lake CR, Chernow B. Catecholamines: study of interspecies variation. Crit Care Med 1989;17:1203–1222 14. Van den BG. Neuroendocrine pathobiology of chronic critical illness. Crit Care Clin 2002;18:509–528 15. Siegel JH, Cerra FB, Coleman B, et al. Physiological and metabolic correlations in human sepsis: invited commentary. Surgery 1979;86:163–193 16. Clowes GH Jr, Martin H, Walji S, Hirsch E, Gazitua R, Goodfellow R. Blood insulin responses to blood glucose levels in high output sepsis and septic shock. Am J Surg 1978;135: 577–583 17. Mizock BA. Alterations in fuel metabolism in critical illness: hyperglycaemia. Best Pract Res Clin Endocrinol Metab 2001;15:533–551 18. Dahn MS, Jacobs LA, Smith S, et al. The relationship of insulin production to glucose metabolism in severe sepsis. Arch Surg 1985;120:166–172 19. Mehta VK, Hao W, Brooks-Worrell BM, Palmer JP. Low- dose interleukin 1 and tumor necrosis factor individually stimulate insulin release but in combination cause suppres- sion. Eur J Endocrinol 1994;130:208–214 20. McCowen KC, Malhotra A, Bistrian BR. Stress-induced hyperglycemia. Crit Care Clin 2001;17:107–124 21. Frankenfield DC, Omert LA, Badellino MM, et al. Corre- lation between measured energy expenditure and clinically obtained variables in trauma and sepsis patients. JPEN J Parenter Enteral Nutr 1994;18:398–403 22. Norhammar AM, Ryden L, Malmberg K. Admission plasma glucose: independent risk factor for long-term prognosis after myocardial infarction even in nondiabetic patients. Diabetes Care 1999;22:1827–1831 23. Zindrou D, Taylor KM, Bagger JP. Admission plasma glucose: an independent risk factor in nondiabetic women after coronary artery bypass grafting. Diabetes Care 2001;24: 1634–1639 24. Malmberg K, Norhammar A, Wedel H, Ryden L. Glyco- metabolic state at admission: important risk marker of mortality in conventionally treated patients with diabetes mellitus and acute myocardial infarction: long-term results from the Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) study. Circulation 1999; 99:2626–2632 25. Capes SE, Hunt D, Malmberg K, Pathak P, Gerstein HC. Stress hyperglycemia and prognosis of stroke in nondiabetic and diabetic patients: a systematic overview. Stroke 2001;32: 2426–2432 26. Malmberg K. Prospective randomised study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus. DIGAMI (Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction) Study Group. BMJ 1997;314:1512– 1515 27. Malmberg K, Ryden L, Efendic S, et al. Randomized trial of insulin-glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction (DIGAMI study): effects on mortality at 1 year. J Am Coll Cardiol 1995;26:57–65 28. Woo J, Lam CW, Kay R, Wong AH, Teoh R, Nicholls MG. The influence of hyperglycemia and diabetes mellitus on immediate and 3-month morbidity and mortality after acute stroke. Arch Neurol 1990;47:1174–1177 29. Garg R, Tripathy D, Dandona P. Insulin resistance as a proinflammatory state: mechanisms, mediators, and therapeutic interventions. Curr Drug Targets 2003;4:487–492 30. Dandona P, Aljada A, Bandyopadhyay A. The potential therapeutic role of insulin in acute myocardial infarction in patients admitted to intensive care and in those with unspecified hyperglycemia. Diabetes Care 2003;26:516–519 31. Hansen TK, Thiel S, Wouters PJ, Christiansen JS, Van den BG. Intensive insulin therapy exerts antiinflammatory effects in critically ill patients and counteracts the adverse effect of low mannose-binding lectin levels. J Clin Endocrinol Metab 2003;88:1082–1088 32. Ceriello A, Bortolotti N, Motz E, et al. Meal-induced oxidative stress and low-density lipoprotein oxidation in diabetes: the possible role of hyperglycemia. Metabolism 1999;48: 1503–1508 33. Mowlavi A, Andrews K, Milner S, Herndon DN, Heggers JP. The effects of hyperglycemia on skin graft survival in the burn patient. Ann Plast Surg 2000;45:629–632 34. Furnary AP, Zerr KJ, Grunkemeier GL, Starr A. Continuous intravenous insulin infusion reduces the incidence of deep sternal wound infection in diabetic patients after cardiac surgical procedures. Ann Thorac Surg 1999;67:352–360 35. Zerr KJ, Furnary AP, Grunkemeier GL, Bookin S, Kanhere V, Starr A. Glucose control lowers the risk of wound infection in diabetics after open heart operations. Ann Thorac Surg 1997;63:356–361 36. McManus LM, Bloodworth RC, Prihoda TJ, Blodgett JL, Pinckard RN. Agonist-dependent failure of neutrophil function in diabetes correlates with extent of hyperglycemia. J Leukoc Biol 2001;70:395–404 E N DOC R INED I SOR DER S /RAGHAVAN, MARIK 283 37. Evans TW. Hemodynamic and metabolic therapy in critically ill patients. N Engl J Med 2001;345:1417–1418 38. Vanhorebeek I, De Vos R, Mesotten D, Wouters PJ, Wolf- Peeters C, Van den BG. Protection of hepatocyte mitochon- drial ultrastructure and function by strict blood glucose control with insulin in critically ill patients. Lancet 2005; 365:53–59 39. Dandona P, Aljada A, Mohanty P, et al. Insulin inhibits intranuclear nuclear factor kappaB and stimulates IkappaB in mononuclear cells in obese subjects: evidence for an antiinflammatory effect? J Clin Endocrinol Metab 2001;86:3257– 3265 40. Langouche L, Vanhorebeek I, Vlasselaers D, et al. Intensive insulin therapy protects the endothelium of critically ill patients. J Clin Invest 2005;115:2277–2286 41. Whalen MJ, Doughty LA, Carlos TM, Wisniewski SR, Kochanek PM, Carcillo JA. Intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 are increased in the plasma of children with sepsis-induced multiple organ failure. Crit Care Med 2000;28:2600–2607 42. Boldt J, Wollbruck M, Kuhn D, Linke LC, Hempelmann G. Do plasma levels of circulating soluble adhesion molecules differ between surviving and nonsurviving critically ill patients? Chest 1995;107:787–792 43. Sakurai Y, Aarsland A, Herndon DN, et al. Stimulation of muscle protein synthesis by long-term insulin infusion in severely burned patients. Ann Surg 1995;222:283–294 44. Gore DC, Wolf SE, Sanford AP, Herndon DN, Wolfe RR. Extremity hyperinsulinemia stimulates muscle protein synthesis in severely injured patients. Am J Physiol Endocrinol Metab 2004;286:E529–E534 45. Woolfson AM, Heatley RV, Allison SP. Insulin to inhibit protein catabolism after injury. N Engl J Med 1979;300:14– 17 46.VandenBG,WoutersPJ,BouillonR,etal.Outcome benefit of intensive insulin therapy in the critically ill: insulin dose versus glycemic control. Crit Care Med 2003;31:359– 366 47. Krinsley J, Grissler B. Intensive glycemic management in critically ill patients. Jt Comm J Qual Patient Saf 2005;31: 308–312 48. Grey NJ, Perdrizet GA. Reduction of nosocomial infections in the surgical intensive-care unit by strict glycemic control. Endocr Pract 2004;10(Suppl 2):46–52 49. Marik PE, Zaloga GP. Early enteral nutrition in acutely ill patients: a systematic review. Crit Care Med 2001;29:2264– 2270 50. Marik PE, Pinsky M. Death by parenteral nutrition. Intensive Care Med 2003;29:867–869 51. Dickerson RN. Hypocaloric feeding of obese patients in the intensive care unit. Curr Opin Clin Nutr Metab Care 2005;8:189–196 52. Moore FA, Feliciano DV, Andrassy RJ, et al. Early enteral feeding, compared with parenteral, reduces postoperative septic complications: the results of a meta-analysis. Ann Surg 1992;216:172–183 53. Jenkins DJ, Ghafari H, Wolever TM, et al. Relationship between rate of digestion of foods and post-prandial glycaemia. Diabetologia 1982;22:450–455 54. Marik PE, Zaloga GP. Gastric versus post-pyloric feeding: a systematic review. Crit Care 2003;7:R46–R51 55. Krishnan JA, Parce PB, Martinez A, Diette GB, Brower RG. Caloric intake in medical ICU patients: consistency of care with guidelines and relationship to clinical outcomes. Chest 2003;124:297–305 56. Marik PE, Zaloga GP. Adrenal insufficiency during septic shock. Crit Care Med 2003;31:141–145 57. Cooper MS, Stewart PM. Corticosteroid insufficiency in acutely ill patients. N Engl J Med 2003;348:727–734 58. Annane D, Sebille V, Troche G, Raphael JC, Gajdos P, Bellissant E. A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin. JAMA 2000;283:1038–1045 59. Marik PE, Kiminyo K, Zaloga GP. Adrenal insufficiency in critically ill patients with human immunodeficiency virus. Crit Care Med 2002;30:1267–1273 60. Harry R, Auzinger G, Wendon J. The clinical importance of adrenal insufficiency in acute hepatic dysfunction. Hepatology 2002;36:395–402 61. Dimopoulou I, Tsagarakis S, Anthi A, et al. High prevalence of decreased cortisol reserve in brain-dead potential organ donors. Crit Care Med 2003;31:1113–1117 62. Kilger E, Weis F, Briegel J, et al. Stress doses of hydrocortisone reduce severe systemic inflammatory response syndrome and improve early outcome in a risk group of patients after cardiac surgery. Crit Care Med 2003;31:1068–1074 63. Marik PE, Zaloga GP. The central nervous system hypothalamic-pituitary-adrenal axis in sepsis. Crit Care Med 2002; 30:490–491 64. Raghavan M, Marik PE. Management of sepsis during the early ‘‘golden hours.’’ J Emerg Med 2006; In press 65. Beishuizen A, Thijs LG, Vermes I. Patterns of corticosteroid- binding globulin and the free cortisol index during septic shock and multitrauma. Intensive Care Med 2001;27:1584– 1591 66. Zaloga GP. Sepsis-induced adrenal deficiency syndrome. Crit Care Med 2001;29:688–690 67. Schroeder S, Wichers M, Klingmuller D, et al. The hypothalamic-pituitary-adrenal axis of patients with severe sepsis: altered response to corticotropin-releasing hormone. Crit Care Med 2001;29:310–316 68. Norbiato G, Bevilacqua M, Vago T, et al. Cortisol resistance in acquired immunodeficiency syndrome. J Clin Endocrinol Metab 1992;74:608–613 69. Ali M, Allen HR, Vedeckis WV, Lang CH. Depletion of rat liver glucocorticoid receptor hormone-binding and its mRNA in sepsis. Life Sci 1991;48:603–611 70. Molijn GJ, Koper JW, van Uffelen CJ, et al. Temperature- induced down-regulation of the glucocorticoid receptor in peripheral blood mononuclear leucocyte in patients with sepsis or septic shock. Clin Endocrinol (Oxf) 1995;43:197– 203 71. Melby JC, Spink WW. Comparative studies on adrenal cortical function and cortisol metabolism in healthy adults and in patients with shock due to infection. J Clin Invest 1958; 37:1791–1798 72. Marik PE, Gayowski T, Starzl TE. The hepatoadrenal syndrome: a common yet unrecognized clinical condition. Crit Care Med 2005;33:1254–1259 73. Singh N, Gayowski T, Marino IR, Schlichtig R. Acute adrenal insufficiency in critically ill liver transplant recipients. Implications for diagnosis. Transplantation 1995;59:1744– 1745 74. Marik PE. Adrenal insufficiency: the link between low apolipoprotein A-1 levels and poor outcome in the critically ill? Crit Care Med 2004;32:1977–1978 284 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 27, NUMBER 3 2006 75. Yaguchi H, Tsutsumi K, Shimono K, Omura M, Sasano H, Nishikawa T. Involvement of high density lipoprotein as substrate cholesterol for steroidogenesis by bovine adrenal fasciculo-reticularis cells. Life Sci 1998;62:1387–1395 76. Borkowski AJ, Levin S, Delcroix C, Mahler A, Verhas V. Blood cholesterol and hydrocortisone production in man: quantitative aspects of the utilization of circulating cholesterol by the adrenals at rest and under adrenocorticotropin stimulation. J Clin Invest 1967;46:797–811 77. Liu J, Heikkila P, Meng QH, Kahri AI, Tikkanen MJ, Voutilainen R. Expression of low and high density lipoprotein receptor genes in human adrenals. Eur J Endocrinol 2000; 142:677–682 78. Calvo D, Gomez-Coronado D, Lasuncion MA, Vega MA. CLA-1 is an 85-kD plasma membrane glycoprotein that acts as a high-affinity receptor for both native (HDL, LDL, and VLDL) and modified (OxLDL and AcLDL) lipoproteins. Arterioscler Thromb Vasc Biol 1997;17:2341–2349 79. van der Voort PH, Gerritsen RT, Bakker AJ, Boerma EC, Kuiper MA, de Heide L. HDL-cholesterol level and cortisol response to synacthen in critically ill patients. Intensive Care Med 2003;29:2199–2203 80. Chenaud C, Merlani PG, Roux-Lombard P, et al. Low apolipoprotein A-1 level at intensive care unit admission and systemic inflammatory response syndrome exacerbation. Crit Care Med 2004;32:632–637 81. Mookerjee RP, Sen S, Davies NA, Hodges SJ, Williams R, Jalan R. Tumour necrosis factor alpha is an important mediator of portal and systemic haemodynamic derangements in alcoholic hepatitis. Gut 2003;52:1182–1187 82. Yokoyama I, Gavaler JS, Todo S, Miyata T, Van Thiel DH, Starzl TE. Endotoxemia is associated with renal dysfunction in liver transplantation recipients during the first postoperative week. Hepatogastroenterology 1995;42: 205–208 83. Rasaratnam B, Kaye D, Jennings G, Dudley F, Chin-Dusting J. The effect of selective intestinal decontamination on the hyperdynamic circulatory state in cirrhosis: a randomized trial. Ann Intern Med 2003;139:186–193 84. Vishnyakova TG, Bocharov AV, Baranova IN, et al. Binding and internalization of lipopolysaccharide by CLA-1, a human orthologue of rodent scavenger receptor B1. J Biol Chem 2003;278:22771–22780 85. Baranova I, Vishnyakova T, Bocharov A, et al. Lipopoly- saccharide down regulates both scavenger receptor B1 and ATP binding cassette transporter A1 in RAW cells. Infect Immun 2002;70:2995–3003 86. Ettinger WH, Varma VK, Sorci-Thomas M, et al. Cytokines decrease apolipoprotein accumulation in medium from Hep G2 cells. Arterioscler Thromb 1994;14:8–13 87. Soni A, Pepper GM, Wyrwinski PM, et al. Adrenal insufficiency occurring during septic shock: incidence, outcome, and relationship to peripheral cytokine levels. Am J Med 1995;98:266–271 88. Marik P, Zaloga G. Prognostic value of cortisol response in septic shock. JAMA 2000;284:308–309 89. Marik PE. Unraveling the mystery of adrenal failure in the critically ill. Crit Care Med 2004;32:596–597 90. Hamrahian AH, Oseni TS, Arafah BM. Measurements of serum free cortisol in critically ill patients. N Engl J Med 2004;350:1629–1638 91. Sun X, Fischer DR, Pritts TA, Wray CJ, Hasselgren PO. Expression and binding activity of the glucocorticoid receptor are upregulated in septic muscle. Am J Physiol Regul Integr Comp Physiol 2002;282:R509–R518 92. Liu DH, Su YP, Zhang W, et al. Changes in glucocorticoid and mineralocorticoid receptors of liver and kidney cytosols after pathologic stress and its regulation in rats. Crit Care Med 2002;30:623–627 93. Dimopoulou I, Tsagarakis S, Kouyialis AT, et al. Hypothala- mic-pituitary-adrenal axis dysfunction in critically ill patients with traumatic brain injury: incidence, pathophysiology, and relationship to vasopressor dependence and peripheral interleukin-6 levels. Crit Care Med 2004;32:404–408 94. Schenarts CL, Burton JH, Riker RR. Adrenocortical dysfunction following etomidate induction in emergency department patients. Acad Emerg Med 2001;8:1–7 95. Drucker D, Shandling M. Variable adrenocortical function in acute medical illness. Crit Care Med 1985;13:477–479 96. Keh D, Boehnke T, Weber-Cartens S, et al. Immunologic and hemodynamic effects of ‘‘low-dose’’ hydrocortisone in septic shock: a double-blind, randomized, placebo-controlled, cross- over study. Am J Respir Crit Care Med 2003;167:512–520 97. Dellinger RP, Carlet JM, Masur H, et al. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med 2004;32:858–873 98. Briegel J, Forst H, Haller M, et al. Stress doses of hydrocortisone reverse hyperdynamic septic shock: a prospective, randomized, double-blind, single-center study. Crit Care Med 1999;27:723–732 99. Mayenknecht J, Diederich S, Bahr V, Plockinger U, Oelkers W. 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 thrombocytopenia and to determine the correct therapy. Reco gnition of heparin-induced thrombocytopenia (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 critically 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 laboratory 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 particularly challenging because many critically ill patients receive multiple medications. Heparin-induced thrombocytopenia 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

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