Blood Transfusion and Its Components

E. Celis-Rodriguez, K. Reinhart, Y. Sakr

Transfusion of blood products in the critical care setting is a common practice that has been performed for many years. Since the 19th century, when James Blundell reported the clinical application of the treatment of hemorrhage for the first time in the Lancet [1], blood transfusion has been the cornerstone in the treatment of severe hemorrhage, not only as a means of improving oxygen transport capacity, but also to maintain homeostasis and reduce mortality rates [1]. The 10/30 rule was the standard of care for decades [2], but the first report of this appeared in the 1940s, when Lundy et al. [3] stated that “It is a clever idea to provide blood before surgery,” referring to patients whose hemoglobin levels were between 8 and 10 g/dL. With the more restrictive use of blood transfusion since the 1980s, there have been attempts to define specific indications for transfusion, minimal hemoglobin levels for critically ill patients, and the benefits and potential risks of transfusion [4].
Recent publications have proposed targeting lower hemoglobin levels (7 g/dL) to reduce complications related to transfusion of blood products, such as transfusion related infections, immunosuppression, transfusion-related acute lung injury (TRALI), hemolytic reactions and fever reactions, in addition to its effects on mortality.
The use of blood derivates, such as fresh frozen plasma (FFP), cryoprecipitates and platelets for the treatment of bleeding is yet to be defined with accuracy. Despite the large amounts of FFP being transfused every year all over the world, there is clinical and laboratory evidence that this may not always be appropriate. In the future, the application of genomic tests to evaluate hemostatic function will make it possi Anemia in Critically Ill Patients
Anemia is common in critically ill patients, and is usually diagnosed after measuring the concentration of hemoglobin (Hb) and the hematocrit (Hct), which reveals the ratio between the existing red blood cells and the plasma volume [5]. Anemia is defined as a concentration of Hb which is below the expected value, taking into account age, gender, pregnancy, and some environmental factors, including altitude above sea level [6] which leads to a reduction in the erythrocyte mass and hence in a lower ability to carry oxygen. The World Health Organization (WHO) has defined anemia as an Hb concentration less than 13 g/dL (Hct <39 %) in adult males, and less than 12 g/dL (Hct <36%) in adult, nonpregnant females [6]. The condition of critically ill patients can worsen in the presence of anemia; however, aggressive treatment of anemia in these patients may be as harmful as no treatment [7].
The incidence of anemia in patients admitted to the intensive care unit (ICU) varies depending on the population studied, and on the severity of the disease and on coexisting comorbidities. The ABC trial [8] reported an average Hb value of 11.3 (g/dL) at ICU admission; 63% of the patients had an Hb level lower than 12 g/dL on admission and in 29% it was less than 10 g/dL. In the CRIT trial [9], nearly two thirds of the 4,892 patients tested had Hb levels less than 12 g/dL on admission to the ICU.
Anemia in critically ill patients is multifactorial and is hematologically similar to chronic anemia, but often patients experience acute onset anemia [7]. Some of the causes (Table 34.1) can be modified, which may facilitate prevention strategies, such as making the collection of blood samples more efficient in order to reduce losses, guiding fluid replacement therapy to avoid extreme hemodilution, and the supply of iron.
Nguyen et al. [10] reported that during a patient’s stay in the ICU, the Hb concentration decreases by up to 0.66 g/dL per day during the first 3 days and then it continues to decrease at a rate of 0.12 g/dL per day. Similar findings have been reported in large observational studies [8,9].
The biochemical characteristics of anemia in critically ill patients include a low serum iron concentration, a low binding affinity for iron, a low ratio between serum iron and total iron, increased ferritin levels, reduced transferrin, low transferrin saturation with normal concentration of receptors for soluble ferritin, normal or high percentages of hypochromic red cells, and a normal or slightly increased concentration of erythropoietin [7,11].
Table 34.1 Etiology of anemia in critical illness. [7]
Etiology of anemia in critical illness
During inflammation, normal erythrogenesis is inhibited, which contributes to critical illness anemia by a similar mechanism to that described by Weiss et al. for chronic inflammatory conditions [12]. In addition, high circulating levels of proinflammatory cytokines, such as tumor necrosis factor (TNF)-a, interleukin (IL)-6, IL1, C-reactive protein (CRP), and interferon (IFN) a, ß, and γ, decreased production of erythropoietin, deficient erythropoiesis, increased free radicals, and a reduction in the average life of erythrocytes are also responsible for the appearance of anemia in less than a week [7,12].
When Should Critically Ill Patients Be Transfused?
Different studies have attempted to determine at which Hb threshold a critically ill patient should be transfused. In the past few years, we have observed that the results obtained in these studies have positively influenced daily medical practice. One of the recent changes was in the guidelines published by the Surviving Sepsis Campaign in 2008, in which they recommend that adult patients suffering from severe sepsis whose tissue hypoperfusion has been resolved after the acute resuscitation period, and who have no prior record of ischemic heart disease, severe hypoxemia, acute hemorrhage, cyanotic heart disease or lactic acidosis should only receive a blood transfusion when the Hb concentration is less than 7.0 g/dL, in order to keep the Hb level between 7.0 and 9.0 g/dL (Grade 1B recommendation) [13].
Although the optimal Hb level for patients with serious sepsis has not yet been established, the TRICC study [14], a randomized, controlled trial including 838 critically ill patients suggested that Hb levels between 7.0 to 9.0 g/dL, as compared with Hb levels between 10.0 and 12.0 g/dL, were not associated with increased mortality rates in adults. These findings support the suggestion that transfusions must be performed only when Hb levels are less than 7.0 g/dL. The exceptions identified in this study include chronic ischemic heart disease and acute coronary syndrome, in which the critical Hb level should be near 9.0 g/dL.
A restrictive approach to transfusion should be considered on an individual basis, based on comorbidities and on physiological knowledge of the different phases of oxygen delivery (DO2), as proposed by Laks et al. in 1972 [15] and Messmer in 1981 [16]. These groups referred to hemodynamic changes as consequences of the acute normovolemic hemodilution technique [16]. In the oxygenation phase, in which the union of oxygen to Hb depends on affinity, transportation, and delivery are not altered. The p50 changed only when the Hct levels were close to 10%, while DO2 increased up to 106% when the Hct levels ranged between 27.5% and 30% (Fig. 34.1) [15,16].
Tissue DO2 is altered in inflammatory processes
Tissue DO2 is altered in inflammatory processes because of changes in the structure of erythrocytes, resulting from the reduction of glycophorins in the cell membrane, which leads to a more spherical shape and a reduction in the capacity to be deformed. This in turn results in altered blood rheology, and a reduction in the concentration of intracell 2,3-DPG, conditions which alter the capture and delivery of oxygen at a tissue level [3,17].
Blood Transfusion in Patients Receiving Mechanical Ventilation
Some studies have evaluated the impact of transfusion on prognosis in patients receiving mechanical ventilation. It has been suggested that blood transfusion might improve DO2 to compensate for the high demand for oxygen as mechanical ventilation is withdrawn [18]. A study published by Hébert et al. compared the duration of ventilatory support and the rate of weaning success in 730 patients. One group received a restrictive transfusion strategy, and the other a liberal transfusion strategy. It was not possible to conclude that the liberal transfusion of red blood cells reduced the length of time during which patients required mechanical ventilation [18].
Levy et al. [19] performed a retrospective analysis of the database of the CRIT study, including 4,892 patients. The reasons for performing transfusions on patients receiving mechanical ventilation and on patients not receiving mechanical ventilation were compared. Nearly 60% of the included patients were receiving mechanical ventilation and had significantly higher APACHE II scores (p <0.0001). Patients receiving mechanical ventilation received more red blood cell units (Hb 8.7 g/dL on average) than patients with no mechanical ventilation (Hb 8.2 g/dL on average). Mortality rates were higher in the mechanical ventilation group (17.2 vs. 4.5%, p <0.001), as was the length of time they stayed in the ICU and the hospital.
Transfusion in Patients With Ischemic Heart Disease
A large number of recent publications support the idea that anemic patients with underlying ischemic heart disease have poorer outcomes, as measured by several variables, than ischemic heart patients with higher Hb concentrations, defining anemia as any Hb concentration below 13 g/dL.
Hébert et al. [20], in a multicenter, randomized, controlled trial including 838 patients, found that patients with heart disease and higher Hb levels had lower mortality rates as compared with those with lower Hb levels. A study by Zeidman et al. [21] compared ischemic heart disease patients with and without anemia. Anemic patients experienced more arrhythmias and congestive heart failure and had higher mortality rates than nonanemic patients. Similar findings have been reported by others in patients with acute coronary syndrome, heart attack with or without ST-segment elevation, recurring ischemic events, and elderly patients younger than 70 with ischemic heart disease [22–25].
However, although the association between anemia and a negative prognosis in these patients is supported by evidence, the existing literature also shows that transfusions do not seem to be routinely prescribed [26].
The Benefits and Risks of Transfusions
In normal physiological conditions, DO2 depends on the metabolic oxygen consumption (VO2). If DO2 is considerably reduced, so is VO2, leading to a critical condition called oxygen debt or anaerobic threshold. Transfusions are performed in order to resolve this situation, mainly occurring as the result of acute blood loss through hemorrhage, by increasing the erythrocyte cell mass and the blood volume. Transfusions are also used in clinical practice in order to increase DO2 , thus alleviating symptoms associated with anemia, such as fatigue, mental confusion, and adynamia, especially in elderly patients. If untreated, serious anemia may lead to anaerobiosis or tissue ischemia. However, the transfusion of red blood cells has not proved to be an efficient way of treating this situation [27,28].
The effects of transfusions on microvascular perfusion are not well defined. In anemic preterm infants, transfusion was associated with a significant increase in functional capillary density, as assessed by an orthogonal polarization spectral (OPS) probe applied to the skin of the upper arm [29]. Functional capillary density increased already 2 h after transfusion and increased further after 24 h, indicating improved microvascular perfusion; there were no changes in clinical variables such as heart rate or blood pressure. In adult ICU patients with sepsis, we recently used OPS to investigate the effects of RBC transfusion on sublingual microvascular perfusion [30]. Microvascular perfusion was not significantly altered by the transfusion of 1–2 units of leukocyte-reduced blood. There was, however, considerable interindividual variability. The change in capillary perfusion after transfusion correlated with baseline capillary perfusion, with baseline capillary perfusion being significantly lower in patients who increased their capillary perfusion following transfusion compared to those who did not. However, hemodynamic and global oxygen transport variables were similar in the two groups. Thus, the microcirculation in septic patients who already have microcirculatory changes may improve with transfusion. Similar observations have been made in anemic patients with traumatic brain injury. Leal Noval et al. [31] observed that RBC transfusions had a variable effect on brain oxygenation. Interestingly, cerebral oxygenation improved only in patients with altered cerebral oxygenation at baseline. Although microcirculatory blood flow was not directly measured in this study, it was estimated by a surrogate measurement (near infra-red spectroscopy).
The transfusion of red blood cells may lead to well-known adverse effects, such as the transmission of viral infectious diseases [hepatitis A, B, C, human immunodeficiency virus (HIV)], bacterial and parasite infections (Chagas’ disease, malaria), and infections caused by prions. Noninfectious complications include volume overload, fever, anaphylactic, allergic or hemolytic reactions, TRALI, multiple organ failure, and a longer hospital stay [32–34]. In a study including 2,085 patients, Taylor et al. [34] reported a higher rate of nosocomial infections in patients who had received transfusions than in those who had not (14.3% vs. 5.8%). The exact mechanism by which transfusions are related to higher morbidity and mortality rates and higher infection rates is not well defined. It is believed that immunomodulation and the transfusion of old erythrocytes could be likely causes [33–40] (Table 34.2).
Blood Transfusion and Mortality
Different studies have reported an increase in mortality rates in critically ill patients who have received red blood cell transfusions during their stay in hospital [8,9]. Results from the ABC trial, which included 3,534 critically ill patients, revealed a 28-day mortality rate of 22.7% in patients receiving transfusions, compared to 17.1% in patients who did not receive a transfusion (p <0.02), showing that receiving a transfusion increased the risk of death by a factor of 1.4 [8]. The CRIT trial yielded similar results [9]. A recently published population-based cohort study by Kamper-Jørgensen et al. carried out in Sweden and Norway [38] on a total of 1,118,261 transfusions reported that the standardized mortality rate in the 3 months following the transfusion was 17.6 times higher compared with the general population; from 1 to 4 years after the first transfusion, the standardized mortality rate was 2.1 times higher, and 17 years later it was still 1.3 times higher.
Table 34.2 Incidence of adverse effects associated with transfusions
Incidence of adverse effects associated with transfusions
However, the SOAP study, which analyzed data from 3,147 patients in 198 European ICUs in May 2002 reported that, unlike the ABC [8] and CRIT [9] studies, transfusion was not linked to an increase in mortality rates in a multivariate analysis. Although the ABC and SOAP studies shared similar design and analyses, a plausible explanation for this important difference in results was the increased use of leukocyte-free blood at the time of the SOAP study [36]. Leukocyte reduction is used to minimize the presence of white cells by means of centrifugation or filtration. Using this technique, it is possible to reduce the presence of leukocytes up to 99% and it has been effective in reducing the number of cell-associated viruses, such as cytomegalovirus, herpes virus, and Epstein-Barr virus. Leukoreduction may also reduce the transmission of parasites and prions, and the incidence of transfusion related fever reactions and TRALI [38–40].
The Use of Fresh Frozen Plasma
Several million units of FFP are transfused every day (>4 million in England and the USA), and use of FFP has increased significantly in recent years. For example, in the USA in 1979, one unit of FFP was transfused compared to 6.6 units of red blood cells. In 2001, the ratio was one unit of FFP to 3.6 units of red blood cells [1,42]. This is possibly due to the fact that the number of invasive procedures is increasing and surgeons attempt to maintain available laboratory tests (PT, PTT, and INR) within normal ranges in order to prevent complications associated with bleeding [1].
However, recent literature shows that the international normalized ratio (INR) and the activated partial thromboplastin time (aPTT) fail to predict which patients will suffer from bleeding as a result of an invasive procedure, and hence they should not be used to make decisions related to prophylactic procedures or transfusions [1]. These tests were not developed for this purpose, but rather to explore hemostatic defects in patients already identified as suffering from coagulopathy. They fail to measure global hemostasis and cannot identify some coagulation defects; most importantly, they wrongly suggest the presence of defects which do not exist [1,43]. The belief that transfusion of FFP may correct mild to moderate coagulation defects is unfounded, as is the idea that the INR predicts bleeding, and that FFP corrects the INR in this type of patient. In the future, genomic applications will help to improve diagnosis and hence treatment [1]. Until then, the recommendation is to use FFP in patients with massive hemorrhage or abundant bleeding with prolonged PT and aPTT (>1.5 times normal). The recommended initial dose is 10–15 ml/kg. Larger doses may be required depending on the diagnosis and the clinical situation [42].
There is no scientific basis for defining a minimal platelet count as 20,000/µL. There is a real danger of massive bleeding when the number of platelets is below 5,000 to 10,000/µL and there is a risk of intracranial hemorrhage when the numbers are below 1,000/µL. Patients with chronic autoimmune thrombocytopenia may tolerate values between 5,000 to 10,000/µL for years and transfusion is not necessary in such patients, especially when their condition is stable [42].
However, in severely traumatized patients with massive hemorrhage, it is recommended that the number of platelets be kept above 50,000/µL and when there is associated cranial trauma, it is suggested that the platelet count be kept greater than 100,000/µL. One possible explanation for this recommendation is that in these situations, patients have increased fibrin degradation products, disseminated intravascular coagulation (DIC), or hyperfibrinolysis, which interferes with platelet function and hence, a larger number of platelets could be beneficial. Evidence supporting this concept is, however, weak [42].
When transfusing platelets, the suggested dose is 4–8 platelet concentrates or 1 unit of plateletpheresis [43]. It is important to carry out a platelet count 15 min after transfusion. A poor platelet count may indicate the presence of HLA antibodies. A good count after 15 min but low after 24 h may reveal consumption related to fever, sepsis, drug toxicity, etc. [43].
Cryoprecipitates are useful to achieve a rapid increase in the fibrinogen levels in patients with DIC or in massive transfusion with hemodilution and active bleeding. They are the third line of action in the treatment of von Willebrand’s disease type 1, and the second line of treatment for other types of von Willebrand’s disease. In trauma patients, evidence supporting cryoprecipitate use is very limited [42,43]. In cirrhotic patients during liver transplant, when low fibrinogen levels are often found, cryoprecipitates are very useful.
It seems appropriate not to transfuse red blood cells to patients tolerating Hb levels of 7 g/dL (Hct 27%) when there is an adequate VO2/DO ratio. Imbalance in oxygen transport becomes evident when clinical signs of tissue hypoperfusion and lactic acidosis appear.
It also seems to be clear that the transfusion of packed red blood cells can bring about serious complications as discussed above, which can increase the number of days in the ICU and in hospital and also morbidity and mortality.
The above recommendation seems not to apply to patients with cardiac decompensation, elderly patients, and some neurological patients for whom hemoglobin levels of 10 g/dL are more appropriate minimum values. It is possible that leukocyte reduction provides some answers to some of the problems associated with transfusions, especially for patients not tolerating low hemoglobin or hematocrit concentrations.
Further studies are required to provide solid evidence and make clear and precise recommendations to help us define more accurately the clinical use of blood derivates, such as FFP, platelets and cryoprecipitate, and to reduce the use of these blood products in cases where they are not indicated.
1. Dzik WH (2007) The James Blundell Award Lecture 2006. Transfusion and the treatment of hemorrhage: past, present and future. Transfus Med 17:367–374
2. Spence RK (1998) Anemia in the patient undergoing surgery and the transfusion decision. A review. Clin Orthop Relat Res 357:19–29
3. Adam RC, Lundy JS (1942) Anesthesia in cases of poor risk: some suggestions for decreas- ing risk. Surg Gynecol Obstet 74:1011–1019
4. Celis-Rodriguez E, Caicedo de Lehman MV (2008) Transfusiones en cuidados intensivos. In: Carrillo-Esper R (ed) Sepsis. Academia Mexicana de Cirugia, pp 417–426
5. Walsh TS, Saleh ED (2006) Anaemia during critical illness. Br J Anaesth 97 (3):278–291
6. Emmanuel JE, McClelland B, Page R (1997) The clinical use of blood in medicine, obstetrics, paediatrics, surgery, anaesthesia, trauma and burns. World Health Organization, pp 337–342
7. Asare K (2008) Anemia of critical illness. Pharmacotherapy 28(10):1267–1282
8. Vincent JL, Baron JF, Reinhart Ket al, for the ABC Investigators (2002) Anemia and blood transfusion in critically ill patients. JAMA 288:1499–1507
9. Corvin HL, Gettinger A, Pearl RG et al (2004) The CRIT Study: anemia and blood transfusion in the critically ill. Current clinical practice in the United States. Crit Care Med 32:39–52
10. Nguyen BV, Bota DP, Melot C, Vincent JL (2003) Time course of hemoglobin concentrations in nonbleeding intensive care unit patients. Crit Care Med 31:406–410
11. Goodnough LT, Skinkne B, Brugnara C (2000) Erythropoietin iron and erythropoiesis. Blood 96:823–833
12. Hosbisch-Hagen P, Wiederman F, Mayr A et al (2001) Blunted erythropoietic response to anemia in multiply traumatized patients. Crit Care Med 29:743–747
13. Dellinger RP, Levy MM, Carlet JM et al (2008) Surviving Sepsis Campaign: international guidelines for the management of severe sepsis and septic shock. Crit Care Med 36:296–327
14. Hébert PC, Wells G, Blajchman MA et al, for the Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Canadian Group (1999) A multicenter, randomized, controlled clinical trial of transfusion in critical care. N Engl J Med 340:409–417
15. Laks H, Pilon RN, Klovekorn WP et al (1974) Acute hemodilution. Its effect on hemodynamics and oxygen transport in anesthetized man. Ann Surg 180:103–109
16. Messmer K (1981) Oxygen transport and tissue oxygenation during moderate normovolemic hemodilution. Ann Clin Res 13(S):56
17. Hogman CF, Knutson F, Loof H, Payrat JM (2002) Improved maintenance of 2,3 DPG and ATP in RBCs stored in a modified additive solution. Transfusion 42:824–829
18. Hébert P, Blajchman MA, Cook DJ et al (2001) Do blood transfusions improve outcomes related to mechanical ventilation? Chest 119:1850–1857
19. Levy M, Abraham E (2005) A descriptive evaluation of transfusion practices in patients receiving mechanical ventilation. Chest 127:928–935
20. Hébert PC, Wells G, Tweeddale M et al (1997) Does transfusion practice affect mortality in critically ill patients? Transfusion requirements in critical care (TRICC) investigators and the Canadian Critical Care Trials Group. Am J Respir Crit Care Med 155:1618–1623
21. Zeidman A, Fradin Z, Blecher A et al (2004) Anemia as a risk factor for ischemic heart disease. Isr Med Assoc J 6:16–18
22. Cavusoglu E, Chopra V, Gupta A et al (2006) Usefulness of anemia in men as an independent predictor of two-year cardiovascular outcome in patients presenting with acute coronary syndrome. Am J Cardiol 98:580–584
23. Sabatine MS, Morrow DA, Giugliano RP et al (2005) Association of hemoglobin levels with clinical outcomes in acute coronary syndromes 111:2042–2049
24. Muzzarelli S, Pfisterer M (2006) TIME Investigators: Anemia as independent predictor of major events in elderly patients with chronic angina. Am Heart J 152:991–996
25. Vaglio J, Safley DM, Rahman M et al (2005) Relation of anemia at discharge to survival after acute coronary syndromes. Am J Cardiol 96:496–499
26. Gerber DR (2008) Transfusion of packed red blood cells in patients with ischemic heart disease. Crit Care Med 36:1068–1074
27. Ronco JJ, Fenwick JC, Tweeddale MG et al (1996) Does increasing oxygen delivery improve outcome in the critically ill? No. Crit Care Clin 12:645–659
28. Hébert PC, Hu LQ, Biro GP (1997) Review of physiologic mechanisms in response to anemia. CMAJ 156:S27–S40
29. Genzel-Boroviczény O, Christ F, Glas V (2004) Blood transfusion increases functional capillary density in the skin of anemic preterm infants. Pediatr Res 56(5):751–755
30. Sakr Y, Chierego M, Piagnerelli M et al (2007) Microvascular response to red blood cell transfusion in patients with severe sepsis. Crit Care Med 35(7):1639–1644
31. Leal-Noval SR, Rincón-Ferrari MD, Marin-Niebla A et al (2006) Transfusion of erythrocyte concentrates produces a variable increment on cerebral oxygenation in patients with severe traumatic brain injury: A preliminary study. Intensive Care Med 32(11):1733–1740
32. Kleinman S, Chan P, Robillard P (2003) Risks associated with transfusion of cellular blood components in Canada. Transfus Med Rev 17:120–162
33. Moore SB (2006) Transfusion-related acute lung injury (TRALI): clinical presentation, treatment and prognosis. Crit Care Med 34:S114–S117
34. Tinmouth AT, McIntyre LA, Fowler RA (2008) Blood conservation strategies to reduce the need for red blood cell transfusion in critically ill patients. CMAJ 178:49–56
35. Taylor RW, O’Brien J, Trottier SJ et al (2006) Red blood cell transfusion and nosocomial infections in critically ill patients. Crit Care Med 34:2302–2308
36. Vincent JL, Sakr Y, Le Gall Jr et al (2008) Is red blood cell transfusion associated with worse outcome? Results of the SOAP Study. Anesthesiology 108:31–39
37. Vamvakas EC (2006) Pneumonia as a complication of blood product transfusion in the critically ill: Transfusion-related immunomodulation (TRIM). Crit Care Med 34:S151-S159
38. Kamper-Jørgensen M, Ahlgren M, Rosgaard K et al (2008) Survival after blood transfusion. Transfusion 48:2577–2584
39. Shapiro MJ (2004) To filter blood or universal leukoreduction: what is the answer? Crit Care 8:S27-S30
40. Vincent JL, Piagnerelli M (2006) Transfusion in the intensive care unit. Crit Care Med 34:S96S101
41. Toy P, Popovsky MA, Abraham E et al (2005) Transfusion-related acute lung injury: definition and review. Crit Care Med 33:721–726
42. Spahn DR, Cerny V, Coats TJ et al (2007) Management of bleeding following major trauma: a European guideline. Crit Care 11:R17
43. DeLoughery TG (2007) Blood component therapy. In: Szalados JE, Rehm CG (eds) Adult multiprofessional critical care review. Society of Critical Care Medicine, Illinois

The Neuroendocrine Response to Sepsis

Acute response to LPS includes the release of a number of proinflammatory mediators that reach the brain in areas free of blood-brain barrier, or via specific transport systems. The hypothalamic-pituitary axis is also activated via neural routes. Then, infection is characterized by high circulating levels of adrenocorticotrope hormone (ACTH), and cortisol which remain in plateau as long as the stressful condition is maintained. Circulating vasopressin levels follow a biphasic response with high concentrations, followed by relative vasopressin insufficiency in about one third of cases. Early response to sepsis is characterized by decreased serum T3 and increased rT3 levels. Serum T4 levels decrease within 24 to 48 h, and thyroid-stimulating (TSH) levels remain normal, and have no more circadian rhythm. Prolonged sepsis is associated with centrally induced hypothyroidism. In the initial response to sepsis, growth hormone levels are high with attenuated oscillatory activity and low insulin-like growth factor (IGF)-1 levels. Later on, growth hormone (GH) secretion shows a reduced pulsatil fraction, and correlates with low circulating levels of IGF1. Exposure to endotoxin caused prompt increase in circulating adrenaline and noradrenaline concentrations. Catecholamines have a very short half-life and are metabolized through captation, enzymatic inactivation, or renal excretion. Plasma catecholamines levels remain elevated in plateau up to few months after recovery. Insulin levels rapidly increased following LPS as a result of both increased secretion and tissue resistance. The clinical consequences of the stress system activation include behavioral changes, cardiovascular, metabolic and immune adaptations. The use of exogenous hormones in critical illness has become a standard of care.
Hypotension can be corrected by administration of catecholamines, and these drugs are routinely administered in the intensive care unit (ICU). Vasopressin can help improve cardiovascular function in vasodilatory shock. There is enough evidence supporting the benefit of corticosteroids or insulin critical illness morbidity, and their benefit on survival remains controversial.
During critical illness, the stressors are multiple and include emotional and physical stress resulting both from an acute aggression such as trauma or infection and various therapeutic or diagnostic interventions such as surgery, arterial or venous catheterization, laryngeal intubation and mechanical ventilation, and drugs. It is also paramount to recognize that stress is sustained at a certain level of intensity for several days with additive and unpredictable surges. Thus, the host has to adapt his response to counteract a prolonged stress while still remaining able to adjust to the unpredictable surges of stress. Therefore, it is needless to say that the integrity and flexibility of host response to these stressors is essential to survive critical illness.
It is now recognized that the “stress system” has two main components: the corticotropin-releasing hormone/vasopressin neurons of the hypothalamus and the Locus Coeruleus noradrenaline/autonomic neurons of the brain stem [1]. We will summarize recent knowledge on how immune molecules such as interleukin or nitric oxide signal the brain to generate both neurological and hormonal responses aimed at turning down the immune system when the inflammatory response is no longer needed to fight off an infection for example.
Physiology of the Endocrine Response
Two pathways are used by the organism for interorgan communication, the central nervous system and its peripherals arms, and the endocrine system [1]. Nowadays, in the vertebrates the endocrine organs include anterior and posterior pituitary, ovary and testis, adrenal cortex and medulla, thyroids and parathyroids, islets of Langerhans in the pancreas, and various parts of the intestinal mucosa. The pineal and thymus can also be considered as endocrine organs. In addition, other organs may have some endocrine properties. For example, the kidney secretes renin and angiotensin; the heart secretes natriuretic factors. The main known hormones are listed in Table 33.1. Basically hormones are divided into steroids (cholesterol derived proteins), peptides, and amines (Table 33.1).
Physiological Control of the Endocrine System
There is probably no uniform mechanism for the regulation of hormone activity. For example, there is no evidence that parathormone is released upon nervous stimulation or action of a specific trophic hormone, in contrast to the thyroid, adrenals, and gonads. We will focus on the main hormones involved in response to stress, i.e., steroids, catecholamines, and vasopressin. There are two main mechanisms of regulation of the endocrine activity: feedback loops and neural control. Experiments in which peripheral glands are disconnected from the pituitary showed full cessation of gonad function whereas the thyroid and adrenal cortex continues to secrete hormones at a lower level depicting their intrinsic activity. Similarly, the anterior pituitary has an intrinsic activity specific to thyroid and adrenal cortex function.
The feedback mechanisms allow circulating hormones from the target organs as well as from the anterior hypophysis to down- or upregulate the release of hypothalamic molecules. The feedback loop involves also central nervous structures such as the hippocampus. This self-balancing system stabilizes the endocrine activity under resting conditions but is insufficient in case of enhanced endocrine activity [1]. Then, the hypothalamus plays a key role in the regulation of these hormones. First, it is directly connected to the neurohypophysis and the adrenal medulla. Second, it modulates the anterior pituitary function by releasing, in synchronous pulses (roughly hourly), stimulatory or inhibitory hormones in the hypophysial portal vessels of the pituitary stalk. Stimulatory peptides include corticotropin-releasing hormone (CRH), LH-releasing hormone (LHRH), FSH-releasing factor (FSHRF), GH-releasing factor (GHRH), prolactin (PRL) stimulating factor and thyrotropin-releasing hormone (TRH). Other peptides are inhibiting factors like GH-inhibiting hormone (somatostatin) and PRL-inhibiting hormone. Vasopressin, natriuretic peptides, and catecholamines also influence the pituitary function. The effect of CRH on ACTH release by the pituitary is permissive and vasopressin acts in synergy with CRH. There are tight interconnections between CRH-synthesizing neurons from the parvocellular nuclei and the Locus Coeruleus in the brain stem [1]. Thereby, noradrenaline, CRH, and vasopressin can stimulate each other. Through collateral fibers, ultra-short negative feedback loops allow permanent adaptation of the synergy between the two systems. Finally, CRH, vasopressin, and noradrenaline are on the stimulatory control of the serotoninergic, cholinergic, and histaminergic systems and are inhibited by the gamma amino butyric acid, benzodiazepine, and opioids systems [1].
Table 33.1. List of hormones

Potential Mechanisms of Regulation of the Endocrine Activity During Critical Illness
Critical illness is a condition involving multiple stressors of both emotional and physical types. The unpredictable nature, duration, and intensity of these stressors render the host response more problematic. Acute inflammatory responses to LPS include the release of a number of mediators such as tumor necrosis (TNF) alpha, interleukin (IL)-1, IL-6, IL-8, nitric oxide, macrophage migration inhibiting factors (MIF), and high mobility group box (HMGB)-1 [2]. These mediators reach the hypophysial portal capillaries in the median eminence via the anterior hypophysial arteries. Cytokines can diffuse into the pituitary as these areas are free of blood-brain barrier [3]. Then, they are carried to the hypothalamus and the brain areas lacking a blood-brain barrier (circumventricular organs), or via specific transport systems [3].
In addition to the blood-borne cytokines, glial cells can produce a number of cytokines such as IL-1, IL-2, and IL-6 [4]. Interestingly, i.p. injection of LPS induces IL-1b followed by inducible NO synthase (iNOS) mRNA within 2 h, peaking in 4–6 h and then returning to basal values by 24 h [3]. The induction of IL-1b and iNOS occurred in this study in the meninges, areas lacking a blood-brain barrier, and also in the parvocellular nuclei and the arcuate nucleus, which contain the hypothalamic releasing and inhibiting hormone producing neurons. Thus, it is likely that delayed overexpression of NO through iNOS activation prolongs the synthesis of hypothalamic hormones induced by LPS [3]. In addition, cytokines via activation of GABAergic neurons block NO-induced LHRH but not FSH release, inhibit GHRH release, and stimulate somatostatin and prolactin release [3].
Various afferent neurons of the peripheral system sense the threat at the inflammatory sites and stimulate the noradrenergic system and the hypothalamus [1]. Activation of vagal afferent fibers by LPS results in activation of the Locus Coeruleus which neurons have projections that synapse on cholinergic interneurons in the parvocellular nucleus [1]. It has been shown that CRH is released upon acetylcholine stimulation of muscarinic receptor, and that this effect is prevented by nonspecific NO antagonists [5].
Endocrine Activity During Critical Illness
Infection, LPS challenge, major surgery, trauma, or burns elicit very similar patterns of pituitary hormone secretion. Plasma ACTH and prolactin increase within a few minutes following the insult and are associated with a rapid inhibition of LH and TSH but not FSH secretion. Growth hormone secretion is also stimulated in humans.
Hypothalamic Pituitary Adrenal Axis
Acute stress induced an immediate increase in the amplitude of hypothalamic hormones pulses, mainly CRH and vasopressin, resulting in increased amplitude and frequency of ACTH and cortisol pulses, and the loss of the circadian rhythm [1]. The common feature is characterized by high circulating levels of ACTH and cortisol, which remain in plateau as long as the stressful condition is maintained. However, circulating levels of cortisol depend on both synthesis and clearance and do not strictly reflect the HPA axis function. Thus, they vary from <5 µg/dl to more than 100 µg/dl [6].
Circulating vasopressin levels are regulated through various stimuli including changes in blood volume or blood pressure and plasma osmolality, cytokines, and other mediators. In sepsis, vasopressin levels in plasma may follow a biphasic response with initially high concentrations, followed by a decline in concentrations down to the limits of normal range within 72 h with relative vasopressin insufficiency as a consequence of NO-induced neuronal loss [7].
The Hypothalamic-Pituitary Thyroid Axis
Low T3–T4 syndrome has been described for more than 20 years in fasting conditions and in a wide variety of diseases (e.g., sepsis, surgery, myocardial infarction, transplantation, heart, renal, hepatic failure, cancers, malnutrition, inflammatory diseases) and is also called euthyroid-sick syndrome or nonthyroidal-illness syndrome (NTIS) [8]. In the early phase of stress, there is a decrease in serum tri-iodothyronine (T3) level, an increase in rT3 level, then serum thyroxine (T4) levels decrease within 24 to 48 h, and TSH levels remain within normal range and show no more circadian rhythm. Underlying mechanisms include (1) decreased conversion of T4 and T3 in extrathyroid tissues due to inhibition of the hepatic 5’-monodeiodination, (2) presence of transport protein inhibitors preventing T4 fixation on the protein, (3) dysfunction of the thyrotrophic negative feedback, (4) cytokines (IL-1, IL-6, TNFa, IFNγ) induced inhibition of the thyrotrophic centers activity and/or affected the expression of thyroid hormones nuclear receptors, and (5) other inhibitory substances such as dopamine. Prolonged critical illness is associated with centrally induced hypothyroidism as suggested by restoration of T3 and T4 pulses by exogenous TRH infusion.
Growth Hormone
The acute phase of critical illness is characterized by high growth hormone levels with attenuated oscillatory activity associated with low levels of IGF-1 [9]. Serum concentrations of GH effectors IGF-1 are low during this phase, suggesting resistance to GH as a result of decreased expression of GH receptor. Subsequently, direct lipolysis and anti-insulin effects of GH might be enhanced, liberating metabolic substrates such as free fatty acids and glucose to vital organs, while costly metabolism mediated by IGF1 is postponed. In prolonged critical illness, the pattern of GH secretion shows a reduced pulsatile fraction that correlated with low circulating levels of IGF-1.
Adrenal Medulla Hormones
It is well known that under resting condition very few amounts of adrenaline and noradrenaline are released from the adrenal medulla (i.e., less than 50 ng/kg/min in the dog). Therefore, removing the adrenal medulla allows an animal to survive the intervention indefinitely. However, exposure to stressors caused prompt increase in circulating adrenaline and noradrenaline concentrations by 2–3 logs, an effect that was prevented by removal of the adrenal medulla. Adrenaline is stored in medulla vesicles. Noradrenaline is present in the subcellular granules of the sympathetic nervous endings. Catecholamines have a very short half-life (10–20 sec for adrenaline) and are metabolized through captation, enzymatic inactivation (methylation in metadrenaline or normetadrenaline in liver or kidney, oxidative deamination by monoamine oxidase), or renal excretion. The hormonal regulation depends on cortisol, which is necessary for the enzymatic degradation of catecholamines synthesis. The nervous regulation involves cholinergic preganglionic parasympathetic pathways via splanchnic nerves. Like cortisol, catecholamines levels in plasma can remain elevated in plateau as long as the stress is maintained and even up to few months after recovery.
Insulin is involved in glucose metabolism through (1) mobilization of store of glucose transport molecules in target cells, such as muscle and fat tissue, (2) activation of hepatic glucokinase gene transcription, and (3) activation of glycogen synthetase and inhibition of glycogen phosphorylase [10]. Other actions of insulin include growth stimulation, cellular differentiation, intracellular traffic, increase of lipogenesis, glycogenesis, and protein synthesis. These effects result from insulin fixation to a ubiquitous membrane receptor belonging to the tyrosine kinase family including insulin-like growth factor receptor (IGF-1) and insulin receptor-related receptor (IRR). Insulin levels in plasma are rapidly increased following an acute stress as a result of both increased secretion and tissue resistance. Insulin suppresses and antagonizes the effects of TNF, macrophage migration inhibitory factor (MIF) and superoxide anions, and decreases the synthesis of the acute phase reactants. Moreover, insulin modulates leptin and other adipokines release from fat cells.
Clinical Consequences of Endocrine Activity in Critical Illness
The main objective of the neuroendocrine response to critical illness is “fight and flight.” Then, the immediate manifestation of the activation for the endocrine system, mainly the sympato-adrenal hormones, include alertness; insomnia; hyperactivity; pupillary dilation; reception of hairs; sweating; salivary secretion; tachycardia; rise in blood pressure with dilation of skeletal muscles, blood vessels, and coronary arteries; bronchiolar dilation and polypnea; skin vasoconstriction; mobilization of glucose from liver and hyperglycemia; increased oxygen capacity of the blood via spleen constriction and mobilization of blood red cells; and shortening of coagulation time. However, in practice, fighting is the only option, and the appropriateness of the neuroendocrine activity to the intensity and duration of the stress is the determinant of host survival and recovery. The clinical consequences of the stress system activation roughly include behavioral changes, and cardiovascular, metabolic, and immune adaptations.
Behavioral Changes
In animals, infections are associated with anorexia and body weight loss, hypersomnia, psychomotor retardation, fatigue, and impaired cognitive abilities. Similar behavioral changes are consistently reported in humans after cytokine or LPS challenge. The socalled depression due to a general medical condition is likely mediated through release of peripheral and brain cytokines [11]. Then, when glucocorticoids and catecholamines responses are insufficient, the critically ill patients will develop brain dysfunction that can result in coma.
Cardiovascular Changes
The cardiovascular adaptation is mainly driven by the sympatho-adrenal hormones even though thyroid hormones and vasopressin contribute respectively to cardiac adaptation and blood volume and vasomotor tone regulation. Corticosteroids exert important actions of the various elements of the cardiovascular system including the capillaries, the arterioles, and the myocardium. The underlying mechanisms are not fully understood and may involve direct mobilization of intracellular calcium, enzymatic metabolism of adrenaline, increased binding affinity of adrenaline for its receptor or facilitation of the intracellular signalization that follows the coupling of adrenaline to its receptor. Whenever the hypothalamic-pituitary adrenal axis or the noradrenergic responses are inappropriate, critically ill patients will develop cardiovascular dysfunction. Indeed, septic shock patients with adrenal insufficiency, as defined by a delta cortisol of 9 µg/dl or less, have more pronounced hypotension than those with presumed normal function, and are more likely to develop refractory shock and to die [6]. Adrenal insufficiency is at best recognized at the bedside of critically ill patients by either low baseline cortisol levels (<10 µg/dl) or cortisol increment after 250 µg of corticotropin of <9 µg/dl [6]. Failure of the noradrenergic system will also result in cardiovascular dysfunction during critical illness. Sepsis is associated with decreased noradrenergic activity that preceded cardiovascular dysfunction [12]. The decrease of the pulsatile activity of the HPA axis and the noradrenergic system result in regularity within the circulatory and respiratory function becoming unable to adjust to stressful conditions, loss in interorgan communications with multiple organ dysfunction, and death [13]. Finally, inappropriately low vasopressin levels contribute to the vasodilatory shock [14].
Metabolic Changes
The net result from the activation of the endocrine system is hyperglycemia. Tissues that are insulin-dependent cannot uptake glucose, which is then available for insulin independent tissues like the brain or inflammatory cells. The main reason for critical-illness-associated insulin resistance is cytokines-induced impairment in GLUT-4 metabolism [15]. Hyperglycemia has been shown to increase mortality in critical ill ness [16]. The mechanisms underlying glucose toxicity for the cells are still unknown and may include an overloading of the insulin-independent cells like neurons. Subsequent to low ATP levels in the cells, the excess of intracellular glucose cannot enter the Krebs cycle and result in the generation of free radicals and peroxynitrites, which in turn block complex IV of the mitochondria. Then, by killing the mitochondria of insulin-independent cells, hyperglycemia may facilitate acquisition of superinfection, damage the central and peripheral nervous systems and the liver, and eventually result in multiple-organ-dysfunction-related death [16]. Excess in the catabolic hormones, cortisol, adrenaline, and glucagon will also elicit an imbalance between the muscle protein breakdown rate and the rate of muscle protein synthesis, resulting in a net catabolism of muscle protein, which may contribute to critical-illness induced muscle weakness and affect long-term prognosis.
Immune Changes
The changes in the immune function again are mainly related to the sympatho-adrenal hormones even though insulin and vasopressin can also influence immunity. Glucocorticoids suppress most, if not all, T-cell derived cytokines, and change the Th1/Th2 balance toward excess Th2 cells [1]. They do not affect IL-10 synthesis by monocytes, and they upregulate lymphocytes-derived IL-10. They also inhibit the synthesis of many other inflammatory mediators such as cyclo-oxygenase and inducible NOS, and down regulate cell surfaces markers such as endotoxin receptor and adhesion molecules. Finally, they enhance the occurrence of apoptosis of thymocytes, mature T-lymphocytes, eosinophils, epithelial cells and precursors of dermal/interstitial dendritic cells, but delay apoptosis of neutrophils [1]. Catecholamines also drive a Th2 shift in both antigen presenting cells and Th1 cells via beta adrenergic receptors. While the stress hormones, glucocorticoids, and catecholamines induced systemically a shift of the Th1/Th2 balance in favor of Th2 cells, catecholamines also promote locally at the level of inflamed tissues the synthesis of proinflammatory mediators via alpha adrenergic receptors. Then, critical-illness associated impaired HPA axis shifted the Th1/Th2 balance to release proinflammatory mediators in the circulation and broadly in body tissues.
Modulating the Endocrine System During Critical Illness
The use of exogenous hormones in the context of critical illness has become a standard of care. Indeed hypotension can be corrected by administration of catecholamines. Even though there is no randomized controlled trial of adrenaline, noradrenaline or dopamine versus a placebo or no treatment, these drugs are routinely administered in critically ill patients with cardiovascular dysfunction. Adrenaline and noradrenaline are equally effective in restoring cardiovascular homeostasis during shock [17]. Vasopressin may also restore hemodynamic stability in critical illness [14]. However, the survival benefit from catecholamines or vasopressin remains uncertain.
There is enough evidence supporting the benefit of corticosteroids on hemodynamic and systemic inflammation and supporting that survival benefit is dose dependent [2,6]. The use of corticosteroids in patients with septic shock continues to be controversial despite two recent, large, well-performed studies [18,19]. The two studies evaluated different patient populations and came to opposite conclusions. Similarities between the two studies included steroids’ beneficial effects on time-toshock reversal, no evidence for increased risk of neuromuscular weakness, and hyperglycemia. Differences between the two studies include for Annane et al. [18] and Sprung et al. [19] respectively: entry window (8 vs. 72 h; SBP <90 mmHg; >1 h vs. <1 h); additional treatment (fludrocortisone vs. no fludrocortisone); treatment duration (7 vs. 11 days); weaning (none vs. present); SAPS II scores (59 vs. 49); nonresponders to corticotropin (77% vs. 47%); differences in steroids effects according to the response to corticotropin (yes vs. no); increased risk of superinfection (no vs. yes); and study occurred after practice guidelines published recommending steroids (no vs. yes). Currently, patients with vasopressor dependent shock should be treated with hydrocortisone.
Recently, intensive treatment with insulin targeting blood glucose of 4.4–6 mmol/L was shown to significantly improve morbidity and mortality in both surgical [20] and medical [21] patients. The benefit is mainly observed in the chronic phase of critical illness (after 72 h) and may be related to protection of cells from glucose toxicity rather than from direct anti-inflammatory effects of insulin. However, two recent multicenter studies did not find any benefit for a tight glucose control with intensive insulin therapy in patients with severe sepsis [22,23]. One may suggest that the very early increase in blood glucose mainly relates to stress hormones and should not be counteracted, whereas later hyperglycemia relates to cytokines-induced insulin resistance and should be treated.
Other attempts to manipulate the endocrine system during critical illness have included thyroid hormones replacement therapy or growth hormone therapy and have been less successful.
The neuroendocrine response to critical illness is paramount for host survival and recovery. The sympathoadrenal hormones are key actors in maintaining homeostasis. When the neuroendocrine response to an acute stress is appropriate both in time and in intensity then critical illness does not develop and recovery is easy. Otherwise, syndrome of multiple organ failure develops. By contrast, if the host response is too excessive, persistent changes in behavior and mood, in metabolic state and in immune function cause increased susceptibility to superinfection, risk for chronic muscle fatigue, and posttraumatic stress disorders. Whether the neuroendocrine system can be manipulated to be adjusted to the inflammatory process remains a controversial issue.
1. Chrousos GP (2000) The stress response and immune function: Clinical implications. The 1999 Novera H. Spector Lecture. Ann NY Acad Sci 917:38–67
2. Annane D, Bellissant E, Cavaillon JM (2005) Septic shock. Lancet 365:63–78
3. McCann SM, Kimura M, Karanth S et al (2000) The mechanism of action of cytokines to control the release of hypothalamic and pituitary hormones in infection. Ann NY Acad Sci 917:4–18
4. Koenig JI (1991) Presence of cytokines in the hypothalamic-pituitary axis. Prog Neuroendocrinoimmunol 4:143–153
5. Karanth S, Lyson K, McCann SM (1999) Effects of cholinergic agonists and antagonists on interleukin-2-induced corticotropin-releasing hormone release from the mediobasal hypothalamus. Neuroimmunomodulation 6:168–174
6. Polito A, Annane D (2008) Adrenal glands/corticosteroids and multiple organ dysfunction syndrome. J Organ Dysfunc 4:(4)208–215
7. Sharshar T, Gray F, Lorin de la Grandmaison G et al (2003) Apoptosis of neurons in cardiovascular autonomic centres triggered by inducible nitric oxide synthase after death from septic shock. Lancet 362:1799–1805
8. De Groot LJ (1999) Dangerous dogmas in medicine: The nonthyroidal illness syndrome. J Clin Endocrinol Metab 84:151–164
9. Ross R, Miell J, Freeman E et al (1991) Critically ill patients have high basal growth hormone levels with attenuated oscillatory activity associated with low levels of insulin-like growth factor-I. Clin Endocrinol (Oxf) 35:47–54
10. Saltiel AR, Kahn CR (2001) Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414:799–806
11. Maier SF, Watkins LR (1998) Cytokines for psychologists: Implications of bidirectional immune-to-brain communication for understanding behaviour, mood, and cognition. Psychol Rev 105:83–107
12. Annane D, Trabold F, Sharshar T et al (1999) Inappropriate sympathetic activation at onset of septic shock: A spectral analysis approach. Am J Respir Crit Care Med 160:458–465
13. Godin PJ, Buchman TG (1996) Uncoupling of biological oscillators: A complementary hypothesis concerning the pathogenesis of multiple organ dysfunction syndrome. Crit Care Med 24:1107–1116
14. Landry DW, Levin HR, Gallant EM et al (1997) Vasopressin deficiency contributes to the vasodilation of septic shock. Circulation 95:1122–1125
15. Minokoshi Y, Kahn CR, Kahn BB (2003) Tissue-specific ablation of the GLUT4 glucose transporter or the insulin receptor challenges assumptions about insulin action and glucose homeostasis. J Bio Chem 278:33609–33612
16. Van den Berghe G (2004) How does blood glucose control with insulin save lives in intensive care? J Clin Invest 114(9):1187–1195
17. Annane D, Vignon P, Bollaert PE et al (2005) Norepinephrine plus dobutamine versus epinephrine alone for the management of septic shock. (Abstract). Intensive Care Med 31:S1-S18
18. Annane D, Sebille V, Charpentier C et al (2002) Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 288:862–871
19. Sprung CL, Annane D, Keh D et al (2008) Hydrocortisone therapy for patients with septic shock. N Engl J Med 358:111–124
20. Van den Berghe G, Wouters P,weekers F et al (2001) Intensive insulin therapy in the critically ill patients. N Engl J Med; 345:1359–1367
21. Van den Berghe G, Wilmer A, Hermans G et al (2006) Intensive insulin therapy in the medical ICU. N Engl J Med 354:449–461
22. Brunkhorst FM, Engel C, Bloos F et al (2008) Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 358:125–139
23. The NICE-SUGAR Investigators (2009) Intensive versus conventional glucose control in critically ill patients. N Engl J Med 360:1283–1297


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