Metabolic response to injury and infection

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Chapter 86 Metabolic response to injury and infection

Ian K S. Tan

Injury and infection evoke in the host a hypermetabolic inflammatory response and a compensatory hypometabolic hypoimmune response. The magnitude of the response is proportional to the extent of injury. Additional components of illness, such as ischaemia and reperfusion or resuscitation, nutritional status, surgical procedures, transfusions, drugs and anaesthetic techniques, genetic polymorphisms and concurrent diseases, impact on the response. Some components of the metabolic response, or the failure to regulate the response, are destructive, and its modulation may improve patient survival.1

MEDIATORS OF THE METABOLIC RESPONSE

Following directed adhesion to endothelium and migration into tissue, neutrophils undergo an oxidative burst, producing a large variety of free radicals (species with one or more unpaired electrons) and reactive oxygen species (ROS), overwhelming natural scavenging and antioxidant defences, such as superoxide dismutase and glutathione peroxidase. These free radicals and ROS directly damage cells. Proteases, arachidonic acid metabolites (leukotrienes, thromboxanes and prostaglandins) and adhesion molecules are produced, amplifying the inflammatory cascade. Inducible nitric oxide synthase is activated, and nitric oxide is produced. Tissue macrophages become primed and activated.

CYTOKINES

Cytokines are soluble, non-antibody, regulatory proteins released from the activated immunocytes, and are responsible primarily for the inflammatory and counter-inflammatory response. Injury and infection cause cytokine release from activated leukocytes, endothelial cells and fibroblasts. T-helper type 1 (TH1) lymphocytes primarily impact cell-mediated immunity and secrete tumour necrosis factor-α (TNF-α), interleukin-2 (IL-2) and interferon-γ (IFN-γ), while TH2 lymphocytes impact antibody-mediated immunity and secrete IL-4 and IL-10. The TH1/TH2 cytokine profile determines the immunostimulatory/immunosuppressive balance. Cytokines generally exert their effects in a paracrine fashion, but in severe injury and infection, they enter the circulation and act as hormones. The following are major cytokines involved in the response to stress:

• TNF-α is a necessary and sufficient proximal mediator. After endotoxin challenge, TNF-α concentrations peak before other mediators. TNF-α administration reproduces all features of septic shock, including hypermetabolism, fever, anorexia, hyperglycaemia, decreased lipogenesis, marked protein catabolism and lactic acidosis. TNF-α activates the hypothalamic–pituitary–adrenal (HPA) axis. Soluble TNF-α receptors, a natural antagonist to TNF-α, also increase; this may be a regulatory response which contributes to later immunosuppression.
• IL-1β (endogenous pyrogen) produces much the same metabolic effects as TNF-α, and the combined effect of the two cytokines is greater than the effect of either alone. IL-1β is a potent inducer of the HPA axis as well as central and peripheral noradrenergic neurons. IL-6 is the main mediator of the acute phase response. Similar to TNF-α and IL-1β, IL-6 levels correlate with severity of illness and outcome. IL-8 induces neutrophil adhesion, chemotaxis and enzyme release. IL-2 generation is decreased. Anti-inflammatory cytokine (IL-4, IL-10, transforming growth factor-β) and antagonist (IL-1 receptor antagonist) levels increase. IL-4 activates B lymphocytes.
• Colony-stimulating factors stimulate the proliferation of haemopoietic cells, superoxide and cytokine production by neutrophils and macrophages. Disproportionate monocytopoiesis over granulocytopoiesis occurs. Erythropoietin production is suppressed.
• IFN-γ stimulates fibroproliferation, upregulates TNF receptors and induces TNF synthesis. IFN-γ production is synergistically induced by IL-12 and IL-18. IFN-α/β secretion is induced in viral infections and is proinflammatory.
• High mobility group box 1 (HMGB1) is a late proinflammatory mediator. It induces the expression of adhesion molecules in endothelial cells, increases enterocyte permeability, and further release of proinflammatory cytokines from leukocytes.
• Counter-inflammatory cytokines accumulate at the site of injury. Prostaglandin E2 inhibits further synthesis of inflammatory cytokines, and spermine inhibits their release. Transforming growth factor-β inhibits monocyte activation.

NEUROENDOCRINE MEDIATORS

Cytokine release from the site of injury or infection triggers vagal afferent impulses to the dorsal vagal complex (DVC) in the medulla oblongata. Synaptic connections with the rostroventral medulla and locus ceruleus, and the hypothalamic nuclei, activate the sympathetic nervous system and the HPA axis respectively.2 High circulating cytokine levels may also cross the blood–brain barrier, or affect neurons at circumventricular organs lacking a blood–brain barrier, such as the area postrema. In general, a biphasic response is observed following injury and infection: an initial neuroendocrine ‘storm’ followed by a decrease. The following are some neuroendocrine mediators involved in the response to stress:

• Reflex vagal efferent nerves secrete acetylcholine, which by binding to α7 subunits of the nicotinic receptor, suppresses proinflammatory cytokine synthesis from immunocytes.
• Reflex sympathetic efferents increase catecholamine levels, causing tachycardia and calorigenesis with increased oxygen consumption. Blood flow redistribution occurs depending on tissue receptor balance. Glycogenolysis, gluconeogenesis and lipolysis are stimulated. Activation of β2-adrenergic receptors decreases synthesis of proinflammatory cytokines and increases the synthesis of anti-inflammatory cytokines. However, α2-adrenoreceptor activation may increase TNF production.
• HPA axis activation results in high adrenocorticotropin hormone (ACTH) and cortisol levels, driving gluconeogenesis, proteolysis and lipolysis. Primarily by suppressing the nuclear factor (NF)-κB pathway, cortisol attenuates damage from excessive proinflammatory cytokine synthesis, while activating synthesis of anti-inflammatory IL-4 and IL-10. With prolonged critical illness, ACTH levels fall, but cortisol remains elevated with persistent loss of diurnal variation in secretion. Corticosteroid-binding globulin levels fall, and free cortisol levels may be increased. TNF decreases glucocorticoid response, and peripheral glucocorticoid resistance may vary between tissues.
• Growth hormone (GH) levels increase acutely with increased pulsatile frequency, but concomitant peripheral GH resistance occurs initially with low levels of GH-binding protein (GHBP) and insulin-like growth factor (IGF-1). Levels of the inversely regulated IGF-binding protein (IGFBP-1) increase, which correlates with mortality. Subsequently, loss of hypothalamic stimulation, as well as decreased ghrelin (a potent growth hormone secretagogue) levels, causes greatly reduced GH burst amplitudes, but peripheral GH sensitivity recovers.3
• The thyroid axis behaves in a similar fashion, with transient increases in thyrotropin (TSH) and thyroxine (T4) levels, and reduced conversion of T4 to tri-iodothyronine (T3). Chronically, reduced thyrotrophin-releasing hormone (TRH) secretion leads to low/normal levels and pulsatility in TSH, low T4 levels and further falls in T3 levels, termed the ‘sick euthyroid syndrome’.
• Prolactin (PRL) levels increase transiently, followed by reduced pulsatile amplitudes. As T-lymphocyte function is prolactin-dependent, this contributes to late loss of immune competence.
• Luteinising hormone (LH) levels increase transiently, followed by reduced pulsatile amplitudes. Low testosterone and high estradiol levels occur.4 Dehydroepiandrosterone levels are low. Estrogens inhibit proinflammatory cytokine production.
• α-Melanocyte stimulating hormone (α-MSH) levels increase, leading to immunosuppression via inhibition of the NF-κB pathway.
• Insulin and glucagon levels are increased but the insulin levels are inappropriately low for the level of hyperglycaemia. Insulin resistance is characterised by impaired glycogen synthesis. The increased glucagon:insulin ratio augments gluconeogenesis. Insulin has anti-inflammatory properties by inhibiting the NF-κB pathway, and prevents mitochondrial ultrastructural abnormalities, possibly by inhibiting hyperglycaemia-induced production of superoxide. Leptin levels increase acutely, then decrease.
• Procalcitonin levels increase and remain high, and its level correlates with severity of illness, so that procalcitonin has become a useful marker of systemic infection and a guide to therapy. Calcitonin levels, however, are variable and not necessarily elevated. Of the other members of the calcitonin superfamily, calcitonin gene-related peptide (CGRP) and adrenomedullin levels greatly increase; they are anti-inflammatory and contribute to vasodilatation.
• The renin–angiotensin–aldosterone axis is activated, causing fluid retention. Subsequently, aldosterone levels fall while renin remains elevated.
• Arginine vasopressin (AVP) levels increase initially, then return to normal or low levels despite persistent shock, in part due to depletion of stored hormone. Downregulation of V1 receptors (which mediate AVP’s vasoconstricting effect) occurs in sepsis.
• Vasoactive intestinal peptide secretion is induced, probably by nitric oxide, inhibiting production of proinflammatory cytokines and stimulating secretion of IL-10.

THE METABOLIC RESPONSE

The metabolic response to injury and infection begins with the activation of receptors throughout the body by the above mediators. These receptors include toll-like receptors (TLR)-2 and TLR-4, and the receptor for advanced glycation end products (RAGE). Subsequent intracellular activation of the NF-κB pathway leads to gene induction and production of mRNA for the synthesis of proinflammatory cytokines. Catecholamines can initiate rapid functional changes via protein phosphorylation, which does not require gene induction. Behavioural effects such as anorexia, possibly due to elevated leptin levels, also affect the metabolic response. The metabolic effects may be described at three levels.

CELLULAR METABOLIC EVENTS

Intracellularly, heat shock protein (HSP) synthesis is induced. Many HSPs are also expressed constitutively. HSPs act as ‘chaperones’, assisting in the assembly, disassembly, stabilisation and internal transport of other intracellular proteins. HSPs facilitate translocation of the glucocorticoid-receptor complex from the cytosol to the nucleus, and inhibit NF-κB activity. HSPs have cellular protective roles in sepsis and ischaemia-reperfusion.5

Mitochondrial dysfunction limits cell metabolism and may be responsible for the ensuing multiorgan dysfunction of severe injury and infection. Electron transport chain complexes are inhibited by excessive nitric oxide and peroxynitrite generated during sepsis.6 Additionally, poly (ADP-ribose) polymerase-1 (PARP-1) is activated, reducing cell nicotinamide adenine dinucleotide (NADH) content, a substrate for ATP generation. The reduced ATP production may have functional consequences, such as diaphragmatic dysfunction.7 It has been hypothesised that this ‘metabolic shutdown’ is an adaptive response similar to hibernation.8

Apoptosis, or programmed cell death, may finally be induced when death receptors are engaged by their ligands, or by mitochondrial-mediated pathways.9 Death receptors include Fas and TNF receptor type I (TNFRI), and this pathway activates caspase. The mitochondrial pathway, mediated in part by glycogen synthase kinase-3β activation, causes activation of caspase. Caspases 8 and 9 activate caspase 3, which commits the cell to death. TNF-α, IL-10, cortisol and nitric oxide all induce apoptosis. Apoptosis further augments immunosuppression. It is probable that bioenergetic failure and the apoptotic death of immune cells are the major causes of death in late sepsis.

INTERMEDIARY METABOLISM

Protein metabolism: IL-1, TNF, related cytokines and hormonal changes trigger an extreme protein catabolism. Glutamine, alanine and other amino acids are mobilised from skeletal muscle and taken up by hepatocytes and gut mucosa. Glutamine depletion may occur. Increased ureagenesis and nitrogen loss occurs. Levels of branch chained amino acids (leucine, isoleucine, valine) fall with peripheral oxidation. The fraction of energy expenditure derived from glucose is reduced, while that derived from amino acid oxidation in the Krebs cycle is increased.

Carbohydrate metabolism: hyperglycaemia results from glycogenolysis, accelerated gluconeogenesis and peripheral insulin resistance. Lactate production increases from peripheral tissue, areas of injury and the white cell mass, and serves as substrate for gluconeogenesis in hepatocytes. In the terminal phase of severe illness, hypoglycaemia may occur.

Fat metabolism: lipolysis is increased with increased turnover of triglycerides and fatty acids, and plasma free fatty acid levels are high. TNF, IL-1 and IL-6 decrease lipoprotein lipase activity, contributing to hypertriglyceridaemia. Both high- and low-density lipoprotein (HDL and LDL) cholesterol levels are low. Ketosis is suppressed, indicating that fat is not a major calorie source. Glycerol generated from lipolysis further contributes to gluconeogenesis. The action of cyclooxygenase and lipoxygenase on arachidonic acid (a tissue phospholipid) produces inflammatory leukotrienes, thromboxanes and prostaglandin E2.

Electrolyte and micronutrient metabolism: salt and water retention occurs, with hyponatraemia, masking the loss of lean tissue. Protein loss is accompanied by potassium, magnesium and phosphate loss. Serum hypocalcaemia with increased intracellular calcium commonly occurs. Zn redistributes to liver and bone marrow. Zn deficiency is associated with impaired IL-2 production and wound healing. Selenium levels are low and correlate with mortality. Selenium is required by glutathione peroxidases and thioredoxin reductases to prevent oxidative damage. Fe levels decrease.

SYSTEMIC PROTEIN SYSTEM RESPONSES

The acute phase response is a systemic response to injury characterised by redirection of hepatic protein synthesis and haematological alterations. Production of proteins involved in defence is increased (protease inhibitors, fibrinogen, C-reactive protein, haptoglobulin, complement C3), while synthesis of serum transport and binding molecules is reduced (albumin, transferrin). Serum levels of acute phase reactants such as C-reactive protein can be used for diagnostic, monitoring and prognostic purposes.

Complement cascade triggering produces the membrane attack complex, chemoattractants (C3a, C5a), vasoactive anaphylatoxins (C3a, C4a, C5a), opsonins (C3b), stimulation of neutrophil and monocyte oxidative burst (C3b) and neutrophil adherence to endothelium (C5a).

TNF-α induces the expression of tissue factor on leukocyte and endothelial cell surfaces, triggering the coagulation cascade. Depletion of endogenous anticoagulants such as antithrombin, protein C, and tissue factor pathway inhibitor (TFPI) occurs. In turn, activated coagulation factors amplify inflammation.

FACTORS AFFECTING THE METABOLIC RESPONSE

ENERGY BALANCE AND OXYGEN DELIVERY

Hypermetabolism increases oxygen demand and consumption. Capillary permeability increases, causing reduced intravascular filling, and inadequate oxygen delivery can lead to anaerobic metabolism and inadequate production of high-energy phosphates. In adequately resuscitated patients, aerobic glycolysis with lactate production rather than anaerobic glycolysis is characteristic of the metabolic response to stress.10 Subsequent cell swelling from injury and resuscitation activates phospholipase A2, augmenting the inflammatory cascade.11

SURGICAL PROCEDURES AND ANAESTHETIC TECHNIQUES

Total afferent neuronal blockade (somatic and autonomic block) (e.g. by epidural anaesthesia), and minimally invasive surgery, both of which greatly attenuate the metabolic changes of surgical injury, have been associated with reduced morbidity.12,13 Improved analgesia, avoidance of endotracheal intubation and maintenance of consciousness may also contribute to the effect.

STARVATION AND NUTRITION

Starvation alone produces adaptive hypometabolism with the use of fat as the primary fuel, sparing protein. In contrast, injury and infection result in hypermetabolism with prominent protein catabolism. Starvation in combination with the metabolic changes of stress produces a hypoalbuminaemic malnourished state. Malnutrition clearly contributes to morbidity and mortality. However, current forms of nutrition do not adequately reduce protein catabolism or promote protein synthesis, so that a positive energy balance often results in fat and fluid gain instead.14

DRUGS AND DISEASE

Adverse effects of steroids include increased infection rates and myopathy (particularly in conjunction with the use of neuromuscular blocking drugs). Commonly used intensive care unit (ICU) drugs such as the catecholamines, dopamine, corticosteroids, theophylline, calcium-channel blockers, antibiotics and blood transfusions all have immunomodulatory effects. Diseases such as diabetes will clearly impact on the metabolic response to stress. Apart from concurrent disease, the inciting organism may itself modulate its host response by affecting cytokine mediators, their production, secretion and elimination, or by interacting with their receptors.15

GENETIC POLYMORPHISMS

From epidemiological studies, a large genetic influence on the outcome of sepsis can be found.16 Unfortunately, studies on specific genetic polymorphisms involving mediators of the metabolic response have generally been underpowered, and the evidence is conflicting.

SECONDARY INSULTS

Secondary insults, such as device-related sepsis, the use of bioincompatible membranes for renal support, mechanical ventilator-induced lung injury, pain and hypothermia, will increase the severity and duration of the metabolic response.

VALUE OF THE METABOLIC RESPONSE

The cytokines and neuroendocrine mediators reprioritise metabolic processes, increasing the supply of substrates to active tissues involved in defence against injury. Inflammation localises the area of injury. Cardiovascular changes divert blood flow to inflamed areas and vital organs, while salt and water retention maintains overall perfusion. Sympathectomised and adrenalectomised animals fare poorly when stressed. Etomidate, which blocks cortisol synthesis, was associated with increased mortality when used for ICU sedation.17

Disadvantages of the metabolic response include increased oxygen consumption and myocardial work, which is detrimental to patients with marginal cardiovascular reserves. The redistribution of blood flow away from the ‘non-vital’ gut organ may result in translocation of bacteria and endotoxin into the circulation. High catecholamine levels are arrhythmogenic to the compromised heart. Systemic inflammation can result in systemic tissue destruction. Hyperglycaemia is associated with an increased incidence of infection.

MODULATING THE METABOLIC RESPONSE

Modulation of the metabolic response in order to accelerate recovery and improve morbidity and mortality is an expanding area of research. Large multicentre trials have failed to show consistent benefits with therapies targeted at specific cytokine components of the metabolic response to infection. This has led to the development of therapies providing non-specific suppression or elimination of circulating mediators, or monitoring the state of ‘immunologic dissonance’ in order to provide individualised therapy.

Antioxidants show promise in improving survival. The substitution of omega-3 fatty acids for omega-6 fatty acids in inflammatory mediators modulates the metabolic response. Clinically, enteral nutrition with eicosapentaenoic acid (EPA or fish oil), γ-linolenic acid (GLA or borage oil) and antioxidant vitamins18 has been shown to reduce mortality. Selenium prevents excessive oxidative damage, but was not shown to reduce mortality when supplemented in pharmacological doses, and a larger trial is needed.19 Ethyl pyruvate is another promising antioxidant able to directly neutralise peroxides and peroxynitrite non-enzymatically. Statins decrease the activation of the NF-κB pathway, and inhibit superoxide production. Experimentally, statins have been shown to prolong survival time in sepsis,20 but randomised controlled trials in humans are required.21

Protein catabolism leading to loss of muscle has functional consequences such as respiratory muscle weakness. A 25% body weight loss in the presence of injury may be fatal. Wound healing and multiple facets of host defence are impaired, increasing the risk of nosocomial infection. Parenteral glutamine supplementation has been reported to reduce mortality.22 Of the anabolic agents (GH, IGF-1 and testosterone derivatives), GH has received the most attention in the setting of critical illness. GH increased mortality in a heterogeneous group of critically ill patients.23 It is possible that patient selection, unmasking of glutamine deficiency and high GH doses (mean 0.1 mg/kg per day) resulted in the adverse outcome. Combined GH, IGF-1 and glutamine-supplemented parenteral nutrition has been shown to produce net protein gain.24

‘Intensive insulin therapy’ to attain a glucose of 4.4–6.1 mmol resulted in significant prevention of acute renal failure, and shortened time to weaning from mechanical ventilatory support.25 The mortality benefit shown in a previous trial could not be corroborated. Frequent hypoglycaemia may accompany the technique and further studies are underway.

A meta-analysis of steroid usage in septic shock found that high-dose steroids given over a short time increased mortality, while lower doses of hydrocortisone for 5–7 days and subsequently tapered resulted in improvement in survival and shock reversal.26 In the largest trial, the benefit was found only in patients who had a less than 9 μg/dl increase in cortisol after 250 μg tetracosactrin intravenously.27 Given the difficulties in free cortisol kinetics and definition of ‘relative adrenal insufficiency’ in the critically ill, this finding requires external validation.

The extracellular fluid is the aqueous medium within which the mediators of the metabolic response function, so that blood purification may modulate the intensity of the metabolic response and hence influence outcome. A randomised trial of 425 ICU patients with acute renal failure to ultrafiltration doses of 20 ml/hour per kg, 35 ml/hour per kg and 45 ml/hour per kg by continuous veno-venous haemofiltration resulted in survival at 15 days after treatment discontinuation of 41%, 57% and 58% respectively.28 Extension of the above approach leads to the inference that high volume haemofiltration (i.e. intensive plasma water exchange) may further improve survival.29

In an initial trial, activated protein C (APC) was found to reduce 28-day mortality in patients with severe sepsis. Longer term follow-up did not reveal an overall improvement in survival, although the study was not powered to detect this end-point.30 In less severely ill patients, APC did not influence outcome, and increased the rates of serious bleeding.31 APC is not indicated in paediatric severe sepsis.

The most logical approach is to monitor the host response so as to provide individualised therapy. Although IFN-γ did not reduce infection or mortality in burns patients,32 it is hypothesised that monitoring HLA-DR expression may be used to identify immunosuppressed patients who may benefit most from IFN-γ.33

REFERENCES

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6 Boulos M, Astiz ME, Barua RS, et al. Impaired mitochondrial function induced by serum from septic shock patients is attenuated by inhibition of nitric oxide synthase and poly(ADP-ribose) synthase. Crit Care Med. 2003;31:353-358.

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12 Rodgers A, Walker N, Schug S, et al. Reduction of postoperative mortality and morbidity with epidural or spinal anaesthesia: results from overview of randomised trials. BMJ. 2000;321:1493-1497.

13 Lacy AM, Garcia-Valdecasas JC, Delgado S, et al. Laparoscopy-assisted colectomy versus open colectomy for treatment of non-metastatic colon cancer: a randomised trial. Lancet. 2002;359:2224-2229.

14 Hart DW, Wolf SE, Herndon DN, et al. Energy expenditure and caloric balance after burn. Increased feeding leads to fat rather than lean mass accretion. Ann Surg. 2002;235:152-161.

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16 Sørensen T, Nielsen G, Andersen P, et al. Genetic and environmental influences on premature death in adult adoptees. N Engl J Med. 1988;318:727-732.

17 Watt I, Ledingham IM. Mortality amongst multiple trauma patients admitted to an intensive therapy unit. Anaesthesia. 1984;39:973-981.

18 Pontes-Arruda A, Aragao A, Albuquerque J. Effects of enteral feeding with eicosapentaenoic acid, γ-linolenic acid, and antioxidants in mechanically ventilated patients with severe sepsis and septic shock. Crit Care Med. 2006;34:2325-2333.

19 Angstwurm M, Engelmann L, Zimmermann T, et al. Selenium in Intensive Care (SIC) study. Results of a prospective randomized, placebo-controlled, multiple-center study in patients with severe systemic inflammatory response syndrome, sepsis, and septic shock. Crit Care Med. 2007;35:118-126.

20 Merx M, Liehn E, Graf J, et al. Statin treatment after onset of sepsis in a murine model improves survival. Circulation. 2005;112:117-124.

21 Majumdar S, McAlister F, Eurich D, et al. Statins and outcomes in patients admitted to hospital with community acquired pneumonia: population based prospective cohort study. BMJ. 2006;333:999.

22 Novak F, Heyland DK, Avenell A, et al. Glutamine supplementation in serious illness: a systematic review of the evidence. Crit Care Med. 2002;30:2022-2029.

23 Takala J, Ruokonen E, Webster N, et al. Increased mortality associated with growth hormone treatment in critically ill adults. N Engl J Med. 1999;341:785-792.

24 Carroll P, Jackson N, Russell-Jones D, et al. Combined growth hormone/insulin-like growth factor I in addition to glutamine-supplemented TPN results in net protein anabolism in critical illness. Am J Physiol Endocrinol Metab. 2004;286:151-157.

25 Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in the medical ICU. N Engl J Med. 2006;354:449-461.

26 Minneci P, Deans K, Banks S, et al. Meta-analysis: the effect of steroids on survival and shock during sepsis depends on the dose. Ann Intern Med. 2004;141:47-56.

27 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.

28 Ronco C, Bellomo R, Homel P, et al. Effects of different doses in continuous veno-venous haemofiltration on outcomes of acute renal failure: a prospective randomised trial. Lancet. 2000;355:26-30.

29 Ratanarat R, Brendolan A, Piccinni P, et al. Pulse high-volume haemofiltration for treatment of severe sepsis: effects on hemodynamics and survival. Critical Care. 2005;9:R294-302.

30 Angus D, Laterre P, Helterbrand J, et al. The effect of drotrecogin alfa (activated) on long term survival after severe sepsis. Crit Care Med. 2006;32:2199-2206.

31 Abraham E, Laterre P, Garg R, et al. Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med. 2005;353:1332-1341.

32 Wasserman D, Ioannovich JD, Hinzmann RD, et al. Interferon-gamma in the prevention of severe burns-related infections: a European phase III clinical trial. Crit Care Med. 1998;26:434-439.

33 Docke WD, Hoflich C, Davis K, et al. Monitoring temporary immunodepression by flow cytometric measurement of monocytic HLA-DR expression: a multicenter standardized study. Clin Chem. 2005;51:2341-2347.

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